Characterization of 24-hour Lung Function Profiles of Inhaled Tiotropium + Olodaterol Fixed Dose Combination in Patients Suffering From Chronic Obstructive Pulmonary Disease

Study Overview
=================
Brief Summary
-----------------
The primary objective of the trial is to determine the 24-hour FEV1-time profile of tiotropium + olodaterol FDC, administered once daily by the RESPIMAT Inhaler after 6 weeks of treatment.

Official Title
-----------------
Randomised, Double-blind, Placebo-controlled, 6 Treatment, 4 Period, Incomplete Cross-over Trial to Characterise the 24-hour Lung Function Profiles of Tiotropium + Olodaterol Fixed Dose Combination (2.5/5 µg, 5/5 µg), Tiotropium (2.5 µg, 5 µg) and Olodaterol (5 µg) (Oral Inhalation, Delivered by the Respimat® Inhaler) After 6 Weeks Once Daily Treatment in Patients With Chronic Obstructive Pulmonary Disease (COPD) [VIVACITOTM]

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

Intervention / Treatment
-----------------
* Drug: tiotropium + olodaterol
* Drug: tiotropium
* Drug: olodaterol
* Drug: tiotropium
* Drug: tiotropium + olodaterol
* Drug: Placebo
* Device: Respimat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Diagnosis of chronic obstructive pulmonary disease Relatively stable airway obstruction with a post-bronchodilator FEV1< 80% of predicted normal and a post-bronchodilator FEV1/FVC <70% Male or female patients, 40 years of age or older Smoking history of more than 10 pack years Ability to perform technically acceptable pulmonary function tests and maintain records Ability 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 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 history of cystic fibrosis clinically evident bronchiectasis history of significant alcohol or drug abuse history of thoracotomy with pulmonary resection oral or patch ß-adrenergics oral corticosteroid medication at unstable doses regular use daytime oxygen therapy for more than one hour per day Pulmonary rehabilitation program in the six weeks prior to the screening visit Investigational drug within one month or six half lives (whichever is greater) prior to screening visit Known hypersensitivity to ß-adrenergic drugs, BAC, EDTA Pregnant or nursing women Women of childbearing potential not using a highly effective method of birth control Patients who have previously been randomised in this study or are currently participating in another study Patients who are unable to comply with pulmonary medication restrictions prior to randomisation

Ages Eligible for Study
-----------------
Minimum Age: 40 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tiotropium+olodaterol FDC low dose<br>tiotropium+olodaterol FDC low dose; 2 inhalations once daily (a.m. dosing) | Drug: tiotropium + olodaterol<br>* low dose + one dose only<br>Device: Respimat<br>* Respimat inhaler<br>|
| Experimental: tiotropium+olodaterol FDC high dose<br>tiotropium+olodaterol FDC high dose; 2 inhalations once daily (a.m. dosing) | Drug: tiotropium + olodaterol<br>* low dose + one dose only<br>Device: Respimat<br>* Respimat inhaler<br>|
| Active Comparator: tiotropium low dose<br>tiotropium low dose; 2 inhalations once daily (a.m. dosing) | Drug: tiotropium<br>* low dose<br>Device: Respimat<br>* Respimat inhaler<br>|
| Active Comparator: tiotropium high dose<br>tiotropium high dose; 2 inhalations once daily (a.m. dosing) | Drug: tiotropium<br>* high dose<br>Device: Respimat<br>* Respimat inhaler<br>|
| Active Comparator: olodaterol<br>one dose only; 2 inhalations once daily (a.m. dosing) | Drug: olodaterol<br>* one dose only<br>Device: Respimat<br>* Respimat inhaler<br>|
| Placebo Comparator: placebo<br>2 inhalations once daily (a.m. dosing) | Drug: Placebo<br>* placebo matching tiotropium+olodaterol FDC<br>Device: Respimat<br>* Respimat inhaler<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment. | Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 24 h post-dose, using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day 1 and week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 AUC0-12h Response [L] After 6 Weeks Treatment. | Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 12 h post-dose, using the trapezoidal rule, divided by the duration (12h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day 1 and week 6 | 
| FEV1 AUC12-24h Response [L] After 6 Weeks Treatment. | Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day 1 and week 6 | 
| Trough FEV1 Response [L] After 6 Weeks Treatment. | Trough Forced Expiratory Volume in 1 second (FEV1) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and Response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day 1 and week 6 | 
| Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment. | Peak (0-3h) Forced Expiratory Volume in 1 second (FEV1) response. The peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day 1 and week 6 | 
| FVC AUC0-24h Response [L] After 6 Weeks Treatment. | Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day 1 and week 6 | 
| FVC AUC0-12h Response [L] After 6 Weeks Treatment. | Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day 1 and week 6 | 
| FVC AUC12-24h Response [L] After 6 Weeks Treatment. | Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day 1 and week 6 | 
| Trough FVC Response [L] After 6 Weeks Treatment. | Trough Forced Vital Capacity (FVC) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day1 and week 6 | 
| Peak (0-3h) FVC Response [L] After 6 Weeks Treatment. | Peak (0-3h) Forced Vital Capacity (FVC) responses after 6 weeks treatment. Peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. | day 1 and week 6 |