An Efficacy and Safety Study to Compare Three Doses of BEA 2180 BR to Tiotropium and Placebo in the Respimat Inhaler.

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to compare the bronchodilator efficacy of three doses (50 µg, 100 µg and 200 µg) of BEA 2180 delivered by the Respimat® once daily to placebo and tiotropium bromide delivered by the Respimat® in patients with COPD. Additional objectives include comparing the effects on dyspnea and health status.

Official Title
-----------------
A Multinational, Randomised, Double-blind, Placebo- and Active-controlled, Parallel Group Efficacy and Safety Comparison Over 24 Weeks of Three Doses (50µg, 100µg, 200µg) of BEA 2180 BR to Tiotropium 5µg, Delivered by the Respimat Inhaler and Placebo in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
-----------------
Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
-----------------
* Drug: BEA 2180 BR
* Drug: Tiotropium Bromide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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 (P95 4381) and must meet the following spirometric criteria: Patients must have relatively stable, moderate to severe airway obstruction with an FEV1 (post-bronchodilator, 30 minutes post salbutamol/albuterol) <80% of predicted normal and FEV1 less than or equal to 70% of FVC at the PFTs at Visit 1 (screening). 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 who have never smoked cigarettes must be excluded. Patients must be able to perform technically acceptable pulmonary function tests and electronic PEFR measurements, and must be able to maintain records (Patient Daily 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 (Appendix I) Exclusion Criteria: Patients with significant diseases other than COPD will be excluded. A significant disease is defined as a disease which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient ability to participate in the study. Patients with clinically relevant abnormal baseline haematology, blood chemistry or urinalysis, if the abnormality defines a significant disease as defined in exclusion criterion No. 1. Patients with a recent history (one year or less) of myocardial infarction. Patients with any unstable or life-threatening cardiac arrhythmia. Patients who have been hospitalized for heart failure within the past 3 years. Patients with a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed. Patients with known symptomatic prostatic hyperplasia or bladder neck obstruction as defined in exclusion criteria No. 1. Patients with known narrow-angle glaucoma. Patients with asthma or a history of asthma. Patients with a history of life-threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis. Patients with known active tuberculosis. Patients with a history of and/or active significant alcohol or drug abuse. See exclusion criterion No. 1.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching Placebo | Drug: Placebo<br>* Solution<br>|
| Experimental: BEA 2180 BR low dose<br>Low dose | Drug: BEA 2180 BR<br>* Solution<br>|
| Experimental: BEA 2180 BR medium dose<br>Medium dose | Drug: BEA 2180 BR<br>* Solution<br>|
| Experimental: BEA 2180 BR high dose<br>High dose | Drug: BEA 2180 BR<br>* Solution<br>|
| Experimental: Tiotropium Bromide<br>Tiotropium Bromide | Drug: Tiotropium Bromide<br>* Solution<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Expiratory Volume in One Second (FEV1) Response After 24 Weeks | Trough Forced expiratory volume in one second (FEV1) response was defined as the change from baseline in trough FEV1. Trough FEV1 was defined as the mean of the two FEV1 measurements recorded at the pre-dose measurements (40 and 15 minutes before the drug administration) at the end of the dosing interval (24 hours post previous drug administration from the Respimat® Inhaler). Baseline FEV1 was pre-treatment FEV1 values measured at Day 1 of treatment period (baseline) prior to administration of the first dose of study medication, which was the mean of the measurements recorded from the pulmonary function tests taken at 40 and 15 minutes prior to drug administration at Day 1 of treatment period. | 40 minutes (min) and 15 min before drug administration at baseline (Day 1 of treatment period) and Week 24. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Expiratory Volume in One Second (FEV1) Response After 1, 2, 4, 8, 12, and 18 Weeks | Trough Forced expiratory volume in one second (FEV1) response was defined as the change from baseline in trough FEV1. Trough FEV1 was defined as the mean of the two FEV1 measurements recorded at the pre-dose measurements (40 and 15 minutes before the drug administration) at the end of the dosing interval (24 hours post previous drug administration from the Respimat® Inhaler). Baseline FEV1 was pre-treatment FEV1 values measured at Day 1 of treatment period (baseline) prior to administration of the first dose of study medication, which was the mean of the measurements recorded from the pulmonary function tests taken at 40 and 15 minutes prior to drug administration at Day 1 of treatment period. | 40 minutes (min) and 15 min before drug administration at baseline (Day 1 of treatment period) and Week 1, 2, 4, 8, 12 and 18. | 
| Trough Forced Vital Capacity (FVC) Response After 1, 2, 4, 8, 12, 18, and 24 Weeks | Trough forced vital capacity (FVC) response was defined as the change from baseline in trough FVC. Trough FVC was defined as the mean of the two FVC measurements recorded at the pre-dose measurements (40 and 15 minutes before drug administration) at the end of the dosing interval (24 hours post previous drug administration from the Respimat® Inhaler), which were obtained through spirometry at the same time points as for forced expiratory volume in one second. Baseline FVC was the mean of the two measurements of FVC taken at 40 and 15 minutes before drug administration at Day 1 of treatment period. | 40 minutes (min) and 15 min before drug administration at baseline (Day 1 of treatment period) and Week 1, 2, 4, 8, 12, 18, and 24. | 
| Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) Response After 0, 4, 12 and 24 Weeks | Forced expiratory volume in one second (FEV1) area under the curve from 0 to 3 hours (AUC0-3h) response after 0, 4, 12 and 24 weeks are reported. The FEV1 AUC0-3h response is the area under the curve from 0 to 3 hours post drug administration for change from baseline values of FEV1. The area under the curve (AUC) is calculated as the area under the curve from 0 to 3 hours at weeks 0, 4, 12 and 24 using the trapezoidal rule and using planned time, divided by the full duration (3 hours) to report in litres. The mean of the pre-dose values (at 40 minutes and 15 minutes before dosing) are used with a time value of zero for calculating the AUC values starting at zero. The baseline FEV1 is the mean of the two measurements taken at 40 and 15 minutes before drug administration at Day 1 of treatment period. | 40 minutes (min) and 15 min before drug administration and 15 min, 30 min, 60 min, 2 hours, 3 hours after drug administration at Week 0 (Day 1 of treatment period), 4, 12, 24. | 
| Forced Vital Capacity (FVC) Area Under the Curve From 0 to 3 Hours (AUC0-3h) Response After 0, 4, 12 and 24 Weeks | Forced vital capacity (FVC) area under the curve from 0 to 3 hours (AUC0-3h) response after 0, 4, 12 and 24 weeks are reported. The FVC AUC0-3h response is the area under the curve from 0 to 3 hours post drug administration for change from baseline values of FVC. The area under the curve (AUC) is calculated as the area under the curve from 0 to 3 hours at weeks 0, 4, 12 and 24 using the trapezoidal rule and using planned time, divided by the full duration (3 hours) to report in litres. The mean of the pre-dose values (at 40 minutes and 15 minutes before dosing) are used with a time value of zero for calculating the AUC values starting at zero. The baseline FVC is the mean of the two measurements taken at 40 and 15 minutes before drug administration at Day 1 of treatment period. | 40 minutes (min) and 15 min before drug administration and 15 min, 30 min, 60 min, 2 hours, 3 hours after drug administration at Week 0 (Day 1 of treatment period), 4, 12, 24. | 
| Forced Expiratory Volume in One Second (FEV1) Peak Response After 0, 4, 12, and 24 Weeks | Forced expiratory volume in one second (FEV1) peak response after 0, 4, 12, and 24 weeks were reported. Peak FEV1 response was the maximum change from baseline for the post-dose measurements of FEV1. Baseline FEV1 is the mean of the two measurements taken at 40 and 15 minutes before drug administration. | 40 minutes (min) and 15 min before drug administration and 15 min, 30 min, 60 min, 2 hours, 3 hours after drug administration at Week 0 (Day 1 of treatment period), 4, 12, 24. | 
| Forced Vital Capacity (FVC) Peak Response After 0, 4, 12, and 24 Weeks | Forced Vital Capacity (FVC) peak response after 0, 4, 12, and 24 weeks were reported. Peak FVC response was the maximum change from baseline for the post-dose measurements of FVC. Baseline FVC is the mean of the two measurements taken at 40 and 15 minutes before drug administration. | 40 minutes (min) and 15 min before drug administration and 15 min, 30 min, 60 min, 2 hours, 3 hours after drug administration at Week 0 (Day 1 of treatment period), 4, 12, 24. | 
| Individual Forced Expiratory Volume in One Second (FEV1) Measurements at Each Time Point | Individual Forced expiratory volume in one second (FEV1) values measured at each time points at Week 0, 4, 12, and 24 were reported. | 15 minutes (min), 30 min, 1 hour (h), 2 h, 3 h after drug administration at Week 0 (Day 1 of treatment period), 4, 12, and 24. At 0 min (at drug administration) at Week 4, 12, and 24. | 
| Individual Forced Vital Capacity (FVC) Measurements at Each Time Point | Individual Forced Vital Capacity (FVC) values measured at each time point at Week 0, 4, 12, and 24 were reported. | 15 minutes (min), 30 min, 1 hour (h), 2 h, 3 h after drug administration at Week 0 (Day 1 of treatment period), 4, 12, and 24. At 0 min (at drug administration) at Week 4, 12, and 24. | 
| Trough Forced Expiratory Volume in One Second (FEV1) Response on Day 3 and 5 | Trough Forced expiratory volume in one second (FEV1) response on Day 3 and 5 are reported, for which the FEV1 response is the change from baseline in trough FEV1. Trough FEV1 for respective day (Day 3 or Day 5)was defined as the mean of the two FEV1 measurements recorded at the pre-dose measurements (40 and 15 minutes before the drug administration) at the end of the dosing interval (24 hours post previous drug administration from the Respimat® Inhaler) at that day. Baseline FEV1 was pre-treatment FEV1 values measured at Day 1 of treatment period (baseline) prior to administration of the first dose of study medication, which was the mean of the measurements recorded from the pulmonary function tests taken at 40 and 15 minutes prior to drug administration at Day 1 of treatment period. | 40 minutes (min) and 15 min before drug administration at Day 1 (baseline) and Day 3 and 5 of treatment period. | 
| Forced Expiratory Volume in One Second (FEV1) at 3 Minutes and 10 Minutes Following Drug Administration | Forced expiratory volume in one second (FEV1) values at 3 minutes and 10 minutes following drug administration at Week 0, 4, 12, and 24 are reported. | 3 minutes (min) and 10 after drug administration at Week 0 (Day 1 of treatment period), 4, 12, and 24. | 
| Forced Vital Capacity (FVC) at 3 Minutes and 10 Minutes Following Drug Administration | Forced Vital Capacity (FVC) values at 3 minutes and 10 minutes following drug administration at Week 0, 4, 12, and 24 are reported. | 3 minutes (min) and 10 min after drug administration at Week 0 (Day 1 of treatment period), 4, 12, and 24. | 
| Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) | The patient recorded twice daily peak flow measurements with an electronic peak flow meter throughout the entire evaluation period. Morning measurements were performed immediately upon arising after the patient had cleared out mucus, prior to administration of trial and/or rescue medication. The evening measurements were performed at bedtime. The weekly mean morning peak expiratory flow rate (PEFR) is reported. | Assessed before drug administration per day during 24 weeks with weekly mean values reporting. | 
| Weekly Mean Evening Peak Expiratory Flow Rate (PEFR) | The patient recorded twice daily peak flow measurements with an electronic peak flow meter throughout the entire evaluation period. Morning measurements were performed immediately upon arising after the patient had cleared out mucus, prior to administration of trial and/or rescue medication. The evening measurements were performed at bedtime. The weekly mean of evening peak expiratory flow rate (PEFR) is reported. | Assessed at bed time per day during 24 weeks with weekly mean values reporting. | 
| Weekly Mean Number of Occasions of Rescue Therapy Used Per Day (as Occasion Requires (PRN) Salbutamol [Albuterol]) | The patient recorded the number of occasions salbutamol (albuterol) Metered Dose Inhaler (MDI) was used each day and night during the entire evaluation period. The weekly mean number of occasions of rescue therapy used per day (PRN salbutamol [albuterol]) is reported. | Assessed once per day during 24 weeks with weekly mean values reporting. | 
| Physician's Global Evaluation | Physicians make a global evaluation reflecting the physician's global opinion of the overall clinical condition of the patient as poor (score 1 or 2), fair (score 3 or 4), good (score 5 or 6), or excellent (score 7 or 8). These assessments are made prior to pulmonary function testing and are summarized on pulmonary function test days. This evaluation was based on the need for concomitant medication, number and severity of exacerbations since the last visit, severity of cough, ability to exercise, amount of wheezing, and other relevant clinical observations. The score ranges from 1 to 8 with higher score indicating better overall clinical condition. | At Week 0, 4, 12, and 24. | 
| Transition Dyspnea Index - Functional Impairment Domain Score | The transitional dyspnea index (TDI) evaluates the patient's condition related to breathlessness. The TDI includes three domains: functional impairment, magnitude of task, and magnitude of effort. The TDI domain score of functional impairment is reported, which domain score ranges from -3 (major deterioration in the ability of working and doing activities due to shortness of breath; the worst score) to 3 (major improvement in the ability of working and doing activities; mild restriction on full activities due to the improvement of shortness of breath; the best score). | At Week 0 (baseline), 4, 12 and 24. | 
| Transition Dyspnea Index - Magnitude of Task Domain Score | The transitional dyspnea index (TDI) evaluates the patient's condition related to breathlessness. The TDI includes three domains: functional impairment, magnitude of task, and magnitude of effort. The TDI domain score of magnitude of task is reported, which domain score ranges from -3 (major deterioration from baseline status; the worst score) to 3 (major improvement from baseline status; the best score). | At week 0 (baseline), 4, 12 and 24 | 
| Transition Dyspnea Index - Magnitude of Effort Domain Score | The transitional dyspnea index (TDI) evaluates the patient's condition related to breathlessness. The TDI includes three domains: functional impairment, magnitude of task, and magnitude of effort. The TDI domain score of magnitude of effort is reported, which sub-score ranges from -3 (severe decrease in effort from baseline to avoid shortness of breath. Activities now take 50-100% longer to complete than required at baseline; the worst score) to 3 (Able to do things with much greater effort than previously with few pauses. Activities may be performed 50- 100% more rapidly than at baseline; the best score). | At Week 0 (baseline), 4, 12 and 24 | 
| St. George's Respiratory Questionnaire (SGRQ) Total Score | The St. George's Respiratory Questionnaire (SGRQ) is a well-established, self-completed tool measuring health-related quality of life in patients with diseases of airways obstruction on three aspects of symptoms, activity, and impacts. The total SGRQ score is reported, which ranges from 0 (the best score) to 100 (the worst score) with smaller score value indicating less limitations due to breathlessness and better quality of life. | At Week 0, 4, 12, and 24. | 
| 36-item-health Survey (SF-36) 8 Domain Scores at Baseline | The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function (10 questions), role physical (4 questions), Bodily pain (2 questions), General physical health (5 questions), Vitality (4 questions), Social functioning (2 questions), role emotional (3 questions), and General mental health (5 questions). Each domain score is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the score value, the better the health condition. | At baseline (Week 0, Day 1 of treatment period). | 
| 36-item-health Survey (SF-36) - Physical Function Domain Score | The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health. The domain score of physical function (based on 10 questions) is reported, which is the weighted sum of the questions in corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the better the physical function. | At Week 4, 12, and 24. | 
| 36-item-health Survey (SF-36) - Role Physical Domain Score | The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health. The domain score of role limitations due to physical health problems (based on 4 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the less limitations in roles due to physical health problems. | At Week 4, 12, and 24. | 
| 36-item-health Survey (SF-36) - Bodily Pain Domain Score | The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health. The domain score of bodily pain (based on 2 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the less severer the bodily pain. | At Week 4, 12, and 24. | 
| 36-item-health Survey (SF-36) - General Physical Health Domain Score | The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health. The domain score of general physical health (based on 5 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the better the physical health in general. | At Week 4, 12, and 24. | 
| 36-item-health Survey (SF-36) - Vitality Domain Score | The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health. The domain score of vitality (based on 4 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the more vitality and less fatigue one has. | At Week 4, 12, and 24. | 
| 36-item-health Survey (SF-36) - Social Functioning Domain Score | The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health. The domain score of Social functioning (based on 2 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the better the social functioning. | At Week 4, 12, and 24. | 
| 36-item-health Survey (SF-36) - Role Emotional Domain Score | The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health. The domain score of role emotional (based on 4 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the less limitation in roles due to emotional problems. | At Week 4, 12, and 24. | 
| 36-item-health Survey (SF-36) - General Mental Health Domain Score | The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health. The domain score of general mental health (based on 5 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the better the mental health in general. | At Week 4, 12, and 24. | 
| Number of Patients With at Least One Chronic Obstructive Pulmonary Disease (COPD) Exacerbation | Number of patients with at least one Chronic Obstructive Pulmonary Disease (COPD) exacerbation is reported. Incidence rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbation is reported. A Chronic Obstructive Pulmonary Disease (COPD) exacerbation is defined as a complex of lower respiratory events / symptoms (increase or new onset) related to the underlying COPD, with a duration of three days or more, requiring a change in treatment, where a complex of lower respiratory events / symptoms means at least two of the following: Shortness of breath, Sputum production (volume), Occurrence of purulent sputum, Cough, Wheezing, Chest tightness. | From first does until 30 days after the end of treatment, up to 205 days. | 
| Incidence Rate of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation | Incidence rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbation is reported. A Chronic Obstructive Pulmonary Disease (COPD) exacerbation is defined as a complex of lower respiratory events / symptoms (increase or new onset) related to the underlying COPD, with a duration of three days or more, requiring a change in treatment, where a complex of lower respiratory events / symptoms means at least two of the following: Shortness of breath, Sputum production (volume), Occurrence of purulent sputum, Cough, Wheezing, Chest tightness. | From first does until 30 days after the end of treatment, up to 205 days. |