A 26-week Treatment Randomized, Double-blind, Double Dummy Study to Assess the Efficacy and Safety of QVA149

Study Overview
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Brief Summary
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To demonstrate the non-inferiority of QVA149 110/50 µg o.d. to fluticasone/salmeterol 500/50 µg b.i.d. in terms of trough Forced Expiratory Volume in one second (FEV1) (mean of 23 hours 15 min and 23 hours 45 min post QVA149 dose) following 26 weeks of treatment in patients with moderate to severe COPD

Detailed Description
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To demonstrate the non-inferiority of QVA149 110/50 µg o.d. to fluticasone/salmeterol 500/50 µg b.i.d. in terms of trough Forced Expiratory Volume in one second (FEV1) (mean of 23 hours 15 min and 23 hours 45 min post QVA149 dose) following 26 weeks of treatment in patients with moderate to severe COPD. The study population will consist of approximate 736 male and female adults (age 40 years and greater) with a clinical diagnosis of stable COPD [GOLD (2010)] and a smoking history of at least 10 pack years. It is anticipated that approximately 981 patients will need to be screened in order to randomize 736 patients into 2 treatment arms of the study with an equal randomization ratio, meaning QVA149 (368 patients), fluticasone/salmeterol (368 patients). Treatment randomization will be stratified by current/ex-smoker status and prior ICS use. It is intended that 552 patients will complete the study at Week 26 without major protocol deviations. Dropouts will not be replaced. This will be a multi-national study, including China, and at least two other countries. Standardization FEV1 AUC0-12h will be performed in a subgroup of around 100 patients (50 patients per treatment arm) in pre-selected centers.

Official Title
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A 26-week Treatment Randomized, Double-blind, Double Dummy, Parallel-group Study to Assess the Efficacy and Safety of QVA149 (Indacaterol / Glycopyrronium Bromide) Compared to Fluticasone/Salmeterol in Patients With Moderate to Severe COPD

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: QVA149
* Drug: Fluticasone/salmeterol
* Drug: Placebo to QVA149
* Drug: Placebo to fluticasone/salmeterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with moderate to severe stable COPD (Stage II or Stage III) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guideline. Current or ex-smokers who have a smoking history of at least 10 pack years. Patients with a post-bronchodilator Forced Expiratory Volume in one second (FEV1) ≥ 30% and < 80% of the predicted normal, and post-bronchodilator FEV1/FVC < 0.7. Modified Medical Research Council (mMRC) grade of at least 2 at Visit 2. Exclusion Criteria: Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Human Chorionic Gonadotropin (hCG) laboratory test. Patents with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH), bladder-neck obstruction, moderate to severe renal impairment or urinary retention. BPH patients who are stable on treatment can be considered. Patients with a history of long QT syndrome or whose QTc measured at run-in (Visit 2) (Fridericia method) is prolonged (>450 ms for males and females) as confirmed by the central Electrocardiogram (ECG) assessor. Patients with Type I or uncontrolled Type II diabetes. Patients who have not achieved spirometry result at Visit 2 in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) criteria for acceptability and repeatability. Patients with, a) any history of asthma or, b) onset of respiratory symptoms prior to age 40 years. Patients with concomitant pulmonary disease (e.g. lung fibrosis, primary bronchiectasis, sarcoidosis, interstitial lung disorder, pulmonary hypertension). Other protocol-defined inclusion/exclusion criteria may apply

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QVA149<br>QVA149 110/50 µg o.d., delivered via a single-dose dry powder inhaler (SDDPI), consisting of a fixed dose combination of indacaterol 110µg and NVA237 50µg | Drug: QVA149<br>* QVA149 110/50 µg capsules q.d. for inhalation, delivered via Novartis single dose dry powder inhaler (SDDPI).<br>* Other names: Experimental: QVA149;Drug: Placebo to fluticasone/salmeterol<br>* Placebo to fluticasone/salmeterol with Accuhaler<br>* Other names: Comparator: fluticasone/salmeterol;|
| Active Comparator: fluticasone/salmeterol<br>Fluticasone/salmeterol 500/50 µg b.i.d., delivered via a dry powder inhaler Accuhaler® device | Drug: Fluticasone/salmeterol<br>* Active fluticasone/salmeterol (500/50µg) b.i.d via a dry power inhaler Accuhaler® device.<br>* Other names: Comparator: Fluticasone/salmeterol;Drug: Placebo to QVA149<br>* Placebo to QVA149 with SDDPI<br>* Other names: Experimental: QVA149;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Expiratory Volume in One Second (FEV1) Following 26 Weeks of Treatment to Demonstrate the Non-inferiority of QVA149 110/50 μg o.d. to Fluticasone/Salmeterol 500/50 μg b.i.d | Measurement of QVA149 110/50 μg o.d. to fluticasone/salmeterol 500/50 μg b.i.d. in terms of trough FEV1 (mean of 23 h 15 min and 23 h 45 min post QVA149 dose) following 26 weeks of treatment in patients with moderate to severe COPD. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Expiratory Volume in One Second (FEV1) Following 26 Weeks of Treatment to Demonstrate the Superiority of QVA 110/50μg o.d. to Fluticasone/Salmeterol 500/50 μg b.i.d |  | 26 weeks | 
| Standardized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) 0-4 Hours | Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 0-4h at Day 1 was measured via spirometry conducted according to internationally accepted standards. Measurements were made at 0, 5, 15, and 30 minutes; and 1, 2, 3 and 4 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. Mixed model used: AUC FEV1 = treatment + baseline FEV1 + FEV1 reversibility components + baseline smoking status + baseline ICS use + country + center (country) + error. Center was included as a random effect nested within country. | Day 1, 12 and 26 weeks | 
| Analysis of FEV1 (L) Trough Response (Pre-dose) Over the Whole Treatment Period | Average of Trough Forced Expiratory Volume in one second (FEV1) | 6,12,18 and 26 weeks | 
| Analysis of Trough FVC (L) Over the Whole Treatment Period | Average of Trough Forced Vital Capacity (FVC) at 23 hours 15 min and the 23 hours 45 min post dose | 12 and 26 weeks | 
| Health Related Quality of Life Analysis of SGRQ Total Score After 26 Weeks of Treatment | A Total and three component scores are calculated: Symptoms; Activity; Impacts. Each component of the questionnaire is scored separately:The score for each component is calculated separately by dividing the summed weights by the maximum possible weight for that component and expressing the result as a percentage: Score = 100 x Summed weights from all positive items in that component divided by Sum of weights for all items in that component The Total score is calculated in similar way: Score = 100 x Summed weights from all positive items in the questionnaire divided by Sum of weights for all items in the questionnaire Sum of maximum possible weights for each component and Total: Symptoms 566.2 Activity 982.9 Impacts 1652.8 Total (sum of maximum for all three components) 3201.9 The proportion of patients who achieve a clinically important improvement of at least 4 units in the total SGRQ will be analyzed. The higher the score the more symptoms of disease are present. | 26 weeks | 
| Analysis of the TDI Focal Score Over the Whole Treatment Period | The Transition Dyspnea Index (TDI) total score after 12 and 26 weeks of treatment will be analyzed using the same mixed model as specified for the primary analysis with the Baseline Dyspnea Index (BDI) total score as the baseline.Total score ranging - 9 to + 9. The lower the score, the more deterioration in severity of dyspnea. One additional option in each category, which does not contribute to the score, allows for circumstances in which impairment is due to reasons other than dyspnea. .Baseline 12 weeks and Baseline 26 weeks, were the baseline scores for available participants analyzed for each time point. | 12 and 26 weeks | 
| Rescue Medication Use: Summary of the Mean Daily, Daytime and Nighttime Number of Puffs of Rescue Medication, by 4 Weekly Intervals | The number of puffs of rescue medication taken in the previous 12 hours will be recorded in the Patient Diary in the morning and evening. Baseline 12 weeks and Baseline 26 weeks, were the baseline scores for available participants analyzed for each time point. Less puffs taken is better. | 12 and 26 weeks | 
| Symptoms Reported Using E-diary Over 12 and 26 Weeks of Treatment | Percentage of nights with 'no nighttime awakenings', percentage of days with 'no daytime symptoms', and percentage of 'days able to perform usual daily activities' over 26 weeks (FAS) | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic obstructive pulmonary disease