Evaluation of the Efficacy and Safety of QVA149 (110/50 μg o.d.) vs Tiotropium (18 µg o.d.) + Salmeterol/Fluticasone Propionate FDC (50/500 µg b.i.d.) in Patients With Moderate to Severe COPD

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02603393
• Collaborator: (none)
• Enrollment: 1,053
• Locations: 167
• Arms: 2
• Actual Duration (Months): 19.9
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of QVA149 (110/50 μg o.d.) vs tiotropium (18 µg o.d.) + salmeterol/fluticasone propionate FDC (50/500 µg b.i.d.) in patients with moderate to severe COPD

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease (COPD)	Drug: QVA149; Drug: Tiotropium; Drug: Salmeterol/fluticasone	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 1053 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 26-week, Randomized, Double Blind, Parallel-group Multicenter Study to Assess the Efficacy and Safety of QVA149 (110/50 μg o.d.) vs Tiotropium (18 µg o.d.) + Salmeterol/Fluticasone Propionate FDC (50/500 µg b.i.d.) in Patients With Moderate to Severe COPD
• Actual Study Start Date: Nov 20, 2015
• Actual Primary Completion Date: Jul 18, 2017
• Actual Study Completion Date: Jul 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: QVA149	Drug: QVA149; QVA149 will be supplied in a capsule form in blister packs for use in the Novartis Concept 1 SDDPI
Active Comparator: Tiotropium + salmeterol/fluticasone	Drug: Tiotropium; Tiotropium will be supplied as commercially available blisters, delivered via HandiHaler®; Drug: Salmeterol/fluticasone; Salmeterol/fluticasone propionate dry inhalation powder delivered via Accuhaler™

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in Post-dose Trough FEV1 [Baseline, 26 weeks]

   Mean change from baseline in post-dose trough forced expiratory volume in 1 second (FEV1) following 26 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values measured at 23 hr 15 min and 23 hr 45 min after the morning dose taken at site on Day 181. Baseline FEV1 is defined as the average of the pre-dose FEV1 measured at -45 min and -15 min at Day 1.

Secondary Outcome Measures

1. Annualized Rate of Moderate or Severe COPD Exacerbations [26 weeks]

   Moderate or severe COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.

2. Annualized Rate of COPD Exacerbations Requiring Treatment With Systemic Glucocorticosteroids and/or Antibiotics, Moderate Exacerbations Only [26 weeks]

   COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event

3. Annualized Rate of COPD Exacerbations Requiring Hospitalisation [26 weeks]

   COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.

4. Mean Change From Baseline in Pre-dose Trough FEV1 [26 weeks]

   Trough FEV1 is defined as the average of the pre-dose FEV1 measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FEV1 measurements at 23h15min and 23h45min after dosing at Day 181. Baseline FEV1 is considered the Day 1 average of pre-dose measurements.

5. Mean Change From Baseline in St. George's Respiratory Questionnaire [Baseline, 12 weeks]

   The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.

6. Mean Change From Baseline in St. George's Respiratory Questionnaire [Baseline, 26 weeks]

   The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.

7. Transition Dyspnea Index (TDI) Score [12 weeks]

   Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline.

8. Transition Dyspnea Index (TDI) Score [26 weeks]

   Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline.

9. Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication [Baseline, 26 weeks]

   Change from baseline in mean daily number of puffs of rescue medication (number of puffs taken in the previous 12 hours) over 26 weeks of treatment.

10. Mean Change From Baseline in Forced Vital Capacity (FVC) [Baseline, 26 weeks]

    Change from baseline in forced vital capacity following 26 weeks of treatment. Trough FVC is defined as the average of the pre-dose FVC measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FVC measurements at 23h15min and 23h45min after dosing at Day 181. Baseline is considered the Day 1 average of pre-dose measurements.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients who have signed Informed Consent Form prior to initiation of any study-related procedure.

• Male and female adults aged ≥ 40 years.

• Patients with moderate to severe airflow obstruction with stable COPD (Stage 2 or Stage 3) according to the 2014 GOLD Guidelines.

• Patients with a post-bronchodilator FEV1 ≥40 and < 80% of the predicted normal value, and post-bronchodilator FEV1/FVC < 0.70 at run-in Visit 101. (Post refers to 15 min after inhalation of 400 µg of salbutamol).

• Current or ex-smokers who have a smoking history of at least 10 pack years (e.g. 10 pack years = 1 pack /day x 10 years, or ½ pack/day x 20 years). An ex-smoker is defined as a patient who has not smoked for ≥ 6 months at screening.

• Patients who are on triple treatment at least for the last 6 months (LAMA +LABA/ICS).

Exclusion Criteria:

• Patients who have not achieved acceptable spirometry results at Visit 101 in accordance with ATS (American Thoracic Society)/ERS (European Respiratory Society) criteria for acceptability (one retest may be performed for patients that don't meet the acceptability criteria) .

• Patients who have had more than one COPD exacerbation that required treatment with antibiotics and/or oral corticosteroids and/or hospitalization in the last year prior to Visit 1.

• Patients who developed a COPD exacerbation of any severity either 6 weeks before the screening (Visit 1) or between screening (Visit 1) and treatment (Visit 201) will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1425BEN
2	Novartis Investigative Site	Lanus	Buenos Aires	Argentina	B8000XAV
3	Novartis Investigative Site	Mar del Plata	Buenos Aires	Argentina	7600
4	Novartis Investigative Site	Mar del Plata	Buenos Aires	Argentina	B7600FZN
5	Novartis Investigative Site	Quilmes	Buenos Aires	Argentina	B1878FNR
6	Novartis Investigative Site	Concepcion del Uruguay	Entre Rios	Argentina	3260
7	Novartis Investigative Site	San Miguel de Tucuman	Tucuman	Argentina	4000
8	Novartis Investigative Site	San Miguel de Tucuman	Tucuman	Argentina	T4000IFL
9	Novartis Investigative Site	Caba		Argentina
10	Novartis Investigative Site	Ciudad Autonoma de Bs As		Argentina	C1425FVH
11	Novartis Investigative Site	Mendoza		Argentina	M5500CBA
12	Novartis Investigative Site	Amstetten		Austria	3300
13	Novartis Investigative Site	Feldbach		Austria	8330
14	Novartis Investigative Site	Feldkirch		Austria	6800
15	Novartis Investigative Site	Grieskirchen		Austria	4710
16	Novartis Investigative Site	Thalheim bei Wels		Austria	4600
17	Novartis Investigative Site	Antwerpen		Belgium	2060
18	Novartis Investigative Site	Eghezee		Belgium	5310
19	Novartis Investigative Site	Erpent		Belgium	5100
20	Novartis Investigative Site	Hasselt		Belgium	3500
21	Novartis Investigative Site	Turnhout		Belgium	2300
22	Novartis Investigative Site	Gabrovo		Bulgaria	5300
23	Novartis Investigative Site	Ruse		Bulgaria	7000
24	Novartis Investigative Site	Stara Zagora		Bulgaria	6000
25	Novartis Investigative Site	Varna		Bulgaria	9000
26	Novartis Investigative Site	Vancouver	British Columbia	Canada	V5Z 4E1
27	Novartis Investigative Site	Moncton	New Brunswick	Canada	E1G 1A7
28	Novartis Investigative Site	Burlington	Ontario	Canada	L7N 3V2
29	Novartis Investigative Site	Toronto	Ontario	Canada	M5T 3A9
30	Novartis Investigative Site	Toronto	Ontario	Canada	M6H 3M2
31	Novartis Investigative Site	Gatineau	Quebec	Canada	J8Y 6S8
32	Novartis Investigative Site	St-Charles-Borromée	Quebec	Canada	J6E 2B4
33	Novartis Investigative Site	Victoriaville	Quebec	Canada	G6P 6P6
34	Novartis Investigative Site	Quebec		Canada	G1G 3Y8
35	Novartis Investigative Site	Quebec		Canada	G1W 4R4
36	Novartis Investigative Site	Quebec		Canada	G3K 2P8
37	Novartis Investigative Site	Rijeka	HRV	Croatia	51000
38	Novartis Investigative Site	Zagreb		Croatia	10000
39	Novartis Investigative Site	Melnik	Czech Republic	Czechia	267 01
40	Novartis Investigative Site	Benesov		Czechia	25601
41	Novartis Investigative Site	Brandys nad Labem		Czechia	25001
42	Novartis Investigative Site	Kyjov		Czechia	697 33
43	Novartis Investigative Site	Plzen		Czechia	32800
44	Novartis Investigative Site	Copenhagen NV		Denmark	2400
45	Novartis Investigative Site	Hvidovre		Denmark	2650
46	Novartis Investigative Site	Kohtla-Jarve		Estonia	30322
47	Novartis Investigative Site	Tallinn		Estonia	10138
48	Novartis Investigative Site	Tallinn		Estonia	13419
49	Novartis Investigative Site	Tartu		Estonia	51014
50	Novartis Investigative Site	Hannover	Niedersachsen	Germany	30159
51	Novartis Investigative Site	Peine	Niedersachsen	Germany	31224
52	Novartis Investigative Site	Warendorf	Nordrhein-Westfalen	Germany	48231
53	Novartis Investigative Site	Koblenz	Rheinland-Pfalz	Germany	56068
54	Novartis Investigative Site	Cottbus	Sachsen	Germany	03050
55	Novartis Investigative Site	Bad Woerishofen		Germany	86825
56	Novartis Investigative Site	Berlin		Germany	10117
57	Novartis Investigative Site	Berlin		Germany	10119
58	Novartis Investigative Site	Berlin		Germany	10367
59	Novartis Investigative Site	Berlin		Germany	10625
60	Novartis Investigative Site	Berlin		Germany	10717
61	Novartis Investigative Site	Berlin		Germany	10787
62	Novartis Investigative Site	Berlin		Germany	10969
63	Novartis Investigative Site	Berlin		Germany	12157
64	Novartis Investigative Site	Berlin		Germany	12159
65	Novartis Investigative Site	Berlin		Germany	12203
66	Novartis Investigative Site	Berlin		Germany	13156
67	Novartis Investigative Site	Bonn		Germany	53123
68	Novartis Investigative Site	Dresden		Germany	01069
69	Novartis Investigative Site	Erlangen		Germany	91052
70	Novartis Investigative Site	Frankfurt am Main		Germany	60389
71	Novartis Investigative Site	Frankfurt		Germany	60596
72	Novartis Investigative Site	Hagen		Germany	58089
73	Novartis Investigative Site	Hamburg		Germany	20354
74	Novartis Investigative Site	Hamburg		Germany	22143
75	Novartis Investigative Site	Leipzig		Germany	04103
76	Novartis Investigative Site	Leipzig		Germany	04109
77	Novartis Investigative Site	Leipzig		Germany	04207
78	Novartis Investigative Site	Leipzig		Germany	04357
79	Novartis Investigative Site	Lubeck		Germany	23552
80	Novartis Investigative Site	Magdeburg		Germany	39112
81	Novartis Investigative Site	Marburg		Germany	35037
82	Novartis Investigative Site	Menden		Germany	58706
83	Novartis Investigative Site	Neu Isenburg		Germany	63263
84	Novartis Investigative Site	Oschatz		Germany	04758
85	Novartis Investigative Site	Potsdam		Germany	14467
86	Novartis Investigative Site	Potsdam		Germany	14469
87	Novartis Investigative Site	Rudersdorf		Germany	15562
88	Novartis Investigative Site	Schleswig		Germany	24837
89	Novartis Investigative Site	Solingen		Germany	42651
90	Novartis Investigative Site	Wiesloch		Germany	69168
91	Novartis Investigative Site	Thessaloniki	GR	Greece	570 10
92	Novartis Investigative Site	Athens		Greece	106 76
93	Novartis Investigative Site	Heraklion - Crete		Greece	711 10
94	Novartis Investigative Site	Szazhalombatta	HUN	Hungary	2440
95	Novartis Investigative Site	Torokbalint	Pest	Hungary	2045
96	Novartis Investigative Site	Balassagyarmat		Hungary	2660
97	Novartis Investigative Site	Budapest		Hungary	1121
98	Novartis Investigative Site	Szekszard		Hungary	7100
99	Novartis Investigative Site	Balvi	LVA	Latvia	4501
100	Novartis Investigative Site	Jurmala	LVA	Latvia	LV-2015
101	Novartis Investigative Site	Liepaja	LV	Latvia	LV-3414
102	Novartis Investigative Site	Riga	LV	Latvia	1011
103	Novartis Investigative Site	Daugavpils		Latvia	LV-5401
104	Novartis Investigative Site	Kraslava		Latvia	5601
105	Novartis Investigative Site	Riga		Latvia	LV 1002
106	Novartis Investigative Site	Riga		Latvia	LV-1038
107	Novartis Investigative Site	Kaunas	LT	Lithuania	LT-50128
108	Novartis Investigative Site	Klaipeda		Lithuania	LT-92231
109	Novartis Investigative Site	Klaipeda		Lithuania	LT-92288
110	Novartis Investigative Site	Utena		Lithuania	LT-28151
111	Novartis Investigative Site	Vilnius		Lithuania	06122
112	Novartis Investigative Site	Vilnius		Lithuania	LT-08661
113	Novartis Investigative Site	Alkmaar		Netherlands	1814HB
114	Novartis Investigative Site	Breda		Netherlands	4819 EV
115	Novartis Investigative Site	Eindhoven		Netherlands	5623 EJ
116	Novartis Investigative Site	Zutphen		Netherlands	7207 AE
117	Novartis Investigative Site	Wroclaw	Dolnoslaskie	Poland	53-301
118	Novartis Investigative Site	Ostrowiec Swietokrzyskie	Swietokrzyskie	Poland	27-400
119	Novartis Investigative Site	Bialystok		Poland	15-044
120	Novartis Investigative Site	Bialystok		Poland	15-270
121	Novartis Investigative Site	Bialystok		Poland	15-351
122	Novartis Investigative Site	Bienkowka		Poland	34-212
123	Novartis Investigative Site	Krakow		Poland	31-023
124	Novartis Investigative Site	Lodz		Poland	90-153
125	Novartis Investigative Site	Lublin		Poland	20-045
126	Novartis Investigative Site	Ostrów Wielkopolski		Poland	63400
127	Novartis Investigative Site	Poznan		Poland	60-214
128	Novartis Investigative Site	Poznan		Poland	60-823
129	Novartis Investigative Site	Sopot		Poland	81-741
130	Novartis Investigative Site	Tarnow		Poland	33-100
131	Novartis Investigative Site	Wroclaw		Poland	50-434
132	Novartis Investigative Site	Bucuresti	District 1	Romania	10457
133	Novartis Investigative Site	Timisoara	Timis	Romania	300310
134	Novartis Investigative Site	Arad		Romania	310013
135	Novartis Investigative Site	Arad		Romania	310416
136	Novartis Investigative Site	Brasov		Romania	500086
137	Novartis Investigative Site	Bucharest		Romania	050159
138	Novartis Investigative Site	Bucharest		Romania	303330
139	Novartis Investigative Site	Bucuresti		Romania	012051
140	Novartis Investigative Site	Cluj Napoca		Romania	400371
141	Novartis Investigative Site	Deva		Romania	330162
142	Novartis Investigative Site	Belgrade		Serbia	11000
143	Novartis Investigative Site	Beograd		Serbia	11000
144	Novartis Investigative Site	Knez Selo		Serbia	18204
145	Novartis Investigative Site	Kragujevac		Serbia	34000
146	Novartis Investigative Site	Valjevo		Serbia	14000
147	Novartis Investigative Site	Humenne		Slovakia	06601
148	Novartis Investigative Site	Poprad		Slovakia	058 01
149	Novartis Investigative Site	Presov		Slovakia	080 01
150	Novartis Investigative Site	Spisska Nova Ves		Slovakia	052 01
151	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
152	Novartis Investigative Site	Centelles	Barcelona	Spain	08540
153	Novartis Investigative Site	Ponferrada	Castilla Y Leon	Spain	24400
154	Novartis Investigative Site	Canet de Mar	Cataluna	Spain	08360
155	Novartis Investigative Site	L´Hospitalet de Llobregat	Cataluña	Spain	08907
156	Novartis Investigative Site	Alzira	Comunidad Valenciana	Spain	46600
157	Novartis Investigative Site	San Juan de Alicante	Comunidad Valenciana	Spain	03550
158	Novartis Investigative Site	Merida	Extremadura	Spain	06800
159	Novartis Investigative Site	Leamington Spa	Warwickshire	United Kingdom	CV32 4RA
160	Novartis Investigative Site	Crawley	West Sussex	United Kingdom	RH10 7DX
161	Novartis Investigative Site	Bradford	West Yorkshire	United Kingdom	BD9 6RJ
162	Novartis Investigative Site	Bath		United Kingdom	BA2 3HT
163	Novartis Investigative Site	Birmingham		United Kingdom	B15 2TH
164	Novartis Investigative Site	Birmingham		United Kingdom	B9 5SS
165	Novartis Investigative Site	Coventry		United Kingdom	CV2 2DX
166	Novartis Investigative Site	Plymouth		United Kingdom	PL5 3JB
167	Novartis Investigative Site	Wolverhampton		United Kingdom	WV10 0QP

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Aug 18, 2017
• Study Protocol - Aug 9, 2017

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02603393
• Other Study ID Numbers: CQVA149A2316; 2015-000114-22
• First Posted: Nov 11, 2015
• Last Update Posted: Apr 29, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Novartis Pharmaceuticals: COPD, QVA149
• Additional relevant MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Fluticasone; Tiotropium Bromide; Salmeterol Xinafoate

Study Results

Participant Flow

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Period Title: Overall Study
STARTED	527	526
COMPLETED	456	472
NOT COMPLETED	71	54

Baseline Characteristics

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone	Total
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)	Total of all reporting groups
Overall Participants	527	526	1053
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.4 (7.99)	65.2 (7.62)	65.3 (7.80)
Sex: Female, Male (Count of Participants)
Female	149 28.3%	161 30.6%	310 29.4%
Male	378 71.7%	365 69.4%	743 70.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	3 0.6%	3 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	526 99.8%	523 99.4%	1049 99.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.2%	0 0%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in Post-dose Trough FEV1
Description	Mean change from baseline in post-dose trough forced expiratory volume in 1 second (FEV1) following 26 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values measured at 23 hr 15 min and 23 hr 45 min after the morning dose taken at site on Day 181. Baseline FEV1 is defined as the average of the pre-dose FEV1 measured at -45 min and -15 min at Day 1.
Time Frame	Baseline, 26 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Least Squares Mean (Standard Error) [Liters]	-0.029 (0.0119)	-0.003 (0.0115)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority will be demonstrated if the 95% confidence interval of the treatment difference lies entirely to the right of (higher than) -50 mL.
Statistical Test of Hypothesis	p-Value	0.0404
	Comments	1 sided
	Method	Mixed Model for Repeated Measures Analys
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.026
	Confidence Interval	() 95%; -0.053 to 0.001
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Annualized Rate of Moderate or Severe COPD Exacerbations
Description	Moderate or severe COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Number (95% Confidence Interval) [COPD exacerbations/year]	0.52	0.48

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5802
	Comments	2 sided
	Method	Generalized Linear Model Analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio of rates
	Estimated Value	1.08
	Confidence Interval	() 95%; 0.83 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Annualized Rate of COPD Exacerbations Requiring Treatment With Systemic Glucocorticosteroids and/or Antibiotics, Moderate Exacerbations Only
Description	COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Number (95% Confidence Interval) [COPD Exacerbations/year]	0.47	0.44

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5651
	Comments	2-sided
	Method	Generalized Linear Model Analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio of rates
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Annualized Rate of COPD Exacerbations Requiring Hospitalisation
Description	COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Number (95% Confidence Interval) [COPD Exacerbations/year]	0.001	0.001

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9665
	Comments	2-sided
	Method	Generalized Linear Model Analysis
	Comments
Method of Estimation	Estimation Parameter	Ratio of rates
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.44 to 2.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Change From Baseline in Pre-dose Trough FEV1
Description	Trough FEV1 is defined as the average of the pre-dose FEV1 measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FEV1 measurements at 23h15min and 23h45min after dosing at Day 181. Baseline FEV1 is considered the Day 1 average of pre-dose measurements.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Least Squares Mean (Standard Error) [Liters]	-0.029 (0.0119)	-0.003 (0.0115)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0573
	Comments	2-Sided
	Method	Mixed Model for Repeated Measures Analys
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.026
	Confidence Interval	() 95%; -0.053 to 0.001
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Change From Baseline in St. George's Respiratory Questionnaire
Description	The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Least Squares Mean (Standard Error) [Score on a scale]	-0.7 (0.53)	-2.5 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments	2-Sided
	Method	Mixed Model for Repeated Measures Analys
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8
	Confidence Interval	() 95%; 0.7 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Mean Change From Baseline in St. George's Respiratory Questionnaire
Description	The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.
Time Frame	Baseline, 26 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Least Squares Mean (Standard Error) [Score on a scale]	-1.0 (0.54)	-2.5 (0.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0221
	Comments	2-Sided
	Method	Mixed Model for Repeated measures Analys
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 0.2 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Transition Dyspnea Index (TDI) Score
Description	Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Least Squares Mean (Standard Error) [Score on a scale]	1.177 (0.1558)	1.418 (0.1508)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1724
	Comments
	Method	Mixed Model for Repeated Measures Analys
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.241
	Confidence Interval	() 95%; -0.587 to 0.105
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Transition Dyspnea Index (TDI) Score
Description	Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Least Squares Mean (Standard Error) [Score on a scale]	1.382 (0.1567)	1.671 (0.1519)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1055
	Comments	2-Sided
	Method	Mixed Model for Repated Measures Analysi
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.288
	Confidence Interval	() 95%; -0.638 to 0.061
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication
Description	Change from baseline in mean daily number of puffs of rescue medication (number of puffs taken in the previous 12 hours) over 26 weeks of treatment.
Time Frame	Baseline, 26 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Least Squares Mean (Standard Error) [Number of puffs per day]	-0.307 (0.1006)	-0.484 (0.0983)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0641
	Comments	2-Sided
	Method	Linear Mixed Model Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.177
	Confidence Interval	() 95%; -0.010 to 0.365
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Mean Change From Baseline in Forced Vital Capacity (FVC)
Description	Change from baseline in forced vital capacity following 26 weeks of treatment. Trough FVC is defined as the average of the pre-dose FVC measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FVC measurements at 23h15min and 23h45min after dosing at Day 181. Baseline is considered the Day 1 average of pre-dose measurements.
Time Frame	Baseline, 26 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.

Arm/Group Title	QVA149	Tiotropium + Salmeterol/Fluticasone
Arm/Group Description	110/50 μg capsules o.d. for inhalation	tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
Measure Participants	527	526
Least Squares Mean (Standard Error) [Liters]	-0.030 (0.0192)	-0.048 (0.0186)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QVA149, Tiotropium + Salmeterol/Fluticasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4107
	Comments	2-Sided
	Method	Mixed Model for Repeated Measures Analys
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95%; -0.025 to 0.061
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
Arm/Group Title	QVA149		Tio+Salm/Flut
Arm/Group Description	110/50 μg capsules o.d. for inhalation		tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
All Cause Mortality
	QVA149		Tio+Salm/Flut
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/527 (0.8%)		5/526 (1%)
Serious Adverse Events
	QVA149		Tio+Salm/Flut
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/527 (6.1%)		34/526 (6.5%)
Blood and lymphatic system disorders
Haemorrhagic anaemia	0/527 (0%)		1/526 (0.2%)
Cardiac disorders
Acute myocardial infarction	2/527 (0.4%)		0/526 (0%)
Angina unstable	1/527 (0.2%)		0/526 (0%)
Atrial fibrillation	1/527 (0.2%)		1/526 (0.2%)
Cardiac arrest	0/527 (0%)		1/526 (0.2%)
Cardiac failure	1/527 (0.2%)		0/526 (0%)
Cardiac failure acute	0/527 (0%)		1/526 (0.2%)
Cardiac tamponade	1/527 (0.2%)		0/526 (0%)
Myocardial infarction	2/527 (0.4%)		2/526 (0.4%)
Myocardial ischaemia	1/527 (0.2%)		0/526 (0%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	1/527 (0.2%)		0/526 (0%)
Gastrointestinal disorders
Anal fissure	0/527 (0%)		1/526 (0.2%)
Duodenal ulcer	0/527 (0%)		1/526 (0.2%)
Haemorrhoids	0/527 (0%)		1/526 (0.2%)
Inguinal hernia	1/527 (0.2%)		0/526 (0%)
General disorders
Non-cardiac chest pain	1/527 (0.2%)		0/526 (0%)
Pyrexia	0/527 (0%)		1/526 (0.2%)
Hepatobiliary disorders
Cholelithiasis	1/527 (0.2%)		0/526 (0%)
Drug-induced liver injury	1/527 (0.2%)		0/526 (0%)
Infections and infestations
Appendicitis	1/527 (0.2%)		0/526 (0%)
Lower respiratory tract infection	0/527 (0%)		1/526 (0.2%)
Ophthalmic herpes zoster	0/527 (0%)		1/526 (0.2%)
Pneumonia	4/527 (0.8%)		3/526 (0.6%)
Soft tissue infection	1/527 (0.2%)		0/526 (0%)
Upper respiratory tract infection	1/527 (0.2%)		0/526 (0%)
Injury, poisoning and procedural complications
Femoral neck fracture	1/527 (0.2%)		0/526 (0%)
Multiple injuries	1/527 (0.2%)		0/526 (0%)
Musculoskeletal and connective tissue disorders
Systemic lupus erythematosus	0/527 (0%)		1/526 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm	0/527 (0%)		1/526 (0.2%)
Cholesteatoma	0/527 (0%)		1/526 (0.2%)
Colon cancer	1/527 (0.2%)		0/526 (0%)
Colon neoplasm	1/527 (0.2%)		0/526 (0%)
Lung neoplasm	0/527 (0%)		1/526 (0.2%)
Lung neoplasm malignant	0/527 (0%)		2/526 (0.4%)
Metastases to central nervous system	0/527 (0%)		1/526 (0.2%)
Pituitary tumour benign	1/527 (0.2%)		0/526 (0%)
Prostate cancer	0/527 (0%)		1/526 (0.2%)
Renal neoplasm	0/527 (0%)		1/526 (0.2%)
Nervous system disorders
Cerebral haemorrhage	1/527 (0.2%)		0/526 (0%)
Ischaemic stroke	0/527 (0%)		1/526 (0.2%)
Syncope	0/527 (0%)		1/526 (0.2%)
Renal and urinary disorders
Renal failure	1/527 (0.2%)		0/526 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/527 (0.2%)		0/526 (0%)
Chronic obstructive pulmonary disease	12/527 (2.3%)		13/526 (2.5%)
Dyspnoea	0/527 (0%)		1/526 (0.2%)
Hypoxia	1/527 (0.2%)		0/526 (0%)
Pneumothorax	0/527 (0%)		1/526 (0.2%)
Pulmonary embolism	0/527 (0%)		1/526 (0.2%)
Skin and subcutaneous tissue disorders
Erythema multiforme	1/527 (0.2%)		0/526 (0%)
Vascular disorders
Aortic aneurysm	0/527 (0%)		1/526 (0.2%)
Aortic aneurysm rupture	0/527 (0%)		1/526 (0.2%)
Aortic dissection	0/527 (0%)		1/526 (0.2%)
Deep vein thrombosis	0/527 (0%)		1/526 (0.2%)
Orthostatic hypotension	1/527 (0.2%)		0/526 (0%)
Peripheral arterial occlusive disease	0/527 (0%)		1/526 (0.2%)
Peripheral artery occlusion	0/527 (0%)		1/526 (0.2%)
Peripheral artery stenosis	1/527 (0.2%)		0/526 (0%)
Other (Not Including Serious) Adverse Events
	QVA149		Tio+Salm/Flut
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	398/527 (75.5%)		392/526 (74.5%)
Cardiac disorders
Atrioventricular block first degree	1/527 (0.2%)		6/526 (1.1%)
Gastrointestinal disorders
Diarrhoea	3/527 (0.6%)		6/526 (1.1%)
General disorders
Non-cardiac chest pain	3/527 (0.6%)		6/526 (1.1%)
Oedema peripheral	7/527 (1.3%)		3/526 (0.6%)
Infections and infestations
Bronchitis	13/527 (2.5%)		5/526 (1%)
Influenza	6/527 (1.1%)		6/526 (1.1%)
Oral candidiasis	12/527 (2.3%)		18/526 (3.4%)
Oropharyngeal candidiasis	6/527 (1.1%)		7/526 (1.3%)
Pneumonia	2/527 (0.4%)		6/526 (1.1%)
Respiratory tract infection viral	1/527 (0.2%)		6/526 (1.1%)
Upper respiratory tract infection bacterial	2/527 (0.4%)		6/526 (1.1%)
Urinary tract infection	7/527 (1.3%)		1/526 (0.2%)
Viral upper respiratory tract infection	57/527 (10.8%)		59/526 (11.2%)
Investigations
Blood creatinine increased	26/527 (4.9%)		24/526 (4.6%)
Musculoskeletal and connective tissue disorders
Back pain	8/527 (1.5%)		9/526 (1.7%)
Pain in extremity	2/527 (0.4%)		6/526 (1.1%)
Nervous system disorders
Headache	7/527 (1.3%)		13/526 (2.5%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	370/527 (70.2%)		353/526 (67.1%)
Cough	24/527 (4.6%)		15/526 (2.9%)
Oropharyngeal pain	7/527 (1.3%)		7/526 (1.3%)
Vascular disorders
Hypertension	7/527 (1.3%)		10/526 (1.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety