1-year Study to Assess the Efficacy, Safety, and Tolerability of Glycopyrronium Bromide (NVA237) in Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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This study was designed to investigate the 1 year efficacy and safety of the 50 µg once daily (od) dose of glycopyrronium bromide (NVA237) in patients with moderate to severe chronic obstructive pulmonary disease.

Official Title
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A 52-week Treatment, Randomized, Double-blind, Placebo-controlled, With Open-label Tiotropium, Parallel-group Study to Assess the Efficacy, Safety, and Tolerability of Glycopyrronium Bromide (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 to glycopyrronium bromide
* Drug: Tiotropium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female adults aged ≥ 40 years, who have signed an Informed Consent Form prior to initiation of any study-related procedure. Patients with moderate to severe stable chronic obstructive pulmonary disease (COPD, Stage II or Stage III) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines 2008. Current or ex-smokers who have a smoking history of at least 10 pack years. Patients with a post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥ 30% and < 80% of the predicted normal, and post-bronchodilator FEV1/forced vital capacity (FVC) < 0.7 at Visit 2 (Day -14). Patients, according to daily electronic diary data between Visit 2 (Day -14) and Visit 3 (Day 1), with a total score of 1 or more on at least 4 of the last 7 days prior to Visit 3 (Day 1). Exclusion Criteria: Pregnant women or nursing mothers (pregnancy confirmed by positive urine pregnancy test). Women of child-bearing potential, unless using an approved method of medical or surgical contraception. Patients requiring long term oxygen therapy (> 15 h a day) on a daily basis for chronic hypoxemia, or who have been hospitalized for an exacerbation of their airways disease in the 6 weeks prior to Visit 1 (Day -21) or between Visit 1 (Day -21) and Visit 3 (Day 1). Patients who have had a respiratory tract infection within 6 weeks prior to Visit 1 (Day -21). Patients who, in the judgment of the investigator or the responsible Novartis personnel, have a clinically relevant laboratory abnormality or a clinically significant condition. Patients with any history of asthma indicated by (but not limited to) a blood eosinophil count > 600/mm^3 (at Visit 1, Day -21) and onset of symptoms prior to age 40 years. Patients with a history of long QT syndrome or whose QTc measured at Visit 1 (Day -21) (Fridericia method) is prolonged (> 450 ms for males or > 470 ms for females. Other protocol-defined inclusion/exclusion criteria may apply to the study.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glycopyrronium bromide 50 μg<br>Patients inhaled glycopyrronium bromide 50 μg once daily in the morning between 8:00 AM and 10:00 AM via a single-dose dry-powder inhaler (SDDPI) for 52 weeks. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | Drug: Glycopyrronium bromide<br>* Glycopyrronium bromide was supplied in powder-filled capsules together with a single-dose dry-powder inhaler (SDDPI) device.<br>* Other names: NVA237;|
| Placebo Comparator: Placebo to glycopyrronium bromide<br>Patients inhaled placebo to glycopyrronium bromide once daily in the morning between 8:00 AM and 10:00 AM via a single-dose dry-powder inhaler (SDDPI) for 52 weeks. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | Drug: Placebo to glycopyrronium bromide<br>* Placebo to glycopyrronium bromide was supplied in powder-filled capsules together with a single-dose dry-powder inhaler (SDDPI) device.<br>|
| Active Comparator: Tiotropium 18 μg<br>Patients inhaled tiotropium 18 μg once daily in the morning between 8:00 AM and 10:00 AM via a single-dose dry-powder inhaler (SDDPI) for 52 weeks. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | Drug: Tiotropium<br>* Tiotropium was supplied in powder-filled capsules together with the Handihaler® device.<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 Week 12 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 15 minutes and 23 hours 45 minutes post-dose. The analysis included baseline FEV1 measurement, baseline inhaled corticosteroid use (Yes/No), FEV1 prior to inhalation of short-acting β2 agonist (SABA), and FEV1 45 min post-inhalation of SABA as covariates. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transition Dyspnea Index (TDI) at Week 26 | The TDI measured changes in dyspnea from baseline during treatment and included 3 domains: Functional impairment (activities of daily living), magnitude of task (intensity of activity), and magnitude of effort (difficulty breathing). Each domain was rated from -3 to 3 (major deterioration-major improvement). The total score ranged from -9 to 9; minus scores indicate deterioration. The analysis included the same covariates as the primary Outcome Measure. | Week 26 | 
| Health-related Quality of Life (QoL) Assessed With the St. George Respiratory Questionnaire (SGRQ) at Week 52 | The SGRQ contained 51 patient-rated items divided into three components: Symptoms (respiratory symptoms, their frequency, and severity), Activity (activities that cause or are limited by breathlessness), and Impacts (social functioning and psychological disturbances resulting from airway disease). A total score for the 3 components was calculated and ranged from 0 to 100. Higher values indicate greater impairment of QoL. The analysis included the same covariates as the primary Outcome Measure. | Week 52 | 
| Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation During the Study (Baseline to Week 52) | Time to first moderate or severe COPD exacerbation was calculated as the number of days from baseline to the day on which the patient experienced the first moderate or severe COPD exacerbation. A COPD exacerbation was considered to be moderate if treatment with systemic corticosteroids and/or antibiotic was required. A COPD exacerbation was considered to be severe if treatment for moderate severity and hospitalization was required. | Baseline to Week 52 (patients with no moderate or severe exacerbations who completed the study were censored at the final visit date, which may have exceeded 52 weeks) | 
| Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Taken During the Study (Baseline to Week 52) | The number of puffs of rescue medication taken in the previous 12 hours was recorded in the Patient Diary in the morning and evening. The mean daily number of puffs of rescue medication taken was calculated by dividing the number of puffs of rescue medication per day over the 52 weeks of the study by the number of days with non-missing rescue medication data. Rescue medication data recorded during the 14 day run-in period was used to calculate the baseline. The analysis included the same covariates as the primary Outcome Measure. A positive change score indicates more puffs taken. | Baseline to Week 52 | 
| Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1, Week 26, and Week 52 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 15 minutes and 23 hours 45 minutes post-dose. The analysis included the same covariates as the primary Outcome Measure. | Day 1, Week 26, and Week 52 | 
| Trough Forced Vital Capacity (FVC) at Day 1, Week 12, Week 26, and Week 52 | Trough FVC is defined as the average of the post-dose 23 h 15 min and the 23 h 45 min FVC values. Just prior to FVC measurement, patients performed normal tidal breathing. The patient was given a few breaths warning before being told At the end of the next normal breath out, take a deep breath all the way in; they were then verbally encouraged to make a maximal effort before relaxing. The analysis included the same covariates as the primary Outcome Measure. | Day 1, Week 12, Week 26, and Week 52 | 
| Forced Expiratory Volume in 1 Second (FEV1) 5, 15, and 30 Minutes; 1, 2, 3, 4, 6, 8, 10, and 12 Hours; 23 Hours 15 Minutes; and 23 Hours 45 Minutes Post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52 | FEV1 was measured with spirometry conducted according to internationally accepted standards. The analysis included the same covariates as the primary Outcome Measure. Data was not collected at all time points for all Days and Weeks. | 5, 15, and 30 minutes; 1, 2, 3, 4, 6, 8, 10, and 12 hours; 23 hours 15 minutes; and 23 hours 45 minutes post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52 | 
| Forced Vital Capacity (FVC) 5, 15, and 30 Minutes; 1, 2, 3, 4, 6, 8, 10, and 12 Hours; 23 Hours 15 Minutes; and 23 Hours 45 Minutes Post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52 | Just prior to FVC measurement, patients performed normal tidal breathing. The patient was given a few breaths warning before being told At the end of the next normal breath out, take a deep breath all the way in; they were then verbally encouraged to make a maximal effort before relaxing. The analysis included the same covariates as the primary Outcome Measure. Data was not collected at all time points for all Days and Weeks. | 5, 15, and 30 minutes; 1, 2, 3, 4, 6, 8, 10, and 12 hours; 23 hours 15 minutes; and 23 hours 45 minutes post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52 | 
| Forced Expiratory Volume in 1 Second (FEV1) 5, 15, and 30 Minutes; and 1, 2, 3, and 4 Hours Post Dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52 | FEV1 was measured with spirometry conducted according to internationally accepted standards. The analysis included the same covariates as the primary Outcome Measure. Data was not collected at all time points for all Days and Weeks. | 5, 15, and 30 minutes; and 1, 2, 3, 4 hours post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52 | 
| Forced Vital Capacity (FVC) 5, 15, and 30 Minutes; and 1, 2, 3, and 4 Hours Post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52 | Just prior to FVC measurement, patients performed normal tidal breathing. The patient was given a few breaths warning before being told At the end of the next normal breath out, take a deep breath all the way in; they were then verbally encouraged to make a maximal effort before relaxing. The analysis included the same covariates as the primary Outcome Measure. Data was not collected at all time points for all Days and Weeks. | 5, 15, and 30 minutes; and 1, 2, 3, 4 hours post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52 | 
| Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours Post-dose at Day 1 and Weeks 12, 26, and 52 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 3, and 4 hours post-dose. Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included the same covariates as the primary Outcome Measure. | From 5 minutes to 4 hours post-dose at Day 1 and Weeks 12, 26, and 52 | 
| Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 12 Hours Post-dose at Day 1 and Weeks 12 and 52 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 3, 4, 6, 8 10, and 12 hours post-dose. Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included the same covariates as the primary Outcome Measure. | From 5 minutes to 12 hours post-dose at Day 1 and Weeks 12 and 52 | 
| Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 23 Hours 45 Minutes and From 12 Hours to 23 Hours 45 Minutes Post-dose at Weeks 12 and 52 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; 1, 2, 3, 4, 6, 8, 10, and 12 hours; 23 hours 15 minutes; and 23 hours 45 minutes post-dose. Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included the same covariates as the primary Outcome Measure. | From 5 minutes to 23 hours 45 minutes post-dose at Weeks 12 and 52 | 
| Number of Moderate or Severe Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) Per Year During the Study (Baseline to Week 52) | The number of moderate or severe exacerbations of COPD per year during the study was calculated by dividing the total number of exacerbations during the study by the total number of years of treatment. A COPD exacerbation was considered to be moderate if treatment with systemic corticosteroids and/or antibiotic was required. A COPD exacerbation was considered to be severe if treatment for moderate severity and hospitalization was required. | Baseline to Week 52 | 
| Percentage of Patients Who Experienced a Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation During the Study (Baseline to Week 52) | A COPD exacerbation was considered to be moderate if treatment with systemic corticosteroids and/or antibiotic was required. A COPD exacerbation was considered to be severe if treatment for moderate severity and hospitalization was required. | Baseline to Week 52 | 
| Percentage of Nights With no Nighttime Awakenings During the Study (Baseline to Week 52) | A night with no nighttime awakenings was defined as any night where the patient did not wake up due to 1 or more of 6 symptoms (respiratory symptoms, cough, wheeze, amount of sputum, color of sputum, and breathlessness). Symptoms occurring during the previous 12 hours were recorded each morning and evening by the patient in an electronic diary. The percentage of nights with 'no nighttime awakenings' was calculated as the total number of nights with no nighttime awakenings over the 52 week treatment period divided by the total number of nights where diary recordings were made. | Baseline to Week 52 | 
| Percentage of Days With no Daytime Symptoms During the Study (Baseline to Week 52) | A day with no daytime symptoms was defined as any day where the patient recorded no cough, no wheeze, no production of sputum, no feeling of breathlessness (other than when running), and no puffs of rescue medication during the previous 12 hours in evening entry in the electronic patient diary. The percentage of days with no daytime symptoms was calculated as the total number of days with no daytime symptoms over the 52 week treatment period divided by the total number of days where diary recordings were made. | Baseline to Week 52 | 
| Percentage of Days Able to Perform Usual Daily Activities During the Study (Baseline to Week 52) | A day able to perform usual daily activities was defined as any day where the patient recorded in their electronic diary in the evening that they were not prevented from performing their usual daily activities due to respiratory symptoms during the previous 12 hours. The percentage of days able to perform usual daily activities was calculated as the total number of days able to perform usual daily activities over the 52 week treatment period divided by the total number of days where diary recordings were made. | Baseline to Week 52 | 
| Change From Baseline in the Mean Daily Total Symptom Score During the Study (Baseline to Week 52) | The daily total symptom score was defined as the sum of the morning and evening patient self-reported diary assessments of 6 symptoms (respiratory symptoms/impact on daily activities, cough, wheeze, amount of sputum, color of sputum, and breathlessness). Means for baseline (14 day maximum run-in period) and the 52 week treatment period were calculated. Mean scores ranged from 0-18, with a higher score indicating worse symptoms. A negative change score indicated improvement. | Baseline to Week 52 | 

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