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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02371629
• Collaborator: (none)
• Enrollment: 776
• Locations: 81
• Arms: 2
• Actual Duration (Months): 16.8
• Patients Per Site: 9.6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This study is a post-authorization commitment to the European Medicines Agency (EMA). The study serves to determine whether the treatment of patients with stable, symptomatic Chronic Obstructive Pulmonary Disease (COPD) with the investigational drug NVA237 is efficient and safe. The efficacy and safety of the drug was tested for twice daily dosing against once daily dosing.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: NVA237; Drug: Placebo; Drug: Salbutamol	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 776 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel Group, 26-week Study Evaluating the Efficacy, Safety and Tolerability of NVA237 Given Once or Twice Daily, in Patients With Moderate and Severe Chronic Obstructive Pulmonary Disease
• Actual Study Start Date: Jun 24, 2015
• Actual Primary Completion Date: Nov 16, 2016
• Actual Study Completion Date: Nov 16, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NVA237 Twice daily Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Drug: NVA237; NVA237 capsules for inhalation, delivered via a Single Dose Dry Powder Inhaler (SDDPI) called Concept1; Other Names: glycopyrronioum bromide ; Drug: Salbutamol; All patients received salbutamol (100 μg) as only rescue medication
Experimental: NVA237 Once daily Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.	Drug: NVA237; NVA237 capsules for inhalation, delivered via a Single Dose Dry Powder Inhaler (SDDPI) called Concept1; Other Names: glycopyrronioum bromide ; Drug: Placebo; Placebo to NVA237; Drug: Salbutamol; All patients received salbutamol (100 μg) as only rescue medication

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 [Baseline, Week 12]

   Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1 at Week 12. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate.

Secondary Outcome Measures

1. Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12 [Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 12]

   The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 12 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.

2. Change From Baseline in Area Under The Curve (AUC 0-12 Hour) for Forced Expiratory Volume in One Second (FEV1) Post Dosing at Day 1 [Baseline, 0-12 hour post dose at Day 1]

   The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for 0-12 hour, post dosing at Day 1 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.

3. Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26 [Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 26]

   The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 26 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.

4. Change From Baseline in Total St. George's Respiratory Questionnaire (SGRQ) Score at Week 12 and Week 26 [Baseline, 12 Weeks, 26 Weeks]

   The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity Part II covers "Activity" and is concerned with activities that caused or are limited by breathlessness Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. Higher values corresponded to greater impairment of health status.

5. Percentage of Patients With a Clinically Significant Improvement in St George Respiratory Questionnaire at Week 12 and Week 26 [Baseline, 12 Weeks, 26 Weeks]

   The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity Part II covers "Activity" and is concerned with activities that caused or are limited by breathlessness Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. A clinically significant improvement is defined as ≥ 4 unit improvement from baseline score (a decrease of ≥ 4).

6. Change From Baseline in Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 [Baseline, 12 Weeks, 26 Weeks]

   Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score.

7. Percentage of Patients With a Clinically Important Improvement on Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26 [Baseline, 12 Weeks, 26 Weeks]

   Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. Clinically important improvement indicates ≥ 1 unit in the TDI focal score at Weeks 12 and 26 in comparison to BDI focal score (an increase of ≥ 1).

8. Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26 [Baseline, Day 1, Week 26]

   Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate.

9. Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26 [Baseline, Week 26 (Day 183-184)]

   Mixed model for repeated measures was used to analyze change from baseline in FVC. Baseline FVC is defined as the average of the -45 min and -15 min FVC values taken on Day 1 prior to first dose.

10. Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26 [Baseline, Week 26 (Day 183-184)]

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

11. Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26 [Baseline, Week 26 (Day 183-184)]

    Mixed model for repeated measures was used to analyze change from baseline in FEV1. Baseline FEV1 is defined as the average of the -45 min and -15 min FEV1 values taken on Day 1 prior to first dose.

12. Change From Baseline in the Percentage of Days With no Rescue Medication Use Over the 26 Weeks [Baseline, 26 Weeks]

    Patients report the number of puffs of rescue medication (salbutamol / albuterol) using an electronic diary. change from baseline in percentage of days without rescue medication usage over 26 weeks was analyzed.

13. Change From Baseline in Mean Daily COPD Symptom Score at Week 26 [Baseline, 26 Weeks]

    Patients reported symptoms by using an electronic diary. The mean daily total symptom score, the mean morning symptom score and the mean evening symptom score were calculated for each patient over 26 weeks. Each symptom measured in a numeric rating scale of 0-10; 0 indicates no symptom and 10 indicates severe symptom. 0 is no waking due to symptoms, 1 woke up once, 2 woke up more than once due to symptoms ; 10 was the worst score.The daily score for an individual symptom score was the worst of the morning and evening scores on a particular day. If either the morning or evening score was missing for a symptom then the non-missing value was taken as the worst. A negative change indicates improvement. Only the scores for the 6 COPD symptoms (respiratory symptoms, cough, wheeze, production of sputum, sputum color, and breathlessness) were used to derive the total symptom score

14. Number of Patients With Adverse Events, Serious Adverse Events and Death [26 Weeks]

    This endpoint reports patients affected by any adverse events (AE), serious adverse events (SAE) and death. Only treatment emergent AE, SAE, deaths are reported for this endpoint.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 41 Years to 84 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent must be obtained before any assessment is performed

• Male and female adults aged ≥40 years

• Patients with stable COPD according to the current GOLD strategy (GOLD 2014)

• Current or ex-smokers who have a smoking history of at least 10 pack years- an ex-smoker may be defined as a subject who has not smoked for ≥ 6 months at screening

• mMRC grade of at least 2 at Visit 101

• Patients with airflow limitation indicated by a post-bronchodilator FEV1 ≥ 30 % and < 80 % of the predicted normal, and a post-bronchodilator FEV1/FVC < 0.70 at Visit 101.

Exclusion Criteria:

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test; Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment

• Patients with Type I or uncontrolled Type II diabetes; Patients with a history of long QT syndrome or whose QTc measured at run-in (Fridericia method) is prolonged (>450 ms for males and >460 for females) and confirmed by a central assessor

• Patients requiring long term oxygen therapy prescribed for >12 h per day; Patients with any history of asthma.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Genk	Limburg	Belgium	3600
2	Novartis Investigative Site	Jambes	Namur	Belgium	5100
3	Novartis Investigative Site	Sevlievo	Gabrovo	Bulgaria	5400
4	Novartis Investigative Site	Sofia	Sofia-Grad	Bulgaria	1336
5	Novartis Investigative Site	Gabrovo		Bulgaria	5300
6	Novartis Investigative Site	Kozloduj		Bulgaria	3320
7	Novartis Investigative Site	Lom		Bulgaria	3600
8	Novartis Investigative Site	Lovech		Bulgaria	5500
9	Novartis Investigative Site	Montana		Bulgaria	3400
10	Novartis Investigative Site	Razgrad		Bulgaria	7200
11	Novartis Investigative Site	Roman		Bulgaria	3130
12	Novartis Investigative Site	Ruse		Bulgaria	7000
13	Novartis Investigative Site	Silistra		Bulgaria	7500
14	Novartis Investigative Site	Sliven		Bulgaria	8800
15	Novartis Investigative Site	Smolyan		Bulgaria	4700
16	Novartis Investigative Site	Sofia		Bulgaria	1202
17	Novartis Investigative Site	Sofia		Bulgaria	1233
18	Novartis Investigative Site	Sofia		Bulgaria	1431
19	Novartis Investigative Site	Troyan		Bulgaria	5600
20	Novartis Investigative Site	Veliko Tarnovo		Bulgaria	5000
21	Novartis Investigative Site	Vidin		Bulgaria	3700
22	Novartis Investigative Site	Turku		Finland	FIN-20100
23	Novartis Investigative Site	Heidelberg	Baden-Württemberg	Germany	69126
24	Novartis Investigative Site	Hannover	Niedersachsen	Germany	30159
25	Novartis Investigative Site	Hannover	Niedersachsen	Germany	30167
26	Novartis Investigative Site	Koblenz	Rheinland-Pfalz	Germany	56068
27	Novartis Investigative Site	Großhansdorf	Schleswig-Holstein	Germany	22927
28	Novartis Investigative Site	Berlin		Germany	10117
29	Novartis Investigative Site	Dresden		Germany	01069
30	Novartis Investigative Site	Frankfurt		Germany	60596
31	Novartis Investigative Site	Greifswald		Germany	17475
32	Novartis Investigative Site	Lubeck		Germany	23552
33	Novartis Investigative Site	Schwerin		Germany	19055
34	Novartis Investigative Site	Wiesbaden		Germany	65187
35	Novartis Investigative Site	Balassagyarmat		Hungary	2660
36	Novartis Investigative Site	Debrecen		Hungary	4032
37	Novartis Investigative Site	Farkasgyepu		Hungary	8582
38	Novartis Investigative Site	Pecs		Hungary	7635
39	Novartis Investigative Site	Sopron		Hungary	H-9400
40	Novartis Investigative Site	Szarvas		Hungary	5540
41	Novartis Investigative Site	Szeged		Hungary	6722
42	Novartis Investigative Site	Rehovot		Israel	7610001
43	Novartis Investigative Site	Wroclaw	Dolnoslaskie	Poland	53-301
44	Novartis Investigative Site	Lodz	Lódzkie	Poland	90-153
45	Novartis Investigative Site	Tarnow	Malopolskie	Poland	33-100
46	Novartis Investigative Site	Chorzow	Slaskie	Poland	41-500
47	Novartis Investigative Site	Bialystok		Poland	15-044
48	Novartis Investigative Site	Gdansk		Poland	80 952
49	Novartis Investigative Site	Kielce		Poland	25-751
50	Novartis Investigative Site	Lodz		Poland	90-141
51	Novartis Investigative Site	Sopot		Poland	81-741
52	Novartis Investigative Site	Wilkowice		Poland	43-365
53	Novartis Investigative Site	Craiova	Dolj	Romania	200515
54	Novartis Investigative Site	Constanta	Jud. Constanta	Romania	900002
55	Novartis Investigative Site	Tg Mures	Mures	Romania	540136
56	Novartis Investigative Site	Timisoara	Timis	Romania	300310
57	Novartis Investigative Site	Baia Mare		Romania
58	Novartis Investigative Site	Bucharest		Romania	030317
59	Novartis Investigative Site	Bucuresti		Romania	050159
60	Novartis Investigative Site	Cluj Napoca		Romania	400162
61	Novartis Investigative Site	Cluj-Napoca		Romania	400371
62	Novartis Investigative Site	Kazan	Tatarstan Republic	Russian Federation	420015
63	Novartis Investigative Site	Chelyabinsk		Russian Federation	454021
64	Novartis Investigative Site	Izhevsk		Russian Federation	426061
65	Novartis Investigative Site	Kemerovo		Russian Federation	650002
66	Novartis Investigative Site	Kemerovo		Russian Federation	650099
67	Novartis Investigative Site	N.Novgorod		Russian Federation	603126
68	Novartis Investigative Site	Nizhny Novgorod		Russian Federation	603011
69	Novartis Investigative Site	Ryazan		Russian Federation	390039
70	Novartis Investigative Site	Sestroretsk		Russian Federation	197706
71	Novartis Investigative Site	Smolensk		Russian Federation	214019
72	Novartis Investigative Site	St Petersburg		Russian Federation	194325
73	Novartis Investigative Site	St. Petersburg		Russian Federation	197022
74	Novartis Investigative Site	Yaroslavl		Russian Federation	150000
75	Novartis Investigative Site	Yaroslavl		Russian Federation	150003
76	Novartis Investigative Site	Yaroslavl		Russian Federation	150062
77	Novartis Investigative Site	Linkoping	Ostergotlands Lan	Sweden	587 58
78	Novartis Investigative Site	Malmo	Skane Lan	Sweden	21152
79	Novartis Investigative Site	Lidingo	Sodermanlands Lan	Sweden	18158
80	Novartis Investigative Site	Göteborg	Vastra Gotalands Lan	Sweden	SE-413 45
81	Novartis Investigative Site	Lund		Sweden	SE-221 85

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02371629
• Other Study ID Numbers: CNVA237A2320
• First Posted: Feb 25, 2015
• Last Update Posted: Aug 9, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Novartis Pharmaceuticals: Anticholinergic; Antimuscarinic; Chronic Obstructive Airway Disease; Chronic Obstructive Lung Disease; Chronic Obstructive Pulmonary Disease; COPD; LAMA; Lung Disease; Lung Diseases, Obstructive; Lung Function; Muscarinic receptor antagonist; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Glycopyrrolate; Bromides; Albuterol

Study Results

Participant Flow

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

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Period Title: Overall Study
STARTED	388	388
COMPLETED	362	363
NOT COMPLETED	26	25

Baseline Characteristics

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily	Total
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.	Total of all reporting groups
Overall Participants	388	388	776
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.2 (7.71)	63.6 (7.66)	63.4 (7.68)
Sex: Female, Male (Count of Participants)
Female	122 31.4%	111 28.6%	233 30%
Male	266 68.6%	277 71.4%	543 70%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12
Description	Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1 at Week 12. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and week 12 were included in this analysis.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	358	360
Least Squares Mean (Standard Error) [Liters]	0.092 (0.0126)	0.059 (0.0125)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NVA237 Twice Daily, NVA237 Once Daily
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.051
	Comments
	Method	Mixed model for repeated measure (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95%; 0.000 to 0.066
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0169
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 12
Description	The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 12 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.
Time Frame	Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at baseline and week 12 in different time spans were included in this analysis.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	373	373
AUC (0-12 hour)	0.136 (0.0119)	0.106 (0.0118)
AUC (0-24 hour)	0.085 (0.0121)	0.043 (0.0120)
AUC (12-24 hour)	0.035 (0.0125)	-0.019 (0.0124)

3. Secondary Outcome

Title	Change From Baseline in Area Under The Curve (AUC 0-12 Hour) for Forced Expiratory Volume in One Second (FEV1) Post Dosing at Day 1
Description	The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for 0-12 hour, post dosing at Day 1 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.
Time Frame	Baseline, 0-12 hour post dose at Day 1

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and Day 1 were included in this analysis.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	387	387
Least Squares Mean (Standard Error) [Liters]	0.143 (0.0089)	0.139 (0.0087)

4. Secondary Outcome

Title	Change From Baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in One Second (FEV1) for Different Time Spans Post Dosing at Week 26
Description	The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 26 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.
Time Frame	Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 26

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and week 26 in different time spans were included in this analysis.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	360	364
AUC (0-12 hour)	0.123 (0.0121)	0.091 (0.0120)
AUC (0-24 hour)	0.076 (0.0122)	0.030 (0.0121)
AUC (12-24 hour)	0.032 (0.0127)	-0.028 (0.0126)

5. Secondary Outcome

Title	Change From Baseline in Total St. George's Respiratory Questionnaire (SGRQ) Score at Week 12 and Week 26
Description	The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity Part II covers "Activity" and is concerned with activities that caused or are limited by breathlessness Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. Higher values corresponded to greater impairment of health status.
Time Frame	Baseline, 12 Weeks, 26 Weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and post-baseline time points were included in this analysis.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	388	388
Change from Baseline to WK 12	-5.320 (0.6000)	-3.563 (0.5987)
Change from Baseline to WK 26	-6.587 (0.6543)	-4.644 (0.6527)

6. Secondary Outcome

Title	Percentage of Patients With a Clinically Significant Improvement in St George Respiratory Questionnaire at Week 12 and Week 26
Description	The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity Part II covers "Activity" and is concerned with activities that caused or are limited by breathlessness Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. A clinically significant improvement is defined as ≥ 4 unit improvement from baseline score (a decrease of ≥ 4).
Time Frame	Baseline, 12 Weeks, 26 Weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. n= the number of patients with a SGRQ total score at both baseline and indicated post-baseline time point

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	388	388
Change from Baseline to WK 12	54.5	46.9
Change from Baseline to WK 26	59.4	49.6

7. Secondary Outcome

Title	Change From Baseline in Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26
Description	Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score.
Time Frame	Baseline, 12 Weeks, 26 Weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and post-baseline time points were included in this analysis.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	388	388
Change from Baseline to WK 12	1.346 (0.1430)	0.849 (0.1433)
Change from Baseline to WK 26	1.523 (0.1539)	1.170 (0.1534)

8. Secondary Outcome

Title	Percentage of Patients With a Clinically Important Improvement on Transitional Dyspnea Index (TDI) Focal Score at Week 12 and Week 26
Description	Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. Clinically important improvement indicates ≥ 1 unit in the TDI focal score at Weeks 12 and 26 in comparison to BDI focal score (an increase of ≥ 1).
Time Frame	Baseline, 12 Weeks, 26 Weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. n= the number of patients with a TDI focal score

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	388	388
Change from Baseline to WK 12	56.9	52.0
Change from Baseline to WK 26	61.1	54.6

9. Secondary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26
Description	Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate.
Time Frame	Baseline, Day 1, Week 26

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and post-baseline time points were included in this analysis.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	388	388
Change from baseline to Day 1	0.119 (0.0099)	0.070 (0.0097)
Change from baseline to Week 26	0.104 (0.0129)	0.056 (0.0128)

10. Secondary Outcome

Title	Change From Baseline in Forced Vital Capacity (FVC) at Individual Timepoints at Week 26
Description	Mixed model for repeated measures was used to analyze change from baseline in FVC. Baseline FVC is defined as the average of the -45 min and -15 min FVC values taken on Day 1 prior to first dose.
Time Frame	Baseline, Week 26 (Day 183-184)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in FAS were analyzed according to the treatment to which they were randomized. n = number of patients included in respective analysis (i.e. who had a FVC at this time point on at least one visit).

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	388	388
Day 183/-45 min:	0.079 (0.0195)	0.025 (0.0192)
Day 183/-15 min:	0.102 (0.0193)	0.029 (0.0191)
Day 183/5 min:	0.159 (0.0194)	0.085 (0.0194)
Day 183/15 min:	0.177 (0.0195)	0.132 (0.0195)
Day 183/30 min:	0.194 (0.0192)	0.144 (0.0191)
Day 183/1 h:	0.190 (0.0194)	0.154 (0.0192)
Day 183/2 h	0.229 (0.0193)	0.200 (0.0191)
Day 183/3 h:	0.229 (0.0197)	0.186 (0.0192)
Day 183/4 h:	0.216 (0.0194)	0.169 (0.0191)
Day 183/6 h	0.146 (0.0196)	0.116 (0.0191)
Day 183/8 h	0.137 (0.0195)	0.085 (0.0193)
Day 183/10 h	0.071 (0.0198)	0.039 (0.0191)
Day 183/12 h	0.041 (0.0200)	0.026 (0.0196)
Day 183/13 h	0.096 (0.0199)	0.004 (0.0197)
Day 184/16 h	-0.014 (0.0207)	-0.081 (0.0206)
Day 184/22 h	-0.036 (0.0198)	-0.076 (0.0195)
Day 184/23 h 15 min	0.075 (0.0201)	0.031 (0.0194)
Day 184/23 h 45 min	0.129 (0.0197)	0.077 (0.0196)

11. Secondary Outcome

Title	Change From Baseline in Inspiratory Capacity (IC) at Individual Timepoints at Week 26
Description	Mixed model for repeated measures was used to analyze change from baseline in IC.
Time Frame	Baseline, Week 26 (Day 183-184)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in FAS were analyzed according to the treatment to which they were randomized. n = number of patients included in respective analysis (i.e. who had a IC at this timepoint on at least one visit).

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	388	388
Day 183/-20 min	0.094 (0.0221)	0.054 (0.0221)
Day 183/25 min	0.181 (0.0224)	0.173 (0.0215)
Day 183/1 h 55 min	0.193 (0.0223)	0.171 (0.0218)
Day 183/3 h 55 min	0.163 (0.0226)	0.159 (0.0221)
Day 183/7 h 55 min	0.108 (0.0228)	0.110 (0.0222)
Day 183/11 h 55 min	0.042 (0.0229)	0.030 (0.0218)
Day 184/23 h 40 min	0.045 (0.0233)	0.062 (0.0224)

12. Secondary Outcome

Title	Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Individual Timepoints at Week 26
Description	Mixed model for repeated measures was used to analyze change from baseline in FEV1. Baseline FEV1 is defined as the average of the -45 min and -15 min FEV1 values taken on Day 1 prior to first dose.
Time Frame	Baseline, Week 26 (Day 183-184)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following intent-to-treat principle, patients in FAS were analyzed according to the treatment to which they were randomized. n = number of patients included in respective analysis (i.e. who had a FEV1 at this timepoint on at least one visit).

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	388	388
Day 183/-45 min	0.058 (0.0120)	0.012 (0.0119)
Day 183/-15 min	0.086 (0.0119)	0.034 (0.0118)
Day 183/5 min	0.111 (0.0120)	0.070 (0.0119)
Day 183/15 min	0.145 (0.0120)	0.106 (0.0120)
Day 183/30 min	0.155 (0.0118)	0.122 (0.0118)
Day 183/1 h	0.158 (0.0120)	0.132 (0.0118)
Day 183/2 h	0.194 (0.0119)	0.163 (0.0118)
Day 183/3 h	0.179 (0.0121)	0.154 (0.0118)
Day 183/4 h	0.166 (0.0120)	0.132 (0.0118)
Day 183/6 h	0.110 (0.0121)	0.080 (0.0118)
Day 183/8 h	0.118 (0.0121)	0.064 (0.0119)
Day 183/10 h	0.067 (0.0122)	0.038 (0.0118)
Day 183/12 h	0.056 (0.0123)	0.024 (0.0121)
Day 183/13 h	0.093 (0.0123)	0.000 (0.0121)
Day 184/16 h	-0.001 (0.0128)	-0.063 (0.0127)
Day 184/22 h	-0.012 (0.0122)	-0.043 (0.0120)
Day 184/23 h 15 min	0.076 (0.0124)	0.032 (0.0120)
Day 184/23 h 45 min	0.122 (0.0122)	0.067 (0.0121)

13. Secondary Outcome

Title	Change From Baseline in the Percentage of Days With no Rescue Medication Use Over the 26 Weeks
Description	Patients report the number of puffs of rescue medication (salbutamol / albuterol) using an electronic diary. change from baseline in percentage of days without rescue medication usage over 26 weeks was analyzed.
Time Frame	Baseline, 26 Weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and week 26 were included in this analysis.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	383	377
Least Squares Mean (Standard Error) [percentage of days]	16.574 (2.3519)	15.363 (2.3927)

14. Secondary Outcome

Title	Change From Baseline in Mean Daily COPD Symptom Score at Week 26
Description	Patients reported symptoms by using an electronic diary. The mean daily total symptom score, the mean morning symptom score and the mean evening symptom score were calculated for each patient over 26 weeks. Each symptom measured in a numeric rating scale of 0-10; 0 indicates no symptom and 10 indicates severe symptom. 0 is no waking due to symptoms, 1 woke up once, 2 woke up more than once due to symptoms ; 10 was the worst score.The daily score for an individual symptom score was the worst of the morning and evening scores on a particular day. If either the morning or evening score was missing for a symptom then the non-missing value was taken as the worst. A negative change indicates improvement. Only the scores for the 6 COPD symptoms (respiratory symptoms, cough, wheeze, production of sputum, sputum color, and breathlessness) were used to derive the total symptom score
Time Frame	Baseline, 26 Weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment to which they were randomized. Patients with evaluable data at both baseline and week 26 were included in the analysis.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	383	377
Change in mean daily	-1.336 (0.1141)	-1.107 (0.1160)
Change in mean morning	-1.032 (0.1304)	-0.828 (0.1318)
Change in mean evening	-1.205 (0.1141)	-1.056 (0.1152)

15. Secondary Outcome

Title	Number of Patients With Adverse Events, Serious Adverse Events and Death
Description	This endpoint reports patients affected by any adverse events (AE), serious adverse events (SAE) and death. Only treatment emergent AE, SAE, deaths are reported for this endpoint.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

The Safety Set (SAF) included all patients who received at least one dose of study drug whether or not they were randomized. Patients were analyzed according to the treatment they received. If patients switched treatment during the study, they were to be analyzed according to the treatment to which they were randomized.

Arm/Group Title	NVA237 Twice Daily	NVA237 Once Daily
Arm/Group Description	Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.	Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
Measure Participants	388	388
Patients with at least one AE	203 52.3%	224 57.7%
Patients with at least one SAE	33 8.5%	30 7.7%
Death	1 0.3%	1 0.3%

Adverse Events

Arm/Group Title	NVA237 22 mcg b.i.d.		NVA237 44 mcg o.d.
Arm/Group Description	NVA237 22 mcg b.i.d.		NVA237 44 mcg o.d.
All Cause Mortality
	NVA237 22 mcg b.i.d.		NVA237 44 mcg o.d.
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/388 (0.3%)		2/388 (0.5%)
Serious Adverse Events
	NVA237 22 mcg b.i.d.		NVA237 44 mcg o.d.
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/388 (8.5%)		30/388 (7.7%)
Cardiac disorders
Angina unstable	2/388 (0.5%)		0/388 (0%)
Atrial fibrillation	3/388 (0.8%)		2/388 (0.5%)
Atrial flutter	1/388 (0.3%)		0/388 (0%)
Atrial tachycardia	1/388 (0.3%)		0/388 (0%)
Cardiac failure chronic	1/388 (0.3%)		0/388 (0%)
Cardiac failure congestive	1/388 (0.3%)		0/388 (0%)
Gastrointestinal disorders
Gastritis erosive	0/388 (0%)		1/388 (0.3%)
Gastrooesophageal reflux disease	1/388 (0.3%)		0/388 (0%)
General disorders
Death	0/388 (0%)		1/388 (0.3%)
Hepatobiliary disorders
Bile duct stone	0/388 (0%)		1/388 (0.3%)
Infections and infestations
Diverticulitis	0/388 (0%)		1/388 (0.3%)
Erysipelas	0/388 (0%)		1/388 (0.3%)
Influenza	0/388 (0%)		1/388 (0.3%)
Otitis externa	1/388 (0.3%)		0/388 (0%)
Pneumonia	3/388 (0.8%)		4/388 (1%)
Sepsis	1/388 (0.3%)		0/388 (0%)
Injury, poisoning and procedural complications
Brachial plexus injury	1/388 (0.3%)		0/388 (0%)
Pubis fracture	0/388 (0%)		1/388 (0.3%)
Spinal compression fracture	1/388 (0.3%)		0/388 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer recurrent	1/388 (0.3%)		0/388 (0%)
Bronchial carcinoma	2/388 (0.5%)		0/388 (0%)
Chronic myeloid leukaemia	1/388 (0.3%)		0/388 (0%)
Invasive ductal breast carcinoma	0/388 (0%)		1/388 (0.3%)
Lung neoplasm malignant	1/388 (0.3%)		1/388 (0.3%)
Metastatic squamous cell carcinoma	0/388 (0%)		1/388 (0.3%)
Rectal adenocarcinoma	0/388 (0%)		1/388 (0.3%)
Nervous system disorders
Carpal tunnel syndrome	0/388 (0%)		1/388 (0.3%)
Cerebrovascular accident	1/388 (0.3%)		0/388 (0%)
Ischaemic stroke	1/388 (0.3%)		0/388 (0%)
Pseudoradicular syndrome	1/388 (0.3%)		0/388 (0%)
Vertebrobasilar insufficiency	0/388 (0%)		1/388 (0.3%)
Psychiatric disorders
Schizophrenia	2/388 (0.5%)		0/388 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/388 (0.5%)		0/388 (0%)
Chronic obstructive pulmonary disease	11/388 (2.8%)		15/388 (3.9%)
Pneumothorax	1/388 (0.3%)		0/388 (0%)
Vascular disorders
Aortic aneurysm	1/388 (0.3%)		0/388 (0%)
Arterial occlusive disease	0/388 (0%)		1/388 (0.3%)
Brachiocephalic artery stenosis	0/388 (0%)		1/388 (0.3%)
Other (Not Including Serious) Adverse Events
	NVA237 22 mcg b.i.d.		NVA237 44 mcg o.d.
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	126/388 (32.5%)		152/388 (39.2%)
Infections and infestations
Bronchitis	10/388 (2.6%)		3/388 (0.8%)
Nasopharyngitis	37/388 (9.5%)		54/388 (13.9%)
Nervous system disorders
Headache	4/388 (1%)		8/388 (2.1%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	74/388 (19.1%)		99/388 (25.5%)
Dyspnoea	9/388 (2.3%)		2/388 (0.5%)
Vascular disorders
Hypertension	10/388 (2.6%)		14/388 (3.6%)

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.