SUPPLEMENTARY APPENDIX - erj.ersjournals.com

SUPPLEMENTARY APPENDIX

This appendix has been provided by the authors to give readers additional information about their

work.

Supplement to: Bateman ED, Guerreros AG, Brockhaus F, et al. Fevipiprant, an oral prostaglandin DP2

receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids”

CONTENTS

SECTION 1. STUDY INVESTIGATORS AND PARTICIPATING CENTRES ...................................................... 3

SECTION 2. FULL INCLUSION AND EXCLUSION CRITERIA (ADDITIONAL DETAILS) .................................. 8

INCLUSION .......................................................................................................................................... 8

EXCLUSION .......................................................................................................................................... 9

SECTION 3. METHODS (ADDITIONAL DETAILS) ..................................................................................... 12

RANDOMISATION AND BLINDING .................................................................................................... 12

ASSESSMENTS ................................................................................................................................... 13

STATISTICAL ANALYSIS ...................................................................................................................... 15

SECTION 4. RESULTS (ADDITIONAL DETAILS) ........................................................................................ 19

PATIENTS ........................................................................................................................................... 19

ACQ ................................................................................................................................................... 19

AQLQs................................................................................................................................................ 20

WPAI-AA ............................................................................................................................................ 20

CARDIAC EVENTS ............................................................................................................................... 20

SECTION 5. SUPPLEMENTARY FIGURES AND TABLES ........................................................................... 22

SECTION 6. REFERENCES ....................................................................................................................... 36

SECTION 1. STUDY INVESTIGATORS AND PARTICIPATING CENTRES

Argentina: Dr Ledit Ardusso (Instituto Especialidades de la Salud, Rosario), Dr Horacio Budani

(FAICEP, Ciudad Autonoma de Buenos Aires, Buenos Aires), Dra. Maria De Salvo (Centro Medico

"Dra. de Salvo" Buenos Aires, Buenos Aires), Dr Cristian Fazio (Instituto Respirar, Mendoza), Dr

Marcelo Fernandez (Centro Respiratorio Quilmes Buenos Aires, Buenos Aires), Dr Ricardo Gene

(Sanatorio Otamendi y Miroli, Ciudad Autonoma de Buenos Aires, Buenos Aires), Dr Jorge Maspero

(CIDEA, Ciudad Autonoma de Buenos Aires, Buenos Aires), Dr Andrea Medina (Centro de

Investigaciones Médicas - CIM, Florencio Varela, Buenos Aires), Dra. Alicia Molina (INSARES,

Mendoza), Dr Ricardo Del Olmo (CIDEA, Ciudad Autonoma de Buenos Aires, Buenos Aires), Dr.

Ramon A. Rojas (Investigaciones en Patologias Respiratorias, Tucuman), Dr Rita Gisela Delgado

Vizcarra (Centro Médico ALAS, Ciudad Autonoma de Buenos Aires, Buenos Aires), Dr Luis Wehbe

(Inst. Ave Pulmo, Mar del Plata, Buenos Aires), Dr Anahi Yañez (INAER, Ciudad Autonoma de Buenos

Aires, Buenos Aires)

Austria: Dr Othmar Ablinger (Thalheim bei Wels 4600), Dr Herbert Riemer (Vienna 1210), Dr Robert

Voves (Feldbach 8330), Dr Josef Würtz (Linz 4020), Dr Peter Würtz (Grieskirchen 4710)

Bulgaria: Dr. Cvetanka OdzhakovaAtanasova (Diagnostic and Consultative Centre Mladost - M Varna,

Varna), Dr. Nina Markova (Multiprofile Hospital for Active Treatment, Plovdiv, Plovdiv), Dr. Hristo

Metev (SHAT for Pneumo-phthisiatric Diseases - Ruse Ltd., Ruse)

Canada: Dr. William Yang (Allergy and Asthma Research Centre, Ottawa)

Colombia: Dr Alvaro Urbina (Clínica de la Costa, Barranquilla), Dr Guido Cardona

(Neumoinvestigaciones LTDA, Bogotá), Dr. Dario Isaza (Clinica Soma, Medellín), Dr Jaime Sanchez

(CEQUIN Cardiomet, Armenia), Dr Francisco Serrano (Hospital Santa Clara, Bogotá)

France: Dr Arnaud Bourdin (Hôpital Arnaud de Villeneuve, Montpellier), Pr Frédéric De Blay (Nouvel

Hopital Civil, Strasbourg), Dr Gilles Devouassoux (Chu Lyon, Lyon), Prof. Anh Tuan Dinh-Xuan (Hôpital

Cochin, Paris), Dr Sandra Dury (CHU Maison Blanche, Reims),

Greece: Dr Asimina Gaga (Sotiria Gen Hosp, Athens), Dr Niki Georgatou (Sotiria Gen Hosp, Athens),

Dr Despoina Papakosta (Papanikolaou Hosp, Thessaloniki)

Guatemala: Dr Esau España (TRIAL, Guatemala City), Dr Jeremias Guerra (Clinica Dr Jeremias Guerra

Guatemala City), Dr Gerardo Martinez (TRIAL, Guatemala City), Dr Juan Moralejo (Clinica Dr Juan

Pablo Moralejo, Guatemala City), Dr Erick Yoc (Clínica Privada Interior Hospital Hermano Pedro.,

Antigua Guatemala Sacatepequez)

Hungary: Dr Beatrix Balint (Mellkasi BetegségekSzakkórháza, Deszk), Dr Marta Czompo

(Tüdőgyógyászat, Győr), Dr Valeria Csajbok (REVAMED Kft., Nyíregyháza), Dr Katalin Gomori (Dr.

Kenessey Albert Kórház, Balassagyarmat), Dr Zsuzsanna Mark (Pest Megyei Tüdőgyógyintézet,

Törökbálint), Dr Eva Radeczky (MEN FOR CARE Kft. Százhalom, Százhalombatta), Dr Peter Szabo

(JAON Kft., Pulmonológia, Nyíregyháza), Dr Zsuzsanna Szalai (Karolina Kórház, Pulmonológia,

Mosonmagyaróvár), Dr Istvan Varkonyi (ClinTrial Audit Kft., Debrecen)

India: Dr. Raj Bhagat (Dr. Bhagat's Allergy Asthma Clinic and Respiratory Care Cent, Gujarat), Dr Anil

Kumar Kashyap, Dr P.A. Mahesh (Allergy, Asthma & Chest Centre, Mysore), Dr Rajendra Mehta

(Allergy & Asthma Care, Indore), Dr Anthony Mesquita (TB & Chest Hospital, st., Goa), Dr Sundeep

Salvi (Chest Research Foundation, Pune), Dr Ravindra Sarnaik (Leela More's Chest Clinic, Nagpur), Dr

Krishnamurthy Srikanth (PSG Hospital, Coimbatore), Dr Rajesh Swarnakar (Ctr for Excellence in Clin

Res, Nagpur), Dr Jagdeep Whig (Dayanand Med college & Hosp, Ludhiana)

Italy: Prof. Alfredo Antonio Chetta (Az.Osped.Universitar.di ParmaUniversità degli Studi Parma,

Parma), Prof. Pier Luigi Paggiaro (A.Osped.Univ.Pisana Pres.Osped.di Cisanello Università Studi, Pisa)

Japan: Dr. Naohiko Ando (Ando Internal Medicine clinic, Hiroshima), Dr Takeo Endo (Mito Medical

Center, Ibaraki), Dr. Yasushi Fukushima (Tokyo-Eki Center-building Clinic, Tokyo), Dr. Toshiyuki

Harada (Hokkaido Social Insurance Hospital, Hokkaido), Dr Yasuko Harada (Nishi Fukuoka Hospital,

Fukuoka), Dr Shu Hashimoto (Nihon Univ Itabashi Hosp, Tokyo), Dr Hiroshi Hayakawa (Tenryu

Hospital, Shizuoka), Dr. Masayuki Hayashi (Hirokuni Clinic, Tokyo), Dr. Asamoto Hitoshi (Asamoto

Internal Medicine Hospital, Kyoto), Dr Soichiro Hozawa (Hiroshima Allergy & Resp Clin, Hiroshima),

Dr. Yumiko Ide (Tokyo Center Clinic, Japan), Dr Motokazu Kato (Kishiwada City Hospital, Osaka), Dr.

Yuji Kawarada (Kawarada Clinic, Fukuoka), Dr Goro Kimura (Minami-Okayama Med Center,

Okayama), Dr Masaharu Kinoshita (Nagata Hospital, Fukuoka), Dr Makoto Koizumi (Koizumi

Kokyukika Naika, Hokkaido), Dr. Yuji Maeda (Sagamihara National Hosp, Kanagawa), Dr. Hiroshi Miki

(National Hospital Organization Sendai Medical Center, Miyagi), Dr. Seijiro Minamoto (Osaka

Prefectural Medical Center for Resp and Allergic, Osaka), Dr Kenji Minoguchi (Sagamihara National

Hosp, Kanagawa), Dr Naoki Miyao (Koukan Clinic, Kanagawa), Dr. Hirotaka Nagashima (Yanagibashi

Hospital, Tokyo), Dr. Toshikazu Nagakura (Yoga Allergy Clinic, Tokyo), Dr Hiroyuki Nakamura (Sakaide

City Hospital, Kagawa), Dr. Yoichi Nakamura (Yokohama City Minato Red Cross Hospital, Kanagawa),

Dr. Yuji Nakatani (Nakatani Hospital, Hyogo), Dr Koichi Nishi (Ishikawa Prefectural Central Hosp,

Ishikawa), Dr. Fumitaka Ogushi (National Hospital Organization Kochi Hospital, Kochi), Dr. Hiroyuki

Ohbayashi (Tohno Chuo Clinic, Gifu), Dr. Joji Ohno (Nishio Municipal Hospital, Aichi), Dr Shinichi

Osaki (Osaki Internal Med/Resp Clinic, Fukuoka), Dr Ichiro Otani (Toyonakamidorigaoka Hosp,

Osaka), Dr. Hisakuni Sekino (Sekino Hospital, Tokyo), Dr Terufumi Shimoda (Fukuoka National

Hospital, Fukuoka), Dr. Shunsuke Shoji (National Hospital Organization Tokyo Hospital, Tokyo), Dr.

Hiroshi Shuto (Minamikoshigaya Kenshinkai Clinic, Saitama), Dr. Isao Tanaka (Mizushima Central

Hospital, Okayama), Dr Kozo Takeguchi (Yuizen Clinic, Tokyo), Dr. Kazuhiro Tomita (Seirei

Hamamatsu General Hospital, Shizuoka), Dr Mikio Toyoshima (Hamamatsu Rosai Hospital, Shizuoka),

Dr Toru Tsuda (Kirigaoka Tsuda Hospital, Fukuoka), Dr. Yasuhiro Yamazaki (National Hospital

Organization Asahikawa Medical Center, Hokkaido)

Mexico: MD Alfredo Gazca Aguilar (Hospital Real San José, Jalisco), MD Efrain Montaño Gonzales

Centro de Investigación Medico, Guadalajara Jalisco), MD Jorge Salas Hernandez Instituto Nacional

de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City), MD Francisco Sanchez Llamas

(Hospital No. 278), MD Juan Merida (Clínica de Asma, Baja California), MD Alicia Ramirez Riveria

(UDICEM, Monterrey Nuevo Leon), MD Rafael Hernandez Zenteno (Centro Respiratorio de México,

Mexico City)

The Netherlands: Dr Henk SinningheDamste (Twenteborg Ziekenhuis, Zilvermeeuw 1), Dr Stephanus

Gans (Harderwijk Wethouder Jansenlaan 90)

Peru: Dr. Socorro Bernardini (Clinica San Borja, Lima), Dr. Alfredo Guerreros (Clinica Internacional -

Sede Cercado de Lima, Lima), Dr. Alberto Matsuno (Clinica San Pablo, Lima), Dr. Carlos Minauro

(Clinica Los Andes, Lima), Dr. Andres Piñeiro (Clinica El Golf, Lima), Dr. Jose Torres (Clinica

Internacional - Sede San Borja, Lima), Dr. Cesar Villaran (Clinica Ricardo Palma, Lima)

Poland: Dr. Jasieniak-Pinis Grazyna (NZOZ Atopia, Krakow), Prof Pierzchala Wladyslaw (NZOZ

Profilaktyka, Katowice)

Romania: Dr Luminita Ambert ("Dr Victor Babes" Foundation, Bucharest), Dr Maria Cozma

(Emergency County Clinical Hospital Arad, Arad), Dr Cristina Gica (Prof Dr. Dimitrie Gerota

Emergency Hospital MAI, Bucharest), Dr Stefan Mihaicuta (Dr Victor Babes Infectious and

Pneumophtziology Diseases Timisoara, Timis), Dr Dana Olar (Dr Dana Olar Medical Center S.R.L,

Arad), Dr Ioan Petrui (S.C. Medical Center S.R.L., Deva), Dr Ana Maria Trailescu (Dr Victor Babes

Infectious and Tropical Diseases Clinical Hospital, Bucharest), Prof Voicu Tudorache (Dr Victor Babes

Infectious and Pneumophtziology Diseases, Timisoara Timis), Prof Ruxandra Ulmeanu (Marius Nasta

PneumophytyziologyInstitute, Bucharest)

Russia: Prof. Vladimir Abrosimov Ryazan State Medical University, Ryazan), Prof. Alexander

Emelyanov (City outpatient clinic #94, Saint-Petersburg), Prof. Galina Ignatova (City Clinical Hospital

#4, Chelyabinsk), Prof. Anatoly Kuzin (City Clinical Hospital #6, Chelyabinsk), Prof. Tatiana

Martynenko (City Hospital №5, Barnaul), Prof. Natalia Shaporova (City Consultative-Diagnostic

Center #1, Saint-Petersburg), Prof. Alexander Sinopalnikov (City Clinical Hospital named after S.P.

Botkin, Moscow)

South Africa: Dr Ismail Abdullah (Medical centre 2, Durban), Dr Ismail Abdullah (308 Gatesville

Medical Centre, Cape Town), Prof Eric Bateman (University of Cape Town, Cape Town), Dr Sabeer

Gaffar (Kings way trial centre, Durban), Dr Mashra Gani (GCT Mercantile Centre, Port Elizabeth), Dr

Haylene Nell (Tiervlei Medical centre, Cape Town), Prof Susanna Visser (Waterkloof Ridge Trial

centre, Pretoria)

Turkey: Prof. Dr. Suna Buyukozturk (Istanbul Faculty of Medicine, Istanbul University, Istanbul),

Munevver Erdinc (Ege University Medical Faculty Hospital, Izmir), Prof.Dr. Sibel Atis Nayci (Mersin

University Med. Faculty, Mersin)

United Kingdom: Dr Bernard Higgins (Freeman Hospital, Newcastle upon Tyne), Dr Dinesh Saralaya

(Bradford Royal Infirmary, Bradford), Prof Neil Thomson (Gartnavel Hospital, Glasgow)

United States of America: Dr Niran Amar (Allergy & Asthma Center, Waco), Dr. Samir Arora

(Columbus Clinical Research, Inc., Columbus), Dr James W. Baker (Baker Allergy Asthma &

Dermatology Ctr., Lake Oswego), Dr George W. Bensch (Bensch Research Associates, Stockton), Dr

Gary D. Berman (Clinical Research Institute, Minneapolis), Dr Kenneth Chinsky (Square 1 Clinical

Research, Erie), Dr Jeremy Cole (IPS Research, Oklahoma City), Andrew Engler (The Allergy and

Asthma Clinic, San Maateo), Dr Linda Ford (Asthma & Allergy Center, P.C. Bellevue), Dr Sherwin

Gillman (CHOC PSF, Orange), Dr Leon S. Greos (Colorado Allergy and Asthma Centers, Centennial), Dr

John Given (Allergy, Respiratory and Sleep Center, Canton), Dr Brad Goodman (AeroAllergy Research

Laboratories of Savannah, Inc., Savannah), Dr Gary Gross (Pharmaceutical Research & Consulting,

Inc., Dallas), Dr. Edward Kent (Timber Lane Allergy & Asthma Research LLC, South Burlington), Dr

Edward M. Kerwin (Clinical Research Institute of Southern Oregon, Medford), Dr Bobby Q. Lanier

(North Texas Institute for Clinical Trials, Benbrook), Huamin Li (Institute for Asthma and Allergy,

Chevy Chase), Dr Edward Lisberg (Asthma & Allergy Center of Chicago, River Forest), Dr S. David

Miller (Northeast Medical Research Associates, Inc., North Dartmouth), Dr. Lawrence Landwehr

(Clinical Research of the Ozarks, Inc., Warrensburg), Dr Nancy Ostrom (Allergy & Asthma Medical

Group and Research Center, San Diego), Amit Patel (Integrated Research Group of Riverside,

Riverside), Dr David S. Pearlman (Colorado Allergy and Asthma Centers, Denver), Dr. Andrew

Pedinoff (Princeton Center for Clinical Research, Skillman), Dr Bruce Prenner (Allergy Associates

Medical Group, San Diego), Dr Warren Pleskow (Warren W. Pleskow, Encinitas), Dr Paul Y. Qaqundah

(Pediatric Care Medical Group, Inc., Huntington Beach), Dr Ned Rupp (National Allergy, Asthma &

Urticaria Centers of Charleston, North Charleston), Dr. Paul Shapero (The Office of Dr. Paul Shapero,

MD, Bangor), Dr Jeffrey Tillinghast (The Clinical Research Center, St. Louis), Dr Robert Townley

(Creighton University, Omaha), Dr. Andrew Wachtel (Southern California Institute for Respiratory

Diseases, Los Angeles), Dr Steven F. Weinstein (Allergy and Asthma Specialists Medical Group and

Research Ct, Huntington Beach), Dr Hugh Harmon Windom (Sarasota Clinical Research, Sarasota), Dr

James D. Wolfe (Allergy & Asthma Research Center, San Jose), Dr John Zwetchkenbaum (AAPRI

Clinical Research Institute, Warwick)

SECTION 2. FULL INCLUSION AND EXCLUSION CRITERIA (ADDITIONAL DETAILS)

INCLUSION

Patients eligible for inclusion in this study must have fulfilled all of the following criteria:

1. Written informed consent must have been obtained before performing any assessment

2. Males and females of any race who were between 18 and 65 years old at the time informed

consent was obtained.

3. Physician diagnosis of asthma, as per GINA (2009) guidelines, and currently prescribed ICS

therapy.

4. Patients with a pre-bronchodilator FEV1 value of 40% to 80% of individual predicted value at

screening and at randomisation. The value at the randomisation was required to be within 15% of

the screening FEV1 and the results of spirometry was required to meet the American Thoracic

society/European Respiratory society (ATS/ERS) criteria for acceptability and repeatability.

5. Patients were allergic or atopic, as diagnosed historically or at screening Visit 3 by either a skin

prick test (≥3mm diameter above background) or a positive specific IgE (e.g. RAST/CAP) test

(≥0.35 IU eq./ml).

6. Patients who demonstrated reversible airway obstruction or airways hyperreactivity (AHR) or had

shown either of such responses in previous test(s) within the last 5 years.

Reversible airway obstruction demonstrated at screening was defined as either:

an increase of ≥12% and ≥200 ml in FEV1 over the patient’s pre-bronchodilator value in litres

or

an increase of ≥10% in % of predicted FEV1 over the patient’s pre-bronchodilator % of

predicted FEV1

within 10–15 minutes after inhaling a total of 360 µg of albuterol or 400 µg salbutamol via

metered dose inhaler (reversibility test). The administration of albuterol or salbutamol for the

reversibility test was to be within 30 minutes after pre-bronchodilator spirometry.

A positive AHR test result was defined as a provoked fall in FEV1 of 20% (PC20) by methacholine

at ≤8 mg/ml when not on ICS or ≤16 mg/ml on ICS therapy. The use of either histamine <10

mg/ml or acetylcholine <20 mg/ml in place of methacholine was also acceptable. Patients who

failed reversibility at screening visit 2 or 3 could not also be tested for AHR or vice versa. In

addition, patients were not to be rescreened if they failed to demonstrate reversibility or AHR.

7. An ACQ score ≥1.5 at randomisation.

EXCLUSION

Patients fulfilling any of the following criteria were not eligible for inclusion in this study:

1. Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of

enrolment, whichever was longer

2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes

(CRTh2 antagonists)

3. History of long QT syndrome or whose current QTc interval (Fridericia’s) was prolonged >450 ms

for males and females at screening as assessed by central ECG interpretation

4. History of malignancy of any organ system (other than localised basal cell carcinoma of the skin),

treated or untreated, within the past 5 years, regardless of whether there was evidence of local

recurrence or metastases

5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after

conception and until the termination of gestation, confirmed by a positive hCG laboratory test

(>5 mIU/mL)

6. Women of child-bearing potential. All women physiologically capable of becoming pregnant,

must have used effective contraception during the study and for 5 days (5 half-lives) after

treatment. Effective contraception methods include:

Barrier method: Barrier methods of contraception: Condom or Occlusive cap

(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal

suppository

Spermicides alone are not a barrier method of contraception and should not be used alone. The

following methods are considered more effective than the barrier method and are also

acceptable:

Total abstinence: When this is in line with the preferred and usual lifestyle of the

subject. [Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation

methods) and withdrawal are not acceptable methods of contraception].

Female sterilisation: have had a surgical hysterectomy or surgical bilateral

oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks

before taking study treatment. In the case of oophorectomy alone, only when the

reproductive status of the woman has been confirmed by follow up hormone level

assessment.

Male partner sterilisation: [For female study subjects, the vasectomised male partner

should be the sole partner for that patient]

Use of established, oral, injected or implanted hormonal methods of contraception,

intrauterine device (IUD) or intrauterine system (IUS)

7. Patients with serious co-morbidities including, but not limited to, uncontrolled diabetes (HbA1c

≥8%), heart failure, cancer, neurodegenerative diseases, rheumatoid arthritis and other

autoimmune diseases, other lung diseases including chronic bronchitis, chronic obstructive

pulmonary disease or emphysema or other conditions characterised by eosinophilia and

pulmonary symptoms (i.e. Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis,

eosinophilic pneumonia, etc.)

8. Acute illness other than asthma at the start of the study

9. History of life-threatening asthma, including a history of significant hypercapnea (pCO2

>45mmHg), prior intubation, respiratory arrest, or seizures as a result of asthma.

10. History of alcohol or other substance abuse

11. Patients who had had a respiratory tract infection within 4 weeks of the screening visit. Patients

who developed a respiratory tract infection between screening and the randomisation visit were

to be screen failed, and could be permitted to re-enrol at a later date

12. Patients who had been hospitalised due to their asthma, or that had required treatment with

systemic steroids, within 6 weeks of the screening visit

13. Patients with clinically significant laboratory abnormalities (not associated with the study

indication) at screening including (but not limited to):

• Total white blood cell count <2500 cells/µL at screening.

• Aspartate aminotransferase (AST) or alanine amino transferase (ALT) >2.0 X upper limit of

normal (ULN) or total bilirubin >1.3 X ULN at screening.

• Estimated glomerular filtration rate (eGFR) by the MDRD equation <55 ml/min/1.73 m2 at

screening

14. Patients who had a clinically significant abnormality on a 12-lead ECG recorded within one

month prior to or at screening

15. Current smokers or ex-smokers who stopped smoking within 6 months prior to screening or had

a smoking history of ≥10 pack years

16. Patients with a body mass index (BMI) <17 or >40 kg/m2

17. Patients receiving or likely to require treatment during the study with any prohibited

medications in the classes or groups listed in Table S1

18. Patients receiving or likely to require treatment during the study with any prohibited asthma

related medications of the classes or groups listed in Table S2. Patients already receiving such

medications must have undergone the required washout period prior to screening and followed

the adjustment to their treatment programme.

19. Patients on maintenance immunotherapy who either began their immunotherapy regimen or

had a clinically relevant change to their immunotherapy within 1 month prior to granting

informed consent. Patients on stable maintenance immunotherapy for at least one month prior

to Visit 1 could be enrolled

20. Patients who had been previously randomised into this study

21. Patients who were unable to perform spirometry and peak flow measurements, complete a

patient diary or complete questionnaires as required by the protocol

22. Patients with any medical or psychological condition that, in the investigators opinion, rendered

the patient unable to understand the nature, scope, and possible consequences of the study

23. Those who were unable/unwilling to take up to 7 pills per day, who were unable to use an

inhaler or who were unlikely to comply with the protocol

24. Use of immunosuppressive medication (except inhaled and topical corticosteroids) within 30

days before randomisation into the study

25. A positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical

history and/or subject’s verbal report

26. A positive human immunodeficiency virus test or was taking anti-retroviral medications, as

determined by medical history and/or subject’s verbal report

27. History of any known immunodeficiency disorder

28. Patients who were severely lactose intolerant, and in the opinion of the investigator would

suffer from participating in the study, as montelukast and placebo to montelukast contain

lactose

29. Any condition that, in the opinion of the investigator, was likely to interfere with evaluation of

the investigational product or interpretation of study results

30. Patients who, in the opinion of the investigator, were unsuitable to take part in this study

31. Patients unable to produce sufficient induced sputum to provide a sample for analysis (100 mg).

This exclusion criterion applied to patients in the sputum sub-study only, and did not preclude

these patients from participation in the study as a whole.

SECTION 3. METHODS (ADDITIONAL DETAILS)

RANDOMISATION AND BLINDING

Patients were assigned randomly to one of 15 treatment arms. The selection of the fevipiprant doses

to be administered in the study (1, 3, 10, 30, 50, 75, 150, 300, and 450 mg qd and 2, 25, 75, and 150

mg bid) was based on the results of earlier fevipiprant studies, that demonstrated that the single

dose of 500 mg and multiple doses up to 250 mg bid for 7 days administered in healthy volunteers

(QAW039A2102) were well tolerated.

Participating sites were split into two groups. Each group used a separate randomisation list, which

comprised 9 of the available 15 treatment groups. Each group list contained fevipiprant 450 mg qd,

montelukast 10 mg qd and placebo, plus 4 other fevipiprant qd doses and 2 fevipiprant bid doses

(Group 1: qd – 1 mg, 10 mg, 50 mg, 150 mg; bid – 2 mg, 75 mg. Group 2: qd – 3 mg, 30 mg, 75 mg,

300 mg; bid – 25 mg, 150 mg). Patients were allocated to treatments equally amongst these 9

treatment groups.

At Visit 4, all eligible patients were randomised via the Interactive Response Technology (IRT) to 1 of

the 15 treatment arms as described above. For each patient, the investigator or his/her delegate

contacted IRT and confirmed that the patient fulfilled all the inclusion/exclusion criteria. The IRT

assigned a randomisation number to the patient, which was used to link the patient to a treatment

arm and specified a unique medication number for the first package of study drug to be dispensed to

the patient. The randomisation number was not communicated to the caller.

The randomisation numbers were generated using the following procedure to ensure that treatment

assignment was unbiased and concealed from patients and investigator staff. A patient

randomisation list was produced by the IRT provider using a validated system that automated the

random assignment of patient numbers to randomisation numbers. These randomisation numbers

were linked to the different treatment arms, which in turn were linked to medication numbers. A

separate medication randomisation list was produced under the responsibility of NDSM using a

validated system that automated the random assignment of medication numbers to medication

packs containing each of the study drugs.

Treatment randomisation was maintained at the regional and/or country level, not centre level. The

randomisation scheme for patients was reviewed and approved by a member of the Biostatistics

Quality Assurance Group.

Patients, investigator staff, persons performing the assessments, and data analysts remained

blinded to the identity of the treatment from the time of randomisation until database lock, using

the following methods:

Randomisation data were kept strictly confidential until unblinding, and were inaccessible by

anyone involved in the study

The identity of the treatments was concealed using identical packaging, labelling, schedule

of administration, appearance, taste and odour.

Investigators and patients were aware of patients’ participation in the sub-study as the

patients had to sign an additional informed consent form for the sub-studies. However, they were

unaware of

the assigned treatment. A double-dummy design was used in the study because the identity of the

study drugs could not be disguised due to their different forms. Unblinding was only permitted in

the case of patient emergencies and at study conclusion.

ASSESSMENTS

FEV1 and forced vital capacity (FVC)

Spirometry measurements were taken at Visits 4, 5, 6, 7 and 8, and were assessed by a central

reader resulting in values for FEV1, FVC in absolute terms and as % predicted. The baseline FEV1 was

the average of two FEV1 assessments taken in the clinic at 50 min and 15 min prior to the first study

drug administration at Visit 4. All other FEV1 assessments were taken in the clinic 15 minutes prior to

the scheduled dose.

Asthma Control Questionnaire (ACQ)

The ACQ was used to assess improvements in asthma symptom control. It consisted of 7 items: 5

items on symptom assessment, 1 item on rescue bronchodilator use, and 1 item on airway calibre

(FEV1 % predicted). The ACQ was fully validated, including a minimal important difference (MID) or

smallest change that could be considered clinically important (0.5). The ACQ was self-administered

at the clinic (questions 1–6 only). Patients were asked how they had been feeling during the past

week and to score each item on a 7-point response scale, where 0 indicates ‘totally controlled’ and 6

indicated ‘severely uncontrolled.’ Study staff scored question 7 based on % predicted FEV1 (ideally

pre-bronchodilator). The total score was calculated as the mean of all questions. The questionnaire

was completed before any other assessments. At randomisation (Visit 4), the -50 min spirometry

manoeuvre result was used to complete question 7 on the ACQ.

Juniper Asthma Control Diary (JACD)

The asthma control diary (ACD) was similar to the ACQ except that it was a patient-reported daily

measure. The symptom questions were similar including waking at night by symptoms, waking in the

morning with symptoms, activity limitation, shortness of breath and wheeze. It included a question

on bronchodilator usage and measured peak expiratory flow measurement instead of FEV1. Patients

were instructed to complete the diary at home on rising in the morning and retiring at bed time.

Asthma Quality of Life Questionnaire – Standardised (AQLQs)

The disease-specific, standardised version of the asthma quality of life questionnaire (AQLQs) was

used to measure patients’ health-related quality of life. The AQLQs is a 32-item questionnaire

designed to measure functional impairments that are most important to patients with asthma. It

consists of 4 domains: symptoms, emotional function, environmental stimuli and activity limitation.

Full validation has been demonstrated, including an MID or smallest change that can be considered

clinically important (0.5). The AQLQs, which takes about 4 to 5 minutes to complete, was self-

administered at the clinic. Given that the AQLQs was administered along with the ACQ, which has a

1-week recall, patients completing the AQLQs were also asked to recall their experiences during the

past week, and to score each item on a 7-point scale (7 = not at all impaired to 1 = severely

impaired). The AQLQs yields domain-specific scores and a total score, which is the mean response to

all 32 questions. It was required that the questionnaire be completed before any other non-patient

reported outcome assessments.

Work Productivity and Activity Impairment Questionnaire Specific Health Problem Allergic Asthma

(WPAI-AA)

Changes in work productivity and daily activities were assessed by the Work Productivity and Activity

Impairment – Allergic Asthma (WPAI-AA) questionnaire specific for asthma. The WPAI-AA

questionnaire measures time missed from work, impairment or productivity loss while at work and

impairment in daily activities. The outcomes are expressed as impairment percentages, with higher

numbers indicating greater impairment and less productivity. It consists of 6 items and takes about 5

minutes to complete. The recall time is 1 week.

Safety

Safety was assessed through recording adverse events (AEs) and serious adverse events (SAEs),

including regular monitoring of haematology, blood chemistry, urinalysis, and regular assessments of

vital signs, physical condition, height and body weight.

STATISTICAL ANALYSIS

The randomised set (RAN), which comprised all randomised patients, regardless of whether or not

they actually received study medication, was used for summaries of patient disposition and analysis

populations.

The modified full analysis set (mFAS) included all randomised patients that took at least one dose of

study drug and had valid baseline and post-baseline spirometry data as confirmed by a quality

control process. Valid baseline spirometry data were defined as ‘baseline % predicted FEV1 ≥40% or

baseline % predicted FEV1 ≤80%’, where baseline was defined as the average of two FEV1

measurements (50 minutes and 15 minutes before dosing on Day 1) prior to randomisation. If these

measurements were not available, then baseline FEV1 was the last available measurement prior to

Day 1. Following the intent-to-treat principle, patients were analysed according to the treatment

they were assigned to at randomisation. The mFAS was used for all efficacy analyses, unless

otherwise stated.

The full analysis set (FAS) included all randomised patients that took at least one dose of study drug.

Following the intent-to-treat principle, data were analysed according to the treatment they were

assigned to at randomisation. The FAS was used in sensitivity analyses for all efficacy variables,

unless otherwise stated.

The per-protocol set (PP) included all patients of the FAS without any major protocol deviations that

could confound the interpretation of analyses conducted on the FAS. Major protocol deviations

were defined in the validation analysis plan prior to database lock and the unblinding of the study.

Patients were analysed according to the treatment they were assigned to. The PP set was used for

the supportive analysis of the primary variable.

The safety set (SAF) included all patients who received at least one dose of study drug whether or

not they underwent randomisation. Patients were analysed according to the treatment they

received. The SAF was used in the analysis of all safety variables.

The primary FEV1 dose response analysis was performed using the generalised multiple comparisons

procedures and modelling (MCP-Mod) approach [1, 2] on the mFAS. The covariate adjusted least-

squares means and corresponding variance covariance matrix needed as inputs for the generalised

MCP-Mod approach were obtained from a linear mixed effects model containing treatment group

and region as fixed effect, centre nested within region as a random effect and the average of the two

baseline FEV1 measurement as a covariate. Missing FEV1 values and those recorded up to 6 h after

rescue medication were imputed using last-observation-carried-forward.

For the multiple-comparison part of MCP-Mod, the null hypothesis of a constant dose-response

curve for the primary efficacy endpoint was tested at a one-sided significance level of 2.5% against

the alternative hypothesis of a non-constant dose response curve using a multiple contrast test. This

test was based on the optimal contrast test statistics and multiplicity adjusted critical values

calculated for the list of pre-specified dose-response shapes shown in Table S3.

For the modelling part of MCP-Mod, 10,000 parametric bootstrap samples were generated from the

multivariate normal distribution defined by the least squares means for each treatment group and

their variance covariance matrix. The generalised Akaike information criterion [2] was used to select

the best fitting model from a set of monotonic candidate models (Emax, Sigmoid Emax and Linear) for

each bootstrap sample. Each of these models included a model parameter that describes what

multiple of the same total daily dose given once daily corresponds to the same total daily dose given

twice daily. The median of the predicted differences to placebo for each dose based on the selected

model for each sample was used as the estimated dose response curve. Pointwise 95% confidence

intervals were based on the 2.5th and 97.5th percentiles of these differences. This bootstrap model

averaging approach reflects model uncertainty in the inference and typically leads to more reliable

confidence intervals as well as more precise estimates of the dose-response curve compared to

selection of a single model [3, 4].

A sensitivity analysis using a repeated measures model that implicitly imputes data under a missing

at random assumption was also conducted. An expanded set of dose response models including

non-monotonic ones was fitted and the primary analysis was repeated for the per-protocol set.

Exploratory analyses based on the following subgroups were carried out for trough FEV1 after 12

weeks of treatment for the mFAS to explore consistency of the treatment effect across subgroups:

Sex (male, female)

Race (Caucasian, black, Asian, other)

Baseline % predicted FEV1 (>40% – ≤50%, >50% – ≤60%, >60% – ≤70%, >70% – ≤80%, >80%)

Baseline % predicted FEV1 (>70%, ≤70%)

Baseline FEV1 (tertile 1, tertile 2, tertile 3) – Blinded data was used to calculate the tertiles,

this was used only in the FEV1 analysis

Baseline eosinophil (≤0.15 x 109/L, >0.15 x 109/L to ≤0.3 x 109/L, >0.3 x 109/L to ≤0.5 x 109/L,

>0.5 x 109/L)

Baseline IgE (tertile 1, tertile 2, tertile 3) – Overall blinded data will be used to calculate the

tertiles

Baseline Th2 (combining IgE and Eosinophil), (high, low) - where high is defined as baseline

IgE > 100 kIU/L AND baseline blood eosinophil ≥ 0.14 x 109 /L; otherwise low

Baseline ACQ score (tertile 1, tertile 2, tertile 3) – Blinded data will be used to calculate the

tertiles

Pre-trial ICS (>800 µg budesonide daily or equivalent, ≤800 µg)

Geographic region (North America, South America, Europe, India, Japan, South Africa,

Philippines)

Japanese vs non-Japanese patients

History of asthma exacerbation (Yes/No) – Use history / condition data to derive this. If the

low level term is equal to ‘Exacerbation of Asthma’ then history of Asthma exacerbation =

‘Yes’; else ‘No’

BMI (≤30 kg/m2, >30 kg/m2)

Baseline FeNO (High/Low): where high is defined as baseline FeNO ≥median; otherwise low

(only applies to the patients in the FeNO subset)

Baseline FeNO (≤30 ppb, >30 ppb)

Baseline FeNO (≤50 ppb, >50 ppb)

The secondary and exploratory efficacy variables were analysed without adjustment for the multiple

outcomes.

Demographics and baseline characteristics were summarised using the SAF. Continuous variables

were summarised using descriptive statistics and categorical variables were summarised in terms of

the number and percentage of subjects in each category.

All safety endpoints (i.e. adverse events, laboratory data, vital signs and ECG) were summarised by

treatment for all patients of the safety population. All data were included in the analysis

regardless of rescue medication use.

It was estimated that 945 randomised patients would ensure 90% power for the primary contrast

test assuming a true maximum treatment effect over placebo of 150 ml, a standard deviation of 380

ml, no difference between the fevipiprant dosing regimens and an 80% trial completion rate.

SECTION 4. RESULTS (ADDITIONAL DETAILS)

PATIENTS

The disposition of all study patients is shown in Table S4.

A total of 23 randomised patients (2.2%) did not receive study drug and were therefore excluded

from the FAS and SAS. One further patient randomised to fevipiprant had been previously

randomised into this study and was therefore also excluded from the FAS. Of all the groups, the

montelukast treatment arm had the highest number of randomised patients who did not receive

study drug (n=6).

In all, 299 patients (28.3%) were excluded from the per protocol set (PPS), with 29.5%, 25.5% and

28.5% being excluded from the montelukast, placebo and fevipiprant treatment groups,

respectively. The most common protocol deviation that led to patients being excluded from the PPS

was the pre-bronchodilator FEV1 at randomisation being outside of the required range. This

deviation led to 10.8%, 10.9% and 9.6% of patients taking montelukast, placebo or fevipiprant,

respectively, being excluded. The second most common protocol deviation was the failure to deliver

spirometry according to ATS/ERS acceptability criteria and this led to the exclusion of 7.2%, 6.6% and

8.7% of patients from the montelukast-, placebo- and fevipiprant-treated cohorts, respectively.

Between them, these two protocol deviations accounted for approximately two thirds of the

exclusions from each of the montelukast, placebo and fevipiprant treatment groups. No other

protocol deviation accounted for the loss of more than 5% of randomised patients from the PPS for

any treatment cohort.

ACQ

Change from baseline in total ACQ score at each assessment time point was performed using a linear

mixed effect model. There was no significant effect in terms of control of asthmatic symptoms by

fevipiprant in the patients as measured by the ACQ, compared to placebo, and these results stood

regardless of whether ACQ5, ACQ6 or ACQ7 were examined.

JACD

The mean JACD scores recorded, pooled over 4-week intervals, did not show any significant

difference for fevipiprant compared to placebo.

AQLQs

There was no clinically or statistical significant improvement in quality-of-life as measured by the

AQLQs, either in the overall score (Table S5) or any of the sub-domains, after 12 weeks’ treatment

with fevipiprant in comparison to placebo. Montelukast also failed to significantly improve any of

the AQLQs parameters compared to placebo after 12 weeks’ treatment.

WPAI-AA

No statistically significant improvements in work productivity or daily activity parameters as

measured by the WPAI-AA questionnaire were observed after 12 weeks of treatment with any of

fevipiprant doses (Table S6). Montelukast also failed to significantly improve any of the WPAI-AA

parameters compared to placebo after 12 weeks’ treatment.

CARDIAC EVENTS

A total of 14 (1.4%) patients (0 patients from the montelukast, 1 patient [0.7%] from the placebo and

13 patients [1.7%] from the fevipiprant treatment groups) were reported as experiencing cardiac

events during the post-randomisation period (Table S7), including one non-suspected SAE of

pericarditis. One further patient (in the fevipiprant 2 mg bid group) had an ongoing cardiac event

(right bundle branch block), which started before the start of study. With the exception of one

angina pectoris reported in the placebo group, the remainder of the cardiac disorders were reported

in the fevipiprant treatment groups. The largest number of cardiac events in the fevipiprant

treatment group was reported in the following treatment arms: 450 mg qd treatment arm (5 events;

in 4 patients; 3.0%), 50 mg qd (3 events in 3 patients; 6.1%), 10 mg qd (2 events in 2 patients; 4.3%),

3 mg qd (1 event in 1 patient; 1.9%), 75 mg bid (2 events in 2 patients; 4.1%) and 150 mg bid (2

events in 1 patient; 1.8%). It should be noted that there were no cardiac events reported for the 150

mg qd or 300 mg qd dose arms even though the total daily dose was the same as for the 75 mg bid

and 150 mg bid doses. Three of the events in the fevipiprant treatment groups occurred during the

washout period and 9 resolved on treatment. The cardiac events are described in detail in Table S7.

Four patients with newly occurring ventricular extrasystoles (VE) were identified. These VEs occurred

separately at various time points during the study. In one case the VE was observed during the

screening period, which lasted until the last visit day. The timing pattern does not indicate an

association with the study drug, but rather a background arrhythmia in this population. One patient

with a history of supraventricular extrasystoles (SVEs) developed mild atrial fibrillation at Day 15,

which was judged unrelated to study medication by the investigator. All cardiac AEs, with the

exception of the pericarditis, were of mild-to-moderate severity. Based on the inability to identify

discernible trends with fevipiprant dose, regimen, time-of-onset, patient age and gender,

concomitant medication, event type and following detailed ECG review, it was considered that these

were most probably coincidental events without a causal association to the study drug. Patients with

asthma are predisposed to display sinus node dysregulation and depression of peripheral autonomic

nervous system regulation in general, which might be associated with the observed cardiac

abnormalities.

SECTION 5. SUPPLEMENTARY FIGURES AND TABLES

Table S1. Prohibited asthma-related medications

Class of medication Minimum washout period prior to screening

(Visit 2)

Oral corticosteroids 30 days

Oral antihistamines* 7 days

LABAs (other than indacaterol) 48 h

Indacaterol 7 days

SABAs (short-acting β2-agonists) (other than

study rescue medication)

6 h

Long-acting anticholinergics 7 days

Short-acting anticholinergics 8 h

Fixed combinations of β2-agonists and inhaled

corticosteroids

48 h

Fixed combinations of short-acting β2-agonists

and short-acting anticholinergics

8 h

Mast cell stabilisers 7 days

Leukotriene receptor antagonists or synthesis

inhibitors

7 days

Xanthines 7 days

Omalizumab 6 months

Injected depot corticosteroids 3 months

*If the treatment regimen has been stable for at least 1 month prior to screening, patients are

allowed to stay on their antihistamine treatment during the run-in period until 1 week before

randomisation

Table S2. Medications allowed under certain conditions

Class of medication Condition

Inactivated vaccine Not administered within 48 h prior to a study visit

Short-acting β2-agonist Rescue medication to be taken as needed

Nasal anticholinergics

Nasal corticosteroids

Nasal or ophthalmological preparations of

nedocromil

Nasal or ophthalmological preparations of

antihistamines

Treatment regimen has been stable for at least 1

month prior to screening

In the case of prn, providing an established

pattern of use has been documented

Table S3. Pre-specified contrast coefficients for primary dose-response test

Dose

(mg)

Linear Emax #1 Emax #2 Emax #3 Emax #4 Sigmoid

Emax #1

Sigmoid

Emax #2

Sigmoid

Emax #3

Sigmoid

Emax #4

0 qd -0.358 -0.816 -0.693 -0.607 -0.525 -0.413 -0.346 -0.470 -0.260

1 qd -0.135 -0.234 -0.241 -0.221 -0.195 -0.157 -0.131 -0.178 -0.099

3 qd -0.133 -0.140 -0.202 -0.202 -0.185 -0.157 -0.131 -0.178 -0.099

2 bid -0.132 -0.108 -0.185 -0.193 -0.181 -0.157 -0.131 -0.178 -0.099

10 qd -0.126 -0.007 -0.106 -0.146 -0.155 -0.157 -0.131 -0.178 -0.099

30 qd -0.105 0.080 0.019 -0.041 -0.083 -0.156 -0.131 -0.157 -0.099

50 qd -0.085 0.103 0.073 0.022 -0.029 -0.151 -0.128 -0.095 -0.099

25 bid -0.085 0.103 0.073 0.022 -0.029 -0.151 -0.128 -0.095 -0.099

75 qd -0.060 0.116 0.108 0.073 0.024 -0.095 -0.115 0.014 -0.098

150 qd 0.017 0.130 0.152 0.149 0.123 0.217 0.033 0.192 -0.082

75 bid 0.017 0.130 0.152 0.149 0.123 0.217 0.033 0.192 -0.082

300 qd 0.169 0.137 0.178 0.203 0.215 0.250 0.264 0.241 0.164

150 bid 0.169 0.137 0.178 0.203 0.215 0.250 0.264 0.241 0.164

450 qd 0.846 0.368 0.493 0.591 0.681 0.658 0.779 0.648 0.887

Optimal contrasts were derived assuming that bid dosing is equally effective as qd dosing for the

same total daily dose. If this is not the case, then the power of the test may be decreased, but would

maintain the power at approximately 90% or higher over a range of plausible scenarios.

Table S4. Patient disposition (randomised set)*

Disposition/Reason Placebo

(n=137)

n (%)¶

Fevipiprant

low-dose*

(n=206)

n (%)¶

Fevipiprant

mid-dose†

(n=224)

n (%)¶

Fevipiprant

high-dose‡

(n=218)

n (%)¶

Fevipiprant

450 mg qd

(n=134)

n (%)¶

Fevipiprant

total§

(n=782)

n (%)¶

Montelukast

10 mg qd

(n=139)

n (%)¶

Completed 111 (81.0) 171 (83.0) 194 (86.6) 181 (83.0) 107 (79.9) 653 (83.5) 113 (81.3)

Discontinued 25 (18.2) 33 (16.0) 26 (11.6) 36 (16.5) 26 (19.4) 121 (15.5) 24 (17.3)

Primary reason for discontinuation

Adverse event(s)

Abnormal laboratory value(s)

Abnormal test procedure result(s)

Unsatisfactory therapeutic effect

Subject withdrew consent

Lost to follow-up

Administrative problems

Patients inability to use the device

Protocol deviation

16 (11.7)

1 (0.7)

2 (1.5)

1 (0.7)

2 (1.5)

2 (1.5)

0

0

1 (0.7)

12 (5.8)

2 (1.0)

1 (0.5)

2 (1.0)

7 (3.4)

0

1 (0.5)

1 (0.5)

7 (3.4)

15 (6.7)

1 (0.4)

2 (0.9)

0

1 (0.4)

2 (0.9)

3 (1.3)

0

2 (0.9)

17 (7.8)

1 (0.5)

1 (0.5)

3 (1.4)

3 (1.4)

5 (2.3)

2 (0.9)

0

4 (1.8)

14 (10.4)

0

1 (0.7)

1 (0.7)

6 (4.5)

2 (1.5)

0

1 (0.7)

1 (0.7)

58 (7.4)

4 (0.5)

5 (0.6)

6 (0.8)

17 (2.2)

9 (1.2)

6 (0.8)

2 (0.3)

14 (1.8)

5 (3.6)

1 (0.7)

1 (0.7)

1 (0.7)

10 (7.2)

1 (0.7)

3 (2.2)

0

2 (1.4)

n= Number of patients randomised per treatment group

*Fevipiprant low-dose: Combination of 1 mg qd, 3 mg qd, 2 mg bid, 10 mg qd.

†Fevipiprant mid-dose: Combination of 30 mg qd, 50 mg qd, 25 mg bid, 75 mg qd.

‡Fevipiprant high-dose: Combination of 150 mg qd, 75 mg bid, 300 mg qd, 150 mg bid.

§Fevipiprant total: Combination of all fevipiprant doses.

¶The percentages do not add up to 100% as about 1% of the patients were randomised in error and no data is available for these patients in study

completion records.

Table S5. Reasons for screen failure in the study

Reason for screen failure N, (%)

Total screen failures (multiple reasons may apply) 1540 (100%)

Unacceptable past medical history/concomitant diagnosis 21 (1.4%)

Intercurrent medical event 47 (3.1%)

Unacceptable laboratory value(s) 165 (10.7%)

Unacceptable test procedure result(s) 605 (39.3%)

Did not meet diagnostic/severity criteria 554 (36.0%)

Unacceptable use of excluded medication or therapies 20 (1.3%)

Subject withdrew consent 111 (7.2%)

Unknown 2 (0.1%)

Other 187 (12.1)

Table S6. Change from baseline in AQLQ overall score

Treatment LS mean Difference to placebo P value

Estimate 95% CI Estimate 95% CI

Fevipiprant 1 mg qd 0.666 (0.433, 0.898) 0.002 (-0.264, 0.268) 0.9870


Fevipiprant 10 mg qd 0.530 (0.292, 0.768) -0.133 (-0.404, 0.137) 0.3341







Fevipiprant 2 mg bid 0.529 (0.303, 0.755) -0.134 (-0.395, 0.127) 0.3129


Fevipiprant 75 mg bid 0.705 (0.452, 0.958) 0.042 (-0.242, 0.325) 0.7739


Montelukast 10 mg 0.651 (0.502, 0.800) -0.013 (-0.207, 0.182) 0.8991

Placebo 0.663 (0.510, 0.817)

AQLQ, Asthma Quality of Life Questionnaire; CI, confidence interval; FEV1, Forced Expiratory Volume

in 1 second; LS, least squares.

All estimates are based on a linear mixed effects model with treatment and region as fixed class

effects, centre nested within region as a random class effect and baseline AQLQ score and baseline

% predicted FEV1 as covariates.

Baseline AQLQ score is defined as AQLQ score reported on day 1.

The baseline FEV1 was defined as the average of two pre-bronchodilator FEV1 assessments taken in

the clinic at 50 min and 15 min prior to the first study drug administration.

Table S7. Change from baseline in WPAI-AA score (Parameter: Percent work time missed due to

allergic asthma)

Treatment LS mean Difference to placebo P value

Estimate 95% CI Estimate 95% CI

Fevipiprant 1 mg qd -0.127 (-4.312, 4.058) -1.118 (-6.043, 3.808) 0.6556


Fevipiprant 10 mg qd 2.292 (-1.474, 6.058) 1.301 (-3.271, 5.872) 0.5761

Fevipiprant 30 mg qd 2.096 (-2.080, 6.271) 1.105 (-3.714, 5.923) 0.6522

Fevipiprant 50 mg qd 0.252 (-3.518, 4.022) -0.740 (-5.321, 3.842) 0.7510



Fevipiprant 300 mg qd 0.826 (-3.068, 4.719) -0.165 (-4.775, 4.445) 0.9438


Fevipiprant 2 mg bid -2.032 (-6.414, 2.351) -3.023 (-8.095, 2.050) 0.2419

Fevipiprant 25 mg bid 4.395 (0.819, 7.970) 3.403 (-0.913, 7.720) 0.1218

Fevipiprant 75 mg bid -0.220 (-4.734, 4.295) -1.211 (-6.408, 3.987) 0.6470

Fevipiprant 150 mg bid 1.692 (-2.061, 5.444) 0.701 (-3.784, 5.185) 0.7588

Montelukast 10 mg 0.048 (-2.338, 2.434) -0.943 (-4.392, 2.505) 0.5908

Placebo 0.991 (-1.684, 3.666)

CI, confidence interval; LS, least squares, WPAI-AA, Work Productivity and Activity Impairment –

Allergic Asthma.

All estimates are based on a linear mixed effects model with treatment and region as fixed class

effects, centre nested within region as a random class effect and baseline WPAI-AA score as

covariate.

Baseline WPAI-AA score is defined as WPAI-AA score reported on Day 1.

Table S8. Cardiac events

Patient Preferred term Day

of

onset

Duration SAE Severity Relationship

to study

drug

(Yes/No)

Action taken Details

Fevipiprant 450 mg qd

1

(58/F/Ca)

Ventricular

extrasystoles

(newly

occurring)

1 4 N Moderate Y Discontinued at Day

1

No cardiac history. ECG screening: APC ectopy, ECG day

1: single VPC ectopies at 3 and 6 h post-dose.

2

(57/M/Ca)

Atrial fibrillation

(newly

occurring)

15 Ongoing N Mild N Discontinued at Day

28, treatment of

event since Day 28

History of supraventricular systoles. ECG screening:

normal, ECG day 1: APC ectopy 1 and 6 h post-dose,

ECG day 15: AF pre- and post-dose; ECG day 36: AF.

Event treated with acetylsalicylic acid 325 mg qd.

3

(46/F/Ca)

Palpitations 1 1 N Mild Y None No cardiac history. Normal ECGs with exception of one

single APC ectopy (palpitation) at day 1, 1 h post-dose.

Received active study drug to Day 82 and placebo to

Day 112.

4

(44/M/Ca)

Angina pectoris 33 2 N Moderate N Discontinued after

Day 34

History of pleural fibrosis. At screening sinus

bradycardia.

Day 1 pre-dose: 1st

degree AV block and sinus

bradycardia.

Day 16: AV block and sinus bradycardia and day 43 only

sinus bradycardia.

Pericarditis 37 Ongoing Y Moderate N Hospitalised at Day

37

History of pleural fibrosis (since 2005). Patient started

study drug on 13 Dec 2012. On 15 Jan 2013 (Day 34)

the medication was withdrawn. On evening of 18 Jan

2013, he experienced thoracic pain with breathing. He

was hospitalised at the same day. AF was observed on

ECG and patient diagnosed with pericarditis. CRP was

65 on 20 Jan 2013, decreasing to 27 d on 21 Jan 2013.

Treatment included colchicine, ibuprofen and

nitrospray. The patient completely recovered on 9 Feb

2013.


5

(37/F/As)

Ventricular

extrasystoles

(newly

occurring)

85 5 N Moderate N None No cardiac history. Normal ECGs at baseline and until

day 85. Day 85 VPC ectopies pre- and post-dose

together with flat T waves. End of study visit ECG

normal.


Day 113.

6

(58/M/As)

Tachycardia 105 1 N Mild N None No cardiac history. All ECGs normal except one sinus

tachycardia at day 1, 3 h post-dose. Event occurred

during wash-out period.


Day 111.

7 Supraventricular 1 1 N Mild N None No cardiac history. ECG screening normal. Day 1 flat T

(35/F/Oth) extrasystoles

(newly

occurring)

waves and APC ectopy 1 h post-dose. Day 16 one single

APC ectopy pre-dose and day 85 one single APC ectopy

6 h post-dose. End of study visit normal.


Day 112.


8

(42/M/As)

Palpitations 3 26 N Mild N None No cardiac history. ECG screening: 1st

degree AV block

continues in all ECG taken until day 84. End of study

visit normal.


Day 112.

9

(63/M/Ca)

Ventricular

extrasystoles

(newly

occurring)

12 20 N Mild N None History of hypertension. ECG screening normal. Day 1

APC ectopy 1 h post-dose. Day 12 and day 83 VPC

ectopy 1 h and 3 h post-dose. End of study visit normal.


Day 109.

Fevipiprant 3 mg qd

10

(44/F/Oth)

Tachycardia 4 1 N Moderate Y Study drug

adjusted/interrupted

on from Day 4–8

No cardiac history. ECG all normal.


Day 112.

Fevipiprant 150 mg bid

11

(19/F/Ca)

Ventricular

extrasystoles

(recurrent),

16 Ongoing N Moderate N Discontinued on Day

30

No cardiac history. ECG screening: VPC ectopy

continues until Day 36.

mitral valve

prolapse


12

(34/M/Ca)

Tachycardia 97 1 N Mild N None No cardiac history. All ECGs normal. Event occurred

during wash-out period.

Received active study drug to Day 82 and placebo to Day

109.

13

(41/F/Ca)

Palpitations 1 85 N Moderate Y None No cardiac history. All ECGs normal with exception of

two sinus bradycardias on day 14 pre-dose and day 84 3

h post-dose.


107.


14

(62/M/Ca)

Right bundle

branch block

-14* 128 N Mild N None Pre-existing event which continued on study. Patient

completed study on Day 113. Event occurred in

screening period.


112.

Placebo

15

(55/F/Ca)

Angina pectoris 83 1 N Mild N Treatment of event History of hypertension. All ECGs normal. Event treated

with glyceryl trinitrate 0.5 mg qd.

Received the last dose of study drug on Day 112.

APC, atrial premature complexes; AV, atrioventricular; CRP, C-reactive protein; ECG, electrocardiogram; SAE, serious adverse event; VPC, ventricular

premature complex

No cardiac events were reported in the fevipiprant 1 mg qd, 30 mg qd, 25 mg bid, 75 mg qd, 150 mg qd, 300 mg bid, and montelukast treatment groups.

*Started prior to start of study

Table S9. Deaths, other serious or clinically significant adverse events or related discontinuations –n (%) of patients (safety set)

Placebo

(n=136)

n (%)

Fevipiprant

Low-dose*

(n=201)

n (%)

Fevipiprant

mid-dose†

(n=219)

n (%)

Fevipiprant

high-dose‡

(n=212)

n (%)

Fevipiprant

450 mg qd

(n=133)

n (%)

Fevipiprant

total§

(n=765)

n (%)

Montelukast

10 mg qd

(n=133)

n (%)

Patients with serious or other significant events 27 (19.9) 28 (13.9) 28 (12.8) 33 (15.6) 19 (14.3) 108 (14.1) 11 (8.3)

Patients who died 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Patients with at least one SAE 2 (1.5) 4 (2.0) 4 (1.8) 2 (0.9) 3 (2.3) 13 (1.7) 1 (0.8)

Patients with at least one clinically-significant AE 26 (19.1) 27 (13.4) 25 (11.4) 32 (15.1) 18 (13.5) 102 (13.3) 10 (7.5)

Patients who discontinued from study due to AE 16 (11.8) 12 (6.0) 16 (7.3) 18 (8.5) 14 (10.5) 60 (7.8) 5 (3.8)

Discontinued from study due to SAEs 1 (0.7) 1 (0.5) 2 (0.9) 1 (0.5) 0 (0.0) 4 (0.5) 0 (0.0)

Discontinued from study due to non-serious AEs 15 (11.0) 11 (5.5) 14 (6.4) 17 (8.0) 14 (10.5) 56 (7.3) 5 (3.8)

Discontinued from study due to clinically-

significant AEs

13 (9.6) 10 (5.0) 8 (3.7) 13 (6.1) 10 (7.5) 41 (5.4) 4 (3.0)

AE, adverse event; SAE, serious adverse event

*Fevipiprant low-dose: Combination of 1 mg qd, 3 mg qd, 2 mg bid, 10 mg qd.

†Fevipiprant mid-dose: Combination of 30 mg qd, 50 mg qd, 25 mg bid, 75 mg qd.

‡Fevipiprant high-dose: Combination of 150 mg qd, 75 mg bid, 300 mg qd, 150 mg bid.

§Fevipiprant total: Combination of all fevipiprant doses.

Other clinically significant AEs comprised at least one of the following AEs: drug-related hepatic disorders, tachyarrhythmia (supraventricular and

ventricular tachyarrhythmias), cardiac failure, and MedDRA high level term “platelet analyses”.

Table S10. Difference from placebo in mean fractional exhaled nitic oxide levels after 12 weeks of

treatment with fevipiprant or montelukast

Treatment group Difference to placebo, ppb (95% CI) P value

Fevipiprant 1 mg qd 3.33 ( -4.75, 11.41) 0.4186


Fevipiprant 10 mg qd -0.53 ( -7.94, 6.88) 0.8880



Fevipiprant 75 mg qd -4.14 (-11.33, 3.06) 0.2589

Fevipiprant 150 mg qd -4.29 (-12.11, 3.52) 0.2813



Fevipiprant 2 mg bid -5.39 (-12.99, 2.21) 0.1643



Fevipiprant 150 mg bid 2.65 ( -4.54, 9.85) 0.4691

Montelukast 10 mg -2.72 ( -8.51, 3.07) 0.3571

CI, Confidence interval; ppb, parts per billion

P values are not adjusted for multiplicity.

All estimates are based on a linear mixed effects model with treatment and region as fixed effects,

centre nested within region as a random effect, and baseline FeNO as a covariate.

The baseline FeNO was defined as FeNO reported on Day 1.

SECTION 6. REFERENCES

1. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in

dose-response studies. Biometrics 2005: 61(3): 738-748.

2. Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding under model uncertainty

using general parametric models. Statistics in medicine 2014: 33(10): 1646-1661.

3. Bornkamp B. Viewpoint: model selection uncertainty, pre-specification, and model averaging.

Pharmaceutical statistics 2015: 14(2): 79-81.

4. Schorning K, Bornkamp B, Bretz F, Dette H. Model selection versus model averaging in dose

finding studies. Statistics in medicine 2016: 35(22): 4021-4040.

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