NVA237 BID Versus Placebo Twelve-week Efficacy Study

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01715298
• Collaborator: (none)
• Enrollment: 432
• Locations: 59
• Arms: 2
• Duration (Months): 13
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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 will be tested against a placebo treatment. The primary criterion to assess efficacy will be the difference between the serial lung function measurements of patients who have been treated for 12 weeks with NVA237 versus those that have received placebo treatment for 12 weeks. A serial lung function measurement (FEV1 testing) will be conducted and the "area under the curve" will be the measure for the ability to breathe.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: NVA237; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 432 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A 12-week Multi-center, Randomized, Double-blind, Placebo Controlled Study to Assess the Efficacy and Safety of NVA237 in Stable COPD Patients
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NVA237 NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Drug: NVA237; NVA237 (Glycopyrronioum bromide) as a powder for inhalation in single-dose capsules
Placebo Comparator: Placebo Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Drug: Placebo; Placebo powder for inhalation in single-dose capsules (matching those for NVA237).

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Standardized Area Under the Curve for Forced Expiratory Volume in One Second Post Dosing [Week 12]

   The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) post dosing (FEV1 AUC) is measured at week 12 of treatment. Serial lung function measurements are taken at the following time points following dosing at week 12 to calculate the FEV1 AUC: 5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. The primary endpoint was the change from baseline in FEV1 AUC0-12h following the morning dose at Week 12 (defined as the mean FEV1 change from baseline (CFB) over 5 min to 11 h 55 mins divided by 11 h 50 mins). Where the FEV1 AUC is smaller than at baseline, a negative value can occur

Secondary Outcome Measures

1. Change From Baseline in Standardized Area Under the Curve (AUC(0-12h)) for Forced Expiratory Volume in One Second Post Dosing [Day 1]

   The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) post dosing (FEV1 AUC) is assessed at day 1 of treatment. Serial lung function measurements are taken at the following various time points post dosing at day 1 to calculate the FEV1 AUC: 5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. .The endpoint was the change from baseline (CFB) in FEV1 AUC0-12h following the morning dose at day 1 (defined as the mean FEV1 change from baseline over 5 min to 11 h 55 mins divided by 11 h 50 mins). Where the FEV1 AUC is smaller than at baseline, a negative value can occur.

2. Change From Baseline in Standardized Area Under The Curve for Forced Expiratory Volume in One Second for Different Time Spans Post Dosing [Day 1 and Week 12]

   The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1FEV1) is assessed for different time spans (0-4 h, 4-8 h, 8-12 h) within the overall serial measurement post dosing (FEV1 AUCs Time Spans), at day 1 and at week 12 of treatment. Serial lung function measurements are taken at various the following time points post dosing on day 1 and at week 12 to calculate the FEV1 AUC for these different time spans: .5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. The endpoint was the change from baseline (CFB) in FEV1 AUC0-12h following the morning dose at day 1 or week 12, respectively, (defined as the mean FEV1 change from baseline over 5 min to 11 h 55 mins divided by 11 h 50 mins). Where the FEV1 AUC is smaller than at baseline, a negative value can occur.

3. Change From Baseline in Forced Expiratory Volume in One Second at All Individual Timepoints [Day 1 and week 12]

   The Forced Expiratory Volume in one second (FEV1) assessments for all individual time points of the serial measurements on day 1 and at week 12 are analyzed. Time points of the serial lung function measurements are 5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. The table indicates the percent change from baseline (CFB) in FEV1 and standard deviation in brackets. Where the FEV1 is lower than at baseline, a negative percent value can occur.

4. Mean Trough Forced Expiratory Volume in One Second [Day 1 and week 12]

   Mean trough Forced Expiratory Volume in one second (FEV1) is assessed as the arithmetic mean of two FEV1 measurements, conducted within the last hour of a 24 hour period from a morning dose, either that of day 1 or at week 12 of treatment. The data is reported as the change from baseline (CFB), with the baseline being the arithmetic mean of the two pre-dose measurements (-45 min and -15 min) preceding the serial lung function measurements on Day 1

5. Change From Baseline in the Health Status Assessed by St. George's Respiratory Questionnaire [Week 12]

   The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ is a 50 item scale assessing symptoms, patient activities and impact of the disease. Scores range from 0 to 100 units, with higher scores indicating more limitations. The assessment is based on total score as well as the percentage of patients with clinically significant improvement at week 12 versus day 1. A clinically meaningful improvement (MCID) in SGRQ is defined as a decrease of 4 or more units of the SGRQ scale in the total score, as compared to baseline (change from baseline).

6. Breathlessness Assessed by Transition Dyspnea Index [Week 12]

   Breathlessness at week 12 is measured using the interviewer-administered Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the interviewer-administered Baseline Dyspnea Index (BDI). The change from BDI to TDI is assessed, with the TDI total score ranging from -9 to +9 units of the scale. The lower the score, the more deterioration in severity of dyspnea. Patients are considered to have clinically significant improvement (MCID) with the TDI score change versus BDI being equal to or greater than 1.

7. Change From Baseline in Mean Number of Puffs of Rescue Medication Per Day [Baseline and week 12]

   Patients report the number of puffs of rescue medication (salbutamol / albuterol) using an electronic diary. The use of rescue medication is analyzed as the change from baseline in the mean daily number of puffs used per patient over the 12 weeks treatment period. The baseline is calculated from the run-in epoch prior to randomization (mean number of puffs per day). A negative number indicates a reduction in the mean daily number of puffs of rescue medication.

8. Change From Baseline in the Percentage of Days Without Rescue Medication Use [Baseline and week 12]

   Patients report the number of puffs of rescue medication (salbutamol / albuterol) using an electronic diary. The use of rescue medication is analyzed as the change from baseline in the percentage of days without usage of rescue medication over the 12 weeks treatment period. The baseline is calculated as the percentage of days without usage of rescue medication from during the the run-in epoch prior to randomization.

9. Change From Baseline in Daily Symptom Scores [day 1 to week 12]

   Patients are reporting symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. Each question can be answered with one of four pre-defined answers, corresponding to a unit value of 0-3, where 0 stands for the lowest and 3 for the most severe symptom experience. Symptom scores are calculated as the mean of the combined daily symptom scores (combined from morning and evening scores) for each patient over 12 weeks (Day 1 to week 12). The baseline is calculated from the run-in epoch prior to randomization. The change from baseline in the least squares mean daily symptom scores over the 12 week treatment period is provided. Where the mean daily symptom score over the 12 week treatment period is lower than the baseline, the result is negative. A negative result indicates an improvement in COPD symptom severity.

10. Change From Baseline in the Percentage of Nights With "no Nighttime Awakenings" [Day 1 and week 12]

    Patients are reporting symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. One of the symptom questions of the morning questionnaire relates to the number of awakenings due to COPD symptoms during the previous night. The answer with the lowest symptom score is "no waking due to symptoms." A night with "no nighttime awakening" is defined from diary data as any night where the patient did not wake up due to symptoms. The change from baseline in the percentage of nights with "no nighttime awakening" is calculated from the mean percentage of nights with this answer over the 12 week treatment period, with the baseline being The baseline is calculated from the run-in epoch prior to randomization.

11. Change From Baseline in the Percentage of Days With "no Daytime Symptoms" [Day 1 to week 12]

    Patients are reporting symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. Each question can be answered with one of four pre-defined answers, corresponding to a unit value of 0-3, where 0 stands for the lowest and 3 for the most severe symptom experience. A day with "no daytime symptoms" is defined from diary data as any day where the patient has recorded in the evening no cough, no wheeze, no production of sputum, and no feeling of breathlessness (other than when running) during the past approximately 12 hours in the evening questionnaire. The change from baseline in the percentage of days with "no daytime symptoms" is calculated from the mean percentage of days with this answer over the 12 week treatment period, with the baseline being. The baseline is calculated from the run-in epoch prior to randomization.

12. Change From Baseline in Percentage of "Days Able to Perform Usual Daily Activities" [Day 1 to week 12]

    Patients are reporting symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. One of the symptom questions of the evening questionnaire relates to the impact of COPD symptoms on the performance of usual daily activities ("Did your respiratory symptoms stop you performing your usual daily activities today"). The answer with the lowest symptom score is "not at all." A "day able to perform usual daily activities" is defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. The change from baseline in the percentage of "days able to perform usual daily activities" is calculated from the mean percentage of days with this answer over the 12 week treatment period, with the baseline beingThe baseline is calculated from the run-in epoch prior to randomization.

13. Change From Baseline in Forced Vital Capacity at All Individual Timepoints [Day 1 and week 12]

    The Forced Vital Capacity (FVC)assessments for all individual time points of the serial measurements on day 1 and at week 12 are analyzed. Serial lung function measurements are taken at the following time points following dosing on Day 1 and at week 12: 5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. For week 12 (day 85), the pre-dose measurements (-45 min and -15 min) and the trough measurements (23:15 h and 23:45 h post-dose) are included. The endpoints are the change from baseline in FVC following the morning dose on Day 1 and at Week 12. Where the FVC at any one timepoint is smaller than at baseline, a negative value can occur.

14. Change From Baseline in Mean Trough Forced Vital Capacity [Day 1 and week 12]

    Mean trough Forced Vital Capacity (FVC) is assessed as the arithmetic mean of two FVC measurements, conducted within the last hour of a 24 hours period from a morning dose, either that of day 1 or at week 12 of treatment (23:15 h and 23:45 h assessments). The endpoints are the change from baseline in trough FVC on Day 1 and at Week 12, with the mean of the -45 min and -15 min measurements on Day 1 as the baseline.

15. Change From Baseline in Morning and Nighttime Symptom Scores [Day 1 to week 12]

    Patients are reporting morning and nighttime symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. Each question can be answered with one of four pre-defined answers, corresponding to a unit value of 0-3, where 0 stands for the lowest and 3 for the most severe symptom experience. Morning and nighttime symptoms scores for each patient over 12 weeks are reported and analyzed. Symptom scores are calculated as the mean of the symptom scores (morning symptom scores or nighttime symptom scores, respectively) for each patient over 12 weeks (Day 1 to week 12). The baseline is calculated from the run-in epoch prior to randomization. The outcome is calculated as the change from baseline in the morning and nighttime symptom scores, respectively. A negative number indicates a reduction in the symptom severity and is owed to the calculation of the change from baseline.

Eligibility Criteria

Criteria

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

Inclusion criteria: 1. Patients with stable, symptomatic Chronic Obstructive Pulmonary Disease (COPD) with airflow obstruction of level 2 and 3 according to the current Global initiative for chronic Obstructive Lung Disease (GOLD) strategy (2011). 2. Patients with Forced Expiratory Volume in one second (FEV1) ≥ 30% and <80 % of the predicted normal, and FEV1/FVC < 0.70 when measured 45 min after the inhalation of 84 µg ipratropium bromide.

1. Current or ex-smokers with at least 10 cigarette pack years smoking history.

Exclusion criteria:

1. Patients with a history of long QT syndrome, with a prolonged QTc measured during screening, or patients who have a clinically significant ECG abnormality at screening.

2. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

3. Pregnant or nursing (lactating) women. Women of childbearing potential unless using an effective method of contraception.

4. Patients who in the judgment of the investigator, would be at potential risk if enrolled into the study.

5. Patients who have a clinically significant concomitant disease at screening, including but not limited to clinically significant laboratory abnormalities, clinically significant renal, cardiovascular, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological abnormalities, or with uncontrolled diabetes, which could interfere with the assessment of the efficacy and safety of the study treatment.

6. Patients with a body mass index (BMI) of more than 40 kg/m2.

7. Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to anticholinergic agents, long and short acting beta-2 agonists, or sympathomimetic amines.

8. Patients with any history of asthma, with onset of symptoms prior to age 40 years, or patients with a high blood eosinophil count during screening.

Other protocol-defnied inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	*See Various Dept.'s*	Arizona	United States
2	Novartis Investigative Site	Chandler	Arizona	United States	85224
3	Novartis Investigative Site	Fresno	California	United States	93726
4	Novartis Investigative Site	Fullerton	California	United States	92835
5	Novartis Investigative Site	Yorba Linda	California	United States	92886-7921
6	Novartis Investigative Site	Yorba Linda	California	United States	92886
7	Novartis Investigative Site	Boulder	Colorado	United States	80304
8	Novartis Investigative Site	Wheat Ridge	Colorado	United States	80033
9	Novartis Investigative Site	Lynn Haven	Florida	United States	32444
10	Novartis Investigative Site	Miami	Florida	United States	33173
11	Novartis Investigative Site	Port Orange	Florida	United States	32127
12	Novartis Investigative Site	Winter Park	Florida	United States	32789
13	Novartis Investigative Site	Conyers	Georgia	United States	30094
14	Novartis Investigative Site	River Forest	Illinois	United States	60305
15	Novartis Investigative Site	Skokie	Illinois	United States	60076
16	Novartis Investigative Site	Evansville	Indiana	United States	47714
17	Novartis Investigative Site	Lexington	Kentucky	United States	40509
18	Novartis Investigative Site	Sunset	Louisiana	United States	70584
19	Novartis Investigative Site	Fall River	Massachusetts	United States	02720
20	Novartis Investigative Site	North Dartmouth	Massachusetts	United States	02747
21	Novartis Investigative Site	Minneapolis	Minnesota	United States	55402
22	Novartis Investigative Site	Plymouth	Minnesota	United States	55441
23	Novartis Investigative Site	Saint Louis	Missouri	United States	63128
24	Novartis Investigative Site	St. Charles	Missouri	United States	63301
25	Novartis Investigative Site	St. Louis	Missouri	United States	63141
26	Novartis Investigative Site	Fremont	Nebraska	United States	68025
27	Novartis Investigative Site	Lincoln	Nebraska	United States	68510
28	Novartis Investigative Site	Omaha	Nebraska	United States	68114
29	Novartis Investigative Site	Cherry Hill	New Jersey	United States	08003
30	Novartis Investigative Site	Albuquerque	New Mexico	United States	87108
31	Novartis Investigative Site	Brooklyn	New York	United States	11229
32	Novartis Investigative Site	Brooklyn	New York	United States	11234
33	Novartis Investigative Site	Great Neck	New York	United States	11021
34	Novartis Investigative Site	Massapequa	New York	United States	11758
35	Novartis Investigative Site	New Windsor	New York	United States	12553
36	Novartis Investigative Site	New York	New York	United States	10003
37	Novartis Investigative Site	New York	New York	United States	10028
38	Novartis Investigative Site	Charlotte	North Carolina	United States	28207
39	Novartis Investigative Site	Cincinnati	Ohio	United States	45231
40	Novartis Investigative Site	Cincinnati	Ohio	United States	45242
41	Novartis Investigative Site	Cincinnati	Ohio	United States	45245
42	Novartis Investigative Site	Columbus	Ohio	United States	43213
43	Novartis Investigative Site	Medford	Oregon	United States	97504-8741
44	Novartis Investigative Site	Medford	Oregon	United States	97504
45	Novartis Investigative Site	Portland	Oregon	United States	97213
46	Novartis Investigative Site	Langhorne	Pennsylvania	United States	19047
47	Novartis Investigative Site	Pittsburgh	Pennsylvania	United States	15243
48	Novartis Investigative Site	Pottstown	Pennsylvania	United States	19464
49	Novartis Investigative Site	Tipton	Pennsylvania	United States	16684
50	Novartis Investigative Site	East Providence	Rhode Island	United States	02914
51	Novartis Investigative Site	Fort Mill	South Carolina	United States	29707
52	Novartis Investigative Site	Rock Hll	South Carolina	United States	29732
53	Novartis Investigative Site	Denton	Texas	United States	76210
54	Novartis Investigative Site	San Antonio	Texas	United States	78229
55	Novartis Investigative Site	Midvale	Utah	United States	84047
56	Novartis Investigative Site	South Burlington	Vermont	United States	05403
57	Novartis Investigative Site	Richmond	Virginia	United States	23219
58	Novartis Investigative Site	Richmond	Virginia	United States	23233
59	Novartis Investigative Site	Tacoma	Washington	United States	98405

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: NCT01715298
• Other Study ID Numbers: CNVA237A2318
• First Posted: Oct 26, 2012
• Last Update Posted: Mar 11, 2015
• Last Verified: Mar 1, 2015

• 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

Study Results

Participant Flow

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Period Title: Overall Study
STARTED	216	216
Full Analysis Set (FAS)	215	214
COMPLETED	209	205
NOT COMPLETED	7	11

Baseline Characteristics

Arm/Group Title	NVA237	Placebo	Total
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Total of all reporting groups
Overall Participants	216	216	432
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.9 (8.55)	64.2 (8.41)	64.1 (8.47)
Sex: Female, Male (Count of Participants)
Female	88 40.7%	90 41.7%	178 41.2%
Male	128 59.3%	126 58.3%	254 58.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Standardized Area Under the Curve for Forced Expiratory Volume in One Second Post Dosing
Description	The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) post dosing (FEV1 AUC) is measured at week 12 of treatment. Serial lung function measurements are taken at the following time points following dosing at week 12 to calculate the FEV1 AUC: 5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. The primary endpoint was the change from baseline in FEV1 AUC0-12h following the morning dose at Week 12 (defined as the mean FEV1 change from baseline (CFB) over 5 min to 11 h 55 mins divided by 11 h 50 mins). Where the FEV1 AUC is smaller than at baseline, a negative value can occur
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. analyzed participants had values at both baseline and the corresponding time frame, i.e. week 12

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	215	213
Least Squares Mean (Standard Error) [Liters]	0.115 (0.0153)	-0.008 (0.0153)

2. Secondary Outcome

Title	Change From Baseline in Standardized Area Under the Curve (AUC(0-12h)) for Forced Expiratory Volume in One Second Post Dosing
Description	The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) post dosing (FEV1 AUC) is assessed at day 1 of treatment. Serial lung function measurements are taken at the following various time points post dosing at day 1 to calculate the FEV1 AUC: 5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. .The endpoint was the change from baseline (CFB) in FEV1 AUC0-12h following the morning dose at day 1 (defined as the mean FEV1 change from baseline over 5 min to 11 h 55 mins divided by 11 h 50 mins). Where the FEV1 AUC is smaller than at baseline, a negative value can occur.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. Day 1

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	215	213
Least Squares Mean (Standard Error) [Liters]	0.121 (0.0096)	0.003 (0.0096)

3. Secondary Outcome

Title	Change From Baseline in Standardized Area Under The Curve for Forced Expiratory Volume in One Second for Different Time Spans Post Dosing
Description	The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1FEV1) is assessed for different time spans (0-4 h, 4-8 h, 8-12 h) within the overall serial measurement post dosing (FEV1 AUCs Time Spans), at day 1 and at week 12 of treatment. Serial lung function measurements are taken at various the following time points post dosing on day 1 and at week 12 to calculate the FEV1 AUC for these different time spans: .5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. The endpoint was the change from baseline (CFB) in FEV1 AUC0-12h following the morning dose at day 1 or week 12, respectively, (defined as the mean FEV1 change from baseline over 5 min to 11 h 55 mins divided by 11 h 50 mins). Where the FEV1 AUC is smaller than at baseline, a negative value can occur.
Time Frame	Day 1 and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. Day 1and Week 12

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	215	214
Day 1 AUC 0-4h (n=215,213)	0.154 (0.0088)	0.014 (0.0088)
Week 12 AUC 0-4h (n=215,213)	0.153 (0.0159)	0.004 (0.0159)
Day 1 AUC 4-8h (n=213,209)	0.118 (0.0107)	0.011 (0.0109)
Week 12 AUC 4-8h (n=213,209)	0.107 (0.0159)	0.000 (0.0158)
Day 1 AUC 8-12h (n=212,210)	0.085 (0.0120)	-0.021 (0.0120)
Week 12 AUC 8-12h (n=212,210)	0.075 (0.0164)	-0.033 (0.0164)

4. Secondary Outcome

Title	Change From Baseline in Forced Expiratory Volume in One Second at All Individual Timepoints
Description	The Forced Expiratory Volume in one second (FEV1) assessments for all individual time points of the serial measurements on day 1 and at week 12 are analyzed. Time points of the serial lung function measurements are 5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. The table indicates the percent change from baseline (CFB) in FEV1 and standard deviation in brackets. Where the FEV1 is lower than at baseline, a negative percent value can occur.
Time Frame	Day 1 and week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. Day 1and Week 12

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	215	214
FEV1, day 1, 5 min (n=207,202)	4.9 (8.67)	-0.3 (7.07)
FEV1, day 1, 15 min (n=209,201)	9.9 (10.05)	0.3 (7.62)
FEV1, day 1, 1 h (n=205,205)	13.9 (11.98)	1.2 (9.05)
FEV1, day 1, 2 h (n=201,205)	16.0 (14.42)	2.5 (9.80)
FEV1, day 1, 4 h (n=199,202)	12.7 (13.39)	2.2 (12.63)
FEV1, day 1, 6h (n=197,197)	10.3 (13.82)	2.2 (11.88)
FEV1, day 1, 8 h (n=200,189)	8.9 (14.43)	-0.5 (12.42)
FEV1, day 1, 11 h 55min (n=184,182)	6.6 (13.44)	-1.7 (14.03)
FEV1, day 85, -45min (n=184,188)	6.4 (17.61)	1.7 (17.95)
FEV1, day 85, -15min (n=180,185)	9.6 (18.23)	2.7 (17.82)
FEV1, day 85, 5min (n=185,178)	10.4 (18.78)	1.8 (17.22)
FEV1, day 85, 15min (n=186,189)	12.9 (20.00)	2.0 (17.08)
FEV1, day 85, 1h (n=184,187)	15.8 (20.49)	1.6 (17.37)
FEV1, day 85, 2h (n=178,187)	16.0 (20.83)	2.4 (18.52)
FEV1, day 85, 4h (n=179,183)	12.5 (19.72)	3.5 (20.25)
FEV1, day 85, 6h (n=174,172)	9.8 (18.78)	2.5 (20.84)
FEV1, day 85, 8h (n=178,174)	7.8 (18.18)	0.2 (18.86)
FEV1, day 85, 11h 55min (n=171,171)	7.2 (19.39)	-2.1 (20.07)

5. Secondary Outcome

Title	Mean Trough Forced Expiratory Volume in One Second
Description	Mean trough Forced Expiratory Volume in one second (FEV1) is assessed as the arithmetic mean of two FEV1 measurements, conducted within the last hour of a 24 hour period from a morning dose, either that of day 1 or at week 12 of treatment. The data is reported as the change from baseline (CFB), with the baseline being the arithmetic mean of the two pre-dose measurements (-45 min and -15 min) preceding the serial lung function measurements on Day 1
Time Frame	Day 1 and week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. Day 1and Week 12

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	213	208
Day 1	0.128 (0.0129)	0.021 (0.0130)
Week 12	0.123 (0.0166)	0.038 (0.0166)

6. Secondary Outcome

Title	Change From Baseline in the Health Status Assessed by St. George's Respiratory Questionnaire
Description	The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ is a 50 item scale assessing symptoms, patient activities and impact of the disease. Scores range from 0 to 100 units, with higher scores indicating more limitations. The assessment is based on total score as well as the percentage of patients with clinically significant improvement at week 12 versus day 1. A clinically meaningful improvement (MCID) in SGRQ is defined as a decrease of 4 or more units of the SGRQ scale in the total score, as compared to baseline (change from baseline).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. Week 12

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	193	194
Least Squares Mean (Standard Error) [Score]	-6.4 (1.08)	-1.2 (1.06)

7. Secondary Outcome

Title	Breathlessness Assessed by Transition Dyspnea Index
Description	Breathlessness at week 12 is measured using the interviewer-administered Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the interviewer-administered Baseline Dyspnea Index (BDI). The change from BDI to TDI is assessed, with the TDI total score ranging from -9 to +9 units of the scale. The lower the score, the more deterioration in severity of dyspnea. Patients are considered to have clinically significant improvement (MCID) with the TDI score change versus BDI being equal to or greater than 1.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. Week 12

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	190	190
Least Squares Mean (Standard Error) [Score]	0.95 (0.280)	0.48 (0.277)

8. Secondary Outcome

Title	Change From Baseline in Mean Number of Puffs of Rescue Medication Per Day
Description	Patients report the number of puffs of rescue medication (salbutamol / albuterol) using an electronic diary. The use of rescue medication is analyzed as the change from baseline in the mean daily number of puffs used per patient over the 12 weeks treatment period. The baseline is calculated from the run-in epoch prior to randomization (mean number of puffs per day). A negative number indicates a reduction in the mean daily number of puffs of rescue medication.
Time Frame	Baseline and week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. Week 12

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	208	201
Least Squares Mean (Standard Error) [Number of puffs]	-1.33 (0.163)	-0.80 (0.160)

9. Secondary Outcome

Title	Change From Baseline in the Percentage of Days Without Rescue Medication Use
Description	Patients report the number of puffs of rescue medication (salbutamol / albuterol) using an electronic diary. The use of rescue medication is analyzed as the change from baseline in the percentage of days without usage of rescue medication over the 12 weeks treatment period. The baseline is calculated as the percentage of days without usage of rescue medication from during the the run-in epoch prior to randomization.
Time Frame	Baseline and week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame, i.e. week 12

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	206	198
Least Squares Mean (Standard Error) [percentage of days]	11.4 (1.95)	7.0 (1.97)

10. Secondary Outcome

Title	Change From Baseline in Daily Symptom Scores
Description	Patients are reporting symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. Each question can be answered with one of four pre-defined answers, corresponding to a unit value of 0-3, where 0 stands for the lowest and 3 for the most severe symptom experience. Symptom scores are calculated as the mean of the combined daily symptom scores (combined from morning and evening scores) for each patient over 12 weeks (Day 1 to week 12). The baseline is calculated from the run-in epoch prior to randomization. The change from baseline in the least squares mean daily symptom scores over the 12 week treatment period is provided. Where the mean daily symptom score over the 12 week treatment period is lower than the baseline, the result is negative. A negative result indicates an improvement in COPD symptom severity.
Time Frame	day 1 to week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug, patients were analyzed according to the treatment they were assigned to at randomization. However, for a given time frame, analyzed participants had values at both baseline and the corresponding time frame.

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	208	201
Least Squares Mean (Standard Error) [Score]	-1.09 (0.103)	-0.80 (0.104)

11. Secondary Outcome

Title	Change From Baseline in the Percentage of Nights With "no Nighttime Awakenings"
Description	Patients are reporting symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. One of the symptom questions of the morning questionnaire relates to the number of awakenings due to COPD symptoms during the previous night. The answer with the lowest symptom score is "no waking due to symptoms." A night with "no nighttime awakening" is defined from diary data as any night where the patient did not wake up due to symptoms. The change from baseline in the percentage of nights with "no nighttime awakening" is calculated from the mean percentage of nights with this answer over the 12 week treatment period, with the baseline being The baseline is calculated from the run-in epoch prior to randomization.
Time Frame	Day 1 and week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	208	200
Least Squares Mean (Standard Error) [Percentage of nights]	13.1 (1.52)	9.2 (1.54)

12. Secondary Outcome

Title	Change From Baseline in the Percentage of Days With "no Daytime Symptoms"
Description	Patients are reporting symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. Each question can be answered with one of four pre-defined answers, corresponding to a unit value of 0-3, where 0 stands for the lowest and 3 for the most severe symptom experience. A day with "no daytime symptoms" is defined from diary data as any day where the patient has recorded in the evening no cough, no wheeze, no production of sputum, and no feeling of breathlessness (other than when running) during the past approximately 12 hours in the evening questionnaire. The change from baseline in the percentage of days with "no daytime symptoms" is calculated from the mean percentage of days with this answer over the 12 week treatment period, with the baseline being. The baseline is calculated from the run-in epoch prior to randomization.
Time Frame	Day 1 to week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	207	195
Least Squares Mean (Standard Error) [Percentage of days]	3.6 (1.17)	2.6 (1.18)

13. Secondary Outcome

Title	Change From Baseline in Percentage of "Days Able to Perform Usual Daily Activities"
Description	Patients are reporting symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. One of the symptom questions of the evening questionnaire relates to the impact of COPD symptoms on the performance of usual daily activities ("Did your respiratory symptoms stop you performing your usual daily activities today"). The answer with the lowest symptom score is "not at all." A "day able to perform usual daily activities" is defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. The change from baseline in the percentage of "days able to perform usual daily activities" is calculated from the mean percentage of days with this answer over the 12 week treatment period, with the baseline beingThe baseline is calculated from the run-in epoch prior to randomization.
Time Frame	Day 1 to week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	207	195
Least Squares Mean (Standard Error) [Percentage of days]	5.2 (1.61)	0.9 (1.65)

14. Secondary Outcome

Title	Change From Baseline in Forced Vital Capacity at All Individual Timepoints
Description	The Forced Vital Capacity (FVC)assessments for all individual time points of the serial measurements on day 1 and at week 12 are analyzed. Serial lung function measurements are taken at the following time points following dosing on Day 1 and at week 12: 5 min, 15 min, 1:00 h, 2:00 h, 4:00 h, 6:00 h, 8:00 h, and 11:55 h after the morning dose. For week 12 (day 85), the pre-dose measurements (-45 min and -15 min) and the trough measurements (23:15 h and 23:45 h post-dose) are included. The endpoints are the change from baseline in FVC following the morning dose on Day 1 and at Week 12. Where the FVC at any one timepoint is smaller than at baseline, a negative value can occur.
Time Frame	Day 1 and week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	215	214
FVC, day 1, 5 min (n=214,211)	0.120 (0.0129)	-0.014 (0.0131)
FVC, day 1, 15 min (n=214,213)	0.233 (0.0155)	0.005 (0.0157)
FVC, day 1, 1 h (n=215,211)	0.304 (0.0175)	0.041 (0.0176)
FVC, day 1, 2 h (n=211,211)	0.322 (0.0193)	0.060 (0.0191)
FVC, day 1, 4 h (n=209,208)	0.247 (0.0196)	0.048 (0.0195)
FVC, day 1, 6 h (n=208,205)	0.225 (0.0219)	0.051 (0.0220)
FVC, day 1, 8 h (n=209,205)	0.200 (0.0228)	-0.002 (0.0232)
FVC, day 1, 11 h 55min (n=203,202)	0.147 (0.0242)	-0.017 (0.0243)
FVC, day 85, -45 min (n=207,204)	0.123 (0.0248)	0.008 (0.0246)
FVC, day 85, -15 min (n=208,204)	0.146 (0.0241)	0.010 (0.0239)
FVC, day 85, 5 min (n=214,211)	0.177 (0.0247)	0.001 (0.0251)
FVC, day 85, 15 min (n=214,213)	0.219 (0.0261)	-0.003 (0.0259)
FVC, day 85, 1 hr (n=215,211)	0.267 (0.0261)	0.010 (0.0260)
FVC, day 85, 2 hr (n=211,211)	0.275 (0.0277)	0.024 (0.0271)
FVC, day 85, 4 hr (n=209,208)	0.204 (0.0281)	0.035 (0.0278)
FVC, day 85, 6 hr (n=208,205)	0.185 (0.0278)	0.016 (0.0278)
FVC, day 85, 8 hr (n=209,205)	0.152 (0.0264)	-0.015 (0.0266)
FVC, day 85, 11 hr 55min (n=203,202)	0.135 (0.0290)	-0.045 (0.0288)
FVC, day 85, 23 hr 15min (n=210,204)	0.207 (0.0289)	0.066 (0.0284)
FVC, day 85, 23 hr 45min (n=213,208)	0.228 (0.0292)	0.095 (0.0290)

15. Secondary Outcome

Title	Change From Baseline in Mean Trough Forced Vital Capacity
Description	Mean trough Forced Vital Capacity (FVC) is assessed as the arithmetic mean of two FVC measurements, conducted within the last hour of a 24 hours period from a morning dose, either that of day 1 or at week 12 of treatment (23:15 h and 23:45 h assessments). The endpoints are the change from baseline in trough FVC on Day 1 and at Week 12, with the mean of the -45 min and -15 min measurements on Day 1 as the baseline.
Time Frame	Day 1 and week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	213	208
Day 1	0.249 (0.0225)	0.078 (0.0227)
Week 12	0.210 (0.0277)	0.080 (0.0276)

16. Secondary Outcome

Title	Change From Baseline in Morning and Nighttime Symptom Scores
Description	Patients are reporting morning and nighttime symptoms by using an electronic diary. The electronic diary has 9 symptom questions each morning and each evening. Each question can be answered with one of four pre-defined answers, corresponding to a unit value of 0-3, where 0 stands for the lowest and 3 for the most severe symptom experience. Morning and nighttime symptoms scores for each patient over 12 weeks are reported and analyzed. Symptom scores are calculated as the mean of the symptom scores (morning symptom scores or nighttime symptom scores, respectively) for each patient over 12 weeks (Day 1 to week 12). The baseline is calculated from the run-in epoch prior to randomization. The outcome is calculated as the change from baseline in the morning and nighttime symptom scores, respectively. A negative number indicates a reduction in the symptom severity and is owed to the calculation of the change from baseline.
Time Frame	Day 1 to week 12

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): all randomized patients who received at least one dose of trial drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization

Arm/Group Title	NVA237	Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks	Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
Measure Participants	215	214
Daytime total symptom score (n=207,195)	-0.86 (0.097)	-0.61 (0.100)
Nighttime total symptom score (n=208,200)	-1.03 (0.101)	-0.76 (0.102)

Adverse Events

Arm/Group Title	NVA237		Placebo
Arm/Group Description	NVA237 will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks		Placebo will be inhaled from a single-dose dry powder inhaler for a period of 12 weeks
All Cause Mortality
	NVA237		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	NVA237		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/216 (4.2%)		5/214 (2.3%)
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION	1/216 (0.5%)		0/214 (0%)
ANGINA PECTORIS	1/216 (0.5%)		0/214 (0%)
Infections and infestations
CELLULITIS	1/216 (0.5%)		0/214 (0%)
HERPES SIMPLEX	1/216 (0.5%)		0/214 (0%)
OPHTHALMIC HERPES ZOSTER	1/216 (0.5%)		0/214 (0%)
PNEUMONIA	1/216 (0.5%)		0/214 (0%)
Injury, poisoning and procedural complications
SPINAL COMPRESSION FRACTURE	0/216 (0%)		1/214 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
METASTATIC SQUAMOUS CELL CARCINOMA	1/216 (0.5%)		0/214 (0%)
SQUAMOUS CELL CARCINOMA OF THE VULVA	1/216 (0.5%)		0/214 (0%)
Respiratory, thoracic and mediastinal disorders
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	3/216 (1.4%)		3/214 (1.4%)
HAEMOPTYSIS	0/216 (0%)		1/214 (0.5%)
PULMONARY MASS	0/216 (0%)		1/214 (0.5%)
RESPIRATORY FAILURE	1/216 (0.5%)		0/214 (0%)
Vascular disorders
PERIPHERAL ARTERY ANEURYSM	1/216 (0.5%)		0/214 (0%)
Other (Not Including Serious) Adverse Events
	NVA237		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	88/216 (40.7%)		81/214 (37.9%)
Eye disorders
VISION BLURRED	1/216 (0.5%)		2/214 (0.9%)
Gastrointestinal disorders
CONSTIPATION	1/216 (0.5%)		2/214 (0.9%)
DIARRHOEA	2/216 (0.9%)		3/214 (1.4%)
DRY MOUTH	2/216 (0.9%)		1/214 (0.5%)
NAUSEA	2/216 (0.9%)		0/214 (0%)
General disorders
FATIGUE	1/216 (0.5%)		2/214 (0.9%)
OEDEMA PERIPHERAL	1/216 (0.5%)		3/214 (1.4%)
PAIN	2/216 (0.9%)		0/214 (0%)
Infections and infestations
BRONCHITIS	0/216 (0%)		4/214 (1.9%)
CANDIDA INFECTION	3/216 (1.4%)		0/214 (0%)
CELLULITIS	2/216 (0.9%)		0/214 (0%)
GASTROENTERITIS	2/216 (0.9%)		0/214 (0%)
GASTROENTERITIS VIRAL	2/216 (0.9%)		3/214 (1.4%)
NASOPHARYNGITIS	5/216 (2.3%)		2/214 (0.9%)
ORAL CANDIDIASIS	2/216 (0.9%)		0/214 (0%)
SINUSITIS	3/216 (1.4%)		2/214 (0.9%)
UPPER RESPIRATORY TRACT INFECTION	7/216 (3.2%)		3/214 (1.4%)
URINARY TRACT INFECTION	3/216 (1.4%)		3/214 (1.4%)
VIRAL UPPER RESPIRATORY TRACT INFECTION	2/216 (0.9%)		3/214 (1.4%)
Injury, poisoning and procedural complications
ACCIDENTAL OVERDOSE	2/216 (0.9%)		1/214 (0.5%)
FALL	1/216 (0.5%)		2/214 (0.9%)
MUSCLE STRAIN	1/216 (0.5%)		2/214 (0.9%)
PROCEDURAL PAIN	2/216 (0.9%)		1/214 (0.5%)
Investigations
BLOOD PRESSURE INCREASED	2/216 (0.9%)		0/214 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	2/216 (0.9%)		0/214 (0%)
ARTHRITIS	2/216 (0.9%)		0/214 (0%)
BACK PAIN	5/216 (2.3%)		1/214 (0.5%)
PAIN IN EXTREMITY	2/216 (0.9%)		0/214 (0%)
Nervous system disorders
DIZZINESS	3/216 (1.4%)		2/214 (0.9%)
HEADACHE	2/216 (0.9%)		7/214 (3.3%)
Respiratory, thoracic and mediastinal disorders
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	43/216 (19.9%)		43/214 (20.1%)
COUGH	6/216 (2.8%)		6/214 (2.8%)
DYSPNOEA	3/216 (1.4%)		3/214 (1.4%)
NASAL CONGESTION	0/216 (0%)		5/214 (2.3%)
OROPHARYNGEAL PAIN	5/216 (2.3%)		1/214 (0.5%)
RESPIRATORY TRACT CONGESTION	2/216 (0.9%)		1/214 (0.5%)
RHINITIS ALLERGIC	3/216 (1.4%)		0/214 (0%)
RHINORRHOEA	1/216 (0.5%)		3/214 (1.4%)
Skin and subcutaneous tissue disorders
RASH	1/216 (0.5%)		2/214 (0.9%)
Vascular disorders
HYPERTENSION	2/216 (0.9%)		2/214 (0.9%)

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