Long Term Safety Study of NVA237 vs QAB149 in COPD Patients

Study Overview
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Brief Summary
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The purpose of the study is to provide long term safety data of NVA237. This study will assess the safety and tolerability of a single dose strength of NVA237.

Official Title
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A Multi-center, Randomized, Double-blind, 52-week Study to Assess the Safety of NVA237 Compared to QAB149 in Patients With Chronic Obstructive Pulmonary Disease (COPD) Who Have Moderate to Severe Airflow Limitation

Conditions
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Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
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* Drug: NVA237
* Drug: Long-acting beta 2-agonist (LABA)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients with COPD according to GOLD 2011 who have signed informed consent. Patients with airflow limitation of 30-80% post-bronchodilator FEV1 at run-in. Current or ex-smokers with a smoking history of at least 10 pack years Patients with a mMRC score of at least 2 at run-in. Exclusion Criteria: Patients contraindicated for muscarinic antagonist agents and beta-2 agonists 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 requiring long term oxygen therapy prescribed for more than 12 hr per day. Patients with a history of asthma. Patients with an onset of respiratory symptoms, including COPD diagnosis, prior to 40 years of age. Patients with a blood eosinophil count of greater than 600 mm/3 during run-in Patients with concomitant pulmonary disease Patients with a history of certain cardiovascular co-morbid conditions 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: NVA237 dose 1<br>NVA237 dose 1 | Drug: NVA237<br>* NVA237 will be supplied in capsule form in blister packs for use in the Novartis Concept 1 SDDPI<br>|
| Active Comparator: Long-acting beta 2-agonist (LABA)<br>QAB149 | Drug: Long-acting beta 2-agonist (LABA)<br>* QAB149 and matching placebo will be supplied in capsule form in blister packs for use in the Novartis Concept 1 SDDPI<br>Drug: Placebo<br>* Placebo to match QAB149<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Reporting Safety and Tolerability in Terms of Adverse Event (AE) Reporting Rate | Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal lab finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgments of the investigators represent significant hazards. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Treatment Discontinuation | Discontinuation rates are calculated using the Kaplan Meier method. The protocol allowed patients to discontinue outside the treatment window, hence we have a patient who discontinued at Day 388. Reasons for discontinuing treatment are Subject/guardian decision, Adverse event, Protocol deviation Lack of efficacy, Physician decision, Dosing error, Disease improvement under study, Pregnancy, Technical problems | 52 Weeks | 
| Change From Baseline in Mean Forced Expiratory Volume (Average of the Two FEV1 Measurements 45 and 15 Minutes Pre-dose) in One Second at Week 52 | Change from baseline in pre-dose trough FEV1 was analyzed using a repeated measures analysis of covariance model which contained treatment, baseline FEV1, visit, baseline smoking status, baseline ICS use, COPD severity and treatment by visit, visit by baseline FEV1 interactions. An unstructured variance-covariance error matrix was used .Pulmonary function assessments were performed using centralized spirometry according to international standards. Pre-dose trough FEV1 was defined as the mean of FEV1 at -45 min and -15 min before the morning dose at Week 52. Baseline FEV1 was defined as the mean of the pre-dose FEV1 at -45 min and -15 min on Day 1. | -45 min and -15 minutes baseline and at Week 52 | 
| Change From Baseline in Pre-dose Forced Expiratory Volume (FEV1) in One Second at All Post Baseline Timepoints | 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. | -45 min and -15 minutes baseline and at Week 52 | 
| Change From Baseline in Pre-dose Forced Vital Capacity (FVC) at All Post-baseline Timepoints | 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. | -45 min and -15 minutes baseline and at Week 52 | 
| Change From Baseline in COPD Symptoms | The total symptom score was defined as the sum of individual cores for respiratory symptoms, cough, wheeze, amount of sputum, color of sputum, and reathlessness. Where a patient had a morning score and an evening score for an individual symptom on one particular day then the worst score was to be taken as the daily score for that symptom. Each symptom scale ranged from 0-3 where 0 was no symptoms and 3 was the worst. The total daily/daytime/nighttime symptom score consists of looking at the score for 6 symptoms and can therefore have a minimum score of 0 or a maximum of 18. | 52 weeks | 
| Change From Baseline in COPD Symptoms | Percentage of days with 'no daytime symptoms' A day with 'no daytime symptoms' was defined from the diary data as any day where the patient had recorded in the evening no cough, no wheeze, no production of sputum and no feeling of breathlessness (other than when running) and no puffs of rescue medication during the past 12 hours (approximately 8 am to 8pm). However, a patient was not considered symptom free if they had used rescue medication that day even if his/her total daytime symptoms score was zero. Percentage of nights with 'no nighttime awakenings' A night with 'no nighttime awakenings' was defined from diary data as any night where the patient did not wake up due to symptoms. The total number of nights with 'no nighttime awakenings' over the treatment period was divided by the total number of nights where diary recordings had been made in order to derive the percentage nights with 'no nighttime awakenings'. | 52 weeks | 
| Change From Baseline in Mean Daily Number of Puffs of Rescue Medication | The number of puffs of rescue medication taken in the previous 12 hours was recorded by the patients in the eDiary in the morning and evening. The total number of puffs of rescue medication per day over the 52 week treatment period was calculated and divided by the total number of days with non-missing rescue data to derive the mean daily number of puffs of rescue medication taken for the patient. If the number of puffs was missing for part of the day (either morning or evening), then a half day was used in the denominator. Change from baseline in number of puffs were analyzed using a linear mixed model which contained treatment, baseline number of puffs, baseline smoking status, baseline ICS use and COPD disease severity as fixed effects with center as a random effect | 52 weeks | 
| Time to First COPD Exacerbation (Moderate or Severe). | COPD exacerbations are considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations are considered to be severe if hospitalizations were required. Rates are calculated using the Kaplan Meier method. | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, NVA237, QAB149, glycopyrronium bromide