Trial Outcomes & Findings for Effect of QVA149 Versus NVA237 and Tiotropium on Chronic Obstructive Pulmonary Disorder (COPD) Exacerbations (NCT NCT01120691)

NCT ID: NCT01120691

Last Updated: 2013-12-02

Results Overview

A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2224 participants

Primary outcome timeframe

64 weeks

Results posted on

2013-12-02

Participant Flow

A total of 3865 participants were screened of whom 2224 were randomized to 1 of the 3 treatment groups (QVA149, NVA237 or tiotropium) in a 1:1:1 ratio for at least 64 weeks (maximum 76 weeks) of treatment period.

5 (QVA149), 2 (NVA237) and 3 (tiotropium) participants were randomized but did not receive study drug.

Participant milestones

Participant milestones
Measure	QVA149 QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Overall Study STARTED	741	741	742
Overall Study Full Analysis Set (FAS)	736	739	739
Overall Study Safety Set (SAF)	736	740	739
Overall Study Modified Safety Set (mSAF)	729	740	737
Overall Study Modified Full Analysis Set (mFAS)	729	739	737
Overall Study COMPLETED	570	538	559
Overall Study NOT COMPLETED	171	203	183

Reasons for withdrawal

Reasons for withdrawal
Measure	QVA149 QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Overall Study Adverse Event	59	67	47
Overall Study Subject withdrew consent	33	50	44
Overall Study Death	21	22	24
Overall Study Unsatisfactory therapeutic effect	18	32	38
Overall Study Administrative problems	15	8	9
Overall Study Protocol deviation	13	12	12
Overall Study Lost to Follow-up	5	6	4
Overall Study Abnormal test procedure result(s)	3	2	1
Overall Study Patient's inability to use the device	3	1	0
Overall Study Abnormal laboratory value(s)	1	3	4

Baseline Characteristics

Effect of QVA149 Versus NVA237 and Tiotropium on Chronic Obstructive Pulmonary Disorder (COPD) Exacerbations

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	QVA149 n=729 Participants QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=740 Participants NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=737 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Total n=2206 Participants Total of all reporting groups
Age Continuous	63.1 years STANDARD_DEVIATION 8.07 • n=5 Participants	63.1 years STANDARD_DEVIATION 7.98 • n=7 Participants	63.6 years STANDARD_DEVIATION 7.79 • n=5 Participants	63.3 years STANDARD_DEVIATION 7.95 • n=4 Participants
Sex: Female, Male Female	173 Participants n=5 Participants	198 Participants n=7 Participants	184 Participants n=5 Participants	555 Participants n=4 Participants
Sex: Female, Male Male	556 Participants n=5 Participants	542 Participants n=7 Participants	553 Participants n=5 Participants	1651 Participants n=4 Participants

PRIMARY outcome

Timeframe: 64 weeks

Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site , which had major issues with Good Clinical Practice (GCP) compliance.

Outcome measures

Outcome measures
Measure	QVA149 n=812 Moderate to Severe COPD Exacerbation QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=900 Moderate to Severe COPD Exacerbation NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period.	0.94 Exacerbations per year	1.07 Exacerbations per year	—

SECONDARY outcome

Timeframe: 76 weeks

Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site, which had major issues with GCP compliance.

Outcome measures

Outcome measures
Measure	QVA149 n=812 Moderate to Severe COPD Exacerbation QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=898 Moderate to Severe COPD Exacerbation NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and Open-label Tiotropium Treatment Arms During the Treatment Period.	0.94 Exacerbations per year	1.06 Exacerbations per year	—

SECONDARY outcome

Timeframe: 64 weeks

Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site, which had major issues with GCP compliance. Only patients with a moderate or severe COPD exacerbation were included in this analysis.

Outcome measures

Outcome measures
Measure	QVA149 n=419 Participants QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=426 Participants NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=402 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period	296 days Interval 267.0 to 358.0	287 days Interval 255.0 to 325.0	331 days Interval 280.0 to 390.0

SECONDARY outcome

Timeframe: 64 weeks

Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site, which had major issues with GCP compliance. The Full Analysis Set (FAS) includes all randomized patients who received at least one dose of study drug and data was available for analysis.

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

Outcome measures

Outcome measures
Measure	QVA149 n=403 exacerbations QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=491 exacerbations NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=461 exacerbations Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics	0.46 exacerbations per year	0.58 exacerbations per year	0.54 exacerbations per year

SECONDARY outcome

Timeframe: 64 weeks

Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site with GCP non-compliance. This is a sub-group analysis with mutually exclusive population in each category for analysis.

The number of exacerbation days is defined as the sum of the duration of days recorded as an exacerbation for all exacerbations recorded per patient.

Outcome measures

Outcome measures
Measure	QVA149 n=528 Participants QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=575 Participants NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=556 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics systemic corticosteroids [n= 97, 108, 109]	20.49 Days Standard Deviation 25.426	25.22 Days Standard Deviation 42.674	17.57 Days Standard Deviation 17.797
Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics antibiotics [n= 195, 177, 177]	25.08 Days Standard Deviation 47.035	18.10 Days Standard Deviation 21.790	25.94 Days Standard Deviation 50.007
Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics corticosteroids and antibiotic [n= 266, 290, 270]	22.10 Days Standard Deviation 49.999	26.18 Days Standard Deviation 52.336	22.03 Days Standard Deviation 42.513

SECONDARY outcome

Timeframe: 64 weeks

Population: Modified safety set (mSAF set) includes all patients in the safety set except patients from a site who had major GCP issues. The Safety set includes all patients who received at least one dose of study drug whether or not being randomized. Analysis population included patients with study withdrawal or premature discontinuation for any reason.

Time to Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase.

Outcome measures

Outcome measures
Measure	QVA149 n=159 Participants QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=202 Participants NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=178 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Time to Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.) During the Treatment Period.	NA days Less than 50% of patients had withdrawn from the study or prematurely discontinued for any reason.	NA days Less than 50% of patients had withdrawn from the study or prematurely discontinued for any reason.	NA days Less than 50% of patients had withdrawn from the study or prematurely discontinued for any reason.

SECONDARY outcome

Timeframe: 64 weeks

Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase.

Outcome measures

Outcome measures
Measure	QVA149 n=729 Participants QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=740 Participants NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=737 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.)During the Treatment Period	21.8 percentage of participants	27.3 percentage of participants	24.2 percentage of participants

SECONDARY outcome

Timeframe: 26, 52, 64, 76 weeks

Population: Modified Full Analysis Set(mFAS) included all patients in the Full Analysis Set (FAS) except patients from a site, which had major issues with GCP compliance. FAS include all randomized patients who received at least one dose of study drug and data was available for analysis.

Cumulative rates were estimated using Anderson and Gill method. Chronic Obstructive Pulmonary Disease (COPD) exacerbations are considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations are considered to be severe if treatment for moderate severity and hospitalization were required. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years

Outcome measures

Outcome measures
Measure	QVA149 n=831 Moderate or Severe COPD Exacerbations QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=926 Moderate or Severe COPD Exacerbations NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=897 Moderate or Severe COPD Exacerbations Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points 26 weeks	0.57 exacerbations per year Interval 0.51 to 0.62	0.65 exacerbations per year Interval 0.58 to 0.71	0.63 exacerbations per year Interval 0.56 to 0.7
Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points 52 weeks	0.99 exacerbations per year Interval 0.91 to 1.09	1.13 exacerbations per year Interval 1.03 to 1.25	1.11 exacerbations per year Interval 1.0 to 1.23
Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points 64 weeks	1.19 exacerbations per year Interval 1.08 to 1.3	1.36 exacerbations per year Interval 1.24 to 1.49	1.31 exacerbations per year Interval 1.19 to 1.46
Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points 76 weeks	1.39 exacerbations per year Interval 1.27 to 1.53	1.59 exacerbations per year Interval 1.45 to 1.74	1.55 exacerbations per year Interval 1.4 to 1.71

SECONDARY outcome

Timeframe: 4, 12, 26, 38, 52 and 64 weeks

Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards. Spirometry measurements taken were FEV1 at -45 minutes and -15 minutes pre-dose. Three acceptable maneuvers had to be performed for each time point. The FEV1 values recorded had to be the highest values measured irrespective of whether or not they occurred on the same curve. The mixed model for analysis contained treatment as a fixed effect with average of the 45 minutes and 15 minutes pre dose FEV1 measurements at day 1 as the baseline measurement, FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at -14 Day) as covariates.

Outcome measures

Outcome measures
Measure	QVA149 n=729 Participants QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=739 Participants NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=737 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FEV1 Week 4 (n= 656,654,630)	1.08 L (liters) Standard Error 0.009	0.99 L (liters) Standard Error 0.009	1.00 L (liters) Standard Error 0.009
Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FEV1 Week 12 (n= 666,663,653)	1.08 L (liters) Standard Error 0.010	1.01 L (liters) Standard Error 0.009	1.01 L (liters) Standard Error 0.009
Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FEV1 Week 26 (n= 604,577,599)	1.07 L (liters) Standard Error 0.010	0.99 L (liters) Standard Error 0.010	1.00 L (liters) Standard Error 0.010
Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FEV1 Week 38 (n= 593,549,583)	1.08 L (liters) Standard Error 0.011	1.00 L (liters) Standard Error 0.011	1.00 L (liters) Standard Error 0.011
Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FEV1 Week 52 (n= 557,538,548)	1.05 L (liters) Standard Error 0.011	0.98 L (liters) Standard Error 0.011	0.99 L (liters) Standard Error 0.011
Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FEV1 Week 64 (n= 549,504,530)	1.05 L (liters) Standard Error 0.011	0.98 L (liters) Standard Error 0.011	0.99 L (liters) Standard Error 0.011

SECONDARY outcome

Timeframe: 4, 12, 26, 38, 52 and 64 weeks

Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards. Pre-dose Forced Vital Capacity (FVC) is defined as the average of the -15 minutes and the -45 minutes FVC values. Baseline is defined as the average of the -45 minutes and -15 minutes FVC values taken on day 1 prior to first dose. FVC data taken within 6h of rescue medication or within 7 days of systemic corticosteroid is excluded from this analysis

Outcome measures

Outcome measures
Measure	QVA149 n=729 Participants QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=739 Participants NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=737 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FVC Week 4 (n= 656,654,630)	2.74 L (liters) Standard Error 0.020	2.59 L (liters) Standard Error 0.019	2.60 L (liters) Standard Error 0.019
Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FVC Week 12 (n= 623,621,619)	2.77 L (liters) Standard Error 0.021	2.63 L (liters) Standard Error 0.021	2.65 L (liters) Standard Error 0.021
Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FVC Week 26 (n= 604,577,599)	2.73 L (liters) Standard Error 0.023	2.60 L (liters) Standard Error 0.022	2.61 L (liters) Standard Error 0.022
Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FVC Week 38 (n= 592,548,580)	2.76 L (liters) Standard Error 0.025	2.65 L (liters) Standard Error 0.025	2.63 L (liters) Standard Error 0.025
Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FVC Week 52 (n= 557,538,547)	2.68 L (liters) Standard Error 0.025	2.58 L (liters) Standard Error 0.025	2.58 L (liters) Standard Error 0.025
Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium predose FVC Week 64 (n= 549,502,526)	2.67 L (liters) Standard Error 0.025	2.57 L (liters) Standard Error 0.025	2.59 L (liters) Standard Error 0.025

SECONDARY outcome

Timeframe: Baseline (14 day run-in), 64 weeks

Population: Modified Full Analysis Set mFAS included all patients in the Full analysis set except patients from a site,which had major issues with GCP compliance. The Full Analysis Set includes all randomized patients who received at least one dose of study drug and data was available for analysis. Patients with evaluable data were included in this analysis

The severe or less FEV1 % predicted (post bronchodilator)\>=30%; very severe=\> FEV1 % predicted(the post bronchodilator)\<30%.Number of puffs of rescue medication taken in the previous 12 hours was recorded 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.

Outcome measures

Outcome measures
Measure	QVA149 n=708 Participants QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=724 Participants NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=709 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period Mean Daily # puffs Severe or Less(n=565,575,561)	-2.3 # puffs Standard Error 0.137	-1.5 # puffs Standard Error 0.135	-1.6 # puffs Standard Error 0.136
Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period Mean Daily # puffs Very Severe (n=143,149,148)	-2.1 # puffs Standard Error 0.234	-1.1 # puffs Standard Error 0.228	-1.0 # puffs Standard Error 0.228

SECONDARY outcome

Timeframe: Baseline (14 day run-in), 64 weeks

Population: Modified Full Analysis Set(mFAS)included all patients in the Full analysis set except patients from a site,which had major issues with GCP compliance. The Full Analysis Set includes all randomized patients who received at least one dose of study drug and data was available for analysis. Patients with evaluable data were included in this 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

Outcome measures
Measure	QVA149 n=701 Participants QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=720 Participants NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=703 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period	29.36 percentage of days Standard Error 1.445	21.65 percentage of days Standard Error 1.410	23.86 percentage of days Standard Error 1.422

SECONDARY outcome

Timeframe: 12, 26, 38, 52 and 64 weeks

St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. Mixed model used baseline SGRQ, baseline inhaled corticosteroid (ICS) use, Forced Expiratory Volume in 1 Second (FEV1) prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. SGRQ total score is the sum of the scores from the three components; symptoms, activity and impacts.

Outcome measures

Outcome measures
Measure	QVA149 n=729 Participants QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 n=739 Participants NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label Tiotropium n=737 Participants Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment Week 38 (n= 648,626,635)	42.72 units on a scale Standard Error 0.667	45.53 units on a scale Standard Error 0.663	45.86 units on a scale Standard Error 0.660
St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment Week 52 (n= 625,593,613)	43.38 units on a scale Standard Error 0.722	45.96 units on a scale Standard Error 0.723	46.21 units on a scale Standard Error 0.714
St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment Week 64 (n= 600,564,579)	43.39 units on a scale Standard Error 0.778	45.46 units on a scale Standard Error 0.780	46.08 units on a scale Standard Error 0.778
St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment Week 12 (n= 694,694,676)	44.69 units on a scale Standard Error 0.612	47.13 units on a scale Standard Error 0.603	47.62 units on a scale Standard Error 0.607
St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment Week 26 (n= 684,677,658)	44.06 units on a scale Standard Error 0.655	45.93 units on a scale Standard Error 0.647	45.77 units on a scale Standard Error 0.651

Adverse Events

QVA149

Serious events: 167 serious events

Other events: 656 other events

Deaths: 0 deaths

NVA237

Serious events: 179 serious events

Other events: 671 other events

Deaths: 0 deaths

Open-label Tiotropium

Serious events: 165 serious events

Other events: 666 other events

Deaths: 0 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