*Complete removal of patient data listings may mean that page … · plot (PPS) ... SAP Statistical...

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.

The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all named

persons associated with the study Patient data listings will be completely removed* to protect patient privacy. Anonymized

data from each patient may be made available subject to an approved researchproposal. For further information please see the Patient Level Data section of the GSKClinical Study Register.

Aggregate data will be included; with any direct reference to individual patientsexcluded

*Complete removal of patient data listings may mean that page numbers are no longer consecutively

numbered

This study includes documents that were originally reported in a language other than English. All documents that are available in English have been made available via the GSK Clinical Study Register.

CONFIDENTIAL 2016N274225_00The GlaxoSmithKline group of companies 201465

1

Division: Worldwide DevelopmentInformation Type: Clinical Pharmacology Study ReportControl: Vehicle- and positive-control

Title: A Phase I Trial to Evaluate Safety and Efficacy of Topically Applied GSK2981278 Ointment in a Psoriasis Plaque Test

Additional Study Design Information: Single-center, randomized, vehicle- and positive-controlled, subject- and evaluator-blind, intra-individual comparison of treatments, 19-day treatment period, male subjects and female subjects of non-reproductive potential (FNRP) with chronic stable plaque-type psoriasis

Phase: I

Compound Number: GSK2981278

EudraCT Number 2015-002614-72

Effective Date: 18-OCT-2016

Keywords: Psoriasis plaque test, infiltrate thickness, inverse agonist of retinoic acid receptor-related orphan receptor gamma (ROR), ultrasound, sonography, echo lucentband (ELB), safety, efficacy, pharmacodynamics and biomarkers

Author: Ph.D.bioskin GmbH, Burchardstrasse 17, 20095 Hamburg, Germany

Contributing Authors:

GlaxoSmithKline, Research & Development Limited

Indication Studied: Plaque-type psoriasis

Initiation Date: 22-OCT-2015

Completion Date: 19-FEB-2016

Sponsor Signatory: (and Medical Officer)

Yamaguchi, Yuji, M.D., Ph.D.Medical Director, Clinical DevelopmentDermatology Therapeutic Area UnitGlaxoSmithKline, Research & Development Limited1250 South, Collegeville Rd, Collegeville, PA 19426; USATel:

This study was performed in compliance with Good Clinical Practices (GCP) and GlaxoSmithKline Standard Operating Procedures (SOPs) for all processes involved, including the archiving of essential documents.

Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited.

1

PPD

PPD

PPD

Table of Contents Page

TITLE PAGE ........................................................................................................................

ABBREVIATIONS ............................................................................................................. ETHICS AND GOOD CLINICAL PRACTICE ............................................................... 1. INTRODUCTION ..........................................................................................................

1.1. Study Rationale ..................................................................................................... 1.2. Brief Background ..................................................................................................

2. STUDY OBJECTIVES & ENDPOINTS ..................................................................... 3. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................... 4. INVESTIGATIONAL PLAN..........................................................................................

4.1. Study Design ......................................................................................................... 4.1.1. Treatment Arms and Duration ................................................................................... 4.1.2. Type and Number of Subjects ...................................................................................

4.2. Discussion of Study Design ................................................................................ 4.2.1. Design Justification................................................................................................... 4.2.2. Dose Justification .....................................................................................................

4.3. Protocol Amendment(s) .......................................................................................

4.4. Selection of Study Population ............................................................................. 4.4.1. Inclusion/Exclusion Criteria ....................................................................................... 4.4.2. Withdrawal/Stopping Criteria .....................................................................................

4.5. Treatments ............................................................................................................. 4.5.1. Investigational Product(s).......................................................................................... 4.5.2. Treatment Assignment .............................................................................................. 4.5.3. Manner of Treatment ................................................................................................ 4.5.4. Blinding ................................................................................................................... 4.5.5. Prior and Concomitant Medications and Non-Drug Therapies ...................................... 4.5.6. Compliance..............................................................................................................

4.6. Study Assessments and Procedures................................................................. 4.6.1. Screening and Critical Baseline Assessments ............................................................ 4.6.2. Safety Assessments ................................................................................................. 4.6.3. Efficacy Assessments ............................................................................................... 4.6.4. Pharmacodynamic Assessments ...............................................................................

4.7. Data Quality Assurance ....................................................................................... 4.8. Statistical Analyses...............................................................................................

4.8.1. Sample Size Considerations ..................................................................................... 4.8.2. Analysis Populations................................................................................................. 4.8.3. Interim Analyses ....................................................................................................... 4.8.4. Final Analyses .......................................................................................................... 4.8.5. Changes in Conduct of the Study or Planned Analyses ...............................................

5. STUDY POPULATION RESULTS .............................................................................

5.1. Subject Disposition ............................................................................................... 5.2. Protocol Deviations...............................................................................................

5.3. Populations Analyzed........................................................................................... 5.4. Demographic and Baseline Characteristics .....................................................

15899910111212121313131415151517181821212122232424252628293131313232353737373738

2

CONFIDENTIAL 2016N274225_00201465

5.5. Prior and Concomitant Medications ................................................................... 5.6. Exposure and Treatment Compliance ...............................................................

6. SAFETY RESULTS ...................................................................................................... 6.1. Adverse Events .....................................................................................................

6.2. Serious and Other Significant Adverse Events ................................................ 6.3. Clinical Laboratory Evaluations .......................................................................... 6.4. Vital Signs ..............................................................................................................

6.5. Electrocardiogram................................................................................................. 6.6. Physical Examination of the Skin and Skin Biopsy Wound Control .............

7. EFFICACY RESULTS.................................................................................................. 7.1. Sonographic measurements – Psoriatic Infiltrate Thickness ......................... 7.2. Clinical Assessment .............................................................................................

8. BIOMARKER(S)/PHARMACODYNAMIC MARKERS RESULTS ........................ 8.1. Biomarker Results ................................................................................................

8.1.1. Gene Expression Analysis by qPCR .......................................................................... 8.1.2. IL-17A and IL-17F mRNA Expression Analysis using Taqman qPCR Method ............... 8.1.3. Transcriptomic Analysis Using Affymetrix Microarray ..................................................

9. DISCUSSION AND CONCLUSIONS ........................................................................ 9.1. Discussion..............................................................................................................

9.2. Conclusions ........................................................................................................... 10. REFERENCES ........................................................................................................... 11. POST-TEXT TABLES AND FIGURES ...................................................................

STUDY POPULATION DATA SOURCE TABLES ........................................................ TABLE 1.01 Subject enrollment and evaluability (Subjects screened) ....................

TABLE 1.02 Subject completion / discontinuation (Subjects randomized) .............. TABLE 1.03 Excluded subjects from the analysis populations (Subjects

randomized).......................................................................................................

TABLE 1.04 Subject demographic characteristics (Subjects randomized) ............. SAFETY DATA SOURCE TABLES .................................................................................

TABLE 3.01 Extent of exposure - Summary (SES) ..................................................... TABLE 3.02 Vital signs - Summary (SES) .................................................................... TABLE 3.03 ECG - Summary (SES)..............................................................................

TABLE 3.04 Hematology - Summary (SES) ................................................................. TABLE 3.05 Clinical chemistry - Summary (SES) .......................................................

TABLE 3.06 Urinalysis - Summary (SES) ..................................................................... TABLE 3.07 Urinalysis - Frequency (SES) ................................................................... TABLE 3.08 Summary of adverse events (SES) .........................................................

EFFICACY DATA SOURCE FIGURES........................................................................... FIGURE 2.01 Psoriatic infiltrate thickness - OC - Line plot (PPS) ............................

FIGURE 2.02 Psoriatic infiltrate thickness - Change from baseline - OC - Line plot (PPS)...........................................................................................................

FIGURE 2.03 Psoriatic infiltrate thickness - Change from baseline - AUC - OC - Bar chart (PPS) .................................................................................................

EFFICACY DATA SOURCE TABLES .............................................................................

TABLE 1.05 Subject baseline characteristics (Subjects randomized) ..................... TABLE 2.01 Psoriatic infi ltrate thickness - OC - Summary (PPS) ............................

39394141414143434445455559595961626464656669727273

74757777787981859091939595

96

979898100

3

CONFIDENTIAL 2016N274225_00201465

TABLE 2.02 Psoriatic infiltrate thickness - Change from baseline - OC - Summary (PPS) ................................................................................................

TABLE 2.03 Psoriatic infiltrate thickness - Change from baseline - OC - AUC MMRM Estimates (PPS)..................................................................................

TABLE 2.04 Psoriatic infiltrate thickness - Change from baseline - OC - AUC MMRM Comparisons (PPS)............................................................................

TABLE 2.05 Psoriatic infiltrate thickness - Change from baseline - OC - MMRM Estimates by visit (PPS) ..................................................................................

TABLE 2.06 Psoriatic infiltrate thickness - Change from baseline - OC- MMRM Comparisons by visit (PPS) ............................................................................

TABLE 2.07 Psoriatic infiltrate thickness - % Change from baseline - OC - Summary (PPS) ................................................................................................

TABLE 2.08 Clinical assessment of improvement - OC - Frequency (PPS) ........... TABLE 2.09 Clinical assessment of improvement - OC - Summary (PPS).............

TABLE 2.10 Efficacy assessments - Missing data - Summary (PPS)......................

102

104

105

106

107

111113115117

4

CONFIDENTIAL 2016N274225_00201465

CONFIDENTIAL 2016N274225_00201465

4

ABBREVIATIONS

ACTH Adrenocorticotropic hormoneAE Adverse eventALT Alanine aminotransferaseAMG German drug law (Arzneimittelgesetz)API Active pharmaceutical ingredientAST Aspartate aminotransferaseAUC Area under the curveAUCss Area under the concentration curve at steady stateBBB Bundle branch blockBpm Beats per minuteBUN Blood urea nitrogenC ConcentrationCI Confidence intervalcDNA Complementary desoxyribonucleic acidCD4 Cluster of differentiation 4 cm2 Centimeter squaredCmax Maximum concentrationCmaxss Maximum concentration at steady stateCONSORT Consolidated Standards of Reporting TrialsCRO Contract research organizationCt Threshold cycleECG Electrocardiogram

Ct Delta Ct

DNA Desoxyribonucleic acideCRF Electronic case report formELB Echo Lucent BandEoT End of treatmentFDR False discovery ratefL Femtoliterfmol FemtomoleFNRP Female of non-reproductive potentialg GramGCP Good Clinical PracticeGCSP Global Clinical Safety and PharmacovigilanceG/L / GI/L Giga per literGOI Gene of interestGSK GlaxoSmithKlineHep Hepatitish/hr HourHBsAg Hepatitis B surface antigenHFUS High frequency ultrasoundHIV Human immunodeficiency virusHKG Housekeeping geneHPA Hypothalamic-pituitary-adrenal

5

CONFIDENTIAL 2016N274225_00201465

5

HRT Hormone replacement therapyIB Investigator’s brochureICF Informed consent formICH International Conference on HarmonisationID IdentifierIL-17 Interleukin 17IRB Institutional review boardkg KilogramL LiterLBD Ligand-binding domainsLLN Lower limit of normalLOCF Last observation carried forwardLS Least squaremAb Monoclonal antibodyMAQC Micro array quality controlMCV Mean corpuscular volumeMCH Mean corpuscular hemoglobinMedDRA Medical Dictionary for Regulatory Activitiesmg MilligramMHz Megahertzmax Maximummin MinimummL MillilitermmHg Millimeter mercury columnmmol/L Millimoles per liter

mol/L Micromole per liter

MMRM Mixed-model repeated-measuresmRNA Messenger ribonucleic acidMSDS Material safety data sheetmsec millisecondsng NanogramNOAEL No observed adverse effect levelOC Observed casesPASI Psoriasis area severity indexPCI Potential clinical importancePD Pharmacodynamicpg PicogramPK PharmacokineticPP Per-ProtocolPPS Per-protocol analysis setPPT Psoriasis plaque testPT Preferred termQC Quality controlqPCR Quantitative polymerase chain reactionQTc Corrected QTQTcB Corrected QT using Bazett’s formula

6

CONFIDENTIAL 2016N274225_00201465

6

RBC Red blood cell countRMA Robust Multi-chip Average

ROR Retinoic acid receptor-related orphan receptor gamma

SAEs Serious adverse eventSAP Statistical analysis planSAS Statistical Analysis SystemSD Standard deviationSEM Standard error of the meanSES Safety evaluation setSOC System organ classSOP Standard Operating ProcedureSRM Study reference manualTh 17 T-helper 17TMF Trial master file

TNF- Tumor necrosis factor alpha

L Microliter

µm MicrometerU UnitU/L Unit per literULN Upper limit of normalUV Ultravioletvs. VersusWBC White blood cell countw/w Weight by weight

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

BETNESOL FixomullSASVarihesiveVaseline

7

CONFIDENTIAL 2016N274225_00201465

7

ETHICS AND GOOD CLINICAL PRACTICE

The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a national, regional, or investigational center ethics committee or institutional review board, in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and applicable country-specific requirements. Ethics committee or institutional review board approvals are maintained in the Sponsor’s study file.

Investigators were trained to conduct the study in accordance with GCPs and the study protocol, as defined in ICH E3, Section 9.6. Written commitments were obtained from investigators to conduct the study in accordance with ICH GCP and all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki (2013 version), and to conduct the study in accordance with the protocol.

The study was monitored in accordance with ICH E6, Section 5.18.

Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. The investigator agreed to provide the subject as much time as necessary to review the document, to inquire about details of the trial, and to decide whether or not to participate in the study. The informed consent was signed and dated by the study subject and by the person who conducted the informed consent discussion. Electronic case report forms (eCRFs) were provided for each subject’s data to be recorded.

8

CONFIDENTIAL 2016N274225_00201465

8

1. INTRODUCTION

GSK2981278 is a highly potent and selective inverse agonist of retinoic acid receptor-related orphan receptor gamma (ROR) that is under development for topical treatment of plaque-type psoriasis suitable for topical therapy.

1.1. Study Rationale

This was the first study to administer GSK2981278 to subjects with psoriasis. This proof-of-concept study evaluated the safety, tolerability and initial efficacy of a range of concentrations of GSK2981278 ointment with repeated topical applications in adult subjects with psoriasis. Results of this study provide first clinical information on the drug’s safety and efficacy in psoriasis and inform the selection of concentration of GSK2981278 ointment to be evaluated in subsequent clinical studies.

1.2. Brief Background

The primary goal of treatment for psoriasis is to improve the signs and symptoms as there is no curative treatment. Approximately 80% of psoriasis patients have mild to moderate disease, which is typically managed with topical agents. In patients with more severe disease, topical agents are often used adjunctively with either phototherapy or systemic medications. Topical corticosteroids are the mainstay of topical therapy and provide relatively high efficacy. However, local safety issues such as skin atrophy, telangiectasia, and striae distensae as well as systemic safety concerns such as hypothalamic-pituitary-adrenal (HPA) axis suppression limit their long-term use and use in sensitive areas [Menter, 2009]. Other topical agents such as vitamin D analogues and topical retinoids are available to complement the corticosteroid therapy. There is a need for an effective novel topical agent without the safety concerns associated with corticosteroids.

Although the pathophysiology of psoriasis is not fully understood, current evidence suggests that a combination of genetic, immunologic and environmental factors contributes to the disease. Growing understanding of the involvement of the immune system in the psoriasis pathophysiology indicates that T-helper 17 (Th17) cells and their signature proinflammatory cytokine Interleukin-17 (IL-17) play a critical role [Malakouti , 2015]. IL-17A is known to drive inflammatory pathways inherent in psoriasis pathogenesis by stimulating keratinocyte expression of multiple chemokines and increasing the expression of antimicrobial peptides and contribute to epidermal hyperproliferation and skin barrier disruption. Increased numbers of IL-17 positive T cells and higher IL-17A messenger ribonucleic acid (mRNA) expression in psoriatic lesions compared with normal skin have been reported as well [Lynde, 2014]. In addition, the involvement of IL-17 cytokines was recently validated with monoclonal antibody (mAb) treatment. Three biologic therapies that inhibit the IL-17 cytokines have been shown to control the signs and symptoms of plaque-type psoriasis. Phase III study results have shown that a greater proportion of patients administered these agents have a higher psoriasis area severity index 75 (PASI75) and PASI100 response compared to patients administered existing biologics that have different mechanisms of action (e.g., tumor necrosis factor (TNF)-α inhibitors and T-cell inhibitors) [Langley, 2014; Sandoval, 2015; Lebwohl, 2015; Gordon, 2015].

9

CONFIDENTIAL 2016N274225_00201465

9

RORt, a truncated isoform of ROR, is a transcription factor involved in Th17 cell differentiation and Th17 cytokine expression. It is expressed in a few distinct types of immune cells and is described as the master regulator of Th17 cytokine expression [Ivanov, 2006]. ROR is widely expressed throughout the body and has identical ligand-binding domains (LBD) as RORt [He, 1998]. Compounds targeting ROR are expected to modulate the activity of RORt as well. Therefore, local delivery of selective RORinverse agonist GSK2981278 to lesional skin of psoriasis via topical application was expected to block the transcriptional activity of RORt leading to the local suppression of cytokine expression from skin-resident T cells and ultimately to improvement in psoriasis, with no or minimal systemic effects.

Pre-clinical data showed that GSK2981278 significantly inhibits production of the Th17 signature cytokines in multiple in vitro and human tissue-based assays, including human peripheral T cells and ex vivo human skin [GlaxoSmithKline Document Number 2015N240000_00; GSK2981278 Investigator’s Brochure (IB)].

2. STUDY OBJECTIVES & ENDPOINTS

Objectives EndpointsPrimary

To evaluate the safety and tolerability of topically applied GSK2981278 in subjects with plaque psoriasis.

To evaluate the efficacy of topical formulation strengths of GSK2981278 ointment in subjects with psoriasis.

Incidence and nature of adverse events (AE).

Change from Baseline in clinical laboratory parameters, vital signs, electrocardiogram (ECG).

The reduction in infiltrate thickness of the psoriatic plaque(s) from Baseline using 22 MHz sonography measurement.

Secondary

To evaluate the improvement of psoriatic lesions following application of GSK2981278 ointment.

Clinical assessment score using a 5-point scale.

Exploratory

To evaluate the pharmacodynamic (PD) effects of topical GSK2981278 in psoriasis plaques.

mRNA biomarkers in skin biopsy samples.

10

CONFIDENTIAL 2016N274225_00201465

10

3. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

This was a single-center study conducted at bioskin GmbH, Hamburg, Germany (Table 1). The first subject was screened/enrolled on 22-OCT-2015 and the last subject completed the study on 19-FEB-2016.

Table 1 Study Conduct

Name and Address Role/ResponsibilitiesEthics Committee

GermanyContract Research Organization (CRO)

bioskin GmbHBurchardstrasse 1720095 Hamburg, Germany

Study management, data management, statistics, medical writing

Monitor Primary Medical Monitor M.D., Ph.D.

GSK1250 South, Collegeville Rd, Collegeville, PA 19426; USA

Secondary Medical Monitor M.D.

bioskin GmbHBurchardstrasse 1720095 Hamburg, Germany

Study Monitor

GSKSachsenstrasse 920097 Hamburg, Germany

Study Monitor

Origio Clinical Monitoring GmbHAn den Deichwiesen 21a30659 Hannover, Germany

11

PPD

PPD

PPD

PPD

PPD

CONFIDENTIAL 2016N274225_00201465

11

Name and Address Role/ResponsibilitiesCentral/Local Laboratories

LKF – Laboratorium fuer klinische ForschungLise Meitner-Strasse 25 – 2924223 Schwentinental,, Germany

Quest DiagnosticsUnit B1 Parkway West, Cranford Lane, Heston, Middlesex, TW5 9QA; UK

Epistem Ltd.48 Grafton StreetManchester, M13 9XX, UK

Haematology, clinical chemistry, serology,

Liver event assessment

PD biomarkers

See the List of Investigators and CRO personnel involved in conduct of the study and their qualifications.

4. INVESTIGATIONAL PLAN

4.1. Study Design

This was a phase I, single-center, randomized, vehicle- and positive- controlled, subject-and evaluator- blind proof-of-concept trial in subjects with chronic plaque-type psoriasis.All subjects received all treatments on stable plaque(s) on the upper extremities, thighs and/or trunk for intra-individual comparison with random assignment of the treatments to the test fields within the identified plaque(s). A blinded evaluator (an investigator or designee) performed the measurements and assessments whereas an unblinded study staff member (not an evaluator) performed biopsy collection.

4.1.1. Treatment Arms and Duration

This study consisted of up to 3 periods: a 14-day screening period, a 19-day treatment period, and an 8-day follow-up period (only for subjects consenting to biopsy). The maximum total duration of study participation was approximately 41 days.

All subjects had a set of 6 randomized test fields treated once daily (except Days 7, 14and 19 [EoT]) over 19 days under semi-occlusive conditions (covered by an adhesive non-woven fabric) with the following study products:

GSK2981278 0.03% ointment



GSK2981278 4% ointment

Vehicle to match GSK2981278 ointment (without active ingredient)

Betamethasone valerate 0.1% cream (positive control)

12

CONFIDENTIAL 2016N274225_00201465

12

The same study products were applied in all subjects. There was no subdivision into separate dosing groups. Refer to Section 4.5.2 for information regarding assignment of treatment.

4.1.2. Type and Number of Subjects

This study was conducted in male subjects with chronic stable plaque-type psoriasis.

Fifteen subjects were randomized and completed the study. Skin biopsies were collected from 13 consenting subjects for PD biomarker evaluation.

4.2. Discussion of Study Design

4.2.1. Design Justification

The objective of this trial was to explore the safety, tolerability and efficacy of GSK2981278 ointment after repeated topical applications in small test fields within plaque(s) in psoriatic subjects. The psoriasis plaque test (PPT) is a standardized model allowing for intra-individual comparison of the safety and efficacy of multiple drugs and/or formulations in subjects with stable plaque psoriasis. PPT is often used as an initial proof-of-concept trial in the early development of topical drugs and can use occlusive, semi- or non-occlusive applications.

In the original test design described by Dumas and Scholtz [Dumas, 1972], the efficacy of corticosteroids for treatment of plaque-type psoriasis was evaluated clinically following standardized occlusive application over several days. Meanwhile biophysical measurement methods have been used in the PPT to objectively measure the inflammatory alterations accompanying psoriasis, greatly improving the sensitivity of the test [Bangha, 1996; Fluhr, 2009]. The clinical relevance of this study design has been established based on the experience translating the efficacy results to later phase trials [Bangha, 1996].

Since the most important guide to potential clinical efficacy in psoriasis in this study design was the extent to which the inflammatory infiltrate in the psoriatic plaque resolved, high-frequency 22 MHz skin ultrasound for the evaluation of the thickness of the inflammatory infiltration was used as the primary efficacy assessment method. The inflammatory infiltrate is seen as a clearly definable echo lucent band (ELB) below the entrance echo [Fluhr, 2009]. Thus, the objective sonographic measurement of the thickness of this ELB at 22 MHz was a relevant outcome. At Baseline (before beginning of treatment) the clinical condition in the test fields of individual subjects had to be comparable.

This study included semi-occlusive applications to allow for testing conditions reflective of a clinical application regimen. The study products were administered once daily (except Days 7, 14 and 19 [EoT]) in a semi-occluded application manner, over a period of 19 days.

The vehicle was included in one test field in order to provide vehicle-related safety and efficacy information. As a positive control a marketed drug (betamethasone valerate

13

CONFIDENTIAL 2016N274225_00201465

13

0.1% cream) was included in an additional test field. The positive control was chosen because it is an approved and marketed product for the treatment of psoriasis and has shown consistent and reproducible results in this type of clinical trial.

4.2.2. Dose Justification

The anti-psoriatic activity of GSK2981278 was evaluated in this PPT (microplaque assay). In order to evaluate the dose-response, 4 different concentrations of GSK2981278, 0.03%, 0.1%, 0.8% and 4% were applied. Each subject received all 4 concentrations of GSK2981278 ointment, along with a positive control, and vehicle ointment once daily (except Days 7, 14 and 19 [EoT]) for 19 days.

Data from ex vivo target engagement studies and repeat dose toxicity studies in rat and minipig were used to select the doses of GSK2981278 ointment for this study. In ex vivo human skin following single topical application of GSK2981278 in the proposed clinical formulation at concentrations ranging from 0.01% to 4%, a potent dose-dependent inhibition of Th17 signature cytokines mRNA levels were observed with effect reaching plateau after 0.1% concentration. Based on this data, concentration ranging from 0.03% to 4% was considered in the early phase clinical trials. Four concentrations of relatively even spread across the dose response curve in this range were selected for the PPT study due to the limit on the number of test fields.

Table 2 represents the predicted exposure and safety covers for clinical evaluation of GSK2981278 [FDA, 2005; CHMP, 2007]. Findings from in vivo pharmacology and toxicology studies with GSK2981278 have provided reasonable assurance that there are no undue or unforeseen risks for the first administration of GSK2981278 to humans at the dose levels proposed in this study.

Table 2 Dose range and exposure predictions of GSK2981278 at steady state following 15 cm2 area of application

Dose (Formulation

strength)

Flux (dermis)

(ng/hr/cm2)

Mean (90% CI)

Cmax AUC1

Predicted Css

(pg/mL)

Mean(90% CI)

Safety Cover

Cmax²(males) =

106 ng/mL

Predicted AUCss

(pg*hr/mL) Mean

(90% CI)

Safety Cover

AUC1

(males) = 437 ng*hr/mL

0.03% 4.82(1.3-11.2)

1.38(0.38-3.21)

76986 33.04(9.05-77.06)

13224

0.1% 11.41(4.7-24.4)

3.26(1.34-6.96)

32528 78.21 (32.13-167.12)

5588

0.8% 34.81(23.0-54.3)

9.95(6.58-15.51)

10658 238.70 (157.83-372.25)

1831

4% 49.25(40.1-59.5)

14.07(11.45-17.01)

7533 337.70 (274.73-408.30)

1294

1AUC of concentration profile2Cmax = Maximum concentration

14

CONFIDENTIAL 2016N274225_00201465

14

In this study the planned total surface area (4 active concentrations at 4 test fields) was5 cm2. Average concentration based on 4 active strength used (0.03%, 0.1%, 0.8% and 4%) was 1.2%. Application of 1.2% concentration over 5 cm2 area provided a safety cover of > 4500 fold for AUC (of concentration profile) and > 20000 fold for Cmax at steady state.

4.3. Protocol Amendment(s)

There were no amendments in this study.

4.4. Selection of Study Population

The selection of subjects was in accordance with the requirements of §§ 40 and 41 of the German drug law (AMG) as well as the recommendations of the currently valid revision of the Helsinki Declaration and the ICH-GCP guideline.

4.4.1. Inclusion/Exclusion Criteria

4.4.1.1. Inclusion Criteria

A subject was eligible for inclusion in this study only if all of the following criteria applied:

AGE

1. 18 years of age and above, at the time of signing the informed consent.

TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY

2. Subjects with stable plaque psoriasis for 6 months, as confirmed by the subject.

3. Up to 3 plaque areas sufficient for 6 test fields. The target lesion(s) should have been on the trunk, upper extremities or thighs (excluding hands and skin folds); psoriatic lesion(s) on the knees or elbows were not to be used as a target lesion. It was recommended, but not required, that all selected plaques were symmetrical in location, size and clinical characteristics.

4. Plaques to be treated should have had a comparable thickness of the ELB (as a surrogate for the psoriatic infiltrate thickness) of at least 200 µm on Day 1.

SEX

5. Male

Male subjects with female partners of child bearing potential had to comply with the following contraception requirements from the time of first dose of study medication until after the last dose of study medication.

a. Vasectomy with documentation of azoospermiab. Male condom

15

CONFIDENTIAL 2016N274225_00201465

15

These allowed methods of contraception were only effective when used consistently, correctly and in accordance with the product label. The investigator was responsible for ensuring that subjects understood how to properly use these methods of contraception.

6. Female of non-reproductive potential (FNRP)

INFORMED CONSENT

7. Capable of giving signed informed consent as described in the protocol, Section 10.2 which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.

4.4.1.2. Exclusion Criteria

A subject was not eligible for inclusion in this study if any of the following criteria applied:

CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc INTERVAL)

1. Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) and bilirubin>1.5x ULN (isolated bilirubin >1.5x ULN was acceptable if bilirubin was fractionated and direct bilirubin < 35%).

2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

3. QTc > 450 msec or QTc > 480 msec in subjects with bundle branch block. The QTc was the QT interval corrected for heart rate according to Bazett’s formula (QTcB), and/or machine-read. The QTc should have been based on single QTc values of ECG obtained over a brief recording period.

4. Any condition that, in the judgement of the investigator, would have put the subject at unacceptable risk for the participation in the trial.

5. Current evidence of another ongoing or any acute cutaneous infection, history of repeated or chronic significant skin infections (unless irrelevant in the opinion of the investigator, i.e., onychomycosis, labial herpes or other minor diagnosis).

6. Clinically relevant skin disease, other skin pathologies, or a history of skin cancer, that, in the opinion of the investigator, might have contraindicated participation or interfered with test field evaluations.

7. History of malignancy within 5 years prior to dosing, except adequately treated non-invasive cancer of the skin (basal or squamous cell).

8. Psoriasis other than plaque variants.

CONCOMITANT MEDICATIONS

9. Use of prohibited concomitant medications or products within the defined washout periods before the Day 1 visit and during the trial (Section 4.5.5.2).

16

CONFIDENTIAL 2016N274225_00201465

16

CONTRAINDICATIONS

10. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicated their participation.

11. Contraindications according to summary of product characteristics of the active positive control.

12. Symptoms of a clinically significant illness that, in the opinion of the investigator, might have influenced the outcome of the trial in the 4 weeks before Baseline visit and during the trial.

DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA

13. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment.

14. A positive pre-study drug/alcohol screen.

15. A positive test for human immunodeficiency virus (HIV) antibody.

16. The subject had participated in a clinical trial and had received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever was longer).

17. Prolonged exposure to natural or artificial sources of ultraviolet (UV) radiation within 2 weeks prior to the Day 1 visit or intention to have such exposure during the study, thought by the investigator likely to modify the subject’s psoriasis.

18. In the opinion of the investigator or physician performing the initial examination the subject should not have participated in the clinical trial, e.g., due to probable noncompliance or inability to understand the trial and give adequately informed consent.

19. Close affiliation with the investigator (e.g., a close relative) or persons working at bioskin GmbH or subject was an employee of sponsor.

20. Subject was institutionalized because of legal or regulatory order.

4.4.2. Withdrawal/Stopping Criteria

A subject may have withdrawn from the study at any time at his/her own request, or might have been withdrawn at any time at the discretion of the investigator for safety, behavioral or administrative reasons.

4.4.2.1. Criteria for Discontinuing Treatments

Conditions under which application of an individual study treatment might have been discontinued in a subject:

17

CONFIDENTIAL 2016N274225_00201465

17

Individual treatments were to be discontinued in the event of the following dermal reactions limited to the respective test fields:

severe blistering

skin necrosis

contact dermatitis

allergic reaction

marked skin discoloration

severe or unexpected itching, burning, or pain

If this occurred, a photograph showing all of the test fields in the affected plaque(s) was to be taken for sponsor review. An additional photograph was to be taken of the affected test field(s) alone. Photographs were not to be used for grading or analysis purposes.

4.4.2.2. General Discontinuation of a Specific Treatment for the Trial

In case of severe reactions due to a specific treatment, the principal investigator, in consultation with the sponsor, might have discontinued prematurely this treatment for the whole trial population. To keep the investigator observer-blind he/she informed the study nurse responsible for the treatment application about the test field(s) he/she deemed necessary to be discontinued. The study nurse determined which treatment was assigned to this test field, the sponsor was to be informed and the respective treatment was to be discontinued in all subjects.

Liver chemistry and QTc stopping criteria were defined in the protocol, Section 5.4.1 and Section 5.4.2 (Protocol and Protocol Amendments).

4.5. Treatments

4.5.1. Investigational Product(s)

The term ‘study treatment’ was used throughout the protocol to describe any combination of products received by the subject as per the protocol design. Study treatment therefore might have referred to the individual study treatments or the combination of those study treatments.

4.5.1.1. Treatments Administered

Topical application of approximately 200 L of the 6 study products—the 4 GSK2981278 ointment formulations (concentrations of 0.03% w/w, 0.1% w/w, 0.8%w/w and 4% w/w), the corresponding vehicle and the positive control—per test field (approximately 1.1 cm2) once daily during a 19-day treatment period (16 applications, except Days 7, 14 and 19 [EoT]).

18

CONFIDENTIAL 2016N274225_00201465

18

GSK2981278 ointment 0.03%daily dosage: approximately 0.06 mg GSK2981278total dosage: approximately 0.96 mg GSK2981278



GSK2981278 ointment 4%daily dosage: approximately 8 mg GSK2981278total dosage: approximately 128 mg GSK2981278

GSK2981278 vehicleactive ingredient-free vehicle

Betamethasone valerate cream 0.1% (positive control)daily dosage: approximately 0.2 mg betamethasone valeratetotal dosage: approximately 3.2 mg betamethasone valerate

Details of the study products are given in Table 3.

Table 3 Details of Study Products

Study TreatmentProduct name: GSK2981278 Vehicle Betamethasone

valerate cream 0.1% (positive control)

Formulation description:

GSK2981278 ointment was supplied as a white to off-white ointment containing GSK2981278A drug substance at 0.03% w/w, 0.1% w/w, 0.8% w/w and 4% w/w for topical administration.

GSK2981278 vehicle was supplied as a white to off-white ointment for topical administration.

Betnesol™-V containing 0.1% betamethasone valerate was supplied as a cream for topical administration.

Dosage form: Ointment Ointment CreamActive ingredient GSK2981278 was a

polycyclic, substituted benzenesulphonamidepossessing a tetrahydropyran moiety.Chemical structure has been unambiguously identified.

--- Betamethasone valerate

19

CONFIDENTIAL 2016N274225_00201465

19

Study TreatmentUnit dose strength(s)/Dosage level(s):

0.03% w/w, 0.1% w/w, 0.8% w/w and 4% w/w

0% 0.1%

Additional ingredients

Polyethylene glycol 3350 (macrogol 3350), polyethylene glycol 400 (macrogol 400), butylated hydroxytoluene

Polyethylene glycol 3350 (macrogol 3350), polyethylene glycol 400 (macrogol 400), butylated hydroxytoluene

Chlorocresol, cetomacrogol 1000, cetostearyl alcohol, , white petrolatum, paraffin wax, sodium dihydrogene phosphate dihydrate, phosphoric acid orsodium hydroxide(for pH value adjustment), purified water.

Batch number GSK2981278 ointment 0.03%: E141511-0001L002, E141511-0002L002

GSK2981278 ointment 0.1%: E141511-0001L003, E141511-0002L003

GSK2981278 ointment 0.8% E141511-0001L004, E141511-0002L004

GSK2981278 ointment 4%: E141511-0001L005, E141511-0002L005

E141511-0001L001, E141511-0002L001

C730272

Route of administration

Topical Topical Topical

Physical description:

The product was packaged into white aluminium tubes.

The product was packaged into white aluminium tubes.

The product was packaged into tubes.

Storage 2 – 8 °C 2 – 8 °C Not more than +25 °C, to be protected from direct sunlight

Manufacturer GlaxoSmithKline Research & Development Limited

GlaxoSmithKline Research & Development Limited

GlaxoSmithKline GmbH & Co. KG

Marketing authorization holder

--- --- GlaxoSmithKline GmbH & Co. KG

20

CONFIDENTIAL 2016N274225_00201465

20

The contents of the label were in accordance with all applicable regulatory requirements. Copies of the labels were filed in the trial master file (TMF).

Only subjects enrolled in the study received study treatment and only authorized site staff supplied or administered study treatment. All study treatments were stored in a secure environmentally controlled and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the investigator and authorized site staff.

A complete record of batch numbers and expiry dates of all study products as well as the labels are maintained in the TMF. The Listing of Subjects Receiving Investigational Products from Specific Batches, if More Than One Batch Was Used lists the subjects and batch numbers of study products each received.

4.5.2. Treatment Assignment

All subjects received the same treatments. There was no subdivision into treatment groups. The 4 concentrations of GSK2981278 ointment (0.03%, 0.1%, 0.8% and 4%) were assigned to the codes A, B, C, and D. The vehicle and positive control were assigned to the codes E and F, respectively.

The test fields were numbered with 1, 2, 3, 4, 5, and 6 beginning with the uppermost or most proximal site on the left from the investigator's view. Fields along the same line were numbered left to right.

For each subject a permutation of the treatment codes A to F were randomly assigned. The treatment code listed first in the respective permutation was assigned to test field 1, the second to test field 2, etc.

A randomization list was generated by the CRO and kept in the TMF in a sealed envelope.

4.5.3. Manner of Treatment

Manner of treatment is described in the clinical study protocol, Section 6.3.

4.5.4. Blinding

This was a subject- and evaluator-blinded study; therefore, the designated evaluator performing the measurements and assessments was unaware of the particular treatment assignment for the subjects. Investigator(s) responsible for biopsy collection was unblinded. Study-center staff responsible for preparation and application of the study products was not blinded to the test field allocations and was instructed not to reveal the identity of the allocations to the blinded evaluator.

The randomization list with the treatment codes was sealed in an envelope and kept in the TMF in a secure manner at the study center.

21

CONFIDENTIAL 2016N274225_00201465

21

The randomization code was only broken after the clinical database was locked. Since each subject was exposed to all study products concurrently and there was no subdivision into separate dosing groups, it was unlikely that unblinding the randomized test field allocations provided any additional knowledge that would have been essential. However, if the investigator determined that the occurrence of a test field-specific or other serious medical condition required the information contained on the randomization list, the study center staff responsible for preparation and application of the test chambers (who were unblinded to the randomization list) determined which treatment was assigned to the test fields(s) of concern and informed the investigator. Should the investigator also have beenthe designated evaluator, they were to remain blinded to the other test site allocations for the subject.

Subjects were to be withdrawn from the study if the blinded evaluator became aware of the test field allocations (i.e., was unblinded). The primary reason for discontinuation (the event or condition that led to the unblinding) was recorded in the eCRF.

4.5.5. Prior and Concomitant Medications and Non-Drug Therapies

All medications and non-drug therapies (including treatments listed in the exclusion criteria) received by the subject within 4 weeks (28 days) before the Screening visit and at any time throughout the study were recorded in the source documents and eCRF with start and end dates, if end dates were available.

4.5.5.1. Permitted Medications and Non-Drug Therapies

Medications permitted during the study included contraceptives (for indications other than pregnancy prevention), antihistamines, selective leukotriene receptor antagonists (e.g., montelukast sodium, zafirlukast), mast cell stabilizers (e.g., cromolyn sodium or nedocromil sodium), acetaminophen/paracetamol, vitamin and mineral supplements, medications for regulation of thyroid function, influenza vaccine, and medications for AEs, unless specifically prohibited.

Subjects were permitted to use medications for chronic stable concomitant medical conditions (e.g., hypertension) that were not expected to affect the study assessments, provided the subject was on a stable dose that was not expected to change during the study.

Other concomitant medication was considered on a case by case basis by the investigator in consultation with the medical monitor if required.

Medicinal shampoos and other topical treatments for psoriasis lesions on the scalp and/or psoriatic plaques that were not part of assessment in this trial were permitted during the study.

Sunscreen might have been used on non-lesional skin.

22

CONFIDENTIAL 2016N274225_00201465

22

4.5.5.2. Prohibited Medications and Non-Drug Therapies

Use of medications or treatments that would have significantly influenced or exaggerate responses to the test products or that would have altered inflammatory or immune response to the products was prohibited. Prohibited concomitant medications, products, and procedures (Table 4) were not to be used from the defined washout periods before the first patch applications at the Day 1 visit and throughout the study.

Table 4 Prohibited Concomitant Medications, Products, and Procedures

Prohibited medications, products, and procedures: Washout period before Day 1

Biologic agents: e.g., alefacept 24 weeks; etanercept 12 weeks; ustekinumab 15 weeks

5 half-lives

Oral retinoids (e.g., acitretin or isotretinoin) 12 weeks

Cyclosporin, interferon, methotrexate, or other systemic immunosuppressive or immunomodulating agents (e.g., mycophenolate or tacrolimus); psoralen plus UVA

8 weeks

Other investigational products or procedures Longer of 4 weeks or 5 half-lives

Systemic corticosteroids or adrenocorticotropic hormone (ACTH) analogs 4 weeks

Immunizations (influenza vaccine was allowed) 2 weeks

Topical treatments: corticosteroids, immunomodulators, anthralin (dithranol), vitamin D derivatives, retinoids, coal tar (used on the psoriatic lesions under evaluation in this study.

2 weeks

Drugs known to possibly worsen psoriasis (unless on a stable dose for > 12 weeks), such as: β-blockers (e.g., propranolol), lithium, iodides, angiotensin-converting enzyme inhibitors, and indomethacin

2 weeks

Any other topical therapy (including emollients) on psoriasis lesions treated in this study

1 day

UV-therapy 2 weeks

4.5.6. Compliance

4.5.6.1. Compliance with Study Treatment Administration

When the individual dose for a subject was prepared from a bulk supply, the preparation of the dose was confirmed by a second member of the study site staff. Syringes of study treatment were weighed before and after administration to each test field for each subject by study personnel. The weight of study treatment applied to each individual subject was documented in the accountability record.

23

CONFIDENTIAL 2016N274225_00201465

23

Subjects were dosed at the site and received study treatment directly from the investigator or designee, under medical supervision. The date and time of each dose administered in the clinic were recorded in the source documents. The dose of study treatment and study subject identification were confirmed at the time of dosing by a member of the study site staff other than the person administering the study treatment.

4.6. Study Assessments and Procedures

Subjects had study visits once daily (except Days 7, 14 and 19 [EoT]), at approximately the same time each day, for 19 consecutive days. Visit schedules should have been timed such that test field evaluations were conducted approximately 24 2 hours on Days 4 and 19 and approximately 48 hours on Days 8 and 15 after the study products were applied(Statistical Methods, Blind Data Review Meeting and Section 4.8.5). This section lists the procedures and parameters of each planned study assessment. The exact timing of each assessment is listed in Section 11, Time and Events Table (Table 23).

4.6.1. Screening and Critical Baseline Assessments

Screening procedures commenced after all relevant study approvals had been obtained and after the informed consent had been signed. The investigator maintained a subject screening log to document identification of subjects who signed the informed consent document.

Screening was conducted within 14 days prior to the Day 1 visit. Baseline tests and procedures were performed before randomization and the first application of study products.

Demographic parameters (year of birth, sex, race and ethnicity) were captured and the subject’s Fitzpatrick skin type (Fitzpatrick, 1988) was documented.

Medical/medication history was assessed as related to the inclusion/exclusion criteria listed in Section 4.4.1. Known drug allergies were captured in the eCRF.

Refer to Section 4.6.2 for Baseline safety assessments (physical exam, vital sign measurement, ECG and laboratory parameters).

Photographic documentation was collected at the Day 1 and Day 19 visits before any procedures were performed using a digital camera. This included overview pictures of all test fields (the number of pictures depended on the number of plaques[s] used and location on the body). If a treatment-related AE occurred, additional photographic documentation of single test fields and of all test fields within the affected plaque(s) was to be taken. Photographs were not used for grading or analysis purposes. Refer to the SRM for additional information on the photographic procedure (Protocol and Protocol Amendments).

At the Screening visit, it was determined whether pre-treatment with 5% salicylic acid in Vaseline was necessary. This was required since it was not possible to perform sonography on psoriasis plaques with extensive scaling. The maximum length of this pre-treatment was 5 days. The last pre-treatment application with salicylic acid had to be

24

CONFIDENTIAL 2016N274225_00201465

24

performed 2 days before the first application of study treatment on Day 1. Washing of the test fields with a mild detergent solution might have occurred at Day 1 and at later time points in the study as outlined in the Time and Events Schedule, Section 11, Table 23.

4.6.2. Safety Assessments

Safety assessments included the monitoring of AEs, clinical laboratory tests, vital signs, ECGs, physical examinations.

Planned time points for all safety assessments are listed in the Time and Events Table (Section 11, Table 23).

Any significant findings of physical examination of skin, vital signs, significant findings of ECG and safety laboratory parameters, and local and systemic AEs were recorded. Spontaneously noted complaints were recorded with duration, intensity and probability of a correlation with the study treatments (Protocol and Protocol Amendments, Section 7.3.1).

The definitions of an AE or SAE can be found in the protocol, Appendix 3 (Protocol and Protocol Amendments).

The investigator and their designees were responsible for detecting, documenting and reporting events that met the definition of an AE or SAE.

All laboratory tests with values that were considered clinically significantly abnormal during participation in the study should have been repeated until the values return to normal or Baseline. If such values did not return to normal within a period judged reasonable by the investigator, the etiology should have been identified and the sponsor notified.

Potential Clinical Importance (PCI) Ranges

Table 5 Hematology Analytes: Potential Clinical Importance (PCI) Ranges

Lab test (SI unit) Low High

WBC (GI/L) ≤ 0.67 x LLN ≥ 1.82 x ULN

Neutrophil (GI/L) ≤ 0.83 x LLN

Hemoglobin (G/L) male ≥ 1.03 x ULN

female ≥ 1.13 x ULN

Hematocrit (1) male ≥ 1.02 x ULN


Platelet count (GI/L) ≤ 0.67 x LLN ≥ 1.57 x ULN

Lymphocytes (GI/L) ≤ 0.81 x LLN

25

CONFIDENTIAL 2016N274225_00201465

25

Table 6 Chemistry Analytes: Potential Clinical Importance (PCI) Ranges

Lab test Low High

Albumin (mmol/L) ≤ 0.86 x LLN

Calcium (mmol/L) ≤ 0.91 x LLN ≥ 1.06 x ULN

Glucose (mmol/L) ≤ 0.71 x LLN ≥ 1.41 x ULN

Potassium (mmol/L) ≤ 0.86 x LLN ≥ 1.10 x ULN

Sodium (mmol/L) ≤ 0.96 x LLN ≥ 1.03 x ULN

Table 7 Liver Function Test Analytes: Potential Clinical Importance (PCI) Ranges

Lab test High

ALT/SGPT (U/L) ≥ 2 x ULN

AST/SGOT (U/L) ≥ 2 x ULN

Alkaline phosphatase (U/L) ≥ 2 x ULN

Total Bilirubin (µmol/L) ≥ 1.5 x ULN

Total Bilirubin (µmol/L) and ALT (U/L) ≥ 1.5 x ULN Total Bilirubin and ≥ 2 x ULN ALT

Table 8 ECG: Potential Clinical Importance (PCI) Ranges

ECG Parameter* Low High

Absolute QTc interval (msec) > 450

Increase from Baseline QTc (msec) > 60

PR interval (msec) < 110 > 220

QRS interval (msec) < 75 > 110

* for specifications of QTc, see QTc stopping criteria (Protocol, Section 5.4.2)

Table 9 Vital Signs: Potential Clinical Importance (PCI) Ranges

Vital Sign Parameter Low High

Systolic blood pressure (mmHg) < 85 > 160

Diastolic blood pressure (mmHg) < 45 > 100

Heart rate (bpm) < 40 > 110

4.6.3. Efficacy Assessments

An objective parameter of efficacy was the evaluation of the infiltrate thickness by ultrasound measurement. The ultrasound measurements of the ELB representing the thickness of the psoriatic infiltrate as a surrogate allowed for greatly improved discrimination and sensitivity compared to clinical assessment. This method has been

26

CONFIDENTIAL 2016N274225_00201465

26

clinically and scientifically accepted for many years (Bangha, 1996; Remitz, 1999; Gassmueller, 1993; Willers, 2002).

The efficacy variable was the change from Baseline in psoriatic infiltrate thickness on Days 4, 8, 15 and 19 (end of treatment/EoT) as assessed by measurement of the thickness of the ELB of the psoriatic infiltrate using 22 MHz sonography.

High frequency ultrasound (HFUS) (sonographic) measurements were performed using a 22 MHz high frequency sonograph. Serial A-scans were composed and presented on a monitor as a section of the skin. A lateral resolution of approximately 200 m and an axial resolution of 80 m were possible. Dependent on the echo patterns, components of the epidermis, dermis and subcutis were presented. Therefore, exact measurement of infiltrate thickness was possible. The inflammatory psoriatic infiltrate was seen as a clearly definable ELB below the entrance echo. The thickness of this EPB was determined and documented. The thickness was measured in μm. At the Day 1 visit, plaques to be treated should have had a comparable thickness of the EPB (as a surrogate for the infiltrate thickness) of at least 200 m.

The efficacy signal was also based on the clinical assessment of improvement of the test site(s) using a 5-point scale.

Clinical assessment was done by the investigator or designated evaluator after removal of treatments but before any gentle de-scaling necessary prior to sonographic measurements. The comparison of single test fields were made to the untreated area of plaque(s) not covered by the hydrocolloid dressing and close to the respective test field. Clinically apparent differences in erythema and infiltration contributed to this global assessment. At Day 1, the score was documented as “0” (unchanged).

With reference to the EMA Guideline for assessment of short-term efficacy of topical treatments [CHMP, 2004] the response to treatment was documented as the difference between Baseline and post-treatment score (Day 19) for the single treated test fields, and in addition assessments were made on Days 4, 8, and 15.

27

CONFIDENTIAL 2016N274225_00201465

27

4.6.4. Pharmacodynamic Assessments

4.6.4.1. Novel Biomarkers/Pharmacodynamic Markers

With the subject’s consent, skin tissue sample(s) were collected during this study and used for the purposes of measuring novel biomarkers to identify factors that might influence psoriasis, and/or medically related conditions, as well as the biological and clinical responses to GSK2981278.

Four 3 mm skin punch biopsies were collected at EoT (Day 19) from a subset of consenting subjects. One biopsy was collected from a non-lesional area, one from a lesional untreated area, another from the vehicle-treated test field, and one biopsy from the 4% GSK2981278-treated test field.

Biomarker analysis in skin biopsies was conducted using global gene expression profiling and quantitative polymerase chain reaction (qPCR) gene expression analysis of relevant biomarkers expected to be modulated by GSK2981278. These biomarkers analyzed by qPCR included IL-17A, IL-17F, DEFB4A, IL-19, IL-22, IL-36, IL-23p19, S100A7a, IL-8, and Krt6A. The analysis of these PD biomarkers allowed for investigation of target engagement of GSK2981278 in the study.

4.6.4.2. Biomarker Assay Validation

On receipt of the target gene list from GSK, multiple designs for each assay were created in accordance with Epistem Ltd. SOP PG017.

All assays were initially assessed across a genomic desoxyribonucleic acid (DNA) standard curve using the acceptance criteria R2 > 0.97, slope between -2.92 to -3.92 and efficiency = 100 (±20).

4.6.4.3. Statistical Analysis Description

1) Delta Ct (Ct) values between each of the gene of interest (GOI) and the housekeeping gene (HKG) for each subject to be calculated.

2) Ct values to be calculated. Ct values (Ct) was the differences of the Ct values between each lesional and the Baseline non-lesional sample from each subject.

3) Fold change -2 (Ct) to be calculated.

4) Ct data and fold change data to be plotted as a scatter-plot.

5) For lesional 4%GSK2981278-treated test field and lesional untreated area comparisons to the lesional vehicle-treated test field were performed using the Wilcoxon signed rank test (Siegel, 1956).

28

CONFIDENTIAL 2016N274225_00201465

28

The comparisons were

Lesional 4% GSK2981278-treated test field vs. lesional vehicle-treated test field on Ct value

Lesional untreated area vs. lesional vehicle-treated test field on Ct value

4.6.4.4. Transcriptomic Analysis Using Affymetrix Microarray

Raw data files (CEL files, Affymetrix HG-U133plus2 array) were analyzed using a battery of data quality checks (Huber, 2015; Parman, version 1.48.0). CEL files were then pre-processed using the robust multi-chip average (RMA) pipeline (Gautier, 2004) in combination with the most current re-annotated probeset definitions (Dai, 2005). To determine differential mRNA expression, a linear model was fit using an empirical Bayes methodology for more robust variance estimates (Ritchie, 2015; Smyth, 2004). The false discovery rate (FDR) was computed as an adjusted p-value (Benjamini, 1995) to account for multiple testing and a cut-off of 10% FDR, as well as an absolute fold change of 1.5 or greater was used to define differential expression. Clustering analysis was performed as previously described (Freudenberg, 2009). Gene expression profiles were also compared to a psoriasis transcriptomics disease signature that was based on a meta-analysis of published clinical transcriptomics datasets as described in Qu, 2014. In order to enable comparison on an individual sample level, each per-gene expression measure (log2 scale) was normalized by subtracting the corresponding per-gene average over the non-lesional samples.

Differential Expression Analysis

After pre-processing raw data files using standard protocols, a gene-wise linear model was fit accounting for treatment and participant as model parameters and using an empirical Bayes methodology to estimate variance. A cut-off of 10% false discovery rate as well as an absolute fold change of 1.5 or greater was used to define differential expression.

4.7. Data Quality Assurance

This study was conducted according to GCP.

Data Management

For this study subject data were entered into GSK/bioskin defined eCRFs, transmitted electronically to GSK or designee and combined with data provided from other sources (e.g., laboratory data) in a validated data system.

Management of clinical data was performed in accordance with applicable GSK/bioskin standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data.

29

CONFIDENTIAL 2016N274225_00201465

29

AEs and concomitant medications terms were coded using MedDRAversion 18.1. (Medical Dictionary for Regulatory Activities) and an internal validated medication dictionary, GSKDrug version 1.3.

eCRFs (including queries and audit trails) were retained by GSK, and copies were sent to the investigator to maintain as the investigator copy. Subject initials were not collected or transmitted to GSK according to GSK policy.

All investigators and responsible study staff attended a study site initiation meeting to review study protocol procedures, study requirements, and GCP responsibilities. Investigators and staff were given opportunity to discuss any aspect of the study protocol and GCP requirements. Training records were reviewed to ensure investigators and staff were qualified to conduct the study and to document training in GCP. Any staff lacking in GCP training were either sent to a GCP training course or provided an electronic GCP training module. Documentation of GCP training was confirmed prior to staff participation in the study.

All protocol deviations collected during the study were reviewed by the GSK study team in order to identify important protocol deviations. Consistent with ICH E3 guidance, only protocol deviations identified as “important” are provided in this clinical study report. Important deviations were defined as deviations that were likely to affect the interpretation of the results and/or led to exclusion of any subject data from an analysis. Important deviations included, but were not limited to, those related to study inclusion or exclusion criteria, adherence to the protocol, conduct of the study, subject management or subject assessment.

Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors contacted the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements.

When reviewing data collection procedures, the discussion also included identification, agreement and documentation of data items for which the eCRF for studies conducted at a GSK Phase I unit served as the source document.

GSK monitored the study and site activity to verify that the:

Data were authentic, accurate, and complete.

Safety and rights of subjects were being protected.

Study was conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agreed to allow the monitor direct access to all relevant documents.

30

CONFIDENTIAL 2016N274225_00201465

30

Quality Assurance

A GCP audit was not performed in this study.

4.8. Statistical Analyses

Refer to the SAP (version 1.1, 14-MAR-2016) for additional details regarding data analyses. Reporting was performed in accordance with applicable GSK and/or bioskin standards.

The statistical evaluation was performed using SAS version 9.3 (Statistical Analysis System, SAS Inc., Cary, NC) software package.

4.8.1. Sample Size Considerations

The sample size was driven by feasibility and prior experience by bioskin (CRO) in conducting these studies (based on published data on clintrial.gov and unpublished bioskin data).

Fifteen subjects were randomized in order to achieve at least 13 evaluable subjects.

4.8.2. Analysis Populations

4.8.2.1. Safety Population

Safety evaluation set (SES) included all subjects exposed to at least one application of study product. The SES was the primary set for safety analyses.

4.8.2.2. Pharmacodynamic Population

PD analysis set included subjects with at least one sample collected for PD assessments. The PD analysis set was the primary set for PD analyses.

4.8.2.3. Efficacy Population

The primary set for efficacy analyses was the per-protocol analysis set (PPS).

The PPS included all randomized subjects who complied closely with the protocol. Protocol deviations were considered exclusionary, if they were deemed to interfere with the trial aims, particularly, if any of the following criterions applied:

violation of inclusion criteria;

insufficient exposure:

o missed more than 2 planned applications or

o missed any consecutive applications or

o had more than 72 hours between applications,

31

CONFIDENTIAL 2016N274225_00201465

31

except for treatment discontinuations, due to treatment related AEs;

missing Day 1/Baseline or Day 19 visit value or more than one missing value of the infiltrate thickness (primary variable).

Prior to breaking the blind, the following criteria were added to the list to clarify the intended study treatment administration and assessment timings: Some clinical study protocol defined time ranges for assessments were in conflict with the planned study procedures, resulting in protocol deviations. The time range of about 24 ± 2 hours from last application to clinical assessment and sonographic measurement stated in the protocol did not account for the study design having no study treatment administered and no assessments and measurements performed on Sundays (Days 7 and 14) resulting in a longer time range prior to the assessments on Mondays (about 48 hours on Days 8 and 15) (Statistical Methods, Analysis Populations and Section 4.8.5). Assignment of subjects to analysis sets was defined within the blind data review meeting (Statistical Methods).

4.8.3. Interim Analyses

Not applicable to this study.

4.8.4. Final Analyses

4.8.4.1. Hypotheses

No confirmatory hypotheses were formulated for this study. The analyses specified in this Section were interpreted non-confirmatory, and the data were evaluated descriptively.

4.8.4.2. Safety Analyses

Safety was evaluated by tabulations of extent of exposure to study drug, AEs, vital signs and electrocardiogram (ECG) parameter.

Extent of Exposure to Study Drug

The extent of exposure to study drug was summarized by the duration of the treatment period in days (date of last removal of study drug minus date of first dose) and the number of days of dosing. For each treatment descriptive statistics and a frequency table are presented.

Adverse Events (AEs)

AEs were summarized by the number of AEs and the number of subjects and percentage of subjects in the SES, having respective AEs. The presentation is given by treatment for AEs related to a treatment site (local) and for all AEs not related to a treatment site (systemic).

Summaries of AEs, treatment-related AEs, AEs leading to discontinuation of study product applications, and serious AEs were tabulated.

32

CONFIDENTIAL 2016N274225_00201465

32

AEs were coded using the MedDRA dictionary version 18.1. All AE terms were coded to the MedDRA primary pathway. Number and percentage of subjects with in each system organ class (SOC) and preferred term (PT) were tabulated, in case of more than 5 AEs.

All AEs were listed by subject with AE onset, seriousness, severity, relationship to study product, action taken, and outcome. A listing of each verbatim term and its assigned SOC and PT is provided.

Laboratory Analyses

Each quantitative laboratory test was summarized at every scheduled time point and as change from Baseline. Subject laboratory parameter profiles (Screening and Days 8, 15 and 19) meeting the PCI criteria given in Table 5, Table 6 and Table 7 were listed with the measurement flagged as high or low, in relation to the PCI ranges.

If applicable, liver event data were listed.

Electrocardiogram (ECG)

ECG value and change from Baseline at every scheduled time point for each ECG parameter were summarized using descriptive statistics. The ECG was evaluated by the investigator as “Normal”, “Abnormal, not clinically significant”, and “Abnormal, clinically significant”. A summary of ECG findings is provided. Also, a listing of ECG values and a listing of ECG findings are provided

Subject ECG parameter profiles (Screening, Days 15 and 19) with any measurement meeting any PCI criteria given in Table 8 and discontinuation criteria (SAP) were listed, with the measurement flagged as high or low, in relation to the ranges.

Other Safety Analyses

Vital sign value and change from Baseline at Day 19 for each vital sign parameter were summarized using descriptive statistics.

Subject vital sign parameter profiles (Screening and Day 19) with any measurement meeting any PCI criteria given in Table 9 were listed with the measurement flagged as high or low, in relation to the PCI criteria.

4.8.4.3. Pharmacodynamic (PD) Analyses

The statistical analysis of the gene expression data was not part of the SAP. The PD biomarker analysis in skin biopsies and the respective results can be found in Section 8.

33

CONFIDENTIAL 2016N274225_00201465

33

4.8.4.4. Efficacy Analyses

Reduction in Psoriatic Infiltrate Thickness

As there were no missing values for the sonographic measurements, the planned analyses for the LOCF population are presented as OC analyses (Statistical Methods, Analysis Populations).

The primary efficacy endpoint was the AUC of change in infiltrate thickness [µm*day] using the linear trapezoidal rule over the changes from Baseline in infiltrate thickness on Days 1 (Baseline), 4, 8, 15 and 19 (EoT).

The AUC of change in infiltrate thickness was analyzed using a mixed-model repeated-measures (MMRM) analysis including a term for treatment. The treatment was treated as repeated measures within the same subject. The MMRM model was determined with an unstructured covariance matrix. In case the model did not converge, a covariance matrix of compound symmetry structure was used. Pair-wise treatment comparisons (Table 10) were performed. The primary comparison was between each active dose and the vehicle ointment. Least-square (LS) means for each treatment and for the difference between treatments, including corresponding 95% confidence interval (CI) and p-value arepresented.

In addition, for each post-baseline assessed time point, the reduction in infiltrate thickness of the psoriatic plaque(s) from Baseline was summarized using the observed cases (OC) approach. Accordingly, the AUC based on OC only was presented. Pair-wise treatment comparisons (Table 10) was performed for change in infiltrate thickness at each study visit using a MMRM model of the change from Baseline in infiltrate thickness similar to that for the primary efficacy endpoint. The model included the additional terms of visit and treatment-by-visit interaction, with treatment and visit treated as repeated measures within the same subject with an unstructured covariance matrix. The LS mean for each treatment, an estimate of the difference between treatments, corresponding 95% CIs and p values are presented. In case the model did not converge, a similar model to the one for the primary efficacy endpoint was applied, for each visit separately.

Moreover, percent change from Baseline in infiltrate thickness was assessed using descriptive statistics.

34

CONFIDENTIAL 2016N274225_00201465

34

Table 10 Pair-wise Comparisons of Test and Control Products

Study products:

GSK2981278 Ointment Controls

0.03% 0.1% 0.8% 4%Vehicle

OintmentPositive Control

GS

K29

8127

8 O

intm

ent

0.03% X X X X X

0.1% X X X X

0.8% X X X

4% X X

Vehicle X

Improvement in Clinical Assessment

Clinical efficacy assessment using a 5-point scale (Section 4.6.3) was evaluated for each post-baseline assessed time point. The ordinal clinical score and the cumulative total score, determined for each subject and treatment as the sum of all post-baseline assessments, are presented by descriptive statistics. Additionally, frequency counts are provided for the clinical scores. Missing data, for summaries and when computing the cumulative score, were to be excluded for OC presentations or imputed by the LOCF approach for LOCF presentations (SAP, Section 3.5.2).

4.8.5. Changes in Conduct of the Study or Planned Analyses

There were no changes in the conduct of this trial or the planned analyses.

A total of 6 file notes were issued during the trial.

One file note (File Note No. 1) serves as protocol clarification for the following: The Time and Events Table of the protocol (Section 7.1) indicates that descaling of the test fields with a mild detergent may occur on Days 1, 8, 15 and 19 as necessary. Although not specifically stated in the Time and Events Table, descaling may also be necessary on Day 4. Taking into account the nature of the procedure and the protocol text regarding the change in timing or addition of time points for any planned study assessments(Section 7 of the protocol), the possible descaling procedure was added to Day 4 (Section 11, Table 23).

Another file note (File Note No. 3) describes the following conflict in the protocol: Some clinical study protocol defined time ranges for assessments were in conflict with the planned study procedures. The time range of about 24 ± 2 hours from last application to clinical assessment and sonographic measurement stated in the protocol did not account for the study design having no study treatment administered and no assessments and measurements performed on Sundays (Days 7 and 14) resulting in a longer time range prior to the assessments on Mondays (about 48 hours on Days 8 and 15). These cases were recorded as protocol deviations (Section 5.2).

35

CONFIDENTIAL 2016N274225_00201465

35

Three further file notes were due to administrative reasons (File Note Nos. 2, 4 and 5) and another file note (File Note No. 6) describes data management procedures.

The file notes can be found in the TMF.

36

CONFIDENTIAL 2016N274225_00201465

36

5. STUDY POPULATION RESULTS

5.1. Subject Disposition

A summary of subject enrollment/evaluability and completion/discontinuation can be found in Table 1.01 and Table 1.02.

A total of 16 male subjects were screened in this trial of which 1 subject was a screening failure. 15 subjects were randomized and all 15 subjects completed the trial as planned. There were no dropouts.

5.2. Protocol Deviations

There were no protocol deviations that excluded subjects from the analysis populations.

A total of 65 protocol deviations were noted in 15 subjects during the trial. All 65 deviations concerned time window violations.

None of these protocol deviations were considered to have an effect on the interpretations of the study results.

5.3. Populations Analyzed

A listing with all subjects assigned to each analysis population can be found in the Statistical Methods, Analysis Populations and Listing 4.

For this trial, a total of 15 male subjects were randomized in order to achieve at least 13 evaluable subjects. The data of all 15 randomized subjects were valid for the PPS and SES analyses (Table 11). There were no subjects excluded from the analysis populations (Table 1.03). Thirteen of the 15 subjects consented to skin biopsies and were valid for the PD population analysis.

Table 11 Populations Analyzed

Analysis Set

DefinitionNo. of

Subjects IncludedDisplays

Safety evaluation set (SES)

Included all subjects exposed toat least one application of study product

15Safety (extent of exposure to study drug, AEs, laboratory, vital signs and ECG parameter)

PD analysis set

Included all subjects with at least one sample collected for PD assessments.

13Biomarker/Pharmacodynamic Marker

Per-protocol analysis set(PPS)

Included all randomized subjects who compiled closely with the clinical trial protocol

15Efficacy (sonographic measurement, clinical assessment)

37

CONFIDENTIAL 2016N274225_00201465

37

5.4. Demographic and Baseline Characteristics

A summary of subject demographic and baseline characteristics can be found in Table 12and in Table 1.04 and Table 1.05.

Table 12 Demographics and Baseline Characteristics (SES and PPS)

SES1

(N = 15)PPS2

(N = 15)Age3 [years]N 15 15Mean ± SD 53.9 ± 8.1 53.9 ± 8.1Median 53.0 53.0Min, max 42 , 67 42 , 67GenderN 15 15Male 15 (100%) 15 (100%)Female 0 ( 0%) 0 ( 0%)EthnicityN 15 15Hispanic or Latino 0 ( 0%) 0 ( 0%)Not Hispanic or Latino 15 (100%) 15 (100%)RaceN 15 15White 15 (100%) 15 (100%)Black or African Indian 0 ( 0%) 0 ( 0%)American Indian or Alaska Native

0 ( 0%) 0 ( 0%)

Asian 0 ( 0%) 0 ( 0%)Native Hawaiian or Other Pacific Islander

0 ( 0%) 0 ( 0%)

Other 0 ( 0%) 0 ( 0%)Fitzpatrick skin typeN 15 15Type I 0 ( 0%) 0 ( 0%)Type II 1 ( 7%) 1 ( 7%)Type III 13 ( 87%) 13 ( 87%)Type IV 1 ( 7%) 1 ( 7%)Type V 0 ( 0%) 0 ( 0%)Type VI 0 ( 0%) 0 ( 0%)Height [cm]N 15 15Mean ± SD 177.1 ± 8.0 177.1 ± 8.0Median 178.0 178.0Min, max 163 , 192 163 , 192

38

CONFIDENTIAL 2016N274225_00201465

38

SES1

(N = 15)PPS2

(N = 15)Weight [kg]N 15 15Mean ± SD 86.9 ± 16.0 86.9 ± 16.0Median 81.0 81.0Min, max 57 , 112 57 , 112BMI [kg/m²]N 15 15Mean ± SD 27.601 ± 4.245 27.601 ± 4.245Median 26.600 26.600Min, max 21.45 , 38.27 21.45 , 38.271 Safety evaluation set (SES): All subjects exposed to at least one application of study product.2 Per-protocol analysis set (PPS): All randomized subjects who complied closely with the protocol.3 Age [years] = Full years between date of informed consent and date of birth, with day of birth set Jan 1st.Source Data: Table 1.04 and Table 1.05

5.5. Prior and Concomitant Medications

Six subjects used one or more concomitant medications during the trial.

Four subjects were taking medication for treatment of hypertension, 1 of whom was also taking medication for treatment of arrhythmia.

Another subject was taking medication for prophylaxis after myocardial infarction(medical history event).

A further subject took paracetamol because of a non-serious AE (nasopharyngitis) on Day 8 (Section 6.1).

5.6. Exposure and Treatment Compliance

Extent of Exposure

The duration of the treatment period (date of last removal of study drug minus date of first dose) and number of treatments is displayed in Table 3.01. A listing of individual study drug exposure, calculated number of dosing days and calculated duration of treatment can be found in Compliance and/or Drug Concentration Data, Listing 12.

Approximately 200 L of each study treatment—the 4 GSK2981278 ointments (0.03%, 0.1%, 0.8% and 4%), GSK2981278 vehicle (active ingredient-free vehicle toGSK2981278 ointment) and the active positive control betamethasone valerate 0.1% cream—were semi-occlusively applied to 6 test fields (each approximately 1.1 cm2) once daily over a 19-day treatment period (16 treatments, no application on Days 7, 14 and 19).

All 15 subjects had a treatment period of 19 days and received the total number of 16 applications of each study treatment which corresponded to a total dosage of approximately 157.8 mg GSK2981278 and 3.2 mg betamethasone valerate.

39

CONFIDENTIAL 2016N274225_00201465

39

Treatment Compliance

All 15 subjects were regarded as compliant. All subjects were dosed at the site and received study treatment directly from the investigator or designee, under medical supervision. The date and time of each dose administered at bioskin were recorded in the source documents and eCRF.

40

CONFIDENTIAL 2016N274225_00201465

40

6. SAFETY RESULTS

6.1. Adverse Events

Only 1 non-serious AE was reported in 1 subject over the entire trial period. Subject experienced nasopharyngitis of moderate intensity; the event was

considered to be not related to study treatment and did not correspond to a specific treatment area. The subject continued study participation and had recovered at the end of the study (Table 3.08).

6.2. Serious and Other Significant Adverse Events

There were no deaths, SAEs or other significant AEs reported in this trial.

6.3. Clinical Laboratory Evaluations

Descriptive statistics for clinical laboratory assessments can be found in Table 3.04 (hematology), Table 3.05 (clinical chemistry), Table 3.06 (urinalysis) and Table 3.07(urinalysis).

There were no abnormalities with clinical significance in any of the clinical laboratory assessments (hematology, clinical chemistry and urinalysis).

Hematology

There were only minor hematologic changes between Screening and Days 8, 15 and 19(EoT). Abnormal values which were out of range (high or low) but of no clinical significance are given in Table 3.04.

Three of the 15 subjects showed abnormal, not clinically significant lymphocytes values meeting the PCI criterion—all values below the normal range lower limit (Table 13 and Listing 3.04). All 3 subjects showed abnormal lymphocytes values already at Screening of which 2 values met the PCI criterion.

Clinical Chemistry

There were only minor changes in clinical chemistry values between Screening and Days 8, 15 and 19 (EoT). ). Abnormal values which were out of range (high or low) but of no clinical relevance are given in Table 3.05.

One of the 15 subjects showed abnormal, not clinically significant glucose valuesmeeting the PCI criterion. The fasting glucose values were above the normal range upper limit already at Screening and at each following assessment time point (Table 13 and Listing 3.04).

41

PPD

CONFIDENTIAL 2016N274225_00201465

41

Table 13 Clinical Laboratory Evaluations of Potential Clinical Importance(PCI) (SES)

PCI: Potential clinical importanceSource Data: Listing 3.04

Urinalysis

The urine drug screening test (dipstick) was negative in all 15 subjects at Screening.

All values evaluated in the urinalysis (specific gravity; dipstick: glucose, protein, erythrocytes, ketones) at Screening and on Days 8, 15 and 19 (EoT) were within the normal range or were negative.

42

PPD

CONFIDENTIAL 2016N274225_00201465

42

In 5 subjects elevated pH-value(s) (7 – 8) were diagnosed and assessed as abnormal, but not clinically significant—in 1 subject already at Screening, in another subject also at Screening and on Day 15 and in 3 further subjects on Day 8, 15 or 19 (EoT), respectively.

Liver Events

There were no subjects with any liver events reported in this trial (Listing 3.05).

Serology

All serology assessments including HIV, hepatitis B and hepatitis C tests were negative in all 15 subjects at Screening.

6.4. Vital Signs

There were no abnormalities with clinical significance in any of the vital signs measurements.

All vital signs were in an acceptable range for this trial. There were only minor changes in the mean systolic and diastolic blood pressure, the mean heart rate and the mean oral temperature between Screening and Day 19 (EoT).

None of the vital signs parameters met the PCI criterion in this trial (Listing 3.01).

In 1 subject an abnormal vital signs parameter was diagnosed: This subject had an elevated systolic blood pressure value of 155 mm Hg (normal range: 80 – 150 mm Hg) on Day 19 (EoT).

Descriptive statistics for vital signs can be found in Table 3.02.

6.5. Electrocardiogram

No subjects had any clinically significant ECG findings (Listing 3.02).

All ECG values were in an acceptable range for this trial. There were only minorchanges in the mean HR, PR, QRS, QT, QTcB and RR intervals between Screening, Day 15 and Day 19 (EoT) (Table 3.03).

In 9 subjects, the ECG outcome was interpreted as abnormal, but not clinically significantby the investigator (Listing 30).

Two of these 9 subjects showed 1 abnormal, not clinically significant ECG parameter(QRS interval) meeting the PCI criterion (Listing 3.03):

In 1 subject (subject identifier: the QRS interval was below the normal range lower limit (˂ 75) on Day 15.

In another subject (subject identifier: the QRS interval was above the normal range upper limit (˃ 110) already at Screening and on Day 15.

No abnormal QRS interval was noted in these 2 subjects on Day 19 (EoT).

43

PPD

PPD

CONFIDENTIAL 2016N274225_00201465

43

Descriptive statistics for ECG can be found in Table 3.03.

6.6. Physical Examination of the Skin and Skin Biopsy Wound Control

In the physical examination of the skin, no adverse changes to the skin which were to be recorded as an AE were noted in any of the 15 subjects at Screening or on Day 19/EoT. However, 2 subjects showed worsening of psoriasis over the trial—1 subject in the test field treated with GSK2981278 ointment 0.03% on Day 8 and another subject in the test field treated with GSK2981278 ointment 0.1% at EoT (Section 7.2).

Furthermore, there were no findings concerning the skin biopsy wound control in any of the 13 subjects consenting to skin biopsies at the Follow-up visit (Day 26).

44

CONFIDENTIAL 2016N274225_00201465

44

7. EFFICACY RESULTS

The primary set for efficacy analyses was the PPS.

7.1. Sonographic measurements – Psoriatic Infiltrate Thickness

AUC of Change in Infiltrate Thickness (Primary Endpoint)

The primary efficacy endpoint was the AUC of the changes in infiltrate thickness [m*day] as measured by change of ELB using the linear trapezoidal rule on Days 1, 4, 8, 15 and 19. A negative AUC means an overall reduction in the infiltrate thickness over the treatment period, whereas a positive value means an overall increase in the infiltrate thickness over time.

As can be seen in Figure 1, mean AUCs of change in infiltrate thickness were positive for all 4 different GSK2981278 ointment concentrations 0.03%, 0.1%, 0.8% and 4% (1306.2, 1787.4, 2028.5 and 2026.1 m*day, respectively) (Table 14).

The mean AUC of change in infiltrate thickness was also positive for the active ingredient-free vehicle (2115.3 m*day).

In contrast, the mean AUC of change in infiltrate thickness was negative (-4982.2 m*day) for the positive control betamethasone valerate 0.1% cream.

Thus, a reduction in infiltrate thickness was shown only for betamethasone valerate 0.1% cream under the conditions of this trial.

Descriptive statistics of AUC of change in infiltrate thickness can be found in Table 2.02.

45

CONFIDENTIAL 2016N274225_00201465

45

Figure 1 Psoriatic Infiltrate Thickness – Change from Baseline – AUC –Bar Chart (PPS)

Source data: Figure 2.03

Infiltrate Thickness Values and Absolute Changes and Percent Changes From Baseline in Infiltrate Thickness

The mean infiltrate thickness was comparable in the test fields at Baseline (Day 1) (481.2 to 512.1 m) (Table 14).

The assessment of the mean infiltrate thickness values (Table 14 and Figure 2) and the mean absolute changes (Table 15 and Figure 3) and mean percent changes from Baseline in infiltrate thickness (Table 16) showed an increase in mean infiltrate thickness following treatment with all 4 GSK2981278 ointment formulations 0.03%, 0.1%, 0.8% and 4% during the first 4 days (mean values: 626.5 to 683.9 m; mean changes from Baseline to Day 4: 122.9, 160.8, 172.1 and 202.7 m corresponding to mean % changes of 22.6, 32.4, 34.4 and 41.5%, respectively). The increase remained until Day 8 and was followed by a decrease in all 4 SK2981278-treated test fields (0.03%, 0.1%, 0.8% and 4%): On Day 19 (EoT) the mean infiltrate thickness values had almost returned to Baseline values (mean changes from Baseline: 28.5, 21.8, 43.4 and 20.5 m corresponding to mean % changes of 13.4%, 18.0%, 15.4% and 10.1%, respectively).

46

CONFIDENTIAL 2016N274225_00201465

46

The active ingredient-free vehicle showed comparable results and comparable courses of the mean infiltrate thickness and changes from Baseline over the trial period: The mean infiltrate thickness had increased within the first 4 days (Day 4: 697.45 m), corresponding to a mean change from Baseline of 199.5 m and a % mean change of 39.3%. At EoT the mean change from Baseline was 31.8 m corresponding to mean % changes of 13.5%.

For the positive control betamethasone valerate 0.1% cream, a clear continuous decrease in infiltrate thickness was seen over the trial period (mean change from Baseline to Day 19: -403.6 µm corresponding to a mean % reduction of 81.5% at EoT).

Descriptive statistics of measurement of infiltrate thickness can be found in Table 2.01. Descriptive statistics of absolute changes and percent changes from Baseline in infiltrate thickness are given in Table 2.02 and Table 2.07, respectively.

Figure 2 Psoriatic Infiltrate Thickness – Line Plot (PPS)


47

CONFIDENTIAL 2016N274225_00201465

47

Figure 3 Psoriatic Infiltrate Thickness – Change from Baseline – Line Plot (PPS)


48

CONFIDENTIAL 2016N274225_00201465

48

Table 14 Psoriatic Infiltrate Thickness (PPS)

Psoriatic infiltrate thickness [m]1

GSK29812780.03%

ointment

GSK29812780.1%

ointment

GSK29812780.8%

ointmentGSK29812784% ointment Vehicle

Betamethasonevalerate 0.1%

creamDay 1 / BaselineN 15 15 15 15 15 15Mean ± SD 503.7 ± 306.5 512.1 ± 314.6 511.4 ± 300.3 481.2 ± 256.3 497.9 ± 318.3 486.9 ± 288.695% CI2 333.9 , 673.4 337.9 , 686.3 345.1 , 677.7 339.3 , 623.1 321.6 , 674.1 327.1 , 646.7Median 359.0 383.0 383.0 352.0 367.0 344.0Min, max 242 , 1344 227 , 1188 242 , 1164 234 , 977 266 , 1359 234 , 1141Day 4N 15 15 15 15 15 15Mean ± SD 626.5 ± 419.1 672.9 ± 456.3 683.5 ± 450.7 683.9 ± 441.5 697.4 ± 514.9 317.8 ± 246.995% CI2 394.5 , 858.6 420.2 , 925.6 433.9 , 933.1 439.5 , 928.4 412.3 , 982.5 181.1 , 454.5Median 539.0 461.0 555.0 586.0 531.0 258.0Min, max 234 , 1555 273 , 1711 320 , 1766 266 , 1680 266 , 2117 117 , 1102Day 8N 15 15 15 15 15 15Mean ± SD 632.3 ± 316.0 692.1 ± 366.2 685.5 ± 406.9 671.3 ± 343.5 673.9 ± 337.0 205.7 ± 126.595% CI2 457.3 , 807.2 489.4 , 894.9 460.2 , 910.8 481.1 , 861.6 487.3 , 860.5 135.7 , 275.8Median 555.0 609.0 633.0 648.0 664.0 172.0Min, max 234 , 1461 258 , 1789 258 , 1898 273 , 1578 211 , 1586 78 , 531Day 15N 15 15 15 15 15 15Mean ± SD 524.0 ± 231.1 546.9 ± 254.0 580.8 ± 317.8 523.0 ± 227.7 567.9 ± 292.1 116.7 ± 87.995% CI2 396.0 , 652.0 406.2 , 687.5 404.8 , 756.8 396.9 , 649.1 406.1 , 729.6 68.0 , 165.4Median 492.0 539.0 484.0 453.0 508.0 102.0Min, max 219 , 953 219 , 1086 203 , 1414 211 , 1008 141 , 1313 0 , 273Day 19/EoT3

N 15 15 15 15 15 15Mean ± SD 532.2 ± 242.9 533.9 ± 220.7 554.8 ± 297.6 501.7 ± 242.1 529.7 ± 289.8 83.3 ± 77.195% CI2 397.7 , 666.7 411.7 , 656.2 390.0 , 719.6 367.6 , 635.7 369.2 , 690.1 40.6 , 126.0Median 453.0 547.0 500.0 430.0 500.0 70.0Min, max 188 , 930 195 , 1000 156 , 1195 211 , 992 117 , 1219 0 , 2581 Psoriatic infiltrate thickness assessed by sonography.2 95% CI: 95% confidence interval3 EoT: End of treatmentSource Data: Table 2.01

49

CONFIDENTIAL 2016N274225_00201465

49

Table 15 Psoriatic Infiltrate Thickness – Absolute Changes from Baseline and AUC of Change from Baseline (PPS)

Change from Baseline in psoriatic infiltrate thickness [m]1

GSK29812780.03%

ointment

GSK29812780.1%

ointment

GSK29812780.8%



creamDay 4N 15 15 15 15 15 15Mean ± SD 122.9 ± 183.7 160.8 ± 186.2 172.1 ± 195.7 202.7 ± 252.8 199.5 ± 273.4 -169.1 ± 153.295% CI2 21.2 , 224.6 57.7 , 263.9 63.7 , 280.5 62.8 , 342.7 48.1 , 350.9 -254.0 , -84.3Median 70.0 86.0 94.0 110.0 117.0 -125.0Min, max -63 , 672 0 , 524 -8 , 657 -47 , 758 -15 , 1070 -617 , -39Day 8N 15 15 15 15 15 15Mean ± SD 128.6 ± 207.3 180.0 ± 210.1 174.1 ± 235.3 190.1 ± 201.7 176.1 ± 225.4 -281.2 ± 210.295% CI2 13.8 , 243.4 63.7 , 296.3 43.8 , 304.5 78.5 , 301.8 51.2 , 300.9 -397.6 , -164.8Median 79.0 140.0 94.0 118.0 140.0 -172.0Min, max -235 , 578 -148 , 601 -132 , 734 -71 , 601 -289 , 539 -695 , -47Day 15N 15 15 15 15 15 15Mean ± SD 20.3 ± 197.8 34.7 ± 167.4 69.4 ± 155.9 41.8 ± 130.6 70.0 ± 222.8 -370.3 ± 263.795% CI2 -89.2 , 129.9 -57.9 , 127.4 -16.9 , 155.7 -30.5 , 114.1 -53.4 , 193.4 -516.3 , -224.2Median 16.0 -31.0 23.0 31.0 39.0 -273.0Min, max -469 , 383 -250 , 335 -132 , 399 -187 , 328 -468 , 445 -890 , -71Day 19/EoT3

N 15 15 15 15 15 15Mean ± SD 28.5 ± 163.5 21.8 ± 197.8 43.4 ± 142.4 20.5 ± 121.3 31.8 ± 196.2 -403.6 ± 259.895% CI2 -62.0 , 119.1 -87.7 , 131.3 -35.5 , 122.3 -46.7 , 87.6 -76.8 , 140.4 -547.5 , -259.7Median 62.0 8.0 -8.0 0.0 47.0 -312.0Min, max -453 , 258 -438 , 343 -133 , 360 -133 , 344 -453 , 390 -899 , -86AUC [m*day]4

N 15 15 15 15 15 15

Mean ± SD1306.2 ± 2544.3

1787.4 ± 2158.1

2028.5 ± 2562.6

2026.1 ± 2356.2

2115.3 ± 3293.4

-4982.2 ± 3442.2

95% CI2-102.8 , 2715.2

592.3 , 2982.5 609.3 , 3447.6 721.3 , 3331.0 291.5 , 3939.2-6888.4 , -

3076.0Median 1134.0 1438.0 1050.0 1734.0 1305.0 -3429.5Min, max -4152 , 6010 -667 , 5586 -801 , 7308 -1416 , 5939 -4111 , 8517 -12627 , -13151 Psoriatic infiltrate thickness assessed by sonography.2 95% CI: 95% confidence interval3 EoT: End of treatment4 AUC: Area under the time curve of change in infiltrate thickness [m*day] using the linear trapezoidal rule over the changes from Baseline in infiltrate thickness on Days 1, 4, 8, 15 and 19.Source Data: Table 2.02

50

CONFIDENTIAL 2016N274225_00201465

50

Table 16 Psoriatic Infiltrate Thickness – % Changes from Baseline (PPS)

% Change from Baseline in psoriatic infiltrate thickness1

GSK29812780.03%

ointment

GSK29812780.1%

ointment

GSK29812780.8%



creamDay 4N 15 15 15 15 15 15Mean ± SD 22.6 ± 30.4 32.4 ± 36.6 34.4 ± 30.2 41.5 ± 40.2 39.3 ± 43.3 -36.1 ± 16.895% CI2 5.8 , 39.4 12.1 , 52.7 17.7 , 51.1 19.3 , 63.8 15.3 , 63.3 -45.4 , -26.8Median 13.3 16.5 26.3 37.7 20.1 -36.3Min, max -21 , 76 0 , 123 -1 , 91 -5 , 129 -5 , 140 -63 , -3Day 8N 15 15 15 15 15 15Mean ± SD 35.9 ± 43.4 49.2 ± 56.5 41.5 ± 53.1 48.7 ± 55.2 48.7 ± 55.7 -55.7 ± 18.595% CI2 11.9 , 60.0 17.9 , 80.5 12.1 , 70.8 18.1 , 79.2 17.8 , 79.5 -65.9 , -45.4Median 32.2 34.4 14.5 29.9 34.1 -59.5Min, max -23 , 112 -13 , 155 -12 , 183 -21 , 170 -25 , 158 -85 , -14Day 15N 15 15 15 15 15 15Mean ± SD 14.5 ± 43.8 18.8 ± 48.5 20.0 ± 43.8 17.3 ± 39.3 25.3 ± 52.7 -73.9 ± 21.095% CI2 -9.8 , 38.8 -8.1 , 45.6 -4.2 , 44.3 -4.5 , 39.0 -3.9 , 54.5 -85.5 , -62.2Median 4.5 -5.4 4.1 3.2 6.7 -78.2Min, max -35 , 107 -26 , 107 -30 , 125 -39 , 113 -55 , 132 -100 , -21Day 19/EoT3

N 15 15 15 15 15 15Mean ± SD 13.4 ± 33.7 18.0 ± 46.8 15.4 ± 43.2 10.1 ± 39.8 13.5 ± 46.0 -81.5 ± 18.195% CI2 -5.3 , 32.1 -7.9 , 43.9 -8.6 , 39.3 -12.0 , 32.1 -11.9 , 39.0 -91.5 , -71.5Median 13.4 1.1 -2.1 0.0 8.4 -83.3Min, max -38 , 81 -37 , 110 -46 , 113 -39 , 119 -63 , 111 -100 , -251 Psoriatic infiltrate thickness assessed by sonography.2 95% CI: 95% confidence interval 3 EoT: End of treatmentSource Data: Table 2.07

AUC - Estimates and Statistical Comparisonwithin an MMRM model with a fixed effect for treatment, and treatment treated as a repeated measure within the same subject with an unstructured covariance matrix

Statistically significant positive estimates of the AUC of change from Baseline to Day 19 (EoT) in psoriatic infiltrate thickness were found for the 3 GSK2981278 ointment concentrations 0.1%, 0.8% and 4% (Table 17 and Table 2.03), reflecting an increase in psoriatic infiltrate thickness.

Whereas, a statistically significant negative estimate was determined for the positive control betamethasone valerate 0.1% cream (Table 17), representing a clear reduction in psoriatic infiltrate thickness.

No statistically significant estimate of the AUC of change from Baseline was found for the lowest GSK2981278 ointment concentration 0.03% (Table 17).

51

CONFIDENTIAL 2016N274225_00201465

51

Table 17 Psoriatic Infiltrate Thickness – Change from Baseline – AUC MMRM Estimates (PPS)

Change fromBaseline inpsoriaticinfiltratethickness [µm]1

GSK29812780.03%

ointment

GSK29812780.1%

ointment

GSK29812780.8%



cream

AUC [µm*day]2,3

Estimate ± SE1306.2 ±

656.91787.4 ±

557.22028.5 ±

661.72026.1 ±

608.42115.3 ±

850.4-4982.2 ± 888.8

95% CI4-102.8 , 2715.2

592.3 , 2982.5 609.3 , 3447.6 721.3 , 3331.0 291.5 , 3939.2-6888.4 , -

3076.0P-value 0.0667 0.0063 0.0084 0.0050 0.0261 < 0.00011 Psoriatic infiltrate thickness assessed by sonography.2 AUC: Area under the time curve of change in infiltrate thickness [µm*day] using the linear trapezoidal rule over the changes from Baseline in infiltrate thickness on Day 1, 4, 8, 15 and 19.3 Estimates of the AUC of change from Baseline in psoriatic infiltrate thickness determined using a mixed-model repeated-measures (MMRM) model with a fixed effect for treatment, and treatment treated as a repeated measure within the same subject with an unstructured covariance matrix.4 95% CI: 95% confidence intervalSource Data: Table 2.03

The statistical treatment comparisons with respect to AUC of change from Baseline to Day 19 (EoT) in psoriatic infiltrate thickness showed no statistically significant LS mean differences between the 4 GSK2981278 ointment formulations (0.03%, 0.1%, 0.8% and 4%) and the vehicle or between the 4 GSK2981278 ointment concentrations (Table 2.04).

In contrast, statistically significant LS mean differences were found between all 4 GSK2981278 ointment concentrations and the positive control as well as between the vehicle and the positive control with p-values ˂ 0.0001, each in favor of betamethasone valerate 0.1% cream (Table 2.04):

Betamethasone valerate 0.1% cream and GSK2981278 0.03% ointment (LS mean difference: -6288.5 m*day, 95% CI: -8471.6 , -4105.3 m*day)



Betamethasone valerate 0.1% cream and GSK2981278 4% ointment (LS mean difference: -7008.4 m*day, 95% CI: -9463.8 , -4553.0 m*day)

Betamethasone valerate 0.1% cream and vehicle (LS mean difference: -7097.6 m*day, 95% CI: -9771.1 , -4424.0 m*day)

52

CONFIDENTIAL 2016N274225_00201465

52

Change in Psoriatic Infiltrate Thickness at Each Trial Visit – Estimates and Statistical Comparisonwithin an MMRM model with a fixed effect for treatment, and treatment treated as a repeated measure within the same subject with an unstructured covariance matrix

Statistically significant positive estimates of change from Baseline in psoriatic infiltrate thickness were found for all 4 GSK2981278 ointment formulations (0.03%, 0.1%, 0.8% and 4%) and the vehicle on Days 4 and 8 (Table 18 and Table 2.05), reflecting an increase during the first week.

Whereas, a statistically significant negative estimate of change from Baseline in psoriatic infiltrate thickness was found for the positive control betamethasone valerate 0.1% cream at each assessment time point with the greatest negative estimate at EoT, indicating a continuous decrease over the trial period (Table 18).

Table 18 Psoriatic Infiltrate Thickness – Change from Baseline – MMRM Estimates by Visit (PPS)

Change fromBaseline inpsoriaticinfiltratethickness [µm]1,2

GSK29812780.03%

ointment

GSK29812780.1%

ointment

GSK29812780.8%



cream

Day 4Estimate ± SE 122.9 ± 47.4 160.8 ± 48.1 172.1 ± 50.5 202.7 ± 65.3 199.5 ± 70.6 -169.1 ± 39.695% CI3 21.2 , 224.6 57.7 , 263.9 63.7 , 280.5 62.8 , 342.7 48.1 , 350.9 -254.0 , -84.3P-value 0.0214 0.0048 0.0043 0.0077 0.0134 0.0008

Day 8Estimate ± SE 128.6 ± 53.5 180.0 ± 54.2 174.1 ± 60.8 190.1 ± 52.1 176.1 ± 58.2 -281.2 ± 54.395% CI3 13.8 , 243.4 63.7 , 296.3 43.8 , 304.5 78.5 , 301.8 51.2 , 300.9 -397.6 , -164.8P-value 0.0307 0.0051 0.0125 0.0026 0.0091 0.0001

Day 15Estimate ± SE 20.3 ± 51.1 34.7 ± 43.2 69.4 ± 40.3 41.8 ± 33.7 70.0 ± 57.5 -370.3 ± 68.195% CI3 -89.2 , 129.9 -57.9 , 127.4 -16.9 , 155.7 -30.5 , 114.1 -53.4 , 193.4 -516.3 , -224.2P-value 0.6965 0.4349 0.1067 0.2354 0.2438 < 0.0001

Day 19/EoT4

Estimate ± SE 28.5 ± 42.2 21.8 ± 51.1 43.4 ± 36.8 20.5 ± 31.3 31.8 ± 50.6 -403.6 ± 67.195% CI3 -62.0 , 119.1 -87.7 , 131.3 -35.5 , 122.3 -46.7 , 87.6 -76.8 , 140.4 -547.5 , -259.7P-value 0.5102 0.6759 0.2575 0.5240 0.5402 < 0.00011 Psoriatic infiltrate thickness assessed by sonography.2 Change from Baseline in psoriatic infiltrate thickness estimates determined for each visit separately using a mixed-model repeated-measures (MMRM) model with a fixed effect for treatment, and treatment treated as repeated measure within the same subject with an unstructured covariance matrix.3 95% CI: 95% confidence interval4 EoT: End of treatmentSource Data: Table 2.05

53

CONFIDENTIAL 2016N274225_00201465

53

The statistical treatment comparisons with respect to the change from Baseline in psoriatic thickness showed no statistically significant LS mean differences between the 4 GSK2981278 ointment formulations (0.03%, 0.1%, 0.8% and 4%) and the vehicle or between any of the GSK2981278 ointment concentrations at any assessment time point (Days 4, 8, 15 and 19/EoT) (Table 2.06).

In contrast, statistically significant LS mean differences were found between all 4 GSK2981278 ointment concentrations and the positive control as well as between the vehicle and the positive control, each in favor of betamethasone valerate 0.1% cream, at each assessment time point (Table 19 and Table 2.06).

Table 19 Psoriatic Infiltrate Thickness – Change from Baseline – MMRM Treatment Comparisons by Visit (PPS)

Day 4 - Treatment difference (Treatment 1 – treatment 2)

Difference in change from Baseline inpsoriatic infiltrate thickness [µm]1,2

Treatment 1 Treatment 2 Estimate ± SE 95% CI3 P-valueBetamethasone valerate 0.1% cream


-292.0 ± 79.8 -463.1 , -120.9 0.0026

Betamethasone valerate 0.1% cream


-329.9 ± 70.4 -480.9 , -179.0 0.0003



-341.2 ± 68.6 -488.3 , -194.1 0.0002



-371.9 ± 84.4 -552.9 , -190.8 0.0006


Vehicle -368.7 ± 102.9 -589.4 , -147.9 0.0030

Day 8 - Treatment difference (Treatment 1 – Treatment 2)Betamethasone valerate 0.1% cream


-409.8 ± 70.6 -561.2 , -258.4 < 0.0001



-461.2 ± 73.8 -619.6 , -302.8 < 0.0001



-455.3 ± 85.1 -637.8 , -272.8 0.0001



-471.3 ± 80.5 -644.1 , -298.6 < 0.0001


Vehicle -457.3 ± 75.7 -619.6 , -294.9 < 0.0001

Day 15 - Treatment difference (Treatment 1 – Treatment 2)Betamethasone valerate 0.1% cream

GSK2981278 0.03%ointment

-390.6 ± 56.0 -510.8 , -270.4 < 0.0001



-405.0 ± 55.5 -524.0 , -286.0 < 0.0001



-439.7 ± 70.5 -590.8 , -288.5 < 0.0001



-412.1 ± 63.9 -549.2 , -274.9 < 0.0001


Vehicle -440.3 ± 72.4 -595.6 , -284.9 < 0.0001

54

CONFIDENTIAL 2016N274225_00201465

54

Day 4 - Treatment difference (Treatment 1 – treatment 2)

Difference in change from Baseline inpsoriatic infiltrate thickness [µm]1,2

Treatment 1 Treatment 2 Estimate ± SE 95% CI3 P-valueDay 19/End of treatment - Treatment difference (Treatment 1 – Treatment 2)Betamethasone valerate 0.1% cream


-432.1 ± 59.7 -560.3 , -304.0 < 0.0001



-425.4 ± 49.0 -530.4 , -320.4 < 0.0001



-447.0 ± 62.2 -580.5 , -313.5 < 0.0001



-424.1 ± 63.6 -560.5 , -287.6 < 0.0001


Vehicle -435.4 ± 67.9 -580.9 , -289.9 < 0.0001

1 Psoriatic infiltrate thickness assessed by sonography.2 Estimates of difference in change from Baseline in psoriatic infiltrate thickness determined for each visit separately using a mixed-model repeated-measures (MMRM) model with a fixed effect for treatment, and treatment treated as repeated measure within the same subject with an unstructured covariance matrix.3 95% CI: 95% confidence intervalSource Data: Table 2.06

7.2. Clinical Assessment

In general, the results of the clinical assessment of improvement showed no improvement of psoriatic lesions following treatment with any of the GSK2981278 ointment formulations over the trial, paralleling the sonographic results.

Overall no relevant change in the ordinal clinical assessment scores was seen for all 4 GSK2981278 ointment formulations (0.03%, 0.1%, 0.8% and 4%) over the trial period, representing no improvement of psoriatic lesions (Table 20 and Table 2.08).

At the end of the trial (Day 19), no effect (score 0) was noted in the majority of the subjects ( 87 %) (Table 21 and Table 2.09). ‘Slight improvement’ (score 1) was only seen in 1 subject (7%) in test fields treated with GSK2981278 ointment 0.03%, 0.1% and 0.8% (Table 21). This subject also showed a decrease in mean infiltrate thickness in all 3 test fields at EoT as measured by sonography.

Worsening (score -1) was seen in 2 subjects over the trial: in 1 subject in the test field treated with GSK2981278 ointment 0.03% on Day 8 and in another subject in the test field treated with GSK2981278 ointment 0.1% at EoT.

Treatment with the active ingredient-free vehicle showed also no relevant change in the clinical assessment scores and therefore no improvement in psoriatic lesions over the trial period (Table 20 and Table 21).

In contrast, a clear improvement of psoriatic lesions was seen for the treatment with the positive control betamethasone valerate 0.1% cream reaching a slight to clear improvement after 4 days which further continuously increased until Day 19/EoT: At EoT ‘clear improvement but not completely healed’ (score 2) was reported in the majority of subjects (10 of 15 subjects, 67%) while ‘completely healed’ (score 3) was

55

CONFIDENTIAL 2016N274225_00201465

55

noted in 4 subjects (27%) and ‘slight improvement’ in 1 subject (7%). No worsening was seen in any subject at any assessment time point. The mean clinical assessment score increased from 1.5 0.6 on Day 4 to 2.2 0.6 on Day 19/EoT. The mean cumulative total score was 7.3 1.8.

56

CONFIDENTIAL 2016N274225_00201465

56

Table 20 Clinical Assessment of Improvement – OC – Descriptive Statistics (PPS)

Clinical assessment

of improvement1

GSK29812780.03%

ointment

GSK29812780.1%

ointment

GSK29812780.8%



cream

Day 1 / BaselineN 15 15 15 15 15 15Mean ± SD 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0Median 0.0 0.0 0.0 0.0 0.0 0.0Min, max 0 , 0 0 , 0 0 , 0 0 , 0 0 , 0 0 , 0

Day 4N 15 15 15 15 15 15Mean ± SD 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 1.5 ± 0.6Median 0.0 0.0 0.0 0.0 0.0 2.0Min, max 0 , 0 0 , 0 0 , 0 0 , 0 0 , 0 0 , 2

Day 8N 15 15 15 15 15 15Mean ± SD -0.1 ± 0.3 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 1.7 ± 0.5Median 0.0 0.0 0.0 0.0 0.0 2.0Min, max -1 , 0 0 , 0 0 , 0 0 , 0 0 , 0 1 , 2

Day 15N 15 15 15 15 15 15Mean ± SD 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 1.9 ± 0.6Median 0.0 0.0 0.0 0.0 0.0 2.0Min, max 0 , 0 0 , 0 0 , 0 0 , 0 0 , 0 1 , 3

Day 19/EoT2

N 15 15 15 15 15 15Mean ± SD 0.1 ± 0.3 0.0 ± 0.4 0.1 ± 0.3 0.0 ± 0.0 0.1 ± 0.3 2.2 ± 0.6Median 0.0 0.0 0.0 0.0 0.0 2.0Min, max 0 , 1 -1 , 1 0 , 1 0 , 0 0 , 1 1 , 3

Cumulative total score3

N 15 15 15 15 15 15Mean ± SD 0.0 ± 0.4 0.0 ± 0.4 0.1 ± 0.3 0.0 ± 0.0 0.1 ± 0.3 7.3 ± 1.8Median 0.0 0.0 0.0 0.0 0.0 7.0Min, max -1 , 1 -1 , 1 0 , 1 0 , 0 0 , 1 4 , 101 Clinical assessment of improvement: -1 = worsened; 0 = unchanged (no effect); 1 = slight improvement; 2 = clear improvement but not completely healed; 3 = completely healed.2 EoT: End of treatment3 Cumulative total score: Sum of all post-baseline assessments by subject and treatment.Source Data: Table 2.09

57

CONFIDENTIAL 2016N274225_00201465

57

Table 21 Clinical Assessment of Improvement – OC – Frequency Counts (PPS)

Clinical assessment

of improvement1

GSK29812780.03%

ointment

GSK29812780.1%

ointment

GSK29812780.8%



creamDay 1 / BaselineN 15 15 15 15 15 15-1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)0 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%)1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)Day 4N 15 15 15 15 15 15-1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)0 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 1 ( 7%)1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 6 ( 40%)2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 8 ( 53%)3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)Day 8N 15 15 15 15 15 15-1 1 ( 7%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)0 14 ( 93%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 0 ( 0%)1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 5 ( 33%)2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 10 ( 67%)3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)Day 15N 15 15 15 15 15 15-1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)0 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 0 ( 0%)1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 ( 20%)2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 10 ( 67%)3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 ( 13%)Day 19/EoT2

N 15 15 15 15 15 15-1 0 ( 0%) 1 ( 7%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)0 14 ( 93%) 13 ( 87%) 14 ( 93%) 15 (100%) 14 ( 93%) 0 ( 0%)1 1 ( 7%) 1 ( 7%) 1 ( 7%) 0 ( 0%) 1 ( 7%) 1 ( 7%)2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 10 ( 67%)3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 ( 27%)

1 Clinical assessment of improvement: -1 = worsened; 0 = unchanged (no effect); 1 = slight improvement; 2 = clear improvement but not completely healed; 3 = completely healed.2 EoT: End of treatmentSource Data: Table 2.08

58

CONFIDENTIAL 2016N274225_00201465

58

8. BIOMARKER(S)/PHARMACODYNAMIC MARKERSRESULTS

8.1. Biomarker Results

Biomarker analysis was conducted using qPCR and whole genome transcriptomic analysis to evaluate target engagement.

8.1.1. Gene Expression Analysis by qPCR

Evaluation of target engagement by GSK2981278 was conducted using qPCR analysis ofselected candidate genes (IL-17A, IL-17F, DEFB4A, IL-19, IL-22, IL-23P19, IL-36, IL-8, KRT6A, S100A7A). These analyses were conducted at Epistem Ltd. using their qPCR assay platform. Assays were run in 384 well screen plates with 3 target genes and a housekeeping gene (POL2RJ) on each plate; each plate was screened twice. Other than IL-17A, all genes produced a design that passed all acceptance criteria. In an attempt to generate a passing assay for IL-17A both designs were assessed across further complementary DNA (cDNA) sources from microarray quality control (MAQC) and leukocyte cluster of differentiation 4 (CD4)+ cells without success. Hence, IL-17A mRNA expression was re-evaluated at the sponsor site using another detection system (Taqman gene expression analysis, Section 8.1.2).

Results

Relative gene expression was calculated using Ct analysis and expressed as fold change (Figure 4). Each skin biopsy sample was normalized to the non-lesional area skin sample within each subject. Statistical analysis was conducted using Wilcoxon signed rank test (Table 22). Data analysis revealed that skin biopsies of the lesional untreated area exhibited increased mRNA expression of all evaluated genes compared to non-lesional area skin samples as expected. Although IL-36 and IL-8 showed a statistically significant difference between the vehicle- and GSK2981278-treated test fields based on the Wilcoxon signed rank test, overall comparison of fold changes of all evaluated genes,suggests no effect of GSK2981278 on inhibition of the mRNA expression, indicating a lack of target engagement. Since IL-17A mRNA expression was not detected using the detection system utilized by Epistem Ltd., a re-analysis of IL-17A mRNA expression was conducted using a different detection system (Section 8.1.2).

59

CONFIDENTIAL 2016N274225_00201465

59

Figure 4 Fold Change Plots of Each Target

LS-U = Lesional untreated area; LS-VEH = Lesional vehicle-treated test field; LS1278= GSK2981278 (4%)-treated test field; NLS = Non-lesional areaSource Data: Listing 31

60

CONFIDENTIAL 2016N274225_00201465

60

Table 22 Summary of Wilcoxon Signed Rank Test Results

LS-U versus LS-Veh LS-U versus LS-1278 (4%)

GenePos.Sum

Neg.Sum

p-value

p < 0.05

Ave Ct

Pos.Sum

Neg.Sum

p-valuep < 0.0

5Ave Ct

DEFB4A 29 -62 0.2734 No -0.30 52 -39 0.6848 No 0.35

IL-17A 27 -64 0.2163 No -0.03 60 -31 0.3396 No -0.62

IL-17F 81 -10 0.0105 Yes 0.55 50 -41 0.7869 No 0.97

IL-19 56 -35 0.4973 No 0.51 50 -41 0.7869 No 1.20

IL-22 66 -25 0.1677 No 0.50 46 -45> 0.999

9 No 0.73IL-

23P19 53 -38 0.6355 No -0.29 51 -40 0.7354 No 0.12

IL-36 52 -39 0.6848 No 0.00 74 -17 0.0479 Yes 0.52

IL-8 39 -52 0.6848 No -1.01 85 -6 0.0034 Yes 0.61

KRT6A 62 -29 0.2734 No 0.21 36 -55 0.5417 No 0.44S100A7

A 52 -39 0.6848 No -0.33 58 -33 0.4143 No 0.45Ave = Average; LS-U = Lesional untreated area; LS-Veh = Lesional vehicle-treated test field; LS-1278 (4%) = GSK2981278 (4%)-treated test field; Neg. = Negative; Pos. = Positive

Source data: Listing 33

8.1.2. IL-17A and IL-17F mRNA Expression Analysis using Taqman qPCR Method

The assay design used at Epistem Ltd. was unable to detect IL-17A mRNA expression. Hence, IL-17A mRNA expression analysis was repeated using a Taqman analysis detection system at GSK. IL-17A and IL-17F gene expression was measured via semi-quantitative real-time PCR with Taqman chemistry. Relative gene expression was calculated using Ct analysis. GAPDH was used as the housekeeping gene and each sample was normalized to the non-lesional sample within each subject. IL-17A mRNA expression was successfully measured and was elevated in lesional biopsies compared to non-lesional controls. However, no differences in IL-17A and IL-17F mRNA expression were seen between the lesional vehicle- and lesional GSK2981278-treated samples (Figure 5), supporting lack of target engagement in the current study.

61

CONFIDENTIAL 2016N274225_00201465

61

Figure 5 IL-17A and IL-17F mRNA Expression

IL-17A IL-17F

LS-U = Lesional untreated area; LS-VEH = Lesional vehicle-treated test field; LS-1278 = GSK2981278 (4%)-treated test field; NLS = Non-lesional areaSource data: Listing 34

8.1.3. Transcriptomic Analysis Using Affymetrix Microarray

Quality Control (QC) Analysis

Global gene expression analysis was conducted using Affymetrix microarray. Quality control was conducted using a battery of data quality checks (Huber, 2015; Parman, version 1.48.0). Each of the quality checks was within the normal range and all 52 skin biopsy samples were included in subsequent analyses.

Differential Expression Analysis

Comparing lesional (untreated) samples to non-lesional samples, 681 genes were identified that passed these criteria. However, none of the 19,702 genes, represented on the Affymetrix HG-U133plus2 array, were statistically significantly changed in the 4% GSK2981278-treated test field vs. vehicle-treated test field comparison using these same thresholds.

Comparison with Previously Reported Psoriasis Gene Disease Signature

To complement the differential expression analysis, the expression profiles in the current study were also compared to a previously reported psoriasis disease signature derived by conducting a re-analysis of published clinical transcriptomics datasets as described in Qu, 2014 (Figure 6). Each average signature represents one published study comparing lesional samples to samples from healthy volunteers (“normal”) or non-lesional patient samples, respectively. These averages were then compared to the individual samples from the current study which were normalized by the average non-lesion expression value for each gene. This comparison shows that the disease vs. control signature in the

62

CONFIDENTIAL 2016N274225_00201465

62

current study is highly consistent with similar, previously published clinical transcriptomics psoriasis studies.

Figure 6 Comparison with Previously Reported Psoriasis Disease GeneSignature

Untreated = Lesional untreated area; ‘1278 = GSK2981278 (4%)-treated test field; Vehicle = Lesional vehicle-treated test fieldSource data: Listing 32 and Listing 34

Conclusion

Based on the whole transcriptome and qPCR analysis, the untreated lesional skin biopsies were associated with a psoriasis gene expression signature. However, results suggest lack of target engagement with GSK2981278 in the current study.

63

PPD PPD PPD PPD

CONFIDENTIAL 2016N274225_00201465

63

9. DISCUSSION AND CONCLUSIONS

9.1. Discussion

In this psoriasis plaque test, GSK2981278 topically applied in 4 different ointment concentrations (0.03%, 0.1%, 0.8% and 4%) showed no reduction in infiltrate thickness, as measured by sonographic measurements and clinical assessment, in subjects with chronic plaque psoriasis after once daily topical application over 19 days.

Overall, there were no safety concerns based on the incidence and nature of adverse events (AE), clinical laboratory assessments (hematology, clinical chemistry, urinalysis), vital signs and ECG measurements as well as physical examinations. Only 1 non-serious AE of moderate intensity was reported in 1 subject which was considered by the investigator to be not related to study treatment.

Results of various analyses of the sonographic measurement with respect to the AUC (primary endpoint) and to changes within individual assessment time points of the ELB did not demonstrate a reduction in infiltrate thickness for any of the 4 strengths of GSK2981278 ointment tested in this study. The mean AUCs of change in infiltrate thickness were positive for all 4 GSK2981278 ointments, comparable to the corresponding vehicle. This was primarily due to the increase in psoriatic infiltrate thickness values noted during the first few days of the treatment period for all 4 concentrations (0.03%, 0.1%, 0.8% and 4%) and the vehicle. However, the infiltrate thickness returned to Baseline levels by EoT (mean % changes at EoT: 13.4%, 18.0%, 15.4%, 10.1% and 13.5%, respectively). Since the initial increase was seen for all 4 ointment formulations of GSK2981278 and the vehicle, it may have been associated with component(s) of the vehicle rather than the active pharmaceutical ingredient.

The positive control betamethasone valerate 0.1% cream showed a negative mean AUC of change in infiltrate thickness and a clinically relevant reduction in mean infiltrate thickness at EoT (81.5%), as expected. The sonographic results of betamethasone valerate 0.1% cream seen in this study are in accord with the literature reports (Rafael, 2016; Snape, 2016). The ability to detect meaningful reduction in infiltrate thickness with the positive control indicates that procedures associated with drug application and assessment were conducted appropriately.

The results of the clinical assessment of improvement generally paralleled thesonographic results showing no improvement of psoriatic lesions following treatment with any of the 4 GSK2981278 ointments but improvement following treatment with the positive control betamethasone valerate 0.1% cream over the trial.

In 1 subject slight improvement (score 1) was seen in 3 GSK2981278-treated test fields (0.03%, 0.1% and 0.8%) in the clinical assessment at EoT. The results of the sonographic measurements showed a decrease in mean infiltrate thickness in all 3 test fields of this subject at EoT (mean % change: -38.36%, -28.57% and -46.02%, respectively) and therefore underscore the respective clinical assessment data. However, a clear reduction in mean infiltrate thickness (38.79%) was also seen in the vehicle-treated test field of this subject at EoT. For the positive control even a reduction of 100%

64

CONFIDENTIAL 2016N274225_00201465

64

was observed at this time point. In fact, the results for GSK2981278 ointment 0.03%, 0.1% and 0.8% are in the same range as for the vehicle preparation. Therefore, the overall reduction in infiltrate thickness cannot be attributed to the application of the test products only, but indicates an additional independent overall reduction during the study period in this subject.

Worsening of psoriatic lesion was seen in 1 subject in the test field treated with GSK2981278 ointment 0.03% on Day 8 and in another subject in the test field treated with GSK2981278 ointment 0.1% at EoT which may be attributed to irritation or lack of efficacy due to repeated application under semi-occlusive conditions. Furthermore, this may indicate that there is no dose-dependent finding in terms of worsening of psoriasis.

Overall, the biomarker results suggest a lack of target engagement with GSK2981278 in this study and are consistent with the results of the sonographic measurement and the clinical assessment. However, the transcriptomic data and measurement of target gene expression are consistent with those reported in the literature for psoriatic subjects, indicating that the patient population in the current study was appropriately selected.

There were no protocol deviations that impacted the data interpretation and no risks or any new or unexpected findings were reported.

Topical application of GSK2981278 to lesional skin of psoriasis was expected to block the transcriptional activity of RORt leading to the local suppression of cytokine expression from skin-resident T cells based on preclinical data, ultimately leading to an improvement in psoriasis, with no or minimal systemic effects (GlaxoSmithKlineDocument number, 2015N240000_00). The anticipated improvement in psoriasisfollowing treatment with GSK2981278 was not seen in this first-in-human study using 4 different strengths of GSK2981278 ointment. No systemic effects were identified as predicted in this trial using semi-occlusive application to small test fields within plaque(s).

The results of this study may be explained by several factors: 1. GSK2981278 did not penetrate through the psoriatic skin to the target cells in the dermis, 2. Higher concentrations and/or longer treatment period are needed to detect an effect, 3. This highly specific and potentially migrating target requires a more global blockade of activity over the entire plaque to produce detectable anti-psoriatic effect than local blockade in a small patch as in this study, 4. Systemic inhibition of RORt, rather than local inhibition in the skin, may be required for efficacy. These hypotheses should be further investigated.

9.2. Conclusions

Overall, the 4 different GSK2981278 ointment formulations 0.03%, 0.1%, 0.8% and 4% showed no reduction in infiltrate thickness but were generally safe and well tolerated in subjects with chronic plaque psoriasis after once daily topical application to small test fields over 19 days in this study.

65

CONFIDENTIAL 2016N274225_00201465

65

10. REFERENCES

Bangha E, Elsner P. Evaluation of antipsoriatic treatment by chromametry, visiometry and 20-MHz ultrasound in the psoriasis plaque test. Skin Pharmacol 1996; 9: 298-306.

Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B (Methodological) 1995; 57(1): 289-300.

CHMP 2004Guideline on Clinical Investigation of Medicinal Products Indicated for the Treatment of Psoriasis. EMEA/CHMP/EWP/2454/02corr.

CHMP 2007. Guideline on Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with Investigational Medicinal Products; Committee For Medicinal Products For Human Use. EMEA/CHMP/SWP/28367/07.

DaiM, Wang P, Boyd AD, et al. Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic acids research 2005; 33(20): e175.

Dumas KJ, Scholtz JR. The psoriasis bio-assay for topical corticosteroid activity. Acta Derm Venereol (Stockh) 1972; 52: 43-8.

FDA 2005. Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2005.

Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol 1988; 124(6): 869-71.

Fluhr JW, Hughes-Formella B, Williams R, et al. bioskin EADV poster: Biophysical measurement methods to establish efficacy in proof of concept studies; 18th Congress of the European Academy of Dermatology October 6th–10th 2009, Berlin, Germany.

Freudenberg JM, Joshi VK, Hu Z, et al. CLustering Enrichment ANalysis. BMC Bioinformatics 2009 Jul 29; 10: 234. doi: 10.1186/1471-2105-10-234.

Gassmueller J, Klinger B, Levy J. The Ultrasound-Erythema Index (USE-Index) for monitoring of therapeutic effects on the psoriatic plaque by 20-MHz Ultrasound and Colorimetry. Regional Meeting of the International Society for Bioengineering and the Skin. Luebeck, 1993; 23-25.

Gautier L, Cope L, Bolstad BM, et al. affy-analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 2004; 20: 307-315.

GlaxoSmithKline Document Number 2015N240000_00, GSK2981278 Investigator’s Brochure (IB). July 2015.

66

CONFIDENTIAL 2016N274225_00201465

66

Gordon K. Ixekizumab for Treatment of Moderate-to-Severe Plaque Psoriasis: 60-week Results from a Double-Blind Phase 3 Induction and Randomized Withdrawal Study (UNCOVER-1). AAD 2015 Late-breaking abstract F010.

He YW, Deftos ML, Ojala EW, et al. RORt, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. Immunity 1998; 9(6): 797-806.

Huber W, Carey VJ, Gentleman R, et al. Orchestrating high-throughput genomic analysis with Bioconductor. Nat Methods 2015 Feb; 12(2): 115-21. doi: 10.1038/nmeth.3252.

Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORt directs the differentiation program of proinflammatory IL-17+ T helper cell. Cell 2006; 126(6): 1121-1133.

Kronenberg HM, Melmed S, Polonsky KS, et al. Williams Textbook of Endocrinology, 11th edition. Philadelphia: Saunders, 2008.

Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis—Results of two phase 3 trials. N Engl J Med 2014; 371(4): 326-338.

Lebwohl, M. AMAGINE-2: A Randomized, Double-blind, Phase 3 Efficacy and Safety Study of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis Patients. AAD 2015 Late-breaking abstract F010.

Lynde CW, Poulin Y, Vender R, et al. Interleukin 17A: Toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol 2014; 71: 141-150.

Malakouti M, Brown GE, Wang E, et al. The role of IL-17 in psoriasis. J Dermatolog Treat 2015; 26(1): 41-44.

Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad Dermatol 2009; 60: 643-659.

Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: A systematic review of incidence and prevalence. J Invest Dermatol 2013; 133: 377-385.

Parman C, Halling C, Gentleman R. QC Report Generation for affyBatch objects. R package version 1.48.0. affyQCReport.

Qu XA, Freudenberg JM, Sanseau P, et al. Integrative clinical transcriptomics analyses for new therapeutic intervention strategies: a psoriasis case study. Drug Discov Today 2014 Sep; 19(9): 1364-1371. doi: 10.1016/j.drudis.2014.03.015.

Rafael A., Torres T. Topical therapy for psoriasis: a promising future. Focus on JAK and phosphodiesterase-4 inhibitors. Eur J Dermatol. 2016 Feb 1; 26(1): 3-8. doi: 10.1684/ejd.2015.2663.

67

CONFIDENTIAL 2016N274225_00201465

67

Remitz A, Reitamo S, Erkko P et al. Tacrolimus ointment improves psoriasis in a microplaque assay. Br J Dermatol 1999; 141: 103-107.

Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic acids research 2015; 43: e47. doi: 10.1093/nar/gkv007.

Russell CB, Rand H, Bigler J, et. al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol 2014 Apr 15; 192(8): 3828-3836.

Sandoval LF, Williams B, Feldman SR. Clinical potential of brodalumab in the management of psoriasis: The evidence to date. Psoriasis: Targets and Therapy. 2015; 5: 35-41.

Sen BB, Rifaioglu EN, Ekiz O, et al. Neutrophil to lymphocyte ratio as a measure of systemic inflammation in psoriasis. Cutan Ocul Toxicol 2014, 33(3): 223-7. doi: 10.3109/15569527.2013.834498.

Siegel S. Non-parametric statistics for the behavioral sciences. New York. McGraw-Hill, 1956: 75-83.

Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Statistical applications in genetics and molecular biology 2004; 3: Article 3.

Snape SD, Wigger-Alberti W, Goehring UM. A Phase I randomized trial to Assess the Relative Antipsoriatic Effect and Tolerability of Topical Phosphodiesterase Inhibitors in the Treatment of Psoriasis Vulgaris Using a Psoriasis Plaque Test. Br J Dermatol 2016.

Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th edition, Philadelphia, Elsevier/Saunders, 2004.

Willers CP, Frase T, Schmidt A. The USE-(Ultrasound-Erythema-)Index in antipsoriatic testing. 20th World Congress of Dermatology, 2002, Paris, France.

68

CONFIDENTIAL 2016N274225_00201465

68

11. POST-TEXT TABLES AND FIGURES

Table 23 Time and Events Table

ProcedureScreening

[Day]

Treatment Period[Days]

Follow-up

[Day]

Notes

Subjects who withdrew early from the study should have completed the Day 19 visit assessments except for biopsy collection.

-14 to -1 1

2 to

6

7 8

9 to

13

14 15

16 to

18

19 27 (2)

Informed consent XInclusion and exclusion criteria X X Was to be assessed prior to randomization.

Demographics/medical history XFitzpatrick skin type was documented. Site had to document any known drug allergies.

Brief physical examination(including height and weight)

X

Physical examination of the skinX X

Any adverse changes to the skin were to be recorded as an AE.

Descaling with salicylic acid X

Descaling of test sites with detergent solution (if necessary)

X X X XWas completed prior to dosing.Descaling might also have been necessary on Day 4 (Section 4.8.5)

HIV, Hep B, and Hep C screen X

ECG X X X

On Day 15, ECG was completed prior to dosing.

Was performed before drug removal and within a time window of 2 hours prior to dosing.

Vital sign X X

Vital signs included heart rate, blood pressure, and oral temperature. Ideally, heart rate and blood pressure were obtained after the subject had been resting in a seated position for at least 5 minutes.

Was performed before drug removal and within a time window of 2 hours prior to dosing

Determination of test fields X

69

CONFIDENTIAL 2016N274225_00201465

69

ProcedureScreening

[Day]


Follow-up

[Day]

Notes


-14 to -1 1

2 to

6

7 8

9 to

13

14 15

16 to

18

19 27 (2)

Laboratory assessments (included liver chemistries) and urinalysis

X* X X X

*Including drug and alcohol screening (Screening visit only). Refer to the Clinical Study Protocol, Section 7.3.5(Protocol and Protocol Amendments) for laboratory and urinalysis assessment information. Assessment occurred before drug removal and within 2 hours prior to dosing on Days 8 and 15.

Study treatment X X X X X X

Syringes should have been weighed before and after application of each study treatment for each subject. Study treatment was re-applied after evaluation and within 1 hour after removal.

Study treatment applied on Days 6 and 13 remained on the skin until subject returned to the clinic on Days 8 and 15, respectively.

AE/SAE review X X X X ======X=======During the Screening visit, only SAEs related to study participation were to be collected. AEs were tobe collected after start of study treatment.

Prior and concomitant medication review X X X X X ======X=======

Photographic documentation X X

Overview pictures were taken of all test fields (number of pictures depending on number of plaques[s] used and location on the body); there was no documentation of single test fields. Additional photographic documentation of single test fields might have been taken if treatment-related AEs occurred.

On Day 1, photographs were taken prior to dosing.

70

CONFIDENTIAL 2016N274225_00201465

70

ProcedureScreening

[Day]


Follow-up

[Day]

Notes


-14 to -1 1

2 to

6

7 8

9 to

13

14 15

16 to

18

19 27 (2)

Clinical assessments X* X X X

At Day 1, the score was documented as “0.”

*Day 4 only.

Assessment occurred within 60 minutes of study product removal.

HFUS (sonography) X X* X X X

Day 1 was Baseline HFUS and completed prior to dosing.

*Day 4 only.

Ultrasound occurred within 60 minutes of study product removal.

Skin biopsies XFour 3 mm punch biopsies were collected from each consenting subject.

Wound assessment XThis assessment applied only to subjects consenting to biopsy collection.

71

1 of 1

Protocol: 201465 Page 1 of 1

Table 1.01:

Subject enrollment and evaluability

(Subjects screened)

Number of subjects screened N = 16

Number of subjects enrolled 16 (100%)

Number of subjects not enrolled 0 ( 0%)

Number of subjects randomized N = 15

Subjects excluded from SES1 0 ( 0%)

Subjects included in SES1 15 (100%)

Subjects excluded from PPS2 0 ( 0%)

Subjects included in PPS2 15 (100%)

1 Safety evaluation set (SES): All subjects exposed to at least one application of study product. 2 Per-protocol analysis set (PPS): All randomized subjects who complied closely with the protocol.

72

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Table 1.02:

Subject completion / discontinuation

(Subjects randomized)

Number of subjects randomized N = 15

Subjects with normal trial completion 15 (100%)

Subjects discontinued 0 ( 0%)

Reasons for discontinuation

Adverse Event 0 ( 0%)

Death 0 ( 0%)

Withdrawal by Subject 0 ( 0%)

Lost To Follow-up 0 ( 0%)

Protocol Violation 0 ( 0%)

Non-Compliance with study conditions or

instructions from the team 0 ( 0%)

Failure to Meet Randomization Criteria 0 ( 0%)

Physician Decision 0 ( 0%)

Study Terminated By Sponsor 0 ( 0%)

Lack of Efficacy 0 ( 0%)

Sponsor decision to amend protocol 0 ( 0%)

Trial Site Terminated by Sponsor 0 ( 0%)

Subject reached protocol-defined stopping criteria 0 ( 0%)

Other 0 ( 0%)

73

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Table 1.03:

Excluded subjects from the analysis populations


There is no subject excluded from the analysis populations.

74

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 1.04:

Subject demographic characteristics


SES1

(N = 15)

PPS2

(N = 15)

Age3 [years]

N 15 15

Mean ± SD 53.9 ± 8.1 53.9 ± 8.1

Median 53.0 53.0

Min, max 42 , 67 42 , 67

Age3 range

N 15 15

Adults (18-64 years) 13 ( 87%) 13 ( 87%)

From 65-84 years 2 ( 13%) 2 ( 13%)

85 years and over 0 ( 0%) 0 ( 0%)

Trial country

N 15 15

Germany 15 (100%) 15 (100%)

Gender

N 15 15

Male 15 (100%) 15 (100%)

Female 0 ( 0%) 0 ( 0%)

1 Safety evaluation set (SES): All subjects exposed to at least one application of study product. 2 Per-protocol analysis set (PPS): All randomized subjects who complied closely with the protocol. 3 Age [years] = Full years between date of informed consent and date of birth, with day of birth set Jan 1st

75

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 1.04:

Subject demographic characteristics


SES1

(N = 15)

PPS2

(N = 15)

Ethnicity

N 15 15

Hispanic or Latino 0 ( 0%) 0 ( 0%)

Not Hispanic or Latino 15 (100%) 15 (100%)

Race

N 15 15

White 15 (100%) 15 (100%)

Black or African Indian 0 ( 0%) 0 ( 0%)

American Indian or Alaska Native 0 ( 0%) 0 ( 0%)

Asian 0 ( 0%) 0 ( 0%)

Native Hawaiian or Other Pacific

Islander 0 ( 0%) 0 ( 0%)

Other 0 ( 0%) 0 ( 0%)

1 Safety evaluation set (SES): All subjects exposed to at least one application of study product. 2 Per-protocol analysis set (PPS): All randomized subjects who complied closely with the protocol. 3 Age [years] = Full years between date of informed consent and date of birth, with day of birth set Jan 1st

76

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Table 3.01:

Extent of exposure - Summary

(SES)

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Treatment

period1 [days]

N 15 15 15 15 15 15

19 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%)

Mean ± SD 19.0 ± 0.0 19.0 ± 0.0 19.0 ± 0.0 19.0 ± 0.0 19.0 ± 0.0 19.0 ± 0.0

Median 19.0 19.0 19.0 19.0 19.0 19.0

Min, max 19 , 19 19 , 19 19 , 19 19 , 19 19 , 19 19 , 19

Number of

treatments

N 15 15 15 15 15 15

16 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%)

Mean ± SD 16.0 ± 0.0 16.0 ± 0.0 16.0 ± 0.0 16.0 ± 0.0 16.0 ± 0.0 16.0 ± 0.0

Median 16.0 16.0 16.0 16.0 16.0 16.0

Min, max 16 , 16 16 , 16 16 , 16 16 , 16 16 , 16 16 , 16

1Treatment period is determined as date of last application minus date of first application + 1.

77

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Table 3.02:

Vital signs - Summary

(SES)

Screening1 Day 19/EoT2 Change3

Systolic blood pressure [mmHg]

N 15 15 15

Mean ± SD 127.7 ± 12.1 126.0 ± 13.8 -1.7 ± 13.3

Median 130.0 120.0 0.0

Min, max 110 , 145 105 , 155 -25 , 20

Diastolic blood pressure [mmHg]

N 15 15 15

Mean ± SD 83.7 ± 6.7 82.7 ± 6.5 -1.0 ± 8.3

Median 85.0 85.0 0.0

Min, max 70 , 90 70 , 90 -20 , 15

Heart Rate [bpm]

N 15 15 15

Mean ± SD 72.7 ± 9.1 78.4 ± 10.9 5.7 ± 9.0

Median 68.0 80.0 4.0

Min, max 60 , 90 64 , 96 -8 , 24

Temperature [C°]

N 15 15 15

Mean ± SD 36.5 ± 0.3 36.4 ± 0.3 -0.2 ± 0.4

Median 36.5 36.3 -0.2

Min, max 36 , 37 36 , 37 -1 , 1

1 Baseline assessment; 2 EoT: End of treatment; 3 Change from baseline (Screening);

78

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 3.03:

ECG - Summary

(SES)

Screening1 Day 15 Day 19/EoT2

Day 15

Change3

Day 19/EoT2

Change3

HR interval [beats/min]

N 15 15 15 15 15

Mean ± SD 68.2 ± 11.4 70.0 ± 11.8 73.9 ± 12.1 1.8 ± 6.7 5.7 ± 10.5

Median 65.0 68.0 72.0 2.0 5.0

Min, max 54 , 86 52 , 89 53 , 93 -9 , 17 -13 , 23

PR interval [msec]

N 15 15 15 15 15

Mean ± SD 161.6 ± 25.1 163.3 ± 23.9 164.7 ± 24.9 1.7 ± 12.6 3.1 ± 19.7

Median 154.0 162.0 166.0 6.0 0.0

Min, max 124 , 200 118 , 200 126 , 208 -30 , 16 -22 , 50

QRS interval [msec]

N 15 15 15 15 15

Mean ± SD 96.4 ± 9.5 93.8 ± 16.3 94.4 ± 8.0 -2.6 ± 12.8 -2.0 ± 4.3

Median 96.0 94.0 94.0 2.0 -2.0

Min, max 82 , 112 45 , 116 82 , 110 -45 , 6 -10 , 4

QT interval [msec]

N 15 15 15 15 15

Mean ± SD 399.9 ± 28.9 394.8 ± 29.1 390.0 ± 24.6 -5.1 ± 21.4 -9.9 ± 26.0

Median 400.0 390.0 400.0 -6.0 -8.0

Min, max 362 , 452 346 , 448 344 , 440 -60 , 20 -68 , 26

1 Baseline assessment; 2 EoT: End of treatment; 3 Change from baseline (Screening).

79

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 3.03:

ECG - Summary

(SES)

Screening1 Day 15 Day 19/EoT2

Day 15

Change3

Day 19/EoT2

Change3

QTcB interval [msec]

N 15 15 15 15 15

Mean ± SD 422.2 ± 17.2 422.0 ± 19.0 428.8 ± 16.4 -0.2 ± 13.4 6.6 ± 16.3

Median 424.0 421.0 430.0 -2.0 6.0

Min, max 385 , 451 386 , 452 406 , 462 -20 , 25 -11 , 42

RR interval [msec]

N 15 15 15 15 15

Mean ± SD 878.1 ± 129.9 870.9 ± 145.3 822.8 ± 127.4 -7.2 ± 73.3 -55.3 ± 107.8

Median 904.0 874.0 820.0 -20.0 -36.0

Min, max 694 , 1092 666 , 1116 648 , 1066 -126 , 160 -318 , 120


80

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 4


Table 3.04:

Hematology - Summary

(SES)

Screening1 Day 8 Day 15 Day 19/EoT2 Day 8 change3

Day 15

change3

Day 19/EoT2

change3

Platelets [109/L]

(150 - 370)

N 15 15 15 15 15 15 15

Mean ± SD 222.2 ± 62.0 238.3 ± 59.6 239.7 ± 63.3 235.5 ± 60.3 16.1 ± 29.0 17.5 ± 32.4 13.3 ± 33.5

Median 234.0 235.0 229.0 211.0 12.0 7.0 12.0

Min, max 131 , 343 156 , 329 154 , 354 168 , 353 -22 , 79 -28 , 107 -37 , 106

Number below lower NR 1 ( 7%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Number above upper NR 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Lymphocytes [109/L]

(1.1 - 4.5)

N 15 15 15 15 15 15 15

Mean ± SD 1.451 ± 0.481 1.489 ± 0.536 1.525 ± 0.514 1.423 ± 0.528 0.037 ± 0.328 0.073 ± 0.266 -0.029 ± 0.241

Median 1.480 1.280 1.450 1.250 0.050 0.100 0.000

Min, max 0.66 , 2.32 0.80 , 2.68 0.77 , 2.71 0.62 , 2.20 -0.50 , 0.47 -0.54 , 0.47 -0.49 , 0.46



Monocytes [109/L]

(0.1 - 0.9)

N 15 15 15 15 15 15 15

Mean ± SD 0.643 ± 0.283 0.598 ± 0.225 0.562 ± 0.202 0.558 ± 0.183 -0.045 ± 0.245 -0.081 ± 0.231 -0.085 ± 0.230

Median 0.640 0.570 0.540 0.550 -0.020 -0.110 -0.040

Min, max 0.30 , 1.13 0.29 , 1.20 0.31 , 0.96 0.30 , 0.99 -0.56 , 0.28 -0.45 , 0.40 -0.56 , 0.38




81

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 4


Table 3.04:


(SES)


Day 15

change3

Day 19/EoT2

change3

Eosinophils [109/L]

(0.02 - 0.5)

N 15 15 15 15 15 15 15

Mean ± SD 0.204 ± 0.087 0.195 ± 0.083 0.212 ± 0.105 0.169 ± 0.088 -0.009 ± 0.053 0.008 ± 0.071 -0.035 ± 0.048

Median 0.180 0.190 0.180 0.140 0.000 0.010 -0.040

Min, max 0.10 , 0.37 0.03 , 0.33 0.08 , 0.38 0.05 , 0.34 -0.11 , 0.08 -0.14 , 0.16 -0.10 , 0.06



Basophils [109/L]

(0 - 0.2)

N 15 15 15 15 15 15 15

Mean ± SD 0.028 ± 0.015 0.031 ± 0.017 0.029 ± 0.016 0.030 ± 0.016 0.003 ± 0.009 0.001 ± 0.008 0.002 ± 0.010

Median 0.030 0.030 0.030 0.030 0.000 0.000 0.000

Min, max 0.00 , 0.05 0.00 , 0.06 0.00 , 0.05 0.00 , 0.06 -0.01 , 0.02 -0.02 , 0.01 -0.02 , 0.02



Erythrocytes [1012/L]

(4 - 5.8)

N 15 15 15 15 15 15 15

Mean ± SD 4.79 ± 0.44 4.93 ± 0.43 4.80 ± 0.36 4.76 ± 0.38 0.14 ± 0.17 0.01 ± 0.19 -0.03 ± 0.19

Median 4.80 5.10 4.90 4.80 0.20 0.00 0.00

Min, max 3.8 , 5.4 4.0 , 5.5 4.0 , 5.4 3.9 , 5.2 -0.2 , 0.4 -0.3 , 0.3 -0.5 , 0.2




82

CONFIDENTIAL 2016N274225_00201465

PPD

3 of 4


Table 3.04:


(SES)


Day 15

change3

Day 19/EoT2

change3

Hemoglobin [mmol/L]

(7.8 - 10.7)

N 15 15 15 15 15 15 15

Mean ± SD 9.23 ± 0.67 9.49 ± 0.70 9.26 ± 0.57 9.17 ± 0.70 0.26 ± 0.36 0.03 ± 0.24 -0.06 ± 0.37

Median 8.90 9.60 9.30 9.30 0.30 0.00 -0.10

Min, max 8.4 , 10.9 8.4 , 11.1 8.5 , 10.5 8.3 , 10.6 -0.4 , 0.9 -0.4 , 0.5 -0.8 , 0.5



Hematocrit [U]

(0.37 - 0.51)

N 15 15 15 15 15 15 15

Mean ± SD 0.437 ± 0.032 0.450 ± 0.031 0.451 ± 0.035 0.429 ± 0.027 0.013 ± 0.018 0.013 ± 0.013 -0.009 ± 0.018

Median 0.440 0.450 0.430 0.420 0.010 0.010 -0.010

Min, max 0.39 , 0.49 0.40 , 0.49 0.40 , 0.50 0.39 , 0.47 -0.02 , 0.04 -0.01 , 0.04 -0.05 , 0.01



Ery. Mean Corpuscular Volume

[fL]

(80 - 101)

N 15 15 15 15 15 15 15

Mean ± SD 91.7 ± 4.8 91.7 ± 4.3 94.2 ± 5.9 90.5 ± 4.4 0.0 ± 1.5 2.5 ± 3.1 -1.2 ± 1.0

Median 89.0 90.0 93.0 90.0 0.0 1.0 -1.0

Min, max 87 , 103 86 , 101 87 , 107 86 , 101 -2 , 3 -2 , 7 -3 , 1




83

CONFIDENTIAL 2016N274225_00201465

PPD

4 of 4


Table 3.04:


(SES)


Day 15

change3

Day 19/EoT2

change3

Ery. Mean Corpuscular

Hemoglobin [fmol]

(1.68 - 2.11)

N 15 15 15 15 15 15 15

Mean ± SD 1.938 ± 0.107 1.933 ± 0.106 1.937 ± 0.120 1.933 ± 0.111 -0.005 ± 0.024 -0.001 ± 0.033 -0.005 ± 0.024

Median 1.900 1.900 1.900 1.910 0.000 0.000 0.000

Min, max 1.80 , 2.19 1.79 , 2.17 1.81 , 2.19 1.79 , 2.20 -0.07 , 0.02 -0.06 , 0.06 -0.07 , 0.02



Leukocytes [109/L]

(3.6 - 10.5)

N 15 15 15 15 15 15 15

Mean ± SD 6.03 ± 1.91 6.34 ± 1.66 6.33 ± 1.61 6.10 ± 2.03 0.31 ± 1.19 0.29 ± 1.20 0.07 ± 0.98

Median 6.20 6.10 6.20 5.80 0.40 0.10 0.00

Min, max 3.3 , 9.2 3.7 , 9.7 3.3 , 8.7 3.8 , 10.1 -1.8 , 2.0 -1.6 , 2.1 -2.3 , 1.8



Neutrophils [109/L]

(1.5 - 7.7)

N 15 15 15 15 15 15 15

Mean ± SD 3.713 ± 1.374 4.017 ± 1.424 4.003 ± 1.214 3.903 ± 1.557 0.304 ± 0.942 0.290 ± 0.846 0.190 ± 0.730

Median 3.290 3.670 4.000 3.200 0.150 0.250 0.030

Min, max 2.01 , 6.02 2.16 , 7.00 1.79 , 6.22 2.17 , 7.15 -1.26 , 1.71 -1.08 , 1.61 -1.22 , 1.53




84

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 5


Table 3.05:

Clinical chemistry - Summary

(SES)


Day 15

change3

Day 19/EoT2

change3

Blood Urea Nitrogen [mmol/L]

(2.1 - 8.2)

N 15 15 15 15 15 15 15

Mean ± SD 5.05 ± 1.51 5.10 ± 1.62 5.00 ± 1.43 5.24 ± 1.11 0.05 ± 0.82 -0.05 ± 1.12 0.19 ± 1.07

Median 5.00 4.60 4.60 5.00 0.00 -0.40 0.30

Min, max 2.5 , 8.2 2.5 , 8.5 2.8 , 7.5 3.6 , 7.5 -1.1 , 1.8 -1.8 , 2.2 -2.1 , 1.8



Creatinine [umol/L]

(59 - 103)

N 15 15 15 15 15 15 15

Mean ± SD 86.1 ± 13.6 87.5 ± 13.0 88.0 ± 13.0 84.7 ± 10.7 1.3 ± 6.7 1.9 ± 5.4 -1.4 ± 5.6

Median 83.0 84.0 85.0 84.0 2.0 3.0 -2.0

Min, max 71 , 112 68 , 109 67 , 111 68 , 103 -13 , 11 -10 , 11 -13 , 8



Glucose [mmol/L]

(3.89 - 5.55)

N 16 15 15 15 15 15 15

Mean ± SD 5.921 ± 1.887 5.706 ± 0.788 5.709 ± 0.917 5.506 ± 0.769 0.227 ± 0.477 0.230 ± 0.403 0.027 ± 0.437

Median 5.380 5.490 5.330 5.270 0.110 0.220 -0.050

Min, max 4.77 , 12.54 5.05 , 8.05 4.77 , 8.44 4.83 , 8.05 -0.50 , 1.34 -0.39 , 0.84 -0.89 , 0.67




85

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 5


Table 3.05:


(SES)


Day 15

change3

Day 19/EoT2

change3

Potassium [mmol/L]

(3.5 - 5.1)

N 15 15 15 15 15 15 15

Mean ± SD 4.44 ± 0.33 4.37 ± 0.21 4.47 ± 0.30 4.41 ± 0.28 -0.07 ± 0.37 0.03 ± 0.39 -0.03 ± 0.36

Median 4.40 4.30 4.50 4.40 0.00 0.00 -0.10

Min, max 4.0 , 5.0 3.9 , 4.7 3.9 , 5.0 3.9 , 5.1 -0.9 , 0.4 -0.7 , 0.7 -0.5 , 0.7



Sodium [mmol/L]

(136 - 145)

N 15 15 15 15 15 15 15

Mean ± SD 140.8 ± 1.7 141.9 ± 2.4 141.1 ± 1.7 140.5 ± 1.8 1.1 ± 1.6 0.3 ± 1.4 -0.3 ± 1.3

Median 141.0 142.0 141.0 140.0 2.0 1.0 0.0

Min, max 139 , 144 137 , 146 139 , 144 138 , 144 -2 , 4 -3 , 2 -3 , 2



Calcium [mmol/L]

(2.15 - 2.55)

N 15 15 15 15 15 15 15

Mean ± SD 2.345 ± 0.067 2.407 ± 0.076 2.363 ± 0.080 2.375 ± 0.085 0.061 ± 0.094 0.017 ± 0.091 0.029 ± 0.107

Median 2.350 2.410 2.340 2.350 0.060 -0.020 0.040

Min, max 2.21 , 2.44 2.27 , 2.54 2.26 , 2.48 2.25 , 2.52 -0.12 , 0.19 -0.10 , 0.18 -0.15 , 0.18




86

CONFIDENTIAL 2016N274225_00201465

PPD

3 of 5


Table 3.05:


(SES)


Day 15

change3

Day 19/EoT2

change3

Aspartate Aminotransferase

[nkat/L]

(0 - 834)

N 15 15 15 15 15 15 15

Mean ± SD 416.7 ± 126.2 377.7 ± 77.1 373.4 ± 110.8 369.9 ± 92.9 -39.0 ± 72.1 -43.3 ± 63.4 -46.7 ± 80.9

Median 383.0 400.0 367.0 383.0 0.0 -50.0 -17.0

Min, max 217 , 633 233 , 483 183 , 550 217 , 550 -184 , 34 -150 , 50 -200 , 67



Alanine Aminotransferase

[nkat/L]

(0 - 834)

N 15 15 15 15 15 15 15

Mean ± SD 452.2 ± 225.0 405.6 ± 173.9 399.0 ± 207.5 379.9 ± 161.2 -46.6 ± 112.5 -53.2 ± 127.0 -72.3 ± 130.0

Median 383.0 333.0 300.0 317.0 -16.0 -33.0 -34.0

Min, max 183 , 1017 167 , 783 167 , 817 200 , 700 -350 , 83 -317 , 200 -367 , 150



Alkaline Phosphatase

[nkat/L]

(667 - 2150)

N 15 15 15 15 15 15 15

Mean ± SD 1124.8 ± 267.3 1169.1 ± 324.1 1128.0 ± 296.0 1120.4 ± 282.5 44.3 ± 133.2 3.2 ± 115.0 -4.4 ± 116.1

Median 1017.0 1100.0 1050.0 1034.0 33.0 -34.0 -34.0

Min, max 717 , 1784 750 , 1817 683 , 1750 800 , 1684 -150 , 283 -266 , 217 -166 , 200




87

CONFIDENTIAL 2016N274225_00201465

PPD

4 of 5


Table 3.05:


(SES)


Day 15

change3

Day 19/EoT2

change3

Bilirubin [umol/L]

(0 - 20.5)

N 15 15 15 15 15 15 15

Mean ± SD 7.40 ± 3.72 6.71 ± 2.79 6.27 ± 2.58 6.61 ± 2.26 -0.69 ± 3.32 -1.13 ± 4.49 -0.79 ± 3.18

Median 5.10 6.80 5.10 5.10 0.00 0.00 0.00

Min, max 3.4 , 13.7 3.4 , 15.4 3.4 , 12.0 3.4 , 12.0 -6.9 , 3.5 -8.6 , 3.5 -8.6 , 5.2



Direct Bilirubin [umol/L]

(0 - 5.1)

N 15 15 15 15 15 15 15

Mean ± SD 2.93 ± 0.93 2.76 ± 0.79 2.59 ± 0.86 2.83 ± 0.78 -0.17 ± 1.22 -0.34 ± 1.26 -0.10 ± 1.05

Median 2.70 2.60 2.40 2.70 -0.20 0.00 0.10

Min, max 1.7 , 4.4 1.5 , 4.6 1.5 , 4.4 1.5 , 4.1 -2.2 , 1.9 -2.5 , 1.6 -2.3 , 1.5



Protein [g/L]

(64 - 83)

N 15 15 15 15 15 15 15

Mean ± SD 67.7 ± 3.4 70.3 ± 1.7 67.9 ± 2.7 67.8 ± 3.6 2.6 ± 3.0 0.2 ± 2.3 0.1 ± 4.0

Median 68.0 70.0 69.0 67.0 3.0 -1.0 1.0

Min, max 61 , 72 68 , 73 63 , 71 60 , 73 -4 , 7 -3 , 5 -8 , 7




88

CONFIDENTIAL 2016N274225_00201465

PPD

5 of 5


Table 3.05:


(SES)


Day 15

change3

Day 19/EoT2

change3

Albumin [g/L]

(35 - 52)

N 15 15 15 15 15 15 15

Mean ± SD 43.0 ± 2.2 45.7 ± 2.2 44.1 ± 1.9 43.2 ± 1.8 2.7 ± 2.5 1.1 ± 2.2 0.2 ± 2.9

Median 42.0 46.0 44.0 43.0 4.0 1.0 0.0

Min, max 39 , 48 41 , 48 42 , 47 40 , 46 -2 , 6 -2 , 6 -6 , 6




89

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Table 3.06:

Urinalysis - Summary

(SES)

Screening1 Day 8 Day 15 Day 19/EoT2 Day 8 change3 Day 15 change3

Day 19/EoT2

change3

Specific gravity

N 15 15 15 15 15 15 15

Mean ± SD 1.0100 ± 0.0068 1.0137 ± 0.0061 1.0130 ± 0.0070 1.0120 ± 0.0065 0.0037 ± 0.0077 0.0030 ± 0.0082 0.0020 ± 0.0096

Median 1.0100 1.0150 1.0150 1.0100 0.0050 0.0050 0.0000

Min, max 1.000 , 1.025 1.000 , 1.020 1.000 , 1.025 1.000 , 1.020 -0.010 , 0.015 -0.010 , 0.015 -0.020 , 0.020

pH

N 15 15 15 15 15 15 15

Mean ± SD 5.5 ± 0.7 5.3 ± 0.6 5.7 ± 1.0 5.5 ± 0.6 -0.2 ± 0.8 0.1 ± 1.0 -0.1 ± 0.7

Median 5.0 5.0 5.0 5.0 0.0 0.0 0.0

Min, max 5 , 7 5 , 7 5 , 8 5 , 7 -2 , 1 -2 , 2 -2 , 1


90

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 3.07:

Urinalysis - Frequency

(SES)

Screening1 Day 8 Day 15 Day 19/EoT2

Specific Gravity

N 15 15 15 15

1.000 2 ( 13%) 1 ( 7%) 2 ( 13%) 1 ( 7%)

1.005 3 ( 20%) 2 ( 13%) 1 ( 7%) 3 ( 20%)

1.010 6 ( 40%) 1 ( 7%) 2 ( 13%) 4 ( 27%)

1.015 2 ( 13%) 7 ( 47%) 7 ( 47%) 3 ( 20%)

1.020 1 ( 7%) 4 ( 27%) 2 ( 13%) 4 ( 27%)

1.025 1 ( 7%) 0 ( 0%) 1 ( 7%) 0 ( 0%)

1.030 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

pH

N 15 15 15 15

5 9 ( 60%) 11 ( 73%) 9 ( 60%) 9 ( 60%)

6 4 ( 27%) 3 ( 20%) 3 ( 20%) 5 ( 33%)

7 2 ( 13%) 1 ( 7%) 2 ( 13%) 1 ( 7%)

8 0 ( 0%) 0 ( 0%) 1 ( 7%) 0 ( 0%)

9 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Glucose

N 15 15 15 15

Normal 15 (100%) 15 (100%) 15 (100%) 15 (100%)

1+ (50 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2+ (100 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

3+ (300 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

4+ (1000 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

1 Baseline assessment; 2 EoT: End of treatment.

91

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 3.07:

Urinalysis - Frequency

(SES)

Screening1 Day 8 Day 15 Day 19/EoT2

Protein

N 15 15 15 15

Negative 15 (100%) 15 (100%) 15 (100%) 15 (100%)

1+ (30 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2+ (100 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

3+ (500 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Erythrocytes

N 15 15 15 15

Negative 15 (100%) 15 (100%) 15 (100%) 15 (100%)

1+ (~5-10 Ery/ul) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2+ (~25 Ery/ul) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

3+ (~50 Ery/ul) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

4+ (~250 Ery/ul) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Ketones

N 15 15 15 15

Negative 15 (100%) 15 (100%) 15 (100%) 15 (100%)

1+ (10 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2+ (50 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

3+ (150 mg/dl) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

1 Baseline assessment; 2 EoT: End of treatment.

92

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 3.08:

Summary of adverse events

(SES)

Count1

Incidence2

(Incidence rate%)3

GSK2981278

0.03% ointment

GSK2981278 0.1%

ointment

GSK2981278 0.8%

ointment

GSK2981278 4%

ointment Vehicle

Betamethasone

valerate 0.1%

cream

Not

corresponding

to a treatment

area

Total

Subjects

N = 15

AEs 0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

1

1( 7%)

1

1( 7%)

Non-serious AEs 0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

1

1( 7%)

1

1( 7%)

Serious AEs 0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

Number of deaths 0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

Number of fatalities

causally related to

the AE

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

AEs related to IMP 0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

AEs leading IMP

withdrawal

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

Treatment related

AEs leading IMP

withdrawal

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

1 Count of AEs reported. 2 Incidence determined as the number of subjects with any respective AE. 3 Incidence rate determined as incidence divided by number of subjects at risk, i.e. size of the SES.

93

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 3.08:

Summary of adverse events

(SES)

Count1

Incidence2

(Incidence rate%)3

GSK2981278

0.03% ointment

GSK2981278 0.1%

ointment

GSK2981278 0.8%

ointment

GSK2981278 4%

ointment Vehicle

Betamethasone

valerate 0.1%

cream

Not

corresponding

to a treatment

area

Total

Severity of AEs

Severe 0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

Moderate 0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

1

1( 7%)

1

1( 7%)

Mild 0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

0

0 ( 0%)

1 Count of AEs reported. 2 Incidence determined as the number of subjects with any respective AE. 3 Incidence rate determined as incidence divided by number of subjects at risk, i.e. size of the SES.

94

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Figure 2.01:

Psoriatic infiltrate thickness – OC – Line plot

(PPS)

95

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Figure 2.02:

Psoriatic infiltrate thickness – Change from baseline - OC – Line plot

(PPS)

96

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Figure 2.03:

Psoriatic infiltrate thickness – Change from baseline – AUC - OC – Bar chart

(PPS)

97

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 1.05:

Subject baseline characteristics


SES1

(N = 15)

PPS2

(N = 15)

Fitzpatrick skin type

N 15 15

Type I 0 ( 0%) 0 ( 0%)

Type II 1 ( 7%) 1 ( 7%)

Type III 13 ( 87%) 13 ( 87%)

Type IV 1 ( 7%) 1 ( 7%)

Type V 0 ( 0%) 0 ( 0%)

Type VI 0 ( 0%) 0 ( 0%)

Height [cm]

N 15 15

Mean ± SD 177.1 ± 8.0 177.1 ± 8.0

Median 178.0 178.0

Min, max 163 , 192 163 , 192

Weight [kg]

N 15 15

Mean ± SD 86.9 ± 16.0 86.9 ± 16.0

Median 81.0 81.0

Min, max 57 , 112 57 , 112


98

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 1.05:

Subject baseline characteristics


SES1

(N = 15)

PPS2

(N = 15)

BMI [kg/m²]

N 15 15

Mean ± SD 27.601 ± 4.245 27.601 ± 4.245

Median 26.600 26.600

Min, max 21.45 , 38.27 21.45 , 38.27


99

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 2.01:

Psoriatic infiltrate thickness - OC – Summary

(PPS)

Psoriatic

infiltrate

thickness [µm]1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 1 / Baseline

N 15 15 15 15 15 15

Mean ± SD 503.7 ± 306.5 512.1 ± 314.6 511.4 ± 300.3 481.2 ± 256.3 497.9 ± 318.3 486.9 ± 288.6

95% CI2 333.9 , 673.4 337.9 , 686.3 345.1 , 677.7 339.3 , 623.1 321.6 , 674.1 327.1 , 646.7

Median 359.0 383.0 383.0 352.0 367.0 344.0

Min, max 242 , 1344 227 , 1188 242 , 1164 234 , 977 266 , 1359 234 , 1141

Day 4

N 15 15 15 15 15 15

Mean ± SD 626.5 ± 419.1 672.9 ± 456.3 683.5 ± 450.7 683.9 ± 441.5 697.4 ± 514.9 317.8 ± 246.9

95% CI2 394.5 , 858.6 420.2 , 925.6 433.9 , 933.1 439.5 , 928.4 412.3 , 982.5 181.1 , 454.5

Median 539.0 461.0 555.0 586.0 531.0 258.0

Min, max 234 , 1555 273 , 1711 320 , 1766 266 , 1680 266 , 2117 117 , 1102

Day 8

N 15 15 15 15 15 15

Mean ± SD 632.3 ± 316.0 692.1 ± 366.2 685.5 ± 406.9 671.3 ± 343.5 673.9 ± 337.0 205.7 ± 126.5

95% CI2 457.3 , 807.2 489.4 , 894.9 460.2 , 910.8 481.1 , 861.6 487.3 , 860.5 135.7 , 275.8

Median 555.0 609.0 633.0 648.0 664.0 172.0

Min, max 234 , 1461 258 , 1789 258 , 1898 273 , 1578 211 , 1586 78 , 531

1 Psoriatic infiltrate thickness assessed by sonography. 2 95% CI: 95% confidence interval 3 EoT: End of treatment

100

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 2.01:

Psoriatic infiltrate thickness - OC – Summary

(PPS)

Psoriatic

infiltrate

thickness [µm]1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 15

N 15 15 15 15 15 15

Mean ± SD 524.0 ± 231.1 546.9 ± 254.0 580.8 ± 317.8 523.0 ± 227.7 567.9 ± 292.1 116.7 ± 87.9

95% CI2 396.0 , 652.0 406.2 , 687.5 404.8 , 756.8 396.9 , 649.1 406.1 , 729.6 68.0 , 165.4

Median 492.0 539.0 484.0 453.0 508.0 102.0

Min, max 219 , 953 219 , 1086 203 , 1414 211 , 1008 141 , 1313 0 , 273

Day 19/EoT3

N 15 15 15 15 15 15

Mean ± SD 532.2 ± 242.9 533.9 ± 220.7 554.8 ± 297.6 501.7 ± 242.1 529.7 ± 289.8 83.3 ± 77.1

95% CI2 397.7 , 666.7 411.7 , 656.2 390.0 , 719.6 367.6 , 635.7 369.2 , 690.1 40.6 , 126.0

Median 453.0 547.0 500.0 430.0 500.0 70.0

Min, max 188 , 930 195 , 1000 156 , 1195 211 , 992 117 , 1219 0 , 258


101

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 2.02:

Psoriatic infiltrate thickness - Change from baseline - OC – Summary

(PPS)

Change from

baseline in

psoriatic

infiltrate

thickness [µm]1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 4

N 15 15 15 15 15 15

Mean ± SD 122.9 ± 183.7 160.8 ± 186.2 172.1 ± 195.7 202.7 ± 252.8 199.5 ± 273.4 -169.1 ± 153.2

95% CI2 21.2 , 224.6 57.7 , 263.9 63.7 , 280.5 62.8 , 342.7 48.1 , 350.9 -254.0 , -84.3

Median 70.0 86.0 94.0 110.0 117.0 -125.0

Min, max -63 , 672 0 , 524 -8 , 657 -47 , 758 -15 , 1070 -617 , -39

Day 8

N 15 15 15 15 15 15

Mean ± SD 128.6 ± 207.3 180.0 ± 210.1 174.1 ± 235.3 190.1 ± 201.7 176.1 ± 225.4 -281.2 ± 210.2

95% CI2 13.8 , 243.4 63.7 , 296.3 43.8 , 304.5 78.5 , 301.8 51.2 , 300.9 -397.6 , -164.8

Median 79.0 140.0 94.0 118.0 140.0 -172.0

Min, max -235 , 578 -148 , 601 -132 , 734 -71 , 601 -289 , 539 -695 , -47

Day 15

N 15 15 15 15 15 15

Mean ± SD 20.3 ± 197.8 34.7 ± 167.4 69.4 ± 155.9 41.8 ± 130.6 70.0 ± 222.8 -370.3 ± 263.7

95% CI2 -89.2 , 129.9 -57.9 , 127.4 -16.9 , 155.7 -30.5 , 114.1 -53.4 , 193.4 -516.3 , -224.2

Median 16.0 -31.0 23.0 31.0 39.0 -273.0

Min, max -469 , 383 -250 , 335 -132 , 399 -187 , 328 -468 , 445 -890 , -71

1 Psoriatic infiltrate thickness assessed by sonography. 2 95% CI: 95% confidence interval 3 EoT: End of treatment 4 AUC: Area under the time curve (AUC) of change in infiltrate thickness [µm*day] using the linear trapezoidal rule

over the changes from baseline in infiltrate thickness on Day 1, 4, 8, 15 and 19.

102

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 2.02:

Psoriatic infiltrate thickness - Change from baseline - OC – Summary

(PPS)

Change from

baseline in

psoriatic

infiltrate

thickness [µm]1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 19/EoT3

N 15 15 15 15 15 15

Mean ± SD 28.5 ± 163.5 21.8 ± 197.8 43.4 ± 142.4 20.5 ± 121.3 31.8 ± 196.2 -403.6 ± 259.8

95% CI2 -62.0 , 119.1 -87.7 , 131.3 -35.5 , 122.3 -46.7 , 87.6 -76.8 , 140.4 -547.5 , -259.7

Median 62.0 8.0 -8.0 0.0 47.0 -312.0

Min, max -453 , 258 -438 , 343 -133 , 360 -133 , 344 -453 , 390 -899 , -86

AUC [µm*day]4

N 15 15 15 15 15 15

Mean ± SD 1306.2 ± 2544.3 1787.4 ± 2158.1 2028.5 ± 2562.6 2026.1 ± 2356.2 2115.3 ± 3293.4 -4982.2 ± 3442.2

95% CI2 -102.8 , 2715.2 592.3 , 2982.5 609.3 , 3447.6 721.3 , 3331.0 291.5 , 3939.2 -6888.4 , -3076.0

Median 1134.0 1438.0 1050.0 1734.0 1305.0 -3429.5

Min, max -4152 , 6010 -667 , 5586 -801 , 7308 -1416 , 5939 -4111 , 8517 -12627 , -1315

1 Psoriatic infiltrate thickness assessed by sonography. 2 95% CI: 95% confidence interval 3 EoT: End of treatment 4 AUC: Area under the time curve (AUC) of change in infiltrate thickness [µm*day] using the linear trapezoidal rule

over the changes from baseline in infiltrate thickness on Day 1, 4, 8, 15 and 19.

103

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Table 2.03:

Psoriatic infiltrate thickness – Change from baseline - OC – AUC MMRM Estimates

(PPS)

Change from

baseline in

psoriatic

infiltrate

thickness [µm]1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

AUC [µm*day]2,3

Estimate ± SE 1306.2 ± 656.9 1787.4 ± 557.2 2028.5 ± 661.7 2026.1 ± 608.4 2115.3 ± 850.4 -4982.2 ± 888.8

95% CI4 -102.8 , 2715.2 592.3 , 2982.5 609.3 , 3447.6 721.3 , 3331.0 291.5 , 3939.2 -6888.4 , -3076.0

P-value 0.0667 0.0063 0.0084 0.0050 0.0261 < 0.0001

1 Psoriatic infiltrate thickness assessed by sonography. 2 AUC: Area under the time curve (AUC) of change in infiltrate thickness [µm*day] using the linear trapezoidal rule

over the changes from baseline in infiltrate thickness on Day 1, 4, 8, 15 and 19. 3 Estimates of the AUC of change from baseline in psoriatic infiltrate thickness determined using a mixed-model

repeated-measures (MMRM) model with a fixed effect for treatment, and treatment treated as a repeated measure within

the same subject with an unstructured covariance matrix. 4 95% CI: 95% confidence interval

104

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Table 2.04:

Psoriatic infiltrate thickness – Change from baseline - OC - AUC MMRM Comparisons

(PPS)

Treatment difference (Treatment 1 – treatment 2)

Difference in AUC [µm*day]1 of change from baseline in

psoriatic infiltrate thickness [µm]1,2

Treatment 1 Treatment 2 Estimate ± SE 95% CI3 P-value

Betamethasone valerate 0.1% cream GSK2981278 0.03% ointment -6288.5 ± 1017.9 -8471.6 , -4105.3 < 0.0001



Betamethasone valerate 0.1% cream GSK2981278 4% ointment -7008.4 ± 1144.8 -9463.8 , -4553.0 < 0.0001

Betamethasone valerate 0.1% cream Vehicle -7097.6 ± 1246.5 -9771.1 , -4424.0 < 0.0001

Vehicle GSK2981278 0.03% ointment 809.1 ± 481.5 -223.7 , 1841.9 0.1151



Vehicle GSK2981278 4% ointment 89.2 ± 697.1 -1406.0 , 1584.4 0.9000

GSK2981278 4% ointment GSK2981278 0.03% ointment 719.9 ± 644.1 -661.6 , 2101.4 0.2825


GSK2981278 4% ointment GSK2981278 0.8% ointment -2.3 ± 527.8 -1134.3 , 1129.6 0.9965

GSK2981278 0.8% ointment GSK2981278 0.03% ointment 722.2 ± 541.5 -439.1 , 1883.6 0.2036



1 AUC: Area under the time curve (AUC) of change in infiltrate thickness [µm*day] using the linear trapezoidal rule

over the changes from baseline in infiltrate thickness on Day 1, 4, 8, 15 and 19. LOCF imputation applied prior to

determination of the AUC. Psoriatic infiltrate thickness assessed by sonography. 2 Estimates of difference in AUC of change from baseline in psoriatic infiltrate thickness determined using a

mixed-model repeated-measures (MMRM) model with a fixed effect for treatment, and treatment treated as a repeated

measure within the same subject with an unstructured covariance matrix. 3 95% CI: 95% confidence interval

105

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Table 2.05:

Psoriatic infiltrate thickness – Change from baseline - OC – MMRM Estimates by visit

(PPS)

Change from

baseline in

psoriatic

infiltrate

thickness [µm]1,2

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 4

Estimate ± SE 122.9 ± 47.4 160.8 ± 48.1 172.1 ± 50.5 202.7 ± 65.3 199.5 ± 70.6 -169.1 ± 39.6

95% CI3 21.2 , 224.6 57.7 , 263.9 63.7 , 280.5 62.8 , 342.7 48.1 , 350.9 -254.0 , -84.3

P-value 0.0214 0.0048 0.0043 0.0077 0.0134 0.0008

Day 8

Estimate ± SE 128.6 ± 53.5 180.0 ± 54.2 174.1 ± 60.8 190.1 ± 52.1 176.1 ± 58.2 -281.2 ± 54.3

95% CI3 13.8 , 243.4 63.7 , 296.3 43.8 , 304.5 78.5 , 301.8 51.2 , 300.9 -397.6 , -164.8

P-value 0.0307 0.0051 0.0125 0.0026 0.0091 0.0001

Day 15

Estimate ± SE 20.3 ± 51.1 34.7 ± 43.2 69.4 ± 40.3 41.8 ± 33.7 70.0 ± 57.5 -370.3 ± 68.1

95% CI3 -89.2 , 129.9 -57.9 , 127.4 -16.9 , 155.7 -30.5 , 114.1 -53.4 , 193.4 -516.3 , -224.2

P-value 0.6965 0.4349 0.1067 0.2354 0.2438 < 0.0001

Day 19/EoT4

Estimate ± SE 28.5 ± 42.2 21.8 ± 51.1 43.4 ± 36.8 20.5 ± 31.3 31.8 ± 50.6 -403.6 ± 67.1

95% CI3 -62.0 , 119.1 -87.7 , 131.3 -35.5 , 122.3 -46.7 , 87.6 -76.8 , 140.4 -547.5 , -259.7

P-value 0.5102 0.6759 0.2575 0.5240 0.5402 < 0.0001

1 Psoriatic infiltrate thickness assessed by sonography. 2 Change from baseline in psoriatic infiltrate thickness estimates determined for each visit separately using a

mixed-model repeated-measures (MMRM) model with a fixed effect for treatment, and treatment treated as repeated

measure within the same subject with an unstructured covariance matrix. 3 95% CI: 95% confidence interval 4 EoT: End of treatment

106

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 4


Table 2.06:

Psoriatic infiltrate thickness – Change from baseline - OC– MMRM Comparisons by visit

(PPS)

Day 4


Difference in change from baseline in



Betamethasone valerate 0.1% cream GSK2981278 0.03% ointment -292.0 ± 79.8 -463.1 , -120.9 0.0026



Betamethasone valerate 0.1% cream GSK2981278 4% ointment -371.9 ± 84.4 -552.9 , -190.8 0.0006

Betamethasone valerate 0.1% cream Vehicle -368.7 ± 102.9 -589.4 , -147.9 0.0030




Vehicle GSK2981278 4% ointment -3.2 ± 50.9 -112.4 , 106.0 0.9508







1 Psoriatic infiltrate thickness assessed by sonography. 2 Estimates of difference in change from baseline in psoriatic infiltrate thickness determined for each visit

separately using a mixed-model repeated-measures (MMRM) model with a fixed effect for treatment, and treatment treated

as repeated measure within the same subject with an unstructured covariance matrix. 3 95% CI: 95% confidence interval

107

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 4


Table 2.06:


(PPS)

Day 8











Vehicle GSK2981278 0.1% ointment -3.9 ± 48.6 -108.2 , 100.3 0.9367


Vehicle GSK2981278 4% ointment -14.1 ± 43.3 -107.0 , 78.9 0.7503





GSK2981278 0.8% ointment GSK2981278 0.1% ointment -5.9 ± 37.2 -85.7 , 74.0 0.8770





108

CONFIDENTIAL 2016N274225_00201465

PPD

3 of 4


Table 2.06:


(PPS)

Day 15























109

CONFIDENTIAL 2016N274225_00201465

PPD

4 of 4


Table 2.06:


(PPS)

Day 19/End of treatment












Vehicle GSK2981278 0.8% ointment -11.6 ± 41.9 -101.5 , 78.3 0.7861







GSK2981278 0.1% ointment GSK2981278 0.03% ointment -6.7 ± 47.0 -107.6 , 94.2 0.8882




110

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 2.07:

Psoriatic infiltrate thickness - % Change from baseline - OC – Summary

(PPS)

% Change from

baseline in

psoriatic

infiltrate

thickness1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 4

N 15 15 15 15 15 15

Mean ± SD 22.6 ± 30.4 32.4 ± 36.6 34.4 ± 30.2 41.5 ± 40.2 39.3 ± 43.3 -36.1 ± 16.8

95% CI2 5.8 , 39.4 12.1 , 52.7 17.7 , 51.1 19.3 , 63.8 15.3 , 63.3 -45.4 , -26.8

Median 13.3 16.5 26.3 37.7 20.1 -36.3

Min, max -21 , 76 0 , 123 -1 , 91 -5 , 129 -5 , 140 -63 , -3

Day 8

N 15 15 15 15 15 15

Mean ± SD 35.9 ± 43.4 49.2 ± 56.5 41.5 ± 53.1 48.7 ± 55.2 48.7 ± 55.7 -55.7 ± 18.5

95% CI2 11.9 , 60.0 17.9 , 80.5 12.1 , 70.8 18.1 , 79.2 17.8 , 79.5 -65.9 , -45.4

Median 32.2 34.4 14.5 29.9 34.1 -59.5

Min, max -23 , 112 -13 , 155 -12 , 183 -21 , 170 -25 , 158 -85 , -14

Day 15

N 15 15 15 15 15 15

Mean ± SD 14.5 ± 43.8 18.8 ± 48.5 20.0 ± 43.8 17.3 ± 39.3 25.3 ± 52.7 -73.9 ± 21.0

95% CI2 -9.8 , 38.8 -8.1 , 45.6 -4.2 , 44.3 -4.5 , 39.0 -3.9 , 54.5 -85.5 , -62.2

Median 4.5 -5.4 4.1 3.2 6.7 -78.2

Min, max -35 , 107 -26 , 107 -30 , 125 -39 , 113 -55 , 132 -100 , -21


111

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 2.07:

Psoriatic infiltrate thickness - % Change from baseline - OC – Summary

(PPS)

% Change from

baseline in

psoriatic

infiltrate

thickness1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 19/EoT3

N 15 15 15 15 15 15

Mean ± SD 13.4 ± 33.7 18.0 ± 46.8 15.4 ± 43.2 10.1 ± 39.8 13.5 ± 46.0 -81.5 ± 18.1

95% CI2 -5.3 , 32.1 -7.9 , 43.9 -8.6 , 39.3 -12.0 , 32.1 -11.9 , 39.0 -91.5 , -71.5

Median 13.4 1.1 -2.1 0.0 8.4 -83.3

Min, max -38 , 81 -37 , 110 -46 , 113 -39 , 119 -63 , 111 -100 , -25


112

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 2.08:

Clinical assessment of improvement – OC – Frequency

(PPS)

Clinical

assessment of

improvement1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 1 / Baseline

N 15 15 15 15 15 15

-1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

0 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%)

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 4

N 15 15 15 15 15 15

-1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

0 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 1 ( 7%)

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 6 ( 40%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 8 ( 53%)

3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 8

N 15 15 15 15 15 15

-1 1 ( 7%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

0 14 ( 93%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 0 ( 0%)

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 5 ( 33%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 10 ( 67%)

3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

1 Clinical assessment of improvement: -1 = worsened; 0 = unchanged (no effect); 1 = slight improvement; 2 = clear

improvement but not completely healed; 3 = completely healed. 2 EoT: End of treatment

113

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 2.08:

Clinical assessment of improvement – OC – Frequency

(PPS)

Clinical

assessment of

improvement1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 15

N 15 15 15 15 15 15

-1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

0 15 (100%) 15 (100%) 15 (100%) 15 (100%) 15 (100%) 0 ( 0%)

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 ( 20%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 10 ( 67%)

3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 ( 13%)

Day 19/EoT2

N 15 15 15 15 15 15

-1 0 ( 0%) 1 ( 7%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

0 14 ( 93%) 13 ( 87%) 14 ( 93%) 15 (100%) 14 ( 93%) 0 ( 0%)

1 1 ( 7%) 1 ( 7%) 1 ( 7%) 0 ( 0%) 1 ( 7%) 1 ( 7%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 10 ( 67%)

3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 ( 27%)


improvement but not completely healed; 3 = completely healed. 2 EoT: End of treatment

114

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 2


Table 2.09:

Clinical assessment of improvement – OC – Summary

(PPS)

Clinical

assessment of

improvement1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 1 / Baseline

N 15 15 15 15 15 15

Mean ± SD 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0

Median 0.0 0.0 0.0 0.0 0.0 0.0

Min, max 0 , 0 0 , 0 0 , 0 0 , 0 0 , 0 0 , 0

Day 4

N 15 15 15 15 15 15

Mean ± SD 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 1.5 ± 0.6

Median 0.0 0.0 0.0 0.0 0.0 2.0

Min, max 0 , 0 0 , 0 0 , 0 0 , 0 0 , 0 0 , 2

Day 8

N 15 15 15 15 15 15

Mean ± SD -0.1 ± 0.3 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 1.7 ± 0.5

Median 0.0 0.0 0.0 0.0 0.0 2.0

Min, max -1 , 0 0 , 0 0 , 0 0 , 0 0 , 0 1 , 2


improvement but not completely healed; 3 = completely healed. 2 EoT: End of treatment 3 Cumulative total score: Sum of all post-baseline assessments by subject and treatment.

115

CONFIDENTIAL 2016N274225_00201465

PPD

2 of 2


Table 2.09:

Clinical assessment of improvement – OC – Summary

(PPS)

Clinical

assessment of

improvement1

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Day 15

N 15 15 15 15 15 15

Mean ± SD 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 1.9 ± 0.6

Median 0.0 0.0 0.0 0.0 0.0 2.0

Min, max 0 , 0 0 , 0 0 , 0 0 , 0 0 , 0 1 , 3

Day 19/EoT2

N 15 15 15 15 15 15

Mean ± SD 0.1 ± 0.3 0.0 ± 0.4 0.1 ± 0.3 0.0 ± 0.0 0.1 ± 0.3 2.2 ± 0.6

Median 0.0 0.0 0.0 0.0 0.0 2.0

Min, max 0 , 1 -1 , 1 0 , 1 0 , 0 0 , 1 1 , 3

Cumulative total

score3

N 15 15 15 15 15 15

Mean ± SD 0.0 ± 0.4 0.0 ± 0.4 0.1 ± 0.3 0.0 ± 0.0 0.1 ± 0.3 7.3 ± 1.8

Median 0.0 0.0 0.0 0.0 0.0 7.0

Min, max -1 , 1 -1 , 1 0 , 1 0 , 0 0 , 1 4 , 10


improvement but not completely healed; 3 = completely healed. 2 EoT: End of treatment 3 Cumulative total score: Sum of all post-baseline assessments by subject and treatment.

116

CONFIDENTIAL 2016N274225_00201465

PPD

1 of 1


Table 2.10:

Efficacy assessments - Missing data - Summary

(PPS)

Missing data

GSK2981278

0.03% ointment

GSK2981278

0.1% ointment

GSK2981278

0.8% ointment

GSK2981278

4% ointment Vehicle

Betamethasone

valerate 0.1%

cream

Number of

subjects N = 15

Psoriatic

infiltrate

thickness [µm]

Day 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 4 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 8 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 15 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 19 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Clinical

assessment of

improvement

Day 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 4 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 8 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 15 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Day 19 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

117

CONFIDENTIAL 2016N274225_00201465

PPD

CONFIDENTIAL 2016N274225_00201465

1

Synopsis

Name of company: GlaxoSmithKline Research & Development Limited

Name of finished product: Not available/known at the time of thisreport

Name of active substance: GSK2981278

Study Number: 201465

Title: A Phase I Trial to Evaluate Safety and Efficacy of Topically Applied GSK2981278 Ointment in a Psoriasis Plaque Test

Principal Investigator: H. Siemetzki, M.D.

Study Center: bioskin GmbH, Burchardstrasse 17, 20095 Hamburg,Germany

Publication(s): None at the time of this report

Study Period: 22-OCT-2015 – 19-FEB-2016

Phase of Development: I

Objectives and Endpoints (criteria for evaluation):

Objectives Endpoints

Primary


To evaluate the efficacy of topical formulation strengths of GSK2981278 ointment in subjectswith psoriasis.

Incidence and nature of adverse events (AE). Change from Baseline in clinical laboratory

parameters, vital signs, electrocardiogram (ECG).

The reduction in infiltrate thickness of the psoriatic plaque(s) from Baseline using 22 MHz sonography measurement.

Secondary



Exploratory

To evaluate the pharmacodynamic (PD) effects of topical GSK2981278 in psoriasis plaques.

messenger ribonucleic acid (mRNA) biomarkers in skin biopsy samples.

CONFIDENTIAL 2016N274225_00201465

2

Methodology:Altogether 6 test fields (each 1.1 cm2) located on the upper extremities, thighs and/or trunk with psoriasis vulgaris in a chronic stable phase were examined per subject. The test fields were treated semi-occlusively with approximately 200 L of each study product (4 GSK2981278 ointments [0.03%, 0.1%, 0.8% and 4% ], the active ingredient-free vehicle and the positive control betamethasone valerate 0.1% cream) administered once daily over a 19-day treatment period (in total 16 applications, no study product application on Days 7, 14 and 19). All subjects received all study treatments. Safety assessments included a brief physical examination (including height and weight) at Screening and a physical examination of the skin at Screening and on Day 19 (end of treatment [EoT]), vital signs (blood pressure, heart rate and oral temperature) at Screening and on Day 19, electrocardiogram (ECG) at Screening and on Days 15 and 19 as well as clinical laboratory assessments (hematology, clinical chemistry including liver chemistries, and urinalysis) at Screening and on Days 8, 15 and 19. Extent of exposure and AEs were documented from the time the subject signed the informed consent form until subject’s last visit. Four 3 mm skin punch biopsies were collected from each consenting subject on Day 19 (EoT). Sonographic measurements of the infiltrate thickness were performed at Baseline (Day 1) and on Days 4, 8, 15 and 19 (EoT). Clinical assessments of improvement were performed on Days 4, 8, 15 and 19 (EoT). Photographic documentation of test fields was done on Days 1 (Baseline) and 19.

Number of Subjects:A total of 15 male subjects were randomized in order to achieve at least 13 evaluable subjects. The data of all 15 randomized subjects were valid for the per-protocol analysis set (PPS) and safety evaluation set (SES) analyses. There were no subjects excluded from the analysis populations. Thirteen of the 15 subjects consented to skin biopsies and were valid for the PD population analysis.

Diagnosis and Main Criteria for Inclusion:Male volunteers or female volunteers of non-reproductive potential (FNRP), aged 18 years or older, with stable plaque psoriasis for 6 months and up to 3 plaque areas sufficient for 6 test fields.

Treatment Administration:Topical application of approximately 200 L of the 6 study products—the 4 GSK2981278 ointment formulations (0.03%, 0.1%, 0.8% and 4%), the corresponding vehicle and the positive control—per test field (approximately 1.1 cm2) once daily during a 19-day treatment period (16 applications, except Days 7, 14 and 19 [EoT]).

Product name:

GSK2981278 Vehicle Betamethasone valerate cream 0.1%

(positive control)Batch number

GSK2981278 ointment 0.03%: E141511-0001L002E141511-0002L002



GSK2981278 ointment 4%: E141511-0001L005E141511-0002L005

E141511-0001L001E141511-0002L001

C730272

CONFIDENTIAL 2016N274225_00201465

3

Statistical Methods:The sample size was driven by feasibility and prior experience by bioskin (CRO) in conducting these studies (based on published data on clinicaltrials.gov and unpublished bioskin data). Fifteen subjects were randomized in order to achieve at least 13 evaluable subjects.

Analysis Populations

Safety Population: Safety evaluation set (SES) included all subjects exposed to at least one application of study product. The SES was the primary set for safety analyses.

Pharmacodynamic Population: PD analysis set included subjects with at least one sample collected for PD assessments. The PD analysis set was the primary set for PD analyses.

Efficacy Population: The primary set for efficacy analyses was the per-protocol analysis set (PPS). The PPS included all randomized subjects who complied closely with the protocol. Protocol deviations were considered exclusionary, if they were deemed to interfere with the trial aims, particularly, if any of the following criterions applied:






except for treatment discontinuations, due to treatment related AEs;

missing Day 1/Baseline or Day 19 visit value or more than one missing value of the infiltrate thickness (primary variable).

Prior to breaking the blind, the following criteria were added to the list to clarify the intended study treatment administration and assessment timings: Some clinical study protocol defined time ranges for assessments were in conflict with the planned study procedures, resulting in protocol deviations. The time range of about 24 ± 2 hours from last application to clinical assessment and sonographic measurement stated in the protocol did not account for the study design having no study treatment administered and no assessments and measurements performed on Sundays (Days 7 and 14) resulting in a longer time range prior to the assessments on Mondays (about 48 hours on Days 8 and 15) (Statistical Methods, Analysis Populations and Section 4.8.5). Assignment of subjects to analysis sets was defined within the blind data review meeting (Statistical Methods).

Final Analyses

Hypotheses: No confirmatory hypotheses were formulated for this study. The analyses were interpreted non-confirmatory, and the data were evaluated descriptively.

CONFIDENTIAL 2016N274225_00201465

4

Safety Analyses: Safety analyses included a summary of extent to exposure, summaries of AEs, laboratory data (hematology, clinical chemistry, and urinalysis), vital signs data, and ECG data. Safety data were listed as well.

PD Analyses: Gene expression of biomarkers from skin punch biopsy sample(s) wasanalyzed.

Efficacy Analyses: The primary efficacy endpoint was the area under the time curve (AUC) of change in infiltrate thickness using the linear trapezoidal rule over the period starting with Day 1 up to Day 19 (EoT). The AUC was analyzed using a mixed-model repeated-measures (MMRM) analysis including treatment. The treatment was treated as repeated measures within the same subject. Pair-wise treatment comparisons wereperformed. The primary comparison was between each active dose and the vehicle ointment. In addition, for each post-baseline assessed time point, the reduction in infiltrate thickness of the psoriatic plaque(s) from Baseline was summarized using the observed cases (OC) approach. Pair-wise treatment comparisons were performed.

Clinical efficacy assessment using a 5-point scale was evaluated for each post-baseline assessed time point. The ordinal clinical score and the cumulative total score arepresented by descriptive statistics. Additionally, frequency counts are provided for the clinical scores.

There were no changes in the conduct of this trial or the planned analyses.

SUMMARY

Demographics:

Number of SubjectsNumber of subjects planned, [N] 15Number of subjects randomized, [N] 15Number of subjects included in All subjects (safety) population, [n (%)] 15 (100%)Number of subjects included in PD population, [n (%)] 13 ( 87%)Number of subjects included in per-protocol (PP)l population, [n (%)] 15 (100%)Number of subjects completed as planned, [n (%)] 15 (100%)Number of subjects withdrawn (any reason), [n (%)] 0 ( 0%)Demographics SES/PPSAge in Years [Mean (SD)] 53.9 ± 8.1Sex [n (%)]Female 0 ( 0%)Male 15 (100%)BMI (kg/m2) [Mean (SD)] 27.601 ± 4.245Height (cm) [Mean (SD)] 177.1 ± 8.0Weight (kg) [Mean (SD)] 86.9 ± 16.0Ethnicity [n (%)]Not Hispanic or Latino 15 (100%)Race [n (%)]White – White/Caucasian/European Heritage 15 (100%)

CONFIDENTIAL 2016N274225_00201465

5

Fitzpatrick Skin Type [n (%)]Type II 1 ( 7%)Type III 13 ( 87%)Type IV 1 ( 7%)

Safety Results

Overall, there were no safety concerns based on the incidence and nature of AEs, clinical laboratory assessments (hematology, clinical chemistry, urinalysis), vital signs and ECG measurements. Furthermore, there were no findings in the physical examinations; however, 2 subjects showed worsening of psoriasis in the clinical assessment over the trial: 1 subject in the test field treated with GSK2981278 ointment 0.03% on Day 8 and another subject in the test field treated with GSK2981278 ointment 0.1% at EoT (Section 7.2). Only 1 non-serious AE was reported in 1 subject over the entire trial period. Subject experienced nasopharyngitis of moderate intensity; the event was considered to be not related to study treatment by the investigator and did not correspond to a specific treatment area. The subject continued study participation and had recovered at the end of the study. There were no deaths, SAEs or other significant AEs reported in this trial. All abnormal hematology, clinical chemistry urinalysis values and all ECG and vital sign outcomes were of no clinical significance. Only a few subjects showed parameters (lymphocytes [N = 3], glucose [N = 1] values and QRS interval [N = 2]) meeting the criteria of potential clinical importance (PCI). However, they were present at Screening (N = 4) and were not considered clinically significant.

Efficacy Results

Psoriatic Infiltrate ThicknessThe sonographic measurements showed no reduction of the echo lucent band (ELB) for all 4 strengths of GSK2981278 ointment indicating no reduction of psoriatic infiltrate thickness. Mean AUCs of change in infiltrate thickness (primary efficacy endpoint) were positive for all 4 different GSK2981278 ointment concentrations 0.03%, 0.1%, 0.8% and 4% (1306.2, 1787.4, 2028.5 and 2026.1 m*day, respectively). The mean AUC of change in infiltrate thickness was also positive for the active ingredient-free vehicle (2115.3 m*day). In contrast, the mean AUC of change in infiltrate thickness was negative (-4982.2 m*day) for the positive control betamethasone valerate 0.1% cream. Thus, a reduction in infiltrate thickness was shown only for betamethasone valerate 0.1% cream under the conditions of this trial.

PPD

CONFIDENTIAL 2016N274225_00201465

6

Psoriatic Infiltrate Thickness – Change from Baseline – AUC – Bar Chart (PPS)

The assessment of the mean infiltrate thickness values, the mean changes and the mean percent changes from Baseline in infiltrate thickness at the different time points showed an increase in infiltrate thickness following treatment with all 4 GSK2981278 concentrations 0.03%, 0.1%, 0.8% and 4% and the vehicle during the first 4 days (mean % changes of 22.6%, 32.4%, 34.4%, 41.5% and 39.3%, respectively), which remained until Day 8, followed by a decrease: On Day 19 (EoT) the infiltrate thickness values had almost returned to Baseline values (mean % changes of 13.4%, 18.0%, 15.4%, 10.1% and 13.5%, respectively). For the positive control betamethasone valerate 0.1% cream, a clear continuous decrease in infiltrate thickness was seen over the trial period (mean % reduction of 81.5% at Day 19/EoT).

AUC - Estimates and Statistical ComparisonStatistically significant positive estimates of the AUC of change from Baseline to Day 19 (EoT) in psoriatic infiltrate thickness were found for the 3 GSK2981278 ointment concentrations 0.1%, 0.8% and 4% and the vehicle (p ≤ 0.0261), reflecting an increase in psoriatic infiltrate thickness. Whereas, a statistically significant negative estimate was determined for the positive control betamethasone valerate 0.1% cream (p < 0.0001), representing a clear reduction in psoriatic infiltrate thickness.

Statistically significant LS mean differences were found between all 4 GSK2981278 ointments and the vehicle versus (vs.) positive control (p ˂ 0.0001, each) in favor of betamethasone valerate 0.1% cream.

Change in Psoriatic Infiltrate Thickness at Each Trial Visit – Estimates and Statistical ComparisonStatistically significant positive estimates of change from Baseline in psoriatic infiltrate thickness were found for all 4 GSK2981278 ointments (0.03%, 0.1%, 0.8% and 4%) and the vehicle on Days 4 and 8, reflecting an increase during the first week (p ≤ 0.0214 and 0.0307, respectively). Whereas, statistically significant negative estimates were found for the positive control betamethasone valerate 0.1% cream at each assessment time point with the greatest negative estimate at EoT (p < 0.0001), indicating a continuous decrease over the trial period.

CONFIDENTIAL 2016N274225_00201465

7

Statistically significant LS mean differences were found between all 4 GSK2981278 ointment concentrations and the vehicle vs. positive control, each in favor of betamethasone valerate 0.1% cream, at each assessment time point (p ≤ 0.0030).

Clinical AssessmentIn general, the results of the clinical assessment of improvement paralleled the sonographic results showing no improvement of psoriatic lesions following treatment with the 4 GSK2981278 ointments over the trial. Low mean cumulative total scores of clinical improvement (sum of all post-baseline assessments by subject and treatment) were seen for all 4 GSK2981278 ointment formulations as well as for the vehicle (≤ 0.1), whereas the mean cumulative total score for the positive control was high (7.3), indicating a clear improvement of psoriatic lesions only for betamethasone valerate 0.1% cream.

Worsening of psoriatic lesion was seen in 1 subject in the test field treated withGSK2981278 ointment 0.03% on Day 8 and in another subject in the test field treated with GSK2981278 ointment 0.1% at EoT which may be attributed to irritation or lack of efficacy due to repeated application under semi-occlusive conditions. Furthermore, this may indicate that there is no dose-dependent finding in terms of worsening of psoriasis.

The biomarker results suggest a lack of target engagement with GSK2981278 in this study and are consistent with the results of the sonographic measurement and the clinical assessment.

Conclusions:Overall, the 4 different GSK2981278 ointment formulations 0.03%, 0.1%, 0.8% and 4% showed no reduction in infiltrate thickness but were generally safe and well tolerated in subjects with chronic plaque psoriasis after once daily topical application to small test fields over 19 days in this study.

Effective Date:18-OCT-2016

2014N215725_00 CONFIDENTIALGlaxoSmithKline group of companies 201465

1

TITLE PAGE

Division: Worldwide Development

Information Type: Clinical Protocol

Title: A Phase I Trial to Evaluate Safety and Efficacy of Topically Applied GSK2981278 Ointment in a Psoriasis Plaque Test.

Compound Number: GSK2981278

Development Phase I

Effective Date: 15-JUL-2015

Author(s):

Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

2016N274225_00

PPD

2016N274225_00

PPD

PPD

2014N215725_00 CONFIDENTIAL201465

3

MEDICAL MONITOR/SPONSOR INFORMATION PAGE

Medical Monitor/SAE Contact Information:

Role Name Day Time Phone Number and email address

After-hours Phone/Cell/Pager Number

Fax Number

Site Address

Primary Medical Monitor

Stiefel, a GSK company 20 TW Alexander Dr, Research Triangle Park, NC 27709

Secondary Medical Monitor

bioskin GmbH, Burchardstrasse 17, 20095 Hamburg, Germany

SAE contact information

Medical monitor as above

Sponsor Legal Registered Address:

GlaxoSmithKline Research & Development Limited980 Great West RoadBrentfordMiddlesex, TW8 9GSUK

Sponsor Contact Address:

Stiefel, a GSK company20 TW Alexander DriveResearch Triangle Park, NC 27709United States

In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate Company (or designee). If applicable, the details of the alternative Sponsor and contact person in the territory will be provided to the relevant regulatory authority as part of the clinical trial application.

Regulatory Agency Identifying Number(s): EudraCT number 2015-002614-72.

2016N274225_00

PPD

2014N215725_00 CONFIDENTIAL201465

4

INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.

Investigator Name:

Investigator Address:

Investigator Phone Number:

Investigator Signature Date

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

5

TABLE OF CONTENTS

PAGE

1. PROTOCOL SYNOPSIS FOR STUDY 201465........................................................8

2. INTRODUCTION....................................................................................................112.1. Study Rationale ..........................................................................................112.2. Brief Background ........................................................................................11

3. OBJECTIVE(S) AND ENDPOINT(S) ......................................................................12

4. STUDY DESIGN ....................................................................................................134.1. Overall Design ............................................................................................134.2. Treatment Arms and Duration.....................................................................134.3. Type and Number of Subjects.....................................................................144.4. Design Justification.....................................................................................144.5. Dose Justification........................................................................................164.6. Benefit:Risk Assessment ............................................................................18

4.6.1. Risk Assessment .........................................................................194.6.2. Benefit Assessment .....................................................................224.6.3. Overall Benefit:Risk Conclusion...................................................22

5. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............225.1. Inclusion Criteria .........................................................................................225.2. Exclusion Criteria........................................................................................245.3. Screening/Baseline/Run-in Failures ............................................................255.4. Withdrawal/Stopping Criteria.......................................................................26

5.4.1. Liver Chemistry Stopping Criteria ................................................275.4.1.1. Study Treatment Restart or Rechallenge....................27

5.4.2. QTc Stopping Criteria ..................................................................285.5. Subject and Study Completion....................................................................28

6. STUDY TREATMENT ............................................................................................296.1. Investigational Product and Other Study Treatment....................................296.2. Assignment of Treatments to Test Sites and Randomization ......................296.3. Manner of Treatment ..................................................................................30

6.3.1. Criteria for discontinuing treatments.............................................316.4. Blinding.......................................................................................................326.5. Packaging and Labeling..............................................................................336.6. Preparation/Handling/Storage/Accountability ..............................................336.7. Compliance with Study Treatment Administration .......................................336.8. Treatment of Study Treatment Overdose....................................................346.9. Treatment after the End of the Study ..........................................................346.10. Lifestyle and/or Dietary Restrictions............................................................34

6.10.1. Alcohol.........................................................................................346.10.2. Activity .........................................................................................35

6.11. Concomitant Medications and Non-Drug Therapies....................................356.11.1. Permitted Medications and Non-Drug Therapies..........................356.11.2. Prohibited Medications and Non-Drug Therapies.........................35

7. STUDY ASSESSMENTS AND PROCEDURES .....................................................367.1. Time and Events Table ...............................................................................38

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

6

7.2. Screening and Critical Baseline Assessments ............................................417.3. Safety .........................................................................................................42

7.3.1. Adverse Events (AE) and Serious Adverse Events (SAEs)..........427.3.1.1. Time period and Frequency for collecting AE

and SAE information...................................................427.3.1.2. Method of Detecting AEs and SAEs ...........................437.3.1.3. Follow-up of AEs and SAEs........................................437.3.1.4. Regulatory Reporting Requirements for SAEs............43

7.3.2. Physical Exams ...........................................................................447.3.3. Vital Signs....................................................................................447.3.4. ECG.............................................................................................447.3.5. Clinical Safety Laboratory Assessments ......................................44

7.4. Efficacy.......................................................................................................467.5. Biomarker(s)/Pharmacodynamic Markers ...................................................47

7.5.1. Novel Biomarkers ........................................................................47

8. DATA MANAGEMENT ...........................................................................................47

9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................479.1. Hypotheses.................................................................................................479.2. Sample Size Considerations.......................................................................489.3. Data Analysis Considerations .....................................................................48

9.3.1. Analysis Populations....................................................................489.3.2. Interim Analysis ...........................................................................48

9.4. Key Elements of Analysis Plan ...................................................................489.4.1. Efficacy Analyses.........................................................................48

9.4.1.1. Reduction in psoriatic infiltrate thickness ....................489.4.1.2. Improvement in clinical assessment ...........................49

9.4.2. Safety Analyses ...........................................................................499.4.3. Other Analyses ............................................................................50

10. STUDY GOVERNANCE CONSIDERATIONS........................................................5010.1. Posting of Information on Publicly Available Clinical Trial Registers............5010.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process ........................................................................................5010.3. Quality Control (Study Monitoring) ..............................................................5110.4. Quality Assurance.......................................................................................5110.5. Study and Site Closure ...............................................................................5210.6. Records Retention ......................................................................................5210.7. Provision of Study Results to Investigators, Posting of Information

on Publically Available Clinical Trials Registers and Publication .................53

11. REFERENCES.......................................................................................................54

12. APPENDICES ........................................................................................................5712.1. Appendix 1 – Abbreviations and Trademarks..............................................5712.2. Appendix 2: Liver Safety Required Actions and Follow up

Assessments ..............................................................................................5912.3. Appendix 3 : Definition of and Procedures for Recording,

Evaluating, Follow-Up and Reporting of Adverse Events ............................6112.3.1. Definition of Adverse Events........................................................6112.3.2. Definition of Serious Adverse Events ...........................................62

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

7

12.3.3. Recording of AEs and SAEs ........................................................6312.3.4. Evaluating AEs and SAEs............................................................6412.3.5. Reporting of SAEs to GSK...........................................................65

12.4. Appendix 4: GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP)...............66

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

8

1. PROTOCOL SYNOPSIS FOR STUDY 201465

Rationale

This is the first study to administer GSK2981278 to patients with psoriasis. This proof-of-concept study will evaluate the safety, tolerability and initial efficacy of a range of concentrations of GSK2981278 ointment with repeated topical applications in adult subjects with psoriasis. Results of this study will provide the first clinical information on the drug’s safety and efficacy in psoriasis and inform the selection of concentration of GSK2981278 ointment to be evaluated in subsequent clinical studies.

Objective(s)/Endpoint(s)


Primary

To evaluate the safety and tolerability

of topically applied GSK2981278 in

subjects with plaque psoriasis.

To evaluate the efficacy of topical

formulation strengths of

GSK2981278 ointment in patients

with psoriasis.

Incidence and nature of adverse

events (AE).

Change from baseline in clinical

laboratory parameters, vital signs,

electrocardiogram (ECG).

The reduction in infiltrate thickness

of the psoriatic plaque(s) from

baseline using 22-MHz sonography

measurement.

Secondary

To evaluate the improvement of

psoriatic lesions following

application of GSK2981278

ointment.


Exploratory

To evaluate the pharmacodynamic

(PD) effects of topical GSK2981278

in psoriasis plaques.

messenger ribonucleic acid (mRNA)

biomarkers in skin biopsy samples.

Overall Design

This is a Phase 1, single-center, randomized, vehicle- and positive- controlled, subject- and evaluator- blind proof-of-concept trial in subjects with chronic plaque type psoriasis.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

9

All subjects will receive all treatments on stable plaque(s) on the upper extremities, thighs and/or trunk for intra-individual comparison with random assignment of the treatments to the test fields within the identified plaque(s).

A blinded evaluator (an investigator or designee) will perform the measurements and assessments whereas an unblinded study staff member (not an evaluator) will perform biopsy collection.

Treatment Arms and Duration

Screening will occur within 14 days preceding the Day 1 visit. Study visits will occur from Day 1 through Day 19 for applications of study treatments and evaluations of dermal reactions. A total of 16 applications will be made over 19 days. Day 19 will be the end of study visit for those subjects who do not consent to biopsy. A follow-up visit will occur at Day 27 (2) for those subjects consenting to biopsies. The total duration of study participation for those subjects who do not consent to biopsy will be approximately 33 days. The total duration of study participation for those subjects consenting to biopsies will be approximately 41 days.

All subjects will have a set of 6 randomized test fields on identified stable plaque(s) on the upper extremities, thighs, and/or trunk, to be treated once-daily (except Days 7 and 14) over 19 days under semi-occlusive conditions (covered by an adhesive non-woven fabric) with the following study products:







The same study products will be applied in all subjects. There will be no subdivision into separate dosing groups.

Type and Number of Subjects

This study will be conducted in male subjects and female subjects of non-reproductive potential (FNRP) with chronic stable plaque type psoriasis.

Approximately 15 subjects will be randomized such that at least 13 evaluable subjects complete the study. Skin biopsies will be collected from at least 8 consenting subjects for PD biomarker evaluation. Additional subjects may need to be randomized in order to achieve 8 consenting subjects for biopsies.

Analysis

The primary efficacy endpoint is the area under the time curve (AUC) of change in infiltrate thickness using the linear trapezoidal rule over the period starting with Day 1 up

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

10

to Day 19. Missing data will be handled by the last observation carried forward (LOCF) approach. The AUC will be analyzed using a mixed-model repeated-measures (MMRM) analysis including treatment. The treatment will be treated as repeated measures within the same subject. Pair-wise treatment comparisons will be performed. The primary comparison is between each active dose and the vehicle ointment.

In addition, for each post-baseline assessed time point, the reduction in infiltrate thickness of the psoriatic plaque(s) from baseline will be summarized using both the Observed Cases (OC) approach and the LOCF approach. Pair-wise treatment comparisons will be performed.

Clinical efficacy assessment using a 5-point scale will be evaluated for each post-baseline assessed time point. The ordinal clinical score and the cumulative total score will be presented by descriptive statistics. Additionally, frequency counts will be provided for the clinical scores.

Safety analyses include a summary of extent to exposure, summaries of AEs, laboratorydata, vital signs data, and ECG data. Safety data will be listed as well.

Gene expression of biomarkers from skin punch biopsy sample(s) will be analyzed.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

11

2. INTRODUCTION

GSK2981278 is a highly potent and selective inverse agonist of retinoic acid receptor-related orphan receptor gamma (ROR) that is under development for topical treatment of plaque type psoriasis suitable for topical therapy.

2.1. Study Rationale

This is the first study to administer GSK2981278 to patients with psoriasis. This proof-of-concept study will evaluate the safety, tolerability and initial efficacy of a range of concentrations of GSK2981278 ointment with repeated topical applications in adult subjects with psoriasis. Results of this study will provide first clinical information on the drug’s safety and efficacy in psoriasis and inform the selection of concentration of GSK2981278 ointment to be evaluated in subsequent clinical studies.

2.2. Brief Background

Psoriasis is a chronic inflammatory skin disorder affecting 0.7 to 2.9% of the population in Europe and the United States [Parisi, 2013]. Plaque type psoriasis is characterized by raised, well-demarcated, erythematous oval plaques with adherent silvery scales [Nestle,2009] and affects approximately 85 to 90% of all psoriasis patients [Griffiths, 2007]. There is substantial impairment of physical and psychological quality of life associated with the disease [De Korte, 2004].

The primary goal of treatment for psoriasis is to improve the signs and symptoms as there is no curative treatment. Approximately 80% of psoriasis patients have mild to moderate disease, which is typically managed with topical agents. In patients with more severe disease, topical agents are often used adjunctively with either phototherapy or systemic medications. Topical corticosteroids are the mainstay of topical therapy and provide relatively high efficacy. However, local safety issues such as skin atrophy, telangiectasia, and striae distensae as well as systemic safety concerns such as hypothalamic-pituitary-adrenal (HPA) axis suppression limit their long-term use and use in sensitive areas[Menter, 2009]. Other topical agents such as vitamin D analogues and topical retinoids are available to complement the corticosteroid therapy. There is a need for an effective novel topical agent without the safety concerns associated with corticosteroids.

Although the pathophysiology of psoriasis is not fully understood, current evidencesuggests that a combination of genetic, immunologic and environmental factors contributes to the disease. Growing understanding of the involvement of the immune system in the psoriasis pathophysiology indicates that T-helper 17 (Th17) cells and their signature proinflammatory cytokine Interleukin-17 (IL-17) plays a critical role [Malakouti, 2015]. IL-17A is known to drive inflammatory pathways inherent in psoriasis pathogenesis by stimulating keratinocyte expression of multiple chemokines and increasing the expression of antimicrobial peptides and contribute to epidermal hyperproliferation and skin barrier disruption. Increased numbers of IL-17 positive T cells and higher IL-17A messenger ribonucleic acid (mRNA) expression in psoriatic lesions compared with normal skin have been reported as well [Lynde, 2014]. In addition, the involvement of IL-17 cytokines was recently validated with monoclonal antibody

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

12

(mAb) treatment. Three biologic therapies that inhibit the IL-17 cytokines have been shown to control the signs and symptoms of plaque-type psoriasis. Phase 3 study results have shown that a greater proportion of patients administered these agents have a higher PASI75 and PASI100 response compared to patients administered existing biologics that have different mechanisms of action (e.g., Tumour necrosis factor (TNF)-α inhibitors and T-cell inhibitors) [Langley, 2014; Sandoval, 2015; Lebwohl, 2015; Gordon, 2015].

RORt, a truncated isoform of ROR, is a transcription factor involved in Th17 cell differentiation and Th17 cytokine expression. It is expressed in a few distinct types of immune cells and is described as the master regulator of Th17 cytokine expression [Ivanov, 2006].

ROR is widely expressed throughout the body and has identical ligand-binding domains (LBD) as RORt [He, 1998]. Compounds targeting ROR is expected to modulate the activity of RORt as well. Therefore, local delivery of selective ROR inverse agonist GSK2981278 to lesional skin of psoriasis via topical application is expected to block the transcriptional activity of RORt leading to the local suppression of cytokine expression from skin-resident T cells and ultimately to improvement in psoriasis, with no or minimalsystemic effects.

Pre-clinical data show that GSK2981278 significantly inhibits production of the Th17 signature cytokines in multiple in vitro and human tissue-based assays, including human peripheral T cells and ex vivo human skin [GlaxoSmithKline Document Number2015N240000_00; GSK2981278 Investigator’s Brochure (IB)].

3. OBJECTIVE(S) AND ENDPOINT(S)


Primary

To evaluate the safety and tolerability

of topically applied GSK2981278 in

subjects with plaque psoriasis.

To evaluate the efficacy of topical

formulation strengths of

GSK2981278 ointment in patients

with psoriasis.

Incidence and nature of adverse

events (AE).

Change from baseline in clinical

laboratory parameters, vital signs,

electrocardiogram (ECG).

The reduction in infiltrate thickness

of the psoriatic plaque(s) from

baseline using 22-MHz sonography

measurement.

Secondary

To evaluate the improvement of

psoriatic lesions following

application of GSK2981278


2016N274225_00

2014N215725_00 CONFIDENTIAL201465

13


ointment.Exploratory

To evaluate the pharmacodynamic

(PD) effects of topical GSK2981278

in psoriasis plaques.

mRNA biomarkers in skin biopsy

samples.

4. STUDY DESIGN

4.1. Overall Design

Screening

Visit Days -14 to -1

Study

VisitsDays 1-19

Follow-up

Visit*Day 27

Sign

ICF

Last dosing

application

Day

18

Day

19

Biopsies

Day

1

Dosing

begins

*Follow-up visit (Day 27) is only for subjects consenting to biopsy. All other subjects complete the study at Day 19.

This is a Phase 1, single-center, randomized, vehicle- and positive- controlled, subject-and evaluator- blind proof-of-concept trial in subjects with chronic plaque type psoriasis. All subjects will receive all treatments on stable plaque(s) on the upper extremities, thighs and/or trunk for intra-individual comparison with random assignment of the treatments to the test fields within the identified plaque(s). A blinded evaluator (an investigator or designee) will perform the measurements and assessments whereas an unblinded study staff member (not an evaluator) will perform biopsy collection.

4.2. Treatment Arms and Duration

Screening will occur within 14 days preceding the Day 1 visit. Study visits will occur from Day 1 through Day 19 for applications of study treatments and evaluations of dermal reactions. A total of 16 applications will be made over 19 days. Refer to Section 6.3.1 for discontinuation and withdraw criteria. Day 19 will be the end of study visit for

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

14

those subjects who do not consent to biopsy. A follow-up visit will occur at Day 27 (2) for those subjects consenting to biopsies. The total duration of study participation for those subjects who do not consent to biopsy will be approximately 33 days. The total duration of study participation for those subjects consenting to biopsies will be approximately 41 days.

All subjects will have a set of 6 randomized test fields on identified stable plaque(s) on the upper extremities, thighs, and/or trunk, to be treated once-daily (except Days 7 and 14) over 19 days under semi-occlusive conditions (covered by a be covered an adhesive non-woven fabric) with the following study products:







The same study products will be applied in all subjects. There will be no subdivision into separate dosing groups. Refer to Section 6.2 and Section 6.3 for information regarding assignment of treatment and manner of treatment.

4.3. Type and Number of Subjects

This study will be conducted in male subjects and female subjects of non-reproductive potential (FNRP) with chronic stable plaque type psoriasis.

Approximately 15 subjects will be randomized such that at least 13 evaluable subjects complete the study. Skin biopsies will be collected from at least 8 consenting subjects for PD biomarker evaluation. Additional subjects may need to be randomized in order to achieve 8 consenting subjects for biopsies.

If subjects prematurely discontinue the study, additional replacement subjects may be randomised at the discretion of the sponsor in consultation with the investigator. Subjectswho discontinue for safety reasons will not be replaced.

4.4. Design Justification

The objective of this trial is to explore the safety, tolerability and efficacy of GSK2981278 ointment after repeated topical applications in small test fields within plaque(s) in psoriatic subjects. The psoriasis plaque test (PPT) is a standardized model allowing for intra-individual comparison of the safety and efficacy of multiple drugs and/or formulations in subjects with stable plaque psoriasis. PPT is often used as an initial proof-of concept trial in the early development of topical drugs and can use occlusive, semi- or non-occlusive applications.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

15

In the original test design described by Dumas and Scholtz [Dumas, 1972], the efficacy of corticosteroids for treatment of plaque-type psoriasis was evaluated clinically following standardized occlusive application over several days. Meanwhile biophysical measurement methods have been used in the PPT to objectively measure the inflammatory alterations accompanying psoriasis, greatly improving the sensitivity of the test [Bangha, 1996; Fluhr, 2009]. The clinical relevance of this study design has been established based on the experience translating the efficacy results to later phase trials[Bangha, 1996].

This study includes semi-occlusive applications to allow for testing conditions reflective of a clinical application regimen. In this trial the study products will be administered once daily (except Days 7 and 14) in a semi-occluded application manner, over a period of 19days. Areas to be treated are selected at the Day 1 visit based on uniformity of the sonographic measurements within the lesion(s). The vehicle is included in one test fieldin order to provide vehicle-related safety and efficacy information. As a positive control amarketed drug (betamethasone valerate 0.1% cream) is included in an additional test field. Approximately 24 2 hours after application, the test sites will be evaluated bysonographic measurement and with clinical scoring on days 4, 8, 15, and 19. A new set of dressings will be applied to the same randomized test sites after evaluation. The final evaluations will be performed on Day 19, at approximately 24 2 hours after final drug application on Day 18. Conditions under which application of a study product may be discontinued are described in Section 6.3.1. Based on predicted low systemic drug levels in this study and the fact that multiple concentrations of GSK2981278 will be applied to each subject simultaneously, pharmacokinetic (PK) assessments would provide at bestonly qualitative information. Therefore, PK information will not be collected in this study.

A 19 day treatment duration was selected based on historical PPT design data coupled with the feasibility of daily clinic visits and the goal to reduce patient burden. The treatment duration of 19 days under semi-occlusive conditions should allow sufficient time for drug penetration and activity. Furthermore, this duration may capture separation of response to the range of GSK2981278 doses, therefore more clearly identifying a dose-response relationship. Sonographic measurements and clinical scoring will allow for evaluation of improvement in psoriatic plaques over 19 days. Changes in gene expression of biomarkers are expected to be observed within the timeframe set up for this study based on gene expression changes observed at 14 days post-treatment with asystemic IL-17a mAb [Russell, 2014].

Since the most important guide to potential clinical efficacy in psoriasis in this study design is the extent to which the inflammatory infiltrate in the psoriatic plaque resolves, high-frequency 22-MHz skin ultrasound for the evaluation of the thickness of the inflammatory infiltration will be used as the primary efficacy assessment method. The inflammatory infiltrate is seen as a clearly definable Echo Lucent Band (ELB) below the entrance echo [Fluhr, 2009]. Thus, the objective sonographic measurement of the thickness of the ELB at 22-MHz is a relevant outcome. At baseline (before beginning of treatment) the clinical condition in the test fields of individual subjects has to be comparable.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

16

A total of four 3mm punch biopsies will be collected at the end of the study from a subset of consenting subjects. One biopsy will be collected from a non-lesional area, one from a lesional untreated area, another from the vehicle-treated test field, and one biopsy from the 4% GSK2981278-treated test field. At the time of the first biopsy collection the unblinded Investigator will assess all available tolerability and safety data from the test field treated with 4% GSK2981278. If data from the 4% GSK2981278-treated test field reveals safety concerns, the Investigator may decide to collect the biopsy from a test field treated with a lower concentration of GSK2981278. The sponsor should be notified of this decision. Exploratory pharmacodynamic assessment of skin biopsies will be evaluated using gene expression analysis of relevant biomarkers reported to be modulated by GSK2981278 including, but not limited to, IL-17A, IL-17F, DEFB4A, IL-19, IL-36, CCL20, S100A7a, IL-8, and Krt6A. The analysis of these PD biomarkers will allow for investigation of target engagement of GSK2981278 in the study.

4.5. Dose Justification

In this study, the anti-psoriatic activity of GSK2891278 will be evaluated in a psoriasis plaque test (microplaque assay). In order to evaluate the dose-response, 4 different concentrations of GSK2981278, 0.03%, 0.1%, 0.8% and 4% will be applied. Each subject will receive all 4 concentrations of GSK2981278 ointment, along with a positive control,and vehicle ointment once daily (except Days 7 and 14) for 19 days.

Data from ex vivo target engagement studies and repeat dose toxicity studies in rat and minipig were used to select the doses of GSK2891278 ointment for this study. In ex vivo human skin following single topical application of GSK2981278 in the proposed clinical formulation at concentrations ranging from 0.01 to 4%, a potent dose-dependent inhibition of Th17 signature cytokines mRNA levels were observed with effect reaching plateau after 0.1% concentration (Figure 1). Based on this data, concentration ranging from 0.03% to 4% will be considered in the early phase clinical trials. Four concentrations of relatively even spread across the dose response curve in this range are selected for the PPT study due to the limit on the number of test fields.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

17

Figure 1 Percent maximum expression of il-17a transcripts in ex-vivo human skin

GSK2981278 has been evaluated in repeat dose toxicity studies following dermal administration for up to 7 days in rats and rabbits and 28 days in minipigs; following oral administration for up to 28 days in rats, 7 days in rabbits, and 28 days in minpigs; and following subcutaneous administration for up to 7 days in rabbits.

The no adverse effect levels (NOAELs) established for systemic effects in the oral 28 day rat and dermal 28 day minipig toxicity studies were 200 mg/kg/day and 400/300 mg/kg/day male/female), respectively. The end of study area under the curve (AUC) and maximum concentration (Cmax) values at 200 mg/kg/day in rats were 437 ng.h/mL(males) and 4700 ng.h/mL (females) and 106 ng/mL (males) and 3030 ng/mL (females), respectively. In minipigs, the end of study AUC and Cmax values at 400/300 mg/kg/day were 1054 ng.h/mL and 350 ng/mL (gender average mean), respectively.

The exposures at the proposed doses were predicted using the mean predicted volume of distribution of 175.9 L and mean expected clearance of 52.5 L/hr. A conservative prediction of systemic exposure to GSK2981278 following topical application of 0.03 to 4% concentrations to 1.13 cm2 area each as proposed in this study suggests that the safety margin against the NOAEL identified are >1000 fold for both AUCss and Cmaxss and supports evaluation of GSK2981278 ointment.

Table 1 represents the predicted exposure and safety covers for clinical evaluation of GSK2891278 [FDA, 2005; CHMP, 2007]. Findings from in vivo pharmacology and toxicology studies with GSK2891278 have provided reasonable assurance that there are no undue or unforeseen risks for the first administration of GSK2891278 to humans at the dose levels proposed in this study.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

18

Table 1 Dose range and exposure predictions of GSK2891278 at steady state following 15cm2 area of application

Dose (Formulation

strength)

Flux (dermis)

(ng/hr/cm2)

Mean (90%CI)

Cmax AUC

Predicted Css

(pg/mL)

Mean (90%CI)

Safety Cover

Cmax (males) =

106 ng/mL

Predicted AUCss

(pg*hr/mL) Mean

(90%CI)

Safety Cover

AUC(males)= 437

ng*hr/mL

0.03% 4.82 (1.3-11.2)

1.38 (0.38-3.21)

76986 33.04 (9.05-77.06)

13224

0.1% 11.41 (4.7-24.4)

3.26 (1.34-6.96)

32528 78.21 (32.13-167.12)

5588

0.8% 34.81 (23.0-54.3)

9.95 (6.58-15.51)

10658 238.70 (157.83-372.25)

1831

4% 49.25 (40.1-59.5)

14.07 (11.45-17.01)

7533 337.70 (274.73-408.30)

1294

In this study the planned total surface area (four active concentrations at four test field) will be ~5cm2. Average concentration based on four active strength used (0.03, 0.1, 0.8 and 4%) is ~1.2%. Application of ~1.2% concentration over ~5cm2 area provides a safety cover of >4500 fold for AUC and >20000 fold for Cmax at steady state.

4.6. Benefit:Risk Assessment

Summaries of findings from both clinical and non-clinical studies conducted with GSK2981278 can be found in the Investigator’s Brochure (IB). The following section outlines the risk assessment and mitigation strategy for this protocol:

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

19

4.6.1. Risk Assessment

Potential Risk of Clinical Significance Summary of Data/Rationale for Risk Mitigation Strategy

Investigational Product (IP) [GSK2981278]

Skin irritation or allergic reaction to GSK2981278 or to components of its vehicle.

GSK2981278 was not a contact sensitizer in the mouse local lymph node assay, and it was not an eye irritant in the bovine corneal opacity and permeability assay.

GSK2981278 is a sulphonamide, chemically distinct from the antibiotic sulphonamides that are one of the most common causes of drug reactions. GSK2981278 does not contain the arylamine group that is known to be associated with allergies and hypersensitivity as the antibiotic sulphonamides do. Evidence suggests no cross-reactivity between arylamine sulphonamides and non-arylamine sulphonamides [Brackett, 2007; Strom, 2003].

The skin will be evaluated for signs of skinreaction and allergic reaction.

Subjects will be informed of the sulphonamide nature of the compound via informed consent and be monitored daily, except on Days 7 and 14, for signs of allergic reactions during the treatment period. Subjects will not be excluded from the trial solely based on a history of sulphonamide allergy.

Subjects with a known or suspected intolerance to the components of GSK2981278 vehicle will be excluded.

If needed, study treatment may be held and an appropriate topical or systemic treatment may be provided.

Systemic reactions including but not limited to end organ toxicity.

The principal test article-related findings observed in repeat dose dermal and oral toxicity studies with GSK2981278 occurred in skin and thymus, with findings in the

Relevant first time in human (FTIH)laboratory tests as well as periodic ECGs and baseline and end of study vital signswill be reviewed.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

20


heart that were considered to be of uncertain relationship to treatment.

GSK2981278 did not produce test-article related acute cardiovascular effects in minipigs or respiratory or neurobehavioural effects in rats in safety pharmacology studies at doses up to 30 and 200 mg/kg, respectively. GSK2981278 inhibited hERG tail current recorded from HEK 293 cells stably transfected with hERG cDNA, with an IC25 of 2.2 µM (1.02 g/mL).

The risk for any end-organ toxicity is considered low due to the limited predicted systemic exposure and large safety margins for this study.

Serious Adverse Events (SAEs)/AEs will be collected and reviewed.

If needed, study treatment may be held and an appropriate treatment may be provided.

Reproductive and developmental toxicity Embryofetal development and female fertility studies have not been conducted with GSK2981278. Data from the literature suggest that the intended drug-target interaction, reduction in Th17 cells, could potentially impact implantation and maintenance of normal pregnancy. However, GSK2981278 at doses up to 200 mg/kg/day for 28 days did not have an effect onactivation of Th17 and regulatory T cells in female rats and multiples of human exposure

Only females of non-reproductive potential will be enrolled in the FTIH study.

In addition, male subjects will be required to use condoms unless they have had a prior vasectomy.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

21


are large.

Study Procedures

Worsening of psoriasis symptoms Subjects discontinuing their current psoriasis treatment may experience a worsening of their psoriasis during the washout period before beginning treatment in this study. A worsening of psoriasis may also occur during the active treatment period.

The informed consent for this study will state the risk of worsening of the symptoms of psoriasis.

Subjects who either choose to withdraw or are withdrawn from the study treatment because they meet withdrawal/stopping criteria may be able to use alternate treatments for their psoriasis.

Punch biopsy Local bleeding and bruising, pain, infection, or allergic reaction (e.g. to an anaesthetic agent) may occur. Scarring may occur at the biopsy site.

Staff performing the procedures will be adequately trained and subjects will be informed about potential risks. Local anesthesia will be used prior to obtaining biopsies. Proper wound care (e.g. application of pressure, antibiotic ointment, dressing) will be provided as needed and subjects will be checked for wound healing at the follow-up visit. Pain medication (i.e., acetaminophen or paracetamol) will be allowed.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

22

4.6.2. Benefit Assessment

Subjects may benefit from the overall health assessment conducted while participating in this study. Subjects participating in the study will contribute to the process of developing a novel anti-inflammatory agent for the topical treatment of plaque psoriasis.

4.6.3. Overall Benefit:Risk Conclusion

Taking into account the risk minimization measures for subjects participating in this study, the potential risks identified in association with exposure to GSK2981278 are justified by the anticipated benefits that may eventually be afforded to subjects withchronic plaque psoriasis.

5. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the IB.

The subjects will be selected according to defined inclusion and exclusion criteria.Deviations from inclusion and exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

The selection of subjects is in accordance with the requirements of §§ 40 and 41 of the German drug law (AMG) as well as the recommendations of the currently valid revision of the Helsinki Declaration and the ICH-GCP guideline.

5.1. Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

AGE

1. 18 years of age and above, at the time of signing the informed consent.


2. Subjects with stable plaque psoriasis for 6 months, as confirmed by the subject.

3. Up to three plaque area(s) sufficient for six test fields. The target lesion(s) should be on the trunk, upper extremities or thighs (excluding hands and skin folds); psoriatic lesion(s) on the knees or elbows are not to be used as a target lesion. It is recommended, but not required, that all selected plaques are symmetrical in location, size and clinical characteristics.

4. Plaques to be treated should have a comparable thickness of the ELB (as a surrogate for the psoriatic infiltrate thickness) of at least 200µm on Day 1.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

23

[4] SEX

5. Male

Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until after the last dose of study medication.

a. Vasectomy with documentation of azoospermia.

b. Male condom

These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

6. Female of non-reproductive potential (FNRP)

A FNRP is eligible to participate in this study if she meets at least one of the following conditions:

a. Females with one of the following procedures documented and no plans to utilize assisted reproductive techniques (e.g., in vitro fertilization or donor embryo transfer):

o Bilateral tubal ligation or salpingectomy

o Hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion

o Hysterectomy

o Bilateral Oophorectomy (surgical menopause)

b. Post-menopausal women (including all women over 60 years of age, see below),

Post-Menopause criteria Females 60 years of age or older A practical definition accepts menopause after 1 year without menses with an

appropriate clinical profile, e.g., age appropriate, >45 years, in the absence of hormone replacement therapy (HRT) or medical suppression of the menstrual cycle (e.g., leuprolide treatment). o In questionable cases for women < 60 years of age, a blood sample with

simultaneous follicle stimulating hormone and estradiol falling into the central laboratory’s post-menopausal reference range is confirmatory (these levels need to be adjusted for specific laboratories/assays) [Kronenberg, 2008; Strauss, 2004].

Females under 60 years of age, who are on HRT and wish to continue, and whose menopausal status is in doubt, are required to use a highly effective method to avoid pregnancy, as outlined in the protocol (Appendix 4). Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2 to 4 weeks will elapse between the

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

24

cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a highly effective method to avoid pregnancy.

INFORMED CONSENT

7. Capable of giving signed informed consent as described in Section 10.2 whichincludes compliance with the requirements and restrictions listed in the consent form and in this protocol.

5.2. Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc INTERVAL)

1. Alanine aminotransferase (ALT) >2xULN and bilirubin >1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

3. QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block. The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB),and/or machine-read. The QTc should be based on single QTc values of ECGobtained over a brief recording period.

4. Any condition that, in the judgement of the investigator, would put the subject at unacceptable risk for the participation in the trial.

5. Current evidence of another ongoing or any acute cutaneous infection, history of repeated or chronic significant skin infections (unless irrelevant in the opinion of the investigator, i.e. onychomycosis, labial herpes or other minor diagnosis).

6. Clinically-relevant skin disease, other skin pathologies, or a history of skin cancer, that may, in the opinion of the investigator, contraindicate participation or interfere with test field evaluations.

7. History of malignancy within 5 years prior to dosing, except adequately treated non-invasive cancer of the skin (basal or squamous cell).

8. Psoriasis other than plaque variants.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

25


9. Use of prohibited concomitant medications or products within the defined washout periods before the Day 1 visit and during the trial (see Section 6.11.2).

CONTRAINDICATIONS

10. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

11. Contraindications according to summary of product characteristics of the active positive control.

12. Symptoms of a clinically significant illness that may, in the opinion of the investigator, influence the outcome of the trial in the 4 weeks before baseline visit and during the trial.


13. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.

14. A positive pre-study drug/alcohol screen.

15. A positive test for human immunodeficiency virus (HIV) antibody.

16. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

17. Prolonged exposure to natural or artificial sources of ultraviolet (UV) radiation within 2 weeks prior to the Day 1 visit or intention to have such exposure during the study, thought by the investigator likely to modify the subject’s psoriasis.

18. In the opinion of the investigator or physician performing the initial examination the subject should not participate in the clinical trial, e.g. due to probable noncompliance or inability to understand the trial and give adequately informed consent.

19. Close affiliation with the investigator (e.g. a close relative) or persons working at Bioskin GmbH or subject is an employee of sponsor.

20. Subject is institutionalized because of legal or regulatory order.

5.3. Screening/Baseline/Run-in Failures

Screen failures are defined as subjects who consent to participate in the clinical trial but are never subsequently randomized. In order to ensure transparent reporting of screen failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and respond to queries from Regulatory authorities, a minimal

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

26

set of screen failure information is required including Demography, Screen Failure details, Eligibility Criteria, and any SAEs.

Subjects who initially do not meet eligibility criteria (eg, due to use of prohibitedconcomitant medications requiring a longer washout than the specified screening period)may be re-screened once if their potential eligibility status has changed. Eligible subjects may then be enrolled in the study.

5.4. Withdrawal/Stopping Criteria

A subject may withdraw from the study at any time at his/her own request, or may be withdrawn at any time at the discretion of the investigator for safety, behavioral or administrative reasons. If a subject withdraws from the study, he/she may request destruction of any samples taken, and the investigator must document this in the site study records. The reason for a subject’s premature discontinuation from the study must be fully documented in the source documents and the electronic case report form (eCRF).

Subjects who withdraw early from the study should complete the Day 19 visit assessments (refer to Section 7.1) except for biopsy collection.

Criteria for study treatment withdrawal or discontinuation of an individual subject from the clinical study may include:

Sponsor terminates the study.

Subject lost to follow-up.

Subject withdraws consent.

Protocol deviation.

Investigator discretion.

Subject experiences a(n) SAE/AE that is considered to be related to study drug or

study procedures and is severe enough in nature to warrant treatment discontinuation.

Refer to Section 6.3.1 for additional criteria for discontinuing study treatments.

The following actions must be taken in relation to a subject who fails to attend the clinic for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon

as possible.

The site must counsel the subject on the importance of maintaining the assigned visit

schedule and ascertain whether or not the subject wishes to and/or should continue in

the study.

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

27

must make every effort to regain contact with the subject (where possible, 3

telephone calls and if necessary a certified letter to the subject’s last known mailing

address or local equivalent methods). These contact attempts should be documented

in the subject’s medical record.

Should the subject continue to be unreachable, only then will he/she be considered to

have withdrawn from the study with a primary reason of “Lost to Follow-up”.

5.4.1. Liver Chemistry Stopping Criteria

Study treatment will be discontinued for a subject if liver chemistry stopping criteria are met; *NB – this protocol will not use the increased monitoring criteria listed below. Therefore, if the subject meets liver stopping criteria outlined below, study treatment will be discontinued:

Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm

Continue Study Treatment

Discontinue Study Treatment

PlusBilirubin≥2xULN (>35%

direct) or plus

INR>1.5, if measured*PossibleHy’s Law

ALT≥3xULN ALT≥5xULN

ALT≥3xULNPlus

Symptoms of liver injury

or hypersensitivity

ALT≥3xULNbut able to monitor

weekly for 4 weeks

No

Yes

YesYes Yes

No No No

No

Yes

ALT≥3xULNpersist for4 weeks or stopping criteria

met

Yes

No

*INR value not applicable to subjects on anticoagulants

Yes

If subject to be monitored weekly must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix

Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix

Report as an SAE if possible Hy’s Law case: ALT≥3xULN and Bilirubin≥2xULN (>35% direct) or

INR>1.5, if measured*

Liver Safety Required Actions and Follow up Assessments can be found in Appendix 2

5.4.1.1. Study Treatment Restart or Rechallenge

Study treatment restart or rechallenge after liver chemistry stopping criteria are met by any subject participating in this study is not allowed.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

28

5.4.2. QTc Stopping Criteria

The same QT correction formula must be used for all subjects to determine eligibility for and discontinuation from the study. This formula may not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB

must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the

same formula must continue to be used for that subject for all QTc data being

collected for data analysis. Safety ECGs and other non-protocol specified

ECGs are an exception.

The QTc should be based on single QTc values of an electrocardiogram obtained over a brief (e.g., 5-10 minute) recording period.

A subject who meets either of the bulleted criteria below will be withdrawn from the study:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec

For patients with underlying bundle branch block, follow the discontinuation criteria listed below:

Baseline QTc with Bundle Branch Block Discontinuation QTc with Bundle Branch Block

< 450 msec > 500 msec

450 – 480 msec ≥ 530 msec

5.5. Subject and Study Completion

For subjects consenting to biopsies, a completed subject is one who has completed all phases of the study including the Day 27 ( 2) follow-up visit. For subjects not consenting or withdrawing consent to biopsies, a completed subject is one who has completed all study visits, including the Day 19 visit.

The end of the study is defined as the last subject’s last visit.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

29

6. STUDY TREATMENT

6.1. Investigational Product and Other Study Treatment

The term ‘study treatment’ is used throughout the protocol to describe any combination of products received by the subject as per the protocol design. Study treatment may therefore refer to the individual study treatments or the combination of those study treatments.

Study TreatmentProduct name: GSK2981278 Vehicle Betamethasone valerate

0.1% (positive control)Formulation description:

GSK2981278 Ointment is supplied as a white to off-white ointment containing GSK2981278A drug substance at 0.03% w/w, 0.1% w/w, 0.8% w/w, and 4% w/w for topical administration.

GSK2981278 Vehicle is supplied as a white to off-white ointment for topical administration.

Betnesol™-V containing 0.1% betamethasone valerate is supplied as a cream for topical administration.

Dosage form: Ointment Ointment CreamUnit dose strength(s)/Dosage level(s):

0.03%0.1%0.8%4%

0% 0.1%

Route of Administration Topical Topical TopicalDosing instructions: Apply

approximately 200 µL to the assigned test field once daily.

Apply approximately 200 µL to the assigned test field once daily.

Apply approximately 200 µL to the assigned test field once daily.

Physical description: The product is packaged into white aluminium tubes.

The product is packaged into white aluminium tubes.

The product is packaged into tubes.

6.2. Assignment of Treatments to Test Sites and Randomization

Upon signature of informed consent each subject receives a screening number. Subjectsmeeting the eligibility criteria will receive their randomization number on Day 1. Once a randomization number has been assigned to a subject, it should not be reassigned to any other subject.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

30

All subjects will receive the same treatments. There will be no subdivision into treatment groups. The 4 concentrations of GSK2981278 ointment (0.03%, 0.1%, 0.8%, and 4%)will be assigned the codes A, B, C, and D. The vehicle and positive control will be assigned the codes E and F, respectively.

The test fields will be numbered with 1,2,3,4, 5, and 6 beginning with the uppermost or most proximal site on the left from the investigator's view. Fields along the same line will be numbered left to right.

For each subject a permutation of the treatment codes A to F will be randomly assigned. The treatment code listed first in the respective permutation will be assigned to test field1, the second to test field 2, etc.

A randomization list will be generated by the CRO and kept in the trial master file in a sealed envelope.

6.3. Manner of Treatment

Individual treatment code templates reflecting the borders of the plaques and the location of the test fields will be prepared for each randomization number for use at the clinical site. The study nurse can use the template as a guide for study product application.

Approximately 200 L of each of the six study treatments will be topically applied to test fields (approximately 1.1 cm2) under semi-occlusive conditions. Six test fields will be treated in all subjects. The distance between the test fields must be at least 1.5 cm. This distance is sufficient to exclude interactions between neighboring test fields. Altogether, 16 topical applications will be performed once daily (except Days 7 and 14) over a 19day study period.

The study treatments will be applied in holes punched in a self-adhesive hydrocolloid dressing (Varihesive E (Convatec), Munich, Germany). The hydrocolloid dressing will be fixed on the skin with adhesive patches (Fixomull (BSN medical), Hamburg, Germany, or comparable) containing the same holes for the study treatments like the hydrocolloid dressing. The test fields will be covered semi-occlusively with an adhesive non-woven fabric (Fixomull (BSN medical), Hamburg, Germany).

All study products will be prepared, applied, and removed at the study center by a trainedstudy nurse not involved in measurements and assessments. Details of the exact time of the applications and assessments (date, hour, minute) will be documented in the source documents and eCRF. Before each new application, remaining preparation residues will be removed with a soft tissue. The hydrocolloid dressing stays in place until the next sonography measurement, but will be replaced more frequently if necessary. On Days 4, 8, 15 and 19, approximately 24 ±2 hours after the last application, the blinded evaluator assesses the test fields for sonographic measurement and clinical scoring within 60minutes of removal of hydrocolloid dressings. New semi-occlusive patches will be applied to the same test fields immediately after completion of the ultrasound and clinical scoring assessments (within 1 hour after removal).

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

31

In the event of scheduling conflicts, subjects may miss a maximum of 2 planned application visits; however, the missed visits may not be on consecutive days with no more than 48 hours between applications and all dressings should remain in place until the next visit (approximately 48 hours after the last application of study products). The subject is advised to return to the clinical center as soon as possible. Trial procedures performed will be such that any procedures that were to be performed on the missed day are performed at this visit. Unless criteria for discontinuing test field applications are met, no other modifications of the dosing regimen are allowed.

6.3.1. Criteria for discontinuing treatments

Conditions under which application of an individual study treatment may be discontinued in a subject:

Individual treatments will be discontinued in the event of the following dermal reactions limited to the respective test fields:

severe blistering

skin necrosis

contact dermatitis

allergic reaction

marked skin discoloration

severe or unexpected itching, burning, or pain

If this occurs, a photograph showing all of the test fields in the affected plaque(s) will be taken for sponsor review. An additional photograph will be taken of the affected test field(s) alone. Photographs will not be used for grading or analysis purposes.

General discontinuation of a specific treatment for the trial:

In case of severe reactions due to a specific treatment, the principal investigator, in consultation with the sponsor, may prematurely discontinue this treatment for the whole trial population. To keep the investigator observer-blind he/she will inform the studynurse responsible for the treatment application about the test field(s) he/she deems necessary to be discontinued. The study nurse will determine which treatment is assigned to this test field, the sponsor will be informed and the respective treatment will be discontinued in all subjects.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

32

6.4. Blinding

This is a subject- and evaluator-blinded study; therefore, the designated evaluator performing the measurements and assessments will be unaware of the particular treatment assignment for the subjects. Investigator(s) responsible for biopsy collection will be unblinded. Study-center staff responsible for preparation and application of the study products will not be blinded to the test field allocations and will be instructed not to reveal the identity of the allocations to the blinded evaluator.

The randomization list with the treatment codes will be sealed in an envelope and kept in the trial master file in a secure manner at the study center.

The randomization code will only be broken after the clinical database is locked or in the case of an emergency or in the event of a serious medical condition, when knowledge of the study treatment allocation is essential for the appropriate clinical management or welfare of the subject, as judged by the investigator. Since each subject will be exposed to all study products concurrently and there will be no subdivision into separate dosing groups, it is unlikely that unblinding the randomized test field allocations will provide any additional knowledge that would be essential. However, if the investigator determines that the occurrence of a test field-specific or other serious medical condition requires the information contained on the randomization list, the study-center staff responsible for preparation and application of the test chambers (who are unblinded to the randomization list) will determine which treatment is assigned to the test fields(s) of concern and inform the investigator. Should the investigator also be the designated evaluator, they are to remain blinded to the other test site allocations for the subject.

It is preferred (but not required) that the investigator first contacts the Medical Monitor or appropriate sponsor study personnel to discuss options before unblinding the subject’s treatment assignment. If the Medical Monitor or appropriate sponsor study personnel are not contacted before the unblinding, the investigator must notify the sponsor as soon as possible after unblinding. The date and reason for the unblinding must be fully documented in the appropriate eCRF. For any AE or SAE associated with breaking the blind, the investigator’s assessment of relationship to investigational product should be performed prior to breaking the blind.

Subjects will be withdrawn from the study if the blinded evaluator becomes aware of the test field allocations (i.e., is unblinded). The primary reason for discontinuation (the event or condition that led to the unblinding) will be recorded in the eCRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for any subject with an SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, identifying the subject’s treatment assignment, may be sent to investigators in accordance with local regulations and/or GSK policy.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

33

6.5. Packaging and Labeling

The contents of the label will be in accordance with all applicable regulatoryrequirements.

6.6. Preparation/Handling/Storage/Accountability

Study product will be supplied in bulk tubes. The site staff will load study product from bulk supply into syringes for administration to subjects. The individual syringes containing study treatment will be weighed before and after each application to each subject. The weight of study treatment applied to each individual subject will be documented in the accountability records. Refer to the study reference manual (SRM) for additional information.

Only subjects enrolled in the study may receive study treatment and only authorized site staff may supply or administer study treatment. All study treatments must be stored in a secure environmentally controlled and monitored (manual or automated) area in accordance with the labelled storage conditions with access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) is responsible for study treatment accountability, reconciliation, and record maintenance (i.e. receipt, reconciliation and final disposition records).

Further guidance and information for final disposition of unused study treatment are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational hazards and recommended handling precautions either will be provided to the investigator, where this is required by local laws, or is available upon request from GSK.

In accordance with local regulatory requirements, the investigator, designated site staff,or head of the medical institution (where applicable) must document the amount ofinvestigational product administered to study subjects, and the amount received from andreturned to Stiefel/GSK, when applicable. Product accountability records must bemaintained throughout the course of the study.

6.7. Compliance with Study Treatment Administration

When the individual dose for a subject is prepared from a bulk supply, the preparation of the dose will be confirmed by a second member of the study site staff. Syringes of study treatment will be weighed before and after administration to each test field for each subject by study personnel to document the amount used.

Subjects will be dosed at the site and will receive study treatment directly from the investigator or designee, under medical supervision. The date and time of each dose

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

34

administered in the clinic will be recorded in the source documents. The dose of study treatment and study subject identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study treatment.

6.8. Treatment of Study Treatment Overdose

Study product will be prepared and applied at the study center by a trained study nurse; therefore, overdose is unlikely.

There is no known specific treatment for overdose of GSK2981278. Symptomatic, supportive treatment should be administered.

6.9. Treatment after the End of the Study

Subjects will not receive any additional treatment from GSK after completion of the study because the indication being studied is not life threatening and other treatment options are available.

The investigator is responsible for ensuring that consideration has been given to the post-study care of the subject’s medical condition, whether or not GSK is providing specific post-study treatment.

6.10. Lifestyle and/or Dietary Restrictions

Test fields must be kept dry. Subjects should not go swimming, sit in a hot tub or sauna, or take deep baths, but may take showers if the test field does not get wet.

Dressings and plasters must not be removed by the subject. If a dressing and/or plaster falls off before the next visit, the subject should not put it back on. Subjects should return the dressing and/or plaster to the study center at the next visit and report the time (or approximate time if unsure) that the dressing/plaster fell off. Study staff will document this information in the source documents and eCRF.

Test fields must not be exposed to sunlight or other sources of ultraviolet light throughout the study.

Subjects should use the same personal care products and laundry detergent throughout the study.

6.10.1. Alcohol

Subjects should limit alcohol consumption during the study and should not exceed the following guidelines:

an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

35

6.10.2. Activity

Subjects should avoid vigorous exercise that results in excessive sweating.

Swimming is prohibited.

6.11. Concomitant Medications and Non-Drug Therapies

All medications and nondrug therapies (including treatments listed in the exclusion criteria) received by the subject within 4 weeks (28 days) before the Screening visit andat any time throughout the study must be recorded in the source documents and eCRF with start and end dates, if end dates are available.

6.11.1. Permitted Medications and Non-Drug Therapies

Medications permitted during the study include contraceptives (for indications other than pregnancy prevention), antihistamines, selective leukotriene receptor antagonists (eg, montelukast sodium, zafirlukast), mast cell stabilizers (eg, cromolyn sodium or nedocromil sodium), acetaminophen/paracetamol, vitamin and mineral supplements, medications for regulation of thyroid function, influenza vaccine, and medications for AEs, unless specifically prohibited.

Subjects may also use medications for chronic stable concomitant medical conditions (eg, hypertension) that are not expected to affect the study assessments, provided the subject is on a stable dose that is not expected to change during the study.

Other concomitant medication may be considered on a case by case basis by the investigator in consultation with the Medical Monitor if required.

Medicinal shampoos and other topical treatments for psoriasis lesions on the scalp and/or psoriatic plaques that are not part of assessment in this trial are permitted during the study.

Sunscreen may be used on nonlesional skin.

6.11.2. Prohibited Medications and Non-Drug Therapies

Use of medications or treatments that would significantly influence or exaggerate responses to the test products or that would alter inflammatory or immune response to the products is prohibited. Prohibited concomitant medications, products, and procedures (Table 2) are not to have been used from the defined washout periods before the first patch applications at the Day 1 visit and throughout the study.

In the event a subject takes a prohibited medication, the investigator should consult with the Medical Monitor to determine if the subject should be withdrawn from the study.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

36



Biologic agents: eg, alefacept 24 weeks; etanercept 12 weeks; ustekinumab 15 weeks

5 half-lives

Oral retinoids (eg, acitretin or isotretinoin) 12 weeks

Cyclosporin, interferon, methotrexate, or other systemic immunosuppressive or immunomodulating agents (eg, mycophenolate or tacrolimus); psoralen plus UVA

8 weeks



Immunizations (influenza vaccine will be allowed) 2 weeks

Topical treatments: corticosteroids, immunomodulators, anthralin (dithranol), Vitamin D derivatives, retinoids, coal tar (used on the psoriatic lesions under evaluation in this study.

2 weeks

Drugs known to possibly worsen psoriasis (unless on a stable dose for >12 weeks), such as: β-blockers (eg, propranolol), lithium, iodides, angiotensin-converting enzyme inhibitors, and indomethacin

2 weeks


1 day

UV-therapy 2 weeks

7. STUDY ASSESSMENTS AND PROCEDURES

Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential and required for study conduct.

Subjects will have study visits once daily (except Days 7 and 14), at approximately the same time each day, for 19 consecutive days. Visit schedules should be timed such that test field evaluations are conducted approximately 24 2 hours after the study productswere applied. This section lists the procedures and parameters of each planned study assessment. The exact timing of each assessment is listed in the Time and Events Table Section 7.1

The following points must be noted:

If assessments are scheduled for the same nominal time, THEN the assessments should occur in the following order:

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

37

1. 12-lead ECG

2. vital signs

3. blood draws

Note: Blood will be collected as close as possible to planned sampling times. Actual times for each of the blood draws taken will be recorded.

The timing and number of planned study assessments, including safetyassessments may be altered during the course of the study based on newly available data to ensure appropriate monitoring.

The change in timing or addition of time points for any planned study assessments must be documented in a Note to File which is approved by the relevant GSK study team member and then archived in the study sponsor and site study files, but this will not constitute a protocol amendment.

The institutional review board (IRB)/ independent ethics committee (IEC) will be informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the Informed Consent Form.

No more than 250 mL of blood will be collected over the duration of the study, including any extra assessments that may be required.

2016N274225_00

2014N215725_00 CONFIDENTIA201465

38

7.1. Time and Events Table

ProcedureScreening

[Day]

Treatment Period [Days]

Follow-up

[Day]

Notes

Subjects who withdraw early from the study should complete the Day 19 visit assessmentsexcept for biopsy collection.

-14 to

-1 1

2 t

o 6

7 8

9 t

o

13

14

15

16

to

1

8

19

27

(2

)

Informed consent XInclusion and exclusion criteria X X Will be assessed prior to randomization.

Demographics/medical history XFitzpatrick skin type (Section 7.2, Table 3) will be documented. Site to document any known drug allergies.

Brief physical exam (including height and weight)

X

Physical examination of the skinX X

Any adverse changes to the skin will be recorded as an AE.

Descaling with salicylic acid XDescaling of test sites with detergent solution (if necessary)

X X X XWill be completed prior to dosing.

HIV, Hep B, and Hep C screen X

ECG X X X

On Day 15 ECG will be completed prior to dosing.

To be performed before drug removal and within a time window of 2 hours prior to dosing

Vital sign X X

Vital signs include heart rate, blood pressure, and oral temperature. Ideally, heart rate and blood pressure will be obtained after the subject has been resting in a seated position for at least 5 minutes.



2016N274225_00

2014N215725_00 CONFIDENTIA201465

39

ProcedureScreening

[Day]


Follow-up

[Day]

Notes


-14 to

-1 1

2 t

o 6

7 8

9 t

o

13

14

15

16

to

1

8

19

27

(2

)

Laboratory assessments (include liver chemistries) and urinalysis

X* X X X

*Including drug and alcohol screening (Screening visit only). Refer to Section 7.3.5 for laboratory and urinalysis assessment information. Assessment to occur before drug removal and within 2 hours prior to dosing on Days 8 and 15.

Study Treatment X X X X X X

Syringes should be weighed before and after application of each study treatment for each subject. Study treatment will be re-applied after evaluation and within 1 hour after removal.

Study treatment applied on days 6 and 13 remains on the skin until subject returns to the clinic on days 8 and 15 respectively.

AE/SAE review X X X X ======X=======During the Screening visit, only SAEs related to study participation will be collected. AEs will be collected after start of study treatment.

Prior and concomitant medication review

X X X X X ======X=======


Overview pictures will be taken of all test fields(number of pictures depending on number of plaques(s) used and location on the body); there won’t be any documentation of single test fields. Additional photographic documentation of single test fields may be taken if treatment-related AEs occur.

On Day 1, photographs will be taken prior to dosing.

2016N274225_00

2014N215725_00 CONFIDENTIA201465

40

ProcedureScreening

[Day]


Follow-up

[Day]

Notes


-14 to

-1 1

2 t

o 6

7 8

9 t

o

13

14

15

16

to

1

8

19

27

(2

)

Clinical assessments X* X X X

At Day 1 the score will be documented as “0.”

*Day 4 only.

Assessment to occur within 60 minutes of study product removal.

HFUS (sonography) X X* X X X

Day 1 is baseline HFUS and completed prior to dosing.

*Day 4 only.

Ultrasound to occur within 60 minutes of study product removal.

Skin biopsies XFour 3mm punch biopsies will be collected from each consenting subject.

Wound assessment XThis assessment applies only to subjects consenting to biopsy collection.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

41

7.2. Screening and Critical Baseline Assessments

Screening procedures should not commence until after all relevant study approvals have been obtained and until after the informed consent has been signed. The investigator must maintain a subject screening log to document identification of subjects who signed the informed consent document.

Subject screening should be conducted within 14 days prior to the Day 1 visit. Baseline tests and procedures must be performed before randomization and the first application of study products.

The following demographic parameters will be captured: year of birth, sex, race and ethnicity.

The subject’s Fitzpatrick skin type (Table 3) will be documented.

Table 3 Fitzpatrick Skin Type Classification

Type Constitutive Skin Color (Unexposed) and Typical Characteristics

Response to Ultraviolet Light Exposure

I White; very fair; red or blond hair; blue eyes; freckles

Always burns, never tans

II White; fair; red, blond, or brown hair; hazel or green eyes

Usually burns, tans with difficulty

III White; any eye or hair color; very common Sometimes mild burn, gradually tans

IV White or light brown; typical Mediterranean Caucasian skin

Rarely burns, tans with ease

V Brown; mid-eastern skin types Very rarely burns, tans very easily

VI Black Never burns, tans very easily

Source: Based on the characteristics originally described in Fitzpatrick, 1988.

Medical/medication history will be assessed as related to the inclusion/exclusion criteria listed in Section 5. Known drug allergies will be captured in the eCRF.

Refer to Section 7.3 for baseline safety assessments (physical exam, vital sign measurement, ECG and laboratory parameters).

Photographic documentation will be collected at the Day 1 and Day 19 visits before any procedures will be performed using a digital camera. This will include overview pictures of all test fields (the number of pictures depends on the number of plaques(s) used and location on the body). If a treatment-related AE occurs, additional photographic documentation of single test fields and of all test fields within the affected plaque(s) willbe taken. Photographs will not be used for grading or analysis purposes. Refer to the SRM for additional information on the photographic procedure.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

42

At the screening visit it will be determined whether pretreatment with 5 % salicylic acid in Vaseline is necessary. This is required since it is not possible to perform sonography on psoriasis plaques with extensive scaling. The maximum length of this pretreatment is five days. The last pre-treatment application with salicylic acid has to be performed twodays before the first application of study treatment on Day 1. Washing of the test fields with a mild detergent solution may occur at Day 1 and at later timepoints in the study as outlined in Section 7.1.

HFUS (sonographic) measurements will be performed using a 22 MHz high frequency sonograph. Serial A-scans will be composed and presented on a monitor as a section of the skin. A lateral resolution of approximately 200 μm and an axial resolution of 80 μm are possible. Dependent on the echo patterns, components of the epidermis, dermis and subcutis are presented. Therefore exact measurement of skin thickness is possible. The inflammatory psoriatic infiltrate is seen as a clearly definable ELB below the entrance echo. The thickness of the echo lucent psoriatic band will be determined and documented. The thickness will be measured in μm. At the Day 1 visit, plaques to be treated should have a comparable thickness of the ELB (as a surrogate for the infiltrate thickness) of at least 200 m.

7.3. Safety

Planned time points for all safety assessments are listed in the Time and Events Table (Section 7.1). Additional time points for safety tests (such as vital signs, physical exams and laboratory safety tests) may be added during the course of the study based on newly available data to ensure appropriate safety monitoring.

Significant findings of physical examination of skin, vital signs, significant findings of ECG and safety laboratory parameters, and local and systemic adverse events will be recorded. Spontaneously noted complaints will be recorded with duration, intensity and probability of a correlation with the study treatments (see Section 7.3.1).

Hematology, clinical chemistry, urinalysis and additional safety laboratory parameters to be tested are listed in Section 7.3.5.

7.3.1. Adverse Events (AE) and Serious Adverse Events (SAEs)

The definitions of an AE or SAE can be found in Appendix 3.

The investigator and their designees are responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

7.3.1.1. Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact (see Section 7.3.1.3), at the timepoints specified in the Time and Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after obtaining informed consent may be recorded on the Medical History/Current Medical Conditions section of the CRF.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

43

Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK product will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated inAppendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former studysubjects. However, if the investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he/she considers the event reasonably related to the study treatment or study participation, the investigator must promptly notify GSK.

NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided in Appendix 3.

7.3.1.2. Method of Detecting AEs and SAEs

Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since your last visit/contact?”

7.3.1.3. Follow-up of AEs and SAEs

After the initial AE/SAE report, the investigator is required to proactively follow each subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in Section 4.6.1 will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up (as defined in Section 5.4). Further information on follow-up procedures is given in Appendix 3.

7.3.1.4. Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator or designee to GSK of SAEs and non-serious AEs related to study treatment (even for non- interventional post-marketing studies) is essential so that legal obligations and ethical responsibilities towards the safety of subjects and the safety of a product under clinical investigation are met.

GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to the regulatory authority, IRB/IEC and investigators.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

44

Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.

7.3.2. Physical Exams

A brief physical examination will be performed by a medically qualified study personnelat screening and include, at a minimum assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Height and weight will also be measured and recorded.

Investigators or delegate should pay special attention to clinical signs related to previous serious illnesses.

7.3.3. Vital Signs

Vital signs will be measured in seated position after 5 minutes rest and will include temperature, systolic and diastolic blood pressure and pulse rate.

Single readings of blood pressure and pulse rate will be taken and recorded in the eCRF.

Vital signs should be collected before drug removal and within a time window of 2 hours prior to dosing.

7.3.4. ECG

Single 12-lead ECGs will be obtained at each specified time point during the study usingan ECG machine that automatically calculates heart rate and measures PR, QRS, QT, andQTc intervals. The same QT correction formula (ie, QTcB) should be used for subjecteligibility, withdrawal criteria, and data analysis. Refer to Section 5.4.2 for QTcwithdrawal criteria and additional readings that may be necessary.

ECG should be performed before drug removal and within a time window of 2 hours prior to dosing. If a plaque is located in the ECG region the dressings, study treatment may be removed before ECG measurement. In this situation, the time window from drug removal to the new application may be 3 hours.

7.3.5. Clinical Safety Laboratory Assessments

All protocol required laboratory assessments, as defined in Table 4, must be conducted in accordance with the Laboratory Manual, and Protocol Time and Events Schedule.Laboratory requisition forms must be completed and samples must be clearly labelled with the subject number, protocol number, site/centre number, and visit date. Details for the preparation and shipment of samples will be provided by the laboratory and are

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

45

detailed in the SRM or the laboratory manual. Reference ranges for all safety parameters will be provided to the site by the laboratory responsible for the assessments.

If additional non-protocol specified laboratory assessments are performed at the institution’s local laboratory and result in a change in subject management or are considered clinically significant by the investigator (e.g., SAE or AE or dose modification) the results must be recorded in the eCRF.

Laboratory assessments should be performed before drug removal and within a time window of 2 hours prior to dosing. Refer to the SRM for appropriate processing and handling of samples to avoid duplicate and/or additional blood draws.

Haematology, clinical chemistry, urinalysis and additional parameters to be tested are listed in Table 4.

Table 4 Protocol Required Safety Laboratory Assessments

Laboratory Assessments

Parameters

Haematology Platelet Count RBC Indices: WBC count with Differential:RBC Count MCV NeutrophilsHemoglobin MCH LymphocytesHematocrit Monocytes

EosinophilsBasophils

Clinical Chemistry 1

BUN Potassium AST (SGOT) Total and direct bilirubin

Creatinine Sodium ALT (SGPT) Total ProteinGlucose Calcium Alkaline phosphatise Albumin

Routine Urinalysis

Specific gravity pH, glucose, protein, blood and ketones by dipstick Microscopic examination (if blood or protein is abnormal)

Other Screening Tests

HIV Hepatitis B (HBsAg) Hepatitis C (Hep C antibody) Alcohol and drug screen (to include at minimum: amphetamines,

barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)NOTES :

1. Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver stopping or monitoring event are given in Section 5.4.1 and Appendix 2: Liver Safety Required Actions and Follow up Assessments.

All laboratory tests with values that are considered clinically significantly abnormal during participation in the study should be repeated until the values return to normal or

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

46

baseline. If such values do not return to normal within a period judged reasonable by the investigator, the etiology should be identified and the sponsor notified.

7.4. Efficacy

An objective parameter of efficacy is the evaluation of the infiltrate thickness by ultrasound measurement (refer to Section 7.2). The ultrasound measurements of the ELB representing the thickness of the psoriatic infiltrate as a surrogate allows for greatly improved discrimination and sensitivity compared to clinical assessment. This method has been clinically and scientifically accepted for many years (Bangha, 1996; Remitz, 1999; Gassmueller, 1993; Willers, 2002).

The efficacy variable is the change from baseline in psoriatic skin thickness on Day 4, 8, 15 and 19 as assessed by measurement of the thickness of the ELB of the psoriatic infiltrate using 22-MHz sonography.

The efficacy signal can also be based on the clinical assessment of improvement of the test site(s) using the following 5-point score:

-1 = worsened

0 = unchanged (no effect)

1 = slight improvement

2 = clear improvement but not completely healed

3 = completely healed

Clinical assessment will be done after removal of treatments but before any gentle de-scaling necessary prior to sonography measurements. The comparison of single test fields will be made to the untreated area of plaque(s) not covered by the hydrocolloid dressing and close to the respective test field. Clinically apparent differences in erythema and infiltration will contribute to this global assessment. At Day 1 the score will be documented as “0” (unchanged).

Ideally, the same investigator or designated evaluator should carry out all assessments for an individual subject. In the event the same evaluator is not available for the duration of the study, another blinded investigator or designated evaluator with comparable training will perform the assessments.

With reference to the EMA Guideline for assessment of short-term efficacy of topical treatments [CHMP, 2004] the response to treatment will be documented as the difference between baseline and post treatment score (Day 19) for the single treated test fields, and in addition assessments will be made on Days 4, 8, and 15.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

47

7.5. Biomarker(s)/Pharmacodynamic Markers

7.5.1. Novel Biomarkers

With the subject’s consent, tissue sample(s) will be collected during this study and may be used for the purposes of measuring novel biomarkers to identify factors that may influence psoriasis, and/or medically related conditions, as well as the biological and clinical responses to GSK2981278.

Four 3 mm punch biopsies scheduled on the Day 19 visit will be performed after all the observer assessments are complete.

Biomarker analysis in skin biopsies will be conducted using gene expression analysis of relevant biomarkers reported to be modulated by GSK2981278. These biomarkers include, but are not limited to, IL-17A, IL-17F, DEFB4A, IL-19, IL-36, CCL20, S100A7a, IL-8, and Krt6A. The analysis of these PD biomarkers will allow for investigation of target engagement of GSK2891278 in the study.

8. DATA MANAGEMENT

For this study subject data will be entered into GSK/bioskin defined eCRFs, transmitted electronically to GSK or designee and combined with data provided from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK/bioskin standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA (Medical Dictionary for Regulatory Activities) and an internal validated medication dictionary, GSKDrug.

eCRFs (including queries and audit trails) will be retained by GSK, and copies will be sent to the investigator to maintain as the investigator copy. Subject initials will not be collected or transmitted to GSK according to GSK policy.

9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES

Refer to the reporting and analysis plan (RAP)/statistical analysis plan (SAP) for additional details regarding data analyses. Reporting will be performed in accordance with applicable GSK and/or CRO standards.

9.1. Hypotheses

There is no formal statistical hypothesis testing for the study.

Descriptive statistics will be used to assess safety and tolerability objectives. An estimation approach will be used to address the efficacy and pharmacodynamic study

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

48

objectives, where point estimates and corresponding confidence intervals will be constructed.

To assess the safety and tolerability of GSK2981278 ointment, adverse events and changes in laboratory parameters, ECGs, and vital signs will be evaluated. Treatment comparisons with vehicle ointment and the positive control will be based on review of descriptive statistics.

Efficacy and PD endpoints will be compared between different doses of GSK2981278 ointment, and vehicle ointment, and the positive control. Point estimates and 95% confidence intervals will be presented for each of the differences.

9.2. Sample Size Considerations

The sample size is driven by feasibility and prior experience by bioskin (CRO) in conducting these studies (based on published data on clintrial.gov and unpublished bioskin data).

Approximately 15 subjects will be randomized in order to achieve at least 13 evaluable subjects.

9.3. Data Analysis Considerations

9.3.1. Analysis Populations

Per Protocol (PP) analysis set will include all randomized subjects who comply closely with the protocol (e.g. have sufficient exposure). PP analysis set details will be defined in the RAP/SAP. The PP analysis set will be the primary set for efficacy analyses.

Safety analysis set will include all subjects exposed to at least 1 application of study product. The safety analysis set will be the primary set for safety analyses.

PD analysis set will include subjects with at least one sample collected for PD assessments. The PD analysis set will be the primary set for PD analyses.

9.3.2. Interim Analysis

No interim analysis is planned.

9.4. Key Elements of Analysis Plan

9.4.1. Efficacy Analyses

9.4.1.1. Reduction in psoriatic infiltrate thickness

The primary efficacy endpoint is the area under the time curve (AUC) of change in infiltrate thickness using the linear trapezoidal rule over the period starting with Day 1 up to Day 19. Missing data will be handled by the last observation carried forward (LOCF) approach. The AUC will be analyzed using a mixed-model repeated-measures (MMRM) analysis including treatment. The treatment will be treated as repeated measures within

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

49

the same subject. Pair-wise treatment comparisons (see Table 5) will be performed. The primary comparison is between each active dose and the vehicle ointment. The least-square mean for each treatment group, an estimate of the difference between treatments, corresponding 95% confidence interval (CI) and p-value will be presented.

In addition, for each post-baseline assessed time point, the reduction in infiltrate thickness of the psoriatic plaque(s) from baseline will be summarized using both theObserved Cases (OC) approach and the LOCF approach. Pair-wise treatment comparisons (see Table 5) will be performed using a MMRM analysis similar to that for the primary efficacy endpoint. The least-square mean for each treatment group, an estimate of the difference between treatments, corresponding 95% CI and p-value will be presented.


Study products:


0.03% 0.1% 0.8% 4%Vehicle ointment

positive control

GS

K29

8127

8O

intm

ent

0.03% X X X X X

0.1% X X X X

0.8% X X X

4% X X

Vehicle X

9.4.1.2. Improvement in clinical assessment

Clinical efficacy assessment using a 5-point scale (see Section 7.4) will be evaluated for each post-baseline assessed time point. The ordinal clinical score and the cumulative total score will be presented by descriptive statistics. Missing data, when computing the cumulative score, will be handled by the LOCF approach. Additionally, frequency counts will be provided for the clinical scores.

9.4.2. Safety Analyses

Extent to exposure will be summarized. A by-subject listing of data on subject exposure to study drug will be produced.

AEs will be tabulated according to the current version of MedDRA. Frequencies and percentages will be presented overall, for each system organ class, and for each preferred term. Summaries of treatment-emergent AEs, treatment-related AEs, AEs leading to discontinuation of study product applications, and SAEs will be completed. AE onset, severity, relationship to study product, action taken, and outcome will be listed by subject.

Each quantitative laboratory test will be summarised at every scheduled time point. The number of subjects with abnormal values based on values relative to the laboratory

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

50

normal ranges will be summarized for each assessed time point. A listing of laboratory data for subjects with values out of the laboratory normal range will be provided.

Vital sign value and change from baseline at Day 19 for each vital sign parameter would be summarised using descriptive statistics. A listing of vital signs and a listing of change from baseline for vital signs will be provided.

ECG value and change from baseline at every scheduled time point for each ECG parameter would be summarised using descriptive statistics. The ECG will be evaluated by the investigator as “Normal”, “Abnormal, not clinically significant”, and “Abnormal, clinically significant”. A summary of ECG findings will be provided. Also, a listing of ECG values and a listing of ECG findings will be provided.

If applicable, liver event data will be listed.

9.4.3. Other Analyses

Gene expression of biomarkers (refer to Section 7.5.1) from skin punch biopsy sample(s)will be analyzed.

10. STUDY GOVERNANCE CONSIDERATIONS

10.1. Posting of Information on Publicly Available Clinical Trial Registers

Study information from this protocol will be posted on publicly available clinical trial registers before enrollment of subjects begins.

10.2. Regulatory and Ethical Considerations, Including the Informed Consent Process

Prior to initiation of a site, GSK will obtain favourable opinion/approval from the appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical Practice (GCP) and applicable country-specific regulatory requirements.

The study will be conducted in accordance with all applicable regulatory requirements, and with GSK policy.

The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable subject privacy requirements, and the guiding principles of the current version of the Declaration of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and amendments as applicable.

Signed informed consent to be obtained for each subject before participation in the study (and for amendments as applicable).

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC).

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

51

GSK will provide full details of the above procedures, either verbally, in writing, or both.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate informed consent) and the clinical protocol should be concurrently submitted for approval unless regulation requires separate submission.

Approval of the optional assessments may occur after approval is granted for the clinical protocol where required by regulatory authorities. In this situation, written approval of the clinical protocol should state that approval of optional assessments is being deferred and the study, with the exception of the optional assessments, can be initiated.

10.3. Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements.

When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the CRF for studies conducted at a GSK Phase I unit will serve as the source document.

GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents

10.4. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study.

In the event of an assessment, audit or inspection, the investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to implement any corrective and/or preventative actions to address any findings/issues identified.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

52

10.5. Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will conduct site closure activities with the investigator or site staff, as appropriate, in accordance with applicable regulations including GCP, and GSK Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter studies, this can occur at one or more or at all sites.

If GSK determines such action is needed, GSK will discuss the reasons for taking such action with the investigator or the head of the medical institution (where applicable). When feasible, GSK will provide advance notification to the investigator or the head of the medical institution, where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK willpromptly inform all investigators, heads of the medical institutions (where applicable) and/or institution(s) conducting the study. GSK will also promptly inform the relevant regulatory authorities of the suspension or premature discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical institution (where applicable) must inform the IRB/IEC promptly and provide the reason for the suspension or premature discontinuation.

10.6. Records Retention

Following closure of the study, the investigator or the head of the medical institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere), in a safe and secure location.

The records must be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff.

Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken.

The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

53

institutional requirements or local laws or regulations, GSK standards/procedures, and/or institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, archival at an off-site facility or transfer of ownership of the records in the event the investigator is no longer associated with the site.

10.7. Provision of Study Results to Investigators, Posting of Information on Publically Available Clinical Trials Registers and Publication

Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

The procedures and timing for public disclosure of the results summary and for development of a manuscript for publication will be in accordance with GSK Policy.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

54

11. REFERENCES

Bangha E, Elsner P. Evaluation of antipsoriatic treatment by chromametry, visiometry and 20-MHz ultrasound in the psoriasis plaque test. Skin Pharmacol 1996; 9: 298-306.

Brackett, C. Sulfonamide allergy and cross-reactivity. Curr Allergy Asthma Rep 2007;7:41-48.

CHMP 2004 Guideline on Clinical Investigation of Medicinal Products Indicated for the Treatment of Psoriasis. EMEA/CHMP/EWP/2454/02corr.

CHMP 2007. Guideline on Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with Investigational Medicinal Products; Committee For Medicinal Products For Human Use. EMEA/CHMP/SWP/28367/07.

De Korte J, Sprangers MA, Mombers FM, Bos JD. Quality of life in patients with psoriasis: a systematic literature review. J Ivestig Dermatol Symp Proc 2004;9:140-7.

Dumas KJ, Scholtz JR. The psoriasis bio-assay for topical corticosteroid activity. Acta Derm. Venereol. (Stockh) 1972; 52: 43 – 8.

FDA 2005. Guidance for Industry Estimating the Maximum Safe Starting Dose in InitialClinical Trials for Therapeutics in Adult Healthy Volunteers. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2005.

Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI.Arch Dermatol. 1988;124(6):869-71.

Fluhr JW, Hughes-Formella B, Williams R, Wigger-Alberti W. bioskin EADV poster: Biophysical measurement methods to establish efficacy in proof of concept studies; 18th Congress of the European Academy of Dermatology October 6th–10th 2009, Berlin, Germany.

Gassmueller J, Klinger B, Levy J. The Ultrasound-Erythema Index (USE-Index) for monitoring of therapeutic effects on the psoriatic plaque by 20-MHz Ultrasound and Colorimetry. Regional Meeting of the International Society for Bioengineering and the Skin. Luebeck, 1993; 23-25.

GlaxoSmithKline Document Number 2015N240000_00, GSK2981278 Investigator’s Brochure (IB).July 2015.

Gordon K. Ixekizumab for Treatment of Moderate-to-Severe Plaque Psoriasis: 60-week Results from a Double-Blind Phase 3 Induction and Randomized Withdrawal Study (UNCOVER-1). AAD 2015 Late-breaking abstract F010.

Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet 2007;370:263-71.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

55

Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-2.

He YW, Deftos ML, Ojala EW, Bevan MJ. RORt, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. Immunity 1998;9(6):797-806.

Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORt directs the differentiation program of proinflammatory IL-17+ T helper cell. Cell 2006;126(6):1121-33.

James LP, Letzig L, Simpson PM, et. al. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook ofEndocrinology, 11th edition. Philadelphia: Saunders, 2008.

Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis-Results of two phase 3 trials. N Engl J Med 2014;371(4):326-38.

Lebwohl, M. AMAGINE-2: A Randomized, Double-blind, Phase 3 Efficacy and Safety Study of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis Patients. AAD 2015 Late-breaking abstract F010.

Lynde CW, Poulin Y, Vender R, Bourcier M, Khalil S. Interleukin 17A: Toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol 2014;71:141-50.

Malakouti M, Brown GE, Wang E, Koo J, Levin EC. The role of IL-17 in psoriasis. J Dermatolog Treat 2015;26 (1):41-44.

Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad Dermatol 2009;60:643-59.

Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361(5):496-509.

Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol 2013;133:377-385.

Remitz A, Reitamo S, Erkko P et al. Tacrolimus ointment improves psoriasis in a microplaque assay. Br. J. Dermatol. 1999; 141: 103 - 107.

Russell CB, Rand H, Bigler J, et. al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol. 2014 Apr 15;192(8):3828-36.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

56

Sandoval LF, Williams B, Feldman SR. Clinical potential of brodalumab in the management of psoriasis: the evidence to date. Psoriasis: Targets and Therapy. 2015;5:35-41.

Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology.5th edition, Philadelphia, Elsevier/Saunders, 2004.

Strom BL, Schinnar R, Apter AJ, et. al. Absence of cross-reactivity between sulphonamide antibiotics and sulphonamide nonantibiotics. N Engl J Med 2003;346:1628-35.

Willers CP, Frase T, Schmidt A. The USE-(Ultrasound-Erythema-)Index in antipsoriatic testing. 20th World Congress of Dermatology, 2002, Paris, France.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

57

12. APPENDICES

12.1. Appendix 1 – Abbreviations and Trademarks

Abbreviations

ACTH Adrenocorticotropic hormoneAE Adverse EventALT Alanine aminotransferaseAMG German drug law (Arzneimittelgesetz)AST Aspartate aminotransferaseAUC Area under the curveBUN Blood urea nitrogenCI Confidence intervalcm2 Centimeter squaredCmax Maximum concentrationCONSORT Consolidated Standards of Reporting TrialsCRO Contract research organizationECG ElectrocardiogrameCRF Electronic case report formELB Echo lucent bandFRP Female of reproductive potentialFNRP Female of non-reproductive potentialFTiH First time in humansGCP Good clinical practiceGCSP Global Clinical Safety and PharmacovigilanceGSK GlaxoSmithKlineh HourHBsAg Hepatitis B surface antigenHFUS High frequency ultrasoundHIV Human immunodeficiency virusHPA Hypothalamic-pituitary-adrenalHRT Hormone replacement therapyIB Investigator’s BrochureICH International conference on harmonisationIEC Independent ethics committeeIL-17 Interleukin 17INR International normalized ratioIRB Institutional review boardLBD Ligand-binding domainsLOCF Last observation carried forwardmAb Monoclonal antibodymg MilligrammL MilliliterMMRM Mixed-model repeated-measuresmRNA messenger ribonucleic acid

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

58

MSDS Material safety data sheetng NanogramNOAEL No observed adverse effect level OC Observed casesPD Pharmacodynamicpg PicogramPK PharmacokineticPP Per protocol PPT Psoriasis plaque testQTc Corrected QTQTcB Corrected QT using Bazett’s formulaRAP Reporting and analysis planRNA Ribonucleic acid

ROR Retinoic acid receptor-related orphan receptor gamma

SAEs Serious adverse eventSAP Statistical analysis planSRM Study reference manualTh 17 T-helper 17

TNF- Tumor necrosis factor alpha

g Microgram

ULN Upper limit of normalUV Ultraviolet

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

BETNESOL FixomullVarihesiveVaseline

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

59

12.2. Appendix 2: Liver Safety Required Actions and Follow up Assessments

Phase II liver chemistry stopping and increased monitoring criteria have been designed to assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf.

Phase II liver chemistry stopping criteria and required follow up assessments

Liver Chemistry Stopping Criteria – Liver Stopping Event

ALT-absolute ALT 5xULN

ALT Increase ALT 3xULN persists for 4 weeks

Bilirubin1, 2 ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)

INR2 ALT 3xULN and INR>1.5, if INR measured

Cannot Monitor ALT 3xULN and cannot be monitored weekly for 4 weeks

Symptomatic3 ALT 3xULN associated with symptoms (new or worsening) believed to be related to liver injury or hypersensitivity

Required Actions and Follow up Assessments following ANY Liver Stopping Event

Actions Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete anSAE data collection tool if the event also meets the criteria for an SAE2

Perform liver event follow up assessments

Monitor the subject until liver chemistriesresolve, stabilize, or return to within baseline (see MONITORING below)

Do not restart/rechallenge subject with study treatment unless allowed per protocol and GSK Medical Governance approval is granted

If restart/rechallenge not allowed per protocol or not granted, permanently discontinue study treatment and may continue subject in the study

Viral hepatitis serology4

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the AE report form

Record use of concomitant medications on the concomitant medications report form including acetaminophen, herbal remedies, other over the counter medications.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

60

for any protocol specified follow up assessments

MONITORING:

For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver event follow up assessments within 24 hrs

Monitor subjects twice weekly until liver chemistries resolve, stabilize or return to within baseline

A specialist or hepatology consultation is recommended

For All other criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver event follow up assessments within 24-72 hrs

Monitor subjects weekly until liver chemistries resolve, stabilize or return to within baseline

Record alcohol use on the liver event alcohol intake case report form

For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma globulins).

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in subjects with definite or likely acetaminophen use in the preceding week, [James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or computerised tomography) and /or liver biopsy to evaluate liver disease; complete Liver Imaging and/or Liver Biopsy CRF forms.

1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.

2. All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will not apply to subjects receiving anticoagulants

3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia)

4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

61

12.3. Appendix 3: Definition of and Procedures for Recording, Evaluating, Follow-Up and Reporting of Adverse Events

12.3.1. Definition of Adverse Events

Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.

Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication (overdose per se will not be reported as an AE/SAE unless this is an intentional overdose taken with possible suicidal/self-harming intent. This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfil the definition of an AE or SAE.

Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

62

leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

12.3.2. Definition of Serious Adverse Events

If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of disease, etc).

Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose:

a. Results in death

b. Is life-threatening

NOTE:

The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c. Requires hospitalization or prolongation of existing hospitalization

NOTE:

In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d. Results in disability/incapacity

NOTE:

The term disability means a substantial disruption of a person’s ability to conduct normal life functions.

This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

63

e. Is a congenital anomaly/birth defect

f. Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse

g. Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.

* Serum bilirubin fractionation should be performed if testing is available; if unavailable, measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported as an SAE.

** INR testing not required per protocol and the threshold value does not apply to subjects receiving anticoagulants. If INR measurement is obtained, the value is to be recorded on the SAE form.

12.3.3. Recording of AEs and SAEs

AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by GSK. In this instance, all subject identifiers, with the exception of the subject number, will be blinded on the copies of the medical records prior to submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis will be documented as the AE/SAE and not the individual signs/symptoms.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

64

12.3.4. Evaluating AEs and SAEs

Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported during the study and will assign it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities

Severe: An event that prevents normal everyday activities. - an AE that is assessed as severe will not be confused with an SAE. Severity is a category utilized for ratingthe intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as described in the definition of an SAE.

Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the study treatment will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal information to include in the initial report to GSK. However, it is very important that the investigator always make an assessment of causality for every event prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory reporting requirements.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

65

Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist. This may include additional laboratory tests or investigations, histopathological examinations or consultation with other health care professionals.

If a subject dies during participation in the study or during a recognized follow-up period, the investigator will provide GSK with a copy of any post-mortem findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated reporting time frames.

12.3.5. Reporting of SAEs to GSK

SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool.

If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE data collection tool and fax it to the Medical Monitor or the SAE coordinator.

Site will enter the serious adverse event data into the electronic system as soon as it becomes available.

The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., InForm system) will be taken off-line to prevent the entry of new data or changes to existing data

If a site receives a report of a new SAE from a study subject or receives updated data on a previously reported SAE after the electronic data collection tool has been taken off-line, the site can report this information on a paper SAE form or to the MedicalMonitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical Monitor Contact Information page.

2016N274225_00

2014N215725_00 CONFIDENTIAL201465

66

12.4. Appendix 4: GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP)

This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis.

A. Contraceptive subdermal implant that meets the SOP effectiveness criteria including a <1% rate of failure per year, as stated in the product label

B. Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a <1% rate of failure per year, as stated in the product label [Hatcher, 2007a]

C. Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a]

D. Injectable progestogen [Hatcher, 2007a]

E. Contraceptive vaginal ring [Hatcher, 2007a]

F. Percutaneous contraceptive patches [Hatcher, 2007a]

G. Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject [Hatcher, 2007a].

H. Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository) [Hatcher, 2007a]

These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

2016N274225_00

Statistical Analysis Plan 201465

Page 1 of 22

Version 1.1, March 14, 2016 SOP ST/05, Template from 20120906

Statistical Analysis Plan

A Phase I Trial to Evaluate Safety and Efficacy of Topically Applied GSK2981278 Ointment

in a Psoriasis Plaque Test

This statistical analysis plan is the property of bioskin GmbH. It may not be reproduced, distributed or otherwise used. The rights to the information in this analysis plan and the resulting trial first become the property of the sponsor when the contract stipulations have been fulfilled on the side of bioskin GmbH and the sponsor.

bioskin GmbH • Burchardstrasse 17 • 20095 Hamburg • Germany

Confidential

1

CONFIDENTIAL 2016N274225_00201465


Page 2 of 22


SIGNATURE PAGE

Manager Statistics, GlaxoSmithKline

______________________________________________________________

Biostatistician, bioskin GmbH

2

CONFIDENTIAL 2016N274225_00201465

PPD

PPD

PPD


Page 3 of 22


TABLE OF CONTENTS

ABBREVIATIONS AND DEFINITIONS ..................................................................................... 5

1. OVERVIEW ................................................................................................................. 6

1.1 Background / rationale ................................................................................................. 6

1.2 Objectives .................................................................................................................... 6

1.3 Modifications from the statistical section in the protocol ............................................... 6

2. INVESTIGATIONAL PLAN .......................................................................................... 6

2.1 Study design and randomization .................................................................................. 6

2.2 Sample size justification ............................................................................................... 8

2.3 Study plan .................................................................................................................... 9

3. STATISTICAL AND ANALYTICAL PROCEDURES ................................................. 11

3.1 Definitions .................................................................................................................. 11

3.2 Analysis variables ...................................................................................................... 15 3.2.1 Pharmacokinetic variables ......................................................................................... 15 3.2.2 Pharmacodynamic variables ...................................................................................... 15 3.2.3 Efficacy variable(s) ..................................................................................................... 16 3.2.4 Safety variables ......................................................................................................... 16 3.2.4.1 Adverse events....................................................................................................... 16 3.2.4.2 Laboratory variables ............................................................................................... 16

3.3 Analysis populations .................................................................................................. 17 3.3.1 Efficacy populations ................................................................................................... 17 3.3.2 Safety population ....................................................................................................... 17

3.4 Statistical methods ..................................................................................................... 17 3.4.1 Demographics and baseline characteristics ............................................................... 18 3.4.2 Discontinuations and dropouts ................................................................................... 18 3.4.3 Efficacy analyses ....................................................................................................... 18 3.4.3.1 Hypotheses ............................................................................................................ 18 3.4.3.2 Statistical analyses ................................................................................................. 18 3.4.4 Safety analyses ......................................................................................................... 19 3.4.4.1 Extent of exposure to study drug ............................................................................ 19 3.4.4.2 Adverse events....................................................................................................... 19 3.4.4.3 Laboratory analyses ............................................................................................... 20 3.4.4.4 ECG ....................................................................................................................... 20 3.4.4.5 Other safety analyses ............................................................................................. 20 3.4.5 Pharmacodynamic and pharmacokinetic analyses ..................................................... 20

(continued)

3

CONFIDENTIAL 2016N274225_00201465


Page 4 of 22


TABLE OF CONTENTS (CONTINUED) 3.5 Data handling conventions ......................................................................................... 20 3.5.1 Baseline definitions .................................................................................................... 21 3.5.2 Missing data............................................................................................................... 21 3.5.3 Window for time points ............................................................................................... 21 3.5.4 Unscheduled visits ..................................................................................................... 21 3.5.5 Pooling of centers for statistical analyses ................................................................... 21 3.5.6 Statistical technical issues ......................................................................................... 22 3.5.7 Database related issues ............................................................................................ 22

4. INTERIM ANALYSIS ................................................................................................. 22

5. SOFTWARE DOCUMENTATION .............................................................................. 22

6. REFERENCES .......................................................................................................... 22

7. TABLES, LISTINGS AND FIGURES ......................................................................... 22

4

CONFIDENTIAL 2016N274225_00201465


Page 5 of 22


Abbreviations and definitions AE adverse event

AUC area under the time curve

CHMP Committee for Medicinal Products for Human Use

CI confidence interval

CRO contract research organization

CTP clinical trial protocol

ECG electrocardiogram

eCRF electronic case report form

EMA European Medicines Agency

HIV human immunodeficiency virus

HFUS high frequency ultrasound

LLN lower limit of normal

LOCF Last observation carried forward

MedDRA Medical Dictionary for Regulatory Activities

MMRM mixed-model repeated-measures

OC observed cases

PCI potential clinical importance

PD pharmacodynamic

PPS per-protocol analysis set

PT preferred term

SAE serious adverse event

SAP statistical analysis plan

SAS Statistical Analysis System

SES safety evaluation set

SOC system organ class

ULN upper limit of normal

5

CONFIDENTIAL 2016N274225_00201465


Page 6 of 22


1. Overview This Statistical Analysis Plan (SAP) is issued to provide a comprehensive and detailed description of strategy, rationale, and statistical technique that will be used to evaluate the safety, tolerability and initial efficacy of a range of concentrations of GSK2981278 ointment.

The credibility of the study findings will be ensured by pre-specifying the statistical approaches to the analysis of the study data prior to unblinding of the randomization schedule. This SAP is based on the clinical trial protocol (CTP) number 201465, dated July 15, 2015.

1.1 Background / rationale This is the first study to administer GSK2981278 to patients with psoriasis. This proof-of-concept study will evaluate the safety, tolerability and initial efficacy of a range of concentrations of GSK2981278 ointment with repeated topical applications in adult subjects with psoriasis. Results of this study will provide the first clinical information on the drug’s safety and efficacy in psoriasis and inform the selection of concentration of GSK2981278 ointment to be evaluated in subsequent clinical studies.

1.2 Objectives Primary objectives:


To evaluate the efficacy of topical formulation strengths of GSK2981278 ointment in patients with psoriasis.

Secondary objective:


Exploratory objective:

To evaluate the pharmacodynamics (PD) effects of topical GSK2981278 in psoriasis plaques.

1.3 Modifications from the statistical section in the protocol Not applicable.

2. Investigational plan

2.1 Study design and randomization This is a Phase 1, single-center, randomized, vehicle- and positive-controlled, subject- and evaluator- blind proof-of-concept trial in subjects with chronic plaque type psoriasis.

All subjects will receive all treatments on stable plaque(s) on the upper extremities, thighs and/or trunk for intra-individual comparison with random assignment of the treatments to the test

6

CONFIDENTIAL 2016N274225_00201465


Page 7 of 22


fields within the identified plaque(s). A blinded evaluator (an investigator or designee) will perform the measurements and assessments whereas an unblinded study staff member (not an evaluator) will perform biopsy collection.

Screening will occur within 14 days preceding the Day 1 visit. Study visits will occur from Day 1 through Day 19 for applications of study treatments and evaluations of dermal reactions. A total of 16 applications will be made over 19 days. Day 19 will be the end of study visit for those subjects who do not consent to biopsy. A follow-up visit will occur at Day 27 ( 2) for those subjects consenting to biopsies. The total duration of study participation for those subjects who do not consent to biopsy will be approximately 33 days. The total duration of study participation for those subjects consenting to biopsies will be approximately 41 days. For a detailed tabulation of times and events see section 2.3.

Treatments All subjects will have a set of 6 randomized test fields on identified stable plaque(s) to be treated with the following study products:







The same study products will be applied in all subjects. There will be no subdivision into separate dosing groups.

Screening Visit

Days -14 to -1

StudyVisits

Days 1-19

Follow-upVisit*Day 27

Sign ICF

Last dosingapplication

Day18

Day19

Biopsies

Day1

Dosingbegins

*Follow-up visit (Day 27) is only for subjects consenting to biopsy. All other subjects complete the study at Day 19.

7

CONFIDENTIAL 2016N274225_00201465


Page 8 of 22


Assignment of Treatments to Test Sites and Randomization Upon signature of informed consent each subject receives a screening number. Subjects meeting the eligibility criteria will receive their randomization number on Day 1. Once a randomization number has been assigned to a subject, it should not be reassigned to any other subject.

The 4 concentrations of GSK2981278 ointment (0.03%, 0.1%, 0.8%, and 4%) will be assigned the codes A, B, C, and D, respectively. The vehicle and positive control will be assigned the codes E and F, respectively.

The test fields will be numbered with 1, 2, 3, 4, 5, and 6 beginning with the uppermost or most proximal site on the left from the investigator's view. Fields along the same line will be numbered left to right.

For each subject a permutation of the treatment codes A to F will be randomly assigned. The treatment code listed first in the respective permutation will be assigned to test field 1, the second to test field 2, etc.

A randomization list will be generated by the contract research organization (CRO) and kept in the trial master file in a sealed envelope.

Blinding This is a subject- and evaluator-blinded study; therefore, the designated evaluator performing the measurements and assessments will be unaware of the particular treatment assignment for the subjects. Investigator(s) responsible for biopsy collection will be unblinded. Study-center staff responsible for preparation and application of the study products will not be blinded to the test field allocations and will be instructed not to reveal the identity of the allocations to the blinded evaluator. The treatments will be unblinded with sponsor’s approval, after the SAP is finalized, the analysis populations are defined and the clinical database is locked.

Compliance with Study Treatment Administration Subjects will be dosed at the site and will receive study treatment directly from the investigator or designee, under medical supervision.

2.2 Sample size justification The sample size is driven by feasibility and prior experience by bioskin (CRO) in conducting these studies (based on published data on clintrial.gov and unpublished bioskin data).

Approximately 15 subjects will be randomized in order to achieve at least 13 evaluable subjects.

8

CONFIDENTIAL 2016N274225_00201465


Page 9 of 22


2.3 Study plan Procedure Screenin

g [Day]


Follow-up

[Day] Notes Subjects who withdraw early from the study should complete the Day 19 visit assessments except for biopsy collection.

-14

to

-1

1

2 to

6

7 8 9 to

13

14

15

16 to

18

19

27

(2)

Informed consent X Inclusion and exclusion criteria X X Will be assessed prior to randomization.

Demographics/medical history X Fitzpatrick skin type (CTP section 7.2, Table 3) will be documented. Site to document any known drug allergies.

Brief physical exam (including height and weight) X

Physical examination of the skin X X Any adverse changes to the skin will be recorded as an AE.

Descaling with salicylic acid X Descaling of test sites with detergent solution (if necessary) X X X X Will be completed prior to dosing.

HIV, Hepatitis B, and Hepatitis C screen X

ECG X X X On Day 15 ECG will be completed prior to dosing.


Vital sign X X Vital signs include heart rate, blood pressure, and oral

temperature. To be performed before drug removal and within a time window of 2 hours prior to dosing.


Laboratory assessments (include liver chemistries) and urinalysis X* X X X

*Including drug and alcohol screening (Screening visit only). Refer to CTP section 7.3.5 for laboratory and urinalysis assessment information. Assessment to occur before drug removal and within 2 hours prior to dosing on Days 8 and 15.

Study Treatment X X X X X X

Syringes should be weighed before and after application of each study treatment for each subject. Study treatment will be re-applied after evaluation and within 1 hour after removal. Study treatment applied on days 6 and 13 remains on the skin until subject returns to the clinic on days 8 and 15 respectively.

9

CONFIDENTIAL 2016N274225_00201465


Page 10 of 22


Procedure Screening [Day]


Follow-up

[Day] Notes Subjects who withdraw early from the study should complete the Day 19 visit assessments except for biopsy collection.

-14

to

-1

1

2 to

6

7 8 9 to

13

14

15

16 to

18

19

27

(2)

AE/SAE review X X X X ======X====== During the Screening visit, only SAEs related to study participation will be collected. AEs will be collected after start of study treatment.

Prior and concomitant medication review X X X X X ======X======


Clinical assessments X* X X X At Day 1 the score will be documented as “0.” *Day 4 only. Assessment to occur within 60 minutes of study product removal.

HFUS (sonography) X X* X X X Day 1 is baseline HFUS and completed prior to dosing. *Day 4 only. Ultrasound to occur within 60 minutes of study product removal.

Skin biopsies X Up to four 3mm punch biopsies will be collected from each consenting subject.

Wound control X This assessment applies only to subjects consenting to biopsy collection.

10

CONFIDENTIAL 2016N274225_00201465


Page 11 of 22


3. Statistical and analytical procedures

3.1 Definitions

Study treatment

Any combination of products received by the subject as per the protocol design

On-treatment phase

The on-treatment phase will be defined as the period starting with the first application of any study treatment and ending with the removal of study treatment at the Day 19 visit.

Past medical conditions

Medical conditions resolved (not on-going) at start of first treatment

Current medical conditions

Medical conditions unresolved (on-going) at start of first treatment

Prohibited medications and non-drug therapies

Prohibited concomitant medications, products, and procedures (Table 1) are not to have been used from the defined washout periods before the first patch applications at the Day 1 visit and throughout the study.



Biologic agents: eg, alefacept 24 weeks; etanercept 12 weeks; ustekinumab 15 weeks

5 half-lives

Oral retinoids (eg, acitretin or isotretinoin) 12 weeks

Cyclosporin, interferon, methotrexate, or other systemic immunosuppressive or immunomodulating agents (eg, mycophenolate or tacrolimus); psoralen plus UVA

8 weeks



Immunizations (influenza vaccine will be allowed) 2 weeks

Topical treatments: corticosteroids, immunomodulators, anthralin (dithranol), Vitamin D derivatives, retinoids, coal tar (used on the psoriatic lesions under evaluation in this study.

2 weeks

Drugs known to possibly worsen psoriasis (unless on a stable dose for >12 weeks), such as: β-blockers (eg, propranolol), lithium, iodides, angiotensin-converting enzyme inhibitors, and indomethacin

2 weeks

11

CONFIDENTIAL 2016N274225_00201465


Page 12 of 22




1 day

UV-therapy 2 weeks

Prior therapies

Medication or therapy taken prior to first dosing, but not ongoing at start of first dosing

Concomitant therapies

Medication or therapy ongoing at start of treatment, or starting after the start of treatment

Safety Laboratory Assessments

Table 2 Protocol Required Safety Laboratory Assessments

Laboratory Assessments

Parameters

Haematology Platelet Count RBC Indices: WBC count with Differential: RBC Count MCV Neutrophils Hemoglobin MCH Lymphocytes Hematocrit Monocytes Eosinophils Basophils

Clinical Chemistry 1

BUN Potassium AST (SGOT) Total and direct bilirubin

Creatinine Sodium ALT (SGPT) Total Protein Glucose Calcium Alkaline phosphatise Albumin

Routine Urinalysis

Specific gravity pH, glucose, protein, blood and ketones by dipstick Microscopic examination (if blood or protein is abnormal)

Other Screening Tests

HIV Hepatitis B (HBsAg) Hepatitis C (Hep C antibody) Alcohol and drug screen (to include at minimum: amphetamines,

barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

NOTES : 1. Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver

stopping or monitoring event are given in Section 5.4.1 and Appendix 2 of the protocol.

Potential clinical importance (PCI) ranges

Table 3 Haematology Analytes: Potential clinical importance (PCI) ranges

Lab test (SI unit) Low High WBC (GI/L) ≤ 0.67 x LLN ≥ 1.82 x ULN Neutrophil (GI/L) ≤ 0.83 x LLN Hemoglobin (G/L) male ≥ 1.03 x ULN


12

CONFIDENTIAL 2016N274225_00201465


Page 13 of 22


Lab test (SI unit) Low High Hematocrit (1) male ≥ 1.02 x ULN

female ≥ 1.17 x ULN Platelet count (GI/L) ≤ 0.67 x LLN ≥ 1.57 x ULN Lymphocytes (GI/L) ≤ 0.81 x LLN

Table 4 Chemistry Analytes: Potential clinical importance (PCI) ranges

Lab test Low High Albumin (mmol/L) ≤ 0.86 x LLN Calcium (mmol/L) ≤ 0.91 x LLN ≥ 1.06 x ULN Glucose (mmol/L) ≤ 0.71 x LLN ≥ 1.41 x ULN Potassium (mmol/L) ≤ 0.86 x LLN ≥ 1.10 x ULN Sodium (mmol/L) ≤ 0.96 x LLN ≥ 1.03 x ULN

Table 5 Liver Function Test Analytes: Potential clinical importance (PCI) ranges

Lab test High ALT/SGPT (U/L) ≥ 2 x ULN AST/SGOT (U/L) ≥ 2 x ULN Alkaline phosphatise (U/L) ≥ 2 x ULN Total Bilirubin (μmol/L) ≥ 1.5 x ULN Total Bilirubin (μmol/L) and ALT (U/L) ≥ 1.5 x ULN Total Bilirubin and ≥ 2 x ULN ALT

Table 6 ECG: Potential clinical importance (PCI) ranges

ECG Parameter* Low High Absolute QTc interval (msec) > 450 Increase from baseline QTc (msec) > 60 PR interval (msec) < 110 > 220 QRS interval (msec) < 75 > 110

* for specifications of QTc see section on QTc Stopping Criteria below

Table 7 Vital Signs: Potential clinical importance (PCI) ranges

VS Parameter Low High Systolic Blood Pressure (mmHg) < 85 > 160 Diastolic Blood Pressure (mmHg) < 45 > 100 Heart Rate (bpm) < 40 > 110

Phase II liver chemistry stopping criteria

Study treatment will be discontinued for a subject if liver chemistry stopping criteria are met; *NB – this protocol will not use the increased monitoring criteria listed below. Therefore, if the subject meets liver stopping criteria outlined below, study treatment will be discontinued:

13

CONFIDENTIAL 2016N274225_00201465


Page 14 of 22


Figure 1 Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm

QTc Stopping Criteria

The same QT correction formula must be used for all subjects to determine eligibility for and discontinuation from the study. This formula may not be changed or substituted once the subject has been enrolled.

o For example, if a subject is eligible for the protocol based on QTcB, then QTcB must be used for discontinuation of this individual subject as well.

o Once the QT correction formula has been chosen for a subject’s eligibility, the same formula must continue to be used for that subject for all QTc data being collected for data analysis. Safety ECGs and other non-protocol specified ECGs are an exception.

The QTc should be based on single QTc values of an electrocardiogram obtained over a brief (e.g., 5-10 minute) recording period.

A subject who meets either of the bulleted criteria below will be withdrawn from the study:

Table 8 ECG: Discontinuation criteria

ECG Parameter* High QT uncorrected (msec) > 600 QTc (msec) > 500 Change from baseline in QTc (msec) > 60

For patients with underlying bundle branch block follow the discontinuation criteria listed below:

Continue Study Treatment

Discontinue Study Treatment

PlusBilirubin≥2xULN (>35%

direct) or plus

INR>1.5, if measured*PossibleHy’s Law

ALT≥3xULN ALT≥5xULN

ALT≥3xULNPlus

Symptoms of liver injury

or hypersensitivity

ALT≥3xULNbut able to monitor

weekly for 4 weeks

No

Yes

YesYes Yes

No No No

No

Yes

ALT≥3xULNpersist for4 weeks or stopping criteria

met

Yes

No

*INR value not applicable to subjects on anticoagulants

Yes

If subject to be monitored weekly must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix

Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix

Report as an SAE if possible Hy’s Law case: ALT≥3xULN and Bilirubin≥2xULN (>35% direct) or INR>1.5, if measured*

14

CONFIDENTIAL 2016N274225_00201465


Page 15 of 22


Table 9 ECG: Discontinuation criteria for patients with underlying bundle branch block

Baseline QTc with Bundle Branch Block

Discontinuation QTc with Bundle Branch Block

< 450 msec > 500 msec

450 – 480 msec ≥ 530 msec

Adverse events (AEs) and serious adverse event (SAEs)

AEs and SAEs will be collected from the start of study treatment until the follow-up contact, or Day 19 (end of treatment), in case of subjects without skin biopsies.

Treatment emergent adverse events (TEAEs)

AEs with onset during the on-treatment phase

Baseline

Last observation collected prior to application of first dose of study drug.

Last observation carried forward (LOCF)

The last observed value (either scheduled or unscheduled) carried forward and used for all subsequent scheduled points where the data is missing.

3.2 Analysis variables

3.2.1 Pharmacokinetic variables Not applicable.

3.2.2 Pharmacodynamic variables With the subject’s consent, tissue sample(s) will be collected during this study and may be used for the purposes of measuring novel biomarkers to identify factors that may influence psoriasis, and/or medically related conditions, as well as the biological and clinical responses to GSK2981278.

Four 3 mm punch biopsies scheduled on the Day 19 visit will be performed after all the observer assessments are complete.

Biomarker analysis in skin biopsies will be conducted using gene expression analysis of relevant biomarkers reported to be modulated by GSK2981278. These biomarkers include, but are not limited to, IL-17A, IL-17F, DEFB4A, IL-19, IL-36, CCL20, S100A7a, IL-8, and Krt6A. The analysis of these PD biomarkers will allow for investigation of target engagement of GSK2891278 in the study.

Skin biopsies will be collected from at least 8 consenting subjects for PD biomarker evaluation.

The statistical analysis of the gene expression data will not be part of this SAP.

15

CONFIDENTIAL 2016N274225_00201465


Page 16 of 22


3.2.3 Efficacy variable(s)

Infiltrate thickness by ultrasound measurement An objective parameter of efficacy is the evaluation of the infiltrate thickness by ultrasound measurement (refer to CTP section 7.2). The ultrasound measurements of the ELB representing the thickness of the psoriatic infiltrate as a surrogate allows for greatly improved discrimination and sensitivity compared to clinical assessment.

The efficacy variable is the change from baseline in infiltrate thickness on Day 4, 8, 15 and 19 as assessed by measurement of the thickness of the ELB of the psoriatic infiltrate using 22-MHz sonography.

Clinical assessment of improvement The efficacy signal can also be based on the clinical assessment of improvement of the test site(s) using the following 5-point score:

-1 = worsened

0 = unchanged (no effect)

1 = slight improvement

2 = clear improvement but not completely healed

3 = completely healed

Clinical assessment will be done after removal of treatments but before any gentle descaling necessary prior to sonography measurements. The comparison of single test fields will be made to the untreated area of plaque(s) not covered by the hydrocolloid dressing and close to the respective test field. Clinically apparent differences in erythema and infiltration will contribute to this global assessment. At Day 1 the score will be documented as “0” (unchanged).

With reference to the EMA Guideline for assessment of short-term efficacy of topical treatments [CHMP, 2004] the response to treatment will be documented as the difference between baseline and post treatment score (Day 19) for the single treated test fields, and in addition assessments will be made on Days 4, 8, and 15.

3.2.4 Safety variables Medical history and vital signs (blood pressure, pulse rate and oral temperature), ECG, Laboratory assessments (including liver chemistries) and urinalysis will be assessed at screening.

Vital signs, ECG and laboratory parameters will be performed on end of treatment Day 19.

ECG will be repeated on Day 15 and laboratory assessments on Day 8 and Day 15.

3.2.4.1 Adverse events Spontaneously noted complaints will be recorded with duration, intensity and probability of a correlation with the study preparation (see CTP, section 7.3.1).

3.2.4.2 Laboratory variables Haematology, clinical chemistry, urinalysis and additional parameters to be tested are listed in Table 2. PCI ranges are given in Table 3 to Table 5.

16

CONFIDENTIAL 2016N274225_00201465


Page 17 of 22


All laboratory tests with values that are considered clinically significantly abnormal during participation in the study should be repeated until the values return to normal or baseline. If such values do not return to normal within a period judged reasonable by the investigator, the etiology should be identified and the sponsor notified.

3.3 Analysis populations

3.3.1 Efficacy populations The primary set for efficacy analyses will be the per-protocol analysis set (PPS).

The PPS will include all randomized subjects who complied closely with the protocol. Protocol deviations are considered exclusionary, if they are deemed to interfere with the trial aims, particularly, if any of the following criterions apply:






except for treatment discontinuations, due to treatment related adverse events;

missing Day 1/baseline or Day 19 visit value or more than one missing value of the infiltrate thickness (primary variable).

Prior to breaking the blind, other criteria may be added to the list to accommodate for unforeseen events that occurred during the conduct of the trial and result in exclusionary protocol deviations. Assignment of subjects to analysis sets will be defined within the blind data review meeting.

3.3.2 Safety population Safety evaluation set (SES) will include all subjects exposed to at least 1 application of study product. The SES will be the primary set for safety analyses.

3.4 Statistical methods Descriptive statistics will be used to assess safety and tolerability objectives. An estimation approach will be used to address the efficacy study objectives, where point estimates and corresponding confidence intervals will be constructed. Two-sided p-values without adjustment for multiplicity will be provided for descriptive interpretation.

To assess the safety and tolerability of GSK2981278 ointment, adverse events and changes in laboratory parameters, ECGs, and vital signs will be evaluated. Treatment comparisons with vehicle ointment and the positive control will be based on review of descriptive statistics.

Efficacy endpoints will be compared between different doses of GSK2981278 ointment, and vehicle ointment, and the positive control. Point estimates and 95% confidence intervals will be presented for each of the differences.

The statistical evaluation will be performed using SAS® version 9.3 (Statistical Analysis System, SAS Inc., Cary, NC) software package.

17

CONFIDENTIAL 2016N274225_00201465


Page 18 of 22


Continuous data and scores will be summarized by descriptive statistics, consisting of the number of subjects, mean, standard deviation, median, minimum and maximum. Categorical data will be summarized by frequency tables, with the number of subjects and percentages and the given population.

3.4.1 Demographics and baseline characteristics Demographic and background data, consisting of age (determined as number of full years of the difference between date of informed consent and date of birth, with day of birth set to January 1st), sex, race and ethnicity assessed at screening will be summarized using descriptive statistical methods for the randomized population. Baseline characteristics as height [cm], weight [kg], BMI [kg/m²] and Fitzpatrick skin type will be presented accordingly. Other baseline assessments of safety or efficacy parameter assessed throughout the trial will be presented within the safety or efficacy analyses.

Past and current medical conditions, as well as previous and concomitant medications will be listed only, including a flag identifying the condition as past and/or current medical condition and the medication as previous and/or concomitant medication, according to the definition in section 3.1.

3.4.2 Discontinuations and dropouts Randomized subjects discontinuing the study will be listed in the clinical study report with reason for discontinuation and last study day given.

3.4.3 Efficacy analyses

3.4.3.1 Hypotheses No confirmatory hypotheses are formulated for this study. The analyses specified in section 3.4.5.2 will be interpreted non-confirmatory, and the data will be evaluated descriptively.

3.4.3.2 Statistical analyses

Reduction in psoriatic infiltrate thickness The primary efficacy endpoint is the area under the time curve (AUC) of change in infiltrate thickness [μm*day] using the linear trapezoidal rule over the changes from baseline in infiltrate thickness on Day 1, 4, 8, 15 and 19. The LOCF imputation will be applied prior to the determination of the AUC.

The AUC will be analyzed using a mixed-model repeated-measures (MMRM) analysis including a term for treatment. The treatment will be treated as repeated measures within the same subject. The MMRM model will be determined with an unstructured covariance matrix. In case the model does not converge, a covariance matrix of compound symmetry structure will be used. Pair-wise treatment comparisons (Table 10) will be performed. The primary comparison is between each active dose and the vehicle ointment. Least-square means for each treatment and for the difference between treatments, including corresponding 95% confidence interval (CI) and p-value will be presented.

In addition, for each post-baseline assessed time point, the reduction in infiltrate thickness of the psoriatic plaque(s) from baseline will be summarized using both the observed cases (OC) approach and the LOCF approach. Accordingly, the AUC based on OC only will be presented.

18

CONFIDENTIAL 2016N274225_00201465


Page 19 of 22


Pair-wise treatment comparisons (Table 10) will be performed for change in infiltrate thickness at each study visit using a MMRM model of the change from baseline in infiltrate thickness similar to that for the primary efficacy endpoint. The model will include the additional terms of visit and treatment-by-visit interaction, with treatment and visit treated as repeated measures within the same subject with an unstructured covariance matrix. The least-square mean for each treatment, an estimate of the difference between treatments, corresponding 95% CIs and p-values will be presented. In case the model does not converge, a similar model to the one for the primary efficacy endpoint will be applied, for each visit separately.

Moreover, percent change from baseline in infiltrate thickness will be assessed using descriptive statistics.


Study products:


0.03% 0.1% 0.8% 4% Vehicle ointment

positive control

GSK

2981

278

Oin

tmen

t 0.03% X X X X X

0.1% X X X X 0.8% X X X 4% X X

Vehicle X

Improvement in clinical assessment Clinical efficacy assessment using a 5-point scale (see section 3.2.3) will be evaluated for each post-baseline assessed time point. The ordinal clinical score and the cumulative total score, determined for each subject and treatment as the sum of all post-baseline assessments, will be presented by descriptive statistics. Additionally, frequency counts will be provided for the clinical scores. Missing data, for summaries and when computing the cumulative score, will be excluded for OC presentations or imputed by the LOCF approach for LOCF presentations (see section 3.5.2).

3.4.4 Safety analyses Safety will be evaluated by tabulations of extent of exposure to study drug, adverse events (AEs), vital signs and ECG parameter.

3.4.4.1 Extent of exposure to study drug The extent of exposure to study drug will be summarized by the duration of the treatment period in days (date of last removal of study drug minus date of first dose) and the number of days of dosing. For each treatment descriptive statistics and a frequency table will be presented.

3.4.4.2 Adverse events AEs will be summarized by the number of AEs and the number of subjects and percentage of subjects in the SES, having respective AEs. The presentation will be given by treatment for AEs related to a treatment site (local) and for all AEs not related to a treatment site (systemic).

Summaries of treatment-emergent AEs, treatment-related AEs, AEs leading to discontinuation of study product applications, and serious AEs will be tabulated.

19

CONFIDENTIAL 2016N274225_00201465


Page 20 of 22


AEs will be coded using the MedDRA dictionary version 18.1. All adverse event terms will be coded to the MedDRA primary pathway. Number and percentage of subjects with in each SOC and PT will be tabulated, in case of more than five TEAEs.

All AEs will be listed by subject with AE onset, seriousness, severity, relationship to study product, action taken, and outcome. A listing of each verbatim term and its assigned system organ class (SOC) and preferred term (PT) will be provided.

3.4.4.3 Laboratory analyses Each quantitative laboratory test will be summarized at every scheduled time point and as change from baseline. Subject laboratory parameter profiles (screening and Days 8, 15 and 19) meeting the PCI criteria given in Table 3 to Table 5 will be listed with the measurement flagged as high or low, in relation to the PCI ranges.

3.4.4.4 ECG ECG value and change from baseline at every scheduled time point for each ECG parameter will be summarized using descriptive statistics. All findings will be presented in a listing.

Subject ECG parameter profiles (screening, Days 15 and 19) with any measurement meeting any PCI criteria given in Table 6 and discontinuation criteria in Table 8 and Table 9 will be listed, with the measurement flagged as high or low, in relation to the ranges.

3.4.4.5 Other safety analyses Vital sign value and change from baseline at Day 19 for each vital sign parameter will be summarized using descriptive statistics.

Subject vital sign parameter profiles (screening and Day 19) with any measurement meeting any PCI criteria given in Table 7 will be listed with the measurement flagged as high or low, in relation to the PCI criteria.

If applicable, liver event data will be listed.

3.4.5 Pharmacodynamic and pharmacokinetic analyses Not applicable.

3.5 Data handling conventions For this study subject data will be entered into GSK/bioskin defined eCRFs (Medrio

eClinical Software Release 34), transmitted electronically to GSK or designee and combined with data provided from other sources in a validated clinical database system.

Management of clinical data will be performed in accordance with applicable GSK/bioskin standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA (Medical Dictionary for Regulatory Activities) version 18.1 and an internal validated medication dictionary, GSKDrug, version 1.3.

Exported SAS® datasets will comprise the SAS® Database. Once all questions are resolved, the database will be locked. The locked SAS® Database will be used to generate a SDTM version 1.3 compliant

representation of the clinical database.

20

CONFIDENTIAL 2016N274225_00201465


Page 21 of 22


The SDTM domains will be used to generate the subject listings, tabulations, and analyses according to the ADaM (version 2.1, ADaMIG version version 1.0) CDISC standard.

3.5.1 Baseline definitions Table 11 Baseline data definitions

Baseline data definition obtained on/at

Age, height, weight screening

Physical examination screening

Vital signs (heart rate, blood pressure, oral temperature) screening

ECG screening

Haematology, clinical chemistry, routine urinalysis screening

Sonography Day 1

3.5.2 Missing data A description of missing data will be provided in the clinical study report.

In general, data of dropouts will be included in safety and tolerability analyses, but will be excluded from efficacy analyses in the PPS (for details see section 3.2).

Psoriatic infiltrate thickness measurements and the reduction from baseline, as well as the clinical efficacy score, will be summarized using both the observed cases (OC) approach and the last observation carried forward (LOCF) approach. The LOCF imputation will be applied prior to the determination of the AUC and the cumulative score.

No imputation will be applied for other data, except for the determination of subject’s age, where the January 1st will be used for day and month of birth.

The identification of past and current medication conditions will be based on the status of the medical condition at first dosing as assessed in the eCRF (as ongoing or not ongoing).

The identification of prior and concomitant therapies will be based on the status of the therapy at first dosing as assessed in the eCRF (as ongoing or not ongoing).

Listings will be provided with the date given.

3.5.3 Window for time points A strict adherence to the visit windows will be required. Visit window violations will be assessed during the blind data review, prior to data base closure and unblinding.

3.5.4 Unscheduled visits Outcomes of unscheduled visits will be listed. For the analysis unscheduled assessments will be assigned to the next planned, but missing, visit, or it will be used as baseline, if it is the last assessment prior to application of first dose of study drug.

3.5.5 Pooling of centers for statistical analyses Not applicable.

21

CONFIDENTIAL 2016N274225_00201465


Page 22 of 22


3.5.6 Statistical technical issues Not applicable.

3.5.7 Database related issues Not applicable.

4. Interim analysis Not applicable.

5. Software documentation The statistical evaluation will be performed at bioskin using the software package SAS (Statistical Analysis System, SAS Inc., Cary, NC).

6. References CHMP 2004 Guideline on Clinical Investigation of Medicinal Products Indicated for the Treatment of Psoriasis. EMEA/CHMP/EWP/2454/02corr.

7. Tables, listings and figures Shells will be provided for tables only and will be given in an appendix to the SAP. A listing of planned listings and figures will be provided.

22

CONFIDENTIAL 2016N274225_00201465

1. Adverse Event Term

2. Location related to test field(s)

2.1 Location, specification(if located at test fields)

3. Intensity

4. Serious AE?1

5. Onset date

6. Check if start time is notdeterminable/unknown

6.1. Start time

7. Frequency

8. Outcome

9. Stop date

10. Check if stop time is notdeterminable/unknown

10.1 Stop time

11. Reasonable causal relationship toStudy Drug

13. Action taken with Study Drug

14.1 Other action - None

14.2 Other action - Remedial drugtherapy

14.3 Other action - Other

14.3.1 Other action taken, specify

15. Did the AE led to the subject'swithdrawal from the trial?

Adverse Events at Adverse Events

0.1 Random no. [1]

Adverse Events [2]

[3]

[4]

Mild [5]

Moderate

Severe

Yes No [6]

1 Please consider completing a SAE form if any adverse event is assigned as Serious Adverse Event.

Now [7]

[8]

[9]

[10]

[11]

Now [12]

[13]

[14]

Yes No [15]

[16]

[17]

[18]

[19]

[20]

Yes No [21]

201465_350209BS_aCRF_unique_d03_20151027

1

CONFIDENTIAL 2016N274225_00201465

17. Any comments?

17.1 Comments

Yes No [22]

[23]

201465_350209BS_aCRF_unique_d03_20151027

2

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Adverse Event Term AETERM Text or Any Value 200[3] 2. Location related to test field(s) AELOC Categorical select one (nominal) 32 At test field(s)

Just around the application areaDistant from test field(s)Not applicable

[4] 2.1 Location, specification (if located at test fields) AE2LOC Categorical select one (nominal) 12 Test field 1Test field 2Test field 3Test field 4Test field 5Test field 6

[5] 3. Intensity AESEV Categorical select one (nominal) 8[6] 4. Serious AE?1 AESER Categorical yes/no (dichotomous) 3[7] 5. Onset date AESTDAT Date 11[8] 6. Check if start time is not determinable/unknown AESTTMND Categorical yes/no (dichotomous) 3[9] 6.1. Start time AESTTIM Time 5[10] 7. Frequency AEPATT Categorical select one (nominal) 14 Single episode

Intermittent[11] 8. Outcome AEOUT Categorical select one (nominal) 32 Recovered/resolved

Recovering/resolvingRecovered/resolved with sequelaeNot recovered/not resolvedFatalUnknown

[12] 9. Stop date AEENDAT Date 11[13] 10. Check if stop time is not determinable/unknown AEENTMND Categorical yes/no (dichotomous) 3[14] 10.1 Stop time AEENTIM Time 5[15] 11. Reasonable causal relationship to Study Drug AEREL Categorical select one (nominal) 3[16] 13. Action taken with Study Drug AEACN Categorical select one (nominal) 16 Drug withdrawn

Dose not changedNot applicableUnknown

[17] 14.1 Other action - None AEACNOTN Categorical yes/no (dichotomous) 3[18] 14.2 Other action - Remedial drug therapy AEACNOTD Categorical yes/no (dichotomous) 3[19] 14.3 Other action - Other AEACNOTO Categorical yes/no (dichotomous) 3[20] 14.3.1 Other action taken, specify AEACOTHS Text or Any Value 200[21] 15. Did the AE led to the subject's withdrawal from

the trial?AEDIS Categorical yes/no (dichotomous) 3

[22] 17. Any comments? AECOYN Categorical yes/no (dichotomous) 3[23] 17.1 Comments COVAL Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

3

CONFIDENTIAL 2016N274225_00201465

1. Were there any Adverse Events?

2. Did the subject experience aserious adverse event during the

study?

Adverse Events Yes/No at Adverse Events

0.1 Random no. [1]

Any Adverse EventsYes No [2]

If any adverse events occurred during the trial, please consider adding an Adverse Event form for each at visit Adverse Events..

Yes No [3]

If any serious adverse events occurred during the trial, please consider adding an SAE form for each.

201465_350209BS_aCRF_unique_d03_20151027

4

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Were there any Adverse Events? AEYN Categorical yes/no (dichotomous) 3[3] 2. Did the subject experience a serious adverse

event during the study?SAEYN Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

5

CONFIDENTIAL 2016N274225_00201465

1. Have biopsies been collected forthis subject?1

2. Actual date of collection

3. Actual time of collection

Biopsies at EoT / ET (Day 19)

0.1 Random no. [1]

Skin biopsiesFour 3mm punch biopsies will be collected from each consenting subject.

Yes No Not Applicable [2]

1 Please capture Yes or No if biopsy sample collection was planned and capture Not Applicable if the subject did not consent for biopsy sample collection..

Now [3]

[4]

4. Biopsy No. [5]

5. Biopsy taken [6] 6. Sample ID [7]

1 #1 Yes No

2 #2 Yes No

3 #3 Yes No

4 #4 Yes No

201465_350209BS_aCRF_unique_d03_20151027

6

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Have biopsies been collected for this subject?1 LBPERF Categorical select one (nominal) 14[3] 2. Actual date of collection LBDAT Date 11[4] 3. Actual time of collection LBTIM Time 5[5] 4. Biopsy No. MISPID Categorical select one (nominal) 2 #1

#2#3#4

[6] 5. Biopsy taken MIPERF Categorical select one (nominal) 3[7] 6. Sample ID MIREFID Number (continuous) 15

201465_350209BS_aCRF_unique_d03_20151027

7

CONFIDENTIAL 2016N274225_00201465

1. Has any biopsy been collected?

Biopsies specific (liver) at Liver event

Liver biopsyYes No [1]

.

2. Date ofassessment [2]

2.1 Visit related to thedate first detected [3]

3.Specimen [4]

4. Biopsysize [5]

5. Biopsy sizeunit [6]

5.1 Biopsy sizeunit, other [7]

6. Parameter [8]

7. Result(Please enter a codefrom the list below) [9]

8. Biopsy result other specification [10]

1 Liverbiopsy

More rows: 1 5 10

A0 NormalA1 Acute hepatitisA2 Chronic hepatitisA3 Cholestatic hepatitisA4 Drug-induced cholestasis A5 Acute viral hepatitis A6 Chronic viral hepatitis A7 Drug-induced hepatitis A8 Autoimmune hepatitis A9 Bridging necrosis A10 Submassive hepatic necrosis A11 Massive hepatic necrosis A12 Steatosis - microvesicular A13 Steatosis - macrovesicular A14 Steatosis - mixed A15 Non-alcoholic steatohepatitis A16 Alcoholic hepatitis A17 Hepatic granulomas A18 Sarcoidosis A19 Fibrosis A20 C irrhosis A21 Primary biliary cirrhosis A22 Primary sclerosing cholangitis A23 Autoimmune overlap syndrome A24 Hemochromatosis A25 Alpha-1-antitrypsin deficiency A26 Wilson's disease A27 Veno-occlusive disease A28 Budd-Chiari syndrome A29 NeoplasiaA99 Other specify

201465_350209BS_aCRF_unique_d03_20151027

8

CONFIDENTIAL 2016N274225_00201465

B1 NormalB2 Bridging fibrosis B3 Diffuse fibrosis B4 Nodular regenerative hyperplasia B5 Congenital hepatic fibrosis B6 C irrhosis B7 Centrilobular congestion B8 Endophlebitis B9 Veno-occlusive disease B10 Canalicular cholestasis B11 Apoptosis B12 Focal (or spotty or mild) hepatocellular necrosis B13 Interface hepatitis (periportal hepatitis or piecemeal necrosis) B14 Ischaemic necrosis B15 Centrolobular (Zone 3) necrosis B16 Focal coagulative necrosis B17 Centrolobular (Zone 3) coagulative necrosis B18 Bridging hepatocellular necrosis B19 Massive, or panlobular hepatocellular necrosis B20 Dysplasia B21 Neoplasia B99 Other specify

C0 Normal C1 Ballooning C2 Acidophilic C3 Pseudoxanthomatous C4 Multinucleated giant hepatocytes C99 Other specify

D0 No inclusions D1 Macrovesicular steatosis D2 Microvesicular steatosis D3 Bile accumulation D4 Diastase-resistant, PAS-positive cytoplasmic inclusions D5 Alpha-1-antitrypsin inclusions D6 Megamitochondria D7 Mallory bodies D8 "Ground Glass" inclusions D9 Lipofuscin pigment D10 Hemosiderin granules D11 Orcein-positive cytoplasmin granules D12 Protoporphyrin crystals (birefringent under polarised light) D13 Uroporphyrin crystals (red fluorescence under ultraviolet light) D99 Other specify

E0 None E1 Hepatocellular mitosis E2 Binucleated or multinucleated hepatocytes E3 CMV inclusion bodies E4 HSV inclusions E5 Varicella inclusions E99 Other specify

F0 None F1 Eosinophils F2 Lymphocytes F3 Plasma cells F4 Neutrophils F5 Macrophages and proliferating Kupffer cells F6 Granulomas F99 Other specify

201465_350209BS_aCRF_unique_d03_20151027

9

CONFIDENTIAL 2016N274225_00201465

G0 NoneG1 Eosinophils G2 Lymphoid aggregates and/ or follicles G3 Plasma cells G4 Neutrophils G5 Histocytes and macrophages G99 Other specify

H0 Normal H1 Proliferation of bile ducts (bile ductular reaction). H2 Dilation, degeneration or disruption of portal bile ducts H3 Paucity of bile ducts H4 Periductal fibrosis H99 Other specify

I0 Normal I1 Pyelophlebitis I2 Thrombosis, sclerosis, or occlusion of portal vein I3 Neoplastic invasion of portal vein I4 Granulomatous compression of portal vein I99 Other specify

J0 Normal J1 Leishmaniasis donovani J2 Plasmodium falciparum J3 Toxoplasmosis J4 C ryptococcus neoformans J5 Histoplasma capsulatum J6 Mycobacterium tuberculosis J7 Other mycobacterial species J99 Other specify

K0 NoneK1 Schistosome and/or ovaK2 Ascaris and/or ova K3 Toxocara and/or ova K4 Echinococcus cysts K5 Hepatic capillariasis worms and/or ova K99 Other specify

L1 Hematoxylin and eosin (or H&E)L2 Masson L3 Toluidine blue or Giemsa L4 Prussian blue L5 Periodic Acidic Schiff (PAS), with or without diastase L6 Oil red O L7 Congo red L8 Hall's stain L9 Gridley's stain L10 Rhodanine (copper) L11 Rubeanic acid (copper) L12 Orcein, aldehyde fuchsin, or Victoria blue L13 Electron microscopy L14 Hepatitis A immunostains positive L15 Hepatitis B core antigen or hepatitis B surface antibody immunostains positive L16 Hepatitis D immunostains L17 Other immunostainsL99 Other specify

201465_350209BS_aCRF_unique_d03_20151027

10

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Has any biopsy been collected? MIPERF Categorical yes/no (dichotomous) 3[2] 2. Date of assessment MIDAT Date 11[3] 2.1 V isit related to the date first detected VISIT Categorical select one (nominal) 17 Screening

Day 1Day 2Day 3Day 4Day 5Day 6Day 8Day 9Day 10Day 11Day 12Day 13Day 15Day 16Day 17Day 18EoT / ET (Day 19)Day 27Unscheduled visit

[4] 3. Specimen MISPEC Categorical select one (nominal) 12[5] 4. Biopsy size MISTRESN Number (continuous) 15[6] 5. Biopsy size unit MISTRESU Categorical select one (nominal) 5 mm2

cm2Other

[7] 5.1 Biopsy size unit, other MISTRESO Text or Any Value 40[8] 6. Parameter MITESTCD Categorical select one (nominal) 39 Bile ducts

Final diagnosisDescription of liver cells/hepatocytesLiver cell/hepatocyte inclusion/vacuoleHepatocyte/liver cell nuclear abnormHistologic staining/add studiesLiver architectureLiver or lobular infiltratesLiver infectionsParasites or ovaPortal tract inflammationPortal veins

[9] 7. Result (Please enter a code from the list below) MIORRES Text or Any Value 3[10] 8. Biopsy result other specification MI2ORRES Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

11

CONFIDENTIAL 2016N274225_00201465

1. Blood sample collected?

2. Actual time of blood samplecollection

Blood sample collection at Screening

Blood sample collection (Hematology, Clinical Chemistry [HIV, Hep B, and Hep C at Screening only])

Yes No [1]

[2]

201465_350209BS_aCRF_unique_d03_20151027

12

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Blood sample collected? LBSTAT Categorical yes/no (dichotomous) 3[2] 2. Actual time of blood sample collection LBTIM Time 5

201465_350209BS_aCRF_unique_d03_20151027

13

CONFIDENTIAL 2016N274225_00201465

1. Blood sample collected?

2. Actual time of blood samplecollection

Blood sample collection at Day 8,Day 15,EoT / ET (Day 19),Unscheduled Visit

0.1 Random no. [1]

Blood sample collection (Hematology, Clinical Chemistry [HIV, Hep B, and Hep C at Screening only])

Yes No [2]

[3]

201465_350209BS_aCRF_unique_d03_20151027

14

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Blood sample collected? LBSTAT Categorical yes/no (dichotomous) 3[3] 2. Actual time of blood sample collection LBTIM Time 5

201465_350209BS_aCRF_unique_d03_20151027

15

CONFIDENTIAL 2016N274225_00201465

1. Clinical assessment performed?

2. Clinical assessment time

Clinical assessment of efficacy at Day 1 (Baseline procedures)

0.1 Random no. [1]

Clinical efficacy assessmentYes No [2]

[3]

.At day 1 the score will be evaluated with "0 - unchanged" for all test fields. .Please assess each test field (compared to surrounding plaque skin) for the specific criteria by chosing the applicable score from the drop down list..

3. Test field [4] 3.1 Check only if assessment for test field was not done [5] 4. Result [6]

1 Test field 1

2 Test field 2

3 Test field 3

4 Test field 4

5 Test field 5

6 Test field 6

201465_350209BS_aCRF_unique_d03_20151027

16

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Clinical assessment performed? SRPERF Categorical yes/no (dichotomous) 3[3] 2. Clinical assessment time SRTIM Time 5[4] 3. Test field SRSPID Categorical select one (nominal) 12 Test field 1

Test field 2Test field 3Test field 4Test field 5Test field 6

[5] 3.1 Check only if assessment for test field was notdone

SRSTAT Categorical yes/no (dichotomous) 3

[6] 4. Result SRORRES Categorical select one (nominal) 47 -1 = worsened0 = unchanged (no effect)1 = slight improvement2 = clear improvement but not completely healed3 = completely healed

201465_350209BS_aCRF_unique_d03_20151027

17

CONFIDENTIAL 2016N274225_00201465

1. Clinical assessment performed?

2. Clinical assessment time

Clinical assessment of efficacy at Day 8,Day 15,Unscheduled Visit,EoT / ET (Day 19),Day 4

0.1 Random no. [1]

Clinical efficacy assessmentYes No [2]

[3]

.Please assess each test field (compared to surrounding plaque skin) for the specific criteria by chosing the applicable score from the drop down list..

3. Test field [4] 3.1 Check only if assessment for test field was not done [5] 4. Result [6]

1 Test field 1

2 Test field 2

3 Test field 3

4 Test field 4

5 Test field 5

6 Test field 6

201465_350209BS_aCRF_unique_d03_20151027

18

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Clinical assessment performed? SRPERF Categorical yes/no (dichotomous) 3[3] 2. Clinical assessment time SRTIM Time 5[4] 3. Test field SRSPID Categorical select one (nominal) 12 Test field 1


[5] 3.1 Check only if assessment for test field was notdone

SRSTAT Categorical yes/no (dichotomous) 3

[6] 4. Result SRORRES Categorical select one (nominal) 47 -1 = worsened0 = unchanged (no effect)1 = slight improvement2 = clear improvement but not completely healed3 = completely healed

201465_350209BS_aCRF_unique_d03_20151027

19

CONFIDENTIAL 2016N274225_00201465

Coding ICDS at End of study / Completion

Coding ICDS.The medical coding is uploaded into the database..

1. External ID [1] 2. Protocol [2] 3. V erbat i m Text [3] 3. 1 M odi f i ed term [4] 4. Form [5] 5. Item [6] 6. Pat i ent i dent i f i er (PID ) [7] 7. Si te [8] 8. V i si t [9] 9. N arrat i ve [10] 10. Indi cat i on [11] 11. 1 R oute Code [12] 11. 2 R oute Text [13] 12. D ose [14] 13. 1 D ose uni t Code [15] 13. 2 D ose uni t Text [16] 14. 1 D ose f ormul at i on Code [17] 14. 2 D ose f ormul at i on Text [18] 15. 1 A ppl i cat i on si te Code [19] 15. 2 A ppl i cat i on si te Text [20] 16. Sex [21] 17. Country [22] 18. Language [23] 19. Internal ID [24] 20. D i ct i onary [25] 21. 1 Encoded [26] 21. 2 Encoded synonym [27] 21. 3 Encoded Code [28] 21. 4 Encoded D ate [29] 21. 5 Encoded Text [30] 22. 1 O pen Q uery [31] 22. 2 Q uery U ser Id [32] 22. 3 Q uery U ser N ame [33] 22. 4 Q uery U ser Emai l [34] 23. 1 Q uery R esponse [35] 23. 2 R esponse U ser Id [36] 23. 3 R esponse U ser N ame [37] 23. 4 R esponse U ser Emai l [38]

1

M or e r ow s: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

20

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. External ID XCREFID Text or Any Value 150[2] 2. Protocol XCGRPID Text or Any Value 50[3] 3. Verbatim Text XCTERM Text or Any Value 2000[4] 3.1 Modified term XCMODIFY Text or Any Value 2000[5] 4. Form XCFORM Text or Any Value 50[6] 5. Item XCITEM Text or Any Value 50[7] 6. Patient identifier (PID) XCSUBJID Text or Any Value 50[8] 7. Site XCSITEID Text or Any Value 50[9] 8. V isit XCVISIT Text or Any Value 60[10] 9. Narrative XCDESC Text or Any Value 2000[11] 10. Indication XCINDC Text or Any Value 200[12] 11.1 Route Code XCROUTE Text or Any Value 10[13] 11.2 Route Text XCROUTET Text or Any Value 60[14] 12. Dose XCDOSE Text or Any Value 40[15] 13.1 Dose unit Code XCDOSEU Text or Any Value 10[16] 13.2 Dose unit Text XCDOSEUT Text or Any Value 10[17] 14.1 Dose formulation Code XCDOSFRM Text or Any Value 10[18] 14.2 Dose formulation Text XCDOSFRT Text or Any Value 100[19] 15.1 Application site Code XCSPID Text or Any Value 10[20] 15.2 Application site Text XCSPIDT Text or Any Value 60[21] 16. Sex XCSEX Text or Any Value 1[22] 17. Country XCCOUNTR Text or Any Value 2[23] 18. Language XCLANG Text or Any Value 2[24] 19. Internal ID XC2REFID Text or Any Value 200[25] 20. Dictionary XCDICT Text or Any Value 200[26] 21.1 Encoded XCENCDYN Text or Any Value 200[27] 21.2 Encoded synonym XCENCDS Text or Any Value 2000[28] 21.3 Encoded Code XCENCDCD Text or Any Value 200[29] 21.4 Encoded Date XCENCDDT Text or Any Value 60[30] 21.5 Encoded Text XCENCDT Text or Any Value 2000[31] 22.1 Open Query XCQUERT Text or Any Value 4000[32] 22.2 Query User Id XCQUERID Text or Any Value 200[33] 22.3 Query User Name XCQUERNM Text or Any Value 200[34] 22.4 Query User Email XCQUERML Text or Any Value 200[35] 23.1 Query Response XCRESPT Text or Any Value 4000[36] 23.2 Response User Id XCRESPID Text or Any Value 200[37] 23.3 Response User Name XCRESPNM Text or Any Value 200[38] 23.4 Response User Email XCRESPML Text or Any Value 200

201465_350209BS_aCRF_unique_d03_20151027

21

CONFIDENTIAL 2016N274225_00201465

1. Date of last visit

Date of Last Visit at End of study / Completion

0.1 Random no. [1]

Date of Last Visit Now [2]

201465_350209BS_aCRF_unique_d03_20151027

22

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Date of last visit DSSTDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

23

CONFIDENTIAL 2016N274225_00201465

1. Did the subject die?

2. Date of death

3. Time of death

Death at End of study / Completion

DeathYes No [1]

[2]

[3]

201465_350209BS_aCRF_unique_d03_20151027

24

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Did the subject die? DSCONT Categorical yes/no (dichotomous) 3[2] 2. Date of death DSSTDAT Date 11[3] 3. Time of death DSSTTIM Time 5

201465_350209BS_aCRF_unique_d03_20151027

25

CONFIDENTIAL 2016N274225_00201465

1. Year of birth

2.1 Age (calculated)

3. Sex

4.1 White

4.1.1 White, heritage

4.2 Black or African American

4.3 Asian

4.2.1 Asian, heritage

4.4 American Indian or Alaska Native

4.5 Native Hawaiian or Other PacificIslander

4.6 Other race

4.6.1 Race, other

5. Ethnic origin

6. Height [cm]

7. Weight [kg]

Demographic data at Screening

Demographic data

[1]

The age is calculated from Date of informed consent subtracted 01/01/[Year of birth].

[2]

Male Female [3]

4. Race:

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

.

Hispanic or Latino Not Hispanic or Latino [13]

.Height and Weight

[14]

[15]

201465_350209BS_aCRF_unique_d03_20151027

26

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Year of birth BRTHYR Number (continuous) 15[2] 2.1 Age (calculated) AGEC Number (continuous) 15[3] 3. Sex SEX Categorical select one (nominal) 6[4] 4.1 White RACEWHIT Categorical yes/no (dichotomous) 3[5] 4.1.1 White, heritage RACEWHIH Categorical select one (nominal) 33 White/Caucasian/European Heritage

Arabic/North African Heritage[6] 4.2 Black or African American RACEBLCK Categorical yes/no (dichotomous) 3[7] 4.3 Asian RACEASIA Categorical yes/no (dichotomous) 3[8] 4.2.1 Asian, heritage RACEASIH Categorical select one (nominal) 28 Central/South Asian Heritage

East Asian HeritageJapanese HeritageSouth East Asian Heritage

[9] 4.4 American Indian or A laska Native RACEINDI Categorical yes/no (dichotomous) 3[10] 4.5 Native Hawaiian or Other Pacific Islander RACEHAWA Categorical yes/no (dichotomous) 3[11] 4.6 Other race RACEOTH Categorical yes/no (dichotomous) 3[12] 4.6.1 Race, other RACEOTHS Text or Any Value 200[13] 5. Ethnic origin ETHNIC Categorical select one (nominal) 22[14] 6. Height [cm] VSHEIGHT Number (continuous) 15[15] 7. Weight [kg] VSWEIGHT Number (continuous) 15

201465_350209BS_aCRF_unique_d03_20151027

27

CONFIDENTIAL 2016N274225_00201465

1. Is/Was a descaling necessary?

Descaling at Screening

DescalingYes No [1]

201465_350209BS_aCRF_unique_d03_20151027

28

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Is/Was a descaling necessary? PRNECYN Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

29

CONFIDENTIAL 2016N274225_00201465


1.1 Descaling performed?

2. Descaling start date

3. Descaling stop date

Descaling at Day 1 (Baseline procedures)

0.1 Random no. [1]

DescalingYes No [2]

.

Yes No [3]

[4]

[5]

201465_350209BS_aCRF_unique_d03_20151027

30

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Is/Was a descaling necessary? PRNECYN Categorical yes/no (dichotomous) 3[3] 1.1 Descaling performed? PRPERF Categorical yes/no (dichotomous) 3[4] 2. Descaling start date PRSTDAT Date 11[5] 3. Descaling stop date PRENDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

31

CONFIDENTIAL 2016N274225_00201465


1.1 Descaling performed?

Descaling at Day 15,Day 8,EoT / ET (Day 19),Unscheduled Visit,Day 4

0.1 Random no. [1]

DescalingYes No [2]

.

Yes No [3]

201465_350209BS_aCRF_unique_d03_20151027

32

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Is/Was a descaling necessary? PRNECYN Categorical yes/no (dichotomous) 3[3] 1.1 Descaling performed? PRPERF Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

33

CONFIDENTIAL 2016N274225_00201465

1. Start date of deviation

2. Deviation description

3. Deviation category

4.1 Informed consent, subcategory

4.3 Withdrawn, subcategory

4.4 Medications, subcategory

4.5 Visit, subcategory

4.6 Assessment, subcategory

4.7 Treatment, subcategory

4.8 Study procedures, subcategory

4.9 Failure to report safety events,subcategory

5. Has this deviation beendetermined to be important by the

study team?

6. Population Analysis ExclusionCriteria

7. Excluded from DV analysisreporting flag

Deviations at Protocol Deviations

0.1 Random no. [1]

Protocol deviations Now [2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

Yes No [13]

Yes No [14]

Yes No [15]

201465_350209BS_aCRF_unique_d03_20151027

34

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Start date of deviation DVSTDAT Date 11[3] 2. Deviation description DVTERM Text or Any Value 1000[4] 3. Deviation category DVCAT Categorical select one (nominal) 50 Informed consent

Eligibility criteria not metNot withdrawn after developing withdrawal criteriaExcluded medication, vaccine or deviceV isit completionAssessment or time point completionWrong study treatment/ administration/ doseStudy ProceduresFailure to report safety events per protocol

[5] 4.1 Informed consent, subcategory DV1SCAT Categorical select one (nominal) 77 Signed informed consent/assent not available on siteWrong informed consent/assent version signedInformed consent/assent not signed and/or dated by subject (parent/Legal rep)Informed consent/assent not signed and/or dated by appropriate site staffInformed consent/assent not signed prior to any study procedureOther informed consent/assent deviations

[6] 4.3 Withdrawn, subcategory DV3SCAT Categorical select one (nominal) 75 Not withdrawn from studyNot discontinued from study treatmentOther deviation of not being withdrawn after developing withdrawal criteria

[7] 4.4 Medications, subcategory DV4SCAT Categorical select one (nominal) 54 Medication, excluded by the protocol, was administeredVaccine, excluded by the protocol, was administeredOther excluded medication, vaccine or device deviation

[8] 4.5 V isit, subcategory DV5SCAT Categorical select one (nominal) 33 Missed visit/phone contactOut of window visit/phone contact

[9] 4.6 Assessment, subcategory DV6SCAT Categorical select one (nominal) 61 Missed assessmentIncomplete assessmentAssessment not properly performedOut of Window efficacy assessmentOut of Window safety assessmentOut of Window treatment administrationOut of Window biomarker collection or exploratory assessment

[10] 4.7 Treatment, subcategory DV7SCAT Categorical select one (nominal) 80 Study treatment not administered per protocolWrong study treatment or assignment administeredExpired study treatment administeredUse of study TRT impacted by temperature excursion - notreported/approved/disap

[11] 4.8 Study procedures, subcategory DV8SCAT Categorical select one (nominal) 80 Randomisation procedure (subj assigned to wrong stratum, subj rand out oforder)Study blinding/unblinding proceduresNon study treatment supply proceduresEquipment proceduresPost study treatment observation not doneBiological sample specimen procedures

[12] 4.9 Failure to report safety events, subcategory DV9SCAT Categorical select one (nominal) 70 Serious Adverse EventsAdverse Events of Special InterestPregnancyLiver function abnormalities per protocolSAE not reported within the expected time frameFailure to confirm causality assessment within the expected time frame

[13] 5. Has this deviation been determined to beimportant by the study team?

DVCLSIG Categorical yes/no (dichotomous) 3

[14] 6. Population Analysis Exclusion Criteria DVPOPEXC Categorical yes/no (dichotomous) 3[15] 7. Excluded from DV analysis reporting flag DVXARFL Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

35

CONFIDENTIAL 2016N274225_00201465

1. Any deviations detected/occurredfor this subject?

Deviations Yes/No at Protocol Deviations

Random no. [1]

Any deviationsYes No [2]

If any deviations occurred during the trial, please consider adding a Deviations form for each at visit Protocol deviations.

201465_350209BS_aCRF_unique_d03_20151027

36

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Any deviations detected/occurred for this

subject?DVYN Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

37

CONFIDENTIAL 2016N274225_00201465

1. ECG measurement performed?

2. Actual time of ECG measurement

8. Any findings?

ECG at Screening

12-lead Safety ECG (Supine Position)Yes No [1]

[2]

.

3. ECG parameter/outcome [3] 3.1 Check only if parameter not done / not measured [4] 4. Result [5] 5. Method of QTc calculation [6] 6. ECG Interpretation [7] 7. Clinically significant [8]

1 PR interval [msec] Manual Machine Yes No

2 QRS interval [msec] Manual Machine Yes No

3 QT interval [msec] Manual Machine Yes No

4 QTcB interval [msec] Manual Machine Yes No

5 RR interval [msec] Manual Machine Yes No

6 Heart rate [beats/min] Manual Machine Yes No

7 Interpretation Manual Machine Yes No

Yes No [9]

Please add any clinical significant findings in the table below. Add for each row one of the listed code (e.g. A35). If further specification is necessary for terms with "other" add description into the text field (8.2. Other, specify).

8.1 ECG findings [10] 8.2 Other, specify [11]

1

More rows: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

38

CONFIDENTIAL 2016N274225_00201465

A36 - ArrhythmiaA16 - Artificial pacemakerA8 - Atrial fibrillationA7 - Atrial flutterA35 - Atrial premature complexA13 - BigeminyA4 - Ectopic supraventricular beatsA20 - Ectopic supraventricular rhythmA9 - Ectopic ventricular beatsA14 - Electrical alternansA43 - Idioventricular rhythmA19 - Idioventricular rhythm - heart rate < 100 beats/minA40 - Junctional escape complexesA25 - Junctional rhythm A5 - Junctional rhythm (<=100/min)A46 - Junctional tachycardiaA24 - Junctional tachycardia (heart rate >100 beats/min)A30 - Monomorphic ventricular tachycardiaA39 - Multifocal atrial tachycardiaA26 - Multifocal atrial tachycardia (wandering atrial pacemaker w/rate >100 beats/min)A37 - Multifocal premature ventricular complexesA11 - Non-sustained ventricular tachycardiaA34 - Normal sinus rhythmA99 - Other abnormal rhythmA31 - Polymorphic (sustained and non-sustained) ventricular tachycardiaA29 - R on T phenomenonA33 - Sinus arrhythmiaA1 - Sinus bradycardiaA23 - Sinus bradycardia (heart rate <30 beats/min)A22 - Sinus bradycardia (heart rate 30-39 beats/min)A21 - Sinus bradycardia (heart rate 40-50 beats/min)A3 - Sinus pauseA44 - Sinus tachycardiaA2 - Sinus tachycardia (heart rate > 100 beats/min)A41 - Supraventricular tachycardiaA6 - Supraventricular tachycardia (>100/min)A10 - Sustained ventricular tachycardiaA15 - Torsade de Pointes (TdP)A28 - TrigeminyA12 - Ventricular coupletsA18 - Ventricular fibrillationA182 - Ventricular fibrillation non-sustainedA181 - Ventricular fibrillation sustainedA38 - Ventricular flutter A45 - Ventricular premature complexesA27 - Ventricular tachycardiaA17 - Wandering atrial pacemakerA32 - Wide QRS Tachycardia (diagnosis unknown)

B5 - Intraatrial conduction delayB16 - Late R wave transitionB9 - Left atrial abnormalityB1 - Left atrial abnormality (P mitrale)B6 - Left ventricular hypertrophyB99 - Other morphologyB7 - Poor R wave progression B10 - Right atrial abnormality B2 - Right atrial abnormality (P pulmonale) B3 - Right ventricular hypertrophy B15 - Unusual P axis

201465_350209BS_aCRF_unique_d03_20151027

39

CONFIDENTIAL 2016N274225_00201465

C32 - 1st degree AV block (PR interval >240msec)C16 - 2:1 AV blockC11 - Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine)C18 - AV dissociationC17 - Bifascicular blockC35 - Diagnostic Q waveC24 - First degree A-V blockC1 - First degree AV block (PR interval > 200msec)C13 - Incomplete left bundle branch blockC7 - Incomplete right bundle branch blockC25 - Intra ventricular conduction delayC14 - Left anterior hemiblock (synonymous to left anterior fascicular block)C26 - Left axis deviationC5 - Left axis deviation (QRS axis more negative than -30 degrees)C9 - Left bundle branch blockC15 - Left posterior hemiblock (synonymous to left posterior fascicular block)C10 - Non-specific intraventricular conduction delay (QRS >= 120 msec)C99 - Other conductionC29 - Prolonged QT >500 msecC28 - Prolonged QT 450-500 msecC19 - Prolonged QT intervalC31 - Prolonged QTc Interval >500 msecC30 - Prolonged QTc Interval 450-500 msecC12 - QT/QTc prolongation >= 500 msecC21 - QTcB prolongation > 500 msecC23 - QTcF prolongationC22 - QTcF prolongation > 500 msecC27 - Right axis deviationC6 - Right axis deviation (QRS axis more positive than +110 degrees)C8 - Right bundle branch blockC2 - Second degree AV block (Mobitz type 1)C3 - Second degree AV block (Mobitz type 2)C20 - Short PR IntervalC34 - Short QTc intervalC4 - Third degree AV blockC33 - Trifascicular blockD23 - Atrial premature depolarizationD26 - Early R wave progressionD27 - Early repolarisationD14 - Increased voltage consistent with left ventricular hypertrophyD19 - J point elevationD22 - Juvenile Twave pattern, early repolarizationD13 - Low QRS voltageD2 - Myocardial infarction, anteriorD5 - Myocardial infarction, inferiorD3 - Myocardial infarction, lateralD20 - Myocardial infarction, non Q-waveD1 - Myocardial infarction, oldD4 - Myocardial infarction, posteriorD6 - Myocardial infarction, septalD7 - Non-specific ST-T changesD18 - Notched T-wavesD99 - Other depolarisation/repolarisationD98 - Other myocardial infarctionD25 - Pathological Q wavesD9 - ST depressionD8 - ST elevationD96 - ST segment abnormalityD21 - ST-elevation - pericarditisD97 - T wave abnormalityD24 - T wave alternansD17 - T wave flattening inversionD11 - T wave inversionD12 - T wave peakedD16 - T waves biphasicD15 - T waves flatD10 - U waves abnormal

201465_350209BS_aCRF_unique_d03_20151027

40

CONFIDENTIAL 2016N274225_00201465

XC8 - 1ST degree AV block PR 180-240XC9 - 1st degree block (PR interval > 250 msec)XA14 - Atrial fibrillation with rapid ventricular response (>120 bpm)XA4 - Atrial fibrillation with rapid ventricular response (rate > 100 bpm)XA16 - Atrial fibrillation with ventricular rate < 120 bpmXA10 - Atrial fibrillation with ventricular rate <= 100 bpmXA19 - Atrial fibrillation with ventricular rate <=120bpmXA15 - Atrial flutter with rapid ventricular response (>120 bpm)XA17 - Atrial flutter with ventricular rate <= 120 bpmXD6 - Dynamic horizontal/down-sloping depressionXD1 - Frequent ventricular premature depolarization (VPD) >= 3XA5 - Increase in Heart Rate >= 40 bpm relative to baselineXC23 - Increase in QTcF (30-60 msec) relative to baselineXC7 - Increase in QTcF >60 msec relative to baselineXD12 - Ischemic T wave inversion >= 0.1 mV in 2 or more contiguous leadXD2 - Occasional ventricular premature depolarization (VPD) <3XD4 - Persistent ST elevationXD7 - Persistent ST elevation >= 0.1 mV in 2 or more leadsXC19 - Prolonged QTc >= 30 msec relative to baselineXC20 - Prolonged QTc >= 60 msec relative to baselineXC12 - QRS duation < 120 ms and QTc(F) >= 500 msecXC10 - QRS duration < 120 ms and QTc (F) >= 450 msecXC24 - QRS duration <= 120 ms and QTc(F) >= 500 msecXC11 - QRS duration >= 120 ms and QTc(F) >= 480 msecXC13 - QRS duration >= 120 ms and QTc(F) >= 530 msecXC25 - QRS duration >120 ms and QTc(F) >= 530 msecXC1 - QT> 600 msec XC22 - QTcF> 530 msec XC2 - QTcF> = 450 msecXC3 - Right bundle branch block with QTc(F) < 480XC5 - Right bundle branch block with QTc(F) < 530XC4 - Right bundle branch block with QTc(F) >= 480XC6 - Right bundle branch block with QTc(F) >= 530XC21 - Sinus arrest or blockXA3 - Sinus bradycardia < 37 bpmXA9 - Sinus bradycardia < 50 bpmXA8 - Sinus bradycardia < 55 bpmXA2 - Sinus bradycardia <45 bpmXA11 - Sinus tachycardia > 120 bpmXA1 - Sinus tachycardia >= 110 bpmXA7 - Sinus tachycardia >= 115 bpmXA6 - Sinus tachycardia >= 125 bpmXA13 - Sinus Tachycardia=>120 bpmXD10 - ST depression >= 0.05 to <0.1 mV in 2 or more leadsXD9 - ST depression >= 0.1 mV in 2 or more contiguous leadsXD3 - ST-T wave abnormalities with the exception of non-specific changesXA18 - Supraventricular tachycardia (>100/min) non-sustainedXA12 - Supraventricular tachycardia (>120 bpm)XD5 - Transient ST elevationXD8 - Transient ST elevation >= 0.1 mV in 2 or more leads

201465_350209BS_aCRF_unique_d03_20151027

41

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. ECG measurement performed? EGPERF Categorical yes/no (dichotomous) 3[2] 2. Actual time of ECG measurement EGTIM Time 5[3] 3. ECG parameter/outcome EGTESTCD Categorical select one (nominal) 22 PR interval [msec]

QRS interval [msec]QT interval [msec]QTcB interval [msec]RR interval [msec]Heart rate [beats/min]Interpretation

[4] 3.1 Check only if parameter not done / not measured EGFYN Categorical yes/no (dichotomous) 3[5] 4. Result EGORRES Number (continuous) 15[6] 5. Method of QTc calculation EGINTMS Categorical select one (nominal) 7[7] 6. ECG Interpretation EGINTP Categorical select one (nominal) 18 Normal

AbnormalUnable to evaluateNo result

[8] 7. Clinically significant EGCLSIG Categorical yes/no (dichotomous) 3[9] 8. Any findings? EGFNDYN Categorical yes/no (dichotomous) 3[10] 8.1 ECG findings EGORRES Text or Any Value 4[11] 8.2 Other, specify EGORRESO Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

42

CONFIDENTIAL 2016N274225_00201465

1. ECG measurement performed?

2. Actual time of ECG measurement

8. Any findings?

ECG at Day 15,EoT / ET (Day 19),Unscheduled Visit

0.1 Random no. [1]

12-lead Safety ECG (Supine Position)Yes No [2]

[3]

.

3. ECG parameter/outcome [4] 3.1 Check only if parameter not done / not measured [5] 4. Result [6] 5. Method of QTc calculation [7] 6. ECG Interpretation [8] 7. Clinically significant [9]

1 PR interval [msec] Manual Machine Yes No

2 QRS interval [msec] Manual Machine Yes No

3 QT interval [msec] Manual Machine Yes No

4 QTcB interval [msec] Manual Machine Yes No

5 RR interval [msec] Manual Machine Yes No

6 Heart rate [beats/min] Manual Machine Yes No

7 Interpretation Manual Machine Yes No

Yes No [10]

Please add any clinical significant findings in the table below. Add for each row one of the listed code (e.g. A35). If further specification is necessary for terms with "other" add description into the text field (8.2. Other, specify).

8.1 ECG findings [11] 8.2 Other, specify [12]

1

More rows: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

43

CONFIDENTIAL 2016N274225_00201465

A36 - ArrhythmiaA16 - Artificial pacemakerA8 - Atrial fibrillationA7 - Atrial flutterA35 - Atrial premature complexA13 - BigeminyA4 - Ectopic supraventricular beatsA20 - Ectopic supraventricular rhythmA9 - Ectopic ventricular beatsA14 - Electrical alternansA43 - Idioventricular rhythmA19 - Idioventricular rhythm - heart rate < 100 beats/minA40 - Junctional escape complexesA25 - Junctional rhythm A5 - Junctional rhythm (<=100/min)A46 - Junctional tachycardiaA24 - Junctional tachycardia (heart rate >100 beats/min)A30 - Monomorphic ventricular tachycardiaA39 - Multifocal atrial tachycardiaA26 - Multifocal atrial tachycardia (wandering atrial pacemaker w/rate >100 beats/min)A37 - Multifocal premature ventricular complexesA11 - Non-sustained ventricular tachycardiaA34 - Normal sinus rhythmA99 - Other abnormal rhythmA31 - Polymorphic (sustained and non-sustained) ventricular tachycardiaA29 - R on T phenomenonA33 - Sinus arrhythmiaA1 - Sinus bradycardiaA23 - Sinus bradycardia (heart rate <30 beats/min)A22 - Sinus bradycardia (heart rate 30-39 beats/min)A21 - Sinus bradycardia (heart rate 40-50 beats/min)A3 - Sinus pauseA44 - Sinus tachycardiaA2 - Sinus tachycardia (heart rate > 100 beats/min)A41 - Supraventricular tachycardiaA6 - Supraventricular tachycardia (>100/min)A10 - Sustained ventricular tachycardiaA15 - Torsade de Pointes (TdP)A28 - TrigeminyA12 - Ventricular coupletsA18 - Ventricular fibrillationA182 - Ventricular fibrillation non-sustainedA181 - Ventricular fibrillation sustainedA38 - Ventricular flutter A45 - Ventricular premature complexesA27 - Ventricular tachycardiaA17 - Wandering atrial pacemakerA32 - Wide QRS Tachycardia (diagnosis unknown)

B5 - Intraatrial conduction delayB16 - Late R wave transitionB9 - Left atrial abnormalityB1 - Left atrial abnormality (P mitrale)B6 - Left ventricular hypertrophyB99 - Other morphologyB7 - Poor R wave progression B10 - Right atrial abnormality B2 - Right atrial abnormality (P pulmonale) B3 - Right ventricular hypertrophy B15 - Unusual P axis

201465_350209BS_aCRF_unique_d03_20151027

44

CONFIDENTIAL 2016N274225_00201465

C32 - 1st degree AV block (PR interval >240msec)C16 - 2:1 AV blockC11 - Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine)C18 - AV dissociationC17 - Bifascicular blockC35 - Diagnostic Q waveC24 - First degree A-V blockC1 - First degree AV block (PR interval > 200msec)C13 - Incomplete left bundle branch blockC7 - Incomplete right bundle branch blockC25 - Intra ventricular conduction delayC14 - Left anterior hemiblock (synonymous to left anterior fascicular block)C26 - Left axis deviationC5 - Left axis deviation (QRS axis more negative than -30 degrees)C9 - Left bundle branch blockC15 - Left posterior hemiblock (synonymous to left posterior fascicular block)C10 - Non-specific intraventricular conduction delay (QRS >= 120 msec)C99 - Other conductionC29 - Prolonged QT >500 msecC28 - Prolonged QT 450-500 msecC19 - Prolonged QT intervalC31 - Prolonged QTc Interval >500 msecC30 - Prolonged QTc Interval 450-500 msecC12 - QT/QTc prolongation >= 500 msecC21 - QTcB prolongation > 500 msecC23 - QTcF prolongationC22 - QTcF prolongation > 500 msecC27 - Right axis deviationC6 - Right axis deviation (QRS axis more positive than +110 degrees)C8 - Right bundle branch blockC2 - Second degree AV block (Mobitz type 1)C3 - Second degree AV block (Mobitz type 2)C20 - Short PR IntervalC34 - Short QTc intervalC4 - Third degree AV blockC33 - Trifascicular blockD23 - Atrial premature depolarizationD26 - Early R wave progressionD27 - Early repolarisationD14 - Increased voltage consistent with left ventricular hypertrophyD19 - J point elevationD22 - Juvenile Twave pattern, early repolarizationD13 - Low QRS voltageD2 - Myocardial infarction, anteriorD5 - Myocardial infarction, inferiorD3 - Myocardial infarction, lateralD20 - Myocardial infarction, non Q-waveD1 - Myocardial infarction, oldD4 - Myocardial infarction, posteriorD6 - Myocardial infarction, septalD7 - Non-specific ST-T changesD18 - Notched T-wavesD99 - Other depolarisation/repolarisationD98 - Other myocardial infarctionD25 - Pathological Q wavesD9 - ST depressionD8 - ST elevationD96 - ST segment abnormalityD21 - ST-elevation - pericarditisD97 - T wave abnormalityD24 - T wave alternansD17 - T wave flattening inversionD11 - T wave inversionD12 - T wave peakedD16 - T waves biphasicD15 - T waves flatD10 - U waves abnormal

201465_350209BS_aCRF_unique_d03_20151027

45

CONFIDENTIAL 2016N274225_00201465

XC8 - 1ST degree AV block PR 180-240XC9 - 1st degree block (PR interval > 250 msec)XA14 - Atrial fibrillation with rapid ventricular response (>120 bpm)XA4 - Atrial fibrillation with rapid ventricular response (rate > 100 bpm)XA16 - Atrial fibrillation with ventricular rate < 120 bpmXA10 - Atrial fibrillation with ventricular rate <= 100 bpmXA19 - Atrial fibrillation with ventricular rate <=120bpmXA15 - Atrial flutter with rapid ventricular response (>120 bpm)XA17 - Atrial flutter with ventricular rate <= 120 bpmXD6 - Dynamic horizontal/down-sloping depressionXD1 - Frequent ventricular premature depolarization (VPD) >= 3XA5 - Increase in Heart Rate >= 40 bpm relative to baselineXC23 - Increase in QTcF (30-60 msec) relative to baselineXC7 - Increase in QTcF >60 msec relative to baselineXD12 - Ischemic T wave inversion >= 0.1 mV in 2 or more contiguous leadXD2 - Occasional ventricular premature depolarization (VPD) <3XD4 - Persistent ST elevationXD7 - Persistent ST elevation >= 0.1 mV in 2 or more leadsXC19 - Prolonged QTc >= 30 msec relative to baselineXC20 - Prolonged QTc >= 60 msec relative to baselineXC12 - QRS duation < 120 ms and QTc(F) >= 500 msecXC10 - QRS duration < 120 ms and QTc (F) >= 450 msecXC24 - QRS duration <= 120 ms and QTc(F) >= 500 msecXC11 - QRS duration >= 120 ms and QTc(F) >= 480 msecXC13 - QRS duration >= 120 ms and QTc(F) >= 530 msecXC25 - QRS duration >120 ms and QTc(F) >= 530 msecXC1 - QT> 600 msec XC22 - QTcF> 530 msec XC2 - QTcF> = 450 msecXC3 - Right bundle branch block with QTc(F) < 480XC5 - Right bundle branch block with QTc(F) < 530XC4 - Right bundle branch block with QTc(F) >= 480XC6 - Right bundle branch block with QTc(F) >= 530XC21 - Sinus arrest or blockXA3 - Sinus bradycardia < 37 bpmXA9 - Sinus bradycardia < 50 bpmXA8 - Sinus bradycardia < 55 bpmXA2 - Sinus bradycardia <45 bpmXA11 - Sinus tachycardia > 120 bpmXA1 - Sinus tachycardia >= 110 bpmXA7 - Sinus tachycardia >= 115 bpmXA6 - Sinus tachycardia >= 125 bpmXA13 - Sinus Tachycardia=>120 bpmXD10 - ST depression >= 0.05 to <0.1 mV in 2 or more leadsXD9 - ST depression >= 0.1 mV in 2 or more contiguous leadsXD3 - ST-T wave abnormalities with the exception of non-specific changesXA18 - Supraventricular tachycardia (>100/min) non-sustainedXA12 - Supraventricular tachycardia (>120 bpm)XD5 - Transient ST elevationXD8 - Transient ST elevation >= 0.1 mV in 2 or more leads

201465_350209BS_aCRF_unique_d03_20151027

46

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. ECG measurement performed? EGPERF Categorical yes/no (dichotomous) 3[3] 2. Actual time of ECG measurement EGTIM Time 5[4] 3. ECG parameter/outcome EGTESTCD Categorical select one (nominal) 22 PR interval [msec]

QRS interval [msec]QT interval [msec]QTcB interval [msec]RR interval [msec]Heart rate [beats/min]Interpretation

[5] 3.1 Check only if parameter not done / not measured EGFYN Categorical yes/no (dichotomous) 3[6] 4. Result EGORRES Number (continuous) 15[7] 5. Method of QTc calculation EGINTMS Categorical select one (nominal) 7[8] 6. ECG Interpretation EGINTP Categorical select one (nominal) 18 Normal

AbnormalUnable to evaluateNo result

[9] 7. Clinically significant EGCLSIG Categorical yes/no (dichotomous) 3[10] 8. Any findings? EGFNDYN Categorical yes/no (dichotomous) 3[11] 8.1 ECG findings EGORRES Text or Any Value 4[12] 8.2 Other, specify EGORRESO Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

47

CONFIDENTIAL 2016N274225_00201465

1. Is the subject eligible for thetreatment phase?

2. Has the subject been randomized?

3. Randomization number

4. Date of randomization

Eligibility status / Randomization at Eligibility

Eligibility statusYes No [1]

Yes No [2]

[3]

Now [4]

201465_350209BS_aCRF_unique_d03_20151027

48

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Is the subject eligible for the treatment phase? DSCONT Categorical yes/no (dichotomous) 3[2] 2. Has the subject been randomized? DSDECOD Categorical yes/no (dichotomous) 3[3] 3. Randomization number DSREFID Number (continuous) 15[4] 4. Date of randomization DSSTDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

49

CONFIDENTIAL 2016N274225_00201465

1. Has the subject completed theFollow-up phase or was discontinued

for the following reason? 1

2. Primary reason, specify

3. Date of last contact during Follow-up phase

4. Check for any comments

4.1 Comment(if applicable)

End of Follow-up at End of Follow-Up

0.1 Random no. [1]

End of Follow-upCompleted [2]

Adverse Event

Death

Withdrawal by Subject

Lost To Follow-up

Protocol Violation

Non-Compliance with study conditions or instructions from the team

Physician Decision

Study Terminated By Sponsor

Sponsor decision to amend protocol

Trial Site Terminated by Sponsor

Subject reached protocol-defined stopping criteria

Other

[3]

Last contact during follow-up phase

Now [4]

.

[5]

[6]

201465_350209BS_aCRF_unique_d03_20151027

50

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Has the subject completed the Follow-up phase or

was discontinued for the following reason? 1DSDECOD Categorical select one (nominal) 66

[3] 2. Primary reason, specify DSTERM Text or Any Value 200[4] 3. Date of last contact during Follow-up phase DSSTDAT Date 11[5] 4. Check for any comments COVALYN Categorical yes/no (dichotomous) 3[6] 4.1 Comment (if applicable) COVAL Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

51

CONFIDENTIAL 2016N274225_00201465

1. Has the subject completed theScreening phase or was discontinued



3. Date of last contact duringScreening phase



End of Screening at Eligibility

End of ScreeningCompleted [1]

Adverse Event

Death


Lost To Follow-up

Protocol Violation


Screen failure (not met inclusion criteria/met exclusion criteria)

Physician Decision




Other

[2]

Last contact during screening phase

Now [3]

[4]

[5]

201465_350209BS_aCRF_unique_d03_20151027

52

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Has the subject completed the Screening phase

or was discontinued for the following reason? 1DSDECOD Categorical select one (nominal) 66

[2] 2. Primary reason, specify DSTERM Text or Any Value 4000[3] 3. Date of last contact during Screening phase DSSTDAT Date 11[4] 4. Check for any comments COVALYN Categorical yes/no (dichotomous) 3[5] 4.1 Comment (if applicable) COVAL Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

53

CONFIDENTIAL 2016N274225_00201465

1. Has the subject completed theTreatment phase or was discontinued



3. Will the subject continue with theFollow-up phase?

4.1 Date of the last known application

4.2 Time of last known application

5.1 Date of last known removal

5.2 Time of last known removal

6. Date of last contact duringTreatment phase


End of Treatment at End of Treatment

0.1 Random no. [1]

End of TreatmentCompleted [2]

Adverse Event

Death


Lost To Follow-up

Protocol Violation


Post-enrollment information indicates subject ineligible for treatment

Physician Decision


Lack of Efficacy



Subject reached protocol-defined stopping criteria

Other

[3]


.Last application

[5]

[6]

Last removal

Now [7]

[8]

Last contact during treatment phase

Now [9]

.

[10]

201465_350209BS_aCRF_unique_d03_20151027

54

CONFIDENTIAL 2016N274225_00201465


[11]

201465_350209BS_aCRF_unique_d03_20151027

55

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Has the subject completed the Treatment phase

or was discontinued for the following reason? 1DSDECOD Categorical select one (nominal) 71

[3] 2. Primary reason, specify DSTERM Text or Any Value 200[4] 3. Will the subject continue with the Follow-up

phase?DSCONT Categorical select one (nominal) 14

[5] 4.1 Date of the last known application EXSTDAT Date 11[6] 4.2 Time of last known application EXSTTIM Time 5[7] 5.1 Date of last known removal EXENDAT Date 11[8] 5.2 Time of last known removal EXENTIM Time 5[9] 6. Date of last contact during Treatment phase DSSTDAT Date 11[10] 7. Check for any comments COVALYN Categorical yes/no (dichotomous) 3[11] 7.1 Comment (if applicable) COVAL Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

56

CONFIDENTIAL 2016N274225_00201465

1. Skin phototype(according to Fitzpatrick)

Fitzpatrick Skin Type at Screening

Fitzpatrick Skin TypeType I [1]

Type II

Type III

Type IV

Type V

Type VI

Type I:Skin Color: White; very fair; red or blond hair; blue eyes; frecklesResponse to Ultraviolet Light Exposure: Always burns, never tans

Type II:Skin Color: White; fair; red, blond, or brown hair; hazel or green eyesResponse to Ultraviolet Light Exposure: Usually burns, tans with difficulty

Type III:Skin Color: White; any eye or hair color; very commonResponse to Ultraviolet Light Exposure: Sometimes mild burn, gradually tans

Type IV:Skin Color: White or light brown; typical Mediterranean Caucasian skinResponse to Ultraviolet Light Exposure: Rarely burns, tans with ease

Type V:Skin Color: Brown; mid-eastern skin typesResponse to Ultraviolet Light Exposure: Very rarely burns, tans very easily

Type VI:Skin Color: BlackResponse to Ultraviolet Light Exposure: Never burns, tans very easily

201465_350209BS_aCRF_unique_d03_20151027

57

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Skin phototype (according to Fitzpatrick) SCSTRESC Categorical select one (nominal) 8

201465_350209BS_aCRF_unique_d03_20151027

58

CONFIDENTIAL 2016N274225_00201465

1. Has there been any contact byphone, mail or else than visit?

Further contacts at End of study / Completion

0.1 Random no. [1]

Contact by phone, mail or elsePlease add all contacts for e.g. AE follow-up or follow-up, with the subject via phone, mail, letter or any other medium else than a visit here.

Please do not capture organizational contacts but rather contact whenever trial relevant information became available.

Yes No [2]

.

2. Contact via [3]

2.1 Contact via, other [4]

3. Date of contact [5]

4. Reason for contact [6]

4.1 Reason, other [7] 5. Check for any relevantinformation [8]

5.1 Relevant information due to contact 1 [9]

1 Now Adverse Eventfollow-up

Follow-up

Other

More rows: 1 5 10

1 Please note that whenever relevant information become available that also the data captured may be changed in the eCRF accordingly e.g. update AE outcome.

201465_350209BS_aCRF_unique_d03_20151027

59

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Has there been any contact by phone, mail or else

than visit?SVCONTYN Categorical yes/no (dichotomous) 3

[3] 2. Contact via SVCAT Categorical select one (nominal) 17 TelephoneE-MailLetter or messageOther

[4] 2.1 Contact via, other SVCATO Text or Any Value 200[5] 3. Date of contact VISDAT Date 11[6] 4. Reason for contact SVSCAT Categorical select one (nominal) 23[7] 4.1 Reason, other SVSCATO Text or Any Value 200[8] 5. Check for any relevant information COVALYN Categorical yes/no (dichotomous) 3[9] 5.1 Relevant information due to contact 1 COVAL Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

60

CONFIDENTIAL 2016N274225_00201465

1. Has any imaging been performed?

Imaging specific (liver) at Liver event

Liver imagingYes No [1]

.

2. Date ofassessment [2]

2.1 Visit related to the dateof assessment [3]

3.Specimen [4]

4. Method [5] 4.1 Method other, specify [6] 5. Are imagestechnically adequate? [7]

5.1 Images adequate other,specify [8]

6. Parameter [9]

7. Result(Enter a codefrom the listbelow) [10]

7.1 Result other, specify [11]

1 Liver

More rows: 1 5 10

A1 Normal sizeA2 Hypertrophy (or enlarged)A3 Atrophy (or smaller than normal)A4 Segmental hypertrophyA99 Other specify

B1 NormalB2 HeterogenousB3 Suggestive of fibrosisB4 Nodular or suggestive of cirrhosisB99 Other specify

C1 Not applicable - No fatty infiltrationC2 Mild (<=25%)C3 Moderate (>25% to <75%)C4 Severe (>=75%)C99 Other specify

D1 None present D2 Yes - small amountD3 Yes - moderate or severe amountD99 Other specify

E0 Not applicable - no hepatic lesionsE1 Solid E2 CysticE3 HemangiomaE4 Focal Nodular HyperplasiaE99 Other specify

201465_350209BS_aCRF_unique_d03_20151027

61

CONFIDENTIAL 2016N274225_00201465

F0 None F1 GallstonesF2 Gallbladder polyp(s) F3 SludgeF4 Gallbladder wall thickening/oedemaF5 Gallbladder wall gasF6 CholecystitisF7 Gallbladder wall calcificationF8 Gallbladder massF99 Other specify

G0 None G1 Intrahepatic ductal dilation (focal involving the right hepatic lobe)G2 Intrahepatic ductal dilation (focal involving the left hepatic lobe)G3 Intrahepatic ductal dilation (involving both right and left hepatic lobes)G4 Extrahepatic ductal dilationG5 Diffuse ductal dilation (involving both intrahepatic and extrahepatic ducts)G6 Acute CholangitisG7 Primary sclerosing cholangitisG8 Choledocholithiasis (gallstone in duct)G9 Ductal filling defect(s), other than gallstoneG10 Ductal wall thickening or oedemaG11 Choledochal cystG12 Ductal massG13 Extrinsic mass compressing bile duct(s)G99 Other specifyH0 NoneH1 Portal vein enlargementH2 Hepatic vein enlargementH3 Nonocclusive portal vein thrombosisH4 Occlusive portal vein thrombosis - bland H5 Hepatic vein thrombosis - bland H6 Occlusive portal vein thrombosis - malignantH7 Hepatic vein thrombosis - malignantH8 Involvement of the main portal veinH9 Involvement of the right portal veinH10 Involvement of the left portal veinH11 Budd-Chiari syndromeH99 Other specify

201465_350209BS_aCRF_unique_d03_20151027

62

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Has any imaging been performed? MOPERF Categorical yes/no (dichotomous) 3[2] 2. Date of assessment MODAT Date 11[3] 2.1 V isit related to the date of assessment VISIT Categorical select one (nominal) 17 Screening


[4] 3. Specimen MOLOC Categorical select one (nominal) 5[5] 4. Method MOMETHOD Categorical select one (nominal) 63 Ultrasound

Magnetic Resonance ImagingComputed TomographyEndoscopic Retrograde Cholangiopancreatography (ERCP)Positron Emission TomographyPositron Emission Tomography / Computerised Tomography (PET/CT)Other

[6] 4.1 Method other, specify MOMETHOO Text or Any Value 200[7] 5. Are images technically adequate? MOIMGAD Categorical select one (nominal) 25 Optimal

Readable, but not optimalNot readableOther specify

[8] 5.1 Images adequate other, specify MOIMGADO Text or Any Value 200[9] 6. Parameter MOTESTCD Categorical select one (nominal) 33 Ascites present

Biliary ductal lesionsFocal hepatic lesions characterGallstones or gallbladder lesionsLiver fatty infiltrate gradeLiver sizeLiver texturePortal/Hepatic vein abnormalities

[10] 7. Result (Enter a code from the list below) MOORRES Text or Any Value 3[11] 7.1 Result other, specify MORRESO Text or Any Value 200

201465_350209BS_aCRF_unique_d03_20151027

63

CONFIDENTIAL 2016N274225_00201465

1. Does the subject meet all inclusionand none of the exclusion criteria?

Inclusion 1. 18 years of age and above,at the time of signing the informed consent.

Inclusion 2. Subjects with stable plaquepsoriasis for 6 months, as confirmed by the

subject.

Inclusion 3. Up to three plaque area(s)sufficient for six test fields. The target

lesion(s) should be on the trunk, upperextremities or thighs (excluding hands andskin folds); psoriatic lesion(s) on the knees

or elbows are not to be used as a targetlesion. It is recommended, but not

required, that all selected plaques aresymmetrical in location, size and clinical

characteristics.

Inclusion 4. Plaques to be treated shouldhave a comparable thickness of the ELB

(as a surrogate for the psoriatic infiltratethickness) of at least 200μm on Day 1.

Inclusion 5. Male Male subjects with female partners of child

bearing potential must comply with thefollowing contraception requirements fromthe time of first dose of study medication

until after the last dose of studymedication.

Inclusion 6. Female of non-reproductivepotential (FNRP) A FNRP is eligible to

participate in this study if she meets atleast one of the following conditions:

Inclusion 7. Capable of giving signedinformed consent as described in Section10.2 which includes compliance with the

requirements and restrictions listed in theconsent form and in this protocol.

Inclusion / exclusion criteria at Screening,Day 1

Inclusion and exclusion criteriaYes No [1]

If No, please list those inclusion criteria not met / exclusion criteria met:Inclusion criteriaAll of the following criteria have to be met for inclusion of a subject in this trial:AGE

[2]


[3]

[4]

[5]

[4] SEX

[6]

[see protocol for details]

[7]

[see protocol for details]INFORMED CONSENT

[8]

Exclusion criteria

Subjects are to be excluded from the trial, when one or more of the following conditions are met:CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc INTERVAL)

201465_350209BS_aCRF_unique_d03_20151027

64

CONFIDENTIAL 2016N274225_00201465

Exclusion 1. Alanine aminotransferase(ALT) >2xULN and bilirubin >1.5x upper

limit of normal (ULN) (isolated bilirubin>1.5xULN is acceptable if bilirubin is

fractionated and direct bilirubin <35%).

Exclusion 2. Current or chronic history ofliver disease, or known hepatic or biliary

abnormalities (with the exception ofGilbert's syndrome or asymptomatic

gallstones)

Exclusion 3. QTc > 450 msec or QTc >480 msec in subjects with Bundle Branch

Block. The QTc is the QT interval correctedfor heart rate according to Bazett’s formula

(QTcB), and/or machine-read. The QTcshould be based on single QTc values of

ECG obtained over a brief recordingperiod.

Exclusion 4. Any condition that, in thejudgement of the investigator, would put

the subject at unacceptable risk for theparticipation in the trial.

Exclusion 5. Current evidence of anotherongoing or any acute cutaneous infection,

history of repeated or chronic significantskin infections (unless irrelevant in the

opinion of the investigator, i.e.onychomycosis, labial herpes or other

minor diagnosis).

Exclusion 6. C linically-relevant skindisease, other skin pathologies, or a

history of skin cancer, that may, in theopinion of the investigator, contraindicate

participation or interfere with test fieldevaluations.

Exclusion 7. History of malignancy within5 years prior to dosing, except adequately

treated noninvasive cancer of the skin(basal or squamous cell).

Exclusion 8. Psoriasis other than plaquevariants.

Exclusion 9. Use of prohibitedconcomitant medications or products within

the defined washout periods before theDay 1 visit and during the trial (see Section

6.11.2).

Exclusion 10. History of sensitivity to anyof the study medications, or components

thereof or a history of drug or other allergythat, in the opinion of the investigator or

Medical Monitor, contraindicates theirparticipation.

Exclusion 11. Contraindicationsaccording to summary of product

characteristics of the active positivecontrol.

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]


[17]

CONTRAINDICATIONS

[18]

[19]

201465_350209BS_aCRF_unique_d03_20151027

65

CONFIDENTIAL 2016N274225_00201465

Exclusion 12. Symptoms of a clinicallysignificant illness that may, in the opinionof the investigator, influence the outcomeof the trial in the 4 weeks before baseline

visit and during the trial.

Exclusion 13. Presence of hepatitis Bsurface antigen (HBsAg), positive hepatitis

C antibody test result at screening or within3 months prior to first dose of study

treatment.

Exclusion 14. A positive pre-studydrug/alcohol screen.

Exclusion 15. A positive test for humanimmunodeficiency virus (HIV) antibody.

Exclusion 16. The subject hasparticipated in a clinical trial and has

received an investigational product withinthe following time period prior to the first

dosing day in the current study: 30 days, 5half-lives or twice the duration of thebiological effect of the investigational

product (whichever is longer).

Exclusion 17. Prolonged exposure tonatural or artificial sources of ultraviolet

(UV) radiation within 2 weeks prior to theDay 1 visit or intention to have such

exposure during the study, thought by theinvestigator likely to modify the subject’s

psoriasis.

Exclusion 18. In the opinion of theinvestigator or physician performing the

initial examination the subject should notparticipate in the clinical trial, e.g. due to

probable noncompliance or inability tounderstand the trial and give adequately

informed consent.

Exclusion 19. C lose affiliation with theinvestigator (e.g. a close relative) orpersons working at Bioskin GmbH or

subject is an employee of sponsor.

Exclusion 20. Subject is institutionalizedbecause of legal or regulatory order.

[20]


[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

201465_350209BS_aCRF_unique_d03_20151027

66

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Does the subject meet all inclusion and none of

the exclusion criteria?IEYN Categorical yes/no (dichotomous) 3

[2] Inclusion 1. 18 years of age and above, at the timeof signing the informed consent.

IEIN01 Categorical yes/no (dichotomous) 3

[3] Inclusion 2. Subjects with stable plaque psoriasisfor 6 months, as confirmed by the subject.


[4] Inclusion 3. Up to three plaque area(s) sufficient forsix test fields. The target lesion(s) should be on thetrunk, upper extremities or thighs (excluding handsand skin folds); psoriatic lesion(s) on the knees orelbows are not to be used as a target lesion. It isrecommended, but not required, that all selectedplaques are symmetrical in location, size and clinicalcharacteristics.


[5] Inclusion 4. Plaques to be treated should have acomparable thickness of the ELB (as a surrogate forthe psoriatic infiltrate thickness) of at least 200μmon Day 1.


[6] Inclusion 5. Male Male subjects with female partnersof child bearing potential must comply with thefollowing contraception requirements from the timeof first dose of study medication until after the lastdose of study medication.


[7] Inclusion 6. Female of non-reproductive potential(FNRP) A FNRP is eligible to participate in this studyif she meets at least one of the following conditions:


[8] Inclusion 7. Capable of giving signed informedconsent as described in Section 10.2 which includescompliance with the requirements and restrictionslisted in the consent form and in this protocol.


[9] Exclusion 1. A lanine aminotransferase (ALT)>2xULN and bilirubin >1.5x upper limit of normal(ULN) (isolated bilirubin >1.5xULN is acceptable ifbilirubin is fractionated and direct bilirubin <35%).

IEEX01 Categorical yes/no (dichotomous) 3

[10] Exclusion 2. Current or chronic history of liverdisease, or known hepatic or biliary abnormalities(with the exception of Gilbert's syndrome orasymptomatic gallstones)


[11] Exclusion 3. QTc > 450 msec or QTc > 480 msecin subjects with Bundle Branch Block. The QTc isthe QT interval corrected for heart rate according toBazett’s formula (QTcB), and/or machine-read. TheQTc should be based on single QTc values of ECGobtained over a brief recording period.


[12] Exclusion 4. Any condition that, in the judgement ofthe investigator, would put the subject atunacceptable risk for the participation in the trial.


[13] Exclusion 5. Current evidence of another ongoing orany acute cutaneous infection, history of repeated orchronic significant skin infections (unless irrelevantin the opinion of the investigator, i.e.onychomycosis, labial herpes or other minordiagnosis).


[14] Exclusion 6. Clinically-relevant skin disease, otherskin pathologies, or a history of skin cancer, thatmay, in the opinion of the investigator,contraindicate participation or interfere with testfield evaluations.


[15] Exclusion 7. History of malignancy within 5 yearsprior to dosing, except adequately treatednoninvasive cancer of the skin (basal or squamouscell).


[16] Exclusion 8. Psoriasis other than plaque variants. IEEX08 Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

67

CONFIDENTIAL 2016N274225_00201465

[17] Exclusion 9. Use of prohibited concomitantmedications or products within the defined washoutperiods before the Day 1 visit and during the trial(see Section 6.11.2).


[18] Exclusion 10. History of sensitivity to any of thestudy medications, or components thereof or ahistory of drug or other allergy that, in the opinion ofthe investigator or Medical Monitor, contraindicatestheir participation.


[19] Exclusion 11. Contraindications according tosummary of product characteristics of the activepositive control.


[20] Exclusion 12. Symptoms of a clinically significantillness that may, in the opinion of the investigator,influence the outcome of the trial in the 4 weeksbefore baseline visit and during the trial.


[21] Exclusion 13. Presence of hepatitis B surfaceantigen (HBsAg), positive hepatitis C antibody testresult at screening or within 3 months prior to firstdose of study treatment.


[22] Exclusion 14. A positive pre-study drug/alcoholscreen.


[23] Exclusion 15. A positive test for humanimmunodeficiency virus (HIV) antibody.


[24] Exclusion 16. The subject has participated in aclinical trial and has received an investigationalproduct within the following time period prior to thefirst dosing day in the current study: 30 days, 5half-lives or twice the duration of the biologicaleffect of the investigational product (whichever islonger).


[25] Exclusion 17. Prolonged exposure to natural orartificial sources of ultraviolet (UV) radiation within2 weeks prior to the Day 1 visit or intention to havesuch exposure during the study, thought by theinvestigator likely to modify the subject’s psoriasis.


[26] Exclusion 18. In the opinion of the investigator orphysician performing the initial examination thesubject should not participate in the clinical trial,e.g. due to probable noncompliance or inability tounderstand the trial and give adequately informedconsent.


[27] Exclusion 19. Close affiliation with the investigator(e.g. a close relative) or persons working at BioskinGmbH or subject is an employee of sponsor.


[28] Exclusion 20. Subject is institutionalized because oflegal or regulatory order.


201465_350209BS_aCRF_unique_d03_20151027

68

CONFIDENTIAL 2016N274225_00201465

1. Date of first informed consentsigned

2. Any additional/new informedconsents?

Informed consent at Screening

Informed consent Now [1]

.

Yes No [2]

.

2.1 Type of updated document [3] 2.2 Version of updated document (e.g. V2, date 16-Jul-2015) [4]

2.3 Date of new informed consent signed [5]

1 Now

More rows: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

69

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Date of first informed consent signed DSSTDAT Date 11[2] 2. Any additional/new informed consents? DSADDYN Categorical yes/no (dichotomous) 3[3] 2.1 Type of updated document DSCAT Categorical select one (nominal) 42 Informed consent to new protocol amendment

New Informed consentInformed consent for biopsies

[4] 2.2 Version of updated document (e.g. V2, date 16-Jul-2015)

DSSCAT Text or Any Value 200

[5] 2.3 Date of new informed consent signed DS2STDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

70

CONFIDENTIAL 2016N274225_00201465

Laboratory at Screening Lab Hematology,Screening Lab Chemistry,Screening Lab Urine examination

LaboratoryThe laboratory data are uploaded into the eCRF.

Please assign clinical significance for parameters where the result is not within the given range.Additionally please check and provide comments to parameter, if applicable..

1. Check i f row i s notval i d [1]

2. Category [2] 2. 1 Subcategory [3] 3. V i si t [4] 4. Ti me poi nt number [5] 5. D ate of sampl ecol l ect i on [6]

6. Ti me of sampl ecol l ect i on [7]

7. Test parameter [8] 7. 1 Test parameter Code [9] 8. Parameter not done / notmeasured [10]

8. 1 R eason not done [11] 9. R esul t(numeri c) [12]

9. 1 R esul t (numeri c,SI) [13]

10. R esul t (text) [14]

10. 1 R esul t (text , SI) [15]

11. U ni t [16] 11. 1 U ni t SI [17] 12. 1 Low er ref erence range(numeri c) [18]

12. 2 U pper ref erence range(numeri c) [19]

12. 1. 1 Low er ref erence rangeSI (numeri c) [20]

12. 2. 1 U pper ref erence rangeSI (numeri c) [21]

13. R ef erence range (text) [22] 13. 1 R ef erence range SI (text) [23] 14. R esul tnormal /abnormal [24]

14. 2 R esul t normal /abnormal(upcase) [25]

14. 1 Cl i ni cal l y si gni f i cant? [26] 15. Speci men Type [27] 15. 1 Speci men Condi t i on [28] 16. V endor name [29] 16. 1 M ethod [30] 17. Check f or anycomments (f rom l ab) [31]

17. 1 Comments (f rom l ab) [32] 18. Check f or anycomments (f rom si te) [33]

18. 1 Comments (f rom si te) [34] 19. R ef erence ID [35]

20. U pl oad ID [36]

20. 1 D ate ofupl oad [37]

1

Yes N o

M or e r ow s: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

71

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Check if row is not valid LBVALYN Categorical yes/no (dichotomous) 3[2] 2. Category LBCAT Text or Any Value 200[3] 2.1 Subcategory LBSCAT Text or Any Value 200[4] 3. V isit VISIT Text or Any Value 200[5] 4. Time point number LBTPTNUM Number (continuous) 15[6] 5. Date of sample collection LBDAT Date 11[7] 6. Time of sample collection LBTIM Time 5[8] 7. Test parameter LBTEST Text or Any Value 200[9] 7.1 Test parameter Code LBTESTCD Text or Any Value 4000[10] 8. Parameter not done / not measured LBSTAT Text or Any Value 40[11] 8.1 Reason not done LBREASND Text or Any Value 200[12] 9. Result (numeric) LBSTRESN Number (continuous) 15[13] 9.1 Result (numeric, SI) LB2SRESN Number (continuous) 15[14] 10. Result (text) LBSTRESC Text or Any Value 200[15] 10.1 Result (text, SI) LB2SRESC Text or Any Value 200[16] 11. Unit LBSTRESU Text or Any Value 40[17] 11.1 Unit SI LB2SRESU Text or Any Value 40[18] 12.1 Lower reference range (numeric) LBSTNRLO Number (continuous) 15[19] 12.2 Upper reference range (numeric) LBSTNRHI Number (continuous) 15[20] 12.1.1 Lower reference range SI (numeric) LB2SNRLO Number (continuous) 15[21] 12.2.1 Upper reference range SI (numeric) LB2SNRHI Number (continuous) 15[22] 13. Reference range (text) LBSTNRC Text or Any Value 200[23] 13.1 Reference range SI (text) LB2STNRC Text or Any Value 200[24] 14. Result normal/abnormal LBNRIND Text or Any Value 40[25] 14.2 Result normal/abnormal (upcase) LB2NRIND Text or Any Value 4000[26] 14.1 Clinically significant? LBCLSIG Categorical yes/no (dichotomous) 3[27] 15. Specimen Type LBSPEC Text or Any Value 40[28] 15.1 Specimen Condition LBSPCCND Text or Any Value 40[29] 16. Vendor name LBNAM Text or Any Value 200[30] 16.1 Method LBMETHOD Text or Any Value 200[31] 17. Check for any comments (from lab) COVALYN Categorical yes/no (dichotomous) 3[32] 17.1 Comments (from lab) COVAL Text or Any Value 1000[33] 18. Check for any comments (from site) CO2VALYN Categorical yes/no (dichotomous) 3[34] 18.1 Comments (from site) CO2VAL Text or Any Value 1000[35] 19. Reference ID LBREFID Text or Any Value 200[36] 20. Upload ID LBGRPID Text or Any Value 200[37] 20.1 Date of upload LBUPDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

72

CONFIDENTIAL 2016N274225_00201465

Laboratory at Screening Lab Other

0.1 Random no.










10. 1 R esul t (text , SI) [15]












1

Yes N o

M or e r ow s: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

73

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Check if row is not valid LBVALYN Categorical yes/no (dichotomous) 3[2] 2. Category LBCAT Text or Any Value 200[3] 2.1 Subcategory LBSCAT Text or Any Value 200[4] 3. V isit VISIT Text or Any Value 200[5] 4. Time point number LBTPTNUM Number (continuous) 15[6] 5. Date of sample collection LBDAT Date 11[7] 6. Time of sample collection LBTIM Time 5[8] 7. Test parameter LBTEST Text or Any Value 200[9] 7.1 Test parameter Code LBTESTCD Text or Any Value 4000[10] 8. Parameter not done / not measured LBSTAT Text or Any Value 40[11] 8.1 Reason not done LBREASND Text or Any Value 200[12] 9. Result (numeric) LBSTRESN Number (continuous) 15[13] 9.1 Result (numeric, SI) LB2SRESN Number (continuous) 15[14] 10. Result (text) LBSTRESC Text or Any Value 200[15] 10.1 Result (text, SI) LB2SRESC Text or Any Value 200[16] 11. Unit LBSTRESU Text or Any Value 40[17] 11.1 Unit SI LB2SRESU Text or Any Value 40[18] 12.1 Lower reference range (numeric) LBSTNRLO Number (continuous) 15[19] 12.2 Upper reference range (numeric) LBSTNRHI Number (continuous) 15[20] 12.1.1 Lower reference range SI (numeric) LB2SNRLO Number (continuous) 15[21] 12.2.1 Upper reference range SI (numeric) LB2SNRHI Number (continuous) 15[22] 13. Reference range (text) LBSTNRC Text or Any Value 200[23] 13.1 Reference range SI (text) LB2STNRC Text or Any Value 200[24] 14. Result normal/abnormal LBNRIND Text or Any Value 40[25] 14.2 Result normal/abnormal (upcase) LB2NRIND Text or Any Value 4000[26] 14.1 Clinically significant? LBCLSIG Categorical yes/no (dichotomous) 3[27] 15. Specimen Type LBSPEC Text or Any Value 40[28] 15.1 Specimen Condition LBSPCCND Text or Any Value 40[29] 16. Vendor name LBNAM Text or Any Value 200[30] 16.1 Method LBMETHOD Text or Any Value 200[31] 17. Check for any comments (from lab) COVALYN Categorical yes/no (dichotomous) 3[32] 17.1 Comments (from lab) COVAL Text or Any Value 1000[33] 18. Check for any comments (from site) CO2VALYN Categorical yes/no (dichotomous) 3[34] 18.1 Comments (from site) CO2VAL Text or Any Value 1000[35] 19. Reference ID LBREFID Text or Any Value 200[36] 20. Upload ID LBGRPID Text or Any Value 200[37] 20.1 Date of upload LBUPDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

74

CONFIDENTIAL 2016N274225_00201465

Laboratory at Day 8 Lab Hematology,Day 8 Lab Chemistry,Day 8 Lab Urine examination,Day 15 Lab Hematology,Day 15 Lab Chemistry,Day 15 Lab Urine examination,EoT / ET (Day 19) Lab Hematology,EoT /ET (Day 19) Lab Chemistry,EoT / ET (Day 19) Lab Urine exam,Unscheduled Lab Hematology,Unscheduled Lab Chemistry,Unscheduled Lab Urine exam,Day 8 Lab Other,Day 15 Lab Other,EoT / ET (Day 19) LabOther,Liver event,Unscheduled Lab Other

0.1 Random no. [1]










10. 1 R esul t (text , SI) [16]












1

Yes N o

M or e r ow s: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

75

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Check if row is not valid LBVALYN Categorical yes/no (dichotomous) 3[3] 2. Category LBCAT Text or Any Value 200[4] 2.1 Subcategory LBSCAT Text or Any Value 200[5] 3. V isit VISIT Text or Any Value 200[6] 4. Time point number LBTPTNUM Number (continuous) 15[7] 5. Date of sample collection LBDAT Date 11[8] 6. Time of sample collection LBTIM Time 5[9] 7. Test parameter LBTEST Text or Any Value 200[10] 7.1 Test parameter Code LBTESTCD Text or Any Value 4000[11] 8. Parameter not done / not measured LBSTAT Text or Any Value 40[12] 8.1 Reason not done LBREASND Text or Any Value 200[13] 9. Result (numeric) LBSTRESN Number (continuous) 15[14] 9.1 Result (numeric, SI) LB2SRESN Number (continuous) 15[15] 10. Result (text) LBSTRESC Text or Any Value 200[16] 10.1 Result (text, SI) LB2SRESC Text or Any Value 200[17] 11. Unit LBSTRESU Text or Any Value 40[18] 11.1 Unit SI LB2SRESU Text or Any Value 40[19] 12.1 Lower reference range (numeric) LBSTNRLO Number (continuous) 15[20] 12.2 Upper reference range (numeric) LBSTNRHI Number (continuous) 15[21] 12.1.1 Lower reference range SI (numeric) LB2SNRLO Number (continuous) 15[22] 12.2.1 Upper reference range SI (numeric) LB2SNRHI Number (continuous) 15[23] 13. Reference range (text) LBSTNRC Text or Any Value 200[24] 13.1 Reference range SI (text) LB2STNRC Text or Any Value 200[25] 14. Result normal/abnormal LBNRIND Text or Any Value 40[26] 14.2 Result normal/abnormal (upcase) LB2NRIND Text or Any Value 4000[27] 14.1 Clinically significant? LBCLSIG Categorical yes/no (dichotomous) 3[28] 15. Specimen Type LBSPEC Text or Any Value 40[29] 15.1 Specimen Condition LBSPCCND Text or Any Value 40[30] 16. Vendor name LBNAM Text or Any Value 200[31] 16.1 Method LBMETHOD Text or Any Value 200[32] 17. Check for any comments (from lab) COVALYN Categorical yes/no (dichotomous) 3[33] 17.1 Comments (from lab) COVAL Text or Any Value 1000[34] 18. Check for any comments (from site) CO2VALYN Categorical yes/no (dichotomous) 3[35] 18.1 Comments (from site) CO2VAL Text or Any Value 1000[36] 19. Reference ID LBREFID Text or Any Value 200[37] 20. Upload ID LBGRPID Text or Any Value 200[38] 20.1 Date of upload LBUPDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

76

CONFIDENTIAL 2016N274225_00201465

1. Any event detected?

Liver event at Liver event

Liver eventYes No [1]

.

2. Date liver stopping event first detected inchemistry lab results [2]

2.1 Visit related to the datefirst detected [3]

3. Date liver stopping event resolved, as indicatedin chemistry lab results [4]

4. Maximum status of thissignal/event code [5]

5. Liver Event resolved at theend of study [6]

1 Liver event stopping criteria Yes No

More rows: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

77

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Any event detected? CEYN Categorical yes/no (dichotomous) 3[2] 2. Date liver stopping event first detected in

chemistry lab resultsCESTDAT Date 11

[3] 2.1 V isit related to the date first detected VISIT Categorical select one (nominal) 17 ScreeningDay 1Day 2Day 3Day 4Day 5Day 6Day 8Day 9Day 10Day 11Day 12Day 13Day 15Day 16Day 17Day 18EoT / ET (Day 19)Day 27Unscheduled visit

[4] 3. Date liver stopping event resolved, as indicated inchemistry lab results

CEENDAT Date 11

[5] 4. Maximum status of this signal/event code CEORRES Categorical select one (nominal) 29[6] 5. Liver Event resolved at the end of study CEOUT Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

78

CONFIDENTIAL 2016N274225_00201465

1. Are there any other medicalhistory / medical surgery findings for

this subject?

Medical History at Screening

Medical HistoryPartial/incomplete dates can be captured with UN (for unknown day) and UNK (for unknown month) e.g. UN-UNK-2001. The year is required at least.

Data for the trial indication are captured separately on a trial indication Medical History form.

Record any relevant past or current diseases, surgical interventions or medical conditions within the last 5 years below with the corresponding date/status information.

Please capture any known allergies on this form as well.

For 7. condition present please specify whether conditions are currently present e.g. current symptoms in allergies.

Yes No [1]

.

2. Findings: Diagnosis / symptom or surgicalintervention [2]

3. Start date [3]

4.1 Ongoing at firstdosing [4]

4.2 Ongoing at end oftrial [5]

5. Stop date [6] 6. Any correspondingmedication? [7]

7. Active at Time of Medicalhistory collection? [8]

1 Yes No Yes No Now Yes No Yes No

More rows: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

79

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Are there any other medical history / medical

surgery findings for this subject?MHYN Categorical yes/no (dichotomous) 3

[2] 2. Findings: Diagnosis / symptom or surgicalintervention

MHTERM Text or Any Value 200

[3] 3. Start date MHSTDAT Date 11[4] 4.1 Ongoing at first dosing MHONGO Categorical yes/no (dichotomous) 3[5] 4.2 Ongoing at end of trial MH2ONGO Categorical yes/no (dichotomous) 3[6] 5. Stop date MHENDAT Date 11[7] 6. Any corresponding medication? MHCONTRT Categorical yes/no (dichotomous) 3[8] 7. Active at Time of Medical history collection? MHOCCUR Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

80

CONFIDENTIAL 2016N274225_00201465

1. Start date of psoriasis

Medical History of Psoriasis at Screening

Medical history of stable plaque psoriasisPartial/incomplete dates can be captured with UN (for unknown day) and UNK (for unknown month) e.g. UN-UNK-2001. The year is required at least.

[1]

Subjects must have a stable plaque psoriasis for >= 6 months, as confirmed by the subject, for eligiblity.

201465_350209BS_aCRF_unique_d03_20151027

81

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Start date of psoriasis MHSTDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

82

CONFIDENTIAL 2016N274225_00201465

1. Has the photographicdocumentation been performed as

planned?

2. Photographic documentation time


3.1 Comment

Photographic documentation at Day 1 (Baseline procedures),Unscheduled Visit,EoT / ET (Day 19)

0.1 Random no. [1]

Photographic documentationPhoto documentation includes one overview photo of the test fields. Photographs are to be taken as per protocol:

Overview pictures will be taken of all test fields (number of pictures depending on number of plaques(s) used and location on the body); there won’t be any documentation of single test fields. Additional photographic documentation of single test fields may be taken if treatmentrelated AEs occur.At Day 1: Photographs will be taken prior to dosing.At Day 19 (ET): Before any procedures.

Yes No [2]

Now [3]

[4]

[5]

201465_350209BS_aCRF_unique_d03_20151027

83

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Has the photographic documentation been

performed as planned?PRPERF Categorical yes/no (dichotomous) 3

[3] 2. Photographic documentation time XPTIM Time 5[4] 3. Check for any comments COVALYN Categorical yes/no (dichotomous) 3[5] 3.1 Comment COVAL Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

84

CONFIDENTIAL 2016N274225_00201465

1. Did the subject become pregnant?1

2. Did the subject's partner becomepregnant?2

Pregnancy Yes/No at End of study / Completion

PregnancyYes No Not Applicable [1]

1 Select either Yes or No, if the subject is of childbearing potential, otherwise select Not Applicable..


2 Select either Yes or No, if the subject's partner is of childbearing potential, otherwise or if the subject does not have a partner select Not Applicable.

201465_350209BS_aCRF_unique_d03_20151027

85

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Did the subject become pregnant?1 CEOCCUR Categorical select one (nominal) 14[2] 2. Did the subject's partner become pregnant?2 CE2OCCUR Categorical select one (nominal) 14

201465_350209BS_aCRF_unique_d03_20151027

86

CONFIDENTIAL 2016N274225_00201465

1. Therapy/medication name

2. Dose amount/strength

3. Dose Unit

3.1 Dose Unit: Other, specify

4. Dosing Frequency

4.1 Dosing Frequency: Other, specify

5. Formulation

5.1 Formulation: Other, specify

6. Route

6.1 Route: Other, specify

7. Taken prior to first dosing?

8. Start date

8.1 Check if start time is notdeterminable/unknown

8.2 Start time

9.1 Ongoing at first dosing

9.2 Ongoing at end of trial

10. Stop date

Prior and Concomitant Therapy/Medication at Prior and Concomitant Therapy

0.1 Random no. [1]

Prior and Concomitant Therapy/MedicationPartial/incomplete dates can be captured with UN (for unknown day) and UNK (for unknown month) e.g. UN-UNK-2001. The year is required at least.

Examples for dose and unit documenation:

1. In tablets e.g. Dose=1 (or 500) + Unit=Tablet (or mg).2. In creams/ointments/solutions other formulations e.g. Dose=1 + Unit=Application.3. In sprays e.g. Dose=2 + Unit=Puff.

All relevant medication that might have to be taken 28 days (4 weeks) prior to Screening and any treatment, including over-the-counter remedies, that might have to be taken during the clinical trial is regarded as a concomitant treatment and must be documented in the eCRF.

.

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

Yes No [12]

[13]

[14]

[15]

Yes No [16]

Yes No [17]

[18]

201465_350209BS_aCRF_unique_d03_20151027

87

CONFIDENTIAL 2016N274225_00201465

10.1 Check if stop time is notdeterminable/unknown

10.2 Stop time

11. Indication Type

12. Indication

[19]

[20]

Treatment of adverse event [21]

Treatment of prior disease/condition

Treatment of concomitant disease/condition

Other (e.g. Contraception)

[22]

201465_350209BS_aCRF_unique_d03_20151027

88

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Therapy/medication name CMTRT Text or Any Value 200[3] 2. Dose amount/strength CMDSTXT Text or Any Value 200[4] 3. Dose Unit CMDOSEU Categorical select one (nominal) 24 Ampule

ApplicationCapsuleChewing GumCoated tabletDropsEffervescent (Tablet)gIU (International Units)LozengemgmLPatchPuff (e.g. in sprays)RingSachetTabletTbsp (Tablespoon Unit)tsp (Teaspoon Unit)ug (Microgram, mcg)uLUnknownOther

[5] 3.1 Dose Unit: Other, specify CMDOSUO Text or Any Value 200[6] 4. Dosing Frequency CMDOSFRQ Categorical select one (nominal) 31 Five Times Weekly

PRNOnceOnce Daily (QD)Once WeeklyQD/28D (e.g. in contraceptions)Three Times Daily (TID)Three Times WeeklyTwice Daily (BID)Other

[7] 4.1 Dosing Frequency: Other, specify CMDOSFQO Text or Any Value 200[8] 5. Formulation CMDOSFRM Categorical select one (nominal) 22 Ampule

CapsuleChewing GumCoated tabletCreamDropsEffervescent (Granule)Effervescent (Tablet)GelImplantInjectionLozengeOintmentPatchPowder (Aerosol)PowderRingSpraySuppositorySyrupTabletUnknownOther

[9] 5.1 Formulation: Other, specify CMDOSFRO Text or Any Value 200

201465_350209BS_aCRF_unique_d03_20151027

89

CONFIDENTIAL 2016N274225_00201465

[10] 6. Route CMROUTE Categorical select one (nominal) 13 BuccalInhalationIntramuscularIntravenousNasalOphthalmicOralRectalSubcutaneousSublingualTopicalVaginalUnknownOther

[11] 6.1 Route: Other, specify CMROUTEO Text or Any Value 200[12] 7. Taken prior to first dosing? CMPRIOR Categorical yes/no (dichotomous) 3[13] 8. Start date CMSTDAT Date 11[14] 8.1 Check if start time is not determinable/unknown EXSTTIMN Categorical yes/no (dichotomous) 3[15] 8.2 Start time CMSTTIM Time 5[16] 9.1 Ongoing at first dosing CMONGO Categorical yes/no (dichotomous) 3[17] 9.2 Ongoing at end of trial CM2ONGO Categorical yes/no (dichotomous) 3[18] 10. Stop date CMENDAT Date 11[19] 10.1 Check if stop time is not determinable/unknown EXENTIMN Categorical yes/no (dichotomous) 3[20] 10.2 Stop time EXENTIM Time 5[21] 11. Indication Type CMINDCTP Categorical select one (nominal) 42[22] 12. Indication CMINDC Text or Any Value 200

201465_350209BS_aCRF_unique_d03_20151027

90

CONFIDENTIAL 2016N274225_00201465

1. Any therapies/medications?

Prior and Concomitant Therapy/Medications Yes/No at Prior and Concomitant Therapy

0.1 Random no. [1]

Any Prior and Concomitant Therapy/MedicationAll relevant medication that might have to be taken 28 days (4 weeks) prior to Screening and any treatment, including over-the-counter remedies, that might have to be taken during the clinical trial is regarded as a concomitant treatment and must be documented in the eCRF.

Yes No [2]

If any therapy was taken prior or during the trial, please consider adding a prior and concomitant therapy form for each at visit Prior and Concomitant Therapy.

201465_350209BS_aCRF_unique_d03_20151027

91

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Any therapies/medications? CMYN Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

92

CONFIDENTIAL 2016N274225_00201465

1. Did any dressing/plaster fall offsince last visit?

3. Removal performed?

4. Removal time

Removal at Day 2,Day 3,Day 4,Day 5,Day 6,Day 8,Day 9,Day 10,Day 11,Day 12,Day 15,EoT / ET (Day 19),Day 13,Day 16,Day 17,Day 18

0.1 Random no. [1]

Dressing/plaster LossYes No [2]

Report the exact time if known or approximate time if unsure.

2.1 Affected testfield [3]

2.2 Dressing/plaster fall off [4]

2.3 Date of dressing/plaster falloff [5]

2.4 Check if time is unknown [6]

2.5 Time of dressing/plasterloss(exact or approximate) [7]

2.6 Description of timepoint for lostdressing/plaster(if time in unknown) [8]

1 Test field 1 Yes No Now






Removal of IMP residuesYes No [9]

Now [10]

201465_350209BS_aCRF_unique_d03_20151027

93

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Did any dressing/plaster fall off since last visit? EXENYN Categorical select one (nominal) 3[3] 2.1 Affected test field EXSPID Categorical select one (nominal) 12 Test field 1


[4] 2.2 Dressing/plaster fall off EX2ENYN Categorical yes/no (dichotomous) 3[5] 2.3 Date of dressing/plaster fall off EXENDATL Date 11[6] 2.4 Check if time is unknown EXENTIMU Categorical yes/no (dichotomous) 3[7] 2.5 Time of dressing/plaster loss (exact or

approximate)EXENTIML Time 5

[8] 2.6 Description of timepoint for lost dressing/plaster(if time in unknown)

EXENTPT Text or Any Value 200

[9] 3. Removal performed? EXENPERF Categorical yes/no (dichotomous) 3[10] 4. Removal time EXENTIM Time 5

201465_350209BS_aCRF_unique_d03_20151027

94

CONFIDENTIAL 2016N274225_00201465

1. RUCAM performed?

RUCAM at Liver event

RUCAMYes No [1]

.

2. Liver stopping event date [2] 2.1 Visit related to the date of stopping event [3] 3. Parameter/Test [4] 4. Result [5] 5. Evaluation interval code(enter a code from the list below) [6]

1

More rows: 1 5 10

1 During the past week2 During the past 4 weeks3 During the last 48 hours4 Today5 During the past 2, weeks including today6 Since baseline7 These days8 Past five days9 Since last visit10 During the last 24 hours11 During the past month12 Since the beginning of this study13 During the past 7 days14 During the past few days15 Past 3 days16 Compared to one year ago17 At this moment in time18 Two hours prior to/During the visit19 Within the past 6 months20 Per week21 Prior to this study22 During the past 12 weeks23 Over the last few weeks24 Over the past week25 Past 2 weeks26 Last 2 weeks27 Compared to condition at admission to study28 Since started taking study drugs29 Worse case ever30 Over the last 2 or 3 weeks or since you last used it

201465_350209BS_aCRF_unique_d03_20151027

95

CONFIDENTIAL 2016N274225_00201465

31 Within the past 3 months32 Baseline33 Since last assessment34 Lifetime 35 Regularly36 8 weeks prior to randomisation37 At time of randomisation38 > 1 month prior to randomisation39 > 3 months prior to randomisation40 Whole sequence of stimulation41 Over the past year42 Since first diagnosis of condition43 Most recent44 Within the past month45 Within the past 2 months46 Within the past 4 months47 Within the past 5 months48 Last night49 During the last 12 hours50 Over the past month51 At the time of visit or in the preceding 10 days52 In the past three hours53 In the past six hours54 In the past 10 hours55 In the past week56 In the past 2 weeks57 Since the Stroke58 More than 6 months59 First day of dose and day 2860 48 hours from onset of symptoms61 Preceding 30 days62 During the 8 weeks prior to study start63 During the 12 months prior to study start64 Within the last 5 years65 Initial exam66 During weeks -16 to -13 prior to study start67 During weeks -12 to -9 prior to study start68 During weeks -8 to -5 prior to study start69 During the past day70 At present71 Past 8 weeks72 At discharge73 30 days after stroke74 Over the past two years75 Since onset of illness76 Past 30 minutes77 During this pregnancy78 Before the C linical Trial79 During the C linical Trial80 End of the C linical Trial

201465_350209BS_aCRF_unique_d03_20151027

96

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. RUCAM performed? QSPERF Categorical yes/no (dichotomous) 3[2] 2. Liver stopping event date QSDAT Date 11[3] 2.1 V isit related to the date of stopping event VISIT Categorical select one (nominal) 17 Screening


[4] 3. Parameter/Test QSTESTCD Categorical select one (nominal) 48 Aged 55 or overWas a biopsy taken?Fasting or significant dietary changeLiver imaging normalLiver imaging performedCriteria involved liver stopping eventWhen did the liver event occur?Is this event serious?Subject become pregnant?Any unconventional medicationsDetails of fasting or significant dietary change

[5] 4. Result QSORRES Categorical select one (nominal) 78 ALT (alanine aminotransferase)AST (aspartate aminotransferase)Total BilirubinA lkaline phosphatase5'-nucleotidaseGammaglutamyltranspeptidaseDirect BilirubinINREosinophilsBilirubinUnable to monitorSigns and symptomsALT >=3xULN and bilirubin >= 2xULNALT >=3xULN and INR>1.5, (in any subject not receiving anti-coagulanttherapy)ALT>= 8xULNALT >=5xULN but <8xULN persists for >=2 weeksALT >=3xULN but <5xULN persists for >=4 weeksALT >=3xULN if associated with symptoms related tohepatitis/hypersensitivityALT >=5xULN but <8xULN and cannot be monitored weekly for >=2 weeksALT >=3xULN but <5xULN and cannot be monitored weekly for >=4 weeksAfter the treatment periodDuring the treatment periodYesNoOtherUnknownNot applicable

[6] 5. Evaluation interval code (enter a code from thelist below)

QSREFID Number (continuous) 15

201465_350209BS_aCRF_unique_d03_20151027

97

CONFIDENTIAL 2016N274225_00201465

1. Event

2. Start date

3. Check if start time is notdeterminable/unknown

3.1. Start time

4. Outcome

5. End date

6. Check if end time is notdeterminable/unknown

6.1 End time

7. Maximum Intensity

8. Action taken with Study Drug

9. Withdrawal

10. Relationship to StudyTreatment(s)

11.[A] Results in death

11.[B] Is life-threatening

11.[C] Requires hospitalisation orprolongation of existing

hospitalisation

11.[D] Results in disability/incapacity

11.[E] Congenital anomaly/birthdefect

11.[F] Other

11.[F].1 Other, specification

11.[G] Possible drug-induced liverinjury

12. Year of birth

12.1 Date of birth (30-Jun-yyyy)

13. Sex

14.1 Weight [kg]

14.2 Height [cm]

15. Recur After Further StudyTreatment(s) were Administered?

Serious Adverse Events at Adverse Events

0.1 Random no. [1]

Serious Adverse Event.SECTION 11. Diagnosis Only(if known) Otherwise Sign/Symptom

[2]

Now [3]

[4]

[5]

[6]

Now [7]

[8]

[9]

[10]

8. Most C linically Significant Action Taken with Study Treatment(s) as a Result of the SAE

[11]

9. Did the subject withdraw from study as a result of this SAE?

Yes No [12]

10. Is there a reasonable possibility the SAE may have been caused by the study treatment?

Yes No [13]

.SECTION 2Seriousness (specify reason(s) for considering this a SAE, all that apply:

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

.SECTION 3Demography Data

[22]

[23]

Male Female [24]

[25]

[26]

.SECTION 415. If Study Treatment(s) was Stopped, Did the Reported Event(s) Recur After Further Study Treatment(s) were Administered?

[27]

201465_350209BS_aCRF_unique_d03_20151027

98

CONFIDENTIAL 2016N274225_00201465

15.1 Event(s) recur after rechallenge

16.1 Disease under study

16.2 Medical condition(s)

16.2.1 Medication condition(s),specification

16.3 Lack of efficacy

16.4 Withdrawal of studytreatment(s)

16.5 Concomitant medication(s)

16.5.1 Concomitant medication(s),specification

16.6 Activity related to studyparticipation

16.7 Other

16.7.1 Other, specification

17. Any RELEVANT Medical Conditions

18. Any Other RELEVANT RiskFactors?

18.1 Other RELEVANT Risk Factors

19. Any medications?

20. Any details of study treatment(s)

20.1 Details of Study Treatment(s)

20.2 Details of Study Treatment(s)(continued)

Yes No [28]

.SECTION 5Possible Causes of SAE Other Than Study Treatment(s), all that apply:

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

.SECTION 6.Specify any RELEVANT past or current medical disorders, allergies,surgeries that can help explain the SAE.Ensure each medical condition recorded in this section is also recorded inthe appropriate Medical Conditions form.

Yes No [39]

17.1 RELEVANT Medical Conditions [40] 17.2 Start date [41] 17.3 Condition Present at Time of the SAE? [42] 17.3.1 If No, Date of Last Occurrence [43]

1 Yes No Now

More rows: 1 5 10

.SECTION 7Other RELEVANT Risk FactorsProvide any family history or social history (e.g., smoking, alcohol, diet, drug abuse, occupational hazard) relevant to the SAE). Ensure each risk factor recorded in this section is also recorded in the appropriate Medical Conditions form.

Yes No [44]

[45]

.SECTION 8RELEVANT Concomitant MedicationsInclude details of any concomitant medication(s) that may help explain the SAE, may have caused the SAE or was used to treat the SAE. Ensure each concomitant medication recorded in this section is also recorded in the Concomitant Medication form.

Yes No [46]

19.1 Drug name [47] 19.2 Dose [48] 19.3 Dose Unit [49]

19.3.1 Dose Unit:Other, specify [50]

19.4. DosingFrequency [51]

19.4.1 DosingFrequency: Other,specify [52]

19.5 Route [53]

19.5.1 Route: Other,specify [54]

19.6Takenprior tostudy? [55]

19.7 Startdate [56]

19.8 Stopdate [57]

19.9Ongoingmedication? [58]

19.10 Reason for Medication [59]

1

Yes NoYes No

More rows: 1 5 10

.SECTION 9Details of Study Treatment(s)

Yes No [60]

[61]

[62]

201465_350209BS_aCRF_unique_d03_20151027

99

CONFIDENTIAL 2016N274225_00201465

21. Was treatment blind broken atinvestigational site?

22. Any RELEVANT Assessments?

22.1 Details of RELEVANTAssessments

22.2 Details of RELEVANTAssessments (continued)

23. Any narrative remarks?

23.1 Narrative Remarks

23.2 Narrative Remarks (continued)

23.3 Narrative Remarks (continued)


.SECTION 10Provide details of any tests or procedures carried out to diagnose or confirm the SAE (e.g., laboratory data with units andnormal range) if data for this SAE have not been previously entered, and the CRF includes a page for the test, ensure the data is also entered on the page.

Yes No [64]

[65]

[66]

.SECTION 11Narrative Remarks(provide a brief narrative description of the SAE and details of treatment given)

Yes No [67]

[68]

[69]

[70]

201465_350209BS_aCRF_unique_d03_20151027

100

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Event AETERM Text or Any Value 200[3] 2. Start date AESTDAT Date 11[4] 3. Check if start time is not determinable/unknown AESTTIMN Categorical yes/no (dichotomous) 3[5] 3.1. Start time AESTTIM Time 5[6] 4. Outcome AEOUT Categorical select one (nominal) 32 Recovered/resolved

Recovering/resolvingNot recovered/not resolvedRecovered/resolved with sequelaeFatal

[7] 5. End date AEENDAT Date 11[8] 6. Check if end time is not determinable/unknown AEENTIMN Categorical yes/no (dichotomous) 3[9] 6.1 End time AEENTIM Time 5[10] 7. Maximum Intensity AESEV Categorical select one (nominal) 14 Mild

ModerateSevereNot applicable

[11] 8. Action taken with Study Drug AEACN Categorical select one (nominal) 28 Study Treatment(s) withdrawnDose reducedDose increasedDose not changedDose interrupted/ DelayedNot applicable

[12] 9. Withdrawal AEDIS Categorical yes/no (dichotomous) 3[13] 10. Relationship to Study Treatment(s) AEREL Categorical select one (nominal) 3[14] 11.[A] Results in death AESDTH Categorical yes/no (dichotomous) 3[15] 11.[B] Is life-threatening AESLIFE Categorical yes/no (dichotomous) 3[16] 11.[C] Requires hospitalisation or prolongation of

existing hospitalisationAESHOSP Categorical yes/no (dichotomous) 3

[17] 11.[D] Results in disability/incapacity AESDISAB Categorical yes/no (dichotomous) 3[18] 11.[E] Congenital anomaly/birth defect AESCONG Categorical yes/no (dichotomous) 3[19] 11.[F] Other AESMIE Categorical yes/no (dichotomous) 3[20] 11.[F].1 Other, specification AESMIEOT Text or Any Value 200[21] 11.[G] Possible drug-induced liver injury AESLIVER Categorical yes/no (dichotomous) 3[22] 12. Year of birth BRTHYR Number (continuous) 15[23] 12.1 Date of birth (30-Jun-yyyy) BRTHDAT Date 11[24] 13. Sex SEX Categorical select one (nominal) 6[25] 14.1 Weight [kg] VSWEIGHT Number (continuous) 15[26] 14.2 Height [cm] VSHEIGHT Number (continuous) 15[27] 15. Recur After Further Study Treatment(s) were

Administered?AERECYN Categorical select one (nominal) 20 Yes

NoUnknown at this timeNot Applicable

[28] 15.1 Event(s) recur after rechallenge AE2RECYN Categorical yes/no (dichotomous) 3[29] 16.1 Disease under study AESOTDUS Categorical yes/no (dichotomous) 3[30] 16.2 Medical condition(s) AESOTMC Categorical yes/no (dichotomous) 3[31] 16.2.1 Medication condition(s), specification AESOTMCS Text or Any Value 200[32] 16.3 Lack of efficacy AESOTLE Categorical yes/no (dichotomous) 3[33] 16.4 Withdrawal of study treatment(s) AESOTWDT Categorical yes/no (dichotomous) 3[34] 16.5 Concomitant medication(s) AESOTCM Categorical yes/no (dichotomous) 3[35] 16.5.1 Concomitant medication(s), specification AESOTCMS Text or Any Value 200[36] 16.6 Activity related to study participation AESOTACT Categorical yes/no (dichotomous) 3[37] 16.7 Other AESOTOT Categorical yes/no (dichotomous) 3[38] 16.7.1 Other, specification AESOTOTS Text or Any Value 200[39] 17. Any RELEVANT Medical Conditions MHYN Categorical yes/no (dichotomous) 3[40] 17.1 RELEVANT Medical Conditions MHTERM Text or Any Value 200[41] 17.2 Start date MHSTDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

101

CONFIDENTIAL 2016N274225_00201465

[42] 17.3 Condition Present at Time of the SAE? MHOCCUR Categorical yes/no (dichotomous) 3[43] 17.3.1 If No, Date of Last Occurrence MHENDAT Date 11[44] 18. Any Other RELEVANT Risk Factors? AERISKYN Categorical yes/no (dichotomous) 3[45] 18.1 Other RELEVANT Risk Factors AERISK Text or Any Value 4000[46] 19. Any medications? CMYN Categorical yes/no (dichotomous) 3[47] 19.1 Drug name CMTRT Text or Any Value 200[48] 19.2 Dose CMDSTXT Text or Any Value 200[49] 19.3 Dose Unit CMDOSEU Categorical select one (nominal) 24 Ampule

ApplicationCapsuleChewing GumCoated tabletDropsEffervescent (Tablet)gIU (International Units)LozengemgmLPatchPuff (e.g. in sprays)RingSachetTabletTbsp (Tablespoon Unit)tsp (Teaspoon Unit)ug (Microgram, mcg)uLUnknownOther

[50] 19.3.1 Dose Unit: Other, specify CMDOSUO Text or Any Value 200[51] 19.4. Dosing Frequency CMDOSFRQ Categorical select one (nominal) 31 Five Times Weekly

OnceOnce Daily (QD)Once WeeklyPRNQD/28D (e.g. in contraceptions)Three Times Daily (TID)Three Times WeeklyTwice Daily (BID)Other

[52] 19.4.1 Dosing Frequency: Other, specify CMDOSFQO Text or Any Value 200[53] 19.5 Route CMROUTE Categorical select one (nominal) 13 Buccal

InhalationIntramuscularIntravenousNasalOphthalmicOralRectalSubcutaneousSublingualTopicalVaginalUnknownOther

[54] 19.5.1 Route: Other, specify CMROUTEO Text or Any Value 200[55] 19.6 Taken prior to study? CMPRDOS Categorical yes/no (dichotomous) 3[56] 19.7 Start date CMSTDAT Date 11[57] 19.8 Stop date CMENDAT Date 11[58] 19.9 Ongoing medication? CMONGO Categorical yes/no (dichotomous) 3[59] 19.10 Reason for Medication CMINDC Text or Any Value 200[60] 20. Any details of study treatment(s) AESTRTYN Categorical yes/no (dichotomous) 3[61] 20.1 Details of Study Treatment(s) AESTRT Text or Any Value 4000[62] 20.2 Details of Study Treatment(s) (continued) AE2STRT Text or Any Value 4000[63] 21. Was treatment blind broken at investigational

site?DSDECOD Categorical select one (nominal) 14

201465_350209BS_aCRF_unique_d03_20151027

102

CONFIDENTIAL 2016N274225_00201465

[64] 22. Any RELEVANT Assessments? AESASSYN Categorical yes/no (dichotomous) 3[65] 22.1 Details of RELEVANT Assessments AESASS Text or Any Value 4000[66] 22.2 Details of RELEVANT Assessments

(continued)AE2SASS Text or Any Value 4000

[67] 23. Any narrative remarks? AESNARYN Categorical yes/no (dichotomous) 3[68] 23.1 Narrative Remarks AESNAR Text or Any Value 4000[69] 23.2 Narrative Remarks (continued) AE2SNAR Text or Any Value 4000[70] 23.3 Narrative Remarks (continued) AE3SNAR Text or Any Value 4000

201465_350209BS_aCRF_unique_d03_20151027

103

CONFIDENTIAL 2016N274225_00201465

1. Has the treatment beenperformed?

2. Has the treatment for all fieldsbeen performed?

3.1 Test field 1

3.2 Test field 2

3.3 Test field 3

3.4 Test field 4

3.5 Test field 5

3.6 Test field 6

4. Date of treatment

4.1 Treatment time

Treatment at Day 1 (Baseline procedures)

0.1 Random no. [1]

Application of topical IMPsYes No [2]

.

Yes No [3]

3. If no, specify below all fields for which no treatment was performed

[4]

[5]

[6]

[7]

[8]

[9]

.

Now [10]

Please enter here the start time of treatment.

Now [11]

201465_350209BS_aCRF_unique_d03_20151027

104

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Has the treatment been performed? EXPERF Categorical yes/no (dichotomous) 3[3] 2. Has the treatment for all fields been performed? EXYN Categorical yes/no (dichotomous) 3[4] 3.1 Test field 1 EX01SPID Categorical yes/no (dichotomous) 3[5] 3.2 Test field 2 EX02SPID Categorical yes/no (dichotomous) 3[6] 3.3 Test field 3 EX03SPID Categorical yes/no (dichotomous) 3[7] 3.4 Test field 4 EX04SPID Categorical yes/no (dichotomous) 3[8] 3.5 Test field 5 EX05SPID Categorical yes/no (dichotomous) 3[9] 3.6 Test field 6 EX06SPID Categorical yes/no (dichotomous) 3[10] 4. Date of treatment EXSTDAT Date 11[11] 4.1 Treatment time EXTIM Time 5

201465_350209BS_aCRF_unique_d03_20151027

105

CONFIDENTIAL 2016N274225_00201465

1. Has the treatment beenperformed?

2. Has the treatment for all fieldsbeen performed?

3.1 Test field 1

3.2 Test field 2

3.3 Test field 3

3.4 Test field 4

3.5 Test field 5

3.6 Test field 6

4.1 Treatment time

Treatment at Day 2,Day 3,Day 4,Day 5,Day 6,Day 8,Day 9,Day 10,Day 11,Day 13,Day 12,Day 15,Day 16,Day 17,Day 18

0.1 Random no. [1]

Application of topical IMPsYes No [2]

.

Yes No [3]

3. If no, specify below all fields for which no treatment was performed

[4]

[5]

[6]

[7]

[8]

[9]

.Please enter here the start time of treatment.

Now [10]

201465_350209BS_aCRF_unique_d03_20151027

106

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Has the treatment been performed? EXPERF Categorical yes/no (dichotomous) 3[3] 2. Has the treatment for all fields been performed? EXYN Categorical yes/no (dichotomous) 3[4] 3.1 Test field 1 EX01SPID Categorical yes/no (dichotomous) 3[5] 3.2 Test field 2 EX02SPID Categorical yes/no (dichotomous) 3[6] 3.3 Test field 3 EX03SPID Categorical yes/no (dichotomous) 3[7] 3.4 Test field 4 EX04SPID Categorical yes/no (dichotomous) 3[8] 3.5 Test field 5 EX05SPID Categorical yes/no (dichotomous) 3[9] 3.6 Test field 6 EX06SPID Categorical yes/no (dichotomous) 3[10] 4.1 Treatment time EXTIM Time 5

201465_350209BS_aCRF_unique_d03_20151027

107

CONFIDENTIAL 2016N274225_00201465

1. Was the treatment blind broken?

Treatment blind broken at End of study / Completion

0.1 Random no. [1]

Blind brokenYes No [2]

.

2. Date treatment blind was broken [3] 3. Time treatment blind was broken [4] 4. Reason for breaking the blind code [5] 4.1 Reason for breaking the blind, other [6]

1

More rows: 1 5 10

201465_350209BS_aCRF_unique_d03_20151027

108

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Was the treatment blind broken? DSUNBLND Categorical yes/no (dichotomous) 3[3] 2. Date treatment blind was broken DSSTDAT Date 11[4] 3. Time treatment blind was broken DSSTTIM Time 5[5] 4. Reason for breaking the blind code DSDECOD Categorical select one (nominal) 61 Medical emergency requiring identification of study treatment

Progressive diseaseDecision to unblind entire study populationPrimary endpoint reachedBlind broken following a planned interim analysisSubject met planned unblinding criterionSuspected hypersensitivity to study treatmentTo inform anti-cancer treatment decision after recurrenceOther

[6] 4.1 Reason for breaking the blind, other DSTERM Text or Any Value 200

201465_350209BS_aCRF_unique_d03_20151027

109

CONFIDENTIAL 2016N274225_00201465

1. Evaluation performed?

2. Evaluation date

Ultrasound evaluation at Day 8,Day 15,Day 1 (Baseline procedures),Unscheduled Visit,EoT / ET (Day 19),Day 4

0.1 Random no. [1]

Evaluation of ultrasound measurementYes No [2]

Now [3]

.

3. Test field [4] 3.1 Check only if test field was not evaluated [5] 4. Result (µm) [6]

5. Check for any comments [7] 5.1 Comment [8]

1 Test field 1

2 Test field 2

3 Test field 3

4 Test field 4

5 Test field 5

6 Test field 6

201465_350209BS_aCRF_unique_d03_20151027

110

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Evaluation performed? MOPERF Categorical yes/no (dichotomous) 3[3] 2. Evaluation date MODAT Date 11[4] 3. Test field MOSPID Categorical select one (nominal) 12 Test field 1


[5] 3.1 Check only if test field was not evaluated MOSTAT Categorical yes/no (dichotomous) 3[6] 4. Result MOORRES Number (continuous) 15[7] 5. Check for any comments COVALYN Categorical yes/no (dichotomous) 3[8] 5.1 Comment COVAL Text or Any Value 1000

201465_350209BS_aCRF_unique_d03_20151027

111

CONFIDENTIAL 2016N274225_00201465

1. Ultrasound measurementperformed?

2. Time of measurement

Ultrasound measurement at Day 8,Day 15,Day 1 (Baseline procedures),Unscheduled Visit,EoT / ET (Day 19),Day 4

0.1 Random no. [1]

Ultrasound measurementPlease consider washing the test fields with a mild detergent solution before ultrasound measurements, if necessary.

Yes No [2]

Now [3]

201465_350209BS_aCRF_unique_d03_20151027

112

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Ultrasound measurement performed? MOPERF Categorical yes/no (dichotomous) 3[3] 2. Time of measurement MOTIM Time 5

201465_350209BS_aCRF_unique_d03_20151027

113

CONFIDENTIAL 2016N274225_00201465

1. Urinalysis performed?

2.1. Specific Gravity Result

2.2. pH Result

2.5. Protein, Urine Result

2.6. Glucose, Urine Result

2.7. Ketones Result

2.10. Blood (erythrocytes) result

Urinalysis at Screening Lab Urine examination

UrinalysisYes No [1]

Result of Urinalysis

[2]

[3]

[4]

[5]

[6]

[7]

3.1. Parameter [8] 3.2. Check if abnormal result [9] 3.2.1. Clinically significant? [10]

1 Specific Gravity Yes No

2 pH Yes No

3 Protein Yes No

4 Glucose Yes No

5 Ketones Yes No

6 Erythrocytes Yes No

201465_350209BS_aCRF_unique_d03_20151027

114

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Urinalysis performed? LBPERF Categorical yes/no (dichotomous) 3[2] 2.1. Specific Gravity Result LBSPGRES Categorical select one (nominal) 5 1.000

1.0051.0101.0151.0201.0251.030

[3] 2.2. pH Result LBPHRRES Categorical select one (nominal) 1 56789

[4] 2.5. Protein, Urine Result LBPRORES Categorical select one (nominal) 22 Negative1+ (30 mg/dL; 0.3 g/L)2+ (100 mg/dL; 1 g/L)3+ (500 mg/dL; 5 g/L)

[5] 2.6. Glucose, Urine Result LBGLURES Categorical select one (nominal) 26 Normal1+ (50 mg/dL; 2.8 mmol/L)2+ (100 mg/dL; 5.5 mmol/L)3+ (300 mg/dL; 17 mmol/L)4+ (1000 mg/dL; 55 mmol/L)

[6] 2.7. Ketones Result LBKETRES Categorical select one (nominal) 25 Negative1+ (10 mg/dL; 1 mmol/L)2+ (50 mg/dL; 5 mmol/L)3+ (150 mg/dL; 15 mmol/L)

[7] 2.10. Blood (erythrocytes) result LBRBCRES Categorical select one (nominal) 20 Negative1+ (ca. 5-10 Ery/uL)2+ (ca. 25 Ery/uL)3+ (ca. 50 Ery/uL)4+ (ca. 250 Ery/uL)

[8] 3.1. Parameter LBTESTCD Categorical select one (nominal) 16 Specific GravitypHProteinGlucoseKetonesErythrocytes

[9] 3.2. Check if abnormal result LBNRIND Categorical yes/no (dichotomous) 3[10] 3.2.1. Clinically significant? LBCLSIG Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

115

CONFIDENTIAL 2016N274225_00201465

1. Urinalysis performed?

2.1. Specific Gravity Result

2.2. pH Result

2.5. Protein, Urine Result

2.6. Glucose, Urine Result

2.7. Ketones Result

2.10. Blood (erythrocytes) result

Urinalysis at Day 8 Lab Urine examination,Day 15 Lab Urine examination,EoT / ET (Day 19) Lab Urine exam,Unscheduled Visit

0.1 Random no. [1]

UrinalysisYes No [2]

Result of Urinalysis

[3]

[4]

[5]

[6]

[7]

[8]

3.1. Parameter [9] 3.2. Check if abnormal result [10] 3.2.1. Clinically significant? [11]

1 Specific Gravity Yes No

2 pH Yes No

3 Protein Yes No

4 Glucose Yes No

5 Ketones Yes No

6 Erythrocytes Yes No

201465_350209BS_aCRF_unique_d03_20151027

116

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Urinalysis performed? LBPERF Categorical yes/no (dichotomous) 3[3] 2.1. Specific Gravity Result LBSPGRES Categorical select one (nominal) 5 1.000

1.0051.0101.0151.0201.0251.030

[4] 2.2. pH Result LBPHRRES Categorical select one (nominal) 1 56789

[5] 2.5. Protein, Urine Result LBPRORES Categorical select one (nominal) 22 Negative1+ (30 mg/dL; 0.3 g/L)2+ (100 mg/dL; 1 g/L)3+ (500 mg/dL; 5 g/L)

[6] 2.6. Glucose, Urine Result LBGLURES Categorical select one (nominal) 26 Normal1+ (50 mg/dL; 2.8 mmol/L)2+ (100 mg/dL; 5.5 mmol/L)3+ (300 mg/dL; 17 mmol/L)4+ (1000 mg/dL; 55 mmol/L)

[7] 2.7. Ketones Result LBKETRES Categorical select one (nominal) 25 Negative1+ (10 mg/dL; 1 mmol/L)2+ (50 mg/dL; 5 mmol/L)3+ (150 mg/dL; 15 mmol/L)

[8] 2.10. Blood (erythrocytes) result LBRBCRES Categorical select one (nominal) 20 Negative1+ (ca. 5-10 Ery/uL)2+ (ca. 25 Ery/uL)3+ (ca. 50 Ery/uL)4+ (ca. 250 Ery/uL)

[9] 3.1. Parameter LBTESTCD Categorical select one (nominal) 16 Specific GravitypHProteinGlucoseKetonesErythrocytes

[10] 3.2. Check if abnormal result LBNRIND Categorical yes/no (dichotomous) 3[11] 3.2.1. Clinically significant? LBCLSIG Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

117

CONFIDENTIAL 2016N274225_00201465

1. Was a microscopic urine analysisperformed?

Urine lab Yes/No at Screening Lab Urine examination

Microscopic urinalysisPlease capture whether a Microscopic examination (if blood or protein is abnormal) was performed.

If Yes, please complete the laboratory form on visit Lab Urine examination.

Yes No [1]

201465_350209BS_aCRF_unique_d03_20151027

118

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Was a microscopic urine analysis performed? LBYN Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

119

CONFIDENTIAL 2016N274225_00201465

1. Was a microscopic urine analysisperformed?

Urine lab Yes/No at Day 8 Lab Urine examination,Day 15 Lab Urine examination,EoT / ET (Day 19) Lab Urine exam,Unscheduled Lab Urine exam

0.1 Random no. [1]

Microscopic urinalysisPlease capture whether a Microscopic examination (if blood or protein is abnormal) was performed.

If Yes, please complete the laboratory form on visit Lab Urine examination.

Yes No [2]

201465_350209BS_aCRF_unique_d03_20151027

120

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Was a microscopic urine analysis performed? LBYN Categorical yes/no (dichotomous) 3

201465_350209BS_aCRF_unique_d03_20151027

121

CONFIDENTIAL 2016N274225_00201465

1. Urine sample collected?

2. Actual time of urine samplecollection

Urine sample collection at Screening

Urine sample collectionYes No [1]

Now [2]

201465_350209BS_aCRF_unique_d03_20151027

122

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. Urine sample collected? LBPERF Categorical yes/no (dichotomous) 3[2] 2. Actual time of urine sample collection LBTIM Time 5

201465_350209BS_aCRF_unique_d03_20151027

123

CONFIDENTIAL 2016N274225_00201465

1. Urine sample collected?

2. Actual time of urine samplecollection

Urine sample collection at Day 8,Day 15,EoT / ET (Day 19),Unscheduled Visit

0.1 Random no. [1]

Urine sample collectionYes No [2]

Now [3]

201465_350209BS_aCRF_unique_d03_20151027

124

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Urine sample collected? LBPERF Categorical yes/no (dichotomous) 3[3] 2. Actual time of urine sample collection LBTIM Time 5

201465_350209BS_aCRF_unique_d03_20151027

125

CONFIDENTIAL 2016N274225_00201465

1.1 Has the visit been performed?

2. Date of visit

Visit performed / Date at Screening,Day 1

VisitYes No [1]

Now [2]

. General instructions:If any adverse events occurs since the last visit and / or at this visit, give details on an adverse event form at visit Adverse Events.

If any changes have been made to prior or concomitant therapy since the last visit and / or at this visit, please give details on the priorand concomitant therapy form at visit Prior and Concomitant Therapy.

Please ensure that all inclusion criteria are still met resp. any of the exclusion criteria is met during the course of the trial, otherwise consider discontinuing the subject from the trial.

201465_350209BS_aCRF_unique_d03_20151027

126

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1.1 Has the visit been performed? VISPERF Categorical yes/no (dichotomous) 3[2] 2. Date of visit VISDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

127

CONFIDENTIAL 2016N274225_00201465


2. Date of visit

Visit performed / Date at Day 2,Day 3,Day 4,Day 5,Day 6,Day 8,Day 9,Day 10,Day 11,Day 12,Day 13,Day 15,Day 27,Day 16,Day 17,Day 18

0.1 Random no. [1]

VisitYes No [2]

Now [3]




201465_350209BS_aCRF_unique_d03_20151027

128

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1.1 Has the visit been performed? VISPERF Categorical yes/no (dichotomous) 3[3] 2. Date of visit VISDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

129

CONFIDENTIAL 2016N274225_00201465

1. Is this visit an early terminationvisit?


2. Date of visit

Visit performed / Date at EoT / ET (Day 19)

0.1 Random no. [1]

VisitYes No [2]

Yes No [3]

Now [4]




201465_350209BS_aCRF_unique_d03_20151027

130

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Is this visit an early termination visit? SVETYN Categorical yes/no (dichotomous) 3[3] 1.1 Has the visit been performed? VISPERF Categorical yes/no (dichotomous) 3[4] 2. Date of visit VISDAT Date 11

201465_350209BS_aCRF_unique_d03_20151027

131

CONFIDENTIAL 2016N274225_00201465


2. Date of visit

3. What was the last scheduled visitbefore that unscheduled visit?

Visit performed / Date at Unscheduled Visit

0.1 Random no. [1]

VisitYes No [2]

Now [3]

[4]




201465_350209BS_aCRF_unique_d03_20151027

132

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1.1 Has the visit been performed? VISPERF Categorical yes/no (dichotomous) 3[3] 2. Date of visit VISDAT Date 11[4] 3. What was the last scheduled visit before that

unscheduled visit?SVLAST Categorical select one (nominal) 17 Screening

Day 1Day 2Day 3Day 4Day 5Day 6Day 8Day 9Day 10Day 11Day 12Day 13Day 15Day 16Day 17Day 18EoT / ET (Day 19)Day 27

201465_350209BS_aCRF_unique_d03_20151027

133

CONFIDENTIAL 2016N274225_00201465

1. Vital signs measured?


Vital signs at Screening

Vital SignsYes No [1]

[2]

Take the vital signs after 5 minutes rest in a sitting position.

3. Parameter

[3]

3.1 Check if parameter not done / not measured [4] 4. Result [5] 5. Position [6]

1 Systolic Blood Pressure (mmHg) Sitting

2 Diastolic Blood Pressure (mmHg) Sitting

3 Heart Rate (BEATS/min) Sitting

4 Temperature [°C] Sitting

201465_350209BS_aCRF_unique_d03_20151027

134

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 1. V ital signs measured? VSPERF Categorical yes/no (dichotomous) 3[2] 2. Time of measurement VSTIM Time 5[3] 3. Parameter VSTESTCD Categorical select one (nominal) 31 Systolic Blood Pressure (mmHg)

Diastolic Blood Pressure (mmHg)Heart Rate (BEATS/min)Temperature [°C]

[4] 3.1 Check if parameter not done / not measured VSSTAT Categorical yes/no (dichotomous) 3[5] 4. Result VSORRES Number (continuous) 15[6] 5. Position VSPOS Categorical select one (nominal) 7

201465_350209BS_aCRF_unique_d03_20151027

135

CONFIDENTIAL 2016N274225_00201465

1. Vital signs measured?


Vital signs at EoT / ET (Day 19),Unscheduled Visit

0.1 Random no. [1]

Vital SignsYes No [2]

[3]

Take the vital signs after 5 minutes rest in a sitting position.

3. Parameter

[4]

3.1 Check if parameter not done / not measured [5] 4. Result [6] 5. Position [7]

1 Systolic Blood Pressure (mmHg) Sitting

2 Diastolic Blood Pressure (mmHg) Sitting

3 Heart Rate (BEATS/min) Sitting

4 Temperature [°C] Sitting

201465_350209BS_aCRF_unique_d03_20151027

136

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. V ital signs measured? VSPERF Categorical yes/no (dichotomous) 3[3] 2. Time of measurement VSTIM Time 5[4] 3. Parameter VSTESTCD Categorical select one (nominal) 31 Systolic Blood Pressure (mmHg)

Diastolic Blood Pressure (mmHg)Heart Rate (BEATS/min)Temperature [°C]

[5] 3.1 Check if parameter not done / not measured VSSTAT Categorical yes/no (dichotomous) 3[6] 4. Result VSORRES Number (continuous) 15[7] 5. Position VSPOS Categorical select one (nominal) 7

201465_350209BS_aCRF_unique_d03_20151027

137

CONFIDENTIAL 2016N274225_00201465

1. Biopsy wound control performed?

2. Result of wound healing evaluation

Wound control at Day 27,Unscheduled Visit

0.1 Random no. [1]

Wound control (after removal of stitches of biopsy wound)Yes No [2]

Normal Abnormal [3]

Please consider adding any abnormal findings to the Adverse Event form.

201465_350209BS_aCRF_unique_d03_20151027

138

CONFIDENTIAL 2016N274225_00201465

Variable details

Name Export Name Type Max length Categories[1] 3. Randomization number DSREFID Number (continuous) 15[2] 1. Biopsy wound control performed? PEPERF Categorical yes/no (dichotomous) 3[3] 2. Result of wound healing evaluation PERES Categorical select one (nominal) 8

201465_350209BS_aCRF_unique_d03_20151027

139

CONFIDENTIAL 2016N274225_00201465

CONFIDENTIAL

1

LIST OF INVESTIGATOR AND IEC FOR STUDY 201465 (EudraCT Number 2015-002614-72)

Investigator Sub-investigator Description of Research Facility, Hospital/Institution, and Address

Name of IEC/IRB Committee, Address, Committee Chair

Heinrich Siemetzki, MD. Uwe Kroncke, MD bioskin GmbHBurchardstrasse 1720095 Hamburg, Germany

Germany

Chairperson: MD

1

2016N274225_00201465

PPD

PPD

PPD

PPD

PPD

PPD

PPD - This section contained Curriculum Vitae(s) and has been excluded to protect personal privacy.

CONFIDENTIAL 2016N274225_00 201465

1

SAMPLE CONSENT FORMS

Sample subject information and informed consent form (ICF)

Attached is the master version (English version) of the subject information and consent form from 14-SEP-2015 (Version 2.0), the subject information and consent form_appendix A: Skin biopsies from 14-SEP-2015 (Version 2.0) as well as of the subject card from 19-AUG-2015 (Version 1.0).

The German versions of the above mentioned versions of the subject information and consent form and the subject card can be found in this appendix.

1

CONFIDENTIAL 2016N274225_00201465

Subject information 201465/350209BSPage 1 of 22

EudraCT Number: 2015-002614-72 201465 EN ICF V2.0, 14SEP2015SOP CLI/PL/05, Template from 20150512

Subject Information

A Phase I Trial to Evaluate Safety and Efficacy of Topically Applied GSK2981278 Ointment in a Psoriasis Plaque Test

Principal InvestigatorH. Siemetzki, M.D.

14. September 2015

Deputy InvestigatorU. Kröncke

EudraCT Nummer: 2015-002614-72

bioskin GmbHBurchardstraße 17 • 20095 Hamburg •

2

CONFIDENTIAL 2016N274225_00201465

PPD



Table of Content

1. Background .................................................................................................. 3

2. Aim of the trial you participate in .................................................................. 4

3. Trial design ................................................................................................... 4

4. Trial medication and treatment ..................................................................... 4

5. Special requirements during the trial ............................................................ 4

6. Course of the trial ......................................................................................... 5

7. Risk, complications ....................................................................................... 9

8. General considerations for a clinical trial .................................................... 11

8.1. Concomitant medication ............................................................................. 12

8.2. Blood and urine samples/ photo documentation ........................................ 13

8.3. Insurance cover .......................................................................................... 14

8.4. Additional obligations ................................................................................. 14

8.5. Data protection ........................................................................................... 15

8.6. What happens to my personal and medical information? .......................... 15

8.7. Information or medical advice .................................................................... 16

8.8. Information about the Sponsor ................................................................... 17

9. Reimbursement of expenses ...................................................................... 17

Informed consent form .................................................................................................. 18

3

CONFIDENTIAL 2016N274225_00201465



Dear Subject,We are pleased with your interest in this clinical trial. On the following pages you will find important information about the background and the conduct of the trial. Please read this information attentively and feel free to ask questions.

This clinical trial has the favorable opinion of the responsible ethics committee and has been approved by the responsible competent authority according to the requirements of the German law.

This consent form has been reviewed and approved by an Independent Review Board (IRB) or Ethics Committee (EC). This board/committee reviews research studies to protect the rights and well-being of the people taking part. Some of the information in this consent form is required by law.

Only you can decide if you want to take part in this trial. You should only make your decision after reading all the questions and answers in this form.

You may talk to your family, friends and or your family doctor to help make your decision. You can take as much time as you like to decide.

After you have read the entire form, you will be given the chance to ask any questions that you may have. When you have had the chance to ask any questions and they have been answered to your satisfaction, if you decide to take part, sign the pages at the end of this form to show that you agree to be part of the trial. This is called “giving your consent”.

Even after you have signed this trial consent form you can change your mind and decide not to participate in the trial. You do not have to give a reason.

1. BackgroundPsoriasis is an inflammatory skin disease that affects more than 125 million people worldwide. Scaly, reddened lesions (plaques) often combined with skin thickening (penetration of substances or cells in the body tissues) are characteristic for psoriasis vulgaris. Currently only therapies which alleviate the symptoms are possible since a causal treatment is still not known.

One of the key elements in the inflammation in psoriasis is a molecule (cytokine) called interleukin-17 (IL-17). The medication tested in this trial (GSK2981278) blocks the production of IL-17 and is therefore expected to materially improve skin changes in this disease.

For the Psoriasis Plaques Test used in this trial the trial preparations with different concentrations of the test substance, the vehicle (without active ingredient) and a market drug (positive control) will be applied to six chosen test fields over a period of 19 days (16treatments). It is the first time GSK2981278 is applied to humans in a clinical trial. Clinical safety and tolerability will be investigated. The change of the diseased skin will be assessed by means of sonographic (ultrasound) measurements as well as clinical evaluation using a scale.Furthermore the changes will be documented photographically. The efficacy of the investigational medicinal product (IMP) in comparison to the vehicle and the standard commercial product can be evaluated with this trial design.

4

CONFIDENTIAL 2016N274225_00201465



There will be no direct benefit to you from being in this trial. This is a mere experimental trial without therapeutic claim. The drug could possibly be used in the treatment of patients who are suffering from psoriasis in the future.

2. Aim of the trial you participate inIn this clinical trial the safety and skin tolerability as well as the antipsoriatic efficacy (effect on psoriasis plaque) of four different concentrations of GSK2981278 ointment shall be investigated and compared to the vehicle and to the positive control Betnesol-V 0.1% Cream.

The positive control Betnesol-V 0.1% Cream is approved in Germany for treatment of psoriasisas well as atopic dermatitis and other inflammatory skin diseases.

3. Trial design15 subjects with psoriasis aged 18 years or older will participate in this trial.

The trial will be performed subject- and observer-blind for all trial medications with randomassignment of the preparations to the test fields. Observer-blind means that the assessing staff member does not know which trial preparation is applied to which field. This is to ensure that the evaluation of the safety and efficacy is carried out without bias. Subject-blind means that you also do not know which trial preparation is applied to which field.

All subjects will be treated with all trial preparations. All test fields will be compared with each other in each individual subject (intraindividually).

4. Trial medication and treatmentTrial preparations:

1. GSK2981278 0.03% ointment2. GSK2981278 0.1% ointment3. GSK2981278 0.8% ointment4. GSK2981278 4% ointment5. vehicle to GSK2981278 ointment without the active ingredient

Positive control6. Betnesol-V 0.1% Creme (0.1% betamethasone valerate)

During the 19-day treatment phase about 200 μl of each of the trial preparations and of the positive control will be applied once a day (except on visit Day 7 and 14) to a test field. There will be 16 treatments in total. Defined test fields are created by punching holes in a self-adhesive hydrocolloid dressing fixed with adhesive patches to the skin. After application the test fields will be covered with an adhesive non-woven fabric (semi-occlusively). In total six test fields will be treated with one preparation each by a bioskin staff member.

The treatments are described in section 6 (Course of the trial).

5. Special requirements during the trialThe test fields must be kept dry. Exercise leading to excessive sweating should be avoided,bathing, swimming and sauna are not allowed during the trial since the adhesive bandages used could loosen. Physical activities are allowed within the scope of your normal activities.

5

CONFIDENTIAL 2016N274225_00201465



Short showering is allowed as long as the test fields are shielded from water. The use of emollients (skin care products) in the test fields is prohibited (see as well section 8.1, concomitant medication).

Dressings and plasters must not be removed. If they fall off they should not be put back on. Instead they should be returned to the trial center at the next visit and the approximate time the dressing/plaster fell off should be reported.

Additionally, excessive exposure to natural or artificial UV-light should be avoided (sunbathing or solarium), since treatment with Betnesol-V Creme could provoke a temporary photosensitivity(sensitivity to light). If you accidentally touch any of the test fields, it is recommended you wash your hands immediately.

The same personal care products and laundry detergents should be used throughout the trial.

The consumption of alcohol is limited and should not exceed an average weekly intake of 21units for males or 14 units for females

o 1 unit = 8g of alcohol:

~240ml of beer

1 glass of wine (125ml)

1 measure of spirits (25ml)

Only women who cannot become pregnant (of non-child bearing potential) are allowed to participate in the trial.

If you were originally screened as being of non-child bearing potential but find out you are pregnant, you must inform the investigator immediately.

Men participating in this trial will be required to use condoms (unless they have undergone a vasectomy).

You are not allowed to participate in another clinical trial in the 30 days preceding and during the trial or within 5 half-lives (time needed to halve substance levels in the body) of the test substance prior to first treatment, whichever is longer.

6. Course of the trialThe trial will be performed at bioskin GmbH, Burchardstrasse 17, 20095 Hamburg.

After signing the informed consent at the screening visit during the two weeks before trial start you will be asked about previous illnesses and medication and a clinical examination for eligibility for the trial will be performed. The examination includes measurement of temperature,blood pressure and pulse as well as an electrocardiogram (ECG). An ECG records the activity of your heart. Your body height and weight will be recorded. In addition you will be asked for blood and urine samples to assess laboratory parameters including liver and kidney parametersand perform HIV and Hepatitis as well as alcohol and drug tests.

Up to three plaques sufficient for 6 test fields on the trunk, the arms and upper legs (thighs) will be selected for treatment.

In case a severe illness is suspected you will be thoroughly informed about further clarification and medical care by an investigator.

If you test positive for the HIV or hepatitis a confirmatory test will be performed. If the positive result of the HIV-test is confirmed it will be transferred with the protection of your privacy to the Robert-Koch-institute as requested by the infection protection act. If the positive result of the

6

CONFIDENTIAL 2016N274225_00201465



hepatitis-test is confirmed it will be transferred with mentioning the name to the health authorities.

At the screening visit the subjects will be advised to pretreatment with 5 % salicylic acid in petrolatum for descaling of the test lesion(s) which will be performed for a maximum of 5 daysaccording to the instructions of the investigator. The last pre-treatment application of salicylic acid has to be performed 2 days before the first application of test preparations on day 1. The descaling may be necessary because scales interfere with the sonographic testing.

First trial day/Day 1:

Eligibility according to inclusion and exclusion criteria will be checked again;

Recording of prior and concomitant medication and Adverse Events (AE);

Documentation of the outline of the plaques and the six test fields on a transparent plastic sheet;

Photo documentation of the test area(s);

Sonography of all test fields (after mild descaling with soap suds, if necessary);

Covering of test area(s) with a gel-like wound dressing (Varihesive® or equivalent),which contains cut-outs corresponding to the sizes of the test fields (1.1 cm2);

Application of the trial preparations, the vehicle and the control onto the test fields;

Covering of test fields with non-woven fabric (Fixomull or equivalent).

Days 2-3, 5-6, 9-13 and 16-18:

Recording of prior and concomitant medication and AEs;

Re-application of the trial preparations once daily as described above.

On day 7 and day 14 no treatment is scheduled and the test field cover stays on the test fields until day 8 or day 15, respectively.

Day 4:


Removal of the gel-like wound dressing;

Clinical assessment of test fields using a 5-point rating scale;


Covering of test areal with a gel-like wound dressing as described above;

Re-application of the trial preparations as described above.

7

CONFIDENTIAL 2016N274225_00201465



Day 8:


Blood and urine sampling for laboratory parameters;






Day 15:


ECG measurement;







Day 19:

Physical examination of the skin;


ECG measurement;

Assessment of vital signs (temperature, blood pressure, pulse rate);




Photo documentation;

Sonography of all test fields (after mild descaling with soap suds, if necessary).

Optional: 4 skin biopsies with Follow-up visit at Day 27.

Skin biopsies are planned for a subgroup of subjects to be taken from test areas on the last day of trial. Participation in this trial part is optional. The biopsies will be taken to gather information on the influence of tested treatments on skin inflammation as seen in plaque psoriasis. If you are willing to participate in the biopsy sampling you will receive a separate subject information/consent form (Appendix A) containing additional information. After being orally informed by the investigator you need to sign a separate informed consent form.

8

CONFIDENTIAL 2016N274225_00201465



Trial scheduleProcedure Screening

[Day]Treatment Period

[Days]

-14 to -1 1 2 to

6 7 8 9 to

13 14 15 16 to

18 19

Informed consent XInclusion and exclusion criteria X XDemographics/medical history XBrief physical exam (including height and weight) X

Physical examination of the skin

X X

Descaling with salicylic acid X*1

Descaling of test sites with detergent solution (if necessary)

X X X*2 X X X

HIV, Hep B, and Hep C screen XECG X X XVital signs including heart rate, blood pressure and oral temperature

X X

Determination of test fields XLaboratory assessments andurinalysis; including drug and alcohol screening at screening

X X X X

Study Treatment X X X X X XAE/SAE review X X X X ==X===Prior and concomitant medication review X X X X X ==X===

Photographic documentation X XClinical assessments X*2 X X XHFUS (sonography) X X*2 X X X

*1 last application to be terminated on day -2.

*2 Only performed on day 4.

The subjects must be present at bioskin for approximately 90 minutes at screening and on days 1, 4, 8, 15, and 19, and for approximately 20 minutes on days 2 - 3, 5 - 6, 9 - 13, and 16 - 18.On days 7 and 14 you do not come to bioskin. On 4 visits a total of 250 ml of blood will be withdrawn during the whole trial.

Please keep in mind how the trial tests and visits described here will affect your work and family schedules. Consider if you need transportation to and from the site. You may find that these tests and visits need some planning. Some tests may be uncomfortable. Ask the investigator ifyou have any questions about the tests and procedures for the trial.

The treatment duration must be kept precisely. Therefore, please return on time to the agreed visit dates!

9

CONFIDENTIAL 2016N274225_00201465



7. Risk, complicationsIn a clinical trial unexpected and unwanted effects even of known substances cannot be ruled out in general.

Please inform us immediately if any such effects occur during the trial.Examinations, such as measurement of blood pressure and pulse, ECG, sonographic measurement, as well as the clinical assessments and the photographic documentation do not pose any risk to you. For sonography only a sensor head will be put onto your skin. Therefore,the measurements are not painful.

The skin patches and the gel-like dressings (Varihesive®) are usually well tolerated. In rare cases a plaster allergy may occur. In cases of plaster allergies the skin under the patch reddens occasionally and will be monitored throughout this trial.

GSK2981278 Topical OintmentThis is the first time GSK 2981278 is applied to humans in a clinical trial. The following risks have been identified for GSK2981278 and the vehicle.

Skin irritation or allergic reaction to GSK2981278 or to components of its vehicle

Skin irritation or allergic reaction to GSK2981278 or to components of its vehicle may occur. GSK2981278 was not a contact sensitizer (causing allergies upon contact) in the animal/pre-clinical studies.

GSK2981278 is a type of sulphonamide. Some sulphonamides are known to cause drug reactions (commonly called sulpha allergy). However, GSK2981278 does not contain the structural part that is commonly known to be associated with allergies and hypersensitivity. You are being informed of the sulphonamide nature of the compound and will be monitored daily, except on Days 7 and 14, for signs of allergic reactions during the treatment period. You will not be excluded from the trial solely based on a history of your sulphonamide allergy.

During this trial, your skin will be evaluated for signs of skin reaction and allergic reaction on a daily basis, except on Days 7 and 14. If you have a known or suspected intolerance to the components of GSK2981278 vehicle you will be excluded.

If needed, study treatment may be held and an appropriate topical or systemic treatment may be provided.

Systemic reactions including damage to organs.As with most drugs, there is potential for adverse systemic drug reaction including damage to the organs. Non-clinical studies with GSK2981278 in animals have not suggested any particular risk for organs in humans. However, appropriate laboratory tests as well as periodic ECGs and vital sign measurements will be reviewed over the course of this trial.

If needed, study treatment may be held and an appropriate treatment may be provided.

10

CONFIDENTIAL 2016N274225_00201465



Reproductive and developmental damageReproductive and developmental toxicity studies have not been conducted with GSK2981278. Based on literature data from molecules/drugs working in a similar manner as GSK2981278, GSK2981278 could potentially impact implantation and maintenance of normal pregnancy. However, preclinical studies to date have not clearly indicated such a risk with GSK2981278. There is no information available at this time on GSK2981278’s effects on embryo-fetal development (birth defects). Due to this potential risk, only women who cannot become pregnant will be enrolled in this trial. In addition, male subjects will be required to use condoms unless they have had a prior vasectomy.

Betnesol-V Cream:The following side effects have occurred during the treatment with Betnesol®-V cream 0.1%:

Infections and parasitic disorders:

Very rarely (< 0.01%): opportunistic infections (pathogenic infections due to a previously-weakened immune system)

Immune system disorders:

Very rarely (< 0.01%): local hypersensitivity reactions

Endocrine disorders:

Very rarely (< 0.01%): suppression of the stress hormone system (hypothalamic pituitary axis, HPA):

Signs of Cushing´s syndrome (e.g. moon face, central obesity), delayed weight gain/growth in children, osteoporosis (bone loss), glaucoma (eye disease with various causes which results in loss of nerve fibers), elevated blood sugar levels/excretion of glucose by urine, cataract (clouding of the lens of the eye), high blood pressure, weight gain, reduced cortisol levels, hair loss and “bamboo” hair (swollen hair follicles).

Prolonged use of large amounts or treatment of extensive areas can result in absorption of enough medication into the body for the signs of Cushing's syndrome to occur. This effect is more likely to occur in infants and children, and if the topical agent is covered (e.g. using a bandage).

Skin and subcutaneous tissue disorders:

- < 10%): itching, local skin burning/pain.

Very rarely (< 0.01%): allergic contact dermatitis (inflammation of the skin, including rashes around the nose and mouth), reddened skin, rash, hives, psoriasis with small blisters, skin thinning (skin atrophy)*, formation of wrinkles in the skin*, dry skin*, stretch marks*, telangiectasia* (dilated small blood vessels), changes in skin pigmentation (color)*, increased hair growth, worsening of underlying symptoms.

(*concomitant symptoms of the suppression of the hypothalamic pituitary axis (HPA)).

Frequency not known: steroid acne (acne caused by abuse of steroids such as cortisone).

General disorders and administration site conditions:

Very rarely (< 0.01%): irritation/pain at administration site.

Prolonged application (more than three weeks) or treatment of extensive areas, especially if the topical agent is covered or applied in skin folds, changes in the treated skin area like skin thinning, stretch marks, steroid acne, telangiectasia, changes in skin pigmentation,

11

CONFIDENTIAL 2016N274225_00201465



hypertrichosis (excessive hair growth over and above the normal for the age, sex and race of an individual) may occur.

5% Salicylic acidUpon topical application skin irritation is possible.

Very rarely (< 0.01%) an allergic contact reaction may be induced.

Risk for Allergic ReactionThe most common side effects reported after topical treatment are skin reactions related to the application site. These reactions may occur sometime after start of treatment but are of temporary nature in the majority of cases.

Allergic reactions or non-allergic (irritant) reactions to the active ingredients or components of the formulations may occur. An allergy or irritant reaction may result in itching, reddening of the skin as well as the occurrence of papules or pustules in the treated area. In exceptional cases, in the presence of corresponding sensitization and disposition, generalized dermal reactions may occur. Such reactions subside after discontinuation of the relevant treatment. Systemic reactions are not expected since only a small total amount is applied during this trial.

It is possible that you will be sensitized by any ingredient of the trial preparations or the active ingredient due to repeated application of the trial preparations. Acquirement of an allergy ispermanent, i.e. each contact with the allergen (substance to provoke the allergy) will lead to an allergic reaction.

General trial procedure riskSubjects discontinuing their current psoriasis treatment may experience a worsening of their psoriasis during the washout period before beginning treatment in this trial. A worsening of psoriasis may also occur during the active treatment period. If you experience worsening of your psoriasis, you can either choose to withdraw from this trial at any time or your doctor may withdraw you from the trial treatment at any time.

You will be informed in a timely manner of new information that becomes available during thetrial that may be relevant to your willingness to continue participation in the trial.

Risks of blood withdrawal are described in section 8.2.

8. General considerations for a clinical trialFor participation in the trial every subject has to give his/her signed informed consent after being informed orally and in writing about the trial at the special information session. Whether the volunteer is suitable for participation in this trial will be decided after the results of the medical examination (screening) are available. We want to emphasize that your participation in this trial is strictly voluntary.

You have the right to terminate participation in this trial at any time without giving reasons. By doing this you will suffer no disadvantages regarding further supervision by bioskin. The principal investigator reserves the right to terminate your trial participation at any time for scientific reasons, reasons for ensuring an accurate trial performance or medical reasons.

The following criteria may result in discontinuing of the trial for individual subjects:

• Discretion of the investigator for safety, behavioral or administrative reasons.

12

CONFIDENTIAL 2016N274225_00201465



• Termination of the trial by the sponsor.

• Subject lost to follow-up.

• Withdrawal of consent.

• Protocol deviations (including failure to comply with trial stipulations, alcohol or drug abuse, use of prohibited medication).

• Alterations of laboratory parameters especially liver parameters.

• Alterations of vital signs and especially of ECG parameters.

• Serious concomitant symptoms related to the trial preparation or procedures.

• If a subject falls ill while participating in the trial and the illness could influence the results.

The following criteria may result in discontinuing specific treatments. This is a listing of side effects, which could be seen with any topical drug, but are unlikely to occur with the substances tested in this trial:

• Individual treatments will be discontinued in the event of the following dermal reactions limited to the test fields:

• Severe blistering

• Skin necrosis

• Contact dermatitis

• Allergic reaction

• Marked skin discoloration

• Severe or unexpected itching, burning, or pain

• In case of severe reactions due to a specific treatment, the principal investigator in consultation with the sponsor may prematurely discontinue this treatment for the whole trial population.

For your own safety you should participate in the planned final examinations, even if you intend to terminate the trial prematurely.

Since the physician might deem it necessary for a subject to have further follow-up visits after the official trial end, you are advised to attend to these visits for your own safety.

8.1. Concomitant medicationAfter having given informed consent (date of signature) and until the end of the trial, you must inform the investigator or supervising physician about the intake or application of any medications as soon as possible. In some cases it may be necessary to confer with the physician who has prescribed the medication. If you were treated by other physicians you have to inform them about the participation in this clinical trial. You will receive a patient card with information to the trial that you should always carry with you for any emergency.

Medications permitted during the trial include contraceptives (for indications other than pregnancy prevention), antihistamines, selective leukotriene receptor antagonists (eg montelukast sodium, zafirlukast), mast cell stabilizers (eg cromolyn sodium or nedocromil sodium), acetaminophen/paracetamol, vitamin and mineral supplements, medications for regulation of thyroid function, influenza vaccine, and medication for AEs, unless specifically prohibited.

13

CONFIDENTIAL 2016N274225_00201465



You may also use medications for chronic stable concomitant medical conditions like hypertension for example that are not expected to affect the trial assessment provided you are on a stable dose that can be expected to stay the same throughout the trial.

You may use medical shampoos and other topical treatment for psoriatic lesions other than the lesions investigated in this trial.

Sunscreen may be used on non-lesional skin.

Medication not permitted during the trial:

Immunizations except influenza vaccination are not allowed within 2 weeks before first treatment and/or during the trial.

Other medication may be considered on a case by case basis by the investigator.

Any systemic (affecting the entire body) antipsoriatic treatments are not allowed during the trial and for different time periods prior to trial start: biologic agents (5 half-lives (time needed to halve substance levels in the body)), oral retinoids (substances related to vitamin A) (12 weeks), immunosuppressive or immunomodulating agents like cyclosporine, interferon, methotrexate, tacrolimus etc. and psoralen plus UVA (8 weeks) as well as systemic corticosteroids (4 weeks).

Any other topical therapy on the lesions of interest is not allowed 2 weeks prior to trial start and during the trial. Topical application of emollients on the lesions of interest is not allowed 1 day before and during the trial.

You must refrain from UV-therapy 2 weeks prior to the first day of and throughout the clinical trial.

Systemic medications for other medical conditions that are known to affect psoriasis (e.g., lithium, beta-adrenergic blockers, antimalarial drugs) are not allowed within 2 weeks prior and during the trial.

8.2. Blood and urine samples/ photo documentationAdditionally to the evaluations and questionings, photos of the treated lesions will be taken during the visits at your trial site. The photos will only be marked with the trial number, your screening number, the date and position. The photos will be used for documentation of treatment effects and may also be used in a future publication.

For the assessment of all blood parameters a maximum of about 250ml total will be withdrawn.If any parameters have to be re-checked, it might be possible, that an additional blood withdrawal during the scheduled visits will be performed. From the medical standpoint, the amount of blood which is taken at each visit is regarded as completely harmless. The blood sampling procedure (HIV and hepatitis analysis etc.) poses the same very small risk as normally associated with this procedure (e.g. infection, bleeding into the surrounding tissue, and very rarely inflammation of the vein, formation of blood clots or local nerve damage). Blood withdrawal will only be conducted by qualified medical personnel. Urine is collected for assessment of laboratory parameters as well as drug tests in a standardized (i.e. non-invasive) manner. Both blood and urine samples will be stored until the end of trial and destroyed thereafter.

If you decide to withdraw your consent to participate in the trial, your samples will be destroyed. All data related to these samples collected before you left the trial will still be used for the trial.

14

CONFIDENTIAL 2016N274225_00201465



8.3. Insurance coverEvery subject participating in the trial will be insured in accordance with § 40 para 1 clause 3 No. 8, para 3 of the German Drug Law against injuries to health which may occur in relation to the trial.

The name of the insurance company is: „ ACE European Group Limited”, Lurgiallee 12, 60439 Frankfurt am Main”, Tel Fax the insurance policy number is Any accidents en route between your home and the clinical site are also covered by this insurance.

Any damage to your health possibly related to this clinical trial or related to an accident on the way to or from the clinical site needs to be reported to the insurer immediately after occurrence and/or diagnosis. The insurance cover shall extend to all damage to health incurred as a consequence of the applied medications or substances or measures taken during the course of the trial for five years after trial participation, reported not later than 10 years after trial completion to the insurer.

Compensation will be the financial loss resulting from health damage. The extent of the insurance cover is according to § 40 para. 3 of the German Drug Law ("The extent has to be in an appropriate relation to the risks associated with the trial participation and amounts in case of death or long-term incapacity to work to at least 500.000,- Euro”). The maximum coverage per insured person is 500.000,- Euro.

Excluded from the insurance, however, are injuries to health and deteriorations of illnesses already in existence which would have occurred or continued to exist even if the subject had not taken part in the clinical trial, genetic damages or damages that occurred due to deliberate failure of the volunteer to follow the instructions of the investigator for trial participation.

The insurance cover is jeopardized if• you undergo any other medical treatment during the trial without consultation of the

investigator or responsible physician, except in emergency cases;

• you don't take all suitable measures to clarify the nature or extent of the impairment as well as to reduce the impairment.

If a volunteer violates purposely, or is grossly negligent of, his/her obligations after the occurrence of health damage the insurer is free of its liabilities. In case of gross negligent violation the liability continues to exist as long as the violation has not influenced the insured case or the scale of benefits.

According to the insurance conditions you yourself have to notify the insurer of any impairment. In case of death your legal successor has to inform the insurer immediately.

We will provide you with a copy of the confirmation of insurance coverage and the general insurance conditions for clinical trials of medicinal products (

Signing this consent form does not change any legal rights you may have.

8.4. Additional obligationsIn addition you have to inform the investigator or responsible physician immediately about any impairment to your health that might have occurred as a consequence of the trial participation.

A drug trial always also serves for determination of safety and tolerability of the tested products. The complete documentation of impairments following a clinical trial is an important requisite

15

CONFIDENTIAL 2016N274225_00201465

PPD PPDPPD

PPD



and is a legally required task of the investigator. Within the scope of his duties the investigator is obliged to inform the insurer immediately.

8.5. Data protectionIn clinical trials personal and medical data will be collected noted in your personal file or saved electronically at the trial site. These personal data referring to information about your health, ethnicity, race, sex, age etc. will be stored electronically, evaluated and forwarded using a code number at bioskin. This code number is a consecutive number that does not constitute of names or birthdates. Real persons can be identified only with a list, which will remain in the occupation of bioskin and will not be forwarded to the sponsor. Substitution of the name and other identifying criteria by a code, for excluding or considerably aggravating the identification of the concerned person is called pseudonymizing. bioskin GmbH, Burchardstr. 17, 20095 Hamburgis responsible for data processing. The data is protected from unauthorized access. A decryption will only be conducted fulfilling the legal requirements. All personal data and medical examination results follow the physician confidentiality and the legal requirements of the Federal Data Protection Law, the German Drug Law (§ 40 para. 2a AMG) and further regulations and guidelines.

The German Drug Law contains further guidelines for the required extent of the consent to thedata collection and use of data. Please find the details, especially regarding the possibility of a withdrawal, in the informed consent form, which is enclosed to the end of this subject information.

8.6. What happens to my personal and medical information?It is very important that your personal and medical information stay confidential and secure. GSK will protect your information in accordance with current German law.

When you sign this consent form (and the separate optional biopsy consent form, if applicable)you agree that GSK can use your personal and medical information as described here:

Your personal and medical information may be checked by GSK and others (like agencies that approve and monitor studies). This is to make sure that the trial is being run properly.

Besides that, only the assigned bioskin staff can use information that identifies you (such as name and address) and only for the purpose of the trial.

Your trial information will be labelled with a code number (for example, It will not include your name or address. The trial doctor will have the link between your name and the code number.

The link between your name and the code number will not be shared. Only the code number and coded information will be sent to GSK.

GSK will use your coded information for research only. This may include research looking at improving the quality and efficiency in conducting clinical research trials in general.

GSK may:keep your coded information electronically, and analyze it by computer to find out what the trial is telling us. This may be done by GSK or a third party, in which case GSK will ensure that the third party is required to keep your data secure,

16

CONFIDENTIAL 2016N274225_00201465

PPD



share the information with regulatory agencies that approve new medicines,

share the information with people who check that the trial is done properly (like the ethics committee or review boards),

combine the information with results from other studies to learn more about the medicine and other medicines, and this disease/condition and other diseases and conditions. This may help us to assess the risks and benefits of GSK (or other) medicines, or to improve disease understanding,

publish trial results for medical journals, meetings and on the internet for other researchers to use; your name will not appear in any publication,

share coded information with other companies, organisations or universities to carry out research. This may include research looking at improving the quality and efficiency in conducting clinical research trials in general.

Personal and medical data collected during the trial may be moved, stored and used in the country where you live or another country where GSK or those working with GSK work.

Use of this information may take place in countries with lower data protection rules than the country where you live. GSK will make sure that if your data are moved to another country, it will still be treated as stated in this Informed Consent Form.

A description of this clinical trial will be available on the GSK Clinical Study Register: http://www.gsk-clinicalstudyregister.com/ and may also appear in clinical trial/study registries in countries in which the clinical trial is conducted and on http://ClinicalTrials.gov, as required by U.S. Law.

GSK will be the owner of the trial results. GSK plans to use the results, and may get patents, or sell the drug in the future, or make profits other ways. You will not be paid any part of this.

If you withdraw your consent for use of your personal information, you will no longer be able to continue in the trial. However all the information collected before you left the trial will still be used as set out in this consent form.

In some circumstances, you may not be able to access your trial information while the trial isongoing. However, the investigator will share any important medical information if it is relevant to your health during the course of the trial.

8.7. Information or medical adviceFor additional or medical information associated with this clinical trial feel free to contact us. During office hours the responsible physician is available under the telephone number

For questions concerning inclusion or final examination or appointments please contact the responsible staff member under

Furthermore, there is a contact point available for patients at the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)):

Bundesinstitut für Arzneimittel und MedizinprodukteFachgebiet Klinische Prüfung / InspektionenKurt-Georg-Kiesinger-Allee 353175 Bonn

Tel.: Fax:

17

CONFIDENTIAL 2016N274225_00201465

PPDPPD

PPD

PPDPPD



E-Mail:

8.8. Information about the SponsorThe trial will be conducted on behalf of GlaxoSmithKline (GSK) Research & Development Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS, UK, Tel. and on behalf of Stiefel, a subsidiary company of GSK, who is involved in this trial (20 TW Alexander Drive, Research Triangle Park, NC 27709, United States, Tel.Fax.

GSK is a company that discovers and makes vaccines, medicines and other health products. GSK is paying the trial doctor and bioskin to run this trial.

9. Reimbursement of expensesFor your participation in this clinical trial you will receive an appropriate reimbursement. The reimbursement consists of a basic amount and a supplement for reliable and complete trial participation. Especially the strict adherence to the stipulated appointments must be stressed. If you are not able to arrive on time or keep an appointment please contact us as soon as possible by phone so that we can arrange the further course of the trial accordingly. Unnecessary waiting periods will be avoided for all volunteers.

All trial tests, examinations, and medical care required as part of this trial are provided at no cost to you.

If you meet all requirements and are enrolled in the trial until the final visit, a financial compensation for a total amount of 930 Euro will be given to you for your time and incurred expenses (travelling, parking, etc) on the last trial day by means of a check for deposit only. In case you decide to withdraw from the trial, this compensation will only be paid proportionally. If you don't meet several appointments or do not contact us in case of lateness or other instructions concerning the trial conduct (treatments!) are not adhered to, we reserve the right to shorten the reimbursement. We ask for your understanding for these measures since unreliability of volunteers may result in a considerable increase of expenses. Don’t forget that the reliability of the trial results depends on your reliability .On the other hand the reimbursement can as well be adapted in case additional visits should be necessary (e.g. for follow-up of your state of health).

If you should have additional effort in the framework of this trial (additional visits e.g. for control of laboratory values, replacement subject…) this will be reimbursed according to you effort.

bioskin will not regularly notify the tax office about this reimbursement, you yourself are responsible for notification of the tax office. In the scope of a tax inspection bioskin might be committed by the tax office to reveal names, address and amount of reimbursement.

18

CONFIDENTIAL 2016N274225_00201465

PPD

PPD

PPDPPD




Informed consent form

............................................................................... Screening No. ..............................

Name of the subject in block letters

Herewith, I confirm, that I

was informed thoroughly orally and in writing with this information sheet about purpose, importance, implications and risks of the planned trial and I have understood its content,

was given sufficient opportunity and time to read this subject information and ask questions,

agree to the trial stipulations based on this subject information,

have not participated in a clinical trial for at least four weeks (30 days),

will inform the investigator or responsible physician as soon as possible about any intake orapplication of medications after receiving the special subject information until the end of the trial participation,

am willing to obey trial-related medical orders of the principal investigator or attending physician of the trial before, during and after the trial.

have read and understood the following printed data protection declaration and agree with the presented approach regarding my personal data:

Data protectionI am aware that in this clinical trial personal data, especially medical results about me, are collected, saved and analyzed. The use of the data will be performed following legal guidelines and requires before the participation in the clinical trial the following voluntarily submitted informed consent, meaning without the following consent, I cannot participate in the clinical trial.

1. I consent, that within the framework of this clinical trial personal data, especially health data und data about my ethnical background, are collected und recorded on paper as well as on electronic data media at bioskin GmbH, Burchardstr. 17, 20095 Hamburg. So far as required, recorded data may be transmitted in pseudomized manner (encrypted):

a) to GSK, the sponsor or a by the sponsor appointed party for the purpose of scientific analysis,

b) in case of an application for marketing authorization: to the applicant and the authority responsible for marketing authorization (BfArM, EMA and/or FDA),

c) in case of adverse event: to GSK, the sponsor, the responsible Ethics Committee and the responsible Competent Authority BfArM, as well as to the European database forwarded by the latter.

19

CONFIDENTIAL 2016N274225_00201465



2. Additionally, I consent that appointees of the sponsor are authorized and obliged to keep the data confidential as well as the responsible national and international supervisory authorities may have access to my data, especially medical data, as made available by the investigator, if necessary for the inspection of the proper conduct of the trial. For these measures, I release the investigators from their doctor-patient confidentiality obligation.

3. I have been informed that I can terminate my participation in this clinical trial at any time. However, the consent to the collection and processing of my personal data, especially information about my health, is irrevocable. I know that in case of a withdrawal of the trial participation, data stored up until this time point may still be used, so far as required to

a) assess the effects of the investigated drug,

b) ensure that interests worthy of protection are not compromised,

c) meet the obligation to present complete marketing authorization documents.

4. The regulation on clinical trials stipulates that data are stored for at least 10 years after the completion or termination of the trial. It is planned to store the data for 15 years. Afterwards, my personal data will be deleted as long as legal, statutory or contractual retention periods are not opposed. I herewith consent to this retention period.

5. I have been informed about the following legal regulation: if I withdraw my consent to participate in this clinical trial, every party, which store my personal data especially health data, has to check immediately to what extent the stored data are required for the purposes mentioned in No. 3 a) to c). No longer required data is to be deleted immediately.

6. I consent that health data are collected or viewed by attending physicians, as long as this is required for the duly conduct and supervision of the trial. In this respect, I release these physicians from their doctor-patient confidentiality obligation.

20

CONFIDENTIAL 2016N274225_00201465



I consent to voluntarily participate in the clinical trial mentioned above

I am aware, that I can withdraw my consent to participate in this trial at any time and without giving any reason (orally or in writing), without resulting in any disadvantages for me regarding my medical treatment.

I have received one original of the written subject information, the informed consent form and the general insurance conditions and the insurance confirmation, as well as the flow chart. One original will stay at the trial site.

...........................................................................................................................Name of the subject in block letters

.................................... . ............................................................................Date Signature of the subject

I have led the informational conversation and collected the informed consent of the subject.

...........................................................................................................................Name of the investigator in block letters

.................................... . ............................................................................Date Signature of the informing physician

I consent to taking photos and utilization of these for publication.






21

CONFIDENTIAL 2016N274225_00201465



I consent to an HIV-test and I have been informed that the results will be transmitted to the health authorities without mentioning my name.






I consent to a hepatitis-test and I have been informed that the results will be transmitted to the health authorities with mentioning my name.






22

CONFIDENTIAL 2016N274225_00201465



I have been informed that a commercial organization will have ownership of the research results and may file patents or otherwise protect and commercialize any research results without me having any financial benefit whatsoever with respect to commercialization.






Stamp of the trial site:

23

CONFIDENTIAL 2016N274225_00201465

Subject information 201465/350209BSAppendix A: skin biopsies

Page 1 of 2

EudraCT Nummer 2015-002614-72 201465 EN ICF V2.0, 14SEP2015

Dear Subject, Within the scope of the clinical trial with the title


Four small tissue samples (skin biopsies) with a diameter of 3 mm will be taken on the last day of the treatment phase (Day 19). The prerequisite is, that you agree to participate by signing a separate informed consent. Joining this part of the trial is optional. You can choose to not provide the optional biopsy and still take part in the main trial.

In the following you will find important information about the conduct and possible risks of biopsy sampling. Please read this information attentively and feel free to ask questions.

Skin biopsy sampling will be conducted in a subgroup of at least eight subjects to gather information on the influence of tested treatments on skin inflammation as seen in plaque psoriasis. The biopsies will be taken from 1. a non-lesional area, 2. from a lesional but untreated area, 3. from the test field site treated with the vehicle, and 4. from the test field site treated with the highest concentration of GSK2981278 without side effects on the skin (usually 4% GSK2981278).

Skin biopsies will be obtained under local anesthesia and sterile conditions. The biopsy site will be carefully cleaned and disinfected. Local anesthesia will be produced by superficial (intracutaneous) administration of a sufficient dose of prilocaine hydrochloride (maximum of 2 mL). The injection of the local anesthetic causes for a few seconds a burning and painful feeling. The biopsy will then be taken using a 3 mm hollow needle (biopsy punch). After stanching, the wound will be closed with a single stitch or surgically dressed. The stitches will be removed after 6 – 10 days. When the healing at the biopsied site has completed, only a small linear trace in the skin with a maximal length of 3 mm will likely remain and be visible.

The biopsy samples will be frozen in RNAlater solution and sent in an encoded manner (to hide your name by assignment of a numerical code) to Epistem, Pharmacogenomics Laboratories, 48 Grafton Street, Manchester, M13 9XX, UK.

What happens to my samples? Similar to information collected in the trial, your skin samples may also be used by GlaxoSmithKline (GSK) or shared by GSK with other companies or universities to better understand psoriasis, other diseases or conditions, or to further develop the trial drug or other drugs.

Your skin samples will be given the same code as your other trial information and kept in locked storage. Anyone who works with your samples will hold the information and results in confidence.

GSK or delegate may store non-genomic material isolated from your skin (RNA and/or reverse transcribed RNA) and conduct gene expression analyses for up to 15 years after the end of the trial after which time your samples will be destroyed. This will allow scientific research to be conducted in the future as new discoveries are made. A precise definition of future analyses is not possible at the moment. Therefore you are asked to explicitly state your consent by checking the respective section in the consent form. You may request destruction of your samples at any time by telling your investigator. If you choose to stop participating in the biopsy part of the trial after giving a sample, we will not conduct any new tests on the sample. We will destroy the sample. GSK will keep and use any results generated before you stopped participating in the biopsy.

Furthermore, you can change your mind at any time in the trial and decide not to provide a

24

CONFIDENTIAL 2016N274225_00201465


Page 2 of 2

EudraCT Nummer 2015-002614-72 201465 EN ICF V2.0, 14SEP2015

biopsy sample.

What benefits can I expect from being in the biopsy part of the trial? You will not receive any direct benefit from taking part in the biopsy. However, if you take part in the biopsy you may help scientists understand why some people get psoriasis or react to or handle GSK2981278 ointment differently. This may help identify better ways to treat psoriasis and who is more likely to benefit from GSK2981278 ointment and who may have side effects.

The personal and medical information obtained by the biopsy will be treated according to the current German law as stated in the main ICF (section 8.7).

Risks, complications Taking punch biopsies is an invasive technique. In general, frequent risks which are associated with this procedure are limited to bleeding, formation of a local bruising (hematoma), localized pain and formation of scar tissue at the biopsy sites. Complications are infection or the damage of structures in the vicinity of the biopsy site such as vessels and skin nerves. Irreversible damage exceeding the formation of a small scar such as functional loss of extremities, septic complications or life-threatening events are considered to be unlikely.

Local anesthesia of the biopsy site will be performed by superficial (intracutaneous) injection of a maximum of 2 mL of prilocaine hydrochloride per biopsy. Prilocaine hydrochloride is well known and frequently used in nearly all fields of clinical and dental medicine. Allergic reactions to prilocaine may occur.

Proper wound care (e.g. application of pressure, antibiotic ointment, bandage, etc.) will be provided as needed and you will be checked for wound healing at the follow-up visit. Pain medication will be allowed.

If infection, numbness, swelling, bleeding or other complications occur after biopsy sampling, please do not hesitate to contact the investigator.

When should you not participate in biopsy sampling? Known allergic reaction to prilocaine hydrochloride or other amide-type anesthetics or

parabene (methyl-4-hydroxy-benzoate).

Known predisposition to excessive scar formation.

Consumption of blood-thinning medication.

Reimbursement of expenses

For complete participation in this part of the trial following the trial stipulations you will receive a remuneration of 400,- Euro on the last trial day by means of a check for deposit only.

bioskin will not regularly notify the tax office about this remuneration, you yourself are responsible for notification of the tax office. In the scope of a tax inspection bioskin might be committed by the tax office to reveal names, address and amount of remuneration.

25

CONFIDENTIAL 2016N274225_00201465


EudraCT Nummer 2015-002614-72 201465 EN ICF V2.0 14SEP2015

Informed Consent (Skin Biopsies) (Page 1 von 1) Screening No.: ________

With my signature I confirm that • I consent to my participation in taking four biopsies at the end of the treatment phase of the

clinical trial with the title “A Phase I Trial to Evaluate Safety and Efficacy of Topically Applied GSK2981278 Ointment in a Psoriasis Plaque Test“,

• I was informed thoroughly orally and in writing with this “Subject Information, Appendix A: Skin Biopsies” sheet about purpose, conduct and risks of biopsy sampling and I have understood its content,

• I was given sufficient opportunity and time to read this subject information and ask questions.

I understand that I may withdraw from participation in the trial and I may demand the destruction of my tissue samples at any time and without giving reasons and without jeopardizing any further medical treatment.

I understand that I will not benefit from the gene expression analysis of my tissue samples and that I will not be informed about the results.

I consent that biological probes may be transferred to the Sponsor or delegate for testing and subsequent research.

I explicitly consent that non-genomic skin-isolated probes (RNA or reverse transcribed RNA) are stored for up to15 years and may be transferred to the Sponsor or delegate for testing and subsequent gene expression research which cannot be specified to date. Upon my withdrawal no further analyses will be performed and my probes will be destroyed.


Only in the case, that new perceptions will be attained from my samples, which are of extensive importance for the maintenance or restoration of my health, the investigator will be informed in order to discuss the further procedure with me.

Subject’s name in block letters (legible!): _______________________________

Date Subject‘s signature

Investigator’s name in block letters (legible!): _______________________________

Date

_______________________________ Investigator’s signature

Investigator's Stamp:

26

CONFIDENTIAL 2016N274225_00201465


EudraCT Nummer 2015-002614-72 201465 EN ICF V2.0 14SEP2015

Informed Consent (Skin Biopsies) (Page 1 von 1) Screening No.: ________

With my signature I confirm that • I consent to my participation in taking four biopsies within the scope of the clinical trial with

the title “A Phase I Trial to Evaluate Safety and Efficacy of Topically Applied GSK2981278 Ointment in a Psoriasis Plaque Test“,

• I was informed thoroughly orally and in writing with this “Subject Information, Appendix A: Skin Biopsies” sheet about purpose, conduct and risks of biopsy sampling and I have understood its content,

• I was given sufficient opportunity and time to read this subject information and ask questions.

I understand that I may withdraw from participation in the trial and I may demand the destruction of my tissue samples at any time and without giving reasons and without jeopardizing any further medical treatment.

I understand that I will do not benefit from the gene expression analysis of my tissue samples and that I will not be informed about the results.

I consent that biological probes may be transferred to the Sponsor or delegate for testing and subsequent research .

I explicitly consent that non-genomic skin-isolated probes (RNA or reverse transcribed RNA) are stored for up to15 years and may be transferred to the Sponsor or delegate for testing and subsequent gene expression which cannot be specified to date Upon my withdrawal no further analyses will be performed and my probes will be destroyed.


Only in the case, that new perceptions will be attained from my samples, which are of extensive importance for the maintenance or restoration of my health, the investigator will be informed in order to discuss the further procedure with me.

Subject’s name in block letters (legible!): _______________________________

Date Subject‘s signature

Investigator’s name in block letters (legible!): _______________________________

Date

_______________________________ Investigator’s signature

Investigator's Stamp:

27

CONFIDENTIAL 2016N274225_00201465

Patient Card Name: __________________________ Randomisation No:___________ Participates in an observer-blind clinical trial from _ _ / _ _ / _ _ _ _ until _ _ / _ _ / _ _ _ _ Study No: 201465 (bioskin Nr. 350209BS) EudraCT No: 2015-002614-72 The subject receives treatments with Betnesol V® Cream (Betamethasone valerate 0.1%) as well as the test substances GSK2981278 0.03%, 0.1%, 0.8% and 4% ointment and the respective ointment without active ingredient (vehicle). Investigators: Heinrich Siemetzki/Uwe Kroencke, Tel. (by day) (24 hours): Sponsor: GlaxoSmithKline Research & Development Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS, UK, Tel.: Loss of this card needs to be reported immediately. If you find this card please mail to: bioskin GmbH, Burchardstr. 17, 20095 Hamburg Version 1.0 EN from 19AUG2015

28

CONFIDENTIAL 2016N274225_00201465

PPDPPD

PPD

Randomization Plan

201465/350209BS

Page 1 of 8

Template from 20140825 Version 1.1 dated 16 October 2015

Randomization

Plan

1

CONFIDENTIAL 2016N274225_00201465

2

CONFIDENTIAL 2016N274225_00201465

PPD

PPD

PPD

PPD

PPD

PPD

PPD

Randomization Plan

201465/350209BS

Page 3 of 8


Table of content

1 Protocol ......................................................................................................................... 4

2 Trial design .................................................................................................................... 4

3 Randomization vendor ................................................................................................... 4

4 Generation of Randomization Documents ..................................................................... 4

4.1 Standard operation procedures ...................................................................................... 4

4.2 Software ........................................................................................................................ 4

4.3 Specifications for randomization .................................................................................... 4

4.4 Treatment codes assignment ......................................................................................... 5

5 Sample outputs .............................................................................................................. 6

5.1 Randomization lists sample outputs ............................................................................... 6

5.2 Emergency letters sample outputs ................................................................................. 6

6 Distribution of the Randomization documents ................................................................ 6

6.1 Unblinded personnel ...................................................................................................... 6

6.2 Blinded personnel .......................................................................................................... 6

6.3 Storage .......................................................................................................................... 6

7 Unblinding...................................................................................................................... 6

8 Contacts ........................................................................................................................ 7

9 Roles and Responsibilities ............................................................................................. 8

3

CONFIDENTIAL 2016N274225_00201465

Randomization Plan

201465/350209BS

Page 4 of 8


1 Protocol

Clinical Protocol from 15-JUL-2015

2 Trial design

This is a Phase 1, single-center, randomized, vehicle- and positive-controlled, subject and evaluator-

blind proof-of-concept trial in subjects with chronic plaque type psoriasis.

All subjects will receive all treatments on stable plaque(s) with random assignment of the treatments

to the test fields within the identified plaque(s). A blinded evaluator (an investigator or designee) will

perform the measurements and assessments whereas an unblinded study staff member (not an

evaluator) will perform biopsy collection.

3 Randomization vendor

bioskin GmbH

4 Generation of Randomization Documents

4.1 Standard operation procedures

The randomization list will be generated according to bioskin’s SOP ST/04 version 3.

The treatment code assignment will be generated according to bioskin’s SOP ST/08 version 2.

4.2 Software

The randomization list will be generated using nQuery Advisior® 6.01 (Statistical Solustions, Saugus,

MA, USA).

4.3 Specifications for randomization

Investigational Medicinal Product(s) (IMP)

• GSK2981278 0.03% ointment



• GSK2981278 4% ointment

• Vehicle to match GSK2981278 ointment (without active ingredient)

• Betamethasone valerate 0.1% cream (positive control)

All subjects will receive the same treatments. There will be no subdivision into treatment groups.

The 4 concentrations of GSK2981278 ointment (0.03%, 0.1%, 0.8%, and 4%) will be assigned the

codes A, B, C, and D, by bioskin. The vehicle and positive control will be assigned the codes E and

F, respectively.

4

CONFIDENTIAL 2016N274225_00201465

Randomization Plan

201465/350209BS

Page 5 of 8


The test fields will be numbered with 1, 2, 3, 4, 5, and 6 beginning with the uppermost or most

proximal site on the left from the investigator's view. Fields along the same line will be numbered left

to right.

For each subject a permutation of the treatment codes A to F will be randomly assigned. The

treatment code listed first in the respective permutation will be assigned to test field 1, the second to

test field 2, etc.

A randomization list will be generated by the CRO and kept in the trial master file in a sealed

envelope.

The permutation of the treatment codes A to F will be dealt with stratified randomization of total size

102. The 6 codes A to F will be randomized using block size 6 and an equal group ratio among the

codes. The 17 strata will be defined to be of equal size, as well. As a result, each stratum is

assigned one block.

For the final randomization list the random number will be derived from the nQuery “Stratum” output

and the test field will be generated from the last digit of the nQuery “Subject ID”.

nQurey randomization specification:

• Treatment codes

o A, B, C, D, E, F

o Ratio = 1 for all treatment codes

• Stratification

o N = 17

o Strata IDs:

o Proportion: 1/17 (equally sized strata)

• Block size

o 6

• Randomization length

o 102

4.4 Treatment codes assignment

The 4 concentrations of GSK2981278 ointment (0.03%, 0.1%, 0.8%, and 4%) will be assigned the

codes A, B, C, and D, by bioskin.

5

CONFIDENTIAL 2016N274225_00201465

PPD

Randomization Plan

201465/350209BS

Page 6 of 8


5 Sample outputs

5.1 Randomization lists sample outputs

Following dummy documents will be generated for review:

• Randomization list DUMMY, Version 1.3 from October 16, 2015

• Treatment Code Assignment DUMMY, Version 1.0 from October 14, 2015

5.2 Emergency letters sample outputs

Not applicable

6 Distribution of the Randomization documents

6.1 Unblinded personnel

This trial is subject and evaluator- blind. For blinded observers please have a look at 6.2.

Unblinded personal to receive the randomization list and treatment code assignment:

• Study Nurse, bioskin GmbH

• Study Nurse , bioskin GmbH

Receipt of the randomization list has to be confirmed via email to statistician Maciej Hoffman-

Wecker.

Additionally, the Clinical Research Associate (CRA) will be unblinded to the treatment code

assignment and the randomization list.

6.2 Blinded personnel

Investigators responsible for measurements and assessments (see protocol 4.1) will be blinded to

the treatment code assignment and the randomization list. Additionally, the sponsor will be kept

blinded in the same way.

6.3 Storage

The randomization list and the treatment code assignment will be stored in a sealed envelope in the

trial master file. One copy of the randomization list and the treatment code assignment will be

provided to the bioskin site personnel.

7 Unblinding

Unblinding of both blinded observers will be performed only after

- finalizing and signing the statistical analysis plan,

- blind data review meeting,

- definition of analysis population and

- database lock.

Unblinding has further to be approved by the sponsor previously.

6

CONFIDENTIAL 2016N274225_00201465

PPDPPD

Randomization Plan

201465/350209BS

Page 7 of 8


8 Contacts

Name Title / Role Address

Biostatistics /

Randomization

Service

bioskin GmbH

Burchardstraße 17

20095 Hamburg, Germany

Phone:

Fax:

eMail:

Ph.D. Clinical Trial

Manager

bioskin GmbH

Burchardstraße 17


Phone:

Fax:

eMail:

Study Nurse,

Site contact

bioskin GmbH

Burchardstraße 17


Phone:

Fax:

eMail:

Study Nurse,

Site contact

bioskin GmbH

Burchardstraße 17


Phone:

Fax:

eMail:

7

CONFIDENTIAL 2016N274225_00201465

PPD

PPDPPD

PPDPPD

PPDPPD

PPD

PPD

PPDPPD

PPD

PPD

PPDPPD

PPD

PPD

Randomization Plan

201465/350209BS

Page 8 of 8


9 Roles and Responsibilities

Activities Sponsor Vendor

(bioskin)

Develop the randomization plan x

Generate a dummy randomization and treatment code

assignment

x

Review and approve the randomization plan, including the

dummy randomization and treatment code assignment

x x

Generate the randomization and treatment code assignment x

Provide the randomization list in PDF and EXCEL format to

bioskin once the signed request for unblinding is send.

x

8

CONFIDENTIAL 2016N274225_00201465

9

CONFIDENTIAL 2016N274225_00201465

PPD

PPD

10

CONFIDENTIAL 2016N274225_00201465

PPD

FINAL Randomization

201465/350209BS

page 3 of 7

Document FINAL Version 1.0 from October 27, 2015, created by at bioskin GmbH, Germany

SOP ST/04, Template from 20130805

Documentation of randomization creation

The randomization list was created using nQuery Advisor® 6.01 (Statistical Solutions, Saugus, MA). Attached is the generated output that formed the basis of the randomization used in this study.

For the final randomization list on page 1 the random number is derived from the nQuery “Stratum” output and the test field from the last digit of the nQuery “Subject ID”, as given in the original nQuery output, below.

201465 350209BS Random List v1.0.nqr

201465/350209BS PPT

Oktober 27 2015

Group/Treatment Ratio

A 1

B 1

C 1

D 1

E 1

F 1

Center/Stratum Name Prefix Starting ID

Number

Proportion Sample

Size

1 0,059 6

2 0,059 6

3 0,059 6

4 0,059 6

5 0,059 6

6 0,059 6

7 0,059 6

8 0,059 6

9 0,059 6

10 0,059 6

11 0,059 6

11

CONFIDENTIAL 2016N274225_00201465

PPDPPD

PPD

FINAL Randomization

201465/350209BS

page 4 of 7



12 0,059 6

13 0,059 6

14 0,059 6

15 0,059 6

16 0,059 6

17 0,059 6

Block size: 6

Random seed: 7289

Total sample size: 102

Subject ID Stratum Assignment

F

C

A

D

E

B

E

F

C

D

A

B

A

D

E

B

C

F

C

E

12

CONFIDENTIAL 2016N274225_00201465

PPD

PPD

PPD

PPD

PPD

FINAL Randomization

201465/350209BS

page 5 of 7



A

F

B

D

D

E

F

A

C

B

A

C

D

E

B

F

E

A

C

D

F

B

A

F

D

E

C

B

F

B

C

A

D

E

13

CONFIDENTIAL 2016N274225_00201465

PPDPPD

PPD

FINAL Randomization

201465/350209BS

page 6 of 7



D

E

F

C

A

B

E

D

F

C

B

A

C

B

E

F

D

A

B

D

A

E

C

F

C

E

A

D

F

B

F

A

D

C

14

CONFIDENTIAL 2016N274225_00201465

PPDPPD

PPD

FINAL Randomization

201465/350209BS

page 7 of 7



B

E

A

D

E

C

B

F

A

C

B

D

F

E

15

CONFIDENTIAL 2016N274225_00201465

PPDPPD

PPD

PPD

1

CONFIDENTIAL 2016N274225_00201465

2

CONFIDENTIAL 2016N274225_00201465

3

CONFIDENTIAL 2016N274225_00201465

PPD - This section has been excluded to protect patient privacy.

7

CONFIDENTIAL 2016N274225_00201465

PPD

PPD

PPD

PPD

PPD

PPD

PPD

PPD

PPD

PPD

PPD

8

CONFIDENTIAL 2016N274225_00201465

9

CONFIDENTIAL 2016N274225_00201465

PPD

PPD

10

CONFIDENTIAL 2016N274225_00201465

11

CONFIDENTIAL 2016N274225_00201465

PPD

PPD

PPD

PPD

PPD

PPD

PPD

PPD

PPD

PPD

PPD

ICH Data Listings Page

LISTING 1 Listing of discontinued subjects (SES) ........................................................

LISTING 3 Listing of protocol deviations (SES) ............................................................. LISTING 3.04 Laboratory - Subjects meeting any PCI criteria (SES) ........................

LISTING 4 Listing of analysis population sets (SES) .................................................... LISTING 5 Listing of subjects with inclusion/exclusion criteria not met (SES) ......... LISTING 6 Listing of demographic characteristics (SES).............................................

LISTING 7 Listing of informed consent and eligibility status (SES) ............................ LISTING 12 Listing of single study drug exposure, calculated number of dosing

days and calculated duration of treatment (SES) .............................................. LISTING 16 Listing of psoriatic infiltrate thickness by ultrasound measurement

and calculated AUC of change in infiltrate thickness (SES) ............................

LISTING 17 Listing of clinical assessment of improvement and calculated cumulative total score (SES) .................................................................................

LISTING 18 Listing of adverse events (SES) ................................................................. LISTING 19 Listing of serious adverse events (SES) ................................................... LISTING 20 Listing of adverse events leading to withdrawal from

study/discontinuation of study treatment (SES) .................................................

232049505152

53

143

188233234

235

1

CONFIDENTIAL 2016N274225_00201465

1 of 1


Listing 19:

Listing of serious adverse events

(SES)

There is no serious adverse event reported.

234

CONFIDENTIAL 2016N274225_00201465

PPD

Other Data Listings Page

LISTING 1.01 Past and current medical conditions (Subjects randomized) ........... LISTING 1.02 Previous and concomitant medications (Subjects randomized) ....... LISTING 2 Listing of screening failures (Subjects screened) .................................. LISTING 3.01 Vital signs - Subjects meeting any PCI criteria (SES) ...................... LISTING 3.02 ECG - Subjects with any clinically significant findings (SES) ........... LISTING 3.03 ECG - Subjects meeting any PCI criteria (SES) .............................. LISTING 3.05 Laboratory - Subjects with any liver events (SES) ........................... LISTING 8 Listing of medical history (SES) ............................................................ LISTING 9 Listing of prior and concomitant medication (SES) ............................... LISTING 10 Listing of visit schedule (SES) ............................................................ LISTING 11 Listing of end of screening / treatment / follow-up (SES) .................... LISTING 13 Listing of descaling (SES) ................................................................... LISTING 14 Listing of skin biopsies (SES) ............................................................. LISTING 15 Listing of wound control (SES) ............................................................ LISTING 21 Listing of clinical laboratory data - hematology (blood) (SES) ............. LISTING 22 Listing of clinical laboratory data - clinical chemistry (serum) (SES) ... LISTING 23 Listing of clinical laboratory data - urinalysis (urine) (SES) ................. LISTING 24 Listing of liver events (SES) ................................................................ LISTING 25 Listing of RUCAM (SES) ..................................................................... LISTING 26 Listing of liver biopsy (SES) ................................................................ LISTING 27 Listing of liver imaging (SES) .............................................................. LISTING 28 Listing of vital signs (SES) .................................................................. LISTING 29 Listing of ECG measurements (SES) ................................................. LISTING 30 Listing of ECG interpretation (SES) .................................................... Listing 31 Epistem study report .............................................................................. Listing 32 Microarray Gene Data ............................................................................ Listing 33 Raw qPCR Data from Epistem ............................................................... Listing 34 Study Report N39268-10 Translational ..................................................

23456711121721222428313283123138139140141142150173176201452460

1

CONFIDENTIAL 2016N274225_00201465

CONFIDENTIAL 2016N274225_00 201465

LISTING(S) OF SUBJECTS RECEIVING INVESTIGATIONAL PRODUCT(S) FROM SPECIFIC BATCHES, IF MORE THAN ONE BATCH WAS USED

Batch number Treatment code Random number Study days

E141511-0001L002 A 1 – 19

E141511-0001L003 B 1 – 19

E141511-0001L004 C 1 – 19

E141511-0001L005 D 1 – 19

E141511-0001L001 E 1 – 19

C730272 F 1 – 19

E141511-0002L002 A 1 – 19

E141511-0002L003 B 1 – 19

E141511-0002L004 C 1 – 19

E141511-0002L005 D 1 – 19

E141511-0002L001 E 1 – 19 A = GSK2981278 0.03% ointment, B = GSK2981278 0.1% ointment, C = GSK2981278 0.8% ointment, D = GSK2981278 4% ointment, E = Vehicle to match GSK2981278 ointment, F = Betamethasone valerate 0.1% cream

1

PPD

1

PPD

1

PPD

PPD

*Complete removal of patient data listings may mean that page … · plot (PPS) ... SAP Statistical...

Documents

Transcript of *Complete removal of patient data listings may mean that page … · plot (PPS) ... SAP Statistical...