Efficacy and Safety of 4 Weeks of Treatment With Orally Inhaled BI1744/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 microgram 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, Cross-over Study to Assess the Efficacy and Safety of 4 Weeks of Once Daily Treatment of 2 Doses of Orally Inhaled BI 1744 CL, Each in Fixed Dose Combination (FDC) With 5 Microgram Tiotropium Bromide (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 plus 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 >= 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). additional 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 additional 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: Crossover 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 plus tiotropium bromide<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 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 plus tiotropium bromide<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> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Expiratory Volume in One Second (FEV1) Response [L] After Four Weeks of Treatment. | Trough FEV1 was defined as the mean of the 2 FEV1 values at the end of the dosing interval, 24 hours post-drug administration. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1 hour (h), 10 minutes (min) before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Response [L] After 2 Weeks of Treatment | Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 15 | 
| Individual FEV1 Measurements | Individual FEV1 measurements [L] at each time point on Day 29. The presented means are adjusted. | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 | 
| FEV1 AUC 0-3h, Response | FEV1 Area Under the Curve (AUC) 0-3h, response [L] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 | 
| FEV1 Peak 0-3h Response | FEV1 peak value over the time from 0 to 3 hours (peak 0-3h) response [L] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 | 
| FEV1, AUC (0-6h) Response | FEV1, AUC (0-6h) response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 | 
| FEV1 (Unsupervised) AUC (6-12h) Response | FEV1 (unsupervised) AUC (6-12h) response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 6 hours (h), 9h and 12h after drug administration on day 29 | 
| Trough FVC Response | Trough Forced Vital Capacity (FVC) response [L] on days 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 15, in addition 4h, 5h, 6h after drug administration on day 29 | 
| Individual FVC Measurements | Individual FVC measurements [L] at each time point The categories correspond to the planned times for FVC measurements on Day 29. The presented means are adjusted. | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 | 
| FVC AUC (0-3h) Response | FVC AUC (0-3h) response [L] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 | 
| FVC AUC (0-6h) Response | FVC AUC (0-6h) response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 | 
| FVC Peak 0-3h Response | FVC peak 0-3h response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 29 | 
| PEFR AUC (0-3h) Response | Peak Expiratory Flow Rate (PEFR) AUC (0-3h) response [L/min] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 | 
| PEFR Peak 0-3h Response | PEFR peak 0-3h response [L/min] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 | 
| PEFR AUC (6-12h) Response | PEFR AUC (6-12h) response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed). | 1 hour (h) and 10 minutes before drug administration on day 1 and 6h, 9h and 12h after drug administration on day 29 | 
| Weekly Mean Morning PEFR | Weekly mean morning PEFR [L/min] on weeks 1,2,3 and 4. The presented means are adjusted. | Weeks 1,2,3 and 4 | 
| Weekly Mean Evening PEFR | Weekly mean evening PEFR [L/min] on weeks 1,2,3 and 4. The presented means are adjusted. | Weeks 1,2,3 and 4 | 
| Weekly Mean Number of Occasions of Rescue Therapy Used Per Day (PRN Salbutamol [Albuterol]) | Weekly mean number of occasions of rescue therapy used per day (as occasion require (PRN) salbutamol [albuterol]) on weeks 1,2,3 and 4. The means presented are the adjusted mean of weekly mean. | Weeks 1,2,3 and 4 | 
| Patient Global Rating | Patient global rating scores treatment comparison after 4 weeks The score was evaluated on a 7-point scale : 1 : very much better 2 : much better 3 : a little better 4 : no change 5 : a little worse 6 : much worse 7 : very much worse The presented means are adjusted. | 4 weeks | 
| Physician's Global Evaluation | Physician's global evaluation score on days 15 and 29 The score was evaluated on a 8-points scale : Poor : 1,2 Fair : 3,4 Good : 5,6 Excellent : 7,8 The presented means are adjusted | Days 15 and 29 | 
| Clinically Significant Abnormalities for Blood Chemistry, Haematology, Urinalysis and Physical Examination | Clinically significant abnormalities for blood chemistry, haematology, urinalysis and physical examination | 14 weeks | 
| Overall Marked Changes From Baseline in Vital Signs | Overall marked changes from baseline in systolic blood pressure, diastolic blood pressure and pulse rate. | Baseline to week 14 | 
| 12-lead ECG Heart Rate | 12-lead Electrocardiogram (ECG) Heart rate baseline and change from baseline values at other time points in Beats Per Minute (BPM) Statistics for each planned time from baseline to day 29. | Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29 | 
| 12-lead ECG PR Intervals | 12-lead ECG PR intervals baseline and change from baseline at other timepoints in milliseconds. Statistics for each planned time from baseline to day 29. | Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29 | 
| 12-lead ECG QRS Intervals | 12-lead ECG QRS intervals baseline and change from baseline at other time points in milliseconds Statistics for each planned time from baseline to day 29. | Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29 | 
| 12-lead ECG QTcF Intervals | 12-lead ECG corrected heart rate (QT) interval, using Fridericia method (QTcF), baseline and change from baseline at other time points in milliseconds. Statistics for each planned time from baseline to day 29. | Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29 | 
| 12-lead ECG QTcB Intervals | 12-lead ECG heart rate corrected QT interval, using Bazett method (QTcB), baseline and change from baseline at other time points in milliseconds. Statistics for each planned time from baseline to day 29. | Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29 | 
| 12-lead ECG QT Intervals | 12-lead ECG QT intervals baseline and change from baseline at other time points in milliseconds. Statistics for each planned time from baseline to day 29. | Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29 | 
| AUC (0-6H) FEV1 (Unsupervised), AUC (0-6H) PEFR (Unsupervised), FVC Peak (0-3h), AUC (6-12h) FEV1 (Unsupervised), AUC (6-12h) PEFR (Unsupervised), Individual PEFR Measurements (Supervised and Unsupervised), Individual PEFR Measurements (Unsupervised) | AUC (0-6h) for FEV1, and PEFR (unsupervised) after first dose and after 2 and 4 weeks of treatment were not analysed in the study report because the pertinent information from the unsupervised Pulmonary Function Tests (PFTs) was for the time interval from 6 to 12 hours post-dosing. FVC peak 0-3h response after the first dose and at Week 2 (supervised) and AUC (6-12h) for FEV1 and PEFR after the first dose and at Week 2 (unsupervised) were not analysed in the study report. Individual PEFR (supervised) measurements and individual FEV1 and PEFR (unsupervised) measurements at each time point were not analysed in the study report. | 4 weeks |