Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD, NVA, FEV1
Brief summary
A study to assess the safety, tolerability and efficacy of NVA237 versus placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).
Interventions
Glycopyrronium bromide 50µg was supplied as inhalation capsules for use via a Single Dose Dry Powder Inhaler (SDDPI)
DRUGPlacebo
Placebo inhalation capsules were provided for use via a SDDPI
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
1. Patients who have had a lower respiratory tract infection within 6 weeks prior to Visit 1 2. Patients with concomitant pulmonary disease 3. Patients with a history of asthma 4. Any patient with lung cancer or a history of lung cancer 5. Patients with a history of certain cardiovascular comorbid conditions 6. Patients with a known history and diagnosis of alpha-1 antitrypsin deficiency 7. Patients in the active phase of a supervised pulmonary rehabilitation program 8. Patients contraindicated for tiotropium or ipratropium treatment or who have shown an untoward reaction to inhaled anticholinergic agents Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough Forced Expiratory Volume in 1 Second (FEV1) at 12 Weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 26 Weeks of Treatment | 26 weeks | 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. |
| Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation During 26 Weeks of Treatment | 26 weeks | 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. |
| Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (Baseline to Week 26) | 26 weeks | 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. |
| FEV1 at Each Time-point on Day 1 and Week 26 | 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. |
| Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | 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. |
| FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 | 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. |
| FEV1 Area Under Curve (AUC) (5 Min - 23 Hour 45 Min) at Week 12 and Week 26 | 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. |
| Transition Dyspnea Index (TDI) Focal Score After 26 Weeks of Treatment | 26 weeks | 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. |
| Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 | Baseline, 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. |
| Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | 26 Weeks and 30 Day follow-up | 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. |
| Rate of Moderate or Severe COPD Exacerbations Over the 26 Week Treatment Period | 26 weeks | 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. |
| Percentage of Nights With no Nighttime Awakenings Over the 26 Week Treatment Period | 26 Weeks | 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. |
| Percentage of Days With no Daytime Symptoms Over the 26 Week Treatment Period | 26 Weeks | 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. |
| Percentage of Days Able to Perform Usual Daily Activities Over the 26 Week Treatment Period | 26 Weeks | 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. |
| Mean Daily Total Symptom Score Over the 26 Week Treatment Period | 26 Weeks | 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. |
| Trough FEV1 and FVC at Day 1 and Week 26 | 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. |
Countries
Australia, Canada, Japan, Netherlands, Romania, Russia, Singapore, South Korea, Spain, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
1324 participants were screened. 822 participants entered the study.
Participants by arm
| Arm | Count |
|---|---|
| Glycopyrronium Bromide 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. | 550 |
| Placebo 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. | 267 |
| Total | 817 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 21 | 13 |
| Overall Study | Adverse Event | 30 | 16 |
| Overall Study | Death | 2 | 3 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | No longer requires study drug | 0 | 1 |
| Overall Study | Patient's inability to use the device | 1 | 1 |
| Overall Study | Protocol Violation | 4 | 3 |
| Overall Study | Unsatisfactory therapeutic effect | 5 | 5 |
| Overall Study | Withdrawal by Subject | 38 | 14 |
Baseline characteristics
| Characteristic | Glycopyrronium Bromide | Placebo | Total |
|---|---|---|---|
| Age, Customized 65 to <75 years | 199 participants | 98 participants | 297 participants |
| Age, Customized <65 years | 278 participants | 134 participants | 412 participants |
| Age, Customized >=75 years | 73 participants | 35 participants | 108 participants |
| Sex: Female, Male Female | 96 Participants | 52 Participants | 148 Participants |
| Sex: Female, Male Male | 454 Participants | 215 Participants | 669 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 132 / 550 | 85 / 267 |
| serious Total, serious adverse events | 41 / 550 | 24 / 267 |
Outcome results
Primary
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.
Time frame: 12 weeks
Population: Full Analysis Set (FAS) The FAS included all randomized patients who received at least one dose of study medication. Patients in this group were analyzed according to the treatment to which they were randomized. Missing trough FEV1 values at week 12 were imputed using LOCF with pre-dose trough FEV1.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Glycopyrronium Bromide | Trough Forced Expiratory Volume in 1 Second (FEV1) at 12 Weeks | 1.408 Liters | Standard Error 0.0105 |
| Placebo | Trough Forced Expiratory Volume in 1 Second (FEV1) at 12 Weeks | 1.301 Liters | Standard Error 0.0137 |
Secondary
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.
Time frame: 26 weeks
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. Patients with observations both at baseline and week 26 were included in this analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Glycopyrronium Bromide | Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (Baseline to Week 26) | -1.21 Puffs per day | Standard Error 0.122 |
| Placebo | Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (Baseline to Week 26) | -0.75 Puffs per day | Standard Error 0.156 |
Secondary
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.
Time frame: Baseline, Day 1, Week 12 and Week 26
Population: The safety set included all patients who received at least one dose of study medication whether or not being randomized. A sub-set of the safety population had 24 hour Holter monitoring. n indicates patients with observations both at baseline and each endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glycopyrronium Bromide | Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 | Day 1: (n = 42, 23) | -1.77 beats per minute | Standard Deviation 7.583 |
| Glycopyrronium Bromide | Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 | Week 12: (n = 42, 20) | -1.99 beats per minute | Standard Deviation 7.489 |
| Glycopyrronium Bromide | Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 | Week 26: (n = 37, 22) | -4.40 beats per minute | Standard Deviation 9.347 |
| Placebo | Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 | Day 1: (n = 42, 23) | -1.28 beats per minute | Standard Deviation 8.676 |
| Placebo | Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 | Week 12: (n = 42, 20) | -1.70 beats per minute | Standard Deviation 7.23 |
| Placebo | Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 | Week 26: (n = 37, 22) | -2.60 beats per minute | Standard Deviation 9.349 |
Secondary
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.
Time frame: Week 12 and Week 26
Population: Serial spirometry group, a sub-set of the full analysis set of patients. Twelve hour serial spirometry was conducted in this subset of patients in selected centers at Day 1. At week 12/13 and week 26/27 a 24 hour serial spirometry was performed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Glycopyrronium Bromide | FEV1 Area Under Curve (AUC) (5 Min - 23 Hour 45 Min) at Week 12 and Week 26 | Week 12 (n = 153, 75) | 1.401 Liters | Standard Error 0.0167 |
| Glycopyrronium Bromide | FEV1 Area Under Curve (AUC) (5 Min - 23 Hour 45 Min) at Week 12 and Week 26 | Week 26 (n = 149, 70) | 1.412 Liters | Standard Error 0.0185 |
| Placebo | FEV1 Area Under Curve (AUC) (5 Min - 23 Hour 45 Min) at Week 12 and Week 26 | Week 12 (n = 153, 75) | 1.268 Liters | Standard Error 0.0228 |
| Placebo | FEV1 Area Under Curve (AUC) (5 Min - 23 Hour 45 Min) at Week 12 and Week 26 | Week 26 (n = 149, 70) | 1.213 Liters | Standard Error 0.0254 |
Secondary
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.
Time frame: Day 1, Week 12 and Week 26
Population: Serial spirometry group, a sub-set of the full analysis set of patients. Twelve hour serial spirometry was conducted in this subset of patients in selected centers at Day 1. At week 12/13 and week 26/27 a 24 hour serial spirometry was performed. n is the number of patients with non-missing observations at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Glycopyrronium Bromide | FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 | Day 1 (n = 169, 83) | 1.475 Liters | Standard Error 0.0129 |
| Glycopyrronium Bromide | FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 | Week 12 (n = 153, 75) | 1.433 Liters | Standard Error 0.0179 |
| Glycopyrronium Bromide | FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 | Week 26 (n = 149, 70) | 1.445 Liters | Standard Error 0.0199 |
| Placebo | FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 | Day 1 (n = 169, 83) | 1.320 Liters | Standard Error 0.0173 |
| Placebo | FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 | Week 12 (n = 153, 75) | 1.284 Liters | Standard Error 0.0244 |
| Placebo | FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 | Week 26 (n = 149, 70) | 1.238 Liters | Standard Error 0.0274 |
Secondary
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.
Time frame: Day 1 and Week 26
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. n indicates number of patients with observation at each time-point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 5 min (n = 497, 240) | 1.388 Liters | Standard Error 0.0057 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 15 min (n = 503, 249) | 1.435 Liters | Standard Error 0.0066 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 30 min (n = 511, 252) | 1.472 Liters | Standard Error 0.007 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 1 hour (n = 513, 253) | 1.493 Liters | Standard Error 0.007 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 2 hours (n = 514, 251) | 1.562 Liters | Standard Error 0.0076 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 3 hours (n = 519, 248) | 1.544 Liters | Standard Error 0.0079 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 4 hours (n = 514, 247) | 1.548 Liters | Standard Error 0.0077 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 23 hours 15 min (n = 499, 244) | 1.400 Liters | Standard Error 0.0078 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 23 hours 45 min (n = 498, 244) | 1.428 Liters | Standard Error 0.0083 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: pre-dose trough (n = 447, 208) | 1.371 Liters | Standard Error 0.01 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: -45 min (n = 447, 208) | 1.373 Liters | Standard Error 0.0104 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: -15 min (n = 443, 205) | 1.368 Liters | Standard Error 0.0104 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 5 min (n = 439, 208) | 1.409 Liters | Standard Error 0.0106 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 15 min (n = 435, 205) | 1.427 Liters | Standard Error 0.0109 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 30 min (n = 440, 207) | 1.433 Liters | Standard Error 0.0112 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 1 hour (n = 438, 206) | 1.459 Liters | Standard Error 0.0115 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 2 hours (n = 438, 203) | 1.508 Liters | Standard Error 0.0114 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 3 hours (n = 439, 204) | 1.504 Liters | Standard Error 0.0124 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 4 hours (n = 438, 205) | 1.489 Liters | Standard Error 0.0114 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 23 hours 15 min (n = 434, 206) | 1.386 Liters | Standard Error 0.0118 |
| Glycopyrronium Bromide | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 23 hours 45 min (n = 434, 206) | 1.396 Liters | Standard Error 0.0116 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: -45 min (n = 447, 208) | 1.256 Liters | Standard Error 0.0145 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 5 min (n = 497, 240) | 1.295 Liters | Standard Error 0.0076 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 4 hours (n = 438, 205) | 1.312 Liters | Standard Error 0.0158 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 15 min (n = 503, 249) | 1.292 Liters | Standard Error 0.0087 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: -15 min (n = 443, 205) | 1.252 Liters | Standard Error 0.0144 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 30 min (n = 511, 252) | 1.299 Liters | Standard Error 0.0093 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 2 hours (n = 438, 203) | 1.299 Liters | Standard Error 0.016 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 1 hour (n = 513, 253) | 1.296 Liters | Standard Error 0.0094 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 5 min (n = 439, 208) | 1.255 Liters | Standard Error 0.0147 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 2 hours (n = 514, 251) | 1.355 Liters | Standard Error 0.0102 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 23 hours 45 min (n = 434, 206) | 1.282 Liters | Standard Error 0.0157 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 3 hours (n = 519, 248) | 1.349 Liters | Standard Error 0.0108 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 15 min (n = 435, 205) | 1.269 Liters | Standard Error 0.0152 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 4 hours (n = 514, 247) | 1.365 Liters | Standard Error 0.0105 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 3 hours (n = 439, 204) | 1.299 Liters | Standard Error 0.017 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 23 hours 15 min (n = 499, 244) | 1.289 Liters | Standard Error 0.0103 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 30 min (n = 440, 207) | 1.259 Liters | Standard Error 0.0155 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Day 1: 23 hours 45 min (n = 498, 244) | 1.328 Liters | Standard Error 0.0108 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 23 hours 15 min (n = 434, 206) | 1.267 Liters | Standard Error 0.0158 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: pre-dose trough (n = 447, 208) | 1.256 Liters | Standard Error 0.014 |
| Placebo | FEV1 at Each Time-point on Day 1 and Week 26 | Week 26: 1 hour (n = 438, 206) | 1.251 Liters | Standard Error 0.0159 |
Secondary
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.
Time frame: Day 1 and Week 26
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. n indicates number of patients with observation at each time-point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 4 hours (n = 514, 247) | 3.064 Liters | Standard Error 0.0161 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 23 hours 15 min (n = 499, 244) | 2.895 Liters | Standard Error 0.0169 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 23 hours 45 min (n = 498, 244) | 2.907 Liters | Standard Error 0.0169 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: Pre-dose trough (n = 447, 208) | 2.827 Liters | Standard Error 0.0238 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: -45 min (n = 447, 208) | 2.859 Liters | Standard Error 0.0271 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: -15 min (n = 443, 205) | 2.798 Liters | Standard Error 0.0235 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 5 min (n = 439, 208) | 2.891 Liters | Standard Error 0.0251 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 15 min (n = 435, 205) | 2.895 Liters | Standard Error 0.024 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 30 min (n = 440, 207) | 2.885 Liters | Standard Error 0.0239 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 1 hour (n = 438, 206) | 2.938 Liters | Standard Error 0.0256 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 2 hours (n = 438, 203) | 2.977 Liters | Standard Error 0.0225 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 3 hours (n = 439, 204) | 3.016 Liters | Standard Error 0.027 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 4 hours (n = 438, 205) | 2.962 Liters | Standard Error 0.0225 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 23 hours 15 min (n = 434, 206) | 2.884 Liters | Standard Error 0.0257 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 23 hours 45 min (n = 434, 206) | 2.859 Liters | Standard Error 0.0234 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 5 min (n = 497, 240) | 2.887 Liters | Standard Error 0.0132 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 15 min (n = 503, 249) | 2.943 Liters | Standard Error 0.0147 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 30 min (n = 511, 252) | 2.948 Liters | Standard Error 0.0155 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 1hour (n = 513, 253) | 3.019 Liters | Standard Error 0.0148 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 2 hours (n = 514, 251) | 3.086 Liters | Standard Error 0.0166 |
| Glycopyrronium Bromide | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 3 hours (n = 519, 248) | 3.096 Liters | Standard Error 0.0168 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 2 hours (n = 438, 203) | 2.687 Liters | Standard Error 0.0302 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 4 hours (n = 514, 247) | 2.760 Liters | Standard Error 0.0217 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 1hour (n = 513, 253) | 2.669 Liters | Standard Error 0.0198 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 23 hours 15 min (n = 499, 244) | 2.693 Liters | Standard Error 0.0221 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 3 hours (n = 439, 204) | 2.742 Liters | Standard Error 0.0345 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 23 hours 45 min (n = 498, 244) | 2.718 Liters | Standard Error 0.0219 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 15 min (n = 503, 249) | 2.660 Liters | Standard Error 0.0188 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: Pre-dose trough (n = 447, 208) | 2.623 Liters | Standard Error 0.0305 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 4 hours (n = 438, 205) | 2.709 Liters | Standard Error 0.0303 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: -45 min (n = 447, 208) | 2.658 Liters | Standard Error 0.0337 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 3 hours (n = 519, 248) | 2.783 Liters | Standard Error 0.0227 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: -15 min (n = 443, 205) | 2.589 Liters | Standard Error 0.0306 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 23 hours 15 min (n = 434, 206) | 2.673 Liters | Standard Error 0.0322 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 5 min (n = 439, 208) | 2.639 Liters | Standard Error 0.0318 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 30 min (n = 511, 252) | 2.637 Liters | Standard Error 0.0199 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 15 min (n = 435, 205) | 2.660 Liters | Standard Error 0.0309 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 23 hours 45 min (n = 434, 206) | 2.669 Liters | Standard Error 0.0306 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 30 min (n = 440, 207) | 2.603 Liters | Standard Error 0.031 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 2 hours (n = 514, 251) | 2.754 Liters | Standard Error 0.0219 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Week 26: 1 hour (n = 438, 206) | 2.625 Liters | Standard Error 0.0329 |
| Placebo | Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 | Day 1: 5 min (n = 497, 240) | 2.675 Liters | Standard Error 0.0173 |
Secondary
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.
Time frame: 26 Weeks
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Glycopyrronium Bromide | Mean Daily Total Symptom Score Over the 26 Week Treatment Period | -1.54 units on a scale | Standard Error 0.097 |
| Placebo | Mean Daily Total Symptom Score Over the 26 Week Treatment Period | -1.18 units on a scale | Standard Error 0.129 |
Secondary
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.
Time frame: 26 Weeks and 30 Day follow-up
Population: The safety set included all patients who received at least one dose of study medication whether or not being randomized. Patients were randomized according to the treatment they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Glycopyrronium Bromide | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Death | 3 participants |
| Glycopyrronium Bromide | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Discontinuation due to non-SAE(s) | 18 participants |
| Glycopyrronium Bromide | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Discontinuation due to AE(s) | 32 participants |
| Glycopyrronium Bromide | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | AE leading to dose interruption | 12 participants |
| Glycopyrronium Bromide | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | SAE(s) | 41 participants |
| Glycopyrronium Bromide | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | AE requiring significant additional therapy | 246 participants |
| Glycopyrronium Bromide | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Discontinuation due to SAE(s) | 15 participants |
| Glycopyrronium Bromide | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | AE leading to new or prolonged hospitalization | 35 participants |
| Glycopyrronium Bromide | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Participants with at least one AE | 317 participants |
| Placebo | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | AE leading to new or prolonged hospitalization | 21 participants |
| Placebo | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Participants with at least one AE | 174 participants |
| Placebo | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Death | 3 participants |
| Placebo | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | SAE(s) | 24 participants |
| Placebo | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Discontinuation due to AE(s) | 19 participants |
| Placebo | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Discontinuation due to SAE(s) | 8 participants |
| Placebo | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | Discontinuation due to non-SAE(s) | 11 participants |
| Placebo | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | AE leading to dose interruption | 8 participants |
| Placebo | Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations | AE requiring significant additional therapy | 155 participants |
Secondary
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.
Time frame: 26 Weeks
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. At 26 weeks, the analysis is based on only patients with a value at both baseline and post-baseline.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Glycopyrronium Bromide | Percentage of Days Able to Perform Usual Daily Activities Over the 26 Week Treatment Period | 40.31 percentage of days | Standard Error 1.473 |
| Placebo | Percentage of Days Able to Perform Usual Daily Activities Over the 26 Week Treatment Period | 35.19 percentage of days | Standard Error 1.907 |
Secondary
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.
Time frame: 26 Weeks
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. At 26 weeks, the analysis is based on only patients with a value at both baseline and post-baseline.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Glycopyrronium Bromide | Percentage of Days With no Daytime Symptoms Over the 26 Week Treatment Period | 5.70 percentage of days with no symptoms | Standard Error 0.799 |
| Placebo | Percentage of Days With no Daytime Symptoms Over the 26 Week Treatment Period | 5.78 percentage of days with no symptoms | Standard Error 1.076 |
Secondary
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.
Time frame: 26 Weeks
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. At 26 weeks, the analysis is based on only patients with a value at both baseline and post-baseline.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Glycopyrronium Bromide | Percentage of Nights With no Nighttime Awakenings Over the 26 Week Treatment Period | 55.96 percentage of nights with no awakenings | Standard Error 1.537 |
| Placebo | Percentage of Nights With no Nighttime Awakenings Over the 26 Week Treatment Period | 54.37 percentage of nights with no awakenings | Standard Error 1.97 |
Secondary
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.
Time frame: 26 weeks
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. Individual component score was imputed with LOCF (last observation carried forward).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Glycopyrronium Bromide | Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 26 Weeks of Treatment | 39.50 Units on a scale | Standard Error 0.813 |
| Placebo | Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 26 Weeks of Treatment | 42.31 Units on a scale | Standard Error 0.992 |
Secondary
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.
Time frame: 26 weeks
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glycopyrronium Bromide | Rate of Moderate or Severe COPD Exacerbations Over the 26 Week Treatment Period | 0.43 exacerbations per year |
| Placebo | Rate of Moderate or Severe COPD Exacerbations Over the 26 Week Treatment Period | 0.59 exacerbations per year |
Secondary
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.
Time frame: 26 weeks
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication.~The median values were not estimable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Glycopyrronium Bromide | Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation During 26 Weeks of Treatment | NA Days |
| Placebo | Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation During 26 Weeks of Treatment | NA Days |
Secondary
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.
Time frame: 26 weeks
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. Patients per treatment group with no missing data were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Glycopyrronium Bromide | Transition Dyspnea Index (TDI) Focal Score After 26 Weeks of Treatment | 1.84 Units on a scale | Standard Error 0.257 |
| Placebo | Transition Dyspnea Index (TDI) Focal Score After 26 Weeks of Treatment | 0.80 Units on a scale | Standard Error 0.294 |
Secondary
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.
Time frame: Day 1 and Week 26
Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. If one of the 23 h 15 min or 23 h 45 min values are missing then the remaining non-missing value is taken as trough FEV1 or trough FVC. If both values are missing, then their trough FEV1 or trough FVC is regarded as missing
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Glycopyrronium Bromide | Trough FEV1 and FVC at Day 1 and Week 26 | Day 1: FEV1 (n = 508, 248) | 1.414 Liters | Standard Error 0.0075 |
| Glycopyrronium Bromide | Trough FEV1 and FVC at Day 1 and Week 26 | Week 26: FEV1 (n = 461, 217) | 1.387 Liters | Standard Error 0.0112 |
| Glycopyrronium Bromide | Trough FEV1 and FVC at Day 1 and Week 26 | Day 1: FVC (n = 508, 248) | 2.901 Liters | Standard Error 0.0154 |
| Glycopyrronium Bromide | Trough FEV1 and FVC at Day 1 and Week 26 | Week 26: FVC (n = 438, 208) | 2.867 Liters | Standard Error 0.0236 |
| Placebo | Trough FEV1 and FVC at Day 1 and Week 26 | Week 26: FVC (n = 438, 208) | 2.668 Liters | Standard Error 0.03 |
| Placebo | Trough FEV1 and FVC at Day 1 and Week 26 | Day 1: FEV1 (n = 508, 248) | 1.309 Liters | Standard Error 0.0099 |
| Placebo | Trough FEV1 and FVC at Day 1 and Week 26 | Day 1: FVC (n = 508, 248) | 2.705 Liters | Standard Error 0.0202 |
| Placebo | Trough FEV1 and FVC at Day 1 and Week 26 | Week 26: FEV1 (n = 461, 217) | 1.275 Liters | Standard Error 0.015 |