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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01120691
• Collaborator: (none)
• Enrollment: 2,224
• Locations: 345
• Arms: 3
• Duration (Months): 27
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is designed to assess the effect of once-daily QVA149 on COPD exacerbations in patients with severe to very severe COPD.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: QVA149; Drug: NVA237; Drug: tiotropium; Drug: Salbutamol/albuterol	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2224 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 64-week Treatment, Multi-center, Randomized, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Effect of QVA149 (110/50 μg o.d.) vs NVA237 (50 μg o.d.) and Open-label Tiotropium (18 μg o.d.) on COPD Exacerbations in Patients With Severe to Very Severe Chronic Obstructive Pulmonary Disease (COPD)
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: QVA149 QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Drug: QVA149; QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks).; Drug: Salbutamol/albuterol; As needed throughout the study
Active Comparator: NVA237 NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Drug: NVA237; NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks).; Drug: Salbutamol/albuterol; As needed throughout the study
Active Comparator: open-label tiotropium Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Drug: tiotropium; Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks).; Drug: Salbutamol/albuterol; As needed throughout the study

Outcome Measures

Primary Outcome Measures

1. Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period. [64 weeks]

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

Secondary Outcome Measures

1. Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and Open-label Tiotropium Treatment Arms During the Treatment Period. [76 weeks]

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

2. Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period [64 weeks]

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

3. Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics [64 weeks]

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

4. Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics [64 weeks]

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

5. Time to Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.) During the Treatment Period. [64 weeks]

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

6. Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.)During the Treatment Period [64 weeks]

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

7. Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points [26, 52, 64, 76 weeks]

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

8. Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium [4, 12, 26, 38, 52 and 64 weeks]

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

9. Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium [4, 12, 26, 38, 52 and 64 weeks]

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

10. Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period [Baseline (14 day run-in), 64 weeks]

    The severe or less FEV1 % predicted (post bronchodilator)>=30%; very severe=> FEV1 % predicted(the post bronchodilator)<30%.Number of puffs of rescue medication taken in the previous 12 hours was recorded in patient diary in the morning and in the evening for 26 weeks.The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient.Rescue medication data recorded during the 14 day run-in was used to calculate the baseline.A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates.

11. Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period [Baseline (14 day run-in), 64 weeks]

    A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. The percentage of days is calculated by the number of days with no rescue medicine use/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.

12. St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment [12, 26, 38, 52 and 64 weeks]

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

Eligibility Criteria

Criteria

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

Inclusion Criteria :

1. Male or female adults aged ≥40 years, who had signed an informed consent form prior to initiation of any study-related procedure.

2. Patients with severe to very severe Chronic Obstructive Pulmonary Disease COPD (Stage III or IV) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines 2008.

3. Current or ex-smokers with a smoking history of at least 10 pack years (Ten pack-years were defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years).

4. Patients with a post-bronchodilator Forced Expiratory Volume in one second ( FEV1) <50% of the predicted normal value, and post-bronchodilator FEV1/ Forced Vital Capacity (FVC) <0.70 at Visit 2 (day -14). (Post refers to 1 h after sequential inhalation of 84 µg (or equivalent dose) of ipratropium bromide and 400 µg of salbutamol).

5. A documented history of at least 1 COPD exacerbation in the previous 12 months that required treatment with systemic glucocorticosteroids and/or antibiotics.

Exclusion Criteria:

1. Pregnant women or nursing mothers (pregnancy confirmed by positive urine pregnancy test).

2. Women of child-bearing potential

3. Patients requiring long term oxygen therapy (> 15 h a day) on a daily basis for chronic hypoxemia.

4. Patients who had a COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to visit 1 or between visit 1 (Day -21) and Visit 3 (Day 1).

5. Patients who developed a COPD exacerbation during a period between visit 1 and 3 were ineligible but were permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation.

6. Patients who had a respiratory tract infection within 4 weeks prior to visit 1 (Day -21)

• Patients who developed an upper or lower respiratory tract infection during the screening period (up to visit 3 (Day 1) were not eligible, but were permitted to be re-screened 4 weeks after the resolution of the respiratory tract infection

1. Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis (unless confirmed by chest x-ray to be no longer active), clinically significant bronchiectasis, sarcoidosis, interstitial lung disorder or pulmonary hypertension.

2. Patients with lung lobectomy, or lung volume reduction or lung transplantation.

3. Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to):

• Unstable ischemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable Atrial Fibrillation (AF). Patients with such events not considered clinically significant by the investigator may be considered for inclusion in the study

• history of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin

• uncontrolled hypo- or hyperthyroidism, hypokalemia or hyper adrenergic state

• narrow-angle glaucoma

• Symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention. (Patients with a Transurethral Resection of Prostate (TURP) were excluded from the study. Patients who underwent full re-section of the prostate could be considered for the study, as well as patients who were asymptomatic and stable on pharmacological treatment for the condition).

• any condition which might have compromised patient safety or compliance, interfered with evaluation, or precluded completion of the study

1. Patients with any history of asthma indicated by (but not limited to) a blood eosinophil count > 600/mm3 (at visit 2), or onset of symptoms prior to 40 years. Patients without asthma were excluded if their eosinophil count was >600/mm3 at visit

3. Patients with allergic rhinitis who used H1 antagonists or intranasal corticosteroids intermittently (treatment with a constant dose was permitted).

4. Patients with eczema (atopic), known high immunoglobulin E (IgE) levels or a known positive skin prick test in the last 5 years.

5. Patients with known history and diagnosis of alpha-1 antitrypsin deficiency.

6. Patients who were participating in the active phase of a supervised pulmonary rehabilitation program.

7. Patients with Type I or uncontrolled Type II diabetes.

8. Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs or drugs of a similar class or any component thereof:

• anticholinergic agents

• long and short acting beta-2 agonists

• sympathomimetic amines.

1. Patients with a history of long QT syndrome or whose corrected QT interval (QTc) measured at visit 2 (Day -14) (Fridericia method) was prolonged (>450 ms for males and females) as confirmed by the central ECG assessor.

2. Patients with a clinically significant abnormality on the screening or baseline ECG who in the judgment of the investigator would be at potential risk if enrolled into the study. (These patients could not be re-screened).

3. Patients who needed treatments for COPD and allied conditions after the start of the study (visit 1)

4. Patients who needed treatments for COPD and allied conditions (e.g. allergic rhinitis) unless they had been stabilized

5. Patients taking other prohibited medications

6. Patients unable to use a dry powder inhaler (e.g. single dose dry powder inhaler (SDDPI), HandiHaler® device, or pressurized Metered Dose Inhaler (MDI) (rescue medication).

7. Patients unable to use an electronic patient diary.

8. Patients who were, in the opinion of the investigator known to be unreliable or non-compliant.

9. Patients who used other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of visit 1 (day -21), whichever was longer.

10. Patients who had live attenuated vaccination within 30 days prior to the screening visit or during the run-in period. Inactivated influenza vaccination, pneumococcal vaccination or any other inactivated vaccine was acceptable provided it was not administered within 48 hours prior to screening and randomization visits.

No additional exclusions were applied by the investigator, in order to ensure that the study population was representative of all eligible patients.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35233
2	Novartis Investigative Site	Fairhope	Alabama	United States	36532
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104	Novartis Investigative Site	Bogotá		Colombia
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106	Novartis Investigative Site	Medellín		Colombia
107	Novartis Investigative Site	Cesky Krumlov		Czech Republic	381 01
108	Novartis Investigative Site	Cvikov		Czech Republic	471 54
109	Novartis Investigative Site	Havlickuv Brod		Czech Republic	580 01
110	Novartis Investigative Site	Jaromer		Czech Republic	551 01
111	Novartis Investigative Site	Karlovy Vary		Czech Republic	360 66
112	Novartis Investigative Site	Kromeriz		Czech Republic	767 55
113	Novartis Investigative Site	Kutna Hora		Czech Republic	284 01
114	Novartis Investigative Site	Kyjov		Czech Republic	697 01
115	Novartis Investigative Site	Liberec		Czech Republic	460 01
116	Novartis Investigative Site	Pardubice		Czech Republic	530 09
117	Novartis Investigative Site	Prague 4		Czech Republic	142 00
118	Novartis Investigative Site	Praha 10		Czech Republic	108 00
119	Novartis Investigative Site	Praha 9		Czech Republic	198 00
120	Novartis Investigative Site	Rokycany		Czech Republic	337 22
121	Novartis Investigative Site	Strakonice		Czech Republic	38601
122	Novartis Investigative Site	Teplice		Czech Republic	415 01
123	Novartis Investigative Site	Zatec		Czech Republic	438 01
124	Novartis Investigative Site	Znojmo		Czech Republic	669 02
125	Novartis Investigative Site	Aalborg		Denmark	DK-9100
126	Novartis Investigative Site	Copenhagen NV		Denmark	DK-2400
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128	Novartis Investigative Site	Hvidovre		Denmark	DK-2650
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130	Novartis Investigative Site	Silkeborg		Denmark	8600
131	Novartis Investigative Site	Sønderborg		Denmark	DK-6400
132	Novartis Investigative Site	Tallinn		Estonia	10138
133	Novartis Investigative Site	Tallinn		Estonia	13419
134	Novartis Investigative Site	Tartu		Estonia	51014
135	Novartis Investigative Site	Helsinki		Finland	00029
136	Novartis Investigative Site	Jyvaskyla		Finland	40100
137	Novartis Investigative Site	Turku		Finland	FIN-20100
138	Novartis Investigative Site	Bayonne Cedex		France	64109
139	Novartis Investigative Site	Beuvry		France	62660
140	Novartis Investigative Site	Ferolles-Attily		France	77150
141	Novartis Investigative Site	Montpellier		France	34059
142	Novartis Investigative Site	Paris		France	75013
143	Novartis Investigative Site	Koblenz	NRW	Germany	56068
144	Novartis Investigative Site	Aschaffenburg		Germany	63739
145	Novartis Investigative Site	Bamberg		Germany	96049
146	Novartis Investigative Site	Berlin		Germany	10117
147	Novartis Investigative Site	Berlin		Germany	10367
148	Novartis Investigative Site	Berlin		Germany	10717
149	Novartis Investigative Site	Berlin		Germany	10969
150	Novartis Investigative Site	Berlin		Germany	12043
151	Novartis Investigative Site	Berlin		Germany	12165
152	Novartis Investigative Site	Berlin		Germany	12203
153	Novartis Investigative Site	Berlin		Germany	13086
154	Novartis Investigative Site	Berlin		Germany	14050
155	Novartis Investigative Site	Berlin		Germany	D-12165
156	Novartis Investigative Site	Bochum		Germany	44787
157	Novartis Investigative Site	Bonn		Germany	53119
158	Novartis Investigative Site	Dresden		Germany	01307
159	Novartis Investigative Site	Dueren		Germany	52349
160	Novartis Investigative Site	Duisburg		Germany	47057
161	Novartis Investigative Site	Frankfurt		Germany	60596
162	Novartis Investigative Site	Freudenberg		Germany	57258
163	Novartis Investigative Site	Fulda		Germany	36039
164	Novartis Investigative Site	Gelsenkirchen		Germany	45879
165	Novartis Investigative Site	Gummersbach		Germany	51643
166	Novartis Investigative Site	Hagen		Germany	59065
167	Novartis Investigative Site	Halle		Germany	06108
168	Novartis Investigative Site	Hamburg		Germany	20354
169	Novartis Investigative Site	Hamburg		Germany	22299
170	Novartis Investigative Site	Hannover		Germany	30167
171	Novartis Investigative Site	Heidelberg		Germany	69117
172	Novartis Investigative Site	Homburg		Germany	66424
173	Novartis Investigative Site	Kiel		Germany	24148
174	Novartis Investigative Site	Langenfeld		Germany	40764
175	Novartis Investigative Site	Leipzig		Germany	04207
176	Novartis Investigative Site	Leipzig		Germany	04357
177	Novartis Investigative Site	Lübeck		Germany	23558
178	Novartis Investigative Site	Marburg		Germany	35037
179	Novartis Investigative Site	Muenchen		Germany	80331
180	Novartis Investigative Site	Nuernberg		Germany	90419
181	Novartis Investigative Site	Oranienburg		Germany	16515
182	Novartis Investigative Site	Potsdam		Germany	14467
183	Novartis Investigative Site	Radebeul		Germany	01445
184	Novartis Investigative Site	Reinfeld		Germany	23858
185	Novartis Investigative Site	Saarbruecken		Germany	66111
186	Novartis Investigative Site	Schwerte		Germany	58239
187	Novartis Investigative Site	Schwetzingen		Germany	68723
188	Novartis Investigative Site	Solingen		Germany	42651
189	Novartis Investigative Site	Stade		Germany	21680
190	Novartis Investigative Site	Teterow		Germany	17166
191	Novartis Investigative Site	Wissen		Germany	57537
192	Novartis Investigative Site	Athens - GR		Greece	10676
193	Novartis Investigative Site	Athens		Greece	GR 11527
194	Novartis Investigative Site	Athens		Greece	GR 12461
195	Novartis Investigative Site	Athens		Greece	GR-106 76
196	Novartis Investigative Site	Larissa		Greece	41110
197	Novartis Investigative Site	Thessaloniki		Greece	GR 570 10
198	Novartis Investigative Site	Thessaloniki		Greece	GR56403
199	Novartis Investigative Site	Baja		Hungary	6500
200	Novartis Investigative Site	Budapest		Hungary	1125
201	Novartis Investigative Site	Cegled		Hungary	2700
202	Novartis Investigative Site	Debrecen		Hungary	4032
203	Novartis Investigative Site	Deszk		Hungary	6772
204	Novartis Investigative Site	Eger		Hungary	3300
205	Novartis Investigative Site	Makó		Hungary	6900
206	Novartis Investigative Site	Mosonmagyarovar		Hungary	9200
207	Novartis Investigative Site	Sopron		Hungary	9400
208	Novartis Investigative Site	Szarvas		Hungary	5540
209	Novartis Investigative Site	Szekszard		Hungary	7100
210	Novartis Investigative Site	Hyderabad	A.p.	India	500 001
211	Novartis Investigative Site	Hyderbabd	Andhra Pradesh	India	500 029
212	Novartis Investigative Site	New Delhi	Delhi	India	110029
213	Novartis Investigative Site	Mysore	Karnataka	India	570004
214	Novartis Investigative Site	Nashik	Maharashtra	India	422005
215	Novartis Investigative Site	Pune	Maharashtra	India	411 014
216	Novartis Investigative Site	Jaipur	Rajasthan	India	302004
217	Novartis Investigative Site	Coimbatore	Tamil Nadu	India	641 002
218	Novartis Investigative Site	Coimbatore	Tamil Nadu	India	641004
219	Novartis Investigative Site	Coimbatore	Tamil Nadu	India	641014
220	Novartis Investigative Site	Nagpur - Maharastra		India	400 012
221	Novartis Investigative Site	Panjim		India	403002
222	Novartis Investigative Site	Secunderabad		India	500002
223	Novartis Investigative Site	Trivandrum		India	695011
224	Novartis Investigative Site	Dublin 15		Ireland
225	Novartis Investigative Site	Dublin 24		Ireland
226	Novartis Investigative Site	Dublin 4		Ireland
227	Novartis Investigative Site	Dublin 9		Ireland
228	Novartis Investigative Site	Dublin		Ireland
229	Novartis Investigative Site	Ashkelon		Israel	78278
230	Novartis Investigative Site	Beer-Sheva		Israel	84101
231	Novartis Investigative Site	Jerusalem		Israel	91031
232	Novartis Investigative Site	Jerusalem		Israel	91120
233	Novartis Investigative Site	Kfar-Sava		Israel	44281
234	Novartis Investigative Site	Petach Tikva		Israel	49100
235	Novartis Investigative Site	Ramat Gan		Israel	52621
236	Novartis Investigative Site	Rehovot		Israel	76100
237	Novartis Investigative Site	Tel-Aviv		Israel	64239
238	Novartis Investigative Site	Osimo	AN	Italy	60027
239	Novartis Investigative Site	Catania	CT	Italy	95125
240	Novartis Investigative Site	Foggia	FG	Italy	71100
241	Novartis Investigative Site	Firenze	FI	Italy	50134
242	Novartis Investigative Site	Arenzano	GE	Italy	16011
243	Novartis Investigative Site	Milano	MI	Italy	20121
244	Novartis Investigative Site	Abano Terme	PD	Italy	35031
245	Novartis Investigative Site	Perugia	PG	Italy	06129
246	Novartis Investigative Site	Pisa	PI	Italy	56124
247	Novartis Investigative Site	Pavia	PV	Italy	27100
248	Novartis Investigative Site	Roma	RM	Italy	00128
249	Novartis Investigative Site	Riccione	RN	Italy	47838
250	Novartis Investigative Site	Siena	SI	Italy	53100
251	Novartis Investigative Site	Pietra Ligure	SV	Italy	17027
252	Novartis Investigative Site	Montecchio Maggiore	VI	Italy	36075
253	Novartis Investigative Site	Pisa		Italy	56124
254	Novartis Investigative Site	Mexico	Distrito Federal	Mexico	06726
255	Novartis Investigative Site	Mexico	Distrito Federal	Mexico	14050
256	Novartis Investigative Site	Guadalajara	Jalisco	Mexico	44670
257	Novartis Investigative Site	Zapopan	Jalisco	Mexico	45200
258	Novartis Investigative Site	Monterrey	Nuevo León	Mexico	64450
259	Novartis Investigative Site	San Luis Potosí		Mexico	78218
260	Novartis Investigative Site	Almelo		Netherlands	7609 PP
261	Novartis Investigative Site	Breda		Netherlands	4819 EV
262	Novartis Investigative Site	Dordrecht		Netherlands	3318AT
263	Novartis Investigative Site	Drachten		Netherlands	9200 DA
264	Novartis Investigative Site	Enschede		Netherlands	7513 ER
265	Novartis Investigative Site	Harderwijk		Netherlands	3840 AC
266	Novartis Investigative Site	Helmond		Netherlands	5707 HA
267	Novartis Investigative Site	Hoofddorp		Netherlands	2134 TM
268	Novartis Investigative Site	Hoorn		Netherlands	1624 NP
269	Novartis Investigative Site	Leeuwarden		Netherlands	8934 AD
270	Novartis Investigative Site	Roermond		Netherlands	6043 CV
271	Novartis Investigative Site	Veldhoven		Netherlands	5504 DB
272	Novartis Investigative Site	Voorburg		Netherlands	2275 CX
273	Novartis Investigative Site	Cercado de Lima	Lima	Peru	01
274	Novartis Investigative Site	San Borja	Lima	Peru	41
275	Novartis Investigative Site	San Isidro	Lima	Peru	27
276	Novartis Investigative Site	San Martin de Porres	Lima	Peru	31
277	Novartis Investigative Site	San Miguel	Lima	Peru	32
278	Novartis Investigative Site	Santiago de Surco	Lima	Peru	33
279	Novartis Investigative Site	Quezon City	Metro Manila	Philippines	1109
280	Novartis Investigative Site	Bulacan		Philippines	3020
281	Novartis Investigative Site	Las Pinas		Philippines	1740
282	Novartis Investigative Site	Manila		Philippines
283	Novartis Investigative Site	Quezon City		Philippines	1100
284	Novartis Investigative Site	Bialystok		Poland	15-010
285	Novartis Investigative Site	Katowice		Poland	40-752
286	Novartis Investigative Site	Krakow		Poland	30-067
287	Novartis Investigative Site	Krakow		Poland	31-159
288	Novartis Investigative Site	Lublin		Poland	20-637
289	Novartis Investigative Site	Mrozy		Poland	05-320
290	Novartis Investigative Site	Warszawa		Poland	01-456
291	Novartis Investigative Site	Humacao		Puerto Rico	00791
292	Novartis Investigative Site	Kazan	Tatarstan Republic	Russian Federation	420015
293	Novartis Investigative Site	Barnaul		Russian Federation	656045
294	Novartis Investigative Site	Chelyabinsk		Russian Federation	454021
295	Novartis Investigative Site	Ekaterinburg		Russian Federation	620109
296	Novartis Investigative Site	Moscow		Russian Federation	105229
297	Novartis Investigative Site	Moscow		Russian Federation	127018
298	Novartis Investigative Site	Rostov-on-Don		Russian Federation	344090
299	Novartis Investigative Site	Ryazan		Russian Federation	390026
300	Novartis Investigative Site	S.-Petersburg		Russian Federation	196247
301	Novartis Investigative Site	Samara		Russian Federation	443079
302	Novartis Investigative Site	Sankt-Peterburg		Russian Federation	197022
303	Novartis Investigative Site	St-Petersburg		Russian Federation	193312
304	Novartis Investigative Site	St. Petersburg		Russian Federation	191015
305	Novartis Investigative Site	St. Petersburg		Russian Federation	194354
306	Novartis Investigative Site	St. Petersburg		Russian Federation	198013
307	Novartis Investigative Site	St.Petersburg		Russian Federation	198044
308	Novartis Investigative Site	Yaroslavl		Russian Federation	150010
309	Novartis Investigative Site	Banska Bystrica	Slovak Republic	Slovakia	975 17
310	Novartis Investigative Site	Bojnice	Slovak Republic	Slovakia	972 01
311	Novartis Investigative Site	Humenne	Slovak Republic	Slovakia	066 01
312	Novartis Investigative Site	Partizanske	Slovak Republic	Slovakia	958 01
313	Novartis Investigative Site	Kosice		Slovakia	040 01
314	Novartis Investigative Site	Kralovsky Chlmec		Slovakia	077 01
315	Novartis Investigative Site	Martin		Slovakia	03601
316	Novartis Investigative Site	Presov		Slovakia	080 01
317	Novartis Investigative Site	Trnava		Slovakia	917 75
318	Novartis Investigative Site	Durban		South Africa	4001
319	Novartis Investigative Site	Newtown, Johannesburg		South Africa	2193
320	Novartis Investigative Site	Pretoria		South Africa	0181
321	Novartis Investigative Site	Pretoria		South Africa	0184
322	Novartis Investigative Site	Pretoria		South Africa
323	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
324	Novartis Investigative Site	L'Hospitalet de Llobregat	Cataluña	Spain	08907
325	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain
326	Novartis Investigative Site	La Coruna	Galicia	Spain	15006
327	Novartis Investigative Site	Alicante		Spain	03114
328	Novartis Investigative Site	Stockton	Cleveland	United Kingdom	TS19 8PE
329	Novartis Investigative Site	Sneinton	Nottingham	United Kingdom	NG3 7DQ
330	Novartis Investigative Site	Taunton	Somerset	United Kingdom	TA1 3JL
331	Novartis Investigative Site	Chertsey	Surrey	United Kingdom	KT16 0PZ
332	Novartis Investigative Site	Blackpool		United Kingdom	FY3 8NR
333	Novartis Investigative Site	Bradford		United Kingdom	BD9 6RJ
334	Novartis Investigative Site	Bristol		United Kingdom	BS10 5NB
335	Novartis Investigative Site	Coventry		United Kingdom	CV6 4DD
336	Novartis Investigative Site	Gillingham		United Kingdom	ME7 5NY
337	Novartis Investigative Site	Glasgow		United Kingdom	G21 3UW
338	Novartis Investigative Site	Hereford		United Kingdom	HR1 2ER
339	Novartis Investigative Site	Huntingdon		United Kingdom	PE29 6NT
340	Novartis Investigative Site	London		United Kingdom	NW3 2PR
341	Novartis Investigative Site	Manchester		United Kingdom	M23 9QZ
342	Novartis Investigative Site	Merseyside		United Kingdom	CH49 5PE
343	Novartis Investigative Site	Portsmouth		United Kingdom	PO6 3AD
344	Novartis Investigative Site	Telford		United Kingdom	TF1 6TF
345	Novartis Investigative Site	Wolverhampton		United Kingdom	WV10 0QP

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: NCT01120691
• Other Study ID Numbers: CQVA149A2304; 2009-013256-69
• First Posted: May 11, 2010
• Last Update Posted: Dec 2, 2013
• Last Verified: Oct 1, 2013

• Keywords provided by Novartis Pharmaceuticals: QVA149; NVA237; COPD; exacerbation; combination bronchodilator
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Glycopyrrolate; Albuterol; Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details	A total of 3865 participants were screened of whom 2224 were randomized to 1 of the 3 treatment groups (QVA149, NVA237 or tiotropium) in a 1:1:1 ratio for at least 64 weeks (maximum 76 weeks) of treatment period.
Pre-assignment Detail	5 (QVA149), 2 (NVA237) and 3 (tiotropium) participants were randomized but did not receive study drug.

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

Baseline Characteristics

Arm/Group Title	QVA149	NVA237	Open-label Tiotropium	Total
Arm/Group Description	QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Total of all reporting groups
Overall Participants	729	740	737	2206
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.1 (8.07)	63.1 (7.98)	63.6 (7.79)	63.3 (7.95)
Sex: Female, Male (Count of Participants)
Female	173 23.7%	198 26.8%	184 25%	555 25.2%
Male	556 76.3%	542 73.2%	553 75%	1651 74.8%

Outcome Measures

1. Primary Outcome

Title	Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period.
Description	A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time Frame	64 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	QVA149	NVA237
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Measure Participants	729	739
Measure Moderate to Severe COPD Exacerbation	812	900
Number [Exacerbations per year]	0.94	1.07

2. Secondary Outcome

Title	Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and Open-label Tiotropium Treatment Arms During the Treatment Period.
Description	A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time Frame	76 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	QVA149	Open-label Tiotropium
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Measure Participants	729	737
Measure Moderate to Severe COPD Exacerbation	812	898
Number [Exacerbations per year]	0.94	1.06

3. Secondary Outcome

Title	Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period
Description	A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time Frame	64 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	QVA149	NVA237	Open-label Tiotropium
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI)for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI)for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Measure Participants	419	426	402
Median (95% Confidence Interval) [days]	296	287	331

4. Secondary Outcome

Title	Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics
Description	Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time Frame	64 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	QVA149	NVA237	Open-label Tiotropium
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI)for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI)for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Measure Participants	729	739	737
Measure exacerbations	403	491	461
Number [exacerbations per year]	0.46	0.58	0.54

5. Secondary Outcome

Title	Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics
Description	The number of exacerbation days is defined as the sum of the duration of days recorded as an exacerbation for all exacerbations recorded per patient.
Time Frame	64 weeks

Outcome Measure Data

Analysis Population Description

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

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

6. Secondary Outcome

Title	Time to Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.) During the Treatment Period.
Description	Time to Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase.
Time Frame	64 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	QVA149	NVA237	Open-label Tiotropium
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Measure Participants	159	202	178
Median (95% Confidence Interval) [days]	NA	NA	NA

7. Secondary Outcome

Title	Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.)During the Treatment Period
Description	Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase.
Time Frame	64 weeks

Outcome Measure Data

Analysis Population Description

Modified safety set (mSAF set) includes all patients in the safety set except patients from a site who had major GCP issues. The Safety set includes all patients who received at least one dose of study drug whether or not being randomized

Arm/Group Title	QVA149	NVA237	Open-label Tiotropium
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Measure Participants	729	740	737
Number [percentage of participants]	21.8 3%	27.3 3.7%	24.2 3.3%

8. Secondary Outcome

Title	Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points
Description	Cumulative rates were estimated using Anderson and Gill method. Chronic Obstructive Pulmonary Disease (COPD) exacerbations are considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations are considered to be severe if treatment for moderate severity and hospitalization were required. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time Frame	26, 52, 64, 76 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	QVA149	NVA237	Open-label Tiotropium
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks.Salbutamol/albuterol was available for rescue medication use throughout the study.
Measure Participants	729	739	737
Measure Moderate or Severe COPD Exacerbations	831	926	897
26 weeks	0.57	0.65	0.63
52 weeks	0.99	1.13	1.11
64 weeks	1.19	1.36	1.31
76 weeks	1.39	1.59	1.55

9. Secondary Outcome

Title	Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium
Description	Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards. Spirometry measurements taken were FEV1 at -45 minutes and -15 minutes pre-dose. Three acceptable maneuvers had to be performed for each time point. The FEV1 values recorded had to be the highest values measured irrespective of whether or not they occurred on the same curve. The mixed model for analysis contained treatment as a fixed effect with average of the 45 minutes and 15 minutes pre dose FEV1 measurements at day 1 as the baseline measurement, FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at -14 Day) as covariates.
Time Frame	4, 12, 26, 38, 52 and 64 weeks

Outcome Measure Data

Analysis Population Description

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

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

10. Secondary Outcome

Title	Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium
Description	Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards. Pre-dose Forced Vital Capacity (FVC) is defined as the average of the -15 minutes and the -45 minutes FVC values. Baseline is defined as the average of the -45 minutes and -15 minutes FVC values taken on day 1 prior to first dose. FVC data taken within 6h of rescue medication or within 7 days of systemic corticosteroid is excluded from this analysis
Time Frame	4, 12, 26, 38, 52 and 64 weeks

Outcome Measure Data

Analysis Population Description

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

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

11. Secondary Outcome

Title	Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period
Description	The severe or less FEV1 % predicted (post bronchodilator)>=30%; very severe=> FEV1 % predicted(the post bronchodilator)<30%.Number of puffs of rescue medication taken in the previous 12 hours was recorded in patient diary in the morning and in the evening for 26 weeks.The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient.Rescue medication data recorded during the 14 day run-in was used to calculate the baseline.A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates.
Time Frame	Baseline (14 day run-in), 64 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	QVA149	NVA237	Open-label Tiotropium
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI)for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI)for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Measure Participants	708	724	709
Mean Daily # puffs Severe or Less(n=565,575,561)	-2.3 (0.137)	-1.5 (0.135)	-1.6 (0.136)
Mean Daily # puffs Very Severe (n=143,149,148)	-2.1 (0.234)	-1.1 (0.228)	-1.0 (0.228)

12. Secondary Outcome

Title	Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period
Description	A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. The percentage of days is calculated by the number of days with no rescue medicine use/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time Frame	Baseline (14 day run-in), 64 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	QVA149	NVA237	Open-label Tiotropium
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI)for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI)for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.	Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
Measure Participants	701	720	703
Least Squares Mean (Standard Error) [percentage of days]	29.36 (1.445)	21.65 (1.410)	23.86 (1.422)

13. Secondary Outcome

Title	St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment
Description	St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. Mixed model used baseline SGRQ, baseline inhaled corticosteroid (ICS) use, Forced Expiratory Volume in 1 Second (FEV1) prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. SGRQ total score is the sum of the scores from the three components; symptoms, activity and impacts.
Time Frame	12, 26, 38, 52 and 64 weeks

Outcome Measure Data

Analysis Population Description

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

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

Adverse Events

Adverse Event Reporting Description	Modified safety set (mSAF set) includes all patients in the safety set except patients from a site who had major GCP issues. The Safety set includes all patients who received at least one dose of study drug whether or not being randomized. Analysis population included patients with study withdrawal or premature discontinuation for any reason.
Arm/Group Title	QVA149		NVA237		Open-label Tiotropium
Arm/Group Description	QVA149 : QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.		NVA237 : NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.		Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device. for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.
All Cause Mortality
	QVA149		NVA237		Open-label Tiotropium
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	QVA149		NVA237		Open-label Tiotropium
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	167/729 (22.9%)		179/740 (24.2%)		165/737 (22.4%)
Blood and lymphatic system disorders
Anaemia	2/729 (0.3%)		0/740 (0%)		1/737 (0.1%)
Idiopathic thrombocytopenic purpura	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Cardiac disorders
Acute coronary syndrome	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Acute myocardial infarction	1/729 (0.1%)		4/740 (0.5%)		2/737 (0.3%)
Angina pectoris	1/729 (0.1%)		3/740 (0.4%)		1/737 (0.1%)
Angina unstable	1/729 (0.1%)		2/740 (0.3%)		0/737 (0%)
Arteriosclerosis coronary artery	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Atrial fibrillation	6/729 (0.8%)		3/740 (0.4%)		4/737 (0.5%)
Atrial flutter	0/729 (0%)		2/740 (0.3%)		1/737 (0.1%)
Cardiac arrest	1/729 (0.1%)		4/740 (0.5%)		2/737 (0.3%)
Cardiac failure	1/729 (0.1%)		1/740 (0.1%)		4/737 (0.5%)
Cardiac failure acute	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Cardiac failure chronic	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Cardiac failure congestive	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Cardio-respiratory arrest	1/729 (0.1%)		3/740 (0.4%)		3/737 (0.4%)
Cardiopulmonary failure	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Cor pulmonale	0/729 (0%)		3/740 (0.4%)		0/737 (0%)
Cor pulmonale chronic	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Coronary artery disease	3/729 (0.4%)		2/740 (0.3%)		1/737 (0.1%)
Ischaemic cardiomyopathy	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Left ventricular dysfunction	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Left ventricular hypertrophy	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Mitral valve incompetence	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Myocardial infarction	2/729 (0.3%)		3/740 (0.4%)		4/737 (0.5%)
Myocardial ischaemia	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Pericardial effusion	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Pericarditis	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Right ventricular failure	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Supraventricular tachyarrhythmia	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Tachycardia	0/729 (0%)		2/740 (0.3%)		0/737 (0%)
Congenital, familial and genetic disorders
Congenital laryngeal stridor	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Phimosis	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Ear and labyrinth disorders
Acute vestibular syndrome	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Vertigo	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Endocrine disorders
Goitre	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Eye disorders
Angle closure glaucoma	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Cataract	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Retinal detachment	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Vision blurred	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Gastrointestinal disorders
Abdominal distension	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Abdominal pain	2/729 (0.3%)		1/740 (0.1%)		1/737 (0.1%)
Abdominal pain upper	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Colitis ulcerative	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Constipation	0/729 (0%)		2/740 (0.3%)		0/737 (0%)
Diarrhoea	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Duodenal ulcer	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Duodenal ulcer perforation	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Enteritis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Food poisoning	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Gastric disorder	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Gastric ulcer	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Gastritis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Gastrointestinal haemorrhage	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Gastrooesophageal reflux disease	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Haemorrhoids	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Hiatus hernia	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Inguinal hernia	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Intestinal congestion	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Intestinal obstruction	0/729 (0%)		2/740 (0.3%)		0/737 (0%)
Intestinal polyp	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Nausea	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Oesophageal ulcer haemorrhage	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Pancreatic mass	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Pancreatitis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Peptic ulcer haemorrhage	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Small intestinal obstruction	0/729 (0%)		1/740 (0.1%)		1/737 (0.1%)
General disorders
Adverse drug reaction	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Chills	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Cyst	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Death	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Generalised oedema	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Multi-organ failure	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Non-cardiac chest pain	2/729 (0.3%)		2/740 (0.3%)		3/737 (0.4%)
Oedema peripheral	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Pyrexia	2/729 (0.3%)		1/740 (0.1%)		2/737 (0.3%)
Sudden cardiac death	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Sudden death	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Thrombosis in device	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Hepatobiliary disorders
Bile duct obstruction	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Cholecystitis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Cholecystitis acute	0/729 (0%)		1/740 (0.1%)		1/737 (0.1%)
Cholelithiasis	2/729 (0.3%)		0/740 (0%)		0/737 (0%)
Hepatitis alcoholic	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Immune system disorders
Allergy to arthropod sting	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Infections and infestations
Abscess	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Abscess intestinal	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Abscess rupture	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Anal abscess	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Appendicitis	1/729 (0.1%)		2/740 (0.3%)		1/737 (0.1%)
Appendicitis perforated	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Bronchitis	4/729 (0.5%)		2/740 (0.3%)		5/737 (0.7%)
Bronchopneumonia	2/729 (0.3%)		0/740 (0%)		1/737 (0.1%)
Cellulitis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Cholecystitis infective	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Haemophilus infection	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Herpes zoster	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Kidney infection	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Laryngitis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Lobar pneumonia	4/729 (0.5%)		2/740 (0.3%)		0/737 (0%)
Lower respiratory tract infection	14/729 (1.9%)		24/740 (3.2%)		13/737 (1.8%)
Lower respiratory tract infection bacterial	2/729 (0.3%)		5/740 (0.7%)		1/737 (0.1%)
Lower respiratory tract infection fungal	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Lower respiratory tract infection viral	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Lung infection	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Lung infection pseudomonal	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Nasopharyngitis	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Oral candidiasis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Oropharyngeal candidiasis	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Otitis media acute	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Otitis media chronic	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Perineal abscess	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Peritonitis	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Pneumonia	23/729 (3.2%)		25/740 (3.4%)		24/737 (3.3%)
Pneumonia bacterial	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Pneumonia legionella	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Pneumonia primary atypical	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Pneumonia staphylococcal	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Pulmonary tuberculosis	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Rabies	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Respiratory tract infection	2/729 (0.3%)		2/740 (0.3%)		0/737 (0%)
Respiratory tract infection bacterial	0/729 (0%)		2/740 (0.3%)		2/737 (0.3%)
Respiratory tract infection viral	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Scrotal abscess	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Sepsis	1/729 (0.1%)		3/740 (0.4%)		0/737 (0%)
Septic shock	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Subcutaneous abscess	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Upper respiratory tract infection	2/729 (0.3%)		0/740 (0%)		0/737 (0%)
Upper respiratory tract infection bacterial	20/729 (2.7%)		20/740 (2.7%)		10/737 (1.4%)
Urinary tract infection	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Viral upper respiratory tract infection	6/729 (0.8%)		5/740 (0.7%)		3/737 (0.4%)
Injury, poisoning and procedural complications
Alcohol poisoning	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Animal bite	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Cervical vertebral fracture	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Clavicle fracture	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Contusion	0/729 (0%)		1/740 (0.1%)		1/737 (0.1%)
Fall	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Femur fracture	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Head injury	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Hip fracture	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Incisional hernia	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Lower limb fracture	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Meniscus lesion	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Muscle rupture	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Pneumothorax traumatic	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Postoperative ileus	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Rib fracture	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Spinal fracture	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Tendon rupture	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Wound dehiscence	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Wrist fracture	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Investigations
Blood pressure increased	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Electrocardiogram abnormal	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Intraocular pressure increased	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Metabolism and nutrition disorders
Cachexia	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Decreased appetite	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Dehydration	0/729 (0%)		2/740 (0.3%)		0/737 (0%)
Hyperglycaemia	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Hyperkalaemia	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Hypokalaemia	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Hyponatraemia	3/729 (0.4%)		1/740 (0.1%)		1/737 (0.1%)
Malnutrition	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Type 2 diabetes mellitus	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Arthritis	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Back pain	1/729 (0.1%)		1/740 (0.1%)		1/737 (0.1%)
Bursitis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Compartment syndrome	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Intervertebral disc protrusion	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Musculoskeletal pain	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Osteoarthritis	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Osteochondritis	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Rhabdomyolysis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Spinal column stenosis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Adrenal neoplasm	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
B-cell lymphoma	0/729 (0%)		2/740 (0.3%)		0/737 (0%)
Bladder cancer	0/729 (0%)		1/740 (0.1%)		1/737 (0.1%)
Bladder neoplasm	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Breast cancer	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Breast cancer recurrent	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Bronchial carcinoma	1/729 (0.1%)		0/740 (0%)		2/737 (0.3%)
Carcinoid tumour of the caecum	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Colon adenoma	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Colon cancer	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Gliosarcoma	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Laryngeal cancer	1/729 (0.1%)		0/740 (0%)		2/737 (0.3%)
Laryngeal cancer stage 0	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Lung neoplasm	1/729 (0.1%)		2/740 (0.3%)		0/737 (0%)
Lung neoplasm malignant	3/729 (0.4%)		0/740 (0%)		4/737 (0.5%)
Lung squamous cell carcinoma stage unspecified	1/729 (0.1%)		1/740 (0.1%)		1/737 (0.1%)
Mediastinum neoplasm	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Metastases to bone	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Metastases to central nervous system	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Metastases to liver	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Metastases to lung	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Non-small cell lung cancer	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Oesophageal carcinoma	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Oesophageal squamous cell carcinoma	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Pancreatic neoplasm	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Prostate cancer	0/729 (0%)		2/740 (0.3%)		0/737 (0%)
Prostatic adenoma	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Rectal cancer	0/729 (0%)		1/740 (0.1%)		2/737 (0.3%)
Renal cancer	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Small cell lung cancer metastatic	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Small intestine carcinoma	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Squamous cell carcinoma	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Nervous system disorders
Ataxia	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Cerebellar syndrome	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Cerebral haemorrhage	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Cerebral infarction	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Cerebral ischaemia	2/729 (0.3%)		0/740 (0%)		0/737 (0%)
Cerebrovascular accident	1/729 (0.1%)		1/740 (0.1%)		3/737 (0.4%)
Cerebrovascular disorder	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Cerebrovascular insufficiency	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Cervicobrachial syndrome	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Convulsion	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Epilepsy	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Grand mal convulsion	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Headache	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Ischaemic stroke	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Lethargy	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Loss of consciousness	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Monoparesis	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Movement disorder	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Neuropathy peripheral	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Syncope	3/729 (0.4%)		0/740 (0%)		0/737 (0%)
Transient ischaemic attack	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Psychiatric disorders
Alcohol withdrawal syndrome	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Completed suicide	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Confusional state	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Delirium	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Depression	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Hallucination	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Major depression	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Mental status changes	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Psychotic disorder	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Renal and urinary disorders
Acute prerenal failure	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Bladder dysfunction	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Calculus ureteric	0/729 (0%)		2/740 (0.3%)		0/737 (0%)
Nephrolithiasis	2/729 (0.3%)		0/740 (0%)		0/737 (0%)
Renal colic	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Urinary retention	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/729 (0.3%)		1/740 (0.1%)		1/737 (0.1%)
Epididymitis	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Acute respiratory failure	7/729 (1%)		6/740 (0.8%)		1/737 (0.1%)
Atelectasis	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Chronic obstructive pulmonary disease	107/729 (14.7%)		116/740 (15.7%)		87/737 (11.8%)
Chronic respiratory failure	1/729 (0.1%)		1/740 (0.1%)		0/737 (0%)
Cough	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Dyspnoea	5/729 (0.7%)		2/740 (0.3%)		3/737 (0.4%)
Epistaxis	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Foreign body aspiration	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Haemoptysis	1/729 (0.1%)		2/740 (0.3%)		1/737 (0.1%)
Hydrothorax	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Hypercapnia	0/729 (0%)		3/740 (0.4%)		1/737 (0.1%)
Hypoxia	1/729 (0.1%)		1/740 (0.1%)		1/737 (0.1%)
Lung consolidation	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Lung disorder	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Oropharyngeal pain	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Pleural effusion	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Pleurisy	0/729 (0%)		1/740 (0.1%)		1/737 (0.1%)
Pneumothorax	0/729 (0%)		5/740 (0.7%)		1/737 (0.1%)
Productive cough	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Pulmonary air leakage	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Pulmonary congestion	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Pulmonary embolism	3/729 (0.4%)		3/740 (0.4%)		1/737 (0.1%)
Pulmonary hypertension	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Pulmonary mass	0/729 (0%)		0/740 (0%)		2/737 (0.3%)
Respiratory distress	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Respiratory failure	5/729 (0.7%)		7/740 (0.9%)		6/737 (0.8%)
Sleep apnoea syndrome	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Sputum increased	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Vocal cord inflammation	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Wheezing	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Skin and subcutaneous tissue disorders
Angioedema	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Dermal cyst	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Social circumstances
Pollution	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Surgical and medical procedures
Coronary arterial stent insertion	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Vascular disorders
Aortic aneurysm	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Aortic aneurysm rupture	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Arterial occlusive disease	0/729 (0%)		0/740 (0%)		2/737 (0.3%)
Arterial stenosis	0/729 (0%)		1/740 (0.1%)		0/737 (0%)
Arteriosclerosis	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Deep vein thrombosis	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Hypertension	2/729 (0.3%)		2/740 (0.3%)		2/737 (0.3%)
Hypotension	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Iliac artery stenosis	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Peripheral arterial occlusive disease	1/729 (0.1%)		0/740 (0%)		1/737 (0.1%)
Peripheral artery aneurysm	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Peripheral ischaemia	0/729 (0%)		0/740 (0%)		1/737 (0.1%)
Phlebitis deep	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Shock haemorrhagic	1/729 (0.1%)		0/740 (0%)		0/737 (0%)
Other (Not Including Serious) Adverse Events
	QVA149		NVA237		Open-label Tiotropium
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	656/729 (90%)		671/740 (90.7%)		666/737 (90.4%)
Cardiac disorders
Tachycardia	3/729 (0.4%)		8/740 (1.1%)		3/737 (0.4%)
Gastrointestinal disorders
Abdominal pain	6/729 (0.8%)		11/740 (1.5%)		9/737 (1.2%)
Abdominal pain upper	7/729 (1%)		7/740 (0.9%)		8/737 (1.1%)
Constipation	8/729 (1.1%)		11/740 (1.5%)		4/737 (0.5%)
Diarrhoea	21/729 (2.9%)		11/740 (1.5%)		15/737 (2%)
Dry mouth	4/729 (0.5%)		13/740 (1.8%)		16/737 (2.2%)
Dyspepsia	13/729 (1.8%)		10/740 (1.4%)		15/737 (2%)
Gastritis	12/729 (1.6%)		5/740 (0.7%)		12/737 (1.6%)
Gastrooesophageal reflux disease	9/729 (1.2%)		4/740 (0.5%)		9/737 (1.2%)
Nausea	9/729 (1.2%)		12/740 (1.6%)		4/737 (0.5%)
Toothache	9/729 (1.2%)		4/740 (0.5%)		6/737 (0.8%)
General disorders
Fatigue	4/729 (0.5%)		8/740 (1.1%)		3/737 (0.4%)
Non-cardiac chest pain	14/729 (1.9%)		11/740 (1.5%)		9/737 (1.2%)
Oedema peripheral	22/729 (3%)		18/740 (2.4%)		16/737 (2.2%)
Pyrexia	26/729 (3.6%)		24/740 (3.2%)		22/737 (3%)
Infections and infestations
Bronchitis	32/729 (4.4%)		36/740 (4.9%)		26/737 (3.5%)
Influenza	23/729 (3.2%)		22/740 (3%)		19/737 (2.6%)
Lower respiratory tract infection	49/729 (6.7%)		68/740 (9.2%)		69/737 (9.4%)
Lower respiratory tract infection bacterial	6/729 (0.8%)		8/740 (1.1%)		4/737 (0.5%)
Nasopharyngitis	98/729 (13.4%)		81/740 (10.9%)		90/737 (12.2%)
Oral candidiasis	11/729 (1.5%)		10/740 (1.4%)		12/737 (1.6%)
Pharyngitis	17/729 (2.3%)		11/740 (1.5%)		10/737 (1.4%)
Pneumonia	11/729 (1.5%)		13/740 (1.8%)		10/737 (1.4%)
Rhinitis	9/729 (1.2%)		10/740 (1.4%)		6/737 (0.8%)
Sinusitis	12/729 (1.6%)		20/740 (2.7%)		21/737 (2.8%)
Upper respiratory tract infection	26/729 (3.6%)		25/740 (3.4%)		28/737 (3.8%)
Upper respiratory tract infection bacterial	119/729 (16.3%)		123/740 (16.6%)		109/737 (14.8%)
Urinary tract infection	27/729 (3.7%)		19/740 (2.6%)		15/737 (2%)
Viral upper respiratory tract infection	70/729 (9.6%)		75/740 (10.1%)		72/737 (9.8%)
Injury, poisoning and procedural complications
Contusion	9/729 (1.2%)		4/740 (0.5%)		4/737 (0.5%)
Metabolism and nutrition disorders
Hypercholesterolaemia	14/729 (1.9%)		11/740 (1.5%)		11/737 (1.5%)
Hyperlipidaemia	9/729 (1.2%)		4/740 (0.5%)		7/737 (0.9%)
Type 2 diabetes mellitus	12/729 (1.6%)		9/740 (1.2%)		5/737 (0.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	12/729 (1.6%)		10/740 (1.4%)		10/737 (1.4%)
Back pain	24/729 (3.3%)		33/740 (4.5%)		36/737 (4.9%)
Muscle spasms	5/729 (0.7%)		9/740 (1.2%)		9/737 (1.2%)
Musculoskeletal pain	12/729 (1.6%)		9/740 (1.2%)		6/737 (0.8%)
Pain in extremity	9/729 (1.2%)		8/740 (1.1%)		5/737 (0.7%)
Nervous system disorders
Dizziness	13/729 (1.8%)		12/740 (1.6%)		8/737 (1.1%)
Headache	30/729 (4.1%)		33/740 (4.5%)		39/737 (5.3%)
Psychiatric disorders
Depression	4/729 (0.5%)		2/740 (0.3%)		9/737 (1.2%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	618/729 (84.8%)		639/740 (86.4%)		629/737 (85.3%)
Cough	40/729 (5.5%)		39/740 (5.3%)		25/737 (3.4%)
Dysphonia	2/729 (0.3%)		5/740 (0.7%)		9/737 (1.2%)
Dyspnoea	21/729 (2.9%)		42/740 (5.7%)		32/737 (4.3%)
Oropharyngeal pain	25/729 (3.4%)		32/740 (4.3%)		29/737 (3.9%)
Sputum increased	7/729 (1%)		13/740 (1.8%)		8/737 (1.1%)
Wheezing	5/729 (0.7%)		9/740 (1.2%)		3/737 (0.4%)
Vascular disorders
Hypertension	30/729 (4.1%)		20/740 (2.7%)		24/737 (3.3%)

Limitations/Caveats

[Not Specified]

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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.