Determining Optimal Free Dose Combination of Tiotropium Bromide and BI 1744 CL in 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 once daily dose of BI 1744 CL and tiotropium in free dose combination (delivered by the Respimat inhaler) after four week treatment in patients with COPD.

Official Title
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A Randomised, Double-blind, 8 Treatments, 4 Periods, Incomplete Crossover Study to Determine the Optimal Free Dose Combination of BI 1744 CL and Tiotropium Bromide (Both Delivered by the Respimat® Inhaler) After 4 Weeks Once Daily Treatment in Patients With COPD

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: olodaterol (BI 1744) low
* Drug: low tiotropium bromide
* Drug: olodaterol (BI 1744) high
* Drug: medium tiotropium bromide
* Drug: high tiotropium bromide
* Drug: Placebo
* Device: Respimat


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: All patients must sign an informed consent All patients must have a diagnosis of chronic obstructive pulmonary disease (COPD) must meet the following spirometric criteria: a post-bronchodilator forced expiratory flow in 1 second (FEV1) =<30% of predicted normal and <80% of predicted normal and a post bronchodilator FEV1 / forced vital capacity (FVC) <70% at Visit 1 4. Male or female patients, 40 years of age or older. 5. Patients must be current or ex-smokers with a smoking history of more than 10 pack years 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 (due to the known class side effect profile of ß2-agonists) a diagnosis of paroxysmal tachycardia - Patients with any of the following conditions: a history of myocardial infarction within 1 year of screening visit a diagnosis of clinically relevant cardiac arrhythmia a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years Patients who have undergone thoracotomy with pulmonary resection Patients being treated with the following concomitant medications: medications that prolong the QT/QTc interval oral Beta-adrenergics 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 - Pregnant or nursing women

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: olodaterol (BI 1744) low and placebo<br>low dose inhaled olodaterol orally once daily from the Respimat inhaler | Drug: olodaterol (BI 1744) low<br>* olodaterol (BI 1744) low<br>Drug: Placebo<br>* Placebo<br>Device: Respimat<br>* Respimat inhaler<br>|
| Experimental: olodaterol (BI 1744) low and low tio<br>low dose inhaled olodaterol and low dose inhaled tiotropium, both from the Respimat inhaler and once daily | Drug: olodaterol (BI 1744) low<br>* olodaterol (BI 1744) low<br>Drug: low tiotropium bromide<br>* low tiotropium bromide<br>Device: Respimat<br>* Respimat inhaler<br>|
| Experimental: olodaterol (BI 1744) low and medium tio<br>low dose inhaled olodaterol and medium dose inhaled tiotropium, both from the Respimat inhaler and once daily | Drug: olodaterol (BI 1744) low<br>* olodaterol (BI 1744) low<br>Drug: medium tiotropium bromide<br>* medium tiotropium bromide<br>Device: Respimat<br>* Respimat inhaler<br>|
| Experimental: olodaterol (BI 1744) low and high tio<br>low dose inhaled olodaterol and high dose inhaled tiotropium, both from the Respimat inhaler and once daily | Drug: olodaterol (BI 1744) low<br>* olodaterol (BI 1744) low<br>Drug: high tiotropium bromide<br>* high tiotropium bromide<br>Device: Respimat<br>* Respimat inhaler<br>|
| Experimental: olodaterol (BI 1744) high and placebo<br>high dose inhaled olodaterol orally once daily from the Respimat inhaler | Drug: olodaterol (BI 1744) high<br>* olodaterol (BI 1744) high<br>Drug: Placebo<br>* Placebo<br>Device: Respimat<br>* Respimat inhaler<br>|
| Experimental: Olodaterol (BI 1744) high and low tio<br>high dose inhaled olodaterol and low dose inhaled tiotropium, both from the Respimat inhaler and once daily | Drug: low tiotropium bromide<br>* low tiotropium bromide<br>Drug: olodaterol (BI 1744) high<br>* olodaterol (BI 1744) high<br>Device: Respimat<br>* Respimat inhaler<br>|
| Experimental: Olodaterol (BI 1744) high and medium tio<br>high dose inhaled olodaterol and medium dose inhaled tiotropium, both from the Respimat inhaler and once daily | Drug: olodaterol (BI 1744) high<br>* olodaterol (BI 1744) high<br>Drug: medium tiotropium bromide<br>* medium tiotropium bromide<br>Device: Respimat<br>* Respimat inhaler<br>|
| Experimental: Olodaterol (BI 1744) high and high tio<br>high dose inhaled olodaterol and high dose inhaled tiotropium, both from the Respimat inhaler and once daily | Drug: olodaterol (BI 1744) high<br>* olodaterol (BI 1744) high<br>Drug: high tiotropium bromide<br>* high tiotropium bromide<br>Device: Respimat<br>* Respimat inhaler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Response | Adjusted means of the trough forced expiratory volume in one second (FEV1) response (L) after four weeks treatment. The trough was defined as the mean of the 1 h pre-dose and 10 min pre-dose measurements on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 hour pre-dose and 10 minutes pre-dose on day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Vital Capacity (FVC) Response | Adjusted means of trough FVC (forced vital capacity) response [L] after 4 weeks treatment. The trough was defined as the mean of the 1 h pre-dose and 10 min pre-dose measurements on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 hour pre-dose and 10 minutes pre-dose on day 29 | 
| FEV1 AUC 0-3h and FEV1 AUC 0-6h Response | Adjusted means of forced expiratory volume in one second (FEV1) area under the curve (AUC) 0-3 hour and AUC 0-6 hour responses [L] after 4 weeks treatment calculated using the trapezoidal rule, divided by the duration (3 h, 6 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post dose for AUC0-3h and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h 4 h, 5 h, 6 h postdose for AUC0-6h on day 29 | 
| FEV1 AUC 0-3h Response After the First Dose | Adjusted means of Forced Expiratory Volume in One Second (FEV1) Area Under Curve (AUC) 0-3h response [L] after the first dose, calculated using the trapezoidal rule, divided by the duration (3 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 | 
| FEV1 Peak 0-3h Response | Adjusted means of the FEV1 peak value over the time from 0 to 3 hours (peak 0-3h) response [L] after 4 weeks of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29 | 
| FEV1 Peak 0-3h Response After the First Dose | Adjusted means of the FEV1 peak 0-3h response [L] after the first dose of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 | 
| FVC AUC 0-3h and FEV1 AUC 0-6h Responses | Adjusted means of the FVC AUC 0-3h and AUC 0-6h responses [L] after 4 weeks of treatment, calculated using the trapezoidal rule, divided by the duration (3 h, 6 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post dose for AUC0-3h and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h 4 h, 5 h, 6 h postdose for AUC0-6h on day 29 | 
| FVC AUC 0-3h Response After First Dose | Adjusted means of the FVC AUC 0-3h response [L] after first dose, calculated using the trapezoidal rule, divided by the duration (3 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on days 1 | 
| FVC Peak 0-3h Response | Adjusted means of the FVC peak 0-3h response [L] after 4 weeks of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29 | 
| FVC Peak 0-3h Response After the First Dose | Adjusted mean of the FVC peak 0-3h response [L] after the first dose. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 | 
| PEF AUC 0-3h and AUC 0-6h Responses | Adjusted means of the Peak Expiratory Flow (PEF) AUC 0-3h and AUC 0-6h responses in Litres / minute (L/min) after 4 weeks of treatment, calculated using the trapezoidal rule, divided by the duration (3 h, 6 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post dose for AUC0-3h and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h 4 h, 5 h, 6 h postdose for AUC0-6h on day 29 | 
| PEF AUC 0-3h Response After the First Dose | Adjusted means of the Area under the curve from 0 to 3 h response in Litres / minutes of the peak expiratory flow after the first dose, calculated using the trapezoidal rule, divided by the duration (3 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 | 
| PEF Peak 0-3h Response | Adjusted means of the peak expiratory flow from 0 to 3 hours (PEF peak 0-3h) response in L/min after 4 weeks of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29 | 
| PEF Peak 0-3h Response After the First Dose | Adjusted means of the Peak Expiratory flow from 0 to 3 hours response in L/min after the first dose of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 | 
| Individual FEV1 Measurements at Each Time Point on Day 29 | Adjusted means of the FEV1 measurements [L] at each time point on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 0 min, 5 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h post-dose on day 29 | 
| Individual FVC Measurements at Each Time Point on Day 29 | Adjusted means of the FVC measurements [L] at each time point on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 0 min, 5 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h post-dose on day 29 | 
| Individual PEF Measurements at Each Time Point on Day 29 | Adjusted means of the PEF measurements [L/min] at each time point on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. | Baseline and 1 h, 10 min pre-dose and 0 min, 5 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h post-dose on day 29 | 
| Weekly Mean Number of Puffs of Rescue Medication Used Per Day | Adjusted means of the weekly mean number of puffs of rescue medication during the whole day : the rescue medication was a salbutamol [albuterol] dose (100 mcg per puff). | Weeks 1 and 4 | 
| Physicians Global Evaluation | Adjusted means of the Physicians Global Evaluation of the patient's respiratory condition on days 1 and 29. The score was evaluated on a 8-points scale : Poor : 1,2 Fair : 3,4 Good : 5,6 Excellent : 7,8 | Days 1 and 29 | 
| Patients Global Rating | Adjusted means of the Global Rating of the patients' health (respiratory condition) on day 29. 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 | Day 29 | 
| Pulse Rate Recorded in Conjunction With Spirometry | Pulse rate recorded in conjunction with spirometry change from baseline at 30 minutes post-dose on day 29 in beats per minute (bpm). | Baseline and 30 min post-dose on day 29 | 
| Systolic and Diastolic Blood Pressure Recorded in Conjunction With Spirometry | Systolic and diastolic blood pressure recorded in conjunction with spirometry change from baseline on day 29 in millimetres of mercury (mmHg). | Baseline and 30 min post-dose on day 29 |