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

Synopsis

ABCDBI Proprietary Name:

Combivent Respimat®

BI Investigational Product:

Combivent Respimat®, ipratropium + albuterol

Page:

2 of 5

Report Date:

29 Oct 2015

Trial No. / Doc. No.:

1012.65/

c02771731-01

Dates of Trial:

15 Nov 2013 –04 Feb 2015

Date of Revision:

Not applicable

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

the trial. Patients must have had a diagnosis of obstructive lung disease and a clinical indication for bronchodilator therapy while on mechanical ventilation.

BI Investigational Product:

Combivent Respimat® with a Respimat® Ventilator adapter. The product tested wasthe Trudell adapter. The Inline Aerosol Tee adapter was not tested.

Dose: 20 μg ipratropium bromide and 100 μg of albuterol (as Combivent Respimat®inhalation aerosol): 1, 2 and 4 puffs at 0, 6 and 12 hours, respectively.

Mode of Admin.:

Endotracheal inhalation from the Respimat® device via the adapter under test and into a mechanical ventilator circuit employed on intubated and mechanically ventilated patients.

Batch No.: PR 13/10021

Comparator Product:

Not applicable

Duration of Treatment:

1 day

Criteria for Evaluation:

Efficacy / ClinicalPharmacology / Other:

This was an exploratory study.

Primary endpoint: Cmax after each dose (Pharmacokinetic parameter)

Secondary endpoint: AUC0-6 after each dose (Pharmacokinetic parameter)

The primary and secondary endpoints were not calculated because of a lack of dose proportionality due to the carry-over effect. Only plasma concentrations (Cmax) were summarized using descriptive statistics.

Safety: Adverse events, vital signs, 3-lead ECG

Statistical Methods:

Descriptive statistics were used to evaluate the pharmacokinetic and ventilator-derived parameters.

SUMMARY - CONCLUSIONS:

Trial Subjects and Compliance with Trial Protocol:

A total of 12 patients were enrolled at 2 centres. Of the 12 patients enrolled, 11 patients were entered and treated in the trial. All 11 patients who were treated in the trial received all 3 doses using the Trudell adapter and completed the trial.

All analyses were conducted on the treated set (TS).

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Page 2 of 5

1012.65 c02771731-01Synopsis

Name of company:

Boehringer Ingelheim

Synopsis

ABCDBI Proprietary Name:

Combivent Respimat®

BI Investigational Product:

Combivent Respimat®, ipratropium + albuterol

Page:

3 of 5

Report Date:

29 Oct 2015

Trial No. / Doc. No.:

1012.65/

c02771731-01

Dates of Trial:

15 Nov 2013 –04 Feb 2015

Date of Revision:

Not applicable

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

Overall, the trial conduct adhered well to the protocol. Important protocol violations were reported for 3 (27.3%) patients. One patient ( ) received prior albuterol that was not washed out prior to the first dose in the trial. Two patients received DuoNeb during the trial.

The patient population was 54.5% males and 45.5% females, and all patients were White. The mean age was 70.4 years (range 46-84 years). Most patients were former (72.7%) or current (18.2%) smokers. All patients had concomitant diagnoses and were receiving pulmonary therapies at baseline.

Efficacy / ClinicalPharmacology / Other Results:

Efficacy was not assessed as part of this trial.

Due to the carry-over effect from pre-treatment medication, both albuterol and ipratropium plasma concentrations and cumulative amounts excreted in urine after 1 puff of Combivent Respimat® through Trudell ventilation adaptors were the highest among the three dose groups (1 puff, 2 puffs and 4 puffs. The pre-dose subtracted Cmax

of ipratropium showed a dose-proportional increase. However, for albuterol pre-dose subtracted Cmax did not show dose correspondence.

Mean albuterol and ipratropium pre-dose subtracted maximum plasma concentration

Ipratropium

Dose

Pre-dose subtracted Cmax

[pg/mL]1Cmax, dose

normalized2N Mean CV%

1 Puff (20/100 µg Ipr/Alb) 5 6.12 66.3 0.306

2 Puff (40/200 µg Ipr/Alb) 9 12.0 46.1 0.300

4 Puff (80/400 µg Ipr/Alb) 6 26.4 44.0 0.330

20/100 µg Ipr/Alb (Study 1012.56) 51 40.1 82.5 2.00

Albuterol

Dose

Pre-dose subtracted Cmax

[ng/mL]N Mean CV%

1 Puff (20/100 µg Ipr/Alb) 7 0.192 183

2 Puff (40/200 µg Ipr/Alb) 10 0.252 173

4 Puff (80/400 µg Ipr/Alb) 10 0.132 62.5

20/100 µg Ipr/Alb (Study 1012.56) 51 1.14 85.1

Abbreviations: Alb=albuterol; CV=coefficient of variation; Ipr=ipratropium.

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Page 3 of 5

1012.65 c02771731-01Synopsis

Name of company:

Boehringer Ingelheim

Synopsis

ABCDBI Proprietary Name:

Combivent Respimat®

BI Investigational Product:

Combivent Respimat®, ipratropium + albuterol

Page:

4 of 5

Report Date:

29 Oct 2015

Trial No. / Doc. No.:

1012.65/

c02771731-01

Dates of Trial:

15 Nov 2013 –04 Feb 2015

Date of Revision:

Not applicable

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

1 Patients with pre-dose concentrations as Cmax were not included in this calculation.2 Dose normalized Cmax is calculated by mean Cmax/dose.

When compared with the Cmax values for ipratropium from Study 1012.56, the estimated loss in the study set up including the Trudell Respimat Ventilator adaptor is about 85%. The estimated loss for albuterol would amount to about 83%-97%.

All ventilators used during the trial were volume controlled. Inspiratory time was only available for 1 patient, but the I:E ratio was available for all 11 patients. Tidal volume increased by an average 28.5 mL to 46.1 mL 30 minutes after treatment. Heart rate decreased by an average of 6.5 beats per minute to 9.8 beats per minute 30 minutes after treatment.

Safety Results:

Safety was assessed by reporting AEs. No AEs were reported during the trial, and no changes in vital signs, ECG, and physical examination results were judged to be clinically relevant by the investigator.

Conclusions: This was an exploratory study to characterize the performance of two adapter devices designed to permit use of the Combivent Respimat® inhaler with patients requiring mechanical ventilation. All 11 patients enrolled in the trial utilized the Trudell adapter. Efficacy was not assessed as part of this trial.

Due to carry-over affect from pre-treatment medications and previous doses and possible loss of drugs from the ventilator adapter, PK exposure and dose correspondence was not observed.

A post-hoc calculation was performed to compare the Cmax in this study to the Cmax

from Study 1012.56 by calculating the percent loss by the Trudell Respimat Ventilator adapter. The percent loss was defined as:

PercentLoss = ����(���������.��)–����������������������(���������.��)

����(���������.��)× 100%

Note that the formula assumes that same dose level for comparisons. The dose in Study 1012.56 was equivalent to the dose from 1 puff in this trial. The pre-dose subtracted Cmax values from the subsequent 2 puffs and 4 puffs need to be divided by 2 and 4, respectively.

Comparing to the results from Study 1012.56, for ipratropium the estimated loss inthe study set up including the Trudell Respimat Ventilator adaptor was about 85%. The estimated loss for albuterol would amount to about 83%–97%.

All ventilators used in the trial were volume controlled. Inspiratory time was only available for 1 patient (0.6 seconds). The required spray duration of Combivent

Boehringer Ingelheim Clinical Trial ReportBI Trial No.:

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Page 4 of 5

1012.65 c02771731-01Synopsis

Name of company:

Boehringer Ingelheim

Synopsis

ABCDBI Proprietary Name:

Combivent Respimat®

BI Investigational Product:

Combivent Respimat®, ipratropium + albuterol

Page:

5 of 5

Report Date:

29 Oct 2015

Trial No. / Doc. No.:

1012.65/

c02771731-01

Dates of Trial:

15 Nov 2013 –04 Feb 2015

Date of Revision:

Not applicable

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

Respimat is 1.5 seconds. The inspiratory time recorded for the single subject was not sufficient to make any conclusions regarding drug delivery through the ventilator adapter.

Safety was assessed by reporting AEs. No AEs were reported during the trial, and no changes in vital signs, ECG, and physical examination results were judged to be clinically relevant by the investigator.

Limitations of the study include:

o The study was designed to characterize the performance of two adapter devices designed to permit use of the Respimat® inhaler with patients requiring mechanical ventilation. On 04 February 2015, BI made the decision to close the study based on results of an interim PK analysis, prior to enrollment of any patients in Cohort 2; therefore, only the Trudell adapter was assessed (in Cohort 1).

o It was assumed that half-lives for ipratropium and albuterol are approximately 2 and 4 hours, respectively, so it was felt that the 6 hour wash-out period would be sufficient to generate 3 determinations of AUC, Cmax, tmax, Aet1-t2, and fet1-t2 per analyte. The 6 h wash-out period before the study and between the doses defined in the study protocol turned out to be not long enough.

o While ipratropium concentrations increased dose proportionally after each dose, albuterol concentrations did not increase dose proportionally.

o Inspiratory time was only available for 1 patient (0.6 seconds). The required spray duration of Combivent Respimat is 1.5 seconds. The inspiratory time recorded for the single subject was not sufficient to make any conclusions regarding drug delivery through the ventilator adapter.

Due to carry-over affect from pre-treatment medications and previous doses and possible loss of drugs from the ventilator adapter, PK exposure and dose correspondence was not observed. Comparing to the results from Study 1012.56, for ipratropium the estimated loss in the study set up including the Trudell Respimat Ventilator adaptor was about 85%. The estimated loss for albuterol would amount to about 83%–97%. No AEs were reported during the trial, and no changes in vital signs, ECG, and physical examination results were judged to be clinically relevant by the investigator.

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Page 5 of 5

1012.65 c02771731-01Synopsis