trial synopsis 1237.3 ds co - boehringer ingelheim · synopsis no.: name of finished product: not...

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.:

2008-000813-31

Name of active ingredient:

BI 1744 CL and tiotropium bromide

Page:

1 of 5

Module:

Volume:

{hyperlink }

Report date:

15 MAY 2009

Trial No. / U No.:

1237.3 / U09-1422-03

Date of trial:

17 JUN 2008 – 20 NOV 2008

Date of revision:

02 February 2012

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.

Title of trial: A randomised, double-blind, 3-way crossover study to compare pharmacokinetics and safety of 10 µg BI 1744 CL plus 5 µg tiotropium bromide given as fixed dose combination via the Respimat® Inhaler with the pharmacokinetics and the safety of the single agents, i.e. 10 µg BI 1744 CL and 5 µg tiotropium bromide, delivered via the Respimat® Inhaler following 21 day-treatment periods in patients with chronic obstructive pulmonary disease (COPD)

Principal/Coordinating Investigator:

Trial sites: Germany

Germany

Germany

Germany

Germany

Germany

Publication (reference): Data of this trial has not been published.

Clinical phase: Ib

Objectives: To compare the systemic exposure to BI 1744 BS and tiotropium at steady state following inhalation of the fixed dose combination of 10 µg BI 1744 CL plus 5 µg tiotropium bromide with the systemic exposure to BI 1744 BS and tiotropium at steady state following inhalation of the single agents, i.e., 10 µg BI 1744 CL and 5 µg tiotropium bromide, when administered once-daily via the Respimat® Inhaler for 21 days.

The secondary objectives were to compare the safety and tolerability (adverse events, 12-lead electrocardiogram recordings, pulmonary function testing) of BI 1744 CL and tiotropium bromide when administered as fixed dose combination or as single-agent therapy.

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Name of company:


Trial Report abcd

Synopsis No.:


not applicable

EudraCT No.:

2008-000813-31



Page:

2 of 5

Module:

Volume:

{hyperlink }

Report date:

15 MAY 2009

Trial No. / U No.:

1237.3 / U09-1422-03

Date of trial:

17 JUN 2008 – 20 NOV 2008

Date of revision:

02 February 2012



Methodology: Double-blind, randomised, 3-way crossover trial with 21 day-treatment periods

No. of subjects:

planned: entered: 36 (at least 42 randomized)

actual: enrolled: 47

Treatment BI 1744 CL plus tiotropium bromide: entered: 47 treated: 47 analysed (for primary endpoint): 47 Treatment BI 1744 CL: entered: 47 treated: 47 analysed (for primary endpoint): 47 Treatment tiotropium bromide: entered: 47 treated: 47 analysed (for primary endpoint): 47

Diagnosis and main criteria for inclusion:

Outpatients of either sex, aged ≥40 years with a diagnosis of COPD; smoking history >10 pack-years; post-bronchodilator forced expiratory volume in one second (FEV1) ≥ 30% and <80% predicted [European Community for Steel and Coal criteria]; post-bronchodilator FEV1/forced vital capacity (FVC) <70%.

Test product: BI 1744 CL plus tiotropium bromide fixed dose combination solution for inhalation – Respimat®

dose: 10 µg BI 1744 CL and 5 µg tiotropium bromide

mode of admin.: Oral inhalation

batch no.: B072000320 (labelled PR08/10179)

Reference therapy 1: BI 1744 CL solution for inhalation - Respimat®

dose: 10 µg BI 1744 CL


batch no.: B072000356 (labelled PR08/10179)

Reference therapy 2: Tiotropium bromide solution for inhalation - Respimat®

dose: 5 µg tiotropium bromide


batch no.: 609410 (labelled PR08/10179)

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Name of company:


Trial Report abcd

Synopsis No.:


not applicable

EudraCT No.:

2008-000813-31



Page:

3 of 5

Module:

Volume:

{hyperlink }

Report date:

15 MAY 2009

Trial No. / U No.:

1237.3 / U09-1422-03

Date of trial:

17 JUN 2008 – 20 NOV 2008

Date of revision:

02 February 2012



Duration of treatment: 21 days for each treatment

Criteria for evaluation:

Efficacy / clinical pharmacology:

Pharmacokinetics

Primary endpoints:

BI 1744 BS: Cmax,ss, AUC0-1,ss Tiotropium: Ae0-24,ss

Secondary endpoints:

BI 1744 BS: Ae0-24,ss Tiotropium: Cmax,ss , AUC0-6,ss

BI 1744 BS and tiotropium: AUC0-tz,ss, AUCτ,ss, tmax,ss, λz,ss, t½,ss, MRTih,ss, CL/F,ss, Vz/F,ss, Aet1-t2,ss, fet1-t2,ss, CLRt1 t2,ss

Safety: Vital signs, 12-lead electrocardiogram, blood pressure, pulse rate, laboratory tests, adverse events, physical examination, pulmonary function testing

Statistical methods: Confidence intervals, analysis of variance, descriptive statistics

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Name of company:


Trial Report abcd

Synopsis No.:


not applicable

EudraCT No.:

2008-000813-31



Page:

4 of 5

Module:

Volume:

{hyperlink }

Report date:

15 MAY 2009

Trial No. / U No.:

1237.3 / U09-1422-03

Date of trial:

17 JUN 2008 – 20 NOV 2008

Date of revision:

02 February 2012



SUMMARY – CONCLUSIONS:

Efficacy / clinical pharmacology results:

Pharmacokinetics of BI 1744 BS

Inhalation of the BI 1744 CL + tiotropium fixed dose combination (FDC) over a period of 21 days resulted in about 11–12% higher Cmax,ss and AUC0-1,ss values for BI 1744 BS than observed after inhalation of BI 1744 CL single agent (90% CI: 101–122% and 99–127%, respectively). However, AUC0-2,ss and Ae0-24,ss after inhalation of the fixed dose combination were only 2–5% higher than after inhalation of the single agent (90% CI: 93–112% and 98–113%, respectively). As the 90% confidence intervals were mostly completely located within the generally accepted bioequivalence limits of 80−125%, no significant effect of tiotropium on the systemic exposure to BI 1744 BS is suggested. The time point of maximum BI 1744 BS plasma concentrations after inhalation of the BI 1744 CL + tiotropium FDC and after inhalation of BI 1744 CL as single agent was identical (median tmax,ss: 0.250 h). The time point of the last measurable BI 1744 BS plasma concentration after both treatments was highly variable, ranging from 0.250 h to 24 h and 0.083 h to 24 h, respectively (median tz,ss: 6 h). As a result, half-lives of BI 1744 BS could be calculated only for some patients and were highly variable, ranging from 5.02 to 38.5 hours.

Pharmacokinetics of tiotropium

For tiotropium, Ae0-24,ss and Cmax,ss after inhalation of the FDC were similar compared to inhalation of tiotropium single agent (ratio: 98 and 96%, 90%CI: 91–106% and 87–107%), and AUC0-4,ss and AUC0-6,ss were 9–10% lower (90%CI: 84–100% and 83–98%). As the 90% confidence intervals were all completely located within the generally accepted bioequivalence limits of 80−125%, no significant effect of BI 1744 BS on the systemic exposure to tiotropium is suggested. The time point of maximum tiotropium plasma concentrations after inhalation of the BI 1744 CL+ tiotropium FDC and after inhalation of tiotropium as single agent was identical (median tmax,ss: 0.083 h). The time point of the last measurable tiotropium plasma concentration after both treatments was highly variable, ranging from 0.333 h to 24 h after both treatments (median tz,ss: 8 h). As a result, half-lives of tiotropium could be calculated only for some patients and were highly variable, ranging from 3.24 to 117 hours.

c03397267

Name of company:


Trial Report abcd

Synopsis No.:


not applicable

EudraCT No.:

2008-000813-31



Page:

5 of 5

Module:

Volume:

{hyperlink }

Report date:

15 MAY 2009

Trial No. / U No.:

1237.3 / U09-1422-03

Date of trial:

17 JUN 2008 – 20 NOV 2008

Date of revision:

02 February 2012



Safety results: In this trial, 47 COPD patients received 10 µg BI 1744 CL and 5 µg tiotropium bromide administered via the Respimat® Inhaler as single agents and as fixed dose combination within the 21 day treatment periods.

Thirty-four of the 47 COPD patients reported at least one adverse event in this trial. One patient had an adverse event of severe intensity (hand fracture). All other events were of mild or moderate intensity. No death, no serious and no significant adverse event occurred in this trial.

The frequency of patients with drug-related adverse events (palpitations, dry mouth, dyspepsia, asthenia, pain in extremity, dizziness, headache, chronic obstructive pulmonary disease, dysphonia, rhinorrhoea) was higher following treatment with the fixed dose combination of BI 1744 CL and tiotropium bromide with 7 of 47 COPD patients (14.9%) compared to the single agent therapy with BI 1744 CL 4 patients (8,5%) and tiotropium bromide with 5 of the 47 patients (10.6%). Headache was the most frequently reported drug-related adverse event.

A safety related influence of BI 1744 CL and tiotropium bromide administered alone or in combination on laboratory parameters, vital sign parameters, or ECG parameters was not observed in this trial.

BI 1744 CL and tiotropium bromide were mainly well tolerated administered as single agents or as fixed dose combination.

Conclusions: In conclusion, once-daily inhalations of 10 µg BI 1744 CL and 5 µg tiotropium bromide as fixed dose combination or single agents administered via the Respimat® Inhaler over 21 days were mainly well tolerated by male and female patients with a diagnosis of COPD. The results of this trial do not alter the current knowledge about the safety pharmacology of BI 1744 CL and tiotropiumbromide.

Pharmacokinetics of BI 1744 BS and tiotropium after inhalation of the fixed dose combination was not significantly altered in comparison to when each of the two compounds was administered alone.

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Boehringer Ingelheim BI trial number 1237-0003 Trial Synopsis - Appendix

Trial Synopsis - Appendix

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

synopsis. They complement disposition results, results for primary and secondary endpoints

(EP) of the trial, and safety information. Note that not all secondary endpoints defined in the

trial protocol are presented in this synopsis, because their numbers were too large to allow

meaningful presentation in this format.

Results for presented in

Patient Disposition Table 15.1.1: 2

BI 1744 BS (olodaterol) Cmax,ss (Primary EP)

BI 1744 BS AUC0-1,ss (Primary EP)

Table 15.6.3: 1

Secondary PK Endpoints of BI 1744 BS including:

BI 1744 BS Ae0-24,ss

BI 1744 BS AUC0-2,ss

BI 1744 BS fe0-24,ss

Table 15.6.3: 1

BI 1744 BS tmax,ss (Secondary Endpoint)

BI 1744 BS tz,ss

Table 15.6.3: 3

Tiotropium Ae0-24,ss (Primary EP) Table 15.6.3: 4

Secondary PK Endpoints of BA 679 (tiotropium) including:

Tiotropium Cmax,ss

Tiotropium AUC0-4,ss

Tiotropium AUC0-6,ss

Tiotropium fe0-24,ss

Table 15.6.3: 4

Tiotropium tmax,ss (Secondary Endpoint)

Tiotropium tz,ss

Table 15.6.3: 6

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Table 15.1.1: 2 Termination of trial medication

___BI 10___ _BI 10 + T 5_ ____T 5____ N (%) N (%) N (%)

Number of entered patients 47(100.0) 47(100.0) 47(100.0)

Termination Plan. time reached 47(100.0) 47(100.0) 47(100.0) AE study dis. worse 0( 0.0) 0( 0.0) 0( 0.0) AE−oth. dis. worse 0( 0.0) 0( 0.0) 0( 0.0) AE−other 0( 0.0) 0( 0.0) 0( 0.0) Lack of efficacy 0( 0.0) 0( 0.0) 0( 0.0) Non compl prot. 0( 0.0) 0( 0.0) 0( 0.0) Lost to follow−up 0( 0.0) 0( 0.0) 0( 0.0) Consent withdrawn 0( 0.0) 0( 0.0) 0( 0.0) Other 0( 0.0) 0( 0.0) 0( 0.0)

Source data: Appendix 16.2.1, Listing 3 s15\et_term.sas 25FEB2009

Page BI Trial No.:

Boehringer Ingelheim 1311237.3 U09-1422-03

1. - 15. CTR Main Part

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Table 15.6.3: 1 Comparison of pharmacokinetic parameters of BI 1744 BS (N, gMean, gCV [%]) after multiple inhaled administration of FDC 10 µg BI 1744 CL + 5 µg Tiotropium bromide or 10 µg BI 1744 CL

________________________________________________________________________

FDC BI 1744 CL + Tiotropium BI 1744 CL N gMean gCV [%] N gMean gCV [%]________________________________________________________________________

AUC0−1,ss [pg*h/mL] 39 4.86 43.4 37 4.30 62.3AUC0−2,ss [pg*h/mL] 37 8.67 38.3 −−− −−− −−−AUC0−tz,ss [pg*h/mL] 45 14.6 349 44 10.3 398Cmax,ss [pg/mL] 45 5.99 56.4 44 5.30 54.2Ae0−24,ss [ng] 46 362 43.8 43 357 47.7fe0−24,ss [%] 46 3.62 43.8 43 3.57 47.7

________________________________________________________________________

Source data: Section 15.6, Table 2.1: 1, 2.1: 2 pk\pksumtab.sas 09MAR2009

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Table 15.6.3: 3 Comparison of pharmacokinetic parameters of BI 1744 BS (N, Median, Min, Max) after multiple inhaled administration of FDC 10 µg BI 1744 CL + 5 µg Tiotropium bromide or 10 µg BI 1744 CL

_____________________________________________________________________

FDC BI 1744 CL + Tiotropium BI 1744 CL N Median Min Max N Median Min Max_____________________________________________________________________

tmax,ss [h] 45 0.250 0.0500 2.02 44 0.250 0.0830 1.00tZ,ss [h] 45 6.02 0.250 24.0 44 6.00 0.0830 24.0

_____________________________________________________________________


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Table 15.6.3: 4 Comparison of pharmacokinetic parameters of BA 679 (N, gMean, gCV [%]) after multiple inhaled administration of FDC 10 µg BI 1744 CL + 5 µg Tiotropium bromide or 5 µg Tiotropium bromide

_______________________________________________________________________

FDC BI 1744 CL + Tiotropium Tiotropium N gMean gCV [%] N gMean gCV [%]_______________________________________________________________________

AUC0−4,ss [pg*h/mL] 44 22.2 33.4 39 25.1 37.2AUC0−6,ss [pg*h/mL] 36 31.4 27.4 35 34.0 33.5AUC0−tz,ss [pg*h/mL] 47 32.7 104 45 32.9 135Cmax,ss [pg/mL] 47 15.3 65.7 45 15.9 63.8Ae0−24,ss [ng] 45 911 41.5 43 932 46.1fe0−24,ss [%] 45 18.2 41.5 43 18.6 46.1

_______________________________________________________________________


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Table 15.6.3: 6 Comparison of pharmacokinetic parameters of BA 679 (N, Median, Min, Max) after multiple inhaled administration of FDC 10 µg BI 1744 CL + 5 µg Tiotropium bromide or 5 µg Tiotropium bromide

______________________________________________________________________

FDC BI 1744 CL + Tiotropium Tiotropium N Median Min Max N Median Min Max______________________________________________________________________

tmax,ss [h] 47 0.0830 0.0330 0.333 45 0.0830 0.0330 0.333tZ,ss [h] 47 8.00 0.333 24.0 45 8.00 0.333 24.1

______________________________________________________________________


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trial synopsis 1237.3 ds co - boehringer ingelheim · synopsis no.: name of finished product: not...

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