Trial Outcomes & Findings for A Study of the Efficacy and Safety of NVA237 in Patients With Moderate to Severe COPD (NCT NCT02371629)

Last Updated: 2019-08-09

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

776 participants

Primary outcome timeframe

Baseline, Week 12

Results posted on

2019-08-09

Participant Flow

A total of 1020 patients were screened for participation in this study; 776 were randomized.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	388	388
Overall Study COMPLETED	362	363
Overall Study NOT COMPLETED	26	25

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Patient decision	14	10
Overall Study Adverse Event	8	8
Overall Study Physician Decision	2	3
Overall Study Death	1	1
Overall Study Noncompliance with study treatment	1	0
Overall Study Lack of Efficacy	0	2
Overall Study Protocol deviation	0	1

Baseline Characteristics

A Study of the Efficacy and Safety of NVA237 in Patients With Moderate to Severe COPD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.	Total n=776 Participants Total of all reporting groups
Age, Continuous	63.2 years STANDARD_DEVIATION 7.71 • n=93 Participants	63.6 years STANDARD_DEVIATION 7.66 • n=4 Participants	63.4 years STANDARD_DEVIATION 7.68 • n=27 Participants
Sex: Female, Male Female	122 Participants n=93 Participants	111 Participants n=4 Participants	233 Participants n=27 Participants
Sex: Female, Male Male	266 Participants n=93 Participants	277 Participants n=4 Participants	543 Participants n=27 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=358 Participants 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.	NVA237 Once Daily n=360 Participants 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.
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12	0.092 Liters Standard Error 0.0126	0.059 Liters Standard Error 0.0125

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=373 Participants 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.	NVA237 Once Daily n=373 Participants 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.
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	0.106 Liters Standard Error 0.0118
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	0.043 Liters Standard Error 0.0120
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	-0.019 Liters Standard Error 0.0124

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=387 Participants 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.	NVA237 Once Daily n=387 Participants 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.
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	0.139 Liters Standard Error 0.0087

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=360 Participants 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.	NVA237 Once Daily n=364 Participants 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.
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	0.091 Liters Standard Error 0.0120
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	0.030 Liters Standard Error 0.0121
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	-0.028 Liters Standard Error 0.0126

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.
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 0.6000	-3.563 score on a scale Standard Error 0.5987
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	-4.644 score on a scale Standard Error 0.6527

SECONDARY outcome

Timeframe: 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

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).

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.
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	46.9 percentage of patients
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	49.6 percentage of patients

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.
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 0.1430	0.849 score on a scale Standard Error 0.1433
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	1.170 score on a scale Standard Error 0.1534

SECONDARY outcome

Timeframe: Baseline, 12 Weeks, 26 Weeks

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.
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	52.0 Percentage of patients
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	54.6 Percentage of patients

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.
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	0.070 Liters Standard Error 0.0097
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	0.056 Liters Standard Error 0.0128

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.
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	0.025 Liters Standard Error 0.0192
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	0.029 Liters Standard Error 0.0191
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	0.085 Liters Standard Error 0.0194
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	0.132 Liters Standard Error 0.0195
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	0.144 Liters Standard Error 0.0191
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	0.154 Liters Standard Error 0.0192
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	0.200 Liters Standard Error 0.0191
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	0.186 Liters Standard Error 0.0192
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	0.169 Liters Standard Error 0.0191
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	0.116 Liters Standard Error 0.0191
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	0.085 Liters Standard Error 0.0193
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	0.039 Liters Standard Error 0.0191
Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 Day 183/12 h	0.041 Liters Standard Error 0.0200	0.026 Liters Standard Error 0.0196
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	0.004 Liters Standard Error 0.0197
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	-0.081 Liters Standard Error 0.0206
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	-0.076 Liters Standard Error 0.0195
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	0.031 Liters Standard Error 0.0194
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	0.077 Liters Standard Error 0.0196

SECONDARY outcome

Timeframe: Baseline, Week 26 (Day 183-184)

Mixed model for repeated measures was used to analyze change from baseline in IC.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.
Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 Day 183/-20 min	0.094 Liters Standard Error 0.0221	0.054 Liters Standard Error 0.0221
Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 Day 183/25 min	0.181 Liters Standard Error 0.0224	0.173 Liters Standard Error 0.0215
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	0.171 Liters Standard Error 0.0218
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	0.159 Liters Standard Error 0.0221
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	0.110 Liters Standard Error 0.0222
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	0.030 Liters Standard Error 0.0218
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	0.062 Liters Standard Error 0.0224

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.
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 0.0120	0.012 Liters Standard Error 0.0119
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	0.034 Liters Standard Error 0.0118
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 0.0120	0.070 Liters Standard Error 0.0119
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 0.0120	0.106 Liters Standard Error 0.0120
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	0.122 Liters Standard Error 0.0118
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 0.0120	0.132 Liters Standard Error 0.0118
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	0.163 Liters Standard Error 0.0118
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	0.154 Liters Standard Error 0.0118
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 0.0120	0.132 Liters Standard Error 0.0118
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	0.080 Liters Standard Error 0.0118
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	0.064 Liters Standard Error 0.0119
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	0.038 Liters Standard Error 0.0118
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	0.024 Liters Standard Error 0.0121
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	0.000 Liters Standard Error 0.0121
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	-0.063 Liters Standard Error 0.0127
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	-0.043 Liters Standard Error 0.0120
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	0.032 Liters Standard Error 0.0120
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	0.067 Liters Standard Error 0.0121

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=383 Participants 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.	NVA237 Once Daily n=377 Participants 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.
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	15.363 percentage of days Standard Error 2.3927

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=383 Participants 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.	NVA237 Once Daily n=377 Participants 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.
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	-1.107 score on a scale Standard Error 0.1160
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	-0.828 score on a scale Standard Error 0.1318
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	-1.056 score on a scale Standard Error 0.1152

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	NVA237 Twice Daily n=388 Participants 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.	NVA237 Once Daily n=388 Participants 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.
Number of Patients With Adverse Events, Serious Adverse Events and Death Patients with at least one AE	203 Count of Participants	224 Count of Participants
Number of Patients With Adverse Events, Serious Adverse Events and Death Patients with at least one SAE	33 Count of Participants	30 Count of Participants
Number of Patients With Adverse Events, Serious Adverse Events and Death Death	1 Count of Participants	1 Count of Participants

Adverse Events

NVA237 22 mcg b.i.d.

Serious events: 33 serious events

Other events: 126 other events

Deaths: 1 deaths

NVA237 44 mcg o.d.

Serious events: 30 serious events

Other events: 152 other events

Deaths: 2 deaths

Serious adverse events

Serious adverse events
Measure	NVA237 22 mcg b.i.d. n=388 participants at risk NVA237 22 mcg b.i.d.	NVA237 44 mcg o.d. n=388 participants at risk NVA237 44 mcg o.d.
Cardiac disorders Angina unstable	0.52% 2/388	0.00% 0/388
Cardiac disorders Atrial fibrillation	0.77% 3/388	0.52% 2/388
Cardiac disorders Atrial flutter	0.26% 1/388	0.00% 0/388
Cardiac disorders Atrial tachycardia	0.26% 1/388	0.00% 0/388
Cardiac disorders Cardiac failure chronic	0.26% 1/388	0.00% 0/388
Cardiac disorders Cardiac failure congestive	0.26% 1/388	0.00% 0/388
Gastrointestinal disorders Gastritis erosive	0.00% 0/388	0.26% 1/388
Gastrointestinal disorders Gastrooesophageal reflux disease	0.26% 1/388	0.00% 0/388
General disorders Death	0.00% 0/388	0.26% 1/388
Hepatobiliary disorders Bile duct stone	0.00% 0/388	0.26% 1/388
Infections and infestations Diverticulitis	0.00% 0/388	0.26% 1/388
Infections and infestations Erysipelas	0.00% 0/388	0.26% 1/388
Infections and infestations Influenza	0.00% 0/388	0.26% 1/388
Infections and infestations Otitis externa	0.26% 1/388	0.00% 0/388
Infections and infestations Pneumonia	0.77% 3/388	1.0% 4/388
Infections and infestations Sepsis	0.26% 1/388	0.00% 0/388
Injury, poisoning and procedural complications Brachial plexus injury	0.26% 1/388	0.00% 0/388
Injury, poisoning and procedural complications Pubis fracture	0.00% 0/388	0.26% 1/388
Injury, poisoning and procedural complications Spinal compression fracture	0.26% 1/388	0.00% 0/388
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer recurrent	0.26% 1/388	0.00% 0/388
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial carcinoma	0.52% 2/388	0.00% 0/388
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chronic myeloid leukaemia	0.26% 1/388	0.00% 0/388
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive ductal breast carcinoma	0.00% 0/388	0.26% 1/388
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.26% 1/388	0.26% 1/388
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic squamous cell carcinoma	0.00% 0/388	0.26% 1/388
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal adenocarcinoma	0.00% 0/388	0.26% 1/388
Nervous system disorders Carpal tunnel syndrome	0.00% 0/388	0.26% 1/388
Nervous system disorders Cerebrovascular accident	0.26% 1/388	0.00% 0/388
Nervous system disorders Ischaemic stroke	0.26% 1/388	0.00% 0/388
Nervous system disorders Pseudoradicular syndrome	0.26% 1/388	0.00% 0/388
Nervous system disorders Vertebrobasilar insufficiency	0.00% 0/388	0.26% 1/388
Psychiatric disorders Schizophrenia	0.52% 2/388	0.00% 0/388
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.52% 2/388	0.00% 0/388
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	2.8% 11/388	3.9% 15/388
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.26% 1/388	0.00% 0/388
Vascular disorders Aortic aneurysm	0.26% 1/388	0.00% 0/388
Vascular disorders Arterial occlusive disease	0.00% 0/388	0.26% 1/388
Vascular disorders Brachiocephalic artery stenosis	0.00% 0/388	0.26% 1/388

Other adverse events

Other adverse events
Measure	NVA237 22 mcg b.i.d. n=388 participants at risk NVA237 22 mcg b.i.d.	NVA237 44 mcg o.d. n=388 participants at risk NVA237 44 mcg o.d.
Infections and infestations Bronchitis	2.6% 10/388	0.77% 3/388
Infections and infestations Nasopharyngitis	9.5% 37/388	13.9% 54/388
Nervous system disorders Headache	1.0% 4/388	2.1% 8/388
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	19.1% 74/388	25.5% 99/388
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.3% 9/388	0.52% 2/388
Vascular disorders Hypertension	2.6% 10/388	3.6% 14/388

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER