Trial Outcomes & Findings for A Study to Assess the Efficacy, Safety and Tolerability of Once-daily (q.d.) QVA149 in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT01202188)

NCT ID: NCT01202188

Last Updated: 2013-09-09

Results Overview

Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 2144 participants
• Primary outcome timeframe: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26
• Results posted on: 2013-09-09

Participant Flow

There was a 14 day run-in period prior to randomization.

Participant milestones

Measure	Indacaterol and Glycopyrronium (QVA149) QVA149 110/50 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) QAB149 150 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) NVA237 50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Tiotropium Tiotropium 18 μg capsules for inhalation delivered once daily via HandiHaler® device for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Overall Study STARTED	475	477	475	483	234
Overall Study Safety Set; Received Study Drug	474	476	473	480	232
Overall Study COMPLETED	437	421	422	441	189
Overall Study NOT COMPLETED	38	56	53	42	45

Reasons for withdrawal

Measure	Indacaterol and Glycopyrronium (QVA149) QVA149 110/50 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) QAB149 150 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) NVA237 50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Tiotropium Tiotropium 18 μg capsules for inhalation delivered once daily via HandiHaler® device for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Overall Study Protocol deviation	14	8	12	10	11
Overall Study Subject withdrew consent	12	13	22	11	13
Overall Study Adverse Event	5	23	13	10	10
Overall Study Administrative problems	3	2	1	1	2
Overall Study Unsatisfactory therapeutic effect	2	8	2	5	8
Overall Study Lost to Follow-up	1	1	0	4	1
Overall Study Death	1	1	1	1	0
Overall Study Abnormal test procedure result (s)	0	0	2	0	0

Baseline Characteristics

A Study to Assess the Efficacy, Safety and Tolerability of Once-daily (q.d.) QVA149 in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

Baseline characteristics by cohort

Measure	Indacaterol and Glycopyrronium (QVA149) n=474 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=476 Participants QAB149 150 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=473 Participants NVA237 50 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Tiotropium n=480 Participants Tiotropium 18 μg capsules for inhalation delivered once daily via HandiHaler® device for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=232 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Total n=2135 Participants Total of all reporting groups
Age Continuous	64.0 years STANDARD_DEVIATION 8.88 • n=5 Participants	63.6 years STANDARD_DEVIATION 8.78 • n=7 Participants	64.3 years STANDARD_DEVIATION 9.04 • n=5 Participants	63.5 years STANDARD_DEVIATION 8.73 • n=4 Participants	64.4 years STANDARD_DEVIATION 8.58 • n=21 Participants	63.9 years STANDARD_DEVIATION 8.83 • n=8 Participants
Sex: Female, Male Female	112 Participants n=5 Participants	122 Participants n=7 Participants	108 Participants n=5 Participants	120 Participants n=4 Participants	63 Participants n=21 Participants	525 Participants n=8 Participants
Sex: Female, Male Male	362 Participants n=5 Participants	354 Participants n=7 Participants	365 Participants n=5 Participants	360 Participants n=4 Participants	169 Participants n=21 Participants	1610 Participants n=8 Participants

PRIMARY outcome

Timeframe: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26

Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis. Data was imputed with last observation carried forward. Data within 6 hours of rescue medication use or 7 days of systemic corticosteroid use is excluded from the analysis.

Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=442 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=435 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=424 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment	1.45 Liters Standard Error 0.010	1.38 Liters Standard Error 0.010	1.36 Liters Standard Error 0.010	—	—

SECONDARY outcome

Timeframe: Week 26

Population: Participants from the Full Analysis Set, included all participants who received at least one dose of study drug, with data available for analysis. Missing data were imputed with Last Observation Carried Forward.

A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. 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. A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=439 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=193 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Transitional Dyspnea Index (TDI) Focal Score at Week 26	2.72 Score on a scale Standard Error 0.170	1.63 Score on a scale Standard Error 0.230	—	—	—

SECONDARY outcome

Timeframe: 26 weeks

Population: Participants from the Full Analysis Set,included all participants who received at least one dose of study drug, with data available for analysis. Missing data were imputed with Last Observation Carried Forward but not more than 14 weeks and data within 4 weeks of day 1 were not carried forward.

SGRQ is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. A mixed model was used with treatment as a fixed effect with Baseline SGRQ and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=441 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=196 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 26	37.01 Score on a scale Standard Error 0.679	40.02 Score on a scale Standard Error 0.941	—	—	—

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Participants from the full analysis, consisting of all randomized participant who received study drug, with data available for analysis.

The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient. Rescue medication data recorded during the 14 day run-in was used to calculate the baseline. A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=419 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=199 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Over 26 Weeks	-1.88 Puffs per day Standard Error 0.105	-0.92 Puffs per day Standard Error 0.147	—	—	—

SECONDARY outcome

Timeframe: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26

Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis. Data was imputed with last observation carried forward. Data within 6 hours of rescue medication use or 7 days of systemic corticosteroid use is excluded from the analysis.

Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=442 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=435 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=424 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=191 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment With QVA149, QAB149 and NVA237 Compared to Placebo	1.45 Liters Standard Error 0.010	1.38 Liters Standard Error 0.010	1.36 Liters Standard Error 0.010	1.25 Liters Standard Error 0.015	—

SECONDARY outcome

Timeframe: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26

Population: Participants from the Per-protocol Set, randomized participants who received at least one dose of study drug without major protocol deviations. Data was imputed with last observation carried forward. Data within 6 hours of rescue medication use or 7 days of systemic corticosteroid use is excluded from the analysis.

Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=387 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=382 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment With QVA149 Compared to Tiotropium	1.46 Liters Standard Error 0.011	1.39 Liters Standard Error 0.011	—	—	—

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 26

Population: Participants from the Full Analysis Set, included all participants who received at least one dose of study drug, with data available for analysis. Missing data were imputed with Last Observation Carried Forward but not more than 14 weeks and data within 4 weeks of day 1 were not carried forward.

A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). BDI/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.

A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators as covariates and included baseline smoking status, baseline inhaled corticosteroids and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=442 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=443 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=435 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=445 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=200 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Baseline Transitional Dyspnea Index (BDI/TDI) Focal Score at Week 12 and Week 26 BDI_ baseline for Week 12	6.45 Score on a scale Standard Error 0.100	6.28 Score on a scale Standard Error 0.096	6.21 Score on a scale Standard Error 0.097	6.43 Score on a scale Standard Error 0.094	6.53 Score on a scale Standard Error 0.154
Baseline Transitional Dyspnea Index (BDI/TDI) Focal Score at Week 12 and Week 26 TDI Week 12	2.44 Score on a scale Standard Error 0.158	2.18 Score on a scale Standard Error 0.157	2.04 Score on a scale Standard Error 0.158	1.81 Score on a scale Standard Error 0.158	1.22 Score on a scale Standard Error 0.215
Baseline Transitional Dyspnea Index (BDI/TDI) Focal Score at Week 12 and Week 26 BDI_baseline for Week 26 (n=439,440,424,441,193)	6.45 Score on a scale Standard Error 0.101	6.28 Score on a scale Standard Error 0.097	6.22 Score on a scale Standard Error 0.097	6.46 Score on a scale Standard Error 0.095	6.56 Score on a scale Standard Error 0.157
Baseline Transitional Dyspnea Index (BDI/TDI) Focal Score at Week 12 and Week 26 TDI Week 26 (n=439,440,424,441,193)	2.72 Score on a scale Standard Error 0.170	2.47 Score on a scale Standard Error 0.171	2.52 Score on a scale Standard Error 0.172	2.21 Score on a scale Standard Error 0.171	1.63 Score on a scale Standard Error 0.230

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Participants from the Full Analysis Set, included all participants who received at least one dose of study drug, with data available for analysis. Missing data were imputed with Last Observation Carried Forward.

A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing) at Week 12 and Week 26. TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI (baseline) was measured at Day 1. The 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.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=474 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=476 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=473 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=480 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=232 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Percentage of Patients With a Clinically Important Improvement of at Least 1 Point in TDI Focal Score After 26 Weeks of Treatment	68.1 Percentage of participants	64.6 Percentage of participants	63.7 Percentage of participants	59.2 Percentage of participants	57.5 Percentage of participants

SECONDARY outcome

Timeframe: Week 12, Week 26

Population: Participants from the Full Analysis Set, included all participants who received at least one dose of study drug, with data available for analysis. Missing data were imputed with Last Observation Carried Forward but not more than 14 weeks and data within 4 weeks of day 1 were not carried forward.

SGRQ is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. A mixed model was used with treatment as a fixed effect with Baseline SGRQ and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=448 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=446 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=441 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=454 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=205 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 and 26 Weeks of Treatment 26 Weeks (n=441,443,430,450,196)	37.01 Score on a scale Standard Error 0.679	38.10 Score on a scale Standard Error 0.680	38.19 Score on a scale Standard Error 0.686	39.14 Score on a scale Standard Error 0.677	40.02 Score on a scale Standard Error 0.941
St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 and 26 Weeks of Treatment 12 Weeks	37.56 Score on a scale Standard Error 0.659	38.55 Score on a scale Standard Error 0.662	39.40 Score on a scale Standard Error 0.663	39.94 Score on a scale Standard Error 0.658	41.55 Score on a scale Standard Error 0.900

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Participants from the Full Analysis Set, that included all participants who received at least one dose of study drug, with data available for analysis. Missing data were imputed with Last Observation Carried Forward but not more than 14 weeks and data within 4 weeks of day 1 were not carried forward.

SGRQ is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=474 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=476 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=473 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=480 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=232 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Percentage of Patients With a Clinically Important Improvement From Baseline of at Least 4 Units in the SGRQ Total Score After 26 Weeks of Treatment	63.7 Percentage of participants	63.0 Percentage of participants	60.5 Percentage of participants	56.4 Percentage of participants	56.6 Percentage of participants

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants from the Full Analysis Set, all randomized participants who received study drug, with evaluable diary data (at least 40 days) for analysis.

A day with no night time awakenings is defined from the diary data as any day where the patient did not wake up due to COPD symptoms. The percentage of nights is calculated by the number of days with no nighttime awakenings/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=418 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=413 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=399 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=422 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=198 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Percentage of Nights With "No Night Time Awakenings" Over 26 Weeks	63.68 Percentage of nights Standard Error 1.473	62.48 Percentage of nights Standard Error 1.479	58.64 Percentage of nights Standard Error 1.500	60.00 Percentage of nights Standard Error 1.469	53.67 Percentage of nights Standard Error 2.047

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants from the Full Analysis Set, all randomized participants who received study drug, with evaluable diary data (at least 40 days) for analysis.

A day with no day time symptoms is defined from the diary data as any day where the patient recorded no coughing, no wheezing, no sputum production and no breathlessness during the previous 12 hours (approximately 8AM to 8PM). The percentage of days is calculated by the number of days with no daytime symptoms/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=415 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=410 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=395 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=418 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=195 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Percentage of Days With "No Daytime Symptoms" Over 26 Weeks	7.49 Percentage of days Standard Error 0.931	9.17 Percentage of days Standard Error 0.933	6.40 Percentage of days Standard Error 0.948	5.54 Percentage of days Standard Error 0.928	4.44 Percentage of days Standard Error 1.294

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants from the Full Analysis Set, all randomized participants who received study drug, with evaluable diary data (at least 40 days) for analysis.

Patients answered the question "Did your respiratory symptoms stop you performing your usual activities today?-Not at all in their daily diary. The percentage of days is calculated by the number of days patient is able to perform daily activities/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of Days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=415 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=410 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=395 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=418 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=195 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Percentage of "Days Able to Perform Usual Daily Activities" Over 26 Weeks	45.97 Percentage of days Standard Error 1.578	40.94 Percentage of days Standard Error 1.582	40.10 Percentage of days Standard Error 1.607	37.52 Percentage of days Standard Error 1.572	34.49 Percentage of days Standard Error 2.197

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 26

Population: Participants from the full analysis, consisting of all randomized participant who received study drug, with data available for analysis at Week 12 and Week 26.

The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient. Rescue medication data recorded during the 14 day run-in was used to calculate the baseline. A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=420 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=420 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=413 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=427 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=203 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication at Week 12 and Week 26 Change from Baseline (BL) at Week 12	-1.82 Puffs per day Standard Error 0.102	-1.46 Puffs per day Standard Error 0.102	-1.22 Puffs per day Standard Error 0.103	-1.28 Puffs per day Standard Error 0.102	-0.83 Puffs per day Standard Error 0.141
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication at Week 12 and Week 26 Change from BL at Week 26 (n=419,416,403,424,199)	-1.88 Puffs per day Standard Error 0.105	-1.57 Puffs per day Standard Error 0.106	-1.22 Puffs per day Standard Error 0.107	-1.34 Puffs per day Standard Error 0.105	-0.92 Puffs per day Standard Error 0.147

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Participants from the full analysis, consisting of all randomized participant who received study drug, with data available for analysis.

The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs in the morning and evening were calculated and divided by the number of days with data to determine the mean daily number of daytime and nighttime puffs. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline (BL) ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=474 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=476 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=473 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=480 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=232 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Change From Baseline (BL) in the Daytime and Night Time Rescue Medication Use (Number of Puffs) Over 26 Weeks Daytime Change from BL (n=415,410,395,418,195)	-1.11 Puffs Standard Error 0.061	-0.96 Puffs Standard Error 0.062	-0.75 Puffs Standard Error 0.063	-0.83 Puffs Standard Error 0.061	-0.58 Puffs Standard Error 0.086
Change From Baseline (BL) in the Daytime and Night Time Rescue Medication Use (Number of Puffs) Over 26 Weeks Nighttime Change from BL (n=418,413,399,422,198)	-0.78 Puffs Standard Error 0.049	-0.63 Puffs Standard Error 0.049	-0.48 Puffs Standard Error 0.050	-0.52 Puffs Standard Error 0.049	-0.34 Puffs Standard Error 0.069

SECONDARY outcome

Timeframe: 26 Weeks

Population: Participants from the full analysis set (all randomized participants who received at least one dose of study drug) with evaluable data (at least 40 days of diary data) available for analysis.

A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. The percentage of days is calculated by the number of days with no rescue medicine use/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=418 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=411 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=397 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=419 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=196 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Percentage of "Days With no Rescue Medication Use" Over 26 Weeks	47.09 Percentage of days Standard Error 1.752	44.81 Percentage of days Standard Error 1.764	37.74 Percentage of days Standard Error 1.790	36.51 Percentage of days Standard Error 1.752	34.76 Percentage of days Standard Error 2.437

SECONDARY outcome

Timeframe: From 5 minutes to 4 hours post-dose Day 1 and Week 26

Population: Participants from full analysis set, all randomized participants who received study drug, with data available for analysis. Data within 6 hours of rescue medication use or 7 days of systemic corticosteroid use is excluded from analysis.

FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, and 4 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=464 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=471 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=464 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=473 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=228 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours at Day 1 and Week 26 Day 1	1.52 Liters Standard Error 0.006	1.46 Liters Standard Error 0.006	1.49 Liters Standard Error 0.006	1.44 Liters Standard Error 0.006	1.30 Liters Standard Error 0.008
Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours at Day 1 and Week 26 Week 26 (n=433,418,412,435,186)	1.57 Liters Standard Error 0.010	1.46 Liters Standard Error 0.010	1.43 Liters Standard Error 0.010	1.44 Liters Standard Error 0.010	1.23 Liters Standard Error 0.015

SECONDARY outcome

Timeframe: From 5 minutes to 12 hours post-dose Day 1 and Week 26

Population: Participants from the 24 hour serial spirometry subset of the full analysis set (all randomized participants who received study drug) with data available for analysis. Data within 6 hours of rescue medication use or 7 days of systemic corticosteroid use is excluded from the analysis.

FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=64 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=64 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=63 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=70 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=31 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 12 Hours at Day 1 and Week 26 Week 26 (n=60,55,58,67,27)	1.52 Liters Standard Error 0.027	1.39 Liters Standard Error 0.027	1.39 Liters Standard Error 0.028	1.39 Liters Standard Error 0.027	1.18 Liters Standard Error 0.036
Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 12 Hours at Day 1 and Week 26 Day1	1.50 Liters Standard Error 0.017	1.40 Liters Standard Error 0.017	1.42 Liters Standard Error 0.018	1.38 Liters Standard Error 0.017	1.24 Liters Standard Error 0.023

SECONDARY outcome

Timeframe: From 5 minutes to 23 hours 45 minutes post-dose Week 26

Population: Participants from the 24 hour serial spirometry subset of the full analysis set (all randomized participants who received study drug) with data available for analysis. Data within 6 hours of rescue medication use or 7 days of systemic corticosteroid use is excluded from the analysis.

FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12, 23 hours 15 minutes and 23 hours 45 minutes post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=60 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=55 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=58 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=67 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=27 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 23 Hours 45 Minutes at Week 26	1.46 Liters Standard Error 0.026	1.35 Liters Standard Error 0.027	1.35 Liters Standard Error 0.027	1.36 Liters Standard Error 0.026	1.15 Liters Standard Error 0.036

SECONDARY outcome

Timeframe: Week 12, Week 26

Population: Safety Set Holter Group-a subset of the Safety participants that included all randomized participants who received at least one dose of study drug and participated in the 24 hour Holter monitoring with evaluable data available for analysis. No participants in the Titotropium arm participated in the Holter Monitoring.

24-hourly mean heart rate was performed using a Holter Monitor at Weeks 12 and 26 in a subgroup of patients. Mixed model: heart rate = treatment + baseline heart rate + baseline smoking status + baseline ICS use + region + center (region) + error. Center was included as a random effect nested within region.

The 24-hourly mean heart rate is the mean heart rate over the 24 hour period, derived using hourly mean heart rate beats per minute.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=59 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=52 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=55 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=24 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
24 Hour Holter Monitoring in a Subset of Patients Week 12 (n=35,38,27,15)	80.8 beats per minute Standard Error 1.5	79.9 beats per minute Standard Error 1.35	79.4 beats per minute Standard Error 1.57	78.9 beats per minute Standard Error 1.95	—
24 Hour Holter Monitoring in a Subset of Patients Week 26 (n=36,36,26,16)	79.8 beats per minute Standard Error 1.68	78.6 beats per minute Standard Error 1.57	80.5 beats per minute Standard Error 1.75	77.0 beats per minute Standard Error 2.09	—

SECONDARY outcome

Timeframe: 26 Weeks

Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=474 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=476 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=473 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=480 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=232 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Rate of Moderate or Severe COPD Exacerbation	0.46 Exacerbations per year	0.59 Exacerbations per year	0.52 Exacerbations per year	0.45 Exacerbations per year	0.75 Exacerbations per year

SECONDARY outcome

Timeframe: 26 Weeks

Population: Full Analysis Set includes all randomized participants who received at least one dose of study drug.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=474 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=476 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=473 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=480 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=232 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Percentage of Patients With at Least One Moderate or Severe COPD Exacerbation Over the 26 Week Treatment Period	17.9 Percentage of participants	21.6 Percentage of participants	18.8 Percentage of participants	17.7 Percentage of participants	25.8 Percentage of participants

SECONDARY outcome

Timeframe: 26 Weeks

Population: Full Analysis Set included all randomized participants who received at least one dose of study drug.

Outcome measures

Measure	Indacaterol and Glycopyrronium (QVA149) n=474 Participants QVA149 110/50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=476 Participants QAB149 150 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=473 Participants NVA237 50 μg capsules for inhalation delivered once daily via a SDDPI for 26 weeks.Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=480 Participants Matching Placebo capsules for inhalation delivered once daily via a SDDPI for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and Salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=232 Participants Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Percentage of Participants With COPD Exacerbations Requiring Hospitalization or Treatment With Systemic Corticosteroids and/or Antibiotics But no Hospitalization Requiring hospitalization	2.1 Percentage of participants	2.5 Percentage of participants	1.9 Percentage of participants	1.0 Percentage of participants	3.0 Percentage of participants
Percentage of Participants With COPD Exacerbations Requiring Hospitalization or Treatment With Systemic Corticosteroids and/or Antibiotics But no Hospitalization Corticosteroids_Antibiotics-No hospitalization	16.7 Percentage of participants	19.7 Percentage of participants	17.8 Percentage of participants	16.9 Percentage of participants	23.3 Percentage of participants

Adverse Events

Indacaterol and Glycopyrronium (QVA149)

Serious events: 22 serious events

Other events: 166 other events

Deaths: 0 deaths

Indacaterol (QAB149)

Serious events: 26 serious events

Other events: 189 other events

Deaths: 0 deaths

Glycopyrronium (NVA237)

Serious events: 29 serious events

Other events: 185 other events

Deaths: 0 deaths

Tiotropium

Serious events: 19 serious events

Other events: 172 other events

Deaths: 0 deaths

Placebo

Serious events: 13 serious events

Other events: 102 other events

Deaths: 0 deaths

Serious adverse events

Measure	Indacaterol and Glycopyrronium (QVA149) n=474 participants at risk QVA149 110/50 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=476 participants at risk QAB149 150 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=473 participants at risk NVA237 50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Tiotropium n=480 participants at risk Tiotropium 18 μg capsules for inhalation delivered once daily via HandiHaler® device for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=232 participants at risk Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Blood and lymphatic system disorders Anaemia	0.00% 0/474	0.21% 1/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Cardiac disorders Acute coronary syndrome	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Angina pectoris	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Cardiac disorders Angina unstable	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Cardiac disorders Atrial fibrillation	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Bradycardia	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Cardiac arrest	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Cardiac failure	0.00% 0/474	0.63% 3/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Cardiac failure congestive	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.21% 1/480	0.00% 0/232
Cardiac disorders Cardio-respiratory arrest	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Cardiomegaly	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Cor pulmonale	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Coronary artery disease	0.00% 0/474	0.00% 0/476	0.42% 2/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Coronary artery insufficiency	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Cardiac disorders Left ventricular dysfunction	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Cardiac disorders Myocardial infarction	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Supraventricular tachycardia	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Cardiac disorders Ventricular extrasystoles	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Ear and labyrinth disorders Vertigo	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Eye disorders Age-related macular degeneration	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Gastrointestinal disorders Abdominal hernia	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Gastrointestinal disorders Abdominal pain upper	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Gastrointestinal disorders Anal fistula	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Gastrointestinal disorders Colonic polyp	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Gastrointestinal disorders Inguinal hernia	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.42% 2/480	0.00% 0/232
Gastrointestinal disorders Mesenteric panniculitis	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Gastrointestinal disorders Oesophageal ulcer	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
General disorders Chest pain	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
General disorders Non-cardiac chest pain	0.21% 1/474	0.00% 0/476	0.42% 2/473	0.21% 1/480	0.00% 0/232
General disorders Temperature intolerance	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Hepatobiliary disorders Cholecystitis	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Hepatobiliary disorders Cholelithiasis	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.42% 2/480	0.00% 0/232
Infections and infestations Bronchitis	0.21% 1/474	0.42% 2/476	0.63% 3/473	0.21% 1/480	0.00% 0/232
Infections and infestations Cellulitis	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Infections and infestations Dengue fever	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Infections and infestations Empyema	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Infections and infestations Gastroenteritis viral	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Infections and infestations Herpes zoster	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Infections and infestations Injection site abscess	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Infections and infestations Liver abscess	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Lobar pneumonia	0.21% 1/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Lower respiratory tract infection	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Infections and infestations Lower respiratory tract infection bacterial	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Moraxella infection	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Oral candidiasis	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Pneumonia	0.42% 2/474	0.42% 2/476	0.63% 3/473	0.62% 3/480	1.3% 3/232
Infections and infestations Respiratory tract infection bacterial	0.42% 2/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Respiratory tract infection viral	0.21% 1/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Septic shock	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Upper respiratory tract infection	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Upper respiratory tract infection bacterial	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Infections and infestations Urosepsis	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Injury, poisoning and procedural complications Contusion	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Injury, poisoning and procedural complications Fall	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Injury, poisoning and procedural complications Femoral neck fracture	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Injury, poisoning and procedural complications Femur fracture	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Injury, poisoning and procedural complications Hip fracture	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Injury, poisoning and procedural complications Muscle injury	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Injury, poisoning and procedural complications Rib fracture	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Injury, poisoning and procedural complications Traumatic intracranial haemorrhage	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Investigations Blood albumin decreased	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Investigations Prostatic specific antigen increased	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Musculoskeletal and connective tissue disorders Osteoporosis	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brain neoplasm malignant	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial carcinoma	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.21% 1/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic neoplasm malignant	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Laryngeal cancer	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.21% 1/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Nervous system disorders Cerebrovascular accident	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Nervous system disorders Dizziness	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Nervous system disorders Syncope	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Nervous system disorders Transient ischaemic attack	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Psychiatric disorders Substance abuse	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Reproductive system and breast disorders Breast mass	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.21% 1/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	2.1% 10/474	3.2% 15/476	1.9% 9/473	1.5% 7/480	3.0% 7/232
Respiratory, thoracic and mediastinal disorders Hydrothorax	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.21% 1/480	0.00% 0/232
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/474	0.21% 1/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.21% 1/474	0.00% 0/476	0.42% 2/473	0.21% 1/480	0.00% 0/232
Vascular disorders Aortic stenosis	0.00% 0/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.43% 1/232
Vascular disorders Arteriosclerosis	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232
Vascular disorders Hypertension	0.00% 0/474	0.00% 0/476	0.21% 1/473	0.00% 0/480	0.00% 0/232
Vascular disorders Peripheral ischaemia	0.21% 1/474	0.00% 0/476	0.00% 0/473	0.00% 0/480	0.00% 0/232

Other adverse events

Measure	Indacaterol and Glycopyrronium (QVA149) n=474 participants at risk QVA149 110/50 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Indacaterol (QAB149) n=476 participants at risk QAB149 150 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Glycopyrronium (NVA237) n=473 participants at risk NVA237 50 μg capsules for inhalation delivered once daily via a single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Tiotropium n=480 participants at risk Tiotropium 18 μg capsules for inhalation delivered once daily via HandiHaler® device for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.	Placebo n=232 participants at risk Matching Placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Infections and infestations Nasopharyngitis	6.5% 31/474	7.4% 35/476	9.7% 46/473	8.3% 40/480	9.9% 23/232
Infections and infestations Upper respiratory tract infection	4.2% 20/474	6.5% 31/476	4.2% 20/473	5.0% 24/480	5.6% 13/232
Infections and infestations Upper respiratory tract infection bacterial	2.1% 10/474	2.5% 12/476	3.2% 15/473	4.6% 22/480	5.6% 13/232
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	27.6% 131/474	30.3% 144/476	30.9% 146/473	27.7% 133/480	37.5% 87/232
Respiratory, thoracic and mediastinal disorders Cough	5.5% 26/474	8.0% 38/476	3.8% 18/473	4.4% 21/480	3.4% 8/232

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.
• Publication restrictions are in place

Restriction type: OTHER