Effect of Treatment BI 1744 CL (5 and 10 mcg) Versus Placebo on Exercise Endurance Time During Constant Work Rate Cycle Ergometry II

Study Overview
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Brief Summary
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To compare the effects of BI 1744 CL versus placebo on exercise tolerance after 6 weeks of treatment in patients with Chronic Obstructive Pulmonary Disease.

Official Title
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Randomised, Double-blind, Placebo-controlled, 3-way Cross-over Study to Determine the Effect of Treatment of Orally Inhaled BI 1744 CL (5 µg [2 Actuations of 2.5 µg] and 10 µg [2 Actuations of 5 µg]) Delivered by the Respimat® Inhaler on Exercise Endurance Time During Constant Work Rate Cycle Ergometry in Patients With Chronic Obstructive Pulmonary Disease.

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Olodaterol (BI 1744)
* Drug: Olodaterol (BI 1744)
* Drug: Placebo
* Drug: Olodaterol (BI1744)
* Drug: Olodaterol (BI 1744) placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed informed consent prior to participation. Diagnosis of chronic obstructive pulmonary disease and post-bronchodilator FEV1(Forced Expiratory Volume in 1 sec) <80% of predicted normal and post-bronchodilator FEV1(Forced Expiratory Volume in 1 sec)/FVC of < 70% at Visit 1. Male or female between 40 and 75 years of age. Current or ex-smokers with smoking history of more than 10-pack years. Able to perform technically acceptable pulmonary function tests, multiple exercise tests and able to maintain records. Able to inhale medication in a competent manner from a metered-dose inhaler and Respimat inhaler. Exclusion criteria: Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an SGOT >x2 ULN, SGPT >x2 ULN, bilirubin >x2 ULN or creatinine >x2 ULN. Patients with a history of asthma and/or total blood eosinophil count of 600 cells/mm3. Patients with thyrotoxicosis, paroxysmal tachycardia (>100 beats per minute). Patients with a history of myocardial infarction within 1 year of screening visit, unstable or life-threatening cardiac arrhythmia, hospitalization for heart failure within the past year, known active tuberculosis, a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years, life-threatening pulmonary obstruction, cystic fibrosis, clinically evident bronchiectasis, significant alcohol or drug abuse or contraindications to exercise. Patients who have undergone thoracotomy with pulmonary resection. Patients being treated with oral beta-adrenergics or oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day. Patients who regularly use daytime oxygen for more than one hour per day. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit or patients who are currently in a pulmonary rehabilitation program. Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnea. Pregnant or nursing women. Women of childbearing potential not using two effective methods of birth control (one barrier and one non-barrier).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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: Olodaterol (BI 1744) Low<br>Low dose inhaled orally once daily from the Respimat inhaler | Drug: Olodaterol (BI 1744)<br>* Comparison of low and high dose on exercise endurance time in COPD patients<br>Drug: Olodaterol (BI1744)<br>* Comparison of low and high dose on exercise endurance time in COPD patients<br>Drug: Olodaterol (BI 1744) placebo<br>* Placebo that represents olodaterol<br>|
| Experimental: Olodaterol (BI 1744) High<br>High dose inhaled orally once daily from the Respimat inhaler | Drug: Olodaterol (BI 1744)<br>* Comparison of low and high dose on exercise endurance time in COPD patients<br>|
| Placebo Comparator: Placebo<br>Olodaterol (BI 1744) placebo inhaled orally from the Respimat inhaler | Drug: Placebo<br>* Comparison of low and high dose and placebo on exercise endurance time in COPD patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Endurance Time After 6 Weeks | Primary endpoint was endurance time during constant work rate ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. Mixed effects model on log10 transformation data. Adjusted means are back transformed to report as geometric means. Standard errors (SEs) are calculated using the delta method. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Inspiratory Capacity at Isotime After 6 Weeks | Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods. | 6 weeks | 
| Adjusted Mean Borg Scale of Breathing Discomfort at Isotime After 6 Weeks | Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods. Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. | 6 weeks | 
| Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks |  | 6 weeks | 
| Adjusted Mean Inspiratory Capacity at End of Exercise After 6 Weeks |  | 6 weeks | 
| Adjusted Mean Borg Scale of Breathing Discomfort at Pre-exercise After 6 Weeks | Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. | 6 weeks | 
| Adjusted Mean Borg Scale of Breathing Discomfort at End of Exercise After 6 Weeks | Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. | 6 weeks | 
| Adjusted Mean Functional Residual Capacity 30 Minutes Pre-dose After 6 Weeks | Measured using body plethysmography | 6 weeks | 
| Adjusted Mean Functional Residual Capacity 1 Hour Post-dose After 6 Weeks | Measured using body plethysmography | 6 weeks | 
| Adjusted Mean Inspiratory Capacity 30 Minutes Pre-dose After 6 Weeks | Measured using body plethysmography | 6 weeks | 
| Adjusted Mean Inspiratory Capacity 1 Hour Post-dose After 6 Weeks |  | 6 weeks | 
| Adjusted Mean Total Lung Capacity 30 Minutes Pre-dose After 6 Weeks | Measured using body plethysmography | 6 weeks | 
| Adjusted Mean Total Lung Capacity 1 Hour Post-dose After 6 Weeks | Measured using body plethysmography | 6 weeks | 
| Adjusted Mean Forced Expiratory Volume in 1 Second, 30 Minutes Pre-dose After 6 Weeks |  | 6 weeks | 
| Adjusted Mean Forced Expiratory Volume in 1 Second, 1 Hour Post-dose After 6 Weeks |  | 6 weeks | 
| Adjusted Mean Forced Vital Capacity, 30 Minutes Pre-dose After 6 Weeks |  | 6 weeks | 
| Adjusted Mean Forced Vital Capacity, 1 Hour Post-dose After 6 Weeks |  | 6 weeks | 
| Adjusted Mean Peak Expiratory Flow Rate, 30 Minutes Pre-dose After 6 Weeks |  | 6 weeks | 
| Adjusted Mean Peak Expiratory Flow Rate, 1 Hour Post-dose After 6 Weeks |  | 6 weeks | 
| Change From Baseline to Day 43 in Blood Pressure | Change from Baseline to Day 43 in Blood Pressure with spirometry. Baseline is defined as mean of pre-treatment values at a given time point. | Baseline and Week 6 | 
| Change From Baseline to Day 43 in Pulse Rate | Change from Baseline to Day 43 in Pulse rate with spirometry. Baseline is defined as mean of pre-treatment values at a given time point. | Baseline and Week 6 | 
| Number of Patients With Notable Changes in Heart Rate | Number of Patients with notable changes in heart rate (HR). Notable HR increase defined as >=25% increase and on-treatment HR > 100 bpm; Notable HR decrease defined as >=25% decrease and on-treatment HR < 50 bpm. | Baseline and Week 6 | 
| Number of Patients With Notable Increase in PR Intervals | Number of Patients with notable increase in PR intervals. Notable PR interval increase defined as >=25% increase and on-treatment PR interval > 200 ms. | Baseline and Week 6 | 
| Number of Patients With Notable Increase in QRS Intervals | Number of Patients with notable increase in QRS intervals. Notable QRS interval increase defined as >=10% increase and on-treatment QRS interval > 110 ms. | Baseline and Week 6 |