Tiotropium+Olodaterol Fixed Dose Combination (FDC) in Chronic Obstructive Pulmonary Disease (OTEMTO 2)

Study Overview
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Brief Summary
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The objective of this study is to assess the efficacy and safety of 12 weeks once daily treatment with orally inhaled tiotropium + olodaterol FDC (delivered by the Respimat inhaler) compared with tiotropium and placebo in patients with COPD.

Official Title
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A Randomised, Double-blind, Placebo- and Active-controlled Parallel Group Study to Assess the Efficacy of 12 Weeks of Once Daily Treatment of Two Doses of Orally Inhaled Tiotropium+ Olodaterol Fixed Dose Combination (Delivered by the Respimat Inhaler) in Patients With Moderate to Severe 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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis chronic obstructive pulmonary disease Relatively stable airway obstruction with post FEV1 >=30 and < 80% predicted normal and post FEV1/ FVC < 70% Male or female patients, 40 years of age or more Smoking history more than 10 pack years Exclusion criteria: Significant diseases other than COPD History of asthma COPD exacerbation in previous 3 months Completion of pulmonary rehabilitation program within previous 6 weeks or current participation in pulmonary rehabilitation program. Pregnant or nursing women Patients unable to comply with pulmonary medication restrictions

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tiotropium + olodaterol low dose<br>Once daily 2 puffs solution for inhalation Respimat | Drug: olodaterol<br>* fixed dose combination<br>Drug: tiotropium<br>* fixed dose combination<br>|
| Experimental: tiotropium + olodaterol high dose<br>Once daily 2 puffs solution for inhalation Respimat | Drug: olodaterol<br>* fixed dose combination<br>Drug: tiotropium<br>* fixed dose combination<br>|
| Active Comparator: tiotropium<br>Once daily 2 puffs solution for inhalation Respimat | Drug: tiotropium<br>* fixed dose combination<br>|
| Placebo Comparator: placebo<br>Once daily 2 puffs solution for inhalation Respimat | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 AUC0-3h Response | Forced expiratory volume in one second (FEV1) Area under the curve (AUC) 0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in litres. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. | baseline and 12 weeks | 
| Trough FEV1 Response (Change From Baseline) | Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FEV1 measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. | baseline and 12 weeks | 
| St. George's Respiratory Questionnaire (SGRQ) Total Score Based on Data From This Individual Study | The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life). The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. | 12 weeks treatment | 
| St. George's Respiratory Questionnaire (SGRQ) Total Score Based on Combined Dataset From This Study and the Replicate Study NCT01964352 | This endpoint was evaluated after combining the data from this and the replicate study NCT01964352 as specified in the analysis plan. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life). The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. | 12 weeks treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Vital Capacity (FVC) Response (Change From Baseline) | Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FVC measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. | baseline and 12 weeks | 
| TDI Focal Score Based on Data From This Individual Study | Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9). The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. | 12 weeks | 
| TDI Focal Score Based on Combined Dataset From This Study and the Replicate Study NCT01964352 | This endpoint was evaluated after combining the data from this and the replicate study NCT01964352 as specified in the analysis plan. Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9). The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. | 12 weeks | 
| FVC AUC0-3h Response (Change From Baseline) | The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. | baseline and 12 weeks |