Comparison of Long-term Safety of the Combination Product QVA149A Against Placebo and Standard of Care Treatment in Chronic Obstructive Pulmonary Disease Patients With Moderate to Severe Airflow Limitation

Study Overview
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Brief Summary
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The study will assess the long-term safety of the fixed combination product QVA149 versus placebo and a standard of care treatment (tiotropium) in Chronic Obstructive Pulmonary Disease (COPD) patients with moderate to severe airflow limitation.

Official Title
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A Placebo and Active Controlled Study to Assess the Long-term Safety of Once Daily QVA149 for 52 Weeks in Chronic Obstructive Pulmonary Disease (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: Tiotropium
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female adults aged ≥40 years. Patients with stable COPD according to GOLD strategy (GOLD 2011). Patients with airflow limitation indicated by a post-bronchodilator FEV1 ≥ 30% and <80% of the predicted normal, 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 Exclusion criteria: History of long QT syndrome or prolonged QTc. Patients who have had a COPD exacerbation that required treatment with antibiotics and/or systemic corticosteroids and/or hospitalization in the 6 weeks prior to Visit 1. Patients with Type I or uncontrolled Type II diabetes. Patients with a history of asthma or have concomitant pulmonary disease. Patients with paroxysmal (e.g. intermittent) atrial fibrillation. Only patients with persistent atrial fibrillation and controlled with a rate control strategy for at least six months could be eligible. Patients who have clinically significant renal, cardiovascular, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological abnormalities which could interfere with the assessment of safety.

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: QVA149<br> | Drug: QVA149<br>* QVA149 110/50 µg will be supplied as capsules in blister packs for once daily inhalation using the Novartis Concept1 SDDPI<br>|
| Active Comparator: Tiotropium<br> | Drug: Tiotropium<br>* Tiotropium 18 µg will be supplied as capsules in blister packs for once daily inhalation using the HandiHaler SDDPI<br>|
| Placebo Comparator: placebo<br> | Drug: placebo<br>* placebo to QVA149A and Tiotropium will be supplied in the appropriate capsule in blister packs for use in either the Novartis Concept1 SDDPI or the HandiHaler SDDPI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Serious Adverse Events | The overall rate of serious adverse events reported from initiation through 30 days post last dose. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Composite Endpoint of All-cause Mortality, and Serious Cardio- and Cerebrovascular (CCV) Events. | The endpoint of all-cause mortality and serious CCV events (composite) was chosen to further characterize any discernible risks. The patients with an event in the analysis were those who had at least one of the 2 events namely, all-cause mortality and serious CCV, during treatment or within 30 days after the date of last dose of study drug. | 52 weeks | 
| Post-hoc Analysis: Percentage of Patients With Composite Endpoint of Cardiovascular Death and MACE | The composite endpoint included all deaths and all serious CCV events, including MACE and events which were not considered MACE. A rigorous post hoc analysis was done on composite endpoint of CV deaths and major adverse cardiovascular events (MACE). The patients with an event in the analysis were those who had at least one of the 2 events namely, CV deaths and MACE, during treatment or within 30 days after the date of last dose of study drug. | 52 weeks | 
| Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (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. | Day 22, 43, 85, 183, 274 and 364 | 
| Change From Baseline in Health Status as Measured by St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) | The SGRQ-C contains 40 items divided into two parts covering three 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 will be calculated for each of these three subscales and a Total score will also be calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. | Measurment at day 364 | 
| Change From Baseline in Daily, Morning and Evening Symptom Scores | Patients will be provided with an electronic diary (eDiary) to record daily clinical symptoms, or rescue medication. The patients will be instructed to routinely complete the patient diary twice daily. There are 9 total symptom questions for a total possible score of 27 at each timepoint. A higher score means the patient is reporting more symptoms related to Chronic Obstructive Pulmonary Disease. The mean daily total symptom score, the mean daytime total symptom score and the mean nighttime total symptom score were calculated for each patient over 52 weeks. Diary data recorded during the 14 day run-in period were used to calculate the baseline. | 52 weeks | 
| Change From Baseline in Percentage of Nights With 'no Nighttime Awakenings | A night with 'no nighttime awakenings' is defined from diary data as any night where the patient did not wake up due to symptoms. | 52 weeks | 
| Change From Baseline in Percentage of no Daytime Symptoms | A day with 'no daytime symptoms' is defined from the diary data as any day where the patient has recorded in the evening no cough, no wheeze, no production of sputum and no feeling of breathlessness (other than when running) during the past 12 hours (approx. 8 am to 8 pm). | 52 weeks | 
| Change From Baseline in Percentage of Days Able to Perform Usual Daily Activities. | A day able to perform usual daily activities' is defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. | 52 weeks | 
| Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Pulmonary function assessments were performed using centralized spirometry according to international standards | Day 1, 22, 43, 85, 183, 274 and 364 | 
| Time to Premature Discontinuation | Time to premature treatment discontinuation for each treatment group was displayed using a Kaplan-Meier curve. The date of last dose of study medication was considered as the event date and also as the censoring date for those patients who did not discontinue treatment early. The range of the 'time to treatment discontinuation' varied from 5-407 days in the Tiotropium group. Hence the model estimated lower limit of the median time to treatment discontinuation is greater than the scheduled treatment period of 52 weeks. | Time varied from 5 - 407 days | 
| Change From Baseline in 1 Hour Post-dose FEV1 Measurements | The avg 60 min post dose forced expiratory volume in 1 second (FEV1) at visit 4, 5, 6, 7, 8 and 9 will be analyzed. | Day 1, 22, 43, 85, 183, 274 and 364 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Indacaterol maleate, Glycopyronnium bromide, chronic obstructive pulmonary disease, COPD, QVA149, QAB149, NVA237