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

Chronic Obstructive Pulmonary Disease Clinical Trial

— SPARK  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01120691
• Other study ID #: CQVA149A2304
• Secondary ID: 2009-013256-69
• Status: Completed
• Phase: Phase 3
• First received: May 5, 2010
• Last updated: October 29, 2013
• Start date: April 2010
• Est. completion date: July 2012

Study information

• Verified date: October 2013
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustralia: Department of Health and Ageing Therapeutic Goods AdministrationBelgium: Federal Agency for Medicinal Products and Health ProductsBrazil: National Health Surveillance AgencyCanada: Health CanadaChile: Comisión Nacional de Investigación Científica y TecnológicaColombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y AlimentosCzech Republic: State Institute for Drug ControlDenmark: Danish Medicines AgencyEstonia: The State Agency of MedicineFinland: Finnish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesGreece: National Organization of MedicinesGuatemala: Ministry of Public Health and Social AssistanceHungary: National Institute of PharmacyIndia: Drugs Controller General of IndiaIreland: Irish Medicines BoardIsrael: Ministry of HealthItaly: The Italian Medicines AgencyKorea: Food and Drug AdministrationMalaysia: Ministry of HealthMexico: Ministry of HealthNetherlands: Medicines Evaluation Board (MEB)New Zealand: Food Safety AuthorityNorway: Norwegian Medicines AgencyPeru: Ministry of HealthPhilippines: Bureau of Food and DrugsPoland: Ministry of HealthRomania: National Medicines AgencyRussia: Ministry of Health of the Russian FederationSingapore: Health Sciences AuthoritySouth Africa: Department of HealthSpain: Spanish Agency of MedicinesThailand: Food and Drug AdministrationTurkey: Ministry of HealthUkraine: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2224
• Est. completion date: July 2012
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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

7. 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.

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

9. 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

10. 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 2.

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

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

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

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

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

16. 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.

17. 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.

18. 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).

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

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

21. Patients taking other prohibited medications

22. 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).

23. Patients unable to use an electronic patient diary.

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

25. 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.

26. 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.

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

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).
• 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).
• 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
As needed throughout the study

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos aires
Argentina	Novartis Investigative Site	Buenos aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Capital Federal	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	La Plata	Buenos Aires
Argentina	Novartis Investigative Site	Mar del Plata	Buenos Aires
Argentina	Novartis Investigative Site	Mar del Plata	Buenos Aires
Argentina	Novartis Investigative Site	Mendoza
Argentina	Novartis Investigative Site	Mendoza
Argentina	Novartis Investigative Site	Paraná Entre Ríos
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	San Isidro	Buenos Aires
Argentina	Novartis Investigative Site	San Miguel de Tucuman	Tucuman
Argentina	Novartis Investigative Site	San Miguel de Tucuman	Tucuman
Argentina	Novartis Investigative Site	Santa Fe
Austria	Novartis Investigative Site	Feldbach
Austria	Novartis Investigative Site	Grieskirchen
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Thalheim bei Wels
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	Joliette	Quebec
Canada	Novartis Investigative Site	Laval	Quebec
Canada	Novartis Investigative Site	Mississauga	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Québec	Quebec
Canada	Novartis Investigative Site	St-Romuald	Quebec
Canada	Novartis Investigative Site	Trois-Rivières	Quebec
Colombia	Novartis Investigative Site	Armenia
Colombia	Novartis Investigative Site	Barranquilla
Colombia	Novartis Investigative Site	Bogota	Cundinamarca
Colombia	Novartis Investigative Site	Bogotá
Colombia	Novartis Investigative Site	Medellin
Colombia	Novartis Investigative Site	Medellín
Czech Republic	Novartis Investigative Site	Cesky Krumlov
Czech Republic	Novartis Investigative Site	Cvikov
Czech Republic	Novartis Investigative Site	Havlickuv Brod
Czech Republic	Novartis Investigative Site	Jaromer
Czech Republic	Novartis Investigative Site	Karlovy Vary
Czech Republic	Novartis Investigative Site	Kromeriz
Czech Republic	Novartis Investigative Site	Kutna Hora
Czech Republic	Novartis Investigative Site	Kyjov
Czech Republic	Novartis Investigative Site	Liberec
Czech Republic	Novartis Investigative Site	Pardubice
Czech Republic	Novartis Investigative Site	Prague 4
Czech Republic	Novartis Investigative Site	Praha 10
Czech Republic	Novartis Investigative Site	Praha 9
Czech Republic	Novartis Investigative Site	Rokycany
Czech Republic	Novartis Investigative Site	Strakonice
Czech Republic	Novartis Investigative Site	Teplice
Czech Republic	Novartis Investigative Site	Zatec
Czech Republic	Novartis Investigative Site	Znojmo
Denmark	Novartis Investigative Site	Aalborg
Denmark	Novartis Investigative Site	Copenhagen NV
Denmark	Novartis Investigative Site	Hellerup
Denmark	Novartis Investigative Site	Hvidovre
Denmark	Novartis Investigative Site	Roskilde
Denmark	Novartis Investigative Site	Silkeborg
Denmark	Novartis Investigative Site	Sønderborg
Estonia	Novartis Investigative Site	Tallinn
Estonia	Novartis Investigative Site	Tallinn
Estonia	Novartis Investigative Site	Tartu
Finland	Novartis Investigative Site	Helsinki
Finland	Novartis Investigative Site	Jyvaskyla
Finland	Novartis Investigative Site	Turku
France	Novartis Investigative Site	Bayonne Cedex
France	Novartis Investigative Site	Beuvry
France	Novartis Investigative Site	Ferolles-Attily
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Paris
Germany	Novartis Investigative Site	Aschaffenburg
Germany	Novartis Investigative Site	Bamberg
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bochum
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Dueren
Germany	Novartis Investigative Site	Duisburg
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Freudenberg
Germany	Novartis Investigative Site	Fulda
Germany	Novartis Investigative Site	Gelsenkirchen
Germany	Novartis Investigative Site	Gummersbach
Germany	Novartis Investigative Site	Hagen
Germany	Novartis Investigative Site	Halle
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Homburg
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Koblenz	NRW
Germany	Novartis Investigative Site	Langenfeld
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Lübeck
Germany	Novartis Investigative Site	Marburg
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Nuernberg
Germany	Novartis Investigative Site	Oranienburg
Germany	Novartis Investigative Site	Potsdam
Germany	Novartis Investigative Site	Radebeul
Germany	Novartis Investigative Site	Reinfeld
Germany	Novartis Investigative Site	Saarbruecken
Germany	Novartis Investigative Site	Schwerte
Germany	Novartis Investigative Site	Schwetzingen
Germany	Novartis Investigative Site	Solingen
Germany	Novartis Investigative Site	Stade
Germany	Novartis Investigative Site	Teterow
Germany	Novartis Investigative Site	Wissen
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens - GR
Greece	Novartis Investigative Site	Larissa
Greece	Novartis Investigative Site	Thessaloniki
Greece	Novartis Investigative Site	Thessaloniki
Hungary	Novartis Investigative Site	Baja
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Cegled
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Deszk
Hungary	Novartis Investigative Site	Eger
Hungary	Novartis Investigative Site	Makó
Hungary	Novartis Investigative Site	Mosonmagyarovar
Hungary	Novartis Investigative Site	Sopron
Hungary	Novartis Investigative Site	Szarvas
Hungary	Novartis Investigative Site	Szekszard
India	Novartis Investigative Site	Coimbatore	Tamil Nadu
India	Novartis Investigative Site	Coimbatore	Tamil Nadu
India	Novartis Investigative Site	Coimbatore	Tamil Nadu
India	Novartis Investigative Site	Hyderabad	A.p.
India	Novartis Investigative Site	Hyderbabd	Andhra Pradesh
India	Novartis Investigative Site	Jaipur	Rajasthan
India	Novartis Investigative Site	Mysore	Karnataka
India	Novartis Investigative Site	Nagpur - Maharastra
India	Novartis Investigative Site	Nashik	Maharashtra
India	Novartis Investigative Site	New Delhi	Delhi
India	Novartis Investigative Site	Panjim
India	Novartis Investigative Site	Pune	Maharashtra
India	Novartis Investigative Site	Secunderabad
India	Novartis Investigative Site	Trivandrum
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Dublin 15
Ireland	Novartis Investigative Site	Dublin 24
Ireland	Novartis Investigative Site	Dublin 4
Ireland	Novartis Investigative Site	Dublin 9
Israel	Novartis Investigative Site	Ashkelon
Israel	Novartis Investigative Site	Beer-Sheva
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Kfar-Sava
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Rehovot
Israel	Novartis Investigative Site	Tel-Aviv
Italy	Novartis Investigative Site	Abano Terme	PD
Italy	Novartis Investigative Site	Arenzano	GE
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Foggia	FG
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Montecchio Maggiore	VI
Italy	Novartis Investigative Site	Osimo	AN
Italy	Novartis Investigative Site	Pavia	PV
Italy	Novartis Investigative Site	Perugia	PG
Italy	Novartis Investigative Site	Pietra Ligure	SV
Italy	Novartis Investigative Site	Pisa
Italy	Novartis Investigative Site	Pisa	PI
Italy	Novartis Investigative Site	Riccione	RN
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Siena	SI
Mexico	Novartis Investigative Site	Guadalajara	Jalisco
Mexico	Novartis Investigative Site	Mexico	Distrito Federal
Mexico	Novartis Investigative Site	Mexico	Distrito Federal
Mexico	Novartis Investigative Site	Monterrey	Nuevo León
Mexico	Novartis Investigative Site	San Luis Potosí
Mexico	Novartis Investigative Site	Zapopan	Jalisco
Netherlands	Novartis Investigative Site	Almelo
Netherlands	Novartis Investigative Site	Breda
Netherlands	Novartis Investigative Site	Dordrecht
Netherlands	Novartis Investigative Site	Drachten
Netherlands	Novartis Investigative Site	Enschede
Netherlands	Novartis Investigative Site	Harderwijk
Netherlands	Novartis Investigative Site	Helmond
Netherlands	Novartis Investigative Site	Hoofddorp
Netherlands	Novartis Investigative Site	Hoorn
Netherlands	Novartis Investigative Site	Leeuwarden
Netherlands	Novartis Investigative Site	Roermond
Netherlands	Novartis Investigative Site	Veldhoven
Netherlands	Novartis Investigative Site	Voorburg
Peru	Novartis Investigative Site	Cercado de Lima	Lima
Peru	Novartis Investigative Site	San Borja	Lima
Peru	Novartis Investigative Site	San Isidro	Lima
Peru	Novartis Investigative Site	San Martin de Porres	Lima
Peru	Novartis Investigative Site	San Miguel	Lima
Peru	Novartis Investigative Site	Santiago de Surco	Lima
Philippines	Novartis Investigative Site	Bulacan
Philippines	Novartis Investigative Site	Las Pinas
Philippines	Novartis Investigative Site	Manila
Philippines	Novartis Investigative Site	Quezon City
Philippines	Novartis Investigative Site	Quezon City	Metro Manila
Poland	Novartis Investigative Site	Bialystok
Poland	Novartis Investigative Site	Katowice
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Lublin
Poland	Novartis Investigative Site	Mrozy
Poland	Novartis Investigative Site	Warszawa
Puerto Rico	Novartis Investigative Site	Humacao
Russian Federation	Novartis Investigative Site	Barnaul
Russian Federation	Novartis Investigative Site	Chelyabinsk
Russian Federation	Novartis Investigative Site	Ekaterinburg
Russian Federation	Novartis Investigative Site	Kazan	Tatarstan Republic
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Rostov-on-Don
Russian Federation	Novartis Investigative Site	Ryazan
Russian Federation	Novartis Investigative Site	S.-Petersburg
Russian Federation	Novartis Investigative Site	Samara
Russian Federation	Novartis Investigative Site	Sankt-Peterburg
Russian Federation	Novartis Investigative Site	St-Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St.Petersburg
Russian Federation	Novartis Investigative Site	Yaroslavl
Slovakia	Novartis Investigative Site	Banska Bystrica	Slovak Republic
Slovakia	Novartis Investigative Site	Bojnice	Slovak Republic
Slovakia	Novartis Investigative Site	Humenne	Slovak Republic
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Kralovsky Chlmec
Slovakia	Novartis Investigative Site	Martin
Slovakia	Novartis Investigative Site	Partizanske	Slovak Republic
Slovakia	Novartis Investigative Site	Presov
Slovakia	Novartis Investigative Site	Trnava
South Africa	Novartis Investigative Site	Durban
South Africa	Novartis Investigative Site	Newtown, Johannesburg
South Africa	Novartis Investigative Site	Pretoria
South Africa	Novartis Investigative Site	Pretoria
South Africa	Novartis Investigative Site	Pretoria
Spain	Novartis Investigative Site	Alicante
Spain	Novartis Investigative Site	L'Hospitalet de Llobregat	Cataluña
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
United Kingdom	Novartis Investigative Site	Blackpool
United Kingdom	Novartis Investigative Site	Bradford
United Kingdom	Novartis Investigative Site	Bristol
United Kingdom	Novartis Investigative Site	Chertsey	Surrey
United Kingdom	Novartis Investigative Site	Coventry
United Kingdom	Novartis Investigative Site	Gillingham
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Hereford
United Kingdom	Novartis Investigative Site	Huntingdon
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Merseyside
United Kingdom	Novartis Investigative Site	Portsmouth
United Kingdom	Novartis Investigative Site	Sneinton	Nottingham
United Kingdom	Novartis Investigative Site	Stockton	Cleveland
United Kingdom	Novartis Investigative Site	Taunton	Somerset
United Kingdom	Novartis Investigative Site	Telford
United Kingdom	Novartis Investigative Site	Wolverhampton
United States	Novartis Investigative Site	Bangor	Maine
United States	Novartis Investigative Site	Beaver	Pennsylvania
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Charleston	South Carolina
United States	Novartis Investigative Site	Charlotte	North Carolina
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Couer D'Alene	Idaho
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Erie	Pennsylvania
United States	Novartis Investigative Site	Fairhope	Alabama
United States	Novartis Investigative Site	Florence	Alabama
United States	Novartis Investigative Site	Florence	Kentucky
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Fridley	Minnesota
United States	Novartis Investigative Site	Ft. Worth	Texas
United States	Novartis Investigative Site	Fullerton	California
United States	Novartis Investigative Site	Gainesville	Florida
United States	Novartis Investigative Site	Great Neck	New York
United States	Novartis Investigative Site	Green Bay	Wisconsin
United States	Novartis Investigative Site	Henderson	Nevada
United States	Novartis Investigative Site	Homewood	Alabama
United States	Novartis Investigative Site	Jasper	Alabama
United States	Novartis Investigative Site	Las Vegas	Nevada
United States	Novartis Investigative Site	Louisville	Kentucky
United States	Novartis Investigative Site	Massapequa	New York
United States	Novartis Investigative Site	Medford	Oregon
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Missoula	Montana
United States	Novartis Investigative Site	Normal	Illinois
United States	Novartis Investigative Site	Opelousas	Louisiana
United States	Novartis Investigative Site	Ozark	Missouri
United States	Novartis Investigative Site	Palo Alto	California
United States	Novartis Investigative Site	Papillion	Nebraska
United States	Novartis Investigative Site	Pensacola	Florida
United States	Novartis Investigative Site	Pine Bluff	Arkansas
United States	Novartis Investigative Site	Pittsburgh	Pennsylvania
United States	Novartis Investigative Site	Portland	Oregon
United States	Novartis Investigative Site	Raleigh	North Carolina
United States	Novartis Investigative Site	Reno	Nevada
United States	Novartis Investigative Site	River Forest	Illinois
United States	Novartis Investigative Site	Riverside	California
United States	Novartis Investigative Site	Salem	Virginia
United States	Novartis Investigative Site	Salt Lake City	Utah
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	Spartanburg	South Carolina
United States	Novartis Investigative Site	St. Charles	Missouri
United States	Novartis Investigative Site	St. Louis	Missouri
United States	Novartis Investigative Site	Stockton	California
United States	Novartis Investigative Site	Tacoma	Washington
United States	Novartis Investigative Site	Wilmington	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Canada,  Colombia,  Czech Republic,  Denmark,  Estonia,  Finland,  France,  Germany,  Greece,  Hungary,  India,  Ireland,  Israel,  Italy,  Mexico,  Netherlands,  Peru,  Philippines,  Poland,  Puerto Rico,  Russian Federation,  Slovakia,  South Africa,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period.	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	64 weeks	No
Secondary	Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and Open-label Tiotropium Treatment Arms During the Treatment Period.	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	76 weeks	No
Secondary	Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period	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	64 weeks	No
Secondary	Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics	Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years	64 weeks	No
Secondary	Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics	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.	64 weeks	No
Secondary	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.	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.	64 weeks	No
Secondary	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	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.	64 weeks	No
Secondary	Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points	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	26, 52, 64, 76 weeks	No
Secondary	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	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.	4, 12, 26, 38, 52 and 64 weeks	No
Secondary	Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium	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	4, 12, 26, 38, 52 and 64 weeks	No
Secondary	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	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.	Baseline (14 day run-in), 64 weeks	No
Secondary	Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period	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.	Baseline (14 day run-in), 64 weeks	No
Secondary	St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment	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.	12, 26, 38, 52 and 64 weeks	No