A Study to Assess the Safety, Tolerability and Efficacy of NVA237 Versus Placebo

Study Overview
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Brief Summary
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A study to assess the safety, tolerability and efficacy of NVA237 versus placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).

Official Title
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A 26-week Treatment, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of NVA237 in Patients With Chronic Obstructive Pulmonary Disease

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Glycopyrronium bromide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Diagnosis of COPD (moderate-to-severe as classified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2008) and: Smoking history of at least 10 pack-years Post-bronchodilator FEV1 < 80% and ≥ 30% of the predicted normal value Post-bronchodilator FEV1/FVC (forced vital capacity) < 70% Exclusion Criteria: Patients who have had a lower respiratory tract infection within 6 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 comorbid 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 tiotropium or ipratropium treatment or who have shown an untoward reaction to inhaled anticholinergic agents 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: Glycopyrronium bromide<br>Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication. | Drug: Glycopyrronium bromide<br>* Glycopyrronium bromide 50µg was supplied as inhalation capsules for use via a Single Dose Dry Powder Inhaler (SDDPI)<br>|
| Placebo Comparator: Placebo<br>Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication. | Drug: Placebo<br>* Placebo inhalation capsules were provided for use via a SDDPI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Expiratory Volume in 1 Second (FEV1) at 12 Weeks | Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 hour 15 minute and 23 hour 45 minute post-dose FEV1 readings. Mixed model used baseline FEV1,baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transition Dyspnea Index (TDI) Focal Score After 26 Weeks of Treatment | Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. Mixed model used baseline TDI, baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. | 26 weeks | 
| Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 26 Weeks of Treatment | SGRQ is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. Mixed model used baseline SGRQ, baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. | 26 weeks | 
| Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation During 26 Weeks of Treatment | The time to the first moderate or severe COPD exacerbation was the study day on which the patient experienced first moderate or severe COPD exacerbation. 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 treatment for moderate severity and hospitalization were required. | 26 weeks | 
| Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (Baseline to Week 26) | Participants recorded the number of puffs of rescue medication taken in the previous 12 hours in the morning and evening. The total number of puffs of rescue medication per day over the full 26 weeks was calculated and divided by the total number of days with non-missing rescue medication data to derive the mean daily number of puffs of rescue medication taken for the patient. | 26 weeks | 
| FEV1 at Each Time-point on Day 1 and Week 26 | Spirometry was conducted according to internationally accepted standards. FEV1 was measured at all time points up to 4 hours post-dose, and at 23 hours 15 min and 23 hours 45 min, by visit. Mixed model used baseline FEV1,baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. | Day 1 and Week 26 | 
| Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Spirometry was conducted according to internationally accepted standards. FVC was calculated at each time point up to 4 hours post-dose and at 23 hours 15 min and 23 hours 45 min, by visit. Mixed model used baseline FVC, baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. | Day 1 and Week 26 | 
| FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 | The standardized (with respect to the length of time) area under the curve (AUC) for FEV1 was calculated using trapezoidal rule between 5 min and 12 h post dose at Week 1 Day 1, Week 12 and Week 26 for every patient in the serial spirometry subgroup. Mixed model used baseline FEV1,baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. | Day 1, Week 12 and Week 26 | 
| FEV1 Area Under Curve (AUC) (5 Min - 23 Hour 45 Min) at Week 12 and Week 26 | The standardized (with respect to the length of time) area under the curve (AUC) for FEV1 was calculated using trapezoidal rule between 5 min and 23 h 45 min post dose at week12/week 13and week 26/week 27 where available for every patient in the serial spirometry subgroup. Mixed model used baseline FEV1,baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. | Week 12 and Week 26 | 
| Trough FEV1 and FVC at Day 1 and Week 26 | Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 hour 15 minute and 23 hour 45 minute post-dose FEV1 readings. Mixed model used baseline FEV1, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates. Trough FVC was defined as the average of the 23 hour 15 minute and 23 hour 45 minute post-dose FVC readings. Mixed model used baseline FVC, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates. | Day 1 and Week 26 | 
| Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 | The mean heart rate was collected with a 24 hour Holter monitor in a sub-set of the safety population. The change between baseline and day 1, week 12 and week 26 was calculated. The analysis of the Holter recordings was performed by a central facility. Data on heart rate, heart rate variability, supraventricular and ventricular ectopy were collected and assessed. | Baseline, Day 1, Week 12 and Week 26 | 
| Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory 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 judgment of investigators represent significant hazards. | 26 Weeks and 30 Day follow-up | 
| Rate of Moderate or Severe COPD Exacerbations Over the 26 Week Treatment Period | One overall rate is calculated for the entire study population. Rate is the number of moderate or severe exacerbations per year = total number of moderate or severe exacerbations for all participants/total number of treatment years for all participants. COPD exacerbations were considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations were considered to be severe if treatment for moderate severity and hospitalization were required. | 26 weeks | 
| Percentage of Nights With no Nighttime Awakenings Over the 26 Week Treatment Period | The percentage of nights with no nighttime awakenings is defined as the total number of nights with no nighttime awakenings over the 26 week treatment period divided by the total number of night where diary recordings have been made. Mixed model used baseline nighttime awakenings, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates. | 26 Weeks | 
| Percentage of Days With no Daytime Symptoms Over the 26 Week Treatment Period | The percentage of days with no daytime symptoms is defined as the total number of days with no daytime symptoms over the 26 week treatment period divided by the total number of days where diary recordings have been made. Mixed model used baseline daytime symptoms, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates. | 26 Weeks | 
| Percentage of Days Able to Perform Usual Daily Activities Over the 26 Week Treatment Period | The percentage of days able to perform usual daily activities is defined as the total number of days able to perform usual activities over the 26 week treatment period divided by the total number of days where diary recordings have been made. Mixed model used baseline ability to perform usual daily activities, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates. | 26 Weeks | 
| Mean Daily Total Symptom Score Over the 26 Week Treatment Period | The daily symptom score was calculated as the sum of the worst of the morning and evening assessments for each symptom (symptoms, cough, wheeze, sputum color/production, and breathlessness). The score can range from 0 to 18 with 0 indicating no symptoms. The higher the score, the worse the symptomatic status. A negative change (lower number) indicates improvement. Mixed model used baseline symptom variables, baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. | 26 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NVA, COPD, FEV1