Efficacy and Safety Study of QVA149 in COPD Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to demonstrate that the efficacy of the combination product QVA149 is similar to the efficacy of the combination product umeclidinium/vilanterol on a pre-specified endpoint of FEV1 AUC0-24h while maintaining an acceptable safety profile.

Official Title
-----------------
A Multi-center, Randomized, Double-blind, Double-dummy, Active Controlled, 2-period Cross-over Study to Assess the Efficacy, Safety and Tolerability of Indacaterol Maleate/Glycopyrronium Bromide Compared to Umeclidinium Bromide/Vilanterol in COPD Patients With Moderate to Severe Airflow Limitation

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

Intervention / Treatment
-----------------
* Drug: QVA149
* Drug: Umeclidinium/vilanterol
* Drug: Placebo (umeclidinium/vilanterol)
* Drug: Placebo (QVA149)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female adults aged ≥40 yrs Smoking history of at least 10 pack years Diagnosis of stable Chronic Obstructive Pulmonary Disease (COPD) as classified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2015) Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)< 80% and ≥ 30% of the predicted normal value and post-bronchodilator FEV1/FVC (forced vital capacity) <70% Modified Medical Research Council questionnaire grade of 2 or higher Exclusion Criteria: Patients who have had a respiratory tract infection within 4 weeks prior to Visit 1 Patients with concomitant pulmonary disease Patients with a history of asthma Any patient with lung cancer or a history of lung cancer Patients with a history of certain cardiovascular co-morbid conditions Patients with a known history and diagnosis of alpha-1 antitrypsin deficiency Patients in the active phase of a supervised pulmonary rehabilitation program Patients contraindicated for inhaled anticholinergic agents and β2 agonists Other protocol-defined inclusion/exclusion criteria may apply

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: First QVA149, then Umeclidinium/vilanterol<br>Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. | Drug: QVA149<br>* QVA149 capsules for inhalation, delivered via QVA149 single dose dry powder inhaler (SDDPI)<br>* Other names: Indecaterol maleate/glycopyrronium bromide;Drug: Umeclidinium/vilanterol<br>* Umeclidinium/vilanterol for inhalation, delivered via ELLIPTA® inhaler<br>* Other names: ELLIPTA®;Drug: Placebo (umeclidinium/vilanterol)<br>* Matching Placebo to umeclidinium/vilanterol for inhalation, delivered via ELLIPTA® inhaler<br>Drug: Placebo (QVA149)<br>* Matching Placebo to QVA149 capsules for inhalation, delivered via QVA149 SDDPI<br>|
| Experimental: First Umeclidinium/vilanterol, then QVA149<br>Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. | Drug: QVA149<br>* QVA149 capsules for inhalation, delivered via QVA149 single dose dry powder inhaler (SDDPI)<br>* Other names: Indecaterol maleate/glycopyrronium bromide;Drug: Umeclidinium/vilanterol<br>* Umeclidinium/vilanterol for inhalation, delivered via ELLIPTA® inhaler<br>* Other names: ELLIPTA®;Drug: Placebo (umeclidinium/vilanterol)<br>* Matching Placebo to umeclidinium/vilanterol for inhalation, delivered via ELLIPTA® inhaler<br>Drug: Placebo (QVA149)<br>* Matching Placebo to QVA149 capsules for inhalation, delivered via QVA149 SDDPI<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Expiratory Volume (FEV1) Area Under the Curve (AUC) 0-24h | FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-24h). A positive change from baseline indicates improvement. | baseline, 0 to 24 hours post-dose at week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Expiratory Volume (FEV1) Area Under the Curve (AUC) 0-24h | FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-24h). A positive change from baseline indicates improvement. | baseline, 0 to 24 hours post-dose at week 12 | 
| Change From Baseline in Trough FEV1 (Mean of 23h 15 Minutes and 23 h 45 Minutes Post Previous Morning Dose) | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 15 minutes and 23 hours 45 minutes post-dose for each treatment | baseline, 23 hours 15 minutes and 23 hours 45 minutes post previous morning dose at week 12 | 
| Change From Baseline in FEV1 AUC 12-24h | FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over 12 hours (AUC 12-24h). | baseline, 12 hours to 24 hours post-dose at week 12 | 
| Change From Baseline in FEV1 AUC 0-12h | FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over 12 hours (AUC 0-12h). | baseline, 0 to 12 hours post-dose at week 12 | 
| Change From Baseline in FEV1 AUC 0-4h, AUC 4-8h, AUC 8-12h, AUC 12-16h, AUC 16-20h and AUC 20-24h | FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over 4 hour intervals FEV1 AUC 0-4h, AUC 4-8h, AUC 8-12h, AUC 12-16h, AUC 16-20h and AUC 20-24h. | baseline, 12 weeks | 
| Change From Baseline in Pre-dose Trough FEV1 (Mean of 15 Minutes and 45 Minutes Pre Morning Dose) | FEV1 was measured with spirometry conducted according to internationally accepted standards. Pre-dose trough FEV1 was defined as the average of measurements made 15 minutes and 45 minutes pre morning dose for each treatment. | baseline, 15 minutes and 45 minutes pre morning dose at week 12 | 
| QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in FEV1 at Any Time Point | FEV1 was measured with spirometry conducted according to internationally accepted standards. | Day 1 (5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 23h 15min, 23h 45min); week 6 (-45min, -15min); week 12 (-45min, -15min, 5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 12h 5min, 12h 15min, 12h 30min, 13, 14, 16, 20, 23h 15min, 23h 45min) | 
| QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in Forced Vital Capacity (FVC) at Any Time Point | FEV1 was measured with spirometry conducted according to internationally accepted standards. | Day 1 (5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 23h 15min, 23h 45min); week 6 (-45min, -15min); week 12 (-45min, -15min, 5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 12h 5min, 12h 15min, 12h 30min, 13, 14, 16, 20, 23h 15min, 23h 45min) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic Obstructive Pulmonary Disease (COPD)