Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
Chronic obstructive pulmonary disease (COPD), NVA237
Brief summary
This study will assess of the efficacy and safety of a once-daily, 50µg inhalation of NVA237 in moderate to severe chronic obstructive pulmonary disease (COPD) patients over 26 weeks treatment.
Interventions
DRUGNVA237
Delivered via a single dose dry powder inhaler
DRUGPlacebo
Delivered via a single dose dry powder inhaler
Sponsors
Novartis Pharmaceuticals
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
* Male or female adults aged ≥40 years, who have signed an Informed Consent Form prior to initiation of any study-related procedure * With moderate to severe stable COPD (Stage II or Stage III). * Current or ex-smokers who have a smoking history of at least 10 pack years (Ten pack- years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years). * Post-bronchodilator FEV1 ≥30% and \< 80% of the predicted normal, and post-bronchodilator FEV1/FVC \< 0.7 at Visit 2 (Day -14) (post means: record FEV1 and FVC 45 min after administering ipratropium). * Symptomatic 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
Exclusion criteria
* With a history of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. * Patients with any history of asthma indicated by (but not limited to) a blood eosinophil count \> 600/mm3 (at Visit 2) or onset of symptoms prior to age 40 years. Patients without asthma but who have a blood eosinophil count \>600/mm3 at Visit 2 are excluded. * Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis (unless confirmed by imaging to be no longer active) or clinically significant bronchiectasis, sarcoidosis and interstitial lung disorder. * Patients with lung lobectomy or lung volume reduction or lung transplantation. * Patients with known history and diagnosis of α-1 antitrypsin deficiency. * Patients who have had a COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to Visit 1 Patients who have had a respiratory tract infection within 6 weeks prior to Visit 1. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough Forced Expiratory Volume in One Second (FEV1) | 12 weeks | Baseline FEV1 was defined as the average of the -45 min and -15 min FEV1 values taken on day 1 prior to the first dose of study medication. Trough FEV1 was defined as the mean of the post-dose 23 h 15 min and the 23 h 45 min FEV1 values. FEV1 was measured using central spirometry according to ATS/ERS standardization. Trough FEV1 was analyzed using a MIXED model for the full analysis set population. The model contained treatment as a fixed effect with the baseline FEV1 measurement, FEV1 prior to inhalation of short acting bronchodilator, FEV1 45 min post inhalation of short acting bronchodilator and baseline inhaled corticosteroids (ICS) use as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Daily Rescue Medication Use (Number of Puffs) | Baseline, 26 weeks | The participant recorded the rescue medication taken in an electronic diary between visits and in the spirometry device during study visits. Daytime and nighttime rescue medication use (number of puffs) over 26 weeks was analyzed. |
| 24h Trough FEV1 | Day 1, Week 26 | Trough FEV1 was defined as the mean of the post-dose 23 h 15 min and the 23 h 45 min FEV1 values. This was measured using central spirometry according to ATS/ERS standardization. This was analyzed using the same MIXED model as specified for the primary analysis. |
| FEV1 and Forced Vital Capacity (FVC) | Day 1 at 5, 15, 30 minutes (min) and 1 hour (h) post dose; days 2, 86, 184 at 23 (h) 15 min and 23 h 45 min post dose; days 29, 85, 183 at -45 and -15 min pre-dose and 5, 15, and 30 min post dose | FEV1 and FVC were measured using central spirometry according to ATS/ERS standardization. Both were analyzed using the same MIXED model as specified for the primary analysis. |
| Peak FEV1 | Day 1, week 12, week 26 | Peak FEV1 was defined as the maximum FEV1 0-4 h post-dose. Peak Fev1 was measured at 45min and 15min pre-dose and up to 4h post dose at day 1, week 12 and week 26, using central spirometry according to ATS/ERS standardization. It was analyzed using the same MIXED model as specified for the primary analysis. |
| Transition Dyspnea Index (TDI) Score | Baseline, week 12, week 26 | Dyspnea was measured at baseline using the Baseline Dyspnea Index (BDI) and during the treatment period using the TDI, which captures changes from baseline. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort, and each domain scored from -3 (major deterioration) to +3 (major improvement), giving an overall score of -9 to +9. A negative score indicates deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. |
| Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Baseline, 26 weeks | In an electronic diary, the participant responded to 6 questions twice daily to report on the degree of symptoms over the past 12 hours of the morning and evening. The questions covered the participant's degree of overall symptoms, and degrees of individual symptoms of coughing, wheezing, amount of sputum, color of sputum and breathlessness. Each question scored from 0 to 3 where 0 represented no symptom present and 3 represented the worst degree of that symptom. A negative change in symptom score indicates improvement. |
| Time to First Moderate or Severe COPD Exacerbation | 26 weeks | A COPD exacerbation was defined as a worsening of the following two or more major symptoms for at least 2 consecutive days:1) dyspnea; 2) sputum volume; 3) sputum purulence; or defined as a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: 1) sore throat; 2) colds (nasal discharge and/or nasal congestion); 3) fever without other cause; 4) cough; 5) wheeze. COPD exacerbations were recorded in the patient diary and other source documents. |
| Number of Moderate and Severe COPD Exacerbations | 26 weeks | COPD exacerbations were recorded in the patient diary and other source documents. The rate of COPD exacerbations during the 26 week treatment period was analyzed using a generalized linear model assuming a negative binomial distribution. |
| The Total Score of the St George's Respiratory Questionnaire (SGRQ) | Week 12, week 26 | SGRQ is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity and impacts. The lowest possible score is zero and the highest possible score is 100. Higher scores correspond to greater impairment in quality of life. The health-related quality of life was measured using SGRQ. It was completed by the participant at the investigators site. |
| Standardized FEV1 Area Under the Curve (AUC(5 Min-4 h)) Post-dose | Day 1, week 12, week 26 | The standardized (with respect to time) AUC for FEV1 was calculated between 5 min and 4h post morning dose at day 1, week 12 and week 26. The AUC (5 min-4 h) for FEV1 at each visit was analyzed using the same MIXED model as specified for the primary analysis. |
Countries
China, India, Philippines, South Korea
Participant flow
Recruitment details
Participants were randomized in a 2: 1 ration to NVA237 and Placebo, respectively.
Participants by arm
| Arm | Count |
|---|---|
| NVA237 NVA237 50 µg once daily delivered via a single dose dry powder inhaler | 305 |
| Placebo Placebo once daily delivered via a single dose dry powder inhaler | 154 |
| Total | 459 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value | 2 | 0 |
| Overall Study | Administrative problems | 1 | 0 |
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | Death | 4 | 1 |
| Overall Study | Lack of Efficacy | 1 | 2 |
| Overall Study | Patient's inability to use the device | 1 | 0 |
| Overall Study | Protocol deviation | 2 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 6 |
Baseline characteristics
| Characteristic | NVA237 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.6 Years STANDARD_DEVIATION 7.84 | 65.0 Years STANDARD_DEVIATION 8.29 | 64.7 Years STANDARD_DEVIATION 7.98 |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 20 Participants |
| Sex: Female, Male Male | 294 Participants | 145 Participants | 439 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 81 / 305 | 48 / 154 |
| serious Total, serious adverse events | 17 / 305 | 14 / 154 |
Outcome results
Primary
Trough Forced Expiratory Volume in One Second (FEV1)
Baseline FEV1 was defined as the average of the -45 min and -15 min FEV1 values taken on day 1 prior to the first dose of study medication. Trough FEV1 was defined as the mean of the post-dose 23 h 15 min and the 23 h 45 min FEV1 values. FEV1 was measured using central spirometry according to ATS/ERS standardization. Trough FEV1 was analyzed using a MIXED model for the full analysis set population. The model contained treatment as a fixed effect with the baseline FEV1 measurement, FEV1 prior to inhalation of short acting bronchodilator, FEV1 45 min post inhalation of short acting bronchodilator and baseline inhaled corticosteroids (ICS) use as covariates.
Time frame: 12 weeks
Population: The number of participants considered for the analysis was from the full analysis set (randomized participants who received at least one dose of study medication). However, participants analyzed had both baseline and week 12 values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 | Trough Forced Expiratory Volume in One Second (FEV1) | 1.204 Liters | Standard Error 0.0135 |
| Placebo | Trough Forced Expiratory Volume in One Second (FEV1) | 1.063 Liters | Standard Error 0.016 |
Secondary
24h Trough FEV1
Trough FEV1 was defined as the mean of the post-dose 23 h 15 min and the 23 h 45 min FEV1 values. This was measured using central spirometry according to ATS/ERS standardization. This was analyzed using the same MIXED model as specified for the primary analysis.
Time frame: Day 1, Week 26
Population: The number of participants considered for the analysis was from the full analysis set (randomized participants who received at least one dose of study medication). However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. day 1 or week 26.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | 24h Trough FEV1 | Day 1 (n=289,151) | 1.230 Liters | Standard Error 0.0084 |
| NVA237 | 24h Trough FEV1 | Week 26 (n=281,143) | 1.195 Liters | Standard Error 0.014 |
| Placebo | 24h Trough FEV1 | Day 1 (n=289,151) | 1.109 Liters | Standard Error 0.0104 |
| Placebo | 24h Trough FEV1 | Week 26 (n=281,143) | 1.059 Liters | Standard Error 0.0171 |
Secondary
Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings)
In an electronic diary, the participant responded to 6 questions twice daily to report on the degree of symptoms over the past 12 hours of the morning and evening. The questions covered the participant's degree of overall symptoms, and degrees of individual symptoms of coughing, wheezing, amount of sputum, color of sputum and breathlessness. Each question scored from 0 to 3 where 0 represented no symptom present and 3 represented the worst degree of that symptom. A negative change in symptom score indicates improvement.
Time frame: Baseline, 26 weeks
Population: The number of participants considered for the analysis was from the full analysis set (randomized participants who received at least one dose of study medication). However, for a given symptom category, analyzed participants had both baseline and week 26 values.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Cough symptom | -0.24 score | Standard Error 0.03 |
| NVA237 | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Sputum production | -0.15 score | Standard Error 0.034 |
| NVA237 | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Respiratory symptom | -0.21 score | Standard Error 0.033 |
| NVA237 | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Sputum color | -0.10 score | Standard Error 0.025 |
| NVA237 | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Wheeze symptom | -0.30 score | Standard Error 0.03 |
| NVA237 | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Breathless symptom | -0.17 score | Standard Error 0.03 |
| NVA237 | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Total symptom (n=296,150) | -1.16 score | Standard Error 0.143 |
| Placebo | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Breathless symptom | -0.10 score | Standard Error 0.035 |
| Placebo | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Total symptom (n=296,150) | -0.85 score | Standard Error 0.164 |
| Placebo | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Respiratory symptom | -0.12 score | Standard Error 0.038 |
| Placebo | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Cough symptom | -0.20 score | Standard Error 0.036 |
| Placebo | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Wheeze symptom | -0.22 score | Standard Error 0.036 |
| Placebo | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Sputum production | -0.11 score | Standard Error 0.039 |
| Placebo | Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Symptoms (Cough, Wheezing, Shortness of Breath, Sputum Volume, Sputum Color and Night Time Awakenings) | Sputum color | -0.10 score | Standard Error 0.031 |
Secondary
Change From Baseline in Daily Rescue Medication Use (Number of Puffs)
The participant recorded the rescue medication taken in an electronic diary between visits and in the spirometry device during study visits. Daytime and nighttime rescue medication use (number of puffs) over 26 weeks was analyzed.
Time frame: Baseline, 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 | Change From Baseline in Daily Rescue Medication Use (Number of Puffs) | -0.77 Number of puffs | Standard Error 0.157 |
| Placebo | Change From Baseline in Daily Rescue Medication Use (Number of Puffs) | -0.55 Number of puffs | Standard Error 0.186 |
Secondary
FEV1 and Forced Vital Capacity (FVC)
FEV1 and FVC were measured using central spirometry according to ATS/ERS standardization. Both were analyzed using the same MIXED model as specified for the primary analysis.
Time frame: Day 1 at 5, 15, 30 minutes (min) and 1 hour (h) post dose; days 2, 86, 184 at 23 (h) 15 min and 23 h 45 min post dose; days 29, 85, 183 at -45 and -15 min pre-dose and 5, 15, and 30 min post dose
Population: The number of participants considered for the analysis was from the full analysis set (randomized participants who received at least one dose of study medication). However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, e.g. day 1, 5 min; day 1, 15 min, etc..
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, - 15 min (n=265,135) | 1.179 Liters | Standard Error 0.013 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, -15 min (n=280,142) | 2.927 Liters | Standard Error 0.0312 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, 30 min (n=279,139) | 1.272 Liters | Standard Error 0.0114 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, 5 min (n=271,136) | 2.970 Liters | Standard Error 0.0292 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, 5 min (n=262,135) | 1.220 Liters | Standard Error 0.0136 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, 15 min (n=272,135) | 2.993 Liters | Standard Error 0.0276 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, 15 min (n=267,133) | 1.246 Liters | Standard Error 0.0117 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, 30 min (n=279,139) | 2.995 Liters | Standard Error 0.0287 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, 15 min (n=261,140) | 1.233 Liters | Standard Error 0.0139 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, -45 min (n=269,130) | 2.854 Liters | Standard Error 0.0321 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, -15 min (n=280,142) | 1.226 Liters | Standard Error 0.0113 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, -15 min (n=271,136) | 2.898 Liters | Standard Error 0.0318 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, 30 min (n=273,137) | 2.977 Liters | Standard Error 0.033 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, 30 min (n=270,138) | 1.265 Liters | Standard Error 0.0134 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, 5 min (n=262,130) | 2.927 Liters | Standard Error 0.0321 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, 30 min (n=273,137) | 1.263 Liters | Standard Error 0.0129 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, 15 min (n=267,133) | 2.954 Liters | Standard Error 0.0328 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, 1 h (n=263,135) | 1.263 Liters | Standard Error 0.0137 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, -45 min (n=269,130) | 1.179 Liters | Standard Error 0.0118 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, 1 h (n=274,133) | 2.987 Liters | Standard Error 0.0347 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 184, 23 h 15 min (n=263,128) | 1.197 Liters | Standard Error 0.0154 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 86, 23 h 15 min (n=261,127) | 2.908 Liters | Standard Error 0.0366 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, 1 h (n=274,133) | 1.275 Liters | Standard Error 0.0125 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 86, 23 h 45 min (n=250,132) | 2.894 Liters | Standard Error 0.036 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 184, 23 h 45 min (n=266,132) | 1.196 Liters | Standard Error 0.0144 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, -45 min (n=262,135) | 2.858 Liters | Standard Error 0.0379 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, 15 min (n=272,135) | 1.259 Liters | Standard Error 0.0117 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, -15 min (n=265,135) | 2.862 Liters | Standard Error 0.0359 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 1, 5 min (n=281,143) | 2.925 Liters | Standard Error 0.0184 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, 5 min (n=262,135) | 2.927 Liters | Standard Error 0.0368 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 86, 23 h 15 min (n=261,127) | 1.195 Liters | Standard Error 0.0146 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, 15 min (n=261,140) | 2.957 Liters | Standard Error 0.0365 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 1, 15 min (n=277,147) | 2.992 Liters | Standard Error 0.0252 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, 30 min (n=270,138) | 2.988 Liters | Standard Error 0.0366 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, -15 min (n=271,136) | 1.190 Liters | Standard Error 0.0106 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, 1 h (n=263,135) | 2.941 Liters | Standard Error 0.0401 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 1, 30 min (n=283,145) | 3.041 Liters | Standard Error 0.0235 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 184, 23 h 15 min (n=263,128) | 2.869 Liters | Standard Error 0.0386 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 86, 23 h 45 min (n=250,132) | 1.203 Liters | Standard Error 0.0138 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 184, 23 h 45 min (n=266,132) | 2.894 Liters | Standard Error 0.0402 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 1, 1 h (n=284,142) | 3.044 Liters | Standard Error 0.024 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 1, 5 min (n=281,143) | 1.199 Liters | Standard Error 0.006 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, 5 min (n=271,136) | 1.240 Liters | Standard Error 0.0118 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 1, 15 min (n=277,147) | 1.245 Liters | Standard Error 0.0075 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 2, 23 h 15 min (n=267,137) | 2.953 Liters | Standard Error 0.0275 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 1, 30 min (n=283,145) | 1.265 Liters | Standard Error 0.0076 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, -45 min (n=262,135) | 1.176 Liters | Standard Error 0.0148 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 1, 1 h (n=284,142) | 1.295 Liters | Standard Error 0.0079 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 2, 23 h 45 min (n=272,140) | 2.981 Liters | Standard Error 0.0261 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 2, 23 h 15 min (n=267,137) | 1.228 Liters | Standard Error 0.0086 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, 5 min (n=262,130) | 1.229 Liters | Standard Error 0.0119 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 2, 23 h 45 min min (n=272,140) | 1.230 Liters | Standard Error 0.0092 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, -45 min (n=273,136) | 2.908 Liters | Standard Error 0.0324 |
| NVA237 | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, -45 min (n=273,136) | 1.208 Liters | Standard Error 0.0114 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, -15 min (n=271,136) | 2.627 Liters | Standard Error 0.0373 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, -15 min (n=280,142) | 1.097 Liters | Standard Error 0.0142 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, 5 min (n=271,136) | 1.097 Liters | Standard Error 0.0148 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, 15 min (n=272,135) | 1.103 Liters | Standard Error 0.0147 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, 30 min (n=279,139) | 1.105 Liters | Standard Error 0.0142 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, -45 min (n=269,130) | 1.050 Liters | Standard Error 0.0147 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, -15 min (n=271,136) | 1.052 Liters | Standard Error 0.0134 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, 5 min (n=262,130) | 1.059 Liters | Standard Error 0.0147 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, 15 min (n=267,133) | 1.061 Liters | Standard Error 0.0147 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, 30 min (n=273,137) | 1.077 Liters | Standard Error 0.0156 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 85, 1 h (n=274,133) | 1.079 Liters | Standard Error 0.0154 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 86, 23 h 15 min (n=261,127) | 1.057 Liters | Standard Error 0.0175 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 86, 23 h 45 min (n=250,132) | 1.067 Liters | Standard Error 0.0163 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, -45 min (n=262,135) | 1.032 Liters | Standard Error 0.0176 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, - 15 min (n=265,135) | 1.052 Liters | Standard Error 0.0165 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, 5 min (n=262,135) | 1.055 Liters | Standard Error 0.017 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, 15 min (n=261,140) | 1.070 Liters | Standard Error 0.0169 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, 30 min (n=270,138) | 1.071 Liters | Standard Error 0.017 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 183, 1 h (n=263,135) | 1.075 Liters | Standard Error 0.0168 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 184, 23 h 15 min (n=263,128) | 1.068 Liters | Standard Error 0.0188 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 184, 23 h 45 min (n=266,132) | 1.058 Liters | Standard Error 0.018 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 1, 5 min (n=281,143) | 2.739 Liters | Standard Error 0.022 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 1, 15 min (n=277,147) | 2.759 Liters | Standard Error 0.0288 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 1, 30 min (n=283,145) | 2.761 Liters | Standard Error 0.028 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 1, 1 h (n=284,142) | 2.755 Liters | Standard Error 0.0286 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 2, 23 h 15 min (n=267,137) | 2.716 Liters | Standard Error 0.0326 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 2, 23 h 45 min (n=272,140) | 2.744 Liters | Standard Error 0.0311 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, -45 min (n=273,136) | 2.690 Liters | Standard Error 0.0375 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, -15 min (n=280,142) | 2.730 Liters | Standard Error 0.0371 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, 5 min (n=271,136) | 2.725 Liters | Standard Error 0.0353 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, 15 min (n=272,135) | 2.751 Liters | Standard Error 0.0339 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 29, 30 min (n=279,139) | 2.737 Liters | Standard Error 0.0341 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, -45 min (n=269,130) | 2.611 Liters | Standard Error 0.0385 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 29, -45 min (n=273,136) | 1.079 Liters | Standard Error 0.0144 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, 5 min (n=262,130) | 2.633 Liters | Standard Error 0.038 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, 15 min (n=267,133) | 2.647 Liters | Standard Error 0.0387 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, 30 min (n=273,137) | 2.695 Liters | Standard Error 0.0383 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 85, 1 h (n=274,133) | 2.662 Liters | Standard Error 0.04 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 86, 23 h 15 min (n=261,127) | 2.612 Liters | Standard Error 0.0429 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 86, 23 h 45 min (n=250,132) | 2.671 Liters | Standard Error 0.0412 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, -45 min (n=262,135) | 2.604 Liters | Standard Error 0.043 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, -15 min (n=265,135) | 2.633 Liters | Standard Error 0.0415 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, 5 min (n=262,135) | 2.672 Liters | Standard Error 0.0426 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, 15 min (n=261,140) | 2.679 Liters | Standard Error 0.042 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, 30 min (n=270,138) | 2.707 Liters | Standard Error 0.0428 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 183, 1 h (n=263,135) | 2.668 Liters | Standard Error 0.0453 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 184, 23 h 15 min (n=263,128) | 2.664 Liters | Standard Error 0.0452 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FVC, day 184, 23 h 45 min (n=266,132) | 2.647 Liters | Standard Error 0.0472 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 1, 5 min (n=281,143) | 1.112 Liters | Standard Error 0.0072 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 1, 15 min (n=277,147) | 1.116 Liters | Standard Error 0.0089 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 1, 30 min (n=283,145) | 1.111 Liters | Standard Error 0.009 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 1, 1 h (n=284,142) | 1.124 Liters | Standard Error 0.0096 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 2, 23 h 15 min (n=267,137) | 1.101 Liters | Standard Error 0.0108 |
| Placebo | FEV1 and Forced Vital Capacity (FVC) | FEV1, day 2, 23 h 45 min min (n=272,140) | 1.107 Liters | Standard Error 0.0112 |
Secondary
Number of Moderate and Severe COPD Exacerbations
COPD exacerbations were recorded in the patient diary and other source documents. The rate of COPD exacerbations during the 26 week treatment period was analyzed using a generalized linear model assuming a negative binomial distribution.
Time frame: 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized patients who received at least one dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NVA237 | Number of Moderate and Severe COPD Exacerbations | 0.2 Number of exacerbations | Standard Deviation 0.48 |
| Placebo | Number of Moderate and Severe COPD Exacerbations | 0.3 Number of exacerbations | Standard Deviation 0.58 |
Secondary
Peak FEV1
Peak FEV1 was defined as the maximum FEV1 0-4 h post-dose. Peak Fev1 was measured at 45min and 15min pre-dose and up to 4h post dose at day 1, week 12 and week 26, using central spirometry according to ATS/ERS standardization. It was analyzed using the same MIXED model as specified for the primary analysis.
Time frame: Day 1, week 12, week 26
Population: The number of participants considered for the analysis was from a Serial Spirometry subgroup of the full analysis set where N = 134 and 58, respectively. However, analyzed participants had values at both baseline and the corresponding time frame, i.e. day 1, week 12 or week 26.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | Peak FEV1 | Day 1 (n=134,57) | 1.376 Liters | Standard Error 0.0119 |
| NVA237 | Peak FEV1 | Week 12 (n=125,56) | 1.347 Liters | Standard Error 0.0207 |
| NVA237 | Peak FEV1 | Week 26 (n=124,57) | 1.308 Liters | Standard Error 0.025 |
| Placebo | Peak FEV1 | Day 1 (n=134,57) | 1.183 Liters | Standard Error 0.0146 |
| Placebo | Peak FEV1 | Week 12 (n=125,56) | 1.140 Liters | Standard Error 0.0245 |
| Placebo | Peak FEV1 | Week 26 (n=124,57) | 1.112 Liters | Standard Error 0.0298 |
Secondary
Standardized FEV1 Area Under the Curve (AUC(5 Min-4 h)) Post-dose
The standardized (with respect to time) AUC for FEV1 was calculated between 5 min and 4h post morning dose at day 1, week 12 and week 26. The AUC (5 min-4 h) for FEV1 at each visit was analyzed using the same MIXED model as specified for the primary analysis.
Time frame: Day 1, week 12, week 26
Population: The number of participants considered for the analysis was from a Serial Spirometry subgroup of the full analysis set where N = 134 and 58, respectively. However, analyzed participants had values at both baseline and the corresponding time frame, i.e. day 1, week 12 or week 26.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | Standardized FEV1 Area Under the Curve (AUC(5 Min-4 h)) Post-dose | Day 1 (n=134,57) | 1.311 Liters | Standard Error 0.0122 |
| NVA237 | Standardized FEV1 Area Under the Curve (AUC(5 Min-4 h)) Post-dose | Week 12 (n=125,56) | 1.286 Liters | Standard Error 0.0204 |
| NVA237 | Standardized FEV1 Area Under the Curve (AUC(5 Min-4 h)) Post-dose | Week 26 (n=124,57) | 1.243 Liters | Standard Error 0.0229 |
| Placebo | Standardized FEV1 Area Under the Curve (AUC(5 Min-4 h)) Post-dose | Day 1 (n=134,57) | 1.117 Liters | Standard Error 0.0142 |
| Placebo | Standardized FEV1 Area Under the Curve (AUC(5 Min-4 h)) Post-dose | Week 12 (n=125,56) | 1.080 Liters | Standard Error 0.0241 |
| Placebo | Standardized FEV1 Area Under the Curve (AUC(5 Min-4 h)) Post-dose | Week 26 (n=124,57) | 1.046 Liters | Standard Error 0.028 |
Secondary
The Total Score of the St George's Respiratory Questionnaire (SGRQ)
SGRQ is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity and impacts. The lowest possible score is zero and the highest possible score is 100. Higher scores correspond to greater impairment in quality of life. The health-related quality of life was measured using SGRQ. It was completed by the participant at the investigators site.
Time frame: Week 12, week 26
Population: The number of participants considered for the analysis was from the full analysis set (randomized participants who received at least one dose of study medication). However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. week 12 or week 26.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | The Total Score of the St George's Respiratory Questionnaire (SGRQ) | week 12 (n=293,147) | 32.35 Score | Standard Error 1.232 |
| NVA237 | The Total Score of the St George's Respiratory Questionnaire (SGRQ) | week 26 (n=288,144) | 31.02 Score | Standard Error 1.48 |
| Placebo | The Total Score of the St George's Respiratory Questionnaire (SGRQ) | week 12 (n=293,147) | 37.39 Score | Standard Error 1.399 |
| Placebo | The Total Score of the St George's Respiratory Questionnaire (SGRQ) | week 26 (n=288,144) | 35.94 Score | Standard Error 1.641 |
Secondary
Time to First Moderate or Severe COPD Exacerbation
A COPD exacerbation was defined as a worsening of the following two or more major symptoms for at least 2 consecutive days:1) dyspnea; 2) sputum volume; 3) sputum purulence; or defined as a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: 1) sore throat; 2) colds (nasal discharge and/or nasal congestion); 3) fever without other cause; 4) cough; 5) wheeze. COPD exacerbations were recorded in the patient diary and other source documents.
Time frame: 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized patients who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NVA237 | Time to First Moderate or Severe COPD Exacerbation | NA Days |
| Placebo | Time to First Moderate or Severe COPD Exacerbation | NA Days |
Secondary
Transition Dyspnea Index (TDI) Score
Dyspnea was measured at baseline using the Baseline Dyspnea Index (BDI) and during the treatment period using the TDI, which captures changes from baseline. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort, and each domain scored from -3 (major deterioration) to +3 (major improvement), giving an overall score of -9 to +9. A negative score indicates deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline.
Time frame: Baseline, week 12, week 26
Population: The number of participants considered for the analysis was from the full analysis set (randomized participants who received at least one dose of study medication). However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. week 12 or week 26.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | Transition Dyspnea Index (TDI) Score | week 12 (n=288,141) | 2.8 score | Standard Error 0.32 |
| NVA237 | Transition Dyspnea Index (TDI) Score | week 26 (n=284,140) | 3.0 score | Standard Error 0.31 |
| Placebo | Transition Dyspnea Index (TDI) Score | week 12 (n=288,141) | 1.6 score | Standard Error 0.34 |
| Placebo | Transition Dyspnea Index (TDI) Score | week 26 (n=284,140) | 2.0 score | Standard Error 0.34 |