trial synopsis 1199.31 ds dr - boehringer ingelheim · pdf fileabcd clinical study synopsis...

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

Name of active ingredient:

BIBF 1120

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Disclosure Synopsis date:

10 NOV 2014

Trial No. / U No.:

1199.31/ U11- 2158-01

Date of trial:

31 MAY 2010 – 30 MAR 2011

Date of revision :

Not applicable

Proprietary confidential information © 2011 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

Methodology: Double-blind (within a dose group), placebo-controlled, multiple rising dose. Stratified according to pirfenidone use in each treatment group (cohort).

No. of patients:

planned: To be entered: 46 patients

actual: Enrolled: 66 patients; entered: 50 patients

BIBF 1120 50 mg b.i.d. dose group (Cohort 1)

Entered, 9; treated, 9; analysed (for safety and pharmacokinetics), 9


Entered, 9; treated, 9; analysed (for safety and pharmacokinetics), 9


Entered, 32; treated, 32; analysed (for safety), 32;

analysed (for pharmacokinetics), 27

Diagnosis and main Diagnosis of IPF according to Japan Respiratory Society (JRS) guideline criteria for inclusion:

Forced vital capacity (FVC) ≥50%, diffusing capacity for carbon monoxide (DLCO) 30-79%

For patients on pirfenidone, treatment with a steady dose (1800 mg/day) for at least 3 months was required. Only for the 150 mg b.i.d. dose group, low dose pirfenidone users (controlled with 1200 mg/day or 600 mg/day) for at least 3 months were allowed to participate.

Test product: BIBF 1120

dose: 50 mg twice a day (b.i.d.), 100 mg b.i.d., 150 mg b.i.d.

mode of admin.: Oral

batch no.: 1376210001 for 50 mg; 1377520001 for 100 mg; 1377530001 for 150 mg

Reference therapy: Placebo

dose: Not applicable

mode of admin.: Oral

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Name of company:


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Not applicable


BIBF 1120

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31 MAY 2010 – 30 MAR 2011

Date of revision :

Not applicable



batch no.: 1391800001 for 50 mg; 1373980001 for 100 mg; 1374010001 for 150 mg

Duration of treatment: 14 days (50 mg b.i.d. and 100 mg b.i.d. dose groups) and 28 days (150 mg b.i.d. dose group)

Criteria for evaluation:

Clinical Individual plasma concentration time profiles for BIBF 1120 after the first dose pharmacology: and at steady state, and the derived pharmacokinetic parameters (Cmax, tmax,

AUC0-24, Cmax,ss, tmax,ss, AUCτ,ss, t1/2,ss, MRTpo,ss, CL/F,ss, and Vz/F,ss)

Individual plasma concentration time profiles for pirfenidone at steady state without administration of BIBF 1120 and at steady state after 2 weeks and 4 weeks of concomitant BIBF 1120, and the derived pharmacokinetic parameters (Cmax,ss, tmax,ss, AUCss, and t1/2,ss)

Safety: Adverse events (AEs), physical examination, vital signs, laboratory data, and lung function

Statistical methods: Descriptive statistics

SUMMARY – CONCLUSIONS:

In this trial, a total of 50 patients were randomly assigned to the treatment. Of the50 patients, 35 (70.0%) patients were male and 15 (30.0%) patients were female. The mean (standard deviation [±SD)] age was 65.2 ± 8.2 years. The treated set included 6 patients on BIBF 1120 50 mg b.i.d. (the BIBF 1120 50 mg b.i.d. group), 8 patients on BIBF 1120 100 mg b.i.d. (the BIBF 1120 100 mg b.i.d. group), 24 patients on BIBF 1120 150 mg b.i.d. (the BIBF 1120 150 mg b.i.d. group), and 12 patients on placebo (the placebo group).

Clinical pharmacology BIBF 1120 and its metabolites: results:

In BIBF 1120 alone administration groups, the plasma concentrations of BIBF 1120 BS reached a maximum at 2 to 4 hours post dose, after multiple oral administrations. The geometric mean (gMean) of terminal half-life at the steady state was 23.4 to 27.5 hours. The accumulation ratios of BIBF 1120 BS based on Cmax and AUC0-12 were 1.12 to 1.52 and 1.53 to 1.95 in the BIBF 1120 100 mg and 150 mg b.i.d groups. The gMean values of Cmax,ss and AUCτ,ss tended to be lower in pirfenidone co-administration groups than those in BIBF 1120 alone

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Not applicable



Clinical pharmacology administration groups in the BIBF 1120 100 mg and 150 mg b.i.d. groups (factorresults: of 0.592 to 0.690 for Cmax,ss and 0.683 to 0.748 for AUCτ,ss). (continued)

Table 1 Comparison of PK parameters of BIBF 1120 BS, BIBF 1202 ZW, and BIBF 1202 glucuronide after oral administration of BIBF 1120 with and without co-administration of 600 mg t.i.d. pirfenidone.

PK Parameter

Pirfenidone co-administration

BIBF 1120 dose 50 mg 100 mg 150 mg

NgMean

(gCV%) NgMean

(gCV%) N gMean

(gCV%)BIBF 1120 BSAUCτ,ss

(h*ng/mL) - 2 33.7 (165) 4 115

(32.4) 9 218

(58.3)

+ 4 67.9 (16.7) 3 86.0

(62.7) 7 149

(18.0) Cmaxss (ng/mL) - 2 9.09

(173) 4 20.0

(64.5) 9 39.7

(68.1)

+ 4 10.9 (50.3)

3 13.8 (113)

7 23.5 (27.2)

BIBF 1202 ZWAUCτ,ss

(h*ng/mL) - 0 133 (NC) 4 161

(42.6) 9 237

(63.0)

+ 4 43.0 (29.2)

3 77.2 (53.9)

7 118 (27.8)

Cmax, ss (ng/mL) - 2 6.47

(415) 4 24.0

(88.8) 9 33.2

(72.5)

+ 4 5.01 (26.5)

3 9.12 (52.2)

7 15.4 (36.4)

BIBF 1202 glucuronideAUCτ,ss

(h*ng/mL) - 2 318 (47.7)

4 835 (44.2)

9 1380 (38.1)

+ 4 216

(49.5) 3 720

(34.9) 7 1100

(80.4) Cmax,ss (ng/mL) - 2 29.9

(49.3) 4 90.5

(69.5) 9 128

(37.6)

+ 4 20.2 (45.6)

3 71.1 (33.1)

7 107 (81.2)

Note: NC=not calculated because only 1 subject was available; N=number of patients (without/ with pirfenidone) −: without pirfenidone co-administration +: with pirfenidone co-administration

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Clinical pharmacology In BIBF 1120 alone administration groups, the plasma concentrations of BIBF results: 1202 ZW reached a maximum at 3 to 4 hours post dose after multiple oral (continued) administrations. The gMean of terminal half-life at the steady state was

approximately 23 hours. The gMean of Cmax,ss and AUCτ,ss tended to be lower in pirfenidone co-administration groups than those in BIBF 1120 alone administration groups in the BIBF 1120 100 mg and 150 mg b.i.d. groups (factor of 0.380 to 0.464 for Cmax,ss and 0.480 to 0.498 for AUCτ,ss). In BIBF 1120 alone administration groups, the plasma concentrations of BIBF 1202 glucuronide reached a maximum at 0.8 to 4 hours post dose after multiple oral administrations. The gMean of terminal half-life at the steady state was approximately 46 to 56 hours. The gMean values of Cmax,ss and AUCτ,ss tended to be lower in pirfenidone co-administration groups than those in BIBF 1120 alone administration groups in the BIBF 1120 100 mg and 150 mg b.i.d. groups (factor of 0.786 to 0.836 for Cmax,ss and 0.797 to 0.862 for AUCτ,ss).

The results of visual inspection indicated that Cmax and AUCs of BIBF 1120 BS, BIBF 1202 ZW, and BIBF 1202 glucuronide in both BIBF 1120 alone administration groups and pirfenidone co-administration groups increased dose- proportionally within the dose range investigated (50 mg to 150 mg b.i.d.).

BIBF 1120 BS was considered to reach steady state by Day 7 (144 hours after the first administration) in both BIBF 1120 alone administration groups and pirfenidone co-administration groups, based on visual inspection. Pirfenidone:

Under pirfenidone alone administration, the plasma concentration of pirfenidone reached a maximum at 1 to 1.6 hours post dose after breakfast and 1 to 2 hours post dose after lunch. The gMean of terminal half-life at the steady state was approximately 3 to 4 hours.

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Clinical pharmacology No relevant effect on the pharmacokinetics of pirfenidone was observed byresults: BIBF 1120 co-administration. (continued)

Table 2 Comparison of pharmacokinetic parameters of pirfenidone after oral administration of 600 mg t.i.d. pirfenidone with and without co-administration of BIBF 1120

PK Parameter

BIBF 1120 co-administration

BIBF 1120 dose 50 mg 100 mg 150 mg

NgMean

(gCV%) NgMean

(gCV%) N gMean

(gCV%)Post dose after breakfastAUC0-4,ss

(h*ng/mL) - 4 34400 (36.3)

3 45800 (26.6)

9 32500 (21.2)

+ 4 34300

(39.9) 3 35000

(32.2) 7 35900

(21.8) Cmax,ss (ng/mL) - 4 11900

(28.9) 4 14600

(41.5) 9 11200

(26.6)

+ 4 12800 (44.3)

3 15300 (51.1)

8 12600 (27.2)

Post dose after lunchAUC0-8,ss

(h*ng/mL) - 4 72800 (40.7)

3 84100 (11.4)

8 60900 (22.9)

+ 4 71000

(40.8) 3 71500

(19.1) 6 63600

(27.7) Cmax,ss (ng/mL) - 4 14600

(20.9) 4 15100

(19.5) 9 12900

(30.2)

+ 4 12000 (37.3)

3 12100 (10.7)

8 12500 (23.0)

N=number of patients (without/with BIBF 1120 co-administration) −: without BIBF 1120 co-administration +: with BIBF 1120 co-administration

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Safety results: Of the 50 patients, 23 (46.0%) patients experienced at least 1 AE: none (0.0%) of

(continued) the 6 patients in the BIBF 1120 50 mg b.i.d. group; 4 (50.0%) of the 8 patients in the BIBF 1120 100 mg b.i.d. group; 15 (62.5%) of the 24 patients in the BIBF 1120 150 mg b.i.d. group; and 4 (33.3%) patients in the placebo group.

Drug-related AEs assessed by the investigator were reported for 13 (26.0%) patients and AEs leading to discontinuation of study medication were experienced by 4 (8.0%) patients.

A serious adverse event was reported for 1 (2.0%) patient, which occurred after completing study medication in the follow-up period. No death occurred.

As expected from the profile of BIBF 1120, AEs classified as gastrointestinal disorders and investigations occurred at a higher incidence in the BIBF 1120 150 mg b.i.d. group: 11 (45.8%) patients experienced gastrointestinal disorders and 3 (12.5%) patients AEs classified as investigations. In gastrointestinal disorders, nausea, vomiting, and diarrhoea were reported frequently and they were experienced only by the patients in the BIBF 1120 150 mg b.i.d. group: 5 (20.8%) patients for nausea, 5 (20.8%) patients for vomiting, and 4 (16.7%) patients for diarrhoea.

AEs in investigations were experienced by 3 (6.0%) patients in total and only observed in the BIBF 1120 150 mg b.i.d. group. The AEs included increased alanine aminotransferase (ALT) (2 [8.3%] patients), increased aspartate aminotransferase (AST) (2 [8.3%] patients), increased blood creatine phosphokinase (CPK) (1 [4.2%] patient), increased gamma-glutamyltransferase (GGT) (1 [4.2%] patient) without pirfenidone, and increased transaminases (1 [4.2%] patient) with pirfenidone.

In the BIBF 1120 150 mg b.i.d. group, 24 patients (9 with pirfenidone 1800 mg/day, 2 with pirfenidone 600 mg/day, 2 with pirfenidone 1200 mg/day, and 11 without pirfenidone) received BIBF 1120. AEs classified as gastrointestinal

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Safety Results: disorders and liver transaminases increase on preferred term levels reported in (continued) more than 1 patient were nausea (5 [20.8%] patients [4 with pirfenidone and 1

without pirfenidone]), vomiting (5 [20.8%] patients [5 with pirfenidone and none without pirfenidone]), diarrhoea (4 [16.7%] patients [2 with pirfenidone and none without pirfenidone]), diarrhoea (4 [16.7%] patients [2 with pirfenidone and 2 without pirfenidone]), ALT increase (2 [8.3%] patients [2 without pirfenidone]), AST increase (2 [8.3%] patients [2 without pirfenidone]).

Overall, patients with pirfenidone experienced nausea and vomiting more frequently than those without pirfenidone, whereas frequency and intensity of AEs in liver transaminases increases did not show any particular difference between with and without pirfenidone background. Analysis in the changes in clinical laboratory parameters also supports this finding.

Changes in blood pressure and pulse rate were occasionally noted during the treatment period, but no tendency of consistent change attributed to study mediation was found, nor was there any dose dependent change.

Respiratory function represented by FVC changes over time by treatment and DLCO changes over time remained stable by the administration of BIBF 1120 for 2 weeks (the BIBF 1120 50 mg and 100 mg b.i.d. groups) or 4 weeks (the BIBF 1120 150 mg b.i.d. group), and tests conducted 1 week after the last administration of study medication revealed no rebounds (rapid respiratory function decrease).

In summary, BIBF 1120 50 mg b.i.d. and 100 mg b.i.d. were well tolerated in the 2-week treatment. With BIBF 1120 150 mg b.i.d., gastrointestinal disorders and increases of ALT and AST were frequently reported as known drug-related AEs of BIBF 1120 in the 4-week treatment and patients with pirfenidone (when added on top of BIBF 1120 150 mg b.i.d.) experienced nausea and vomiting more frequently than those without pirfenidone, whereas frequency and intensity of liver transaminases increase did not show any particular difference between with and without pirfenidone background. Gastrointestinal disorders and increase of liver transaminases are known drug-related AEs of BIBF 1120, which are returned to normal by discontinuing administration and are thus considered manageable.

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Conclusions: The exposure (Cmax and AUC) to BIBF 1120 BS and its metabolites tended to be lower in pirfenidone co-administration groups than in BIBF 1120 alone administration groups, but the distributions of values overlapped between BIBF 1120 alone and pirfenidone co-administration. Co-administration of BIBF 1120 had no significant effect on the pharmacokinetics of pirfenidone.

Tolerability of BIBF 1120 administered to Japanese patients with IPF was good for 50 mg b.i.d. (2 weeks) and 100 mg b.i.d. (2 weeks) and was acceptable for 150 mg b.i.d. (4 weeks). No specific concerns were found for the safety and tolerability of BIBF 1120 150 mg b.i.d. administered for 4 weeks regardless of co-administration with pirfenidone except nausea and vomiting, which were reported more frequently in patients on BIBF 1120 150 mg b.i.d. co-administred with pirfenidone than those on BIBF 1120 150 mg b.i.d. alone. The results of this trial would support conducting a long-term clinical trial of BIBF 1120 150 mg b.i.d. in Japanese patients with IPF in the future.

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Trial Synopsis - Appendix

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

synopsis. They complement disposition results, primary and secondary endpoints of the trial,

and safety information.

Results for presented in

Patient Disposition Table 15.1.1: 1

AEs Summarized by Pirfenidone Background (Primary and Secondary EP) Table 15.3.2: 2

Blood Pressure, Pulse Rate, and Change From Baseline Through Day 35 Regardless of Pirfenidone Background (Secondary EP)

Table 15.3.4: 1

Summary of Lung Functions including FEV1, FVC, %FVC, DLCO, and %DLCO Summarized by Pirfenidone Background From Baseline Through Day 35 (Secondary EP)

Table 15.3.4: 3

AE Summary Regardless of Pirfenidone Background Table 15.3.2: 1

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Table 15.1.1: 1 Disposition of patients

__________________________________________________________________________________________________________________________________ Placebo BIBF 50 mg BIBF 100 mg BIBF 150 mg Total

Enrolled 66 Not entered/randomised 16 Entered/randomised 12 6 8 24 50 Not treated 0 0 0 0 0 Treated 12( 100.0) 6( 100.0) 8( 100.0) 24( 100.0) 50( 100.0)

Not prematurely discontinued from trial medication 12( 100.0) 6( 100.0) 8( 100.0) 20( 83.3) 46( 92.0)

Prematurely discontinued from trial medication 0( 0.0) 0( 0.0) 0( 0.0) 4( 16.7) 4( 8.0) Adverse event 0( 0.0) 0( 0.0) 0( 0.0) 4( 16.7) 4( 8.0) Worsening of disease under study 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) Worsening of other pre−existing disease 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) Other adverse event 0( 0.0) 0( 0.0) 0( 0.0) 4( 16.7) 4( 8.0) 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) Refused to continue taking trial medication 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 3 ctr15\disp.sas 17MAY2011

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Table 15.3.2: 2 Adverse event overall summary by pirfenidone background − treated set

Treatment analysis: On−treatment,total

Pirfenidone background: No_________________________________________________________________________________________________________________________ Placebo BIBF 50 mg BIBF 100 mg BIBF 150 mg Total N (%) N (%) N (%) N (%) N (%)_________________________________________________________________________________________________________________________

Number of patients 7 (100.0) 2 (100.0) 4 (100.0) 11 (100.0) 24 (100.0)

Patients with any AE 2 ( 28.6) 0 ( 0.0) 3 ( 75.0) 6 ( 54.5) 11 ( 45.8)

Patients with severe AEs 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Patients with investigator defined drug−related 1 ( 14.3) 0 ( 0.0) 1 ( 25.0) 3 ( 27.3) 5 ( 20.8)AEs

Patients with other significant AEs (according to 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 2 ( 18.2) 2 ( 8.3)ICH E3)

Patients with AEs leading to discontinuation of 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 2 ( 18.2) 2 ( 8.3)trial drug

Patients with serious AEs 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 9.1) 1 ( 4.2) Fatal 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Imm life−threatening 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Disability/incap. 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Req.hospitalisation 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Prol.hospitalisation 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Congenital anomaly 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) 1 ( 9.1) 1 ( 4.2)_________________________________________________________________________________________________________________________

A patient may be counted in more than one seriousness criterion.Percentages are calculated using total number of patients per treatment as the denominator.MedDRA version used for reporting: 13.1

Source data: Appendix 16.2.7, Listing 4 ctr15\ae1s.sas 17MAY2011

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Table 15.3.2: 2 Adverse event overall summary by pirfenidone background − treated set


Pirfenidone background: Yes_________________________________________________________________________________________________________________________ Placebo BIBF 50 mg BIBF 100 mg BIBF 150 mg Total N (%) N (%) N (%) N (%) N (%)_________________________________________________________________________________________________________________________









Source data: Appendix 16.2.7, Listing 4 ctr15\ae1s.sas 17MAY2011

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Table 15.3.4: 1 Blood pressure, pulse rate and change from baseline over time − treated set

___________________________________________________________________________________________________________________________________

Placebo (N=12) BIBF 50 mg (N=6) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− N Mean SD Min Median Max N Mean SD Min Median Max___________________________________________________________________________________________________________________________________

Diastolic blood pressure [mmHg] Baseline 12 78.5 13.2 62 77 100 6 64.3 17.2 53 59 99 Day 2 12 78.0 10.3 62 80 94 6 72.5 8.2 60 74 80 Day 7 12 76.8 12.1 55 80 94 6 77.3 13.7 65 76 102 Day 14 12 77.1 10.5 60 80 96 6 65.2 14.3 46 65 88 Day 21 12 75.8 10.2 55 80 87 6 69.2 12.4 53 70 90 Day 28 8 78.1 12.3 53 78 91 0 Day 35 8 78.8 8.7 64 81 88 0 Change from baseline at Day 2 12 −0.5 11.6 −23 −1 23 6 8.2 14.4 −19 11 20 Change from baseline at Day 7 12 −1.7 13.5 −21 −2 30 6 13.0 8.4 3 15 21 Change from baseline at Day 14 12 −1.4 11.4 −19 0 19 6 0.8 10.8 −14 5 12 Change from baseline at Day 21 12 −2.7 12.8 −26 −1 17 6 4.8 8.1 −9 7 13 Change from baseline at Day 28 8 −0.1 11.2 −10 −4 19 0 Change from baseline at Day 35 8 0.5 13.3 −19 2 20 0

___________________________________________________________________________________________________________________________________

Source data: Appendix 16.2.8, Listing 3 ctr15\phys.sas 17MAY2011

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BIBF 100 mg (N=8) BIBF 150 mg (N=24) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− N Mean SD Min Median Max N Mean SD Min Median Max___________________________________________________________________________________________________________________________________

Diastolic blood pressure [mmHg] Baseline 8 75.3 13.8 60 73 92 24 76.6 14.3 52 79 106 Day 2 8 73.9 9.7 58 78 84 24 75.7 15.7 46 77 106 Day 7 8 68.9 4.8 62 70 77 23 75.4 13.9 54 75 108 Day 14 8 69.5 6.4 56 71 77 22 77.8 13.6 45 79 101 Day 21 8 78.4 8.8 66 81 90 21 77.1 14.5 54 78 105 Day 28 0 20 76.9 15.2 53 76 113 Day 35 0 24 75.8 13.9 52 75 105 Change from baseline at Day 2 8 −1.4 14.8 −30 1 20 24 −0.9 13.3 −24 −3 28 Change from baseline at Day 7 8 −6.4 14.4 −26 −5 17 23 −1.0 10.9 −22 −1 18 Change from baseline at Day 14 8 −5.8 15.0 −23 −9 17 22 1.5 10.5 −22 3 32 Change from baseline at Day 21 8 3.1 13.4 −22 5 19 21 0.9 9.1 −26 2 14 Change from baseline at Day 28 0 20 0.4 11.1 −19 0 30 Change from baseline at Day 35 0 24 −0.8 10.8 −24 1 23

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Pulse rate [bpm] Baseline 12 80.9 12.0 66 79 100 6 69.0 11.6 62 65 92 Day 2 12 74.5 8.6 58 74 86 6 68.5 7.3 62 67 82 Day 7 12 73.1 11.6 53 75 88 6 75.0 5.7 70 74 86 Day 14 12 71.3 10.3 56 73 88 6 71.2 12.4 60 66 92 Day 21 12 79.9 10.8 60 82 96 6 74.0 5.1 68 75 81 Day 28 8 77.0 13.0 64 74 101 0 Day 35 8 80.6 16.2 60 85 101 0 Change from baseline at Day 2 12 −6.4 14.1 −29 −5 20 6 −0.5 13.2 −22 0 19 Change from baseline at Day 7 12 −7.8 17.1 −43 2 6 6 6.0 12.5 −17 10 19 Change from baseline at Day 14 12 −9.7 15.3 −40 −6 8 6 2.2 17.1 −24 −1 24 Change from baseline at Day 21 12 −1.0 13.4 −27 5 14 6 5.0 9.0 −11 8 14 Change from baseline at Day 28 8 −6.1 15.3 −23 −6 21 0 Change from baseline at Day 35 8 −2.5 15.4 −27 −4 21 0

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Pulse rate [bpm] Baseline 8 70.5 15.9 53 67 98 24 79.0 17.0 56 78 127 Day 2 8 73.6 13.3 50 74 93 24 79.8 13.9 46 81 103 Day 7 8 74.9 8.1 66 75 92 23 80.4 14.7 52 80 105 Day 14 8 73.6 12.4 58 73 94 22 80.5 13.6 58 78 104 Day 21 8 74.8 10.0 55 77 84 21 79.6 15.0 54 76 107 Day 28 0 19 72.6 14.2 46 76 94 Day 35 0 24 80.9 15.4 50 82 107 Change from baseline at Day 2 8 3.1 14.9 −26 4 23 24 0.8 16.1 −37 2 41 Change from baseline at Day 7 8 4.4 13.5 −24 4 24 23 2.3 11.8 −34 3 19 Change from baseline at Day 14 8 3.1 13.2 −12 1 31 22 2.8 11.1 −29 3 18 Change from baseline at Day 21 8 4.3 10.3 −16 8 14 21 3.2 14.8 −43 2 22 Change from baseline at Day 28 0 19 −4.9 14.3 −38 −3 16 Change from baseline at Day 35 0 24 1.9 13.6 −37 2 26

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Systolic blood pressure [mmHg] Baseline 12 129.0 19.6 98 129 170 6 118.7 20.0 102 109 147 Day 2 12 124.1 14.0 98 123 148 6 120.2 9.6 105 124 130 Day 7 12 126.4 20.5 74 126 152 6 130.7 13.6 113 135 148 Day 14 12 125.8 16.7 98 127 162 6 112.8 20.1 90 108 148 Day 21 12 126.9 16.2 90 132 146 6 120.7 17.0 93 125 140 Day 28 8 118.3 11.1 97 120 137 0 Day 35 8 127.8 16.9 101 132 149 0 Change from baseline at Day 2 12 −4.9 15.0 −35 −6 28 6 1.5 18.3 −23 5 25 Change from baseline at Day 7 12 −2.6 22.4 −46 3 32 6 12.0 22.6 −28 20 33 Change from baseline at Day 14 12 −3.3 7.5 −18 −1 10 6 −5.8 19.4 −39 −2 17 Change from baseline at Day 21 12 −2.1 17.2 −32 −1 36 6 2.0 13.6 −10 −1 25 Change from baseline at Day 28 8 −8.3 17.9 −33 −8 27 0 Change from baseline at Day 35 8 1.3 19.2 −28 5 34 0

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Systolic blood pressure [mmHg] Baseline 8 129.5 22.5 106 125 176 24 121.7 18.2 96 118 163 Day 2 8 127.0 23.7 100 124 166 24 120.8 15.7 92 123 151 Day 7 8 122.5 19.7 104 116 157 23 126.0 17.7 93 126 164 Day 14 8 126.4 14.4 108 121 152 22 125.8 17.3 98 123 157 Day 21 8 129.3 14.0 114 131 156 21 127.0 17.9 94 128 159 Day 28 0 20 123.6 17.7 99 120 167 Day 35 0 24 124.3 17.2 102 123 170 Change from baseline at Day 2 8 −2.5 18.0 −38 5 14 24 −0.9 19.7 −56 −1 26 Change from baseline at Day 7 8 −7.0 22.6 −48 −6 25 23 4.0 17.4 −32 4 40 Change from baseline at Day 14 8 −3.1 12.2 −24 1 10 22 5.0 18.1 −29 3 47 Change from baseline at Day 21 8 −0.3 17.4 −23 −2 30 21 6.8 17.2 −38 5 39 Change from baseline at Day 28 0 20 4.4 19.3 −33 1 56 Change from baseline at Day 35 0 24 2.5 14.4 −31 4 39

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Table 15.3.4: 3 FVC, %FVC, FEV1, DLco, %DLco and change from baseline over time − treated set stratified by pirfenidone background

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Pirfenidone background: No Placebo (N=7) BIBF 50 mg (N=2) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− N Mean SD Min Median Max N Mean SD Min Median Max___________________________________________________________________________________________________________________________________

DLCO [mL/min/mmHg] Baseline 7 11.029 2.791 7.16 11.800 14.97 2 14.100 0.707 13.60 14.100 14.60 Day 2 0 0 Day 7 0 0 Day 14 3 8.600 1.168 7.74 8.130 9.93 2 12.005 0.035 11.98 12.005 12.03 Day 21 3 8.873 1.695 7.89 7.900 10.83 2 11.905 2.567 10.09 11.905 13.72 Day 28 4 11.658 2.846 8.15 11.900 14.68 0 Day 35 4 10.808 3.293 7.57 10.845 13.97 0 Change from baseline at Day 2 0 0 Change from baseline at Day 7 0 0 Change from baseline at Day 14 3 −0.613 1.226 −1.87 −0.550 0.58 2 −2.095 0.742 −2.62 −2.095 −1.57 Change from baseline at Day 21 3 −0.340 0.940 −0.97 −0.790 0.74 2 −2.195 3.274 −4.51 −2.195 0.12 Change from baseline at Day 28 4 −0.733 0.751 −1.71 −0.600 −0.02 0 Change from baseline at Day 35 4 −1.583 1.793 −4.05 −1.245 0.21 0

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Source data: Appendix 16.2.8, Listing 4 ctr15\pulm.sas 17MAY2011

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Pirfenidone background: No BIBF 100 mg (N=4) BIBF 150 mg (N=11) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− N Mean SD Min Median Max N Mean SD Min Median Max___________________________________________________________________________________________________________________________________

DLCO [mL/min/mmHg] Baseline 4 11.015 4.706 5.74 10.865 16.59 11 9.476 3.091 5.71 9.270 17.26 Day 2 0 0 Day 7 0 0 Day 14 4 9.178 4.085 4.87 8.740 14.36 0 Day 21 4 10.068 3.976 6.79 9.075 15.33 0 Day 28 0 9 9.381 2.848 6.09 9.370 15.67 Day 35 0 11 9.142 2.640 5.54 9.100 15.30 Change from baseline at Day 2 0 0 Change from baseline at Day 7 0 0 Change from baseline at Day 14 4 −1.838 0.754 −2.60 −1.940 −0.87 0 Change from baseline at Day 21 4 −0.948 1.356 −1.85 −1.495 1.05 0 Change from baseline at Day 28 0 9 −0.297 1.174 −2.12 −0.270 1.98 Change from baseline at Day 35 0 11 −0.335 1.186 −1.96 −0.630 1.64

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DLCO % predicted [%] Baseline 7 57.321 12.515 38.01 57.369 72.39 2 78.736 1.947 77.36 78.736 80.11 Day 2 0 0 Day 7 0 0 Day 14 3 52.809 12.761 41.39 50.452 66.59 2 67.369 4.131 64.45 67.369 70.29 Day 21 3 53.603 10.597 42.57 54.549 63.70 2 67.133 17.235 54.95 67.133 79.32 Day 28 4 55.545 11.140 42.13 56.164 67.72 0 Day 35 4 52.285 10.668 39.49 52.293 65.07 0 Change from baseline at Day 2 0 0 Change from baseline at Day 7 0 0 Change from baseline at Day 14 3 −0.579 5.546 −6.92 1.799 3.38 2 −11.367 2.184 −12.91 −11.367 −9.82 Change from baseline at Day 21 3 0.215 3.857 −2.82 −1.090 4.56 2 −11.603 15.288 −22.41 −11.603 −0.79 Change from baseline at Day 28 4 −4.726 4.811 −11.57 −3.169 −1.00 0 Change from baseline at Day 35 4 −7.986 10.653 −22.76 −5.818 2.45 0

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DLCO % predicted [%] Baseline 4 59.093 21.085 32.22 62.927 78.30 11 52.659 10.369 36.71 50.923 70.08 Day 2 0 0 Day 7 0 0 Day 14 4 49.536 17.758 27.92 51.430 67.36 0 Day 21 4 54.473 15.785 39.72 52.805 72.56 0 Day 28 0 9 51.293 12.676 27.76 50.602 67.38 Day 35 0 10 54.384 10.482 36.16 53.027 67.78 Change from baseline at Day 2 0 0 Change from baseline at Day 7 0 0 Change from baseline at Day 14 4 −9.557 3.738 −13.05 −10.439 −4.30 0 Change from baseline at Day 21 4 −4.621 8.349 −10.52 −7.736 7.50 0 Change from baseline at Day 28 0 9 0.066 5.053 −8.95 −0.321 8.60 Change from baseline at Day 35 0 10 0.130 6.252 −7.36 −0.975 10.97

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FEV1 [L] Baseline 7 2.189 0.571 1.26 2.310 3.07 2 1.585 1.011 0.87 1.585 2.30 Day 2 7 2.197 0.573 1.30 2.320 3.13 2 1.595 0.926 0.94 1.595 2.25 Day 7 7 2.179 0.565 1.28 2.310 3.09 2 1.620 0.919 0.97 1.620 2.27 Day 14 7 2.183 0.575 1.27 2.180 3.13 2 1.570 0.962 0.89 1.570 2.25 Day 21 7 2.141 0.625 1.16 2.220 3.16 2 1.590 0.891 0.96 1.590 2.22 Day 28 4 2.448 0.389 2.17 2.300 3.02 0 Day 35 4 2.500 0.414 2.12 2.395 3.09 0 Change from baseline at Day 2 7 0.009 0.043 −0.07 0.020 0.06 2 0.010 0.085 −0.05 0.010 0.07 Change from baseline at Day 7 7 −0.010 0.056 −0.12 0.020 0.03 2 0.035 0.092 −0.03 0.035 0.10 Change from baseline at Day 14 7 −0.006 0.093 −0.16 0.010 0.09 2 −0.015 0.049 −0.05 −0.015 0.02 Change from baseline at Day 21 7 −0.047 0.096 −0.12 −0.100 0.09 2 0.005 0.120 −0.08 0.005 0.09 Change from baseline at Day 28 4 −0.058 0.025 −0.09 −0.055 −0.03 0 Change from baseline at Day 35 4 −0.005 0.100 −0.14 0.010 0.10 0

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FEV1 [L] Baseline 4 1.800 0.456 1.12 1.995 2.09 11 2.180 0.501 1.62 2.030 3.08 Day 2 4 1.778 0.462 1.09 1.965 2.09 11 2.193 0.529 1.62 2.060 3.17 Day 7 4 1.815 0.440 1.16 1.995 2.11 11 2.201 0.516 1.66 2.120 3.22 Day 14 4 1.815 0.490 1.08 2.045 2.09 11 2.186 0.495 1.63 2.000 3.17 Day 21 4 1.825 0.491 1.09 2.060 2.09 9 2.234 0.504 1.78 1.950 3.08 Day 28 0 9 2.224 0.572 1.63 1.900 3.26 Day 35 0 11 2.205 0.515 1.70 1.970 3.16 Change from baseline at Day 2 4 −0.023 0.082 −0.12 −0.025 0.08 11 0.013 0.070 −0.17 0.020 0.09 Change from baseline at Day 7 4 0.015 0.084 −0.10 0.030 0.10 11 0.021 0.077 −0.09 0.040 0.14 Change from baseline at Day 14 4 0.015 0.064 −0.04 0.010 0.08 11 0.006 0.116 −0.23 0.020 0.14 Change from baseline at Day 21 4 0.025 0.083 −0.06 0.025 0.11 9 −0.002 0.113 −0.21 0.000 0.20 Change from baseline at Day 28 0 9 −0.012 0.099 −0.13 −0.030 0.18 Change from baseline at Day 35 0 11 0.025 0.058 −0.07 0.030 0.09

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FVC [L] Baseline 7 2.590 0.739 1.56 2.620 3.55 2 1.900 0.990 1.20 1.900 2.60 Day 2 7 2.569 0.701 1.56 2.640 3.47 2 1.960 0.948 1.29 1.960 2.63 Day 7 7 2.537 0.692 1.54 2.630 3.41 2 1.970 0.933 1.31 1.970 2.63 Day 14 7 2.564 0.695 1.57 2.560 3.44 2 1.905 0.940 1.24 1.905 2.57 Day 21 7 2.511 0.750 1.41 2.600 3.41 2 1.870 0.849 1.27 1.870 2.47 Day 28 4 2.940 0.368 2.53 2.975 3.28 0 Day 35 4 2.975 0.440 2.44 3.045 3.37 0 Change from baseline at Day 2 7 −0.021 0.059 −0.12 0.000 0.03 2 0.060 0.042 0.03 0.060 0.09 Change from baseline at Day 7 7 −0.053 0.077 −0.14 −0.020 0.02 2 0.070 0.057 0.03 0.070 0.11 Change from baseline at Day 14 7 −0.026 0.061 −0.11 −0.030 0.07 2 0.005 0.049 −0.03 0.005 0.04 Change from baseline at Day 21 7 −0.079 0.068 −0.16 −0.050 −0.01 2 −0.030 0.141 −0.13 −0.030 0.07 Change from baseline at Day 28 4 −0.118 0.109 −0.27 −0.095 −0.01 0 Change from baseline at Day 35 4 −0.083 0.156 −0.25 −0.065 0.05 0

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FVC [L] Baseline 4 2.220 0.601 1.36 2.385 2.75 11 2.685 0.768 1.82 2.450 4.28 Day 2 4 2.178 0.652 1.28 2.295 2.84 11 2.711 0.750 1.88 2.450 4.20 Day 7 4 2.210 0.603 1.38 2.320 2.82 11 2.716 0.765 1.88 2.480 4.34 Day 14 4 2.220 0.619 1.32 2.415 2.73 11 2.701 0.755 1.89 2.520 4.26 Day 21 4 2.220 0.622 1.33 2.385 2.78 9 2.814 0.758 1.90 2.480 4.17 Day 28 0 9 2.803 0.786 1.86 2.410 4.26 Day 35 0 11 2.733 0.755 1.92 2.460 4.28 Change from baseline at Day 2 4 −0.043 0.092 −0.12 −0.070 0.09 11 0.026 0.091 −0.19 0.040 0.12 Change from baseline at Day 7 4 −0.010 0.115 −0.18 0.035 0.07 11 0.032 0.137 −0.30 0.060 0.18 Change from baseline at Day 14 4 0.000 0.043 −0.04 −0.010 0.06 11 0.016 0.161 −0.33 0.070 0.22 Change from baseline at Day 21 4 0.000 0.062 −0.07 0.000 0.07 9 0.023 0.122 −0.18 0.040 0.23 Change from baseline at Day 28 0 9 0.012 0.073 −0.12 0.020 0.14 Change from baseline at Day 35 0 11 0.048 0.085 −0.12 0.050 0.17

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FVC % predicted [%] Baseline 7 73.099 13.921 49.41 72.560 91.68 2 64.075 11.095 56.23 64.075 71.92 Day 2 7 72.557 12.855 49.98 73.390 88.37 2 66.595 8.704 60.44 66.595 72.75 Day 7 7 71.690 12.842 49.98 73.110 88.37 2 67.065 8.040 61.38 67.065 72.75 Day 14 7 72.480 12.868 51.41 70.610 90.85 2 64.595 9.185 58.10 64.595 71.09 Day 21 7 70.714 14.581 47.98 72.280 90.85 2 63.915 6.230 59.51 63.915 68.32 Day 28 4 78.340 8.540 68.06 78.190 88.92 0 Day 35 4 79.315 11.195 65.64 79.280 93.06 0 Change from baseline at Day 2 7 −0.541 1.580 −3.31 0.000 0.85 2 2.520 2.390 0.83 2.520 4.21 Change from baseline at Day 7 7 −1.409 1.998 −3.76 −0.820 0.57 2 2.990 3.055 0.83 2.990 5.15 Change from baseline at Day 14 7 −0.619 1.614 −2.64 −0.830 2.00 2 0.520 1.909 −0.83 0.520 1.87 Change from baseline at Day 21 7 −2.384 2.283 −6.19 −1.430 −0.28 2 −0.160 4.865 −3.60 −0.160 3.28 Change from baseline at Day 28 4 −2.990 2.577 −6.49 −2.590 −0.29 0 Change from baseline at Day 35 4 −2.015 3.966 −6.01 −1.730 1.41 0

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FVC % predicted [%] Baseline 4 73.665 15.588 57.84 74.300 88.22 11 79.015 19.956 46.91 76.880 114.04 Day 2 4 72.213 17.886 54.44 71.650 91.11 11 79.658 19.046 49.49 77.590 111.91 Day 7 4 73.750 17.734 58.16 73.185 90.47 11 79.942 19.954 48.46 75.000 115.64 Day 14 4 73.635 16.597 56.14 75.175 88.05 11 79.389 19.360 49.75 74.750 113.50 Day 21 4 73.785 17.433 56.57 74.695 89.18 9 79.350 21.688 48.98 72.620 111.11 Day 28 0 9 78.964 22.039 47.95 74.040 113.50 Day 35 0 11 80.408 19.541 49.49 79.310 114.04 Change from baseline at Day 2 4 −1.453 2.938 −3.40 −2.650 2.89 11 0.643 2.762 −6.39 1.210 3.06 Change from baseline at Day 7 4 0.085 3.185 −4.61 1.350 2.25 11 0.926 4.368 −10.09 1.630 6.49 Change from baseline at Day 14 4 −0.030 1.656 −1.70 −0.320 2.22 11 0.374 4.957 −11.10 1.980 6.42 Change from baseline at Day 21 4 0.120 2.035 −1.80 −0.155 2.59 9 0.770 3.287 −4.26 1.210 6.72 Change from baseline at Day 28 0 9 0.384 2.022 −2.84 0.510 4.09 Change from baseline at Day 35 0 11 1.393 2.497 −4.03 1.520 4.96

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Pirfenidone background: Yes Placebo (N=5) BIBF 50 mg (N=4) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− N Mean SD Min Median Max N Mean SD Min Median Max___________________________________________________________________________________________________________________________________

DLCO [mL/min/mmHg] Baseline 5 11.844 5.112 6.11 12.110 17.49 4 9.593 1.786 7.22 9.800 11.55 Day 2 0 0 Day 7 0 0 Day 14 1 10.830 10.83 10.830 10.83 4 8.328 1.306 6.69 8.370 9.88 Day 21 1 12.330 12.33 12.330 12.33 4 8.448 1.088 6.91 8.760 9.36 Day 28 4 10.900 6.638 3.52 10.955 18.17 0 Day 35 4 11.098 6.015 4.87 10.930 17.66 0 Change from baseline at Day 2 0 0 Change from baseline at Day 7 0 0 Change from baseline at Day 14 1 −1.280 −1.28 −1.280 −1.28 4 −1.265 0.529 −1.67 −1.430 −0.53 Change from baseline at Day 21 1 0.220 0.22 0.220 0.22 4 −1.145 0.837 −2.19 −1.040 −0.31 Change from baseline at Day 28 4 −0.878 1.538 −2.59 −0.800 0.68 0 Change from baseline at Day 35 4 −0.680 0.890 −1.63 −0.630 0.17 0

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Pirfenidone background: Yes BIBF 100 mg (N=4) BIBF 150 mg (N=13) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− N Mean SD Min Median Max N Mean SD Min Median Max___________________________________________________________________________________________________________________________________

DLCO [mL/min/mmHg] Baseline 4 9.135 0.976 8.25 8.925 10.44 13 9.159 4.724 4.10 7.730 22.67 Day 2 0 0 Day 7 0 0 Day 14 4 9.010 1.460 6.97 9.355 10.36 0 Day 21 4 8.390 1.355 7.18 8.155 10.07 0 Day 28 0 11 7.941 3.696 3.62 7.550 16.64 Day 35 0 13 8.137 3.156 4.28 7.390 13.72 Change from baseline at Day 2 0 0 Change from baseline at Day 7 0 0 Change from baseline at Day 14 4 −0.125 1.219 −1.58 −0.160 1.40 0 Change from baseline at Day 21 4 −0.745 0.469 −1.37 −0.620 −0.37 0 Change from baseline at Day 28 0 11 −1.842 2.228 −6.50 −0.930 0.09 Change from baseline at Day 35 0 13 −1.022 2.510 −8.95 −0.600 1.55

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DLCO % predicted [%] Baseline 5 61.805 16.133 40.76 63.227 77.35 4 62.392 8.065 51.24 64.008 70.32 Day 2 0 0 Day 7 0 0 Day 14 1 72.101 72.10 72.101 72.10 4 53.640 5.282 49.09 52.761 59.95 Day 21 1 82.762 82.76 82.762 82.76 4 54.800 4.400 50.70 54.494 59.51 Day 28 4 55.160 22.707 26.36 56.665 80.95 0 Day 35 4 56.584 17.525 36.57 55.673 78.42 0 Change from baseline at Day 2 0 0 Change from baseline at Day 7 0 0 Change from baseline at Day 14 1 −5.248 −5.25 −5.248 −5.25 4 −8.752 5.712 −15.68 −8.594 −2.15 Change from baseline at Day 21 1 5.413 5.41 5.413 5.41 4 −7.592 6.634 −13.73 −8.052 −0.53 Change from baseline at Day 28 4 −2.759 8.089 −14.40 −0.294 3.95 0 Change from baseline at Day 35 4 −1.335 2.663 −4.19 −1.286 1.42 0

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DLCO % predicted [%] Baseline 4 57.957 14.790 42.45 55.828 77.72 13 53.329 16.591 31.67 46.567 78.96 Day 2 0 0 Day 7 0 0 Day 14 4 57.475 13.695 44.02 54.935 76.01 0 Day 21 4 53.782 15.506 39.47 50.498 74.67 0 Day 28 0 11 47.583 16.413 28.65 41.675 77.63 Day 35 0 13 51.119 15.690 31.66 42.894 79.60 Change from baseline at Day 2 0 0 Change from baseline at Day 7 0 0 Change from baseline at Day 14 4 −0.482 7.352 −8.96 −0.957 8.94 0 Change from baseline at Day 21 4 −4.175 2.474 −7.88 −3.019 −2.78 0 Change from baseline at Day 28 0 11 −3.553 2.862 −8.46 −3.237 1.47 Change from baseline at Day 35 0 13 −2.210 5.741 −11.02 −3.708 9.44

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FEV1 [L] Baseline 5 2.270 0.613 1.28 2.470 2.91 4 1.985 0.261 1.62 2.040 2.24 Day 2 5 2.272 0.650 1.25 2.370 3.00 4 1.955 0.276 1.66 1.945 2.27 Day 7 5 2.306 0.586 1.35 2.340 2.90 4 1.958 0.284 1.58 1.990 2.27 Day 14 5 2.188 0.661 1.10 2.310 2.85 4 1.945 0.297 1.60 1.940 2.30 Day 21 5 2.260 0.676 1.13 2.390 2.91 4 1.963 0.295 1.58 1.985 2.30 Day 28 4 2.215 0.610 1.34 2.385 2.75 0 Day 35 4 2.170 0.755 1.10 2.355 2.87 0 Change from baseline at Day 2 5 0.002 0.075 −0.10 −0.010 0.09 4 −0.030 0.140 −0.24 0.035 0.05 Change from baseline at Day 7 5 0.036 0.109 −0.13 0.070 0.14 4 −0.028 0.039 −0.05 −0.045 0.03 Change from baseline at Day 14 5 −0.082 0.172 −0.31 −0.060 0.14 4 −0.040 0.112 −0.20 −0.010 0.06 Change from baseline at Day 21 5 −0.010 0.107 −0.15 0.000 0.11 4 −0.023 0.056 −0.06 −0.045 0.06 Change from baseline at Day 28 4 0.008 0.136 −0.16 0.015 0.16 0 Change from baseline at Day 35 4 −0.037 0.128 −0.18 −0.050 0.13 0

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FEV1 [L] Baseline 4 1.630 0.385 1.19 1.660 2.01 13 1.816 0.466 0.98 1.740 2.71 Day 2 4 1.675 0.390 1.25 1.685 2.08 13 1.846 0.474 1.09 1.770 2.75 Day 7 4 1.703 0.361 1.29 1.755 2.01 12 1.909 0.423 1.23 1.860 2.73 Day 14 4 1.638 0.377 1.20 1.675 2.00 11 1.935 0.441 1.29 1.880 2.77 Day 21 4 1.710 0.369 1.32 1.735 2.05 11 1.925 0.522 1.25 1.730 3.06 Day 28 0 11 1.905 0.439 1.23 1.840 2.80 Day 35 0 13 1.861 0.517 1.02 1.730 2.91 Change from baseline at Day 2 4 0.045 0.024 0.02 0.045 0.07 13 0.030 0.065 −0.05 0.030 0.19 Change from baseline at Day 7 4 0.073 0.050 0.00 0.090 0.11 12 0.023 0.046 −0.04 0.025 0.10 Change from baseline at Day 14 4 0.008 0.013 −0.01 0.010 0.02 11 0.018 0.070 −0.10 0.030 0.13 Change from baseline at Day 21 4 0.080 0.047 0.04 0.075 0.13 11 0.009 0.151 −0.21 −0.010 0.35 Change from baseline at Day 28 0 11 −0.011 0.075 −0.15 −0.010 0.09 Change from baseline at Day 35 0 13 0.045 0.093 −0.09 0.040 0.20

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FVC [L] Baseline 5 2.688 0.648 1.66 2.850 3.37 4 2.253 0.466 1.81 2.150 2.90 Day 2 5 2.690 0.638 1.68 2.870 3.36 4 2.240 0.483 1.85 2.105 2.90 Day 7 5 2.668 0.692 1.52 2.880 3.36 4 2.230 0.454 1.79 2.140 2.85 Day 14 5 2.562 0.751 1.31 2.650 3.31 4 2.235 0.496 1.80 2.120 2.90 Day 21 5 2.654 0.717 1.44 2.910 3.23 4 2.278 0.477 1.84 2.165 2.94 Day 28 4 2.625 0.757 1.58 2.815 3.29 0 Day 35 4 2.568 0.910 1.27 2.850 3.30 0 Change from baseline at Day 2 5 0.002 0.016 −0.01 −0.010 0.02 4 −0.013 0.095 −0.15 0.020 0.06 Change from baseline at Day 7 5 −0.020 0.118 −0.14 −0.010 0.10 4 −0.023 0.025 −0.05 −0.025 0.01 Change from baseline at Day 14 5 −0.126 0.221 −0.37 −0.060 0.10 4 −0.018 0.091 −0.14 −0.005 0.08 Change from baseline at Day 21 5 −0.034 0.136 −0.22 0.060 0.07 4 0.025 0.024 −0.01 0.035 0.04 Change from baseline at Day 28 4 −0.023 0.067 −0.08 −0.025 0.04 0 Change from baseline at Day 35 4 −0.080 0.217 −0.39 −0.005 0.08 0

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FVC [L] Baseline 4 2.048 0.568 1.40 2.095 2.60 13 2.135 0.574 1.22 2.050 3.34 Day 2 4 2.098 0.595 1.49 2.110 2.68 13 2.162 0.580 1.30 2.070 3.39 Day 7 4 2.133 0.579 1.50 2.135 2.76 12 2.236 0.564 1.36 2.140 3.44 Day 14 4 2.060 0.548 1.46 2.085 2.61 11 2.265 0.549 1.43 2.150 3.40 Day 21 4 2.138 0.583 1.59 2.080 2.80 11 2.232 0.575 1.38 2.120 3.44 Day 28 0 11 2.246 0.557 1.32 2.160 3.41 Day 35 0 13 2.187 0.618 1.28 2.140 3.50 Change from baseline at Day 2 4 0.050 0.073 −0.06 0.085 0.09 13 0.028 0.062 −0.07 0.030 0.15 Change from baseline at Day 7 4 0.085 0.060 0.02 0.080 0.16 12 0.025 0.061 −0.09 0.030 0.10 Change from baseline at Day 14 4 0.013 0.033 −0.01 0.000 0.06 11 0.016 0.101 −0.26 0.040 0.11 Change from baseline at Day 21 4 0.090 0.123 −0.04 0.100 0.20 11 −0.017 0.106 −0.27 −0.020 0.10 Change from baseline at Day 28 0 11 −0.003 0.095 −0.20 0.010 0.17 Change from baseline at Day 35 0 13 0.052 0.090 −0.09 0.020 0.19

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FVC % predicted [%] Baseline 5 72.714 17.403 53.66 74.540 95.78 4 70.583 9.413 58.53 71.860 80.08 Day 2 5 72.804 17.246 54.31 74.310 95.46 4 70.393 11.553 54.27 73.610 80.08 Day 7 5 71.848 17.362 49.14 74.310 91.34 4 69.893 9.161 57.68 71.595 78.70 Day 14 5 68.580 17.631 42.35 73.210 84.04 4 70.095 11.054 54.56 72.870 80.08 Day 21 5 71.716 20.044 46.55 71.440 97.68 4 71.408 10.030 58.25 73.095 81.19 Day 28 4 69.780 20.094 51.08 65.655 96.73 0 Day 35 4 67.795 23.836 41.06 66.220 97.68 0 Change from baseline at Day 2 5 0.090 0.481 −0.32 −0.230 0.65 4 −0.190 2.837 −4.26 0.835 1.83 Change from baseline at Day 7 5 −0.866 3.475 −4.52 −0.230 2.59 4 −0.690 0.713 −1.38 −0.845 0.31 Change from baseline at Day 14 5 −4.134 6.879 −11.74 −1.330 2.27 4 −0.488 2.642 −3.97 −0.210 2.44 Change from baseline at Day 21 5 −0.998 4.010 −7.11 1.590 1.90 4 0.825 0.739 −0.28 1.165 1.25 Change from baseline at Day 28 4 −0.623 1.823 −2.58 −0.430 0.95 0 Change from baseline at Day 35 4 −2.608 6.853 −12.60 0.135 1.90 0

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FVC % predicted [%] Baseline 4 73.183 3.207 70.29 72.350 77.74 13 73.950 11.036 57.09 72.310 93.73 Day 2 4 74.878 1.514 72.88 75.035 76.56 13 74.943 10.893 57.93 73.480 90.79 Day 7 4 76.398 3.990 70.87 77.160 80.40 12 75.388 11.121 59.89 73.820 92.74 Day 14 4 73.838 3.092 70.00 74.030 77.29 11 75.478 9.676 60.17 76.490 90.10 Day 21 4 76.650 4.681 70.58 77.160 81.70 11 74.301 10.976 59.33 74.340 91.86 Day 28 0 11 75.056 12.351 58.77 75.630 90.98 Day 35 0 13 75.415 10.465 60.44 73.110 89.95 Change from baseline at Day 2 4 1.695 3.093 −2.67 2.415 4.62 13 0.993 2.322 −2.94 0.840 5.02 Change from baseline at Day 7 4 3.215 2.046 0.58 3.570 5.14 12 0.584 2.155 −3.78 0.810 3.01 Change from baseline at Day 14 4 0.655 1.647 −0.45 −0.005 3.08 11 0.262 3.892 −10.93 1.460 3.08 Change from baseline at Day 21 4 3.468 5.221 −1.78 2.945 9.76 11 −0.915 3.983 −11.35 −0.860 2.43 Change from baseline at Day 28 0 11 −0.160 3.030 −5.26 0.400 5.69 Change from baseline at Day 35 0 13 1.465 2.912 −3.78 0.860 5.35

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Table 15.3.2: 1 Adverse event overall summary − treated set


______________________________________________________________________ _____________ _____________ _____________ ________ Placebo BIBF 50 mg BIBF 100 mg BIBF 150 mg Total N (%) N (%) N (%) N (%) N (%)_________________________________________________________________________________________________________________________









Source data: Appendix 16.2.7, Listing 4 ctr15\ae1.sas 17MAY2011

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trial synopsis 1199.31 ds dr - boehringer ingelheim · pdf fileabcd clinical study synopsis...

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