trial synopsis 1012.57 ds co - boehringer ingelheim · 21 mcg of ipratropium bromide and 120 mcg of...

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:

Combivent® Inhalation Aerosol

Combivent® Respimat®

Name of active ingredient:

Ipratropium bromide and albuterol sulfate

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Report date: 13 September 2010

Trial No. / U No.: 1012.57/ U10-3568-01

Date of trial: 23 DEC 2008 – 21 SEP 2009

Date of revision : Not applicable

Proprietary confidential information © 2010 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 multicenter, randomized study starting with a 4-week, 2-way crossover double-blind treatment phase comparing the efficacy and safety of Combivent® CFC MDI to albuterol HFA MDI followed by a 4-week open-label Combivent® Respimat® treatment phase when all study drugs are used for symptom relief “as needed” in patients with moderate-to-severe asthma (GINA 2007 Treatment Steps 3-5)

Coordinating Investigator:

MD

Trial sites: Multicentre Study, cf. Appendix 16.1.4

Publication (reference): None

Clinical phase: II

Objectives: The primary objective of this study was to evaluate the efficacy of Combivent® CFC MDI measured by lung function, “as needed” medication use, asthma symptoms and quality of life and compare it to that of albuterol HFA MDI in patients with moderate-to-severe asthma.

Methodology: Randomized, double-blind, active controlled, 2-way crossover treatment phase (Treatment Phases I and II) followed by an open-label treatment phase (Treatment Phase III) where patients were randomized to blinded study medication only at clinic visits at the beginning and end of the treatment phase. The bronchodilator efficacy of Combivent® was evaluated at clinic visits following supervised administration of the blinded study medication: between clinic visits, the blinded study medication was used by the patient for symptom relief “as needed”.

After a 4-week period, changes in symptoms (ACQ), health related quality of life (mini-AQLQ) and rescue medication use were evaluated.

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No. of subjects:

planned: Entered (randomized): 200

actual: Entered (randomized): 226

Treatment A: Combivent® CFC MDI Entered: 219 Treated: 219 Analyzed (for primary endpoint): 212 Treatment B: Albuterol HFA MDI Entered: 222 Treated: 222 Analyzed (for primary endpoint): 215

Treatment C: Combivent® Respimat® Entered: 139 Treated: 139 Analyzed: 139

Treatment D: Placebo Respimat® Entered: 26 Treated: 26 Analyzed: 26

Diagnosis and main criteria for inclusion:

Outpatients ≥18 years of age, physician diagnosis of moderate-to-severe asthma (GINA Guidelines) existing for >1 year, reversible airway obstruction ≥12% or at least 200 mL improvement in FEV1

post-bronchodilator after 4 puffs of albuterol HFA), clinic measured pre-bronchodilator FEV1 ≤80% of predicted normal value, continuous treatment with inhaled corticosteroids (ICS) with or without long-acting beta agonists (LABA) and/or other controller medication(s) for at least 6 weeks prior to screening, no change in dose and regimen of ICS and LABA or other controller medications for at least 2 weeks prior to Visit 2, use of short acting bronchodilator for at least three times a week for symptom relief in the 2 weeks prior to Visit 1, score of ≥1.5 points on the Asthma Control Questionnaire (ACQ) at Visit 3.

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Test product: Combivent® CFC (inhalation aerosol) , ipratropium bromide/albuterol sulfate

Combivent® Respimat® (inhalation spray), ipratropium bromide/albuterol sulfate

dose: Combivent® CFC (inhalation aerosol) delivered via a MDI: Each actuation meters 21 mcg of ipratropium bromide and 120 mcg of albuterol sulfate from the valve and delivers 18 mcg of ipratropium bromide and 103 mcg of albuterol sulfate (equivalent to 90 mcg albuterol base) from the mouthpiece.

Combivent® (inhalation spray) delivered via a Respimat® inhaler: Each actuation delivers 20 mcg ipratropium bromide and 100 mcg albuterol (equivalent to 120 mcg albuterol sulfate) from the mouthpiece.

mode of administration:

Combivent® CFC MDI : inhalation aerosol

Combivent® Respimat® : inhalation spray

batch no.: Combivent® CFC MDI – 865050A

Combivent® Respimat® - 709875

Reference therapy: Albuterol HFA

dose: Each actuation delivers 120 mcg of albuterol sulfate from the canister valve and 108 mcg of albuterol sulfate from the actuator mouthpiece (equivalent to 90 mcg albuterol base).

mode of administration:

Albuterol HFA MDI: Inhalation aerosol

batch no.: ADW77A

Duration of treatment: 29 days

Criteria for evaluation:

Efficacy: The primary analysis was the ANCOVA comparing the bronchodilator efficacy of Combivent® CFC MDI and albuterol HFA MDI as determined by FEV1 AUC0-6

response, and separately as determined by peak FEV1 response, after four weeks of “as needed” use of blinded rescue medication.

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Safety: 1. All adverse events. 2. Pulse rate and blood pressure recorded in conjunction with spirometry. 3. Premature discontinuation from trial due to exacerbation of asthma. 4. Severe exacerbations of asthma.

Statistical methods: Mixed models repeated measures analysis of covariance; McNemar’s sign test.

SUMMARY – CONCLUSIONS

Efficacy / clinical pharmacology results:

The study demonstrated significant differences in favor of Combivent® CFC MDI in both co-primary endpoints of mean changes from test-day baseline in FEV1 AUC0-6 (85 mL, p<0.0001) and peak FEV1 (77 mL, p<0.0001) after four weeks of “as needed” use of study medication, for the comparison between Combivent® CFC MDI and albuterol HFA MDI. Other spirometry endpoint findings consistently supported the superior bronchodilator properties of Combivent® CFC over albuterol HFA MDI, after four weeks of “as needed” treatment. Despite the improvement in lung function there were no relevant changes in mini-AQLQ, ACQ or rescue medication use in any of the treatment groups. In the parallel phase of the study, the superior bronchodilator properties of Combivent® Respimat® relative to placebo Respimat® were demonstrated. For the endpoints of FEV1 AUC0-6 and peak FEV1 after four weeks of “as needed” use of study medication, the significant differences in favor of Combivent® Respimat®

were 195 mL and 213 mL, respectively, with p<0.0001 for both.

The comparisons between Combivent® Respimat® and Combivent® CFC were confounded by time and treatment effects. The spirometry and rescue medication use comparisons consistently favored Combivent® CFC, while the mini-AQLQ, ACQ, asthma symptoms total score, and number of nighttime awakenings comparisons consistently favored Combivent® Respimat®.

The geometric means of albuterol AUC0-6 in the sub-PK population were 3.02 ng.h/mL in Combivent® CFC treatment (N=53), 2.77 ng.h/mL in albuterol HFA treatment (N=52), 2.00 ng.h/mL in Combivent® Respimat® treatment (N=30). In addition, the pharmacokinetic results of a lack of systemic ipratropium concentrations in patients taking the albuterol HFA treatment demonstrated the internal consistency of the study design.

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Safety results: In the crossover phase, a total of 68 (30.1%) patients reported at least one AE: 31 (14.0%) in the albuterol HFA group and 50 (22.8%) in the Combivent® CFC group. The most common AE was cough, reported in 11 patients in the Combivent® CFC group and in 1 patient in the albuterol HFA group.

In the parallel phase, a total of 7 (4.2%) patients reported at least one AE on the test days or the day after the test days. In addition, a total of 13 (7.9%) patients reported at least one AE when open-label Combivent® Respimat® was available for “as needed” use between the two test days.

There were a total of 6 SAEs reported in 5 patients: none of them were related to the study drug according to the investigator. Severe asthma exacerbations as defined in the protocol were reported in 10 patients: 2 in the albuterol HFA group, 7 in the Combivent® CFC group, and 1 in the parallel phase. Four patients discontinued from the study due to an AE: 2 in Combivent® CFC group, 1 in albuterol HFA group, and 1 in parallel phase.

Conclusions: In conclusion, the results of the study support the feasibility and efficacy of the use of Combivent® CFC and Combivent® Respimat® for symptom relief in asthma. Further investigation of the safety and efficacy of Combivent® Respimat®

in patients with asthma is recommended.

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Boehringer Ingelheim BI trial number 1012.0057 Trial Synopsis - Appendix

Trial Synopsis - Appendix

The appended tables on the following page supplements the trial results presented in the Trial

Synopsis. They complement disposition results and results for secondary endpoints of the

trial.

Results for presented in

Disposition of subjects, Treatment phase I Table 15.1.1: 1

Disposition of subjects, Treatment phase II Table 15.1.1: 2

Disposition of subjects, Treatment phase III Table 15.1.1: 3

Mini−AQLQ change from baseline after 4 weeks Table 15.2.1.3.2: 1

ACQ change from baseline after 4 weeks Table 15.2.1.3.2: 2

Weekly mean number of AM puffs of blinded study medication used

Table 15.2.1.4.2: 1

Weekly mean number of PM puffs of blinded study medication used

Table 15.2.1.4.2: 2

Weekly mean number of AM puffs of open label albuterol used Table 15.2.1.4.2: 3

Weekly mean number of PM puffs of open label albuterol used Table 15.2.1.4.2: 4

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Table 15.1.1: 1 Disposition of subjects, Treatment phase I

___________________________________________________________________________________ ALB HFA 108 CVT C 18/103 Total N(%) N(%) N(%)

Enrolled¹ 548 Not entered/randomized 322 Entered/randomized 115 111 226 Not treated 0 0 0 Treated 115(100.0) 111(100.0) 226(100.0)

Not prematurely discontinued 112( 97.4) 110( 99.1) 222( 98.2) from trial medication²

Prematurely discontinued from 3( 2.6) 1( 0.9) 4( 1.8) trial medication Adverse event 0( 0.0) 1( 0.9) 1( 0.4) AE study dis. worse 0( 0.0) 1( 0.9) 1( 0.4) AE oth. dis. worse 0( 0.0) 0( 0.0) 0( 0.0) AE other 0( 0.0) 0( 0.0) 0( 0.0) Non compl. protocol 0( 0.0) 0( 0.0) 0( 0.0) Lost to follow−up 0( 0.0) 0( 0.0) 0( 0.0) Refused cont. medicat 0( 0.0) 0( 0.0) 0( 0.0) Other 3( 2.6) 0( 0.0) 3( 1.3)

¹ For Phase I, there were 19 patients that were screened twice, and one additional patient that was screened three times. Number of enrolled is the count of patient numbers used, which in this case is greater than the count of patients who enrolled.² For Phase I, this is assessed at the end of Phase I (Visit 4).

Source data: Appendix 16.2, Listing 1.1 disp.sas 04DEC2009

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Table 15.1.1: 2 Disposition of subjects, Treatment phase II

___________________________________________________________________________________ ALB HFA 108 CVT C 18/103 Total N(%) N(%) N(%)

Entered/randomizedº 110 112 222 Not treated¹ 3 4 7 Adverse event 1 1 2 AE study dis. worse 0 1 1 AE other 1 0 1 Non compl. protocol 0 2 2 Other 2 1 3 Treated 107(100.0) 108(100.0) 215(100.0)

Not prematurely discontinued 106( 99.1) 106( 98.1) 212( 98.6) from trial medication² Accelerated patients³ 19( 17.8) 14( 13.0) 33( 15.3)


º For Phase II, this is the number not prematurely discontinued from trial medication at the end of Phase I (Visit 4).¹ For Phase II, this is the number of patients who discontinued between the end of Phase I (Visit 4) and the beginning of Phase II (Visit 5).² For Phase II, this is assessed at the end of Phase II (Visit 6).³ For Phase II, these were patients that stopped using blinded study medication prior to their regularly scheduled end of the crossover phase in accordance with Amendment 3, and who subsequently came into the clinic for a Visit 6.


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Table 15.1.1: 3 Disposition of subjects, Treatment phase III

___________________________________________________________________________________ PLACEBO R CVT R 20/100 Total N(%) N(%) N(%)

Enrolled¹ 212 Not entered/randomized² 47 Entered/randomized 26 139 165 Not treated 0 0 0 Treated 26(100.0) 139(100.0) 165(100.0)

Not prematurely discontinued 26(100.0) 138( 99.3) 164( 99.4) from trial medication


¹ For Phase III, this is the number not prematurely discontinued from trial medication at the end of Phase II (Visit 6).² For Phase III, this includes patients who did not meet the stability criteria for continuing to Randomization 2.


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Table 15.2.1.3.2: 1 Estimated changes from baseline after 4 weeks in Mini−AQLQ using ANCOVA − full analysis set 1

________ALB HFA 108________ _______CVT C 18/103________ ____Difference (CVT C 18/103 − ALB HFA 108)____ N Mean (SE) N Mean (SE) Mean (95% CI) P−value

Day 1 (Baseline) 219 4.51 219 4.51

Day 29 191 0.15 (0.05) 193 0.22 (0.05) 0.06 (−0.03 , 0.15) 0.1590

Source data: Appendix 16.1.9.2, Statdoc 6.1.3.2.1 type14.sas 04JAN2010

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Table 15.2.1.3.2: 2 Estimated changes from baseline after 4 weeks in ACQ using ANCOVA − full analysis set 1

________ALB HFA 108________ _______CVT C 18/103________ ____Difference (CVT C 18/103 − ALB HFA 108)____ N Mean (SE) N Mean (SE) Mean (95% CI) P−value

Day 1 (Baseline) 219 2.46 219 2.46

Day 29 191 −0.25 (0.04) 193 −0.25 (0.04) 0.01 (−0.07 , 0.08) 0.8278

Source data: Appendix 16.1.9.2, Statdoc 6.1.3.2.2 type14.sas 04JAN2010

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Table 15.2.1.4.2: 1 Weekly mean number of AM puffs of blinded study medication used ANCOVA results − full analysis set 1

______ALB HFA 108_______ ______CVT C 18/103______ _ Difference (CVT C 18/103 − ALB HFA 108)_

N Mean (SE) N Mean (SE) Mean (95% CI) p−value

Week 0 (AM baseline) 219 2.58 219 2.58

Week 4 176 −0.49 (0.07) 178 −0.53 (0.07) −0.04 (−0.17 , 0.08) 0.5098

Source data: Appendix 16.1.9.2, Statdoc 6.1.4.2.1 diary_stat_co.sas 18DEC2009

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Table 15.2.1.4.2: 2 Weekly mean number of PM puffs of blinded study medication used ANCOVA results − full analysis set 1



Week 0 (PM baseline) 219 1.04 219 1.04

Week 4 178 −0.10 (0.05) 180 −0.12 (0.05) −0.02 (−0.12 , 0.08) 0.6591


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Table 15.2.1.4.2: 3 Weekly mean number of AM puffs of open label albuterol used ANCOVA results − full analysis set 1



Week 0 (AM baseline) 219 2.58 219 2.58

Week 4 176 −2.24 (0.05) 178 −2.28 (0.05) −0.04 (−0.14 , 0.05) 0.3631


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Table 15.2.1.4.2: 4 Weekly mean number of PM puffs of open label albuterol used ANCOVA results − full analysis set 1



Week 0 (PM baseline) 219 1.04 219 1.04

Week 4 178 −0.92 (0.02) 180 −0.93 (0.02) −0.01 (−0.06 , 0.04) 0.6787


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trial synopsis 1012.57 ds co - boehringer ingelheim · 21 mcg of ipratropium bromide and 120 mcg of...

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