A 12-week Treatment, Multi-center, Randomized, Double-blind, Parallel-group, Placebo and Active Controlled Study to Assess the Efficacy, Safety, and Tolerability of Indacaterol Maleate / Glycopyrronium Bromide in COPD Patients With Moderate to Severe Airflow Limitation

Study Overview
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Brief Summary
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This study will assess the efficacy, safety and tolerability of indacaterol maleate/glycopyrronium bromide in patients with moderate to severe airflow limitation.

Official Title
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A 12-week Treatment, Multi-center, Randomized, Double-blind, Parallel-group, Placebo and Active Controlled Study to Assess the Efficacy, Safety, and Tolerability of Indacaterol Maleate / Glycopyrronium Bromide in COPD Patients With Moderate to Severe Airflow Limitation

Conditions
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Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
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* Drug: QVA149
* Drug: QAB149
* Drug: NVA237
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients that have signed informed consent and are >/= 40 years of age. Patients with stable COPD according to GOLD 2011. Patients with a post-bronchodilator FEV1 of >/= 30% and < 80% predicted and a post-bronchodilator FEV1/FVC <0.70. Current or ex-smokers who have a smoking history of at least 10 pack years. Patients with an mMRC grade 2 or greater. Exclusion Criteria: Patients with Type I or uncontrolled Type II diabetes - Patients with a history of long QT syndrome or whose QTc measured at Visit 101 (Fridericia method) is prolonged (>450 ms for males and females) and confirmed by a central assessor. (These patients should not be re-screened.) Patients who have a clinically significant ECG abnormality at Visit 101 or Visit 102. (These patients should not be re-screened.) Patients with a history of malignancy of any organ system, treated or untreated, within the last five years. Patients with narrow-angle glaucoma, BPH or bladder-neck obstruction or moderate-severe renal impairment or urinary retention. Patients who had a COPD exacerbation within 6 weeks prior to screening. Patients who have a respiratory tract infection within 4 weeks prior to screening. Patients requiring long term oxygen therapy prescribed for more than 12 hr per day. Patients with a history of asthma. 8. Patients with an onset of respiratory symptoms, including COPD diagnosis, prior to age 40 years. Patients with a blood eosinophil count of greater than 600 mm/3 during run-in. Patients with concomitant pulmonary disease. Patients with a diagnosis of alpha-1 anti-trypsin deficiency. Patients with active pulmonary tuberculosis. Patients in the active phase of a pulmonary rehabilitation programme. 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>27.5/12.5 ug twice daily (b.i.d.) Single Dose Dry Powder Inhaler (SDDPI | Drug: QVA149<br>* QVA149 was supplied in a capsule form in blister packs for use in the Novartis Concept1 SDDPI<br>|
| Active Comparator: QAB149<br>27.5 ug b.i.d. | Drug: QAB149<br>* QAB149 was supplied in capsule form in blister packs for use in the Novartis Concept1 SDDPI.<br>|
| Active Comparator: NVA237<br>12.5 ug b.i.d. | Drug: NVA237<br>* NVA237 was supplied in capsule form in blister packs for use in the Novartis Concept1 SDDPI.<br>|
| Placebo Comparator: Placebo<br>b.i.d. | Drug: Placebo<br>* Placebo was supplied in capsule form in blister packs for use in the Novartis Concept1 SDDPI.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary: Change From Baseline in Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) (0-12 Hours (h)) | Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. Missing values of FEV1 AUC0-12 at Day 1 and Week 12 will not imputed. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time. | baseline (BL), 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score | Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. Missing week 12 data were imputed with Last Observation Carried Forward (LOCF) method but only if measured at day >= 29. A negative change from baseline indicates improvement. | BL, 12 Weeks | 
| Percentage of Participants With a Clinically Important Improvement of at Least 4 Units in the SGRQ Total Score | Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. | 12 weeks | 
| Change From Baseline in Trough FEV1 | Pulmonary function assessments were performed using centralized spirometry according to international standards. Trough FEV1 was analyzed using the same MMRM as specified for FEV1. Trough FEV1 was defined as the mean of FEV1 at 23 h 15 min and 23 h 45 min after the morning dose of the previous day. Before the mean was calculated, a time window of 10 - 13 hours post-evening dose was applied to these 2 measurements. Recordings outside the time window were set to missing. | BL, day 2, day 86 | 
| Change From Baseline in Pre-dose Trough FEV1 | Pulmonary function assessments were performed using centralized spirometry according to international standards. Pre-dose trough FEV1 was analyzed using the same MMRM as specified for FEV1. Pre-dose trough FEV1 was defined as the mean of FEV1 at -45 min and -15 min before the morning dose. Since the time of evening dose of the previous day was not recorded at these visits, no time window was applied. | BL, day 85 | 
| Change From Baseline in FEV1 | Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. | BL, Day 1: 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h55 min; Day 2: 23h15min, 23h45min; Day 15: -45min, -15min, 1h; Day 29: -45 min, -15min, 1h; Day 57: -45min, -15min, 1h; day 85: -45min, -15min, 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h; day 86: 23h15min; 23h45min | 
| Change From Baseline in FVC | Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FVC was defined as the average of the pre-dose FVC measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FVC measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. | BL, Day 1: 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h55 min; Day 2: 23h15min, 23h45min; Day 15: -45min, -15min, 1h; Day 29: -45 min, -15min, 1h; Day 57: -45min, -15min, 1h; day 85: -45min, -15min, 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h; day 86: 23h15min; 23h45min | 
| Secondary: Change From Baseline in Standardized FEV1 AUC (0-4 h), FEV1 AUC (4-8h), FEV1 AUC (8-12h) and FEV1 AUC (0-12 h) | Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time. | BL, day 1, 12 weeks | 
| Transitional Dyspnea Index (TDI) Focal Score | The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline. | BL, 12 weeks | 
| Secondary: Change From Baseline in Mean Daily Number of Puffs of Rescue Medication | Participants completed an electronic diary (eDiary) twice daily at the same time in the morning and evening to record the number of puffs of rescue medication taken in the previous 12 hours. A negative change from baseline indicates improvement. | BL, 12 weeks | 
| Secondary: Change From Baseline in Mean Total Daily Symptom Score, Mean Daytime Total Symptom Score and Mean Nighttime Total Symptom Score | The participant recorded symptom scores twice daily in the eDiary. The daily clinical symptoms included: cough, wheezing, shortness of breath, sputum volume, sputum color, and night time awakening. The range of scores for each assessment is 0 to 3 where 0 indications No symptom and 3 indicates a Severe symptom. The maximum daytime total score is 27 and the maximum nighttime total score is 27. The total daily symptom score is obtained by adding the scores for the morning and evening symptoms for each day. The maximum possible total daily score is 54. A negative change from baseline indicated improvement. | BL, 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, QVA149