trial synopsis 1199.162 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

EudraCT No.:

2012-002507-18

Name of active ingredient:

Nintedanib (BIBF 1120)

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Report date: 08 AUG 2013

Trial No. / U No.: 1199.162 / U13-1478-01

Date of trial: 21 JAN 2013 – 04 MAR 2013

Date of revision: Not applicable

Proprietary confidential information © 2013 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.

Test product 2: Rifampicin (Eremfat® 600), film-coated tablets

dose: 600 mg

mode of admin.: Oral administration with 240 mL water

batch no.: 039121 (600 mg tablets; Riemser Arzneimittel AG)

Duration of treatment: Reference treatment (R): single dose of 150 mg nintedanib

Washout period of at least 14 days between administrations of nintedanib

Test treatment (T): 600 mg rifampicin every evening from Day -7 to Day -1, followed by a single dose of 150 mg nintedanib in the morning of Day 1

Criteria for evaluation:

Clinical pharmacology: Primary PK endpoints: AUCo-∞ and Cmax for nintedanib

Secondary PK endpoint: AUC0-tz for nintedanib

The urinary concentration ratio of 6β-hydroxycortisol to cortisol was evaluated as a marker for the induction effect of rifampicin.

Safety: Analysis of adverse events, clinical laboratory assessments, vital signs (blood pressure [BP], pulse rate [PR]), 12-lead electrocardiograms (ECG), and physical examinations.

Statistical methods: AUCo-∞, AUC0-tz, and Cmax were log-transformed before fitting an ANOVA model. The model included effects for 'treatment' and 'subjects'. The 90% confidence intervals were computed for the primary endpoints, then back-transformed to the original scale to give the point estimator and interval estimates for the geometric mean ratio (Test/Reference).

Descriptive statistics were calculated for all other parameters.

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SUMMARY – CONCLUSIONS:

Pharmacokinetic results:

All 26 subjects entered into the trial received trial medication and 25 subjects completed the trial according to the clinical trial protocol. The trial population consisted of healthy male white subjects. The mean age was 37.3 years (± standard deviation [SD] 8.7 years) and the mean BMI was 25.7 kg/m2 (± 2.3 kg/m2. Pharmacokinetic parameters of nintedanib are listed in Table 2: 1.

Table 2: 1 Pharmacokinetic parameters of nintedanib after administration of a single dose of nintedanib 150 mg alone (reference) and following multiple administrations of rifampicin 600 mg once daily for 7 days (test)

Pharmacokinetic parameter

Nintedanib alone (reference) 1

Nintedanib + rifamipicin (test) 1

gMean %gCV gMean %gCV AUC0-∞[ng·h/mL] 183 36.1 89.4 36.8 AUC0-tz [ng·h/mL] 173 36.9 84.1 38.1 Cmax [ng/mL] 22.1 51.8 12.8 43.4 tmax

2 [h] 3.00 0.500–6.00 4.00 1.00–6.02 t1/2 [h] 22.5 22.8 23.4 24.0 MRTpo [h] 19.1 21.2 19.4 21.7 CL/F [mL/min] 13 700 36.1 28 000 36.8 Vz/F [L] 26 600 46.7 56 600 50.7

1 Reference: N=26, test: N=25 2 For tmax, median and range are given instead of gMean and %gCV Compared with the administration of nintedanib alone (reference treatment), administration with steady state rifampicin (test treatment) resulted in decreased exposure to nintedanib. Values of apparent oral clearance (CL/F) and apparent volume of distribution (Vz/F) increased in the test treatment. Other pharmacokinetic parameters were similar between treatments. Rifampicin also decreased exposure to BIBF 1202 and BIBF 1202-glucuronide.

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Pharmacokinetic results (continued):

Statistical comparison of the primary and secondary endpoints for the treatments showed that the relative bioavailability of nintedanib was decreased when it was administered in the presence of steady state rifampicin. The 90% confidence intervals were outside the bioequivalence acceptance range of 80 to 125% (see Table 2: 2).

Table 2: 2 Analysis of relative bioavailability of nintedanib after single oral administration of nintedanib 150 mg alone (reference) and following multiple oral administrations of rifampicin 600 mg once daily for 7 days (test)

Pharmacokinetic parameter

Adjusted gMean ratio of

test to reference treatment (T/R)1

[%]

2-sided 90% CI of gMean ratio Intra-

individual gCV [%]

Lower limit[%]

Upper limit [%]

AUC0-∞ [ng·h/mL] 50.12 47.16 53.28 12.7 AUC0-tz [ng·h/mL] 49.98 46.89 53.29 13.3 Cmax [ng/mL] 59.76 53.83 66.35 21.9

1 Reference: N=26, test: N=25

Safety results: Adverse events were assigned to different treatment periods according to their time of onset. In treatment period 1, adverse events reported during the 72-hour period immediately following administration of nintedanib were assigned to the study period 'nintedanib alone.' Adverse events reported after this 72-hour period, but before the first dose of trial medication in treatment period 2 were assigned to the study period 'washout.' During treatment period 2, adverse events reported after the first administration of rifampicin but before the administration of nintedanib were assigned to the study period 'rifampicin alone'. Adverse events reported during the 72 hours immediately following the administration of nintedanib in treatment period 2 were assigned to the study period 'nintedanib at steady-state rifampicin.'

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Safety results (continued):

Of the 26 subjects entered into the trial, 25 subjects received all of the intended doses of trial medication, as planned. This comprised 7 consecutive daily doses of 600 mg rifampicin, and 2 single doses of 150 mg nintedanib. One subject received 1 single dose of 150 mg nintedanib, before the trial medication was discontinued due to a severe adverse event (severe influenza) that was reported in the washout period. The investigator did not judge this adverse event to be related to the administration of trial medication.

During the 2 treatment periods of this study, all 26 subjects were reported with at least 1 adverse event. The frequency of subjects with treatment-emergent adverse events was comparable in the treatment period of nintedanib alone and in the treatment period of nintedanib at steady-state rifampicin (each observed for 72 hours): 5 out of 26 subjects (19.2%), and 4 out of 25 subjects (16.0%), respectively. All 25 subjects treated in the 7-day rifampicin alone period were reported with at least 1 adverse event. The most-frequently reported adverse event overall at the SOC level was renal and urinary disorders (25 subjects, 96.2%), followed by gastrointestinal disorders (12 subjects, 46.2%), and then nervous system disorders (9 subjects, 34.6%). The most-frequent adverse event by preferred term was chromaturia (25 subjects, 96.2%). Headache was reported by 8 subjects (30.8%), diarrhoea was reported by 7 subjects (26.9%), discoloured faeces was reported by 3 subjects (11.5%), while flatulence, dizziness, and fatigue were each reported by 2 subjects (7.7%). All other adverse events were each reported in 1 subject (3.8%). Chromaturia was reported for all 25 subjects (100%) in the treatment period of rifampicin alone; no subject was reported with this adverse event in any other treatment period. The frequency of subjects with headache was higher under treatment with rifampicin alone (5 subjects, 20%) than under treatment with nintedanib at steady-state rifampicin (2 subjects, 8.0%), or under treatment with nintedanib alone (1 subject, 3.8%). The frequency of subjects with diarrhoea was highest under treatment with nintedanib alone (5 subjects, 19.2%), followed by treatment with nintedanib at steady-state rifampicin (3 subjects, 12.0%), and treatment with rifampicin alone (1 subject, 4.0%). The frequency of adverse events was grossly similar under treatment with nintedanib alone and under treatment with nintedanib at steady-state rifampicin; however, the longer observation period for the treatment period of rifampicin alone does not allow a comparison to be made with either of the two nintedanib treatment periods.

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Safety results (continued):

The investigator classified at least 1 adverse event for all 26 subjects as possibly related to the trial medication. The majority of the drug-related adverse events were reported in the rifampicin alone period, where 25 subjects (100%) were reported with chromaturia. Diarrhoea was the second-most-common drug-related adverse event: 5 subjects (19.2%) were reported with this adverse event in the nintedanib alone period, whereas 3 subjects (12.0%) were reported in nintedanib at steady-state rifampicin period, and 1 subject (4.0%) was reported in the rifampicin alone period. In addition, there were 3 subjects (12.0%) reported with drug-related discoloured faeces, 2 subjects (8.0%) reported with drug-related dizziness, 2 subjects (8.0%) reported with drug-related fatigue, and 1 subject (4.0%) reported each for drug-related eye pain, flatulence, and nausea in the rifampicin alone period. There were also 2 subjects (8.0%) reported with drug-related headache in the nintedanib at steady-state rifampicin period. All other adverse events were not judged to be drug-related by the investigator. No death and no other serious adverse events were reported during the conduct of this trial.

There were no clinically relevant findings with regard to safety laboratory measurements, ECG recordings, physical examinations, or vital-sign measurements.

Conclusions: Noncompartmental analysis of plasma pharmacokinetic parameters of nintedanib showed that induction of P-gp expression by multiple-dose administration of rifampicin resulted in decreased exposure to nintedanib administered as a single dose, as evidenced in lower AUC0-∞, AUC0-tz, and Cmax values. The adjusted gMean ratios between test and reference treatment were 50.12% for AUC0-∞, 49.98% for AUC0-tz, and 59.76% for Cmax.

Administration of nintedanib, either alone, or after achieving a steady state for rifampicin, was generally safe and well tolerated by the healthy male subjects in this trial. No meaningful differences were noted in the safety parameters between the nintedanib alone treatment period and the nintedanib at steady-state rifampicin treatment period.

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Safety results The investigator classified at least 1 adverse event for all 26 subjects as possibly (continued): related to the trial medication. The majority of the drug-related adverse events

were reported in the rifampicin alone period, where 25 subjects (100%) were reported with chromaturia. Diarrhoea was the second-most-common drug-related adverse event: 5 subjects (19.2%) were reported with this adverse event in the nintedanib alone period, whereas 3 subjects (12.0%) were reported in nintedanib at steady-state rifampicin period, and 1 subject (4.0%) was reported in the rifampicin alone period. In addition, there were 3 subjects (12.0%) reported with drug-related discoloured faeces, 2 subjects (8.0%) reported with drug-related dizziness, 2 subjects (8.0%) reported with drug-related fatigue, and 1 subject (4.0%) reported each for drug-related eye pain, flatulence, and nausea in the rifampicin alone period. There were also 2 subjects (8.0%) reported with drug- related headache in the nintedanib at steady-state rifampicin period. All other adverse events were not judged to be drug-related by the investigator. No death and no other serious adverse events were reported during the conduct of this trial.

There were no clinically relevant findings with regard to safety laboratory measurements, ECG recordings, physical examinations, or vital-sign measurements.

Conclusions: Noncompartmental analysis of plasma pharmacokinetic parameters of nintedanib showed that induction of P-gp expression by multiple-dose administration of rifampicin resulted in decreased exposure to nintedanib administered as a single dose, as evidenced in lower AUC0-∞, AUC0-tz, and Cmax values. The adjusted gMean ratios between test and reference treatment were 50.12% for AUC0-∞, 49.98% for AUC0-tz, and 59.76% for Cmax.

Administration of nintedanib, either alone, or after achieving a steady state for rifampicin, was generally safe and well tolerated by the healthy male subjects in this trial. No meaningful differences were noted in the safety parameters between the nintedanib alone treatment period and the nintedanib at steady-state rifampicin treatment period.

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Boehringer Ingelheim BI trial number 1199.162 Trial Synopsis - Appendix

Trial Synopsis - Appendix

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

Synopsis. The appended tables complement the results for the primary and secondary

endpoints as summarized below.

Results for presented in

AUC0-∞ (primary endpoint) Table 15.5.1.1: 2

Cmax (primary endpoint) Table 15.5.1.2: 2

AUC0-tz (secondary endpoint) Section 16.1.9.3. Table 1.3.5

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Table 15.5.1.1: 2 Adjusted by−treatment geometric means and relative bioavailability comparison NIN+RIF : NIN AUCinfpred [ng*h/mL] for BIBF 1120 BS (PLASMA EDTA) Treated set

NIN+RIF NIN Ratio gSE 90% Intra− p−value for ratio N gMean N gMean NIN+RIF : Confidence indiv. outside interval NIN interval gCV 80% − 125% [%] [%] [%] [%]

25 91.785 26 183.124 50.12 1.036 47.155 53.275 12.7 1.0000

Source data: Appendix 16.1.9.3, Statdoc 1.1.3 stat\pk15_ba.sas 29APR2013

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Table 15.5.1.2: 2 Adjusted by−treatment geometric means and relative bioavailability comparison NIN+RIF : NIN Cmax [ng/mL] for BIBF 1120 BS (PLASMA EDTA) Treated set


25 13.204 26 22.094 59.76 1.063 53.829 66.348 21.9 1.0000


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Table 1.3.5 Adjusted by−treatment geometric means and relative bioavailability comparison NIN+RIF : NIN AUClast [ng*h/mL] for BIBF 1120 BS (PLASMA EDTA) Treated set


25 86.422 26 172.902 49.98 1.038 46.886 53.286 13.3 1.0000


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16.1.9.3 Statistical analysis of clinical pharmacology

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