Combination of Orally Inhaled BI1744CL/Tiotropium Bromide in Patients With Chronic Obstructive Pulmonary Disease ( COPD)

Study Overview
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Brief Summary
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The primary objective of this study is to determine the optimum dose(s) of BI 1744 CL administered with 5 micrograms tiotropium bromide solution for inhalation, delivered by the Respimat inhaler, once daily for four weeks in patients with chronic obstructive pulmonary disease (COPD).

Official Title
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Randomised, Double-Blind, Parallel Group Study to Assess the Efficacy and Safety of 4 Weeks of Once Daily Treatment of 3 Doses of Orally Inhaled BI 1744 CL, Each in Fixed Dose Combination With 5 Microgram Tiotropium Bromide (Delivered by the Respimat Inhaler) Compared With 5 Microgram Tiotropium Bromide Monoproduct (Delivered by the Respimat Inhaler) in Patients With COPD

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: BI 1744 CL/tiotropium bromide fixed dose combination
* Drug: tiotropium bromide
* Device: Respimat® Inhaler


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator FEV1 greater or equal 30% of predicted normal and <80% of predicted normal and a post-bronchodilator FEV1 / FVC <70% at Visit 1 Male or female patients, 40 years of age or older Patients must be current or ex-smokers with a smoking history of more than 10 pack years Patients must be able to perform technically acceptable pulmonary function tests and PEF measurements, and must be able to maintain records (Patient Daily e-Diary) during the study period as required in the protocol Patients must be able to inhale medication in a competent manner from the Respimat inhaler and from a metered dose inhaler (MDI). Further inclusion criteria apply Exclusion Criteria: Patients with a significant disease other than COPD Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; Patients with a history of asthma or a total blood eosinophil count >= 600/mm3. Patients with any of the following conditions:a diagnosis of thyrotoxicosis, a diagnosis of paroxysmal tachycardia (>100 beats per minute), a marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTcF* interval > 450 ms), a history of additional risk factors for Torsade de Pointes (TdP) (e.g. heart failure, hypokalemia, family history of Long QT Syndrome) Patients with any of the following conditions:a history of myocardial infarction within 1 year of screening visit (Visit 1), a diagnosis of clinically relevant cardiac arrhythmia, known active tuberculosis, a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years, a history of life-threatening pulmonary obstruction, a history of cystic fibrosis, clinically evident bronchiectasis, a history of significant alcohol or drug abuse Patients who have undergone thoracotomy with pulmonary resection Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits. Pregnant or nursing women Women of childbearing potential not using two effective method of birth control (one barrier and one non-barrier). Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years Patients who have previously been randomized in this study or are currently participating in another study Patients who are unable to comply with pulmonary medication restrictions prior to randomization Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to Screening Visit Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 1744 CL low dose/tiotropium bromide<br>BI 1744 CL low dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation | Drug: BI 1744 CL/tiotropium bromide fixed dose combination<br>* BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation<br>Device: Respimat® Inhaler<br> <br> |
| Experimental: BI1744CL medium dose/tiotropium bromide<br>BI 1744 CL medium dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation | Drug: BI 1744 CL/tiotropium bromide fixed dose combination<br>* BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation<br>Device: Respimat® Inhaler<br> <br> |
| Experimental: BI 1744 CL high dose/tiotropium bromide<br>BI 1744 CL high dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation | Drug: BI 1744 CL/tiotropium bromide fixed dose combination<br>* BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation<br>Device: Respimat® Inhaler<br> <br> |
| Experimental: tiotropium bromide<br>tiotropium bromide; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation | Drug: tiotropium bromide<br>* tiotropium bromide; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation<br>Device: Respimat® Inhaler<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Response [L] After 4 Weeks of Treatment | Trough FEV1 (Forced expiratory volume in 1 second) was defined as the mean of the two FEV1 values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response was defined as the change from baseline in trough FEV1. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed). | Baseline and 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Response [L] After 1 and 2 Weeks of Treatment. | Trough FEV1 (forced expiratory volume in 1 second) was defined as the mean of the 2 FEV1 values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response was defined as the change from baseline in trough FEV1. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 15. | Baseline, 1 week and 2 weeks | 
| Trough FVC Response [L] After 1, 2 and 4 Weeks of Treatment | Trough FVC (forced vital capacity) was defined as the mean of the 2 FVC values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FVC response was defined as the change from baseline in trough FVC. Baseline FVC was defined as the mean of the 2 pre-treatment FVC values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29. | Baseline, 1 week, 2 weeks and 4 weeks | 
| FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment | Response is defined as change from the baseline value. AUC(0-3h) (area under the curve) was calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29. | 1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks | 
| FVC AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment. | FVC (forced vital capacity) AUC(0-3h) response is defined as change from the baseline value. AUC(0-3h) was calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres. Baseline FVC was defined as the mean of the 2 pre-treatment FVC values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29. | 1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks | 
| PEF AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment. | PEF (peak expiratory flow rate L/min) AUC(0-3h) response is defined as change from the baseline value. AUC(0-3h) will be calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres/min. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29. | 1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks | 
| FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment | FEV1 (forced expiratory volume in 1 second) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed). | 1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29) | 
| FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment | FVC (forced vital capacity) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). | 1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29) | 
| PEF AUC(0-6h) Response [L] After 4 Weeks of Treatment | PEF (peak expiratory flow rate L/min) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). | 1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29) | 
| FEV1 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment | FEV1 (forced expiratory volume in 1 second) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29. | 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks | 
| FVC Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment | FVC (forced vital capacity) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29. | 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks | 
| PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment | PEF (peak expiratory flow rate L/min) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29. | 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks | 
| FEV1 and PEF (Unsupervised) AUC(0-6h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment | AUC(0-6h) for FEV1, and PEF (unsupervised) were not studied because the pertinent information from the unsupervised pulmonary function tests was for the time interval from 9 to 12 hours post-dosing. | After first administration, 1 week, 2 weeks and 4 weeks | 
| FEV1 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment | FEV1 (forced expiratory volume in 1 second) AUC(6-12h) response is defined as change from the baseline value. AUC(6-12h) will be calculated as the area under the curve from 6 to 12 hours on the various test days using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29. | 6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks | 
| PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment | PEF (peak expiratory flow rate L/min) AUC(6-12h) response is defined as change from the baseline value. AUC(6-12h) will be calculated as the area under the curve from 6 to 12 hours on the various test days using the trapezoidal rule, divided by the full duration (6 hours) to report in litres/min. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication. The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed). Comparisons between groups are presented for Day 29. | 6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks | 
| Weekly Mean Pre-dose Morning PEF [L/Min] | The patient will record twice daily peak flow measurements using an Asthma Monitor®Am2+ (AM2+) device. Morning measurements will be performed immediately upon arising after the patient has cleared out mucus, prior to administration of trial and/or rescue medication. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). | Throughout the 4 week treatment period | 
| Weekly Mean Evening PEF [L/Min] | The patient will record twice daily peak flow measurements using an AM2+ device. The evening measurement will be performed at bedtime. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). | Throughout the 4 weeks treatment period | 
| Weekly Mean Number of Occasions of Rescue Therapy Used Per Day | The means are adjusted, Based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). | Throughout the 4 weeks treatment period | 
| Physician's Global Evaluation | Measured a 8-point scale, from 1 (poor) to 8 (excellent), as judged by the physician, over 4 weeks of treatment. The physician made a global evaluation at the end of the Baseline Period (Test Day 1) and at each visit thereafter. These assessments were made prior to pulmonary function testing and reflected the physician's opinion of the patient's overall clinical condition. This evaluation was based on the need for concomitant medication, number and severity of COPD exacerbations since the last visit, severity of cough, ability to exercise, amount of wheezing, and other relevant clinical observations. The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). | 1 week, 2 weeks and 4 weeks | 
| Patient's Global Rating | Patient's Global Rating at the end of the 4 week treatment period. Patients rated their health (respiratory condition) at Day 29 (compared to the day before they commenced treatment with study medication) on a 7-point scale as very much better (1), much better (2), a little better (3), no change (4), a little worse (5), much worse (6), or very much worse (7). The assessment was made prior to pulmonary function testing and all other study procedures. The Patient's Global Rating was also completed before the Physician's Global Evaluation. The means are adjusted, based on an ANCOVA with terms for treatment, centre (centre random, treatment effect fixed). | 4 weeks | 
| Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities | Possible clinically significant anormalities (laboratory data); marked changes from baseline for vital signs, notable change in ECG and new onset of ECG abnormalities. New abnormal findings or worsening of baseline conditions were reported as Adverse Events (AEs). All AEs with an onset after the first dose of study medication up to 21 days after the last dose of study medication were to have been assigned to the Treatment Period. | From first dose up to 21 days after last dose of study medication. | 
| Cmax,ss Olodaterol [pg/mL] | Maximum measured concentration of Olodaterol in plasma at steady state (Cmax,ss) after 4 weeks of treatment. No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure. | Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose. | 
| Tmax,ss Olodaterol [h] | Time from last dosing to maximum concentration of Olodaterol in plasma at steady state (tmax,ss) after 4 weeks treatment. No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure. | Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose. | 
| AUC(0-1h,ss) Olodaterol [pg*h/mL] | Area under the concentration-time curve of Olodaterol in plasma at steady state (AUC(0-1h,ss)) from 0 to 1 hour post dosing after 4 weeks of treatment. No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure. | Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose. | 
| Cmax,ss Tiotropium [pg/mL] | Maximum measured concentration of Tiotropium in plasma at steady state (Cmax,ss) after 4 weeks treatment. | Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose. | 
| Tmax,ss Tiotropium [h] | Time from last dosing to maximum concentration of Tiotropium in plasma at steady state (tmax,ss) after 4 weeks of treatment. | Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose. | 
| AUC(0-3h,ss) Tiotropium [pg*h/mL] | Area under the concentration-time curve of Tiotropium at steady state (AUC(0-3h,ss)) from 0 to 3 hours post dosing after 4 weeks of treatment. | Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose. |