Trial synopsis 1241.2 DS DR - Boehringer Ingelheim...period at least 12 months prior to screening....

abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis ‐ which is part of the clinical study report ‐ had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non‐approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim.

Name of Company:

Boehringer Ingelheim Tabulated

Trial Report

ABCD

Synopsis No.:

Name of finished product:

Not applicable

EudraCT No.:

2007-004068-38

Name of active ingredient:

BI 207127 NA

Page:

2 of 7

Module:

Volume:

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Disclosure Synopsis date:

15 JUL 2015

Trial No. / U No.:

1241.2 / U10-4102-02

Dates of trial:

18 DEC 2007 – 01 DEC 2009

Date of revision:

26 NOV 2013

Proprietary confidential information 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.

This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

No. of subjects:

planned: entered: 72

actual: entered: 75

Patients without cirrhosis Treatment: 100 mg BI 207127 (Dose Group 1) entered: 9 treated: 9 analysed (for primary endpoint): 9

Treatment: 200 mg BI 207127 (Dose Group 2) entered: 9 treated: 9 analysed (for primary endpoint): 9


Treatment: 800 mg BI 207127: (Dose Group 4) entered: 9 treated: 9 analysed (for primary endpoint): 8

Treatment: 1200 mg BI 207127: (Dose Group 5) entered: 10 treated: 10 analysed (for primary endpoint): 8

Treatment: Placebo: (Dose Groups 1 to 5) entered: 15 treated: 14 analysed (for primary endpoint): 14

Patients with cirrhosis Treatment: 400 mg BI 207127 (Dose Group 6) entered: 8 treated: 8 analysed (for primary endpoint): 8


Diagnosis and main criteria for inclusion:

Inclusion criteria were chronic HCV GT1 and viral load >100000 IU/mL; male, or female with documented hysterectomy or menopause with last menstrual period at least 12 months prior to screening. Within 3 years prior to trial start, a liver biopsy with an Ishak (Metavir) score ≤2 was required in patients without cirrhosis. At any time prior to screening, a liver biopsy or Fibroscan consistent with liver cirrhosis was required for patients with cirrhosis. Evidence of decompensated liver disease in the previous 12 months was grounds for exclusion, as was therapy with interferon or pegylated interferon-α (PegIFN) and/or ribavirin (RBV) within 3 months prior to entry in the trial..

c03709900

Name of Company:


Trial Report

ABCD

Synopsis No.:


Not applicable

EudraCT No.:

2007-004068-38


BI 207127 NA

Page:

3 of 7

Module:

Volume:

{hyperlink }


15 JUL 2015

Trial No. / U No.:

1241.2 / U10-4102-02

Dates of trial:

18 DEC 2007 – 01 DEC 2009

Date of revision:

26 NOV 2013



Test product: BI 207127 NA as tablet

dose: 2x50 mg (Dose Group 1); 200 mg (Dose Group 2); 2x200 mg (Dose Groups 3 and 6); 4x200 mg (Dose Group 4); 6x200 mg (Dose Group 5); 3x200 mg (Dose Group 7); each dose given 3 times daily (every 8 h)

mode of admin.: Oral, taken with 240 mL water after a meal

batch no.: B073000489 (50 mg); B073000490 (200 mg)

Reference therapy: Placebo as tablet

dose: Not applicable

mode of admin.: Oral, taken with 240 mL water after a meal

batch no.: B073000587 (matching 50 mg test product); B073000588 (matching 200 mg test product)

Duration of treatment: 5 days (4 days of 3 times daily dosing and morning dose on Day 5)

Criteria for evaluation:

Efficacy

Clinical pharmacology:

The primary efficacy endpoint was virologic response (VR), defined as a ≥1 log10 reduction in serum HCV RNA level from baseline at any time up to Day 5. The secondary efficacy endpoint was determination of the time-dependent change in viral load (VL) up to Day 7. VL was determined by the Roche Taqman reverse transcriptase-polymerase chain reaction quantitative assay.

Secondary endpoints were the determination of pharmacokinetic parameters Cmax, Cmin, tmax, AUCτ, Cmax,ss, tmax,ss, Cmin,ss, AUCτ,ss, AUC0-∞,ss, λz,ss, t1/2,ss, CL/F,ss, and Vz/F,ss.

Safety: Safety was monitored through recording of adverse events (AEs), physical examination, vital signs, 12-lead ECG, and safety laboratory tests including urine protein diagnostics, and adrenocorticotripic hormone (ACTH) and cortisol measurements. Global tolerability was assessed by the investigator.

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Name of Company:


Trial Report

ABCD

Synopsis No.:


Not applicable

EudraCT No.:

2007-004068-38


BI 207127 NA

Page:

4 of 7

Module:

Volume:

{hyperlink }


15 JUL 2015

Trial No. / U No.:

1241.2 / U10-4102-02

Dates of trial:

18 DEC 2007 – 01 DEC 2009

Date of revision:

26 NOV 2013



Statistical methods: Descriptive statistics for efficacy, safety and PK endpoints were calculated. The proportion of patients fulfilling response criteria (≥1 log10 decrease in VL) was calculated, along with the corresponding confidence interval based on the Beta function. Dose proportionality of BI 207127 was explored using a regression model. A 95% confidence interval for the slope was computed. The attainment of steady state drug levels and the relationship between VL and pharmacokinetic parameters were explored.

SUMMARY – CONCLUSIONS:

Efficacy results:

In total, 73 patients were randomised and treated with BI 207127 or placebo (60 patients without cirrhosis and 13 patients with cirrhosis), and 70 were included in the analysis of the primary endpoint. All patients but 2 were of white race. The majority of participants were male (58 patients). HCV subgenotype profiles did not differ substantially between TN and TE patients in patients without cirrhosis. However, the group of patients with cirrhosis included a higher proportion infected with genotype 1b (GT1b).

The number of patients meeting the primary endpoint (VR through Day 5) varied directly with dose of BI 207127, with 100% of patients at the highest dose levels (1200 mg for patients without cirrhosis, and 600 mg for patients with cirrhosis) achieving a VL reduction of ≥1 log10. Assessment of the time-dependent change in VL up to Day 7 indicated a rapid initial VL reduction in all patients who responded to BI 207127 treatment. The viral load level did not increase more than 1 log10 within the 24 h after the last treatment was completed, and there was no evidence of a rebound effect in the mean VL measurements for any dose level. There was no noticeable difference in VL reduction when comparing patients with and without cirrhosis. For placebo-treated patients, no noteworthy mean change in VL was seen.

Multivariate analysis clearly indicated that log10(dose) of BI 207127 must be included in any model that predicts treatment response. Genotype was also shown to correspond with response; a less-robust anti-HCV effect of BI 207127 was observed in patients infected with GT1a relative to those with GT1b.

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Name of Company:


Trial Report

ABCD

Synopsis No.:


Not applicable

EudraCT No.:

2007-004068-38


BI 207127 NA

Page:

5 of 7

Module:

Volume:

{hyperlink }


15 JUL 2015

Trial No. / U No.:

1241.2 / U10-4102-02

Dates of trial:

18 DEC 2007 – 01 DEC 2009

Date of revision:

26 NOV 2013



Clinical pharmacology results:

For all dose levels, steady-state was by 24 h, as trough plasma concentrations of BI 207127 remained constant from this time onward. The terminal half-life (t1/2)

was short in patients without cirrhosis (median values of 3.6 to 5.1 h), and only slightly longer (5.4 to 6.0 h) in patients with cirrhosis. With all dose groups included, exposure at steady state relative to single dose ranged between 113 to 296% (AUC) and from 108 to 228% (Cmax). Exposure increased with dose: for patients without cirrhosis, gMean values of AUCτ,ss ranged from 1930 ng*h/ml at the 100 mg dose level to 88500 ng*h/ml at the 1200 mg dose level. For patients with cirrhosis treated at the highest dose level of 600 mg, gMean AUCτ,ss was 86400 ng*h/ml.

Pharmacokinetic (PK) data indicated a strong inverse relationship between oral clearance and exposure. In patients without cirrhosis treated at dose levels between 100 and 1200 mg, exposure to BI 207127 was supraproportional with respect to dose, with the exponent beta ranged from 1.4 to 1.6 for all exposure parameters evaluated. For patients with cirrhosis, plasma exposure to BI 207127 at steady state at the same dose level (400 mg) was approximately 2-fold higher than in patients without cirrhosis.

There was overall a great deal of variability in PK exposure indices of BI 207127 (gCVs between 27 to 118%) and VL decreases (SD from 0.45 to 1.25 log10). Therefore, no overall PK/pharmacodynamic relationship was observed in the dose range of 100 to 1200 mg for patients without cirrhosis. However, for AUC exposures from 0 and 8 h of less than 20000 ng*h/mL (corresponding to a dose level between 400 mg and 800 mg), some correlation between exposure and VL was seen. For patients with cirrhosis, no noticeable correlation was observed between VL and plasma exposure to BI 207127 for the first 24 h of the study or for the overall 5-day treatment period.

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Name of Company:


Trial Report

ABCD

Synopsis No.:


Not applicable

EudraCT No.:

2007-004068-38


BI 207127 NA

Page:

6 of 7

Module:

Volume:

{hyperlink }


15 JUL 2015

Trial No. / U No.:

1241.2 / U10-4102-02

Dates of trial:

18 DEC 2007 – 01 DEC 2009

Date of revision:

26 NOV 2013



Safety results: Of the 73 patients entered in the trial, all received at least 1 dose of trial medication or placebo and were included in the analysis of safety. Overall, 3 patients (4.1%) were removed from the trial as a result of AEs.

For patients without cirrhosis, during administration of BI 207127, 27 of 46 patients (58.7%) reported AEs, which were considered by the investigator to be related to treatment in 22 patients (47.8%). The overall incidence of AEs appeared to correlate with dose. During BI 207127 treatment, 1 SAE (moderate drug eruption) was reported for a patient treated at the 800 mg dose level. This SAE was considered to be treatment-related and led to removal of the patient from the trial. One other AE leading to discontinuation of treatment (suspected QT prolongation, considered related to treatment) was reported for 1 patient treated at the 400 mg dose level, for a total discontinuation rate of 2 of 46 patients treated with BI 207127 (4.3%). During administration of placebo, 4 of 14 patients (28.6%) reported AEs, which were considered as related to treatment in 3 patients (21.4%).

All patients with cirrhosis received active treatment with BI 207127. During administration of BI 207127, 9 of 13 patients (69.2%) reported AEs, and in 8 patients (61.5%), AEs were considered by the investigator as related to treatment. It was unclear whether AE incidence correlated with dose. For 1 of 13 patients (7.7%), an AE (suspected QT interval prolongation, considered treatment-related) was reported that led to discontinuation of trial medication. No AEs of severe intensity or SAEs were reported for patients with cirrhosis.

The most common category of on-treatment AE associated with administration of BI 207127 was gastrointestinal (GI) disorders. For all actively treated patients (with or without cirrhosis), 24 of 59 patients (40.7%) reported 1 or more AEs in this category; a higher incidence of GI events was observed in patients receiving higher doses. Patients treated with placebo reported GI disorders at a substantially lower rate (2 of 14 patients, 14.3%). Nervous system disorders were the second most common category of treatment-emergent AEs, with 13 of 59 patients treated with BI 207127 (22.0%) reporting AEs. However, the overall rates were similar for placebo-treated patients (3 of 14, 21.4%). At the highest dose level of 1200 mg, preferred terms (PTs) hyperaesthesia or paraesthesia were reported for 5 of 10 patients (50.0%). These PTs were not reported by patients at any other dose level or the placebo group.

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Name of Company:


Trial Report

ABCD

Synopsis No.:


Not applicable

EudraCT No.:

2007-004068-38


BI 207127 NA

Page:

7 of 7

Module:

Volume:

{hyperlink }


15 JUL 2015

Trial No. / U No.:

1241.2 / U10-4102-02

Dates of trial:

18 DEC 2007 – 01 DEC 2009

Date of revision:

26 NOV 2013



Safety results (continued):

Skin and subcutaneous tissue disorders were frequently reported for patients treated with BI 207127. Overall, during the on-treatment phase of the trial, a total of 9 out of the 59 actively-treated patients (15.3%) reported an AE in this category. No skin or subcutaneous tissue AEs were reported by patients receiving placebo. The incidence of skin and subcutaneous tissue disorders corresponded to dose of BI 207127.

For 2 the actively-treated patients for whom suspected QT interval prolongations were reported, later reassessment of the automated on-site ECG by the core EGC lab indicated no substantial QT interval prolongation for either patient. No relevant mean QT interval prolongation was seen for actively-treated patients, and there did not appear to be a correlation of QT interval changes with dose of BI 207127. Thus, there is no indication at this point that QT prolongation is associated with BI 207127 treatment.

Clinical laboratory evaluation did not indicate any substantial differences in ACTH levels for patients treated with BI 207127 relative to those treated with placebo, and no notable changes in cortisol concentrations.

Conclusions: BI 207127 was demonstrated to be effective in patients with or without cirrhosis infected with HCV genotype 1. At the highest dose levels administered, 100% of patients achieved VR.

Plasma exposure to BI 207127 was substantially higher for HCV-infected patients without cirrhosis relative to healthy subjects, and exposure was higher still for patients with cirrhosis. For HCV-infected patients, exposure was also supraproprotional with respect to dose.

Treatment with BI 207127 was well-tolerated by most patients. However, in contrast to previous trials in healthy volunteers, skin and subcutaneous tissue disorders were frequently reported for HCV-infected patients treated with BI 207127, including in one patient a drug eruption classified as an SAE. These safety findings indicate the need to closely monitor on-treatment emergence of skin and subcutaneous tissue disorders in future trials.

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Boehringer Ingelheim BI trial number 1241.0002 Trial Synopsis - Appendix

Trial Synopsis - Appendix

The appended tables on the following pages supplement the trial results presented in the Trial

Synopsis. They complement patient disposition results and results for primary and secondary

endpoints results for the trial. The number of secondary endpoints defined for this trial was

too large to allow meaningful presentation in this format; therefore, not all results for

secondary endpoints are provided in the Trial Synopsis and the following tables.

Results for presented in

Patient disposition for non-cirrhotic patients Table 15.1.1: 1

Patient disposition for cirrhotic patients Table 15.1.1: 2

Virologic response up to day for non-cirrhotic patients (Primary Endpoint) Table 15.2.1.3: 2

Virologic response up to day for cirrhotic patients (Primary Endpoint) Table 15.2.2.1: 2

Change from baseline in viral load (Log10) up to day 7 for non-cirrhotic patients (Secondary EP)

Table 15.2.1.3: 4

Change from baseline in viral load (Log10) up to day 7 for cirrhotic patients (Secondary EP)

Table 15.2.2.1: 4

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Table 15.1.1: 1 Patient disposition − enrolled patients with Fibrosis

Disposition Placebo 100mg 200mg 400mg 800mg

Enrolled Not entered/randomised Entered/randomised 15 9 9 9 9 Not treated 1 0 0 0 0 Treated 14 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) NOT prematurely discontinued from trial medication 14 (100.0) 9 (100.0) 9 (100.0) 8 ( 88.9) 8 ( 88.9) Prematurely discontinued from trial medication 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 11.1) 1 ( 11.1) Adverse events 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 11.1) 1 ( 11.1) Worsening of disease/condition under study 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Worsening of other pre−existing disease/condition 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 11.1) 0 ( 0.0) Other adverse event 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 11.1) Non compliant with protocol 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Lost to follow−up 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Consent withdrawn (not due to AE) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Other 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Source data: Appendix 16.2.1, Listing 2, 3, Appendix 16.2.3, Listing 1 safety\disp.sas 01SEP2010

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1. - 15. CTR Main Part

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Table 15.1.1: 1 Patient disposition − enrolled patients with Fibrosis

Disposition 1200mg Total

Enrolled 90 Not entered/randomised 29 Entered/randomised 10 61 Not treated 0 1 Treated 10 (100.0) 60 (100.0) NOT prematurely discontinued from trial medication 10 (100.0) 58 ( 96.7) Prematurely discontinued from trial medication 0 ( 0.0) 2 ( 3.3) Adverse events 0 ( 0.0) 2 ( 3.3) Worsening of disease/condition under study 0 ( 0.0) 0 ( 0.0) Worsening of other pre−existing disease/condition 0 ( 0.0) 1 ( 1.7) Other adverse event 0 ( 0.0) 1 ( 1.7) Non compliant with protocol 0 ( 0.0) 0 ( 0.0) Lost to follow−up 0 ( 0.0) 0 ( 0.0) Consent withdrawn (not due to AE) 0 ( 0.0) 0 ( 0.0) Other 0 ( 0.0) 0 ( 0.0)


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Table 15.1.1: 2 Patient disposition − enrolled patients with Cirrhosis CLASS A

Disposition 400mg 600mg Total

Enrolled 16 Not entered/randomised 2 Entered/randomised 8 6 14 Not treated 0 1 1 Treated 8 (100.0) 5 (100.0) 13 (100.0) NOT prematurely discontinued from trial medication 7 ( 87.5) 5 (100.0) 12 ( 92.3) Prematurely discontinued from trial medication 1 ( 12.5) 0 ( 0.0) 1 ( 7.7) Adverse events 1 ( 12.5) 0 ( 0.0) 1 ( 7.7) Worsening of disease/condition under study 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Worsening of other pre−existing disease/condition 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Other adverse event 1 ( 12.5) 0 ( 0.0) 1 ( 7.7) Non compliant with protocol 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Lost to follow−up 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Consent withdrawn (not due to AE) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Other 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)


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Table 15.2.1.3: 2 Summary of maximal reduction in viral load (log10 IU/mL) within 5 days of treatment with BI207127 monotherapy, Fibrosis patients − FAS

Endpoint Placebo 100mg 200mg 400mg

Number of patients 14 9 9 9

Maximum decrease in log10 VL upto 96 hrs Mean −0.333 −0.728 −1.550 −2.005 Median −0.215 −0.544 −1.064 −1.636 Min − Max −0.993 − −0.013 −2.040 − −0.106 −3.519 − −0.393 −3.935 − −0.782 Q1 − Q3 −0.445 − −0.135 −1.020 − −0.276 −2.571 − −0.725 −3.052 − −1.099 SD 0.294 0.641 1.178 1.187

Maximum decrease in log10 VL upto day 6 Mean −0.424 −0.816 −1.595 −2.023 Median −0.231 −0.721 −1.064 −1.636 Min − Max −1.701 − −0.013 −2.091 − −0.146 −3.519 − −0.572 −3.935 − −0.823 Q1 − Q3 −0.538 − −0.196 −1.043 − −0.379 −2.659 − −0.789 −3.164 − −1.099 SD 0.451 0.618 1.154 1.193

Decrease of VL by >= 1 log10 step # responders 2 2 5 8 % responders 14.3 22.2 55.6 88.9 95% C.I. LL−UL* 4 − 40 7 − 56 26 − 81 55 − 97




* Bounds for the C.I. calculated using the Beta function

Source data: Appendix 16.2.3, Listing 1, Appendix 16.2.4, Listing 1.1, Appendix 16.2.6, Listing 3 efficacy\viral_ci.sas 01SEP2010

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Table 15.2.1.3: 2 Summary of maximal reduction in viral load (log10 IU/mL) within 5 days of treatment with BI207127 monotherapy, Fibrosis patients − FAS

Endpoint 600mg 800mg 1200mg

Number of patients 0 9 10

Maximum decrease in log10 VL upto 96 hrs Mean −3.242 −3.135 Median −3.829 −3.284 Min − Max −4.227 − −0.905 −4.056 − −1.939 Q1 − Q3 −4.099 − −2.605 −3.527 − −2.657 SD 1.200 0.645

Maximum decrease in log10 VL upto day 6 Mean −3.400 −3.234 Median −4.025 −3.369 Min − Max −4.569 − −0.950 −4.234 − −1.939 Q1 − Q3 −4.163 − −2.784 −3.697 − −2.680 SD 1.249 0.683

Decrease of VL by >= 1 log10 step # responders 8 10 % responders 88.9 100.0 95% C.I. LL−UL* 55 − 97 76 − 100






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Table 15.2.2.1: 2 Summary of maximal reduction in viral load (log10 IU/mL) within 5 days of treatment with BI207127 monotherapy, Cirrhosis CLASS A − FAS

Endpoint Placebo 100mg 200mg 400mg

Number of patients 0 0 0 8

Maximum decrease in log10 VL upto 96 hrs Mean −2.702 Median −3.006 Min − Max −3.759 − −0.862 Q1 − Q3 −3.317 − −2.175 SD 0.935

Maximum decrease in log10 VL upto day 6 Mean −2.857 Median −3.225 Min − Max −4.212 − −0.862 Q1 − Q3 −3.492 − −2.175 SD 1.065

Decrease of VL by >= 1 log10 step # responders 7 % responders 87.5 95% C.I. LL−UL* 52 − 97






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Table 15.2.2.1: 2 Summary of maximal reduction in viral load (log10 IU/mL) within 5 days of treatment with BI207127 monotherapy, Cirrhosis CLASS A − FAS

Endpoint 600mg 800mg 1200mg

Number of patients 5 0 0

Maximum decrease in log10 VL upto 96 hrs Mean −3.270 Median −3.241 Min − Max −3.829 − −2.379 Q1 − Q3 −3.762 − −3.137 SD 0.585

Maximum decrease in log10 VL upto day 6 Mean −3.437 Median −3.360 Min − Max −4.288 − −2.379 Q1 − Q3 −3.829 − −3.329 SD 0.710







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Table 15.2.1.3: 4 Descriptive statistics for HCV RNA (Log10) change from baseline by visit, Fibrosis patients − FAS

Planned Visit time Placebo 100mg 200mg 400mg 600mg 800mg 1200mg

Total N 14 9 9 9 0 9 10 Treated

VISIT 2_2 −0:05 N 14 8 9 9 0 9 10 Mean 0.00 0.00 0.00 0.00 0.00 0.00 SD 0.00 0.00 0.00 0.00 0.00 0.00 SE 0.000 0.000 0.000 0.000 0.000 0.000 95% CI mean (lower) 95% CI mean (upper) Min 0.0 0.0 0.0 0.0 0.0 0.0 Median 0.00 0.00 0.00 0.00 0.00 0.00 Max 0.0 0.0 0.0 0.0 0.0 0.0

2:00 N 14 8 9 9 0 8 10 Mean −0.01 −0.03 −0.06 −0.13 0.05 0.03 SD 0.15 0.15 0.26 0.11 0.25 0.11 SE 0.040 0.052 0.087 0.037 0.087 0.034 95% CI mean (lower) −0.10 −0.15 −0.26 −0.21 −0.16 −0.05 95% CI mean (upper) 0.07 0.10 0.14 −0.04 0.25 0.10 Min −0.3 −0.3 −0.4 −0.3 −0.1 −0.2 Median −0.02 −0.01 −0.02 −0.14 −0.04 0.06 Max 0.2 0.1 0.5 0.0 0.6 0.2

4:00 N 14 8 9 9 0 9 10 Mean −0.11 −0.02 −0.16 −0.25 −0.26 −0.15 SD 0.09 0.21 0.18 0.17 0.17 0.20 SE 0.024 0.074 0.059 0.057 0.057 0.064 95% CI mean (lower) −0.16 −0.19 −0.30 −0.38 −0.39 −0.30 95% CI mean (upper) −0.05 0.16 −0.02 −0.12 −0.12 −0.01 Min −0.3 −0.4 −0.5 −0.6 −0.5 −0.5 Median −0.09 0.06 −0.15 −0.26 −0.29 −0.16 Max −0.0 0.2 0.1 0.0 −0.1 0.1

Source data: Appendix 16.2.3, Listing 1, Appendix 16.2.4, Listing 1.1, Appendix 16.2.6, Listing 2 efficacy\viral_ds.sas 01SEP2010

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VISIT 2_2 7:55 N 14 8 9 9 0 9 9 Mean −0.16 −0.33 −0.53 −0.96 −1.41 −1.11 SD 0.37 0.37 0.60 0.51 0.53 0.51 SE 0.098 0.133 0.199 0.169 0.176 0.172 95% CI mean (lower) −0.37 −0.64 −0.99 −1.35 −1.82 −1.51 95% CI mean (upper) 0.05 −0.02 −0.07 −0.57 −1.01 −0.72 Min −1.0 −0.8 −1.6 −1.7 −1.9 −2.1 Median −0.06 −0.27 −0.47 −0.86 −1.62 −1.16 Max 0.4 0.1 0.5 −0.3 −0.4 −0.3

10:00 N 14 8 9 9 0 9 10 Mean −0.06 −0.55 −0.80 −1.21 −1.82 −1.59 SD 0.19 0.49 0.59 0.60 0.59 0.54 SE 0.050 0.172 0.197 0.201 0.198 0.172 95% CI mean (lower) −0.17 −0.95 −1.25 −1.67 −2.28 −1.98 95% CI mean (upper) 0.05 −0.14 −0.34 −0.75 −1.36 −1.20 Min −0.4 −1.3 −1.9 −2.0 −2.7 −2.3 Median −0.03 −0.53 −0.70 −1.20 −1.91 −1.63 Max 0.4 0.0 −0.1 −0.5 −0.8 −0.8

15:55 N 14 8 9 9 0 9 10 Mean −0.00 −0.53 −0.96 −1.66 −2.40 −2.31 SD 0.19 0.57 0.78 0.96 0.76 0.57 SE 0.051 0.200 0.261 0.321 0.254 0.179 95% CI mean (lower) −0.11 −1.01 −1.56 −2.40 −2.99 −2.71 95% CI mean (upper) 0.11 −0.06 −0.36 −0.93 −1.82 −1.90 Min −0.4 −1.6 −2.6 −2.9 −3.3 −3.3 Median −0.00 −0.41 −0.76 −1.64 −2.66 −2.36 Max 0.4 0.0 −0.2 −0.3 −0.9 −1.4

18:00 N 14 8 9 9 0 9 10 Mean −0.01 −0.43 −0.94 −1.64 −2.51 −2.40 SD 0.18 0.55 0.69 0.96 0.86 0.63 SE 0.047 0.193 0.229 0.320 0.288 0.200 95% CI mean (lower) −0.11 −0.88 −1.47 −2.38 −3.17 −2.85 95% CI mean (upper) 0.09 0.03 −0.41 −0.91 −1.84 −1.95 Min −0.3 −1.5 −2.3 −3.1 −3.4 −3.4 Median −0.00 −0.31 −0.89 −1.46 −2.88 −2.32 Max 0.4 0.1 −0.3 −0.4 −0.8 −1.4


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c03709900



VISIT 3 23:55 N 14 8 9 9 0 9 10 Mean 0.01 −0.53 −0.93 −1.67 −2.46 −2.45 SD 0.17 0.64 0.82 1.02 1.04 0.83 SE 0.045 0.225 0.274 0.340 0.346 0.261 95% CI mean (lower) −0.09 −1.06 −1.56 −2.46 −3.26 −3.04 95% CI mean (upper) 0.11 0.01 −0.29 −0.89 −1.67 −1.86 Min −0.2 −1.7 −2.4 −3.3 −3.5 −3.6 Median −0.03 −0.39 −0.73 −1.38 −2.88 −2.61 Max 0.4 0.1 −0.1 −0.5 −0.7 −1.1

VISIT 4 47:55 N 13 7 9 9 0 9 10 Mean −0.01 −0.46 −1.14 −1.79 −3.00 −3.01 SD 0.18 0.65 1.26 1.25 1.14 0.59 SE 0.049 0.246 0.421 0.416 0.380 0.187 95% CI mean (lower) −0.11 −1.06 −2.11 −2.75 −3.88 −3.44 95% CI mean (upper) 0.10 0.15 −0.17 −0.83 −2.13 −2.59 Min −0.2 −1.8 −3.5 −3.8 −4.0 −3.7 Median −0.01 −0.12 −0.72 −1.03 −3.56 −3.02 Max 0.4 −0.1 −0.1 −0.7 −0.9 −1.9

VISIT 5 71:55 N 14 8 9 8 0 9 10 Mean −0.06 −0.50 −1.16 −1.84 −3.02 −2.97 SD 0.16 0.65 0.92 1.43 1.30 0.82 SE 0.044 0.229 0.306 0.504 0.433 0.258 95% CI mean (lower) −0.15 −1.05 −1.87 −3.04 −4.02 −3.56 95% CI mean (upper) 0.04 0.04 −0.46 −0.65 −2.02 −2.39 Min −0.4 −2.0 −2.8 −3.9 −4.2 −3.9 Median −0.07 −0.32 −0.94 −1.32 −3.61 −3.21 Max 0.3 0.0 −0.1 −0.3 −0.6 −1.3

VISIT 6 95:55 N 14 8 9 8 0 9 10 Mean −0.04 −0.61 −1.07 −1.87 −3.11 −2.94 SD 0.27 0.65 0.94 1.33 1.23 0.83 SE 0.073 0.231 0.313 0.470 0.408 0.261 95% CI mean (lower) −0.19 −1.16 −1.79 −2.98 −4.05 −3.53 95% CI mean (upper) 0.12 −0.07 −0.34 −0.75 −2.17 −2.35 Min −0.5 −2.0 −2.6 −3.7 −4.1 −4.1 Median −0.03 −0.41 −0.81 −1.31 −3.81 −3.21 Max 0.4 −0.1 0.0 −0.5 −0.6 −1.4


Page BI Trial No.:



c03709900



VISIT 6 98:00 N 14 8 9 8 0 9 10 Mean −0.08 −0.66 −1.08 −1.93 −3.17 −3.01 SD 0.26 0.65 0.89 1.29 1.29 0.77 SE 0.069 0.230 0.297 0.456 0.430 0.245 95% CI mean (lower) −0.23 −1.21 −1.77 −3.01 −4.16 −3.57 95% CI mean (upper) 0.07 −0.12 −0.39 −0.85 −2.18 −2.46 Min −0.7 −2.0 −2.6 −3.8 −4.1 −4.2 Median −0.03 −0.54 −0.68 −1.50 −3.94 −3.14 Max 0.3 −0.1 −0.1 −0.6 −0.5 −1.6

100:00 N 14 8 9 8 0 8 10 Mean −0.17 −0.60 −1.05 −1.94 −3.06 −3.02 SD 0.24 0.58 0.80 1.24 1.40 0.78 SE 0.063 0.207 0.268 0.438 0.494 0.245 95% CI mean (lower) −0.30 −1.09 −1.66 −2.98 −4.23 −3.57 95% CI mean (upper) −0.03 −0.11 −0.43 −0.91 −1.89 −2.46 Min −0.7 −1.8 −2.4 −3.7 −4.2 −4.0 Median −0.13 −0.49 −0.69 −1.42 −3.70 −3.22 Max 0.3 0.0 −0.2 −0.7 −0.7 −1.5

104:00 N 13 8 9 8 0 8 10 Mean −0.07 −0.77 −1.08 −1.96 −3.27 −3.11 SD 0.19 0.63 0.92 1.25 1.30 0.82 SE 0.053 0.221 0.307 0.442 0.458 0.260 95% CI mean (lower) −0.18 −1.29 −1.79 −3.00 −4.36 −3.70 95% CI mean (upper) 0.05 −0.24 −0.37 −0.91 −2.19 −2.52 Min −0.4 −2.1 −2.6 −3.8 −4.6 −4.2 Median −0.08 −0.67 −0.85 −1.37 −3.88 −3.34 Max 0.3 −0.0 0.0 −0.7 −0.9 −1.5

108:00 N 14 8 9 8 0 8 10 Mean −0.06 −0.56 −0.90 −1.80 −3.11 −3.03 SD 0.20 0.53 1.01 1.25 1.20 0.83 SE 0.052 0.186 0.337 0.441 0.425 0.261 95% CI mean (lower) −0.17 −1.00 −1.68 −2.85 −4.12 −3.62 95% CI mean (upper) 0.05 −0.12 −0.12 −0.76 −2.11 −2.43 Min −0.4 −1.7 −2.7 −3.6 −4.2 −4.1 Median −0.07 −0.49 −0.50 −1.13 −3.69 −3.32 Max 0.3 −0.1 0.1 −0.7 −0.9 −1.6


Page BI Trial No.:



c03709900



VISIT 6 112:00 N 14 8 9 8 0 8 10 Mean −0.03 −0.56 −0.87 −1.64 −2.98 −2.91 SD 0.18 0.50 0.85 1.35 1.30 0.90 SE 0.048 0.175 0.283 0.477 0.460 0.285 95% CI mean (lower) −0.14 −0.97 −1.53 −2.77 −4.06 −3.56 95% CI mean (upper) 0.07 −0.14 −0.22 −0.51 −1.89 −2.27 Min −0.2 −1.6 −2.4 −3.4 −4.3 −4.1 Median −0.08 −0.48 −0.65 −0.92 −3.36 −3.27 Max 0.5 0.1 0.2 −0.5 −0.9 −1.5

VISIT 7 120:00 N 14 8 9 8 0 8 10 Mean −0.14 −0.37 −0.70 −1.47 −2.82 −2.64 SD 0.50 0.41 0.68 1.29 1.40 1.07 SE 0.133 0.145 0.226 0.455 0.495 0.337 95% CI mean (lower) −0.42 −0.71 −1.22 −2.55 −3.99 −3.41 95% CI mean (upper) 0.15 −0.03 −0.17 −0.39 −1.65 −1.88 Min −1.7 −1.2 −1.9 −3.2 −4.3 −4.0 Median −0.03 −0.38 −0.67 −1.00 −3.19 −2.95 Max 0.4 0.1 0.2 −0.2 −0.6 −0.8

VISIT 8 144:00 N 14 8 9 8 0 6 10 Mean 0.02 −0.19 −0.40 −0.76 −1.88 −1.61 SD 0.76 0.38 0.93 1.07 1.64 0.87 SE 0.203 0.133 0.311 0.378 0.669 0.276 95% CI mean (lower) −0.41 −0.50 −1.12 −1.65 −3.60 −2.23 95% CI mean (upper) 0.46 0.13 0.32 0.14 −0.17 −0.98 Min −1.9 −0.7 −2.7 −2.2 −3.8 −2.8 Median −0.04 −0.11 −0.06 −0.43 −2.15 −1.57 Max 1.8 0.2 0.3 0.4 0.0 −0.0

EOT 312:00 N 6 5 7 4 0 2 2 Mean −0.15 −0.03 −0.11 −0.21 −0.35 −0.28 SD 0.25 0.13 0.70 0.23 0.64 0.17 SE 0.101 0.058 0.263 0.114 0.454 0.118 95% CI mean (lower) −0.41 −0.19 −0.76 −0.57 −6.12 −1.77 95% CI mean (upper) 0.11 0.13 0.53 0.16 5.41 1.22 Min −0.5 −0.2 −0.8 −0.5 −0.8 −0.4 Median −0.11 −0.08 −0.24 −0.18 −0.35 −0.28 Max 0.2 0.2 1.2 0.0 0.1 −0.2


Page BI Trial No.:



c03709900

Table 15.2.2.1: 4 Descriptive statistics for HCV RNA (Log10) change from baseline by visit, Cirrhosis CLASS A − FAS


Total N 0 0 0 8 5 0 0 Treated

VISIT 2_2 −0:05 N 0 0 0 8 5 0 0 Mean 0.00 0.00 SD 0.00 0.00 SE 0.000 0.000 95% CI mean (lower) 95% CI mean (upper) Min 0.0 0.0 Median 0.00 0.00 Max 0.0 0.0

2:00 N 0 0 0 8 5 0 0 Mean 0.09 −0.01 SD 0.10 0.16 SE 0.035 0.071 95% CI mean (lower) 0.01 −0.21 95% CI mean (upper) 0.17 0.18 Min −0.0 −0.2 Median 0.10 −0.06 Max 0.2 0.2

4:00 N 0 0 0 8 5 0 0 Mean −0.07 −0.03 SD 0.22 0.34 SE 0.077 0.151 95% CI mean (lower) −0.25 −0.45 95% CI mean (upper) 0.11 0.39 Min −0.5 −0.5 Median −0.03 0.07 Max 0.2 0.4


Page BI Trial No.:



c03709900



VISIT 2_2 7:55 N 0 0 0 8 5 0 0 Mean −0.90 −1.05 SD 0.53 0.30 SE 0.188 0.136 95% CI mean (lower) −1.34 −1.43 95% CI mean (upper) −0.46 −0.67 Min −1.5 −1.3 Median −0.96 −1.12 Max −0.2 −0.5

10:00 N 0 0 0 8 5 0 0 Mean −1.26 −1.57 SD 0.53 0.56 SE 0.188 0.251 95% CI mean (lower) −1.70 −2.26 95% CI mean (upper) −0.81 −0.87 Min −1.9 −2.3 Median −1.33 −1.53 Max −0.6 −0.8




Page BI Trial No.:



c03709900



VISIT 3 23:55 N 0 0 0 7 5 0 0 Mean −2.03 −2.75 SD 0.79 0.77 SE 0.299 0.342 95% CI mean (lower) −2.76 −3.70 95% CI mean (upper) −1.29 −1.80 Min −2.8 −3.6 Median −2.30 −2.96 Max −0.6 −1.7





Page BI Trial No.:



c03709900





104:00 N 0 0 0 0 0 0 0 Mean SD SE 95% CI mean (lower) 95% CI mean (upper) Min Median Max



Page BI Trial No.:



c03709900





VISIT 8 144:00 N 0 0 0 0 1 0 0 Mean −2.93 SD SE 95% CI mean (lower) 95% CI mean (upper) Min −2.9 Median −2.93 Max −2.9

EOT 312:00 N 0 0 0 1 0 0 0 Mean −0.06 SD SE 95% CI mean (lower) 95% CI mean (upper) Min −0.1 Median −0.06 Max −0.1


Page BI Trial No.:



c03709900

Trial synopsis 1241.2 DS DR - Boehringer Ingelheim...period at least 12 months prior to screening....

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Transcript of Trial synopsis 1241.2 DS DR - Boehringer Ingelheim...period at least 12 months prior to screening....