Study to Evaluate the Effect on Lung Function and ECG When a Combination of Tiotropium Plus Olodaterol is Administered to Patients With COPD Either From a Single Inhaler or Each Compound is Administered After Each Other From Two Different Inhalers

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy and safety of orally inhaled tiotropium and olodaterol as both a fixed dose combination and a free combination with respect to lung function and ECG parameters

Official Title
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A Randomised, Placebo-controlled, Double-blind, Single Dose, Cross-over Study to Evaluate the Efficacy and Safety of Orally Inhaled Tiotropium + Olodaterol as Both a Fixed Dose Combination and a Free Combination (Both Delivered by the Respimat® Inhaler) in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: olodaterol
* Drug: tiotropium
* Drug: Placebo
* Drug: tiotropium
* Drug: olodaterol


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: patients must sign informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions. Patients must have a diagnosis of COPD and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator (10 to 45 minutes after 400mcg salbutamol) FEV1>30% and < 80% of predicted normal (ECSC, GOLD II - III) 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 who have never smoked cigarettes must be excluded. Patients must be able to perform technically acceptable pulmonary function tests according to ATS/ERS guidelines and maintain records in a paper diary Patients must be able to inhale medication in a competent manner from the RESPIMAT inhaler and from a metered dose inhaler (MDI). Exclusion criteria: Significant disease other than COPD Clinically relevant abnormal lab values. History of asthma. Diagnosis of thyrotoxicosis Diagnosis of paroxysmal tachycardia 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 Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years History of life-threatening pulmonary obstruction and patients with chronic respiratory failure History of cystic fibrosis Clinically evident bronchiectasis History of significant alcohol or drug abuse Thoracotomy with pulmonary resection Patients treated with oral or patch ß-adrenergics Patients treated with oral corticosteroid medication at unstable doses or at doses in excess of 10mg prednisolone per day or equivalent Regular use of daytime oxygen therapy for more than one hour per day Pulmonary rehabilitation program in the six weeks prior to the screening visit or patients currently in a pulmonary rehabilitation program Investigational drug within one month or six half lives (whichever is greater) prior to screening visit Known hypersensitivity to ß-adrenergic and/or anticholinergic drugs, BAC, EDTA Pregnant or nursing women Women of childbearing potential not using a highly effective method of birth control Patient 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

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: Tiotropium/Olodaterol FDC<br>patient will receive tiotropium and olodaterol in a fixed dose combination | Drug: tiotropium<br>* fixed dose combination with olodaterol<br>Drug: olodaterol<br>* fixed dose combination with tiotropium<br>|
| Experimental: Tiotropium and Olodaterol FC<br>patient will receive tiotropium and olodaterol in a free combination | Drug: olodaterol<br>* free combination with tiotropium<br>Drug: tiotropium<br>* free combination with olodaterol<br>|
| Placebo Comparator: Placebo<br>patient will receive placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response After Single-dose Administration | The response was defined as the change from patient baseline. Patient baseline was the average of the mean pre-dose values (period baseline) on each test day (Visit 2 (Day 1), Visit 3 (Day 22 (±7days)), and Visit 4 (Day 43±7days)). For patients who did not complete all periods, patient baseline was the average of the available period baselines. The means presented are the adjusted means. | 1 hour (h) and 10 min pre-dose and at 15 min, 30 min, 1 h, 2 h and 3 h post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean (Heart Rate Corrected QT Interval (Using Fredericia Adjustment)) QTcF Interval Change From Patient Baseline Over All Post-dose Time Points | Mean QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Peak QTcF Interval Change From Patient Baseline Over All Post-dose Time Points | Peak QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Mean Heart Rate Change From Patient Baseline Over All Post-dose Time Points | Mean heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Peak Heart Rate Change From Patient Baseline Over All Post-dose Time Points | Peak heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Heart Rate Change From Patient Baseline at Individual Post-dose Time Points | Heart rate change from patient baseline at individual post-dose time points | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Mean RR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points | Mean RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Peak RR Change From Patient Baseline Over All Post-dose Time Points | Peak RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| RR Change From Patient Baseline at Individual Post-dose Time Points | RR change from patient baseline at individual post-dose time points | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Mean QT (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points | Mean QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Peak QT (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points | Peak QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| QT Change From Patient Baseline at Individual Post-dose Time Points | QT change from patient baseline at individual post-dose time points | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Mean QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment)) Change From Patient Baseline Over All Post-dose Time Points | Mean QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Peak QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment)) Change From Patient Baseline Over All Post-dose Time Points | Peak QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| QTcB Change From Patient Baseline at Individual Post-dose Time Points | QTcB change from patient baseline at individual post-dose time points | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Mean PR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points | Mean PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Peak PR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points | Peak PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| PR Change From Patient Baseline at Individual Post-dose Time Points | PR change from patient baseline at individual post-dose time points | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Mean QRS (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points | Mean QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| Peak QRS (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points | Peak QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose | 
| QRS Change From Patient Baseline at Individual Post-dose Time Points | QRS change from patient baseline at individual post-dose time points | 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose |