A Study to Assess the Efficacy, Safety and Tolerability of Once-daily (q.d.) QVA149 in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease (COPD) Clinical Trial

— SHINE  

Official title:

A 26-week Treatment Multi-center, Randomized, Double-blind, Parallel-group, Placebo and Active Controlled (Open Label) Study to Assess the Efficacy, Safety and Tolerability of QVA149 (110/50 μg q.d.) in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01202188
• Other study ID #: CQVA149A2303
• Secondary ID: 2009-017772-25
• Status: Completed
• Phase: Phase 3
• First received: September 13, 2010
• Last updated: August 26, 2013
• Start date: September 2010
• Est. completion date: March 2012

Study information

• Verified date: August 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 MedicaArgentina: Human Research Bioethics CommitteeArgentina: Ministry of HealthAustralia: Department of Health and Ageing Therapeutic Goods AdministrationAustralia: Human Research Ethics CommitteeAustralia: National Health and Medical Research CouncilBulgaria: Bulgarian Drug AgencyBulgaria: Ministry of HealthCanada: Health CanadaChina: Food and Drug AdministrationFinland: Ethics CommitteeFinland: Ministry of Social Affairs and HealthFinland: Finnish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: Direction Générale de la SantéFrance: French Data Protection AuthorityFrance: Haute Autorité de Santé Transparency CommissionFrance: Institutional Ethical CommitteeFrance: Ministry of HealthFrance: National Consultative Ethics Committee for Health and Life SciencesGermany: Ethics CommissionGermany: Federal Institute for Drugs and Medical DevicesGermany: Federal Ministry of Education and ResearchGermany: Federal Ministry of Food, Agriculture and Consumer ProtectionGermany: German Institute of Medical Documentation and InformationGermany: Ministry of HealthGermany: Paul-Ehrlich-InstitutGuatemala: MSPAS - Ministerio de Salud Pública y Asistencia Social: Programa Nacional de FarmacovigilanciaHungary: Research Ethics Medical CommitteeHungary: National Institute of PharmacyIndia: Central Drugs Standard Control OrganizationIndia: Department of Atomic EnergyIndia: Drugs Controller General of IndiaIndia: Indian Council of Medical ResearchIndia: Institutional Review BoardIndia: Ministry of HealthIndia: Ministry of Science and TechnologyIndia: Science and Engineering Research CouncilJapan: Ministry of Health, Labor and WelfareMexico: Ethics CommitteeMexico: Federal Commission for Protection Against Health RisksMexico: Federal Commission for Sanitary Risks ProtectionMexico: Ministry of HealthMexico: National Council of Science and TechnologyMexico: National Institute of Public Health, Health SecretariatNetherlands: Independent Ethics CommitteeNetherlands: Dutch Health Care InspectorateNetherlands: Medical Ethics Review Committee (METC)Netherlands: Medicines Evaluation Board (MEB)Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)Panama: Ministry of HealthPhilippines: Department of HealthPhilippines: Bureau of Food and DrugsPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsPoland: Ministry of HealthPoland: Ministry of Science and Higher Education
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to provide pivotal efficacy and safety data for QVA149 in patients with moderate to severe COPD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2144
• Est. completion date: March 2012
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Male or female adults aged =40 yrs

• Smoking history of at least 10 pack years

• Diagnosis of COPD (moderate-to-severe as classified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2008)

• Post-bronchodilator FEV1 < 80% and = 30% of the predicted normal value and post-bronchodilator FEV1/FVC (forced vital capacity) <70%

Exclusion Criteria:

• Patients who have had a respiratory tract infection within 4 weeks prior to Visit 1

• Patients with concomitant pulmonary disease

• Patients with a history of asthma

• Any patient with lung cancer or a history of lung cancer

• Patients with a history of certain cardiovascular co-morbid conditions

• Patients with a known history and diagnosis of alpha-1 antitrypsin deficiency

• Patients in the active phase of a supervised pulmonary rehabilitation program

• Patients contraindicated for inhaled anticholinergic agents and ß2 agonists

• Other protocol-defined inclusion/exclusion criteria may apply

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 (COPD)
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• indacaterol and glycopyrronium (QVA149)
Capsules for inhalation delivered via SDDPI.
• glycopyrronium (NVA237)
Capsules for inhalation delivered via SDDPI.
• indacaterol (QAB149)
Capsules for inhalation delivered via SDDPI.
• tiotropium
Capsules for inhalation delivered via HandiHaler® device.
• placebo
Placebo to match capsules for inhalation delivered via SDDPI.

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Daw Park
Australia	Novartis Investigative Site	Glebe
Australia	Novartis Investigative Site	Kogarah
Australia	Novartis Investigative Site	Nedlands
Australia	Novartis Investigative site	New lambton
Bulgaria	Novartis Investigative Site	Pleven
Bulgaria	Novartis Investigative Site	Russe
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Stara Zagora
Bulgaria	Novartis Investigative Site	Varna
Canada	Novartis Investigative Site	Burlington	Ontario
Canada	Novartis Investigative Site	Courtice	Ontario
Canada	Novartis Investigative Site	Mississuaga	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
France	Novartis Investigative Site	Beuvry
France	Novartis Investigative Site	Bourges
France	Novartis Investigative Site	Ferolles-Attily
France	Novartis Investigative Site	Rennes
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Erfurt
Germany	Novartis Investigative Site	Geesthacht
Germany	Novartis Investigative Site	Hanover
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Minden
Germany	Novartis Investigative Site	Witten
Guatemala	Novartis Investigative Site	Guatemala City
Hungary	Novartis INvestigative Site	Balassagyarmat
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Gyor
Hungary	Novartis Investigative Site	Komarom
Hungary	Novartis Investigative Site	Nyiregyhaza
Hungary	Novartis Investigative Site	Tatabanya
Japan	Novartis Investigative Site	Asahikawa
Japan	Novartis Investigative Site	Chiba
Japan	Novartis Investigative Site	Chuo-ku
Japan	Novartis Investigative Site	Fukuoka
Japan	Novartis Investigative Site	Hachioji
Japan	Novartis Investigative Site	Hamakita
Japan	Novartis Investigative Site	Himeji
Japan	Novartis Investigative Site	Hiroshima
Japan	Novartis Investigative Site	Hitachi
Japan	Novartis Investigative Site	Itabashi
Japan	Novartis Inverstigative Site	Iwata
Japan	Novartis Investigative Site	Kamogawa
Japan	Novartis Investigative Site	Kishiwada
Japan	Novartis Investigative Site	Kiyose
Japan	Novartis Investigative Site	Kurashiki
Japan	Novartis Investigative Site	Matsusaka
Japan	Novartis Investigative Site	Matumoto
Japan	Novartis Investigative Site	Minato-ku
Japan	Novartis Investigative Site	Moriya
Japan	Novartis Investigative Site	Nagaoka
Japan	Novartis Investigative Site	Nagoya
Japan	Novartis Investigative Site	Niigata
Japan	Novartis Investigative Site	Obihiro
Japan	Novartis Investigative Site	Sakai
Japan	Novartis Investigative Site	Sakaide
Japan	Novartis Investigative Site	Sapporo
Japan	Novartis Investigative Site	Tachikawa
Japan	Novartis Investigative Site	Takatsuki
Japan	Novartis Investigative Site	Tsu
Japan	Novartis Investigative Site	Yabu
Japan	Novartis Investigative Site	Yanagawa
Japan	Novartis Investigative Site	Yatsushiro
Japan	Novartis Investigative Site	Yonezawa
Philippines	Novartis Investigative Site	Bulacan
Philippines	Novartis Investigative Site	Las Pinas City
Philippines	Novartis Investigative Site	Manila
Philippines	Novartis Investigative Site	Pasay City
Philippines	Novartis Investigative Site	Quezon City
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Proszowice
Poland	Novartis Investigative Site	Tarnov
Poland	Novartis Investigative Site	Warsaw
Russian Federation	Novartis Investigative Site	Barnaul
Russian Federation	Novartis Investigative Site	Kazan
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Nizhny Novgorod
Russian Federation	Novartis Investigative Site	Nizhny Novogorod
Russian Federation	Novartis Investigative Site	Samara
Russian Federation	Novartis Investigative Site	Saratov
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	Ufa
Slovakia	Novartis Investigative Site	Bardejov
Slovakia	Novartis Investigative Site	Bojnice
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Humenne
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Liptovsky Hradok
Slovakia	Novartis Investigative Site	Partizanske
Slovakia	Novartis Investigative Site	Prievidza
Slovakia	Novartis Investigative Site	Spisska Nova Ves
Slovakia	Novartis Investigative Site	Trstena
Slovakia	Novartis Investigative Site	Zilina
Slovakia	Novartis Investigative Site	Zvolen
South Africa	Novartis Investigative Site	Cape Town
South Africa	Novartis Investigative Site	Durban
South Africa	Novartis Investigative Site	Johannesburg
South Africa	Novartis Investigative Site	Lyttleton
South Africa	Novartis Investigative Site	Pretoria
Spain	Novartis Investigative Site	Alcira
Spain	Novartis Investigative Site	Badalona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Canet de Mar
Spain	Novartis Investigative Site	Centelles
Spain	Novartis Investigative Site	Ferrol
Spain	Novartis Investigative Site	Fuenlabrada
Spain	Novartis Investigative Site	Les Borges del Camp
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Mataro
Spain	Novartis Investigative Site	Merida
Spain	Novartis Investigative Site	Mostoles
Spain	Novartis Investigative Site	Motril
Spain	Novartis Investigative Site	Palma de Mallorca
Spain	Novartis Investigative Site	Ponferrada
Spain	Novartis Investigative Site	Salamanca
Spain	Novartis Investigative Site	Salt
Spain	Novartis Investigative Site	Valencia
Spain	Novartis Investigative Site	Vic
Switzerland	Novartis Investigative Site	Basel
Switzerland	Novartis Investigative Site	Lugano
Switzerland	Novartis Investigative Site	Munchenstein
Switzerland	Novartis Investigative Site	Neuchatel
Switzerland	Novartis Investigative Site	Zurich
Taiwan	Novartis Investigative Site	Chai-Yi
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Bolu
Turkey	Novartis Investigative Site	Bursa
Turkey	Novartis Investigative Site	Canakkale
Turkey	Novartis Investigative Site	Denizli
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Kocaeli
Turkey	Novartis Investigative Site	Manisa
Turkey	Novartis Investigative Site	Mersin
United Kingdom	Novartis Investigative Site	Bath
United Kingdom	Novartis Investigative Site	Blackpool
United Kingdom	Novartis Investigative Site	Bradford
United Kingdom	Novartis Investigative Site	Cambs
United Kingdom	Novartis Investigative Site	Chelmsford
United Kingdom	Novartis Investigative Site	Chesterfield
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Herts
United Kingdom	Novartis Investigative Site	Isle of Wight
United Kingdom	Novartis Investigative Site	London
United States	Novartis Investigative Site	Charlotte	North Carolina
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Fullerton	California
United States	Novartis Investigative Site	Greenville	South Carolina
United States	Novartis Investigative Site	Johnson City	Tennessee
United States	Novartis Investigative Site	Medford	Oregon
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Portland	Oregon
United States	Novartis Investigative Site	Riverside	California
United States	Novartis Investigative Site	St. Charles	Missouri
United States	Novartis Investigative Site	St. Louis	Missouri
United States	Novartis Investigative Site	St. Petersburg	Florida
United States	Novartis Investigative Site	Troy	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Bulgaria,  Canada,  France,  Germany,  Guatemala,  Hungary,  Japan,  Philippines,  Poland,  Russian Federation,  Slovakia,  South Africa,  Spain,  Switzerland,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment	Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 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.	23 hours 15 minutes and 23 hour 45 minute post-dose Week 26	No
Secondary	Transitional Dyspnea Index (TDI) Focal Score at Week 26	A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. Each domain is scored from -3 (major deterioration) to 3 (major improvement) to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score 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.	Week 26	No
Secondary	St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 26	SGRQ is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. A mixed model was used with treatment as a fixed effect with Baseline SGRQ 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.	26 weeks	No
Secondary	Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Over 26 Weeks	The number of puffs of rescue medication taken in the previous 12 hours was record 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. 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, Week 26	No
Secondary	Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment With QVA149, QAB149 and NVA237 Compared to Placebo	Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 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.	23 hours 15 minutes and 23 hour 45 minute post-dose Week 26	No
Secondary	Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment With QVA149 Compared to Tiotropium	Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 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.	23 hours 15 minutes and 23 hour 45 minute post-dose Week 26	No
Secondary	Baseline Transitional Dyspnea Index (BDI/TDI) Focal Score at Week 12 and Week 26	A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). BDI/TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score.; A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators as covariates and included baseline smoking status, baseline inhaled corticosteroids and region as fixed effects with center nested within region as a random effect.	Baseline, Week 12, Week 26	No
Secondary	Percentage of Patients With a Clinically Important Improvement of at Least 1 Point in TDI Focal Score After 26 Weeks of Treatment	A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing) at Week 12 and Week 26. TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI (baseline) was measured at Day 1. The TDI captures changes from baseline. Each domain is scored from -3 (major deterioration) to 3 (major improvement) to give an overall TDI focal score of -9 to 9.	Baseline, Week 26	No
Secondary	St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 and 26 Weeks of Treatment	SGRQ is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. A mixed model was used with treatment as a fixed effect with Baseline SGRQ 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.	Week 12, Week 26	No
Secondary	Percentage of Patients With a Clinically Important Improvement From Baseline of at Least 4 Units in the SGRQ Total Score After 26 Weeks of Treatment	SGRQ is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status.	Baseline, Week 26	No
Secondary	Percentage of Nights With "No Night Time Awakenings" Over 26 Weeks	A day with no night time awakenings is defined from the diary data as any day where the patient did not wake up due to COPD symptoms. The percentage of nights is calculated by the number of days with no nighttime awakenings/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent days 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.	26 Weeks	No
Secondary	Percentage of Days With "No Daytime Symptoms" Over 26 Weeks	A day with no day time symptoms is defined from the diary data as any day where the patient recorded no coughing, no wheezing, no sputum production and no breathlessness during the previous 12 hours (approximately 8AM to 8PM). The percentage of days is calculated by the number of days with no daytime symptoms/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of days 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.	26 Weeks	No
Secondary	Percentage of "Days Able to Perform Usual Daily Activities" Over 26 Weeks	Patients answered the question "Did your respiratory symptoms stop you performing your usual activities today?-Not at all in their daily diary. The percentage of days is calculated by the number of days patient is able to perform daily activities/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of Days 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.	26 Weeks	No
Secondary	Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication at Week 12 and Week 26	The number of puffs of rescue medication taken in the previous 12 hours was record 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. 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, Week 12, Week 26	No
Secondary	Change From Baseline (BL) in the Daytime and Night Time Rescue Medication Use (Number of Puffs) Over 26 Weeks	The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs in the morning and evening were calculated and divided by the number of days with data to determine the mean daily number of daytime and nighttime puffs. 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 (BL) ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.	Baseline, Week 26	No
Secondary	Percentage of "Days With no Rescue Medication Use" Over 26 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.	26 Weeks	No
Secondary	Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours at Day 1 and Week 26	FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, and 4 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 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.	From 5 minutes to 4 hours post-dose Day 1 and Week 26	No
Secondary	Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 12 Hours at Day 1 and Week 26	FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 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.	From 5 minutes to 12 hours post-dose Day 1 and Week 26	No
Secondary	Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 23 Hours 45 Minutes at Week 26	FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12, 23 hours 15 minutes and 23 hours 45 minutes post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 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.	From 5 minutes to 23 hours 45 minutes post-dose Week 26	No
Secondary	24 Hour Holter Monitoring in a Subset of Patients	24-hourly mean heart rate was performed using a Holter Monitor at Weeks 12 and 26 in a subgroup of patients. Mixed model: heart rate = treatment + baseline heart rate + baseline smoking status + baseline ICS use + region + center (region) + error. Center was included as a random effect nested within region.; The 24-hourly mean heart rate is the mean heart rate over the 24 hour period, derived using hourly mean heart rate beats per minute.	Week 12, Week 26	Yes
Secondary	Rate of Moderate or Severe COPD Exacerbation	Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years	26 Weeks	No
Secondary	Percentage of Patients With at Least One Moderate or Severe COPD Exacerbation Over the 26 Week Treatment Period		26 Weeks	No
Secondary	Percentage of Participants With COPD Exacerbations Requiring Hospitalization or Treatment With Systemic Corticosteroids and/or Antibiotics But no Hospitalization		26 Weeks	No