Efficacy, Tolerability and Safety of NVA237 in Patients With Chronic Obstructive Pulmonary Disease

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01513460
• Collaborator: (none)
• Enrollment: 773
• Locations: 68
• Arms: 3
• Duration (Months): 20
• Patients Per Site: 11.4
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This study will assess the efficacy, tolerability and safety of NVA237 compared to tiotropium when added on to fluticasone/salmeterol in patients with chronic obstructive pulmonary disease.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: NVA237 50µg once daily; Drug: Tiotropium 18µg once daily; Drug: Flu/Sal; Drug: NVA237 placebo + Tiotropium placebo.	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 773 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Blinded, Active-controlled, Parallel-group Study to Compare the Efficacy, Tolerability and Safety of NVA237 Compared to Tiotropium Added on to Fluticasone/Salmeterol in Patients With Chronic Obstructive Pulmonary Disease
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NVA237 + Fluticasone/Salmeterol (Flu/Sal) NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Drug: NVA237 50µg once daily; NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI); Drug: Flu/Sal; Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device; Drug: NVA237 placebo + Tiotropium placebo.; Tiotropium 18 μg o.d. delivered via a proprietary inhalation device
Active Comparator: Tiotropium + Flu/Sal Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Drug: Tiotropium 18µg once daily; Tiotropium 18 μg o.d. delivered via a proprietary inhalation device; Drug: Flu/Sal; Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device; Drug: NVA237 placebo + Tiotropium placebo.; Tiotropium 18 μg o.d. delivered via a proprietary inhalation device
Placebo Comparator: Flu/Sal Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Drug: Flu/Sal; Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device; Drug: NVA237 placebo + Tiotropium placebo.; Tiotropium 18 μg o.d. delivered via a proprietary inhalation device

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Mean Trough Forced Expiratory Volume in 1 Second (FEV1) (NVA237 Versus Tiotropium) [baseline, 12 weeks]

   Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15 hours and 23:45 hours after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45 min and 15 min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement.

Secondary Outcome Measures

1. Change From Baseline in Mean Trough FEV1 (Flu/Sal Versus NVA237/Tiotropium+Flu/Sal) [baseline, 4 weeks, 8 weeks, 12 weeks]

   Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement.

2. Change From Baseline in Mean Trough FEV1 [baseline, 4 weeks, 8 weeks, 12 weeks]

   Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement.

3. Change From Baseline in Total Score of the St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) After 12 Weeks of Treatment [12 weeks]

   SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest is 100. Higher values corresponded to greater impairment in quality of life. An analysis model included terms for treatment, baseline total SGRQ score, FEV1 and baseline smoking status. The model also contained as fixed effects the baseline total SGRQ score, FEV1 prior to inhalation of short acting bronchodilator, FEV1 post inhalation of short acting bronchodilator and stratification factors as covariates. A negative change from baseline indicates improvement.

4. Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Use [baseline, 12 weeks]

   The total number of puffs of rescue medication used over the last 12 h recorded in the morning (nighttime use) and in the evening (daytime use) over the full 12 weeks was divided by the total number of days with non-missing rescue data to derive the mean daytime and nighttime number of puffs of rescue medication. Change from baseline in the mean daytime and nighttime number of puffs of rescue medication was analyzed as for the change from baseline in the mean daily number of puffs of rescue medication.

5. Mean Percentage of Nights With 'no Nighttime Awakenings' [12 weeks]

   A night with 'no nighttime awakenings' is defined from diary data as any night where patient did not wake up due to symptoms. Total number of nights with 'no nighttime awakenings' over treatment period was divided by total number of nights where diary recordings have been made in order to derive percentage of 'no nighttime awakenings' which will be summarized by treatment and analyzed using a similar mixed model as specified for primary analysis. Diary data recorded during the 7 day run-in period was used to calculate baseline percentage of nights 'no nighttime awakenings'.

6. Mean Percentage of Days With Performance of Usual Activities [12 weeks]

   A 'day able to perform usual daily activities' was defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. The percentage of 'days able to perform usual daily activities' was derived and analyzed using a similar mixed model as specified for primary analysis as for the percentage of nights with 'no nighttime awakenings'.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with Moderate to Severe COPD (Stage II or Stage III) according to the GOLD 2010 guideline

• Current or ex-smokers who have a smoking history of at least 10 pack years

• Qualifying FEV1 at Visit 2 (day -7)

Exclusion Criteria:

• Patients with a history of asthma or a history of high blood eosinophil count (>600/mm³)

• Patients with concomitant pulmonary disease

• Patients with lung lobectomy or lung volume reduction or lung transplantation

• Patients with α-1 antitrypsin deficiency

• Patients who have had live attenuated vaccinations within 30 days prior to screening visit or during run-in period

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Baulkham Hills	New South Wales	Australia	2153
2	Novartis Investigative Site	Brookvale	New South Wales	Australia	2100
3	Novartis Investigative Site	Castle Hill	New South Wales	Australia	2067
4	Novartis Investigative Site	Dapto	New South Wales	Australia
5	Novartis Investigative Site	Darlinghurst	New South Wales	Australia	2010
6	Novartis Investigative Site	Ermington	New South Wales	Australia
7	Novartis Investigative Site	Gosford	New South Wales	Australia	2250
8	Novartis Investigative Site	Hinchinbrook	New South Wales	Australia	2168
9	Novartis Investigative Site	Kingswood	New South Wales	Australia	2747
10	Novartis Investigative Site	Sydney	New South Wales	Australia	2089
11	Novartis Investigative Site	Arundel	Queensland	Australia	4214
12	Novartis Investigative Site	Aspley	Queensland	Australia	4034
13	Novartis Investigative Site	Beenleigh	Queensland	Australia	4207
14	Novartis Investigative Site	Browns Plains	Queensland	Australia	4118
15	Novartis Investigative Site	Chemside	Queensland	Australia	4032
16	Novartis Investigative Site	Deception Bay	Queensland	Australia	4508
17	Novartis Investigative Site	Everton Plaza	Queensland	Australia	4053
18	Novartis Investigative Site	Holland Park	Queensland	Australia	4121
19	Novartis Investigative Site	Jimboomba	Queensland	Australia	4032
20	Novartis Investigative Site	Kedron	Queensland	Australia
21	Novartis Investigative Site	Kenmore	Queensland	Australia	4069
22	Novartis Investigative Site	Kippa Ring	Queensland	Australia	4021
23	Novartis Investigative Site	Logan Central	Queensland	Australia	4114
24	Novartis Investigative Site	Loganholme	Queensland	Australia	4129
25	Novartis Investigative Site	Mermaid Beach	Queensland	Australia	4218
26	Novartis Investigative Site	Morayfield	Queensland	Australia	4506
27	Novartis Investigative Site	Nerang	Queensland	Australia	4211
28	Novartis Investigative Site	Woolloongabba	Queensland	Australia	4102
29	Novartis Investigative Site	Adelaide	South Australia	Australia	5000
30	Novartis Investigative Site	Daw Park	South Australia	Australia	5041
31	Novartis Investigative Site	Glenelg East	South Australia	Australia	5045
32	Novartis Investigative Site	Golden Grove	South Australia	Australia	5125
33	Novartis Investigative Site	Hamley Bridge	South Australia	Australia	5401
34	Novartis Investigative Site	Kensington Gardens	South Australia	Australia	5065
35	Novartis Investigative Site	Prospect	South Australia	Australia	5082
36	Novartis Investigative Site	Dandenong	Victoria	Australia
37	Novartis Investigative Site	Lalor	Victoria	Australia	3075
38	Novartis Investigative Site	Malvern	Victoria	Australia	3144
39	Novartis Investigative Site	Melbourne	Victoria	Australia
40	Novartis Investigative Site	Noble Park	Victoria	Australia	3174
41	Novartis Investigative Site	Oakleigh East	Victoria	Australia	3166
42	Novartis Investigative Site	Preston	Victoria	Australia
43	Novartis Investigative Site	Rosebud	Victoria	Australia	3063
44	Novartis Investigative Site	Bicton	Western Australia	Australia
45	Novartis Investigative Site	East Fremantle	Western Australia	Australia	6158
46	Novartis Investigative Site	East Victoria Park	Western Australia	Australia	6101
47	Novartis Investigative Site	Fremantle	Western Australia	Australia	6160
48	Novartis Investigative Site	Mirrabooka	Western Australia	Australia	6061
49	Novartis Investigative Site	Morley	Western Australia	Australia	6062
50	Novartis Investigative Site	Nedlands	Western Australia	Australia	6009
51	Novartis Investigative Site	Noranda	Western Australia	Australia
52	Novartis Investigative Site	Perth	Western Australia	Australia	6000
53	Novartis Investigative Site	Perth	Western Australia	Australia	6069
54	Novartis Investigative Site	Perth	Western Australia	Australia
55	Novartis Investigative Site	Pinjarra	Western Australia	Australia
56	Novartis Investigative Site	Spearwood	Western Australia	Australia	6163
57	Novartis Investigative Site	Woodvale	Western Australia	Australia	6026
58	Novartis Investigative Site	Yokine	Western Australia	Australia	6060
59	Novartis Investigative Site	Auckland		New Zealand	1051
60	Novartis Investigative Site	Auckland		New Zealand
61	Novartis Investigative Site	Christchurch		New Zealand
62	Novartis Investigative Site	Dunedin		New Zealand
63	Novartis Investigative Site	Grafton, Auckland		New Zealand	1010
64	Novartis Investigative Site	Hamilton		New Zealand	3240
65	Novartis Investigative Site	Tauranga		New Zealand	3143
66	Novartis Investigative Site	Tauranga		New Zealand
67	Novartis Investigative Site	Wellington		New Zealand	6021
68	Novartis Investigative Site	Wellington		New Zealand

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01513460
• Other Study ID Numbers: CNVA237AAU01
• First Posted: Jan 20, 2012
• Last Update Posted: Jan 5, 2015
• Last Verified: Dec 1, 2014

• Keywords provided by Novartis Pharmaceuticals: Chronic Obstructive Pulmonary Disease,; NVA 237,; glycopyrronium,; COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Glycopyrrolate; Tiotropium Bromide

Study Results

Participant Flow

Arm/Group Title	NVA237 + Fluticasone/Salmeterol (Flu/Sal)	Tiotropium + Flu/Sal	Flu/Sal
Arm/Group Description	NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.
Period Title: Overall Study
STARTED	258	258	257
Full Analysis Set	257	258	257
Per-protocol Set	196	186	166
COMPLETED	229	226	201
NOT COMPLETED	29	32	56

Baseline Characteristics

Arm/Group Title	NVA237 + Fluticasone/Salmeterol (Flu/Sal)	Tiotropium + Flu/Sal	Flu/Sal	Total
Arm/Group Description	NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Total of all reporting groups
Overall Participants	257	258	257	772
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	68.2 (8.38)	68.0 (7.74)	67.8 (8.49)	68.0 (8.20)
Sex: Female, Male (Count of Participants)
Female	94 36.6%	98 38%	83 32.3%	275 35.6%
Male	163 63.4%	160 62%	174 67.7%	497 64.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Trough Forced Expiratory Volume in 1 Second (FEV1) (NVA237 Versus Tiotropium)
Description	Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15 hours and 23:45 hours after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45 min and 15 min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement.
Time Frame	baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

Participants from the per-protocol set (PPS), who had values at both baseline and week 12, were included in the analysis. The PPS included all randomized participants who had at least one dose of study drug and who were without any major protocol or non-protocol deviations.

Arm/Group Title	NVA237 + Fluticasone/Salmeterol (Flu/Sal)	Tiotropium + Flu/Sal
Arm/Group Description	NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.
Measure Participants	194	185
Mean (Standard Error) [liters]	0.095 (0.0131)	0.102 (0.0135)

2. Secondary Outcome

Title	Change From Baseline in Mean Trough FEV1 (Flu/Sal Versus NVA237/Tiotropium+Flu/Sal)
Description	Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement.
Time Frame	baseline, 4 weeks, 8 weeks, 12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Flu/Sal	NVA237/Tiotropium+Flu/Sal
Arm/Group Description	Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	NVA237+Flu/Sal and Tiotropium+Flu/Sal arms
Measure Participants	257	515
Week 4	-0.010 (0.0099)	0.077 (0.0073)
Week 8	-0.002 (0.0099)	0.088 (0.0073)
Week 12	-0.012 (0.0099)	0.088 (0.0073)

3. Secondary Outcome

Title	Change From Baseline in Mean Trough FEV1
Description	Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement.
Time Frame	baseline, 4 weeks, 8 weeks, 12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	NVA237 + Fluticasone/Salmeterol (Flu/Sal)	Tiotropium + Flu/Sal	Flu/Sal
Arm/Group Description	NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.
Measure Participants	257	258	257
Week 4	0.077 (0.0100)	0.077 (0.0101)	-0.010 (0.0099)
Week 8	0.084 (0.0100)	0.092 (0.0101)	-0.002 (0.0099)
Week 12	0.089 (0.0100)	0.087 (0.0101)	-0.012 (0.0099)

4. Secondary Outcome

Title	Change From Baseline in Total Score of the St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) After 12 Weeks of Treatment
Description	SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest is 100. Higher values corresponded to greater impairment in quality of life. An analysis model included terms for treatment, baseline total SGRQ score, FEV1 and baseline smoking status. The model also contained as fixed effects the baseline total SGRQ score, FEV1 prior to inhalation of short acting bronchodilator, FEV1 post inhalation of short acting bronchodilator and stratification factors as covariates. A negative change from baseline indicates improvement.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	NVA237 + Fluticasone/Salmeterol (Flu/Sal)	Tiotropium + Flu/Sal	Flu/Sal
Arm/Group Description	NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.
Measure Participants	257	258	257
Mean (Standard Error) [units on a scale]	-2.806 (0.6772)	-3.902 (0.6920)	-0.652 (0.6871)

5. Secondary Outcome

Title	Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Use
Description	The total number of puffs of rescue medication used over the last 12 h recorded in the morning (nighttime use) and in the evening (daytime use) over the full 12 weeks was divided by the total number of days with non-missing rescue data to derive the mean daytime and nighttime number of puffs of rescue medication. Change from baseline in the mean daytime and nighttime number of puffs of rescue medication was analyzed as for the change from baseline in the mean daily number of puffs of rescue medication.
Time Frame	baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had outcome measure data with applicable fixed effects/covariates according to the analysis model, were analyzed only. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	NVA237 + Fluticasone/Salmeterol (Flu/Sal)	Tiotropium + Flu/Sal	Flu/Sal
Arm/Group Description	NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.
Measure Participants	247	251	241
Mean (Standard Error) [puffs of rescue medication]	2.191 (0.1384)	2.093 (0.1397)	2.908 (0.1395)

6. Secondary Outcome

Title	Mean Percentage of Nights With 'no Nighttime Awakenings'
Description	A night with 'no nighttime awakenings' is defined from diary data as any night where patient did not wake up due to symptoms. Total number of nights with 'no nighttime awakenings' over treatment period was divided by total number of nights where diary recordings have been made in order to derive percentage of 'no nighttime awakenings' which will be summarized by treatment and analyzed using a similar mixed model as specified for primary analysis. Diary data recorded during the 7 day run-in period was used to calculate baseline percentage of nights 'no nighttime awakenings'.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had outcome measure data with applicable fixed effects/covariates according to the analysis model, were analyzed only. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	NVA237 + Fluticasone/Salmeterol (Flu/Sal)	Tiotropium + Flu/Sal	Flu/Sal
Arm/Group Description	NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.
Measure Participants	242	251	239
Mean (Standard Error) [Percentage of nights]	0.834 (0.0124)	0.816 (0.0124)	0.823 (0.0124)

7. Secondary Outcome

Title	Mean Percentage of Days With Performance of Usual Activities
Description	A 'day able to perform usual daily activities' was defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. The percentage of 'days able to perform usual daily activities' was derived and analyzed using a similar mixed model as specified for primary analysis as for the percentage of nights with 'no nighttime awakenings'.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had outcome measure data with applicable fixed effects/covariates according to the analysis model, were analyzed only. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	NVA237 + Fluticasone/Salmeterol (Flu/Sal)	Tiotropium + Flu/Sal	Flu/Sal
Arm/Group Description	NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.
Measure Participants	243	248	237
Mean (Standard Error) [Percentage of days]	0.934 (0.0087)	0.946 (0.0088)	0.903 (0.0088)

Adverse Events

Arm/Group Title	NVA237 + Fluticasone/Salmeterol (Flu/Sal)		Tiotropium + Flu/Sal		Flu/Sal
Arm/Group Description	NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.		Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.		Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.
All Cause Mortality
	NVA237 + Fluticasone/Salmeterol (Flu/Sal)		Tiotropium + Flu/Sal		Flu/Sal
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	NVA237 + Fluticasone/Salmeterol (Flu/Sal)		Tiotropium + Flu/Sal		Flu/Sal
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/257 (5.8%)		22/258 (8.5%)		15/257 (5.8%)
Blood and lymphatic system disorders
Anaemia	0/257 (0%)		0/258 (0%)		1/257 (0.4%)
Cardiac disorders
Acute coronary syndrome	0/257 (0%)		1/258 (0.4%)		1/257 (0.4%)
Angina pectoris	0/257 (0%)		1/258 (0.4%)		1/257 (0.4%)
Atrial fibrillation	0/257 (0%)		2/258 (0.8%)		1/257 (0.4%)
Atrial flutter	1/257 (0.4%)		1/258 (0.4%)		0/257 (0%)
Atrioventricular block complete	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Cardiac failure congestive	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Tachyarrhythmia	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Ventricular fibrillation	0/257 (0%)		0/258 (0%)		1/257 (0.4%)
Ear and labyrinth disorders
Vertigo	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Duodenal ulcer	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Erosive oesophagitis	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Inguinal hernia strangulated	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Oral disorder	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Small intestinal obstruction	2/257 (0.8%)		0/258 (0%)		0/257 (0%)
General disorders
Chest discomfort	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Chest pain	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Multi-organ failure	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Hepatobiliary disorders
Ischaemic hepatitis	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Infections and infestations
Breast abscess	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Cellulitis	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Herpes zoster	0/257 (0%)		0/258 (0%)		1/257 (0.4%)
Infective exacerbation of chronic obstructive airways disease	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Lobar pneumonia	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Pharyngitis	0/257 (0%)		0/258 (0%)		1/257 (0.4%)
Pneumonia	0/257 (0%)		2/258 (0.8%)		2/257 (0.8%)
Pneumonia viral	0/257 (0%)		0/258 (0%)		1/257 (0.4%)
Urosepsis	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Wound infection	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Contusion	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Fall	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Femoral neck fracture	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Foreign body	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Post procedural haematoma	0/257 (0%)		0/258 (0%)		1/257 (0.4%)
Radius fracture	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Spinal compression fracture	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Investigations
International normalised ratio increased	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Metabolism and nutrition disorders
Dehydration	0/257 (0%)		0/258 (0%)		1/257 (0.4%)
Gout	0/257 (0%)		0/258 (0%)		1/257 (0.4%)
Musculoskeletal and connective tissue disorders
Joint effusion	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Lumbar spinal stenosis	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	0/257 (0%)		1/258 (0.4%)		1/257 (0.4%)
Nervous system disorders
Subarachnoid haemorrhage	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Renal and urinary disorders
Nephrolithiasis	0/257 (0%)		0/258 (0%)		1/257 (0.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/257 (0%)		1/258 (0.4%)		2/257 (0.8%)
Dyspnoea	0/257 (0%)		1/258 (0.4%)		1/257 (0.4%)
Lung disorder	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Pleural effusion	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Pleurisy	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Pulmonary embolism	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Pulmonary oedema	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Vascular disorders
Deep vein thrombosis	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Femoral artery aneurysm	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Haematoma	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Orthostatic hypotension	1/257 (0.4%)		0/258 (0%)		0/257 (0%)
Peripheral ischaemia	0/257 (0%)		1/258 (0.4%)		0/257 (0%)
Other (Not Including Serious) Adverse Events
	NVA237 + Fluticasone/Salmeterol (Flu/Sal)		Tiotropium + Flu/Sal		Flu/Sal
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	114/257 (44.4%)		124/258 (48.1%)		111/257 (43.2%)
Cardiac disorders
Palpitations	0/257 (0%)		3/258 (1.2%)		0/257 (0%)
Eye disorders
Conjunctivitis	0/257 (0%)		3/258 (1.2%)		3/257 (1.2%)
Gastrointestinal disorders
Constipation	4/257 (1.6%)		2/258 (0.8%)		2/257 (0.8%)
Diarrhoea	5/257 (1.9%)		2/258 (0.8%)		2/257 (0.8%)
Dry mouth	5/257 (1.9%)		9/258 (3.5%)		2/257 (0.8%)
Gastrooesophageal reflux disease	2/257 (0.8%)		3/258 (1.2%)		2/257 (0.8%)
Mouth ulceration	3/257 (1.2%)		0/258 (0%)		0/257 (0%)
Nausea	3/257 (1.2%)		9/258 (3.5%)		3/257 (1.2%)
General disorders
Chest discomfort	2/257 (0.8%)		3/258 (1.2%)		0/257 (0%)
Chest pain	3/257 (1.2%)		2/258 (0.8%)		3/257 (1.2%)
Fatigue	0/257 (0%)		5/258 (1.9%)		2/257 (0.8%)
Oedema peripheral	3/257 (1.2%)		3/258 (1.2%)		1/257 (0.4%)
Infections and infestations
Bronchitis	2/257 (0.8%)		1/258 (0.4%)		3/257 (1.2%)
Diverticulitis	0/257 (0%)		1/258 (0.4%)		3/257 (1.2%)
Gastroenteritis	1/257 (0.4%)		3/258 (1.2%)		2/257 (0.8%)
Lower respiratory tract infection	7/257 (2.7%)		5/258 (1.9%)		4/257 (1.6%)
Nasopharyngitis	3/257 (1.2%)		7/258 (2.7%)		5/257 (1.9%)
Oral candidiasis	12/257 (4.7%)		13/258 (5%)		9/257 (3.5%)
Sinusitis	2/257 (0.8%)		2/258 (0.8%)		5/257 (1.9%)
Upper respiratory tract infection	17/257 (6.6%)		13/258 (5%)		11/257 (4.3%)
Viral upper respiratory tract infection	3/257 (1.2%)		4/258 (1.6%)		5/257 (1.9%)
Wound infection	3/257 (1.2%)		1/258 (0.4%)		0/257 (0%)
Injury, poisoning and procedural complications
Fall	3/257 (1.2%)		2/258 (0.8%)		3/257 (1.2%)
Laceration	2/257 (0.8%)		3/258 (1.2%)		2/257 (0.8%)
Limb injury	1/257 (0.4%)		3/258 (1.2%)		0/257 (0%)
Muscle strain	4/257 (1.6%)		3/258 (1.2%)		4/257 (1.6%)
Investigations
Weight increased	3/257 (1.2%)		2/258 (0.8%)		1/257 (0.4%)
Musculoskeletal and connective tissue disorders
Back pain	4/257 (1.6%)		8/258 (3.1%)		5/257 (1.9%)
Muscle spasms	11/257 (4.3%)		9/258 (3.5%)		5/257 (1.9%)
Myalgia	1/257 (0.4%)		4/258 (1.6%)		1/257 (0.4%)
Osteoarthritis	0/257 (0%)		2/258 (0.8%)		3/257 (1.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	3/257 (1.2%)		1/258 (0.4%)		2/257 (0.8%)
Nervous system disorders
Aphonia	0/257 (0%)		3/258 (1.2%)		2/257 (0.8%)
Dizziness	2/257 (0.8%)		4/258 (1.6%)		4/257 (1.6%)
Headache	3/257 (1.2%)		4/258 (1.6%)		13/257 (5.1%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/257 (0%)		3/258 (1.2%)		4/257 (1.6%)
Cough	16/257 (6.2%)		15/258 (5.8%)		11/257 (4.3%)
Dysphonia	6/257 (2.3%)		15/258 (5.8%)		5/257 (1.9%)
Dyspnoea	7/257 (2.7%)		8/258 (3.1%)		9/257 (3.5%)
Epistaxis	4/257 (1.6%)		4/258 (1.6%)		1/257 (0.4%)
Oropharyngeal pain	9/257 (3.5%)		10/258 (3.9%)		8/257 (3.1%)
Productive cough	2/257 (0.8%)		3/258 (1.2%)		1/257 (0.4%)
Rhinorrhoea	6/257 (2.3%)		1/258 (0.4%)		3/257 (1.2%)
Sputum increased	3/257 (1.2%)		3/258 (1.2%)		2/257 (0.8%)
Skin and subcutaneous tissue disorders
Pruritus	3/257 (1.2%)		0/258 (0%)		1/257 (0.4%)
Vascular disorders
Hypertension	3/257 (1.2%)		6/258 (2.3%)		5/257 (1.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.