Trial Outcomes & Findings for Evaluation of the Efficacy and Safety of QVA149 (110/50 μg o.d.) vs Tiotropium (18 µg o.d.) + Salmeterol/Fluticasone Propionate FDC (50/500 µg b.i.d.) in Patients With Moderate to Severe COPD (NCT NCT02603393)

Last Updated: 2019-04-29

Results Overview

Mean change from baseline in post-dose trough forced expiratory volume in 1 second (FEV1) following 26 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values measured at 23 hr 15 min and 23 hr 45 min after the morning dose taken at site on Day 181. Baseline FEV1 is defined as the average of the pre-dose FEV1 measured at -45 min and -15 min at Day 1.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

1053 participants

Primary outcome timeframe

Baseline, 26 weeks

Results posted on

2019-04-29

Participant Flow

Participant milestones

Participant milestones
Measure	QVA149 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Overall Study STARTED	527	526
Overall Study COMPLETED	456	472
Overall Study NOT COMPLETED	71	54

Reasons for withdrawal

Reasons for withdrawal
Measure	QVA149 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Overall Study Patient/guardian decision	32	18
Overall Study Adverse Event	17	15
Overall Study Technical problems	4	7
Overall Study Lack of Efficacy	7	2
Overall Study Death	3	4
Overall Study Physician Decision	3	3
Overall Study Protocol deviation	2	3
Overall Study Lost to Follow-up	1	2
Overall Study Non-compliance with study treatment	1	0
Overall Study Sponsor decision	1	0

Baseline Characteristics

Evaluation of the Efficacy and Safety of QVA149 (110/50 μg o.d.) vs Tiotropium (18 µg o.d.) + Salmeterol/Fluticasone Propionate FDC (50/500 µg b.i.d.) in Patients With Moderate to Severe COPD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)	Total n=1053 Participants Total of all reporting groups
Age, Continuous	65.4 Years STANDARD_DEVIATION 7.99 • n=5 Participants	65.2 Years STANDARD_DEVIATION 7.62 • n=7 Participants	65.3 Years STANDARD_DEVIATION 7.80 • n=5 Participants
Sex: Female, Male Female	149 Participants n=5 Participants	161 Participants n=7 Participants	310 Participants n=5 Participants
Sex: Female, Male Male	378 Participants n=5 Participants	365 Participants n=7 Participants	743 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	526 Participants n=5 Participants	523 Participants n=7 Participants	1049 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 26 weeks

Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Mean Change From Baseline in Post-dose Trough FEV1	-0.029 Liters Standard Error 0.0119	-0.003 Liters Standard Error 0.0115

SECONDARY outcome

Timeframe: 26 weeks

Moderate or severe COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Annualized Rate of Moderate or Severe COPD Exacerbations	0.52 COPD exacerbations/year Interval 0.43 to 0.63	0.48 COPD exacerbations/year Interval 0.4 to 0.58

SECONDARY outcome

Timeframe: 26 weeks

COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Annualized Rate of COPD Exacerbations Requiring Treatment With Systemic Glucocorticosteroids and/or Antibiotics, Moderate Exacerbations Only	0.47 COPD Exacerbations/year Interval 0.39 to 0.58	0.44 COPD Exacerbations/year Interval 0.36 to 0.53

SECONDARY outcome

Timeframe: 26 weeks

COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Annualized Rate of COPD Exacerbations Requiring Hospitalisation	0.001 COPD Exacerbations/year Interval 0.0 to NA - Not estimable No patient in either treatment group had an event	0.001 COPD Exacerbations/year Interval 0.0 to NA - Not estimable No patient in either treatment group had an event

SECONDARY outcome

Timeframe: 26 weeks

Trough FEV1 is defined as the average of the pre-dose FEV1 measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FEV1 measurements at 23h15min and 23h45min after dosing at Day 181. Baseline FEV1 is considered the Day 1 average of pre-dose measurements.

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Mean Change From Baseline in Pre-dose Trough FEV1	-0.029 Liters Standard Error 0.0119	-0.003 Liters Standard Error 0.0115

SECONDARY outcome

Timeframe: Baseline, 12 weeks

The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. 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 cause 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 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Mean Change From Baseline in St. George's Respiratory Questionnaire	-0.7 Score on a scale Standard Error 0.53	-2.5 Score on a scale Standard Error 0.51

SECONDARY outcome

Timeframe: Baseline, 26 weeks

Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. patients in the FAS were analyzed according to the treatment they were randomized to.

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Mean Change From Baseline in St. George's Respiratory Questionnaire	-1.0 Score on a scale Standard Error 0.54	-2.5 Score on a scale Standard Error 0.52

SECONDARY outcome

Timeframe: 12 weeks

Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline.

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Transition Dyspnea Index (TDI) Score	1.177 Score on a scale Standard Error 0.1558	1.418 Score on a scale Standard Error 0.1508

SECONDARY outcome

Timeframe: 26 weeks

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Transition Dyspnea Index (TDI) Score	1.382 Score on a scale Standard Error 0.1567	1.671 Score on a scale Standard Error 0.1519

SECONDARY outcome

Timeframe: Baseline, 26 weeks

Change from baseline in mean daily number of puffs of rescue medication (number of puffs taken in the previous 12 hours) over 26 weeks of treatment.

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication	-0.307 Number of puffs per day Standard Error 0.1006	-0.484 Number of puffs per day Standard Error 0.0983

SECONDARY outcome

Timeframe: Baseline, 26 weeks

Change from baseline in forced vital capacity following 26 weeks of treatment. Trough FVC is defined as the average of the pre-dose FVC measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FVC measurements at 23h15min and 23h45min after dosing at Day 181. Baseline is considered the Day 1 average of pre-dose measurements.

Outcome measures

Outcome measures
Measure	QVA149 n=527 Participants 110/50 μg capsules o.d. for inhalation	Tiotropium + Salmeterol/Fluticasone n=526 Participants tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Mean Change From Baseline in Forced Vital Capacity (FVC)	-0.030 Liters Standard Error 0.0192	-0.048 Liters Standard Error 0.0186

Adverse Events

QVA149

Serious events: 32 serious events

Other events: 398 other events

Deaths: 4 deaths

Tio+Salm/Flut

Serious events: 34 serious events

Other events: 392 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

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

Measure	QVA149 n=527 participants at risk 110/50 μg capsules o.d. for inhalation	Tio+Salm/Flut n=526 participants at risk tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Blood and lymphatic system disorders Haemorrhagic anaemia	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Cardiac disorders Acute myocardial infarction	0.38% 2/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Cardiac disorders Angina unstable	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Cardiac disorders Atrial fibrillation	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Cardiac disorders Cardiac arrest	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Cardiac disorders Cardiac failure	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Cardiac disorders Cardiac failure acute	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Cardiac disorders Cardiac tamponade	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Cardiac disorders Myocardial infarction	0.38% 2/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.38% 2/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Cardiac disorders Myocardial ischaemia	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Endocrine disorders Inappropriate antidiuretic hormone secretion	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Gastrointestinal disorders Anal fissure	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Gastrointestinal disorders Duodenal ulcer	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Gastrointestinal disorders Haemorrhoids	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Gastrointestinal disorders Inguinal hernia	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
General disorders Non-cardiac chest pain	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
General disorders Pyrexia	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Hepatobiliary disorders Cholelithiasis	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Hepatobiliary disorders Drug-induced liver injury	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Appendicitis	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Lower respiratory tract infection	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Ophthalmic herpes zoster	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Pneumonia	0.76% 4/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.57% 3/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Soft tissue infection	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Upper respiratory tract infection	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Injury, poisoning and procedural complications Femoral neck fracture	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Injury, poisoning and procedural complications Multiple injuries	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Musculoskeletal and connective tissue disorders Systemic lupus erythematosus	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder neoplasm	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cholesteatoma	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon neoplasm	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.38% 2/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pituitary tumour benign	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal neoplasm	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Nervous system disorders Cerebral haemorrhage	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Nervous system disorders Ischaemic stroke	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Nervous system disorders Syncope	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Renal and urinary disorders Renal failure	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	2.3% 12/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	2.5% 13/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Respiratory, thoracic and mediastinal disorders Hypoxia	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Skin and subcutaneous tissue disorders Erythema multiforme	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Vascular disorders Aortic aneurysm	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Vascular disorders Aortic aneurysm rupture	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Vascular disorders Aortic dissection	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Vascular disorders Deep vein thrombosis	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Vascular disorders Orthostatic hypotension	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Vascular disorders Peripheral artery occlusion	0.00% 0/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Vascular disorders Peripheral artery stenosis	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.00% 0/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).

Measure	QVA149 n=527 participants at risk 110/50 μg capsules o.d. for inhalation	Tio+Salm/Flut n=526 participants at risk tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Cardiac disorders Atrioventricular block first degree	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.1% 6/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Gastrointestinal disorders Diarrhoea	0.57% 3/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.1% 6/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
General disorders Non-cardiac chest pain	0.57% 3/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.1% 6/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
General disorders Oedema peripheral	1.3% 7/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.57% 3/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Bronchitis	2.5% 13/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.95% 5/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Influenza	1.1% 6/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.1% 6/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Oral candidiasis	2.3% 12/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	3.4% 18/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Oropharyngeal candidiasis	1.1% 6/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.3% 7/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Pneumonia	0.38% 2/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.1% 6/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Respiratory tract infection viral	0.19% 1/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.1% 6/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Upper respiratory tract infection bacterial	0.38% 2/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.1% 6/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Urinary tract infection	1.3% 7/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	0.19% 1/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Infections and infestations Viral upper respiratory tract infection	10.8% 57/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	11.2% 59/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Investigations Blood creatinine increased	4.9% 26/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	4.6% 24/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Musculoskeletal and connective tissue disorders Back pain	1.5% 8/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.7% 9/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Musculoskeletal and connective tissue disorders Pain in extremity	0.38% 2/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.1% 6/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Nervous system disorders Headache	1.3% 7/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	2.5% 13/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	70.2% 370/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	67.1% 353/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Respiratory, thoracic and mediastinal disorders Cough	4.6% 24/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	2.9% 15/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	1.3% 7/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.3% 7/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Vascular disorders Hypertension	1.3% 7/527 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).	1.9% 10/526 • The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).