Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Anticholinergic, Antimuscarinic, Chronic Obstructive Airway Disease, Chronic Obstructive Lung Disease, Chronic Obstructive Pulmonary Disease, COPD, LAMA, Lung Disease, Lung Diseases, Obstructive, Lung Function, Muscarinic receptor antagonist, Pulmonary Disease, Chronic Obstructive, Respiratory Tract Diseases
Brief summary
This study is a post-authorization commitment to the European Medicines Agency (EMA). The study serves to determine whether the treatment of patients with stable, symptomatic Chronic Obstructive Pulmonary Disease (COPD) with the investigational drug NVA237 is efficient and safe. The efficacy and safety of the drug was tested for twice daily dosing against once daily dosing.
Interventions
DRUGNVA237
NVA237 capsules for inhalation, delivered via a Single Dose Dry Powder Inhaler (SDDPI) called Concept1
DRUGPlacebo
Placebo to NVA237
DRUGSalbutamol
All patients received salbutamol (100 μg) as only rescue medication
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
41 Years to 84 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed * Male and female adults aged ≥40 years * Patients with stable COPD according to the current GOLD strategy (GOLD 2014) * Current or ex-smokers who have a smoking history of at least 10 pack years- an ex-smoker may be defined as a subject who has not smoked for ≥ 6 months at screening * mMRC grade of at least 2 at Visit 101 * Patients with airflow limitation indicated by a post-bronchodilator FEV1 ≥ 30 % and \< 80 % of the predicted normal, and a post-bronchodilator FEV1/FVC \< 0.70 at Visit 101.
Exclusion criteria
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test; Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment * Patients with Type I or uncontrolled Type II diabetes; Patients with a history of long QT syndrome or whose QTc measured at run-in (Fridericia method) is prolonged (\>450 ms for males and \>460 for females) and confirmed by a central assessor * Patients requiring long term oxygen therapy prescribed for \>12 h per day; Patients with any history of asthma.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | Baseline, Week 12 | Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1 at Week 12. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Area Under The Curve (AUC 0-12 Hour) for Forced Expiratory Volume in One Second (FEV1) Post Dosing at Day 1 | Baseline, 0-12 hour post dose at Day 1 | The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for 0-12 hour, post dosing at Day 1 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. |
| Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26 | Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 26 | The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 26 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. |
| Change From Baseline in Total St. George's Respiratory Questionnaire (SGRQ) Score at Week 12 and Week 26 | Baseline, 12 Weeks, 26 Weeks | The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: * Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity * Part II covers Activity and is concerned with activities that caused or are limited by breathlessness * Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. Higher values corresponded to greater impairment of health status. |
| Percentage of Patients With a Clinically Significant Improvement in St George Respiratory Questionnaire at Week 12 and Week 26 | Baseline, 12 Weeks, 26 Weeks | The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: * Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity * Part II covers Activity and is concerned with activities that caused or are limited by breathlessness * Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. A clinically significant improvement is defined as ≥ 4 unit improvement from baseline score (a decrease of ≥ 4). |
| Change From Baseline in Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Baseline, 12 Weeks, 26 Weeks | Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. |
| Percentage of Patients With a Clinically Important Improvement on Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Baseline, 12 Weeks, 26 Weeks | Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. Clinically important improvement indicates ≥ 1 unit in the TDI focal score at Weeks 12 and 26 in comparison to BDI focal score (an increase of ≥ 1). |
| Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12 | Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 12 | The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 12 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. |
| Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Baseline, Week 26 (Day 183-184) | Mixed model for repeated measures was used to analyze change from baseline in FVC. Baseline FVC is defined as the average of the -45 min and -15 min FVC values taken on Day 1 prior to first dose. |
| Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Baseline, Week 26 (Day 183-184) | Mixed model for repeated measures was used to analyze change from baseline in IC. |
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Baseline, Week 26 (Day 183-184) | Mixed model for repeated measures was used to analyze change from baseline in FEV1. Baseline FEV1 is defined as the average of the -45 min and -15 min FEV1 values taken on Day 1 prior to first dose. |
| Change From Baseline in the Percentage of Days With no Rescue Medication Use Over the 26 Weeks | Baseline, 26 Weeks | Patients report the number of puffs of rescue medication (salbutamol / albuterol) using an electronic diary. change from baseline in percentage of days without rescue medication usage over 26 weeks was analyzed. |
| Change From Baseline in Mean Daily COPD Symptom Score at Week 26 | Baseline, 26 Weeks | Patients reported symptoms by using an electronic diary. The mean daily total symptom score, the mean morning symptom score and the mean evening symptom score were calculated for each patient over 26 weeks. Each symptom measured in a numeric rating scale of 0-10; 0 indicates no symptom and 10 indicates severe symptom. 0 is no waking due to symptoms, 1 woke up once, 2 woke up more than once due to symptoms ; 10 was the worst score.The daily score for an individual symptom score was the worst of the morning and evening scores on a particular day. If either the morning or evening score was missing for a symptom then the non-missing value was taken as the worst. A negative change indicates improvement. Only the scores for the 6 COPD symptoms (respiratory symptoms, cough, wheeze, production of sputum, sputum color, and breathlessness) were used to derive the total symptom score |
| Number of Patients With Adverse Events, Serious Adverse Events and Death | 26 Weeks | This endpoint reports patients affected by any adverse events (AE), serious adverse events (SAE) and death. Only treatment emergent AE, SAE, deaths are reported for this endpoint. |
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26 | Baseline, Day 1, Week 26 | Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate. |
Countries
Belgium, Bulgaria, Finland, Germany, Hungary, Israel, Poland, Romania, Russia, Sweden
Participant flow
Pre-assignment details
A total of 1020 patients were screened for participation in this study; 776 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| NVA237 Twice Daily Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine. | 388 |
| NVA237 Once Daily Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine. | 388 |
| Total | 776 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 8 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Noncompliance with study treatment | 1 | 0 |
| Overall Study | Patient decision | 14 | 10 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Protocol deviation | 0 | 1 |
Baseline characteristics
| Characteristic | NVA237 Twice Daily | NVA237 Once Daily | Total |
|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 7.71 | 63.6 years STANDARD_DEVIATION 7.66 | 63.4 years STANDARD_DEVIATION 7.68 |
| Sex: Female, Male Female | 122 Participants | 111 Participants | 233 Participants |
| Sex: Female, Male Male | 266 Participants | 277 Participants | 543 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 388 | 2 / 388 |
| other Total, other adverse events | 126 / 388 | 152 / 388 |
| serious Total, serious adverse events | 33 / 388 | 30 / 388 |
Outcome results
Primary
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12
Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1 at Week 12. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate.
Time frame: Baseline, Week 12
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and week 12 were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | 0.092 Liters | Standard Error 0.0126 |
| NVA237 Once Daily | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | 0.059 Liters | Standard Error 0.0125 |
p-value: 0.05195% CI: [0, 0.066]Mixed model for repeated measure (MMRM)
Secondary
Change From Baseline in Area Under The Curve (AUC 0-12 Hour) for Forced Expiratory Volume in One Second (FEV1) Post Dosing at Day 1
The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for 0-12 hour, post dosing at Day 1 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.
Time frame: Baseline, 0-12 hour post dose at Day 1
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and Day 1 were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Area Under The Curve (AUC 0-12 Hour) for Forced Expiratory Volume in One Second (FEV1) Post Dosing at Day 1 | 0.143 Liters | Standard Error 0.0089 |
| NVA237 Once Daily | Change From Baseline in Area Under The Curve (AUC 0-12 Hour) for Forced Expiratory Volume in One Second (FEV1) Post Dosing at Day 1 | 0.139 Liters | Standard Error 0.0087 |
Secondary
Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12
The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 12 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.
Time frame: Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 12
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at baseline and week 12 in different time spans were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12 | AUC (0-12 hour) | 0.136 Liters | Standard Error 0.0119 |
| NVA237 Twice Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12 | AUC (0-24 hour) | 0.085 Liters | Standard Error 0.0121 |
| NVA237 Twice Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12 | AUC (12-24 hour) | 0.035 Liters | Standard Error 0.0125 |
| NVA237 Once Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12 | AUC (12-24 hour) | -0.019 Liters | Standard Error 0.0124 |
| NVA237 Once Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12 | AUC (0-12 hour) | 0.106 Liters | Standard Error 0.0118 |
| NVA237 Once Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12 | AUC (0-24 hour) | 0.043 Liters | Standard Error 0.012 |
Secondary
Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26
The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 26 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.
Time frame: Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 26
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and week 26 in different time spans were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26 | AUC (0-12 hour) | 0.123 Liters | Standard Error 0.0121 |
| NVA237 Twice Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26 | AUC (0-24 hour) | 0.076 Liters | Standard Error 0.0122 |
| NVA237 Twice Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26 | AUC (12-24 hour) | 0.032 Liters | Standard Error 0.0127 |
| NVA237 Once Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26 | AUC (0-12 hour) | 0.091 Liters | Standard Error 0.012 |
| NVA237 Once Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26 | AUC (0-24 hour) | 0.030 Liters | Standard Error 0.0121 |
| NVA237 Once Daily | Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26 | AUC (12-24 hour) | -0.028 Liters | Standard Error 0.0126 |
Secondary
Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26
Mixed model for repeated measures was used to analyze change from baseline in FEV1. Baseline FEV1 is defined as the average of the -45 min and -15 min FEV1 values taken on Day 1 prior to first dose.
Time frame: Baseline, Week 26 (Day 183-184)
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in FAS were analyzed according to the treatment to which they were randomized. n = number of patients included in respective analysis (i.e. who had a FEV1 at this timepoint on at least one visit).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/-45 min | 0.058 Liters | Standard Error 0.012 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/-15 min | 0.086 Liters | Standard Error 0.0119 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/5 min | 0.111 Liters | Standard Error 0.012 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/15 min | 0.145 Liters | Standard Error 0.012 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/30 min | 0.155 Liters | Standard Error 0.0118 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/1 h | 0.158 Liters | Standard Error 0.012 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/2 h | 0.194 Liters | Standard Error 0.0119 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/3 h | 0.179 Liters | Standard Error 0.0121 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/4 h | 0.166 Liters | Standard Error 0.012 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/6 h | 0.110 Liters | Standard Error 0.0121 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/8 h | 0.118 Liters | Standard Error 0.0121 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/10 h | 0.067 Liters | Standard Error 0.0122 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/12 h | 0.056 Liters | Standard Error 0.0123 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/13 h | 0.093 Liters | Standard Error 0.0123 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 184/16 h | -0.001 Liters | Standard Error 0.0128 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 184/22 h | -0.012 Liters | Standard Error 0.0122 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 184/23 h 15 min | 0.076 Liters | Standard Error 0.0124 |
| NVA237 Twice Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 184/23 h 45 min | 0.122 Liters | Standard Error 0.0122 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/13 h | 0.000 Liters | Standard Error 0.0121 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/-45 min | 0.012 Liters | Standard Error 0.0119 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/6 h | 0.080 Liters | Standard Error 0.0118 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/-15 min | 0.034 Liters | Standard Error 0.0118 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 184/23 h 45 min | 0.067 Liters | Standard Error 0.0121 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/5 min | 0.070 Liters | Standard Error 0.0119 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/8 h | 0.064 Liters | Standard Error 0.0119 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/15 min | 0.106 Liters | Standard Error 0.012 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 184/16 h | -0.063 Liters | Standard Error 0.0127 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/30 min | 0.122 Liters | Standard Error 0.0118 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/10 h | 0.038 Liters | Standard Error 0.0118 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/1 h | 0.132 Liters | Standard Error 0.0118 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 184/23 h 15 min | 0.032 Liters | Standard Error 0.012 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/2 h | 0.163 Liters | Standard Error 0.0118 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/12 h | 0.024 Liters | Standard Error 0.0121 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/3 h | 0.154 Liters | Standard Error 0.0118 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 184/22 h | -0.043 Liters | Standard Error 0.012 |
| NVA237 Once Daily | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 | Day 183/4 h | 0.132 Liters | Standard Error 0.0118 |
Secondary
Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26
Mixed model for repeated measures was used to analyze change from baseline in FVC. Baseline FVC is defined as the average of the -45 min and -15 min FVC values taken on Day 1 prior to first dose.
Time frame: Baseline, Week 26 (Day 183-184)
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in FAS were analyzed according to the treatment to which they were randomized. n = number of patients included in respective analysis (i.e. who had a FVC at this time point on at least one visit).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/-45 min: | 0.079 Liters | Standard Error 0.0195 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/-15 min: | 0.102 Liters | Standard Error 0.0193 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/5 min: | 0.159 Liters | Standard Error 0.0194 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/15 min: | 0.177 Liters | Standard Error 0.0195 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/30 min: | 0.194 Liters | Standard Error 0.0192 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/1 h: | 0.190 Liters | Standard Error 0.0194 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/2 h | 0.229 Liters | Standard Error 0.0193 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/3 h: | 0.229 Liters | Standard Error 0.0197 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/4 h: | 0.216 Liters | Standard Error 0.0194 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/6 h | 0.146 Liters | Standard Error 0.0196 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/8 h | 0.137 Liters | Standard Error 0.0195 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/10 h | 0.071 Liters | Standard Error 0.0198 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/12 h | 0.041 Liters | Standard Error 0.02 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/13 h | 0.096 Liters | Standard Error 0.0199 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 184/16 h | -0.014 Liters | Standard Error 0.0207 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 184/22 h | -0.036 Liters | Standard Error 0.0198 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 184/23 h 15 min | 0.075 Liters | Standard Error 0.0201 |
| NVA237 Twice Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 184/23 h 45 min | 0.129 Liters | Standard Error 0.0197 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/13 h | 0.004 Liters | Standard Error 0.0197 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/-45 min: | 0.025 Liters | Standard Error 0.0192 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/6 h | 0.116 Liters | Standard Error 0.0191 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/-15 min: | 0.029 Liters | Standard Error 0.0191 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 184/23 h 45 min | 0.077 Liters | Standard Error 0.0196 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/5 min: | 0.085 Liters | Standard Error 0.0194 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/8 h | 0.085 Liters | Standard Error 0.0193 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/15 min: | 0.132 Liters | Standard Error 0.0195 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 184/16 h | -0.081 Liters | Standard Error 0.0206 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/30 min: | 0.144 Liters | Standard Error 0.0191 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/10 h | 0.039 Liters | Standard Error 0.0191 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/1 h: | 0.154 Liters | Standard Error 0.0192 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 184/23 h 15 min | 0.031 Liters | Standard Error 0.0194 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/2 h | 0.200 Liters | Standard Error 0.0191 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/12 h | 0.026 Liters | Standard Error 0.0196 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/3 h: | 0.186 Liters | Standard Error 0.0192 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 184/22 h | -0.076 Liters | Standard Error 0.0195 |
| NVA237 Once Daily | Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 | Day 183/4 h: | 0.169 Liters | Standard Error 0.0191 |
Secondary
Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26
Mixed model for repeated measures was used to analyze change from baseline in IC.
Time frame: Baseline, Week 26 (Day 183-184)
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in FAS were analyzed according to the treatment to which they were randomized. n = number of patients included in respective analysis (i.e. who had a IC at this timepoint on at least one visit).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/1 h 55 min | 0.193 Liters | Standard Error 0.0223 |
| NVA237 Twice Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/7 h 55 min | 0.108 Liters | Standard Error 0.0228 |
| NVA237 Twice Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/25 min | 0.181 Liters | Standard Error 0.0224 |
| NVA237 Twice Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/11 h 55 min | 0.042 Liters | Standard Error 0.0229 |
| NVA237 Twice Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/3 h 55 min | 0.163 Liters | Standard Error 0.0226 |
| NVA237 Twice Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 184/23 h 40 min | 0.045 Liters | Standard Error 0.0233 |
| NVA237 Twice Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/-20 min | 0.094 Liters | Standard Error 0.0221 |
| NVA237 Once Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 184/23 h 40 min | 0.062 Liters | Standard Error 0.0224 |
| NVA237 Once Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/-20 min | 0.054 Liters | Standard Error 0.0221 |
| NVA237 Once Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/25 min | 0.173 Liters | Standard Error 0.0215 |
| NVA237 Once Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/1 h 55 min | 0.171 Liters | Standard Error 0.0218 |
| NVA237 Once Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/3 h 55 min | 0.159 Liters | Standard Error 0.0221 |
| NVA237 Once Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/7 h 55 min | 0.110 Liters | Standard Error 0.0222 |
| NVA237 Once Daily | Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 | Day 183/11 h 55 min | 0.030 Liters | Standard Error 0.0218 |
Secondary
Change From Baseline in Mean Daily COPD Symptom Score at Week 26
Patients reported symptoms by using an electronic diary. The mean daily total symptom score, the mean morning symptom score and the mean evening symptom score were calculated for each patient over 26 weeks. Each symptom measured in a numeric rating scale of 0-10; 0 indicates no symptom and 10 indicates severe symptom. 0 is no waking due to symptoms, 1 woke up once, 2 woke up more than once due to symptoms ; 10 was the worst score.The daily score for an individual symptom score was the worst of the morning and evening scores on a particular day. If either the morning or evening score was missing for a symptom then the non-missing value was taken as the worst. A negative change indicates improvement. Only the scores for the 6 COPD symptoms (respiratory symptoms, cough, wheeze, production of sputum, sputum color, and breathlessness) were used to derive the total symptom score
Time frame: Baseline, 26 Weeks
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and week 26 were included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Mean Daily COPD Symptom Score at Week 26 | Change in mean daily | -1.336 score on a scale | Standard Error 0.1141 |
| NVA237 Twice Daily | Change From Baseline in Mean Daily COPD Symptom Score at Week 26 | Change in mean morning | -1.032 score on a scale | Standard Error 0.1304 |
| NVA237 Twice Daily | Change From Baseline in Mean Daily COPD Symptom Score at Week 26 | Change in mean evening | -1.205 score on a scale | Standard Error 0.1141 |
| NVA237 Once Daily | Change From Baseline in Mean Daily COPD Symptom Score at Week 26 | Change in mean daily | -1.107 score on a scale | Standard Error 0.116 |
| NVA237 Once Daily | Change From Baseline in Mean Daily COPD Symptom Score at Week 26 | Change in mean morning | -0.828 score on a scale | Standard Error 0.1318 |
| NVA237 Once Daily | Change From Baseline in Mean Daily COPD Symptom Score at Week 26 | Change in mean evening | -1.056 score on a scale | Standard Error 0.1152 |
Secondary
Change From Baseline in the Percentage of Days With no Rescue Medication Use Over the 26 Weeks
Patients report the number of puffs of rescue medication (salbutamol / albuterol) using an electronic diary. change from baseline in percentage of days without rescue medication usage over 26 weeks was analyzed.
Time frame: Baseline, 26 Weeks
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and week 26 were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in the Percentage of Days With no Rescue Medication Use Over the 26 Weeks | 16.574 percentage of days | Standard Error 2.3519 |
| NVA237 Once Daily | Change From Baseline in the Percentage of Days With no Rescue Medication Use Over the 26 Weeks | 15.363 percentage of days | Standard Error 2.3927 |
Secondary
Change From Baseline in Total St. George's Respiratory Questionnaire (SGRQ) Score at Week 12 and Week 26
The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: * Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity * Part II covers Activity and is concerned with activities that caused or are limited by breathlessness * Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. Higher values corresponded to greater impairment of health status.
Time frame: Baseline, 12 Weeks, 26 Weeks
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and post-baseline time points were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Total St. George's Respiratory Questionnaire (SGRQ) Score at Week 12 and Week 26 | Change from Baseline to WK 12 | -5.320 score on a scale | Standard Error 0.6 |
| NVA237 Twice Daily | Change From Baseline in Total St. George's Respiratory Questionnaire (SGRQ) Score at Week 12 and Week 26 | Change from Baseline to WK 26 | -6.587 score on a scale | Standard Error 0.6543 |
| NVA237 Once Daily | Change From Baseline in Total St. George's Respiratory Questionnaire (SGRQ) Score at Week 12 and Week 26 | Change from Baseline to WK 12 | -3.563 score on a scale | Standard Error 0.5987 |
| NVA237 Once Daily | Change From Baseline in Total St. George's Respiratory Questionnaire (SGRQ) Score at Week 12 and Week 26 | Change from Baseline to WK 26 | -4.644 score on a scale | Standard Error 0.6527 |
Secondary
Change From Baseline in Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26
Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score.
Time frame: Baseline, 12 Weeks, 26 Weeks
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and post-baseline time points were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Change from Baseline to WK 12 | 1.346 score on a scale | Standard Error 0.143 |
| NVA237 Twice Daily | Change From Baseline in Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Change from Baseline to WK 26 | 1.523 score on a scale | Standard Error 0.1539 |
| NVA237 Once Daily | Change From Baseline in Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Change from Baseline to WK 12 | 0.849 score on a scale | Standard Error 0.1433 |
| NVA237 Once Daily | Change From Baseline in Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Change from Baseline to WK 26 | 1.170 score on a scale | Standard Error 0.1534 |
Secondary
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26
Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate.
Time frame: Baseline, Day 1, Week 26
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and post-baseline time points were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 Twice Daily | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26 | Change from baseline to Day 1 | 0.119 Liters | Standard Error 0.0099 |
| NVA237 Twice Daily | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26 | Change from baseline to Week 26 | 0.104 Liters | Standard Error 0.0129 |
| NVA237 Once Daily | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26 | Change from baseline to Day 1 | 0.070 Liters | Standard Error 0.0097 |
| NVA237 Once Daily | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26 | Change from baseline to Week 26 | 0.056 Liters | Standard Error 0.0128 |
Secondary
Number of Patients With Adverse Events, Serious Adverse Events and Death
This endpoint reports patients affected by any adverse events (AE), serious adverse events (SAE) and death. Only treatment emergent AE, SAE, deaths are reported for this endpoint.
Time frame: 26 Weeks
Population: The Safety Set (SAF) included all patients who received at least one dose of study drug whether or not they were randomized. Patients were analyzed according to the treatment they received. If patients switched treatment during the study, they were to be analyzed according to the treatment to which they were randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NVA237 Twice Daily | Number of Patients With Adverse Events, Serious Adverse Events and Death | Patients with at least one AE | 203 Count of Participants |
| NVA237 Twice Daily | Number of Patients With Adverse Events, Serious Adverse Events and Death | Patients with at least one SAE | 33 Count of Participants |
| NVA237 Twice Daily | Number of Patients With Adverse Events, Serious Adverse Events and Death | Death | 1 Count of Participants |
| NVA237 Once Daily | Number of Patients With Adverse Events, Serious Adverse Events and Death | Patients with at least one AE | 224 Count of Participants |
| NVA237 Once Daily | Number of Patients With Adverse Events, Serious Adverse Events and Death | Patients with at least one SAE | 30 Count of Participants |
| NVA237 Once Daily | Number of Patients With Adverse Events, Serious Adverse Events and Death | Death | 1 Count of Participants |
Secondary
Percentage of Patients With a Clinically Important Improvement on Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26
Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. Clinically important improvement indicates ≥ 1 unit in the TDI focal score at Weeks 12 and 26 in comparison to BDI focal score (an increase of ≥ 1).
Time frame: Baseline, 12 Weeks, 26 Weeks
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. n= the number of patients with a TDI focal score
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NVA237 Twice Daily | Percentage of Patients With a Clinically Important Improvement on Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Change from Baseline to WK 12 | 56.9 Percentage of patients |
| NVA237 Twice Daily | Percentage of Patients With a Clinically Important Improvement on Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Change from Baseline to WK 26 | 61.1 Percentage of patients |
| NVA237 Once Daily | Percentage of Patients With a Clinically Important Improvement on Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Change from Baseline to WK 12 | 52.0 Percentage of patients |
| NVA237 Once Daily | Percentage of Patients With a Clinically Important Improvement on Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 | Change from Baseline to WK 26 | 54.6 Percentage of patients |
Secondary
Percentage of Patients With a Clinically Significant Improvement in St George Respiratory Questionnaire at Week 12 and Week 26
The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: * Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity * Part II covers Activity and is concerned with activities that caused or are limited by breathlessness * Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. A clinically significant improvement is defined as ≥ 4 unit improvement from baseline score (a decrease of ≥ 4).
Time frame: Baseline, 12 Weeks, 26 Weeks
Population: The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. n= the number of patients with a SGRQ total score at both baseline and indicated post-baseline time point
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NVA237 Twice Daily | Percentage of Patients With a Clinically Significant Improvement in St George Respiratory Questionnaire at Week 12 and Week 26 | Change from Baseline to WK 12 | 54.5 percentage of patients |
| NVA237 Twice Daily | Percentage of Patients With a Clinically Significant Improvement in St George Respiratory Questionnaire at Week 12 and Week 26 | Change from Baseline to WK 26 | 59.4 percentage of patients |
| NVA237 Once Daily | Percentage of Patients With a Clinically Significant Improvement in St George Respiratory Questionnaire at Week 12 and Week 26 | Change from Baseline to WK 12 | 46.9 percentage of patients |
| NVA237 Once Daily | Percentage of Patients With a Clinically Significant Improvement in St George Respiratory Questionnaire at Week 12 and Week 26 | Change from Baseline to WK 26 | 49.6 percentage of patients |