Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Combinations of Long-acting β2-agonists (LABA) and Inhaled Glucocorticosteroid (ICS)

Chronic Obstructive Pulmonary Disease Clinical Trial

— REACT  

Official title:

Effect of Roflumilast on Exacerbation Rate in Patients With COPD Treated With Fixed Combinations of LABA and ICS. A 52-week, Randomised Double-blind Trial With Roflumilast 500 µg Versus Placebo. The REACT Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01329029
• Other study ID #: RO-2455-404-RD
• Secondary ID: 2010-019685-87U1
• Status: Completed
• Phase: Phase 4
• First received: March 30, 2011
• Last updated: September 25, 2015
• Start date: May 2011
• Est. completion date: May 2014

Study information

• Verified date: September 2015
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Department of Health and Ageing Therapeutic Goods AdministrationAustria: Federal Office for Safety in Health CareBelgium: Federal Agency for Medicinal Products and Health ProductsBrazil: National Health Surveillance AgencyCanada: Health CanadaDenmark: Danish 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 MedicinesHungary: National Institute of PharmacyIsrael: Israeli Health Ministry Pharmaceutical AdministrationItaly: The Italian Medicines AgencyNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Ministry of Health of the Russian FederationSlovakia: State Institute for Drug ControlSouth Africa: Medicines Control CouncilSouth Korea: Korea Food and Drug Administration (KFDA)Spain: Agencia Española de Medicamentos y Productos SanitariosTurkey: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

The objective of the REACT trial is to investigate the effect of roflumilast 500 μg tablets once daily versus placebo on exacerbation rate and pulmonary function in COPD patients who are concomitantly treated with a fixed combination of long-acting β2-agonists (LABA) and inhaled glucocorticosteroids (ICS). In addition, data on safety and tolerability of roflumilast will be obtained. An additional objective is to further characterize the population pharmacokinetic profile of roflumilast and roflumilast N oxide and to further characterize their pharmacokinetics/pharmacodynamics (PK/PD) relationship in terms of efficacy and relevant safety aspects.

Patients to be included are required to have severe COPD associated with chronic bronchitis and a history of frequent exacerbations and must be concomitantly treated with a fixed combination of LABA and ICS. Two parallel treatment arms (roflumilast 500 μg once daily and placebo) are included.

Description:

The drug tested in this study is called Roflumilast. Roflumilast is being developed to treat people who have chronic obstructive pulmonary disease (COPD). This study investigated the effect of roflumilast 500 μg tablets once daily versus placebo on exacerbation rate, pulmonary function, and major adverse cardiovascular events (MACE) in COPD patients who were concomitantly treated with a fixed combination of long-acting beta-agonists (LABA) and inhaled glucocorticosteroids.

The study was targeted to enroll approximately 1934 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups—which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need):

• Roflumilast 500 μg once daily

• Placebo (dummy inactive pill) - this was a tablet that looked like the study drug but had no active ingredient

Trial treatment was taken in the morning by mouth after breakfast with some water.

The trial consisted of the following periods:

• Single-blind baseline period (4 weeks) during which all patients received placebo.

• Double-blind treatment period (52 weeks) during which patients received either roflumilast or matching placebo.

• Safety follow-up (30 days after end of treatment (Vend) or premature discontinuation date) in case of ongoing Adverse Events at Vend, if necessary.

• Follow-up visit 12 weeks after end of treatment, at Week 64 (VFU), only for patients who completed the trial as scheduled.

This multi-center trial was conducted worldwide. The overall time to participate in this study was up to 64 weeks. Participants made multiple visits to the clinic which included a follow-up visit at week 64.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1945
• Est. completion date: May 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Giving written informed consent

• History of COPD (according to GOLD 2009) for at least 12 months prior to baseline Visit V0 associated with chronic productive cough for 3 months in each of the 2 years prior to baseline visit (with other causes of productive cough excluded)

• Age = 40 years

• Forced expiratory volume after one second (FEV1)/forced vital capacity (FVC) ratio (post-bronchodilator) < 70%

• FEV1 (post-bronchodilator) = 50% of predicted

• At least two documented moderate or severe COPD exacerbations within one year prior to baseline visit

• Patients must be pre-treated with LABA and ICS for at least 12 months before baseline Visit V0. Up to 3 months before baseline Visit V0 free or fixed combinations of LABA and ICS are allowed, including changes in dose, active substances, and brands. In the last 3 months before baseline Visit V0 patients must be pre-treated with fixed combinations of LABA and ICS at a constant dose (maximum approved dosage strength of the combination).

• Former smoker (defined as smoking cessation at least one year ago) or current smoker both with a smoking history of at least 20 pack years

Main Exclusion Criteria:

• Exacerbations not resolved at first baseline visit

• Diagnosis of asthma and/or other relevant lung disease

• Known alpha-1-antitrypsin deficiency

• Other protocol-defined exclusion criteria may apply

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Roflumilast
500 µg, once daily
• Placebo
once daily

Locations

Country	Name	City	State
Australia	Nycomed Investigational Site	Box Hill
Australia	Nycomed Investigational Site	Clayton
Australia	Nycomed Investigational Site	Concord
Australia	Nycomed Investigational site	Daws Park
Australia	Nycomed Investigational Site	Frankston
Australia	Nycomed Investigational Site	Heidelberg
Australia	Nycomed Investigational Site	Parkville
Australia	Nycomed Investigational Site	Toorak Gardens
Austria	Nycomed Investigational Site	Feldbach
Austria	Nycomed Investigational Site	Graz
Austria	Nycomed Investigational Site	Salzburg
Austria	Nycomed Investigational Site	Wien
Belgium	Nycomed Investigational Site	Bruxelles
Belgium	Nycomed Investigational Site	Bruxelles
Belgium	Nycomed Investigational Site	Halen
Belgium	Nycomed Investigational Site	Liege
Belgium	Nycomed Investigational Site	Malmedy
Brazil	Nycomed Investigational Site	Belo Horizonte
Brazil	Nycomed Investigational Site	Botucatu
Brazil	Nycomed Investigational Site	Florianópolis
Brazil	Nycomed Investigational Site	Goiânia
Brazil	Nycomed Investigational Site	Porto Alegre
Brazil	Nycomed Investigational Site	Rio de Janeiro
Brazil	Nycomed Investigational Site	Sao Paolo
Brazil	Nycomed Investigational Site	Vitória
Canada	Nycomed Investigational Site	Hamilton
Canada	Nycomed Investigational Site	Kingston
Canada	Nycomed Investigational Site	Lachine
Canada	Nycomed Investigational Site	Niagara Falls
Canada	Nycomed Investigational Site	Richmond Hill
Canada	Nycomed Investigational Site	Toronto
Canada	Nycomed Investigational Site	Toronto
Canada	Nycomed Investigational Site	Winnepeg
Denmark	Nycomed Investigational Site	Hellerup
Denmark	Nycomed Investigational Site	Hillerød
Denmark	Nycomed Investigational Site	Hvidovre
Denmark	Nycomed Investigational Site	København NV
France	Nycomed Investigational Site	Férolles Attilly
France	Nycomed Investigational Site	Nîmes
France	Nycomed Investigational Site	Poitiers
France	Nycomed Investigational Site	Saint-Laurent du Var
France	Nycomed Investigational Site	Strasbourg
Germany	Nycomed Investigational Site	Berlin
Germany	Nycomed Investigational Site	Berlin
Germany	Nycomed Investigational Site	Berlin
Germany	Nycomed Investigational Site	Fürth
Germany	Nycomed Investigational Site	Großhansdorf
Germany	Nycomed Investigational Site	Hannover
Germany	Nycomed Investigational Site	Homburg
Germany	Nycomed Investigational Site	Koblenz
Germany	Nycomed Investigational Site	Marburg
Germany	Nycomed Investigational Site	Rüdersdorf
Greece	Nycomed Investigational Site	Alexandroupolis
Greece	Nycomed Investigational Site	Athens
Greece	Nycomed Investigational Site	Athens
Greece	Nycomed Investigational Site	Heraklion, Crete
Greece	Nycomed Investigational Site	Kavala
Greece	Nycomed Investigational Site	Larissa
Greece	Nycomed Investigational Site	Marousi
Greece	Nycomed Investigational Site	Thessaloniki
Hungary	Nycomed Investigational Site	Balassagyarmat
Hungary	Nycomed Investigational Site	Budapest
Hungary	Nycomed Investigational Site	Cegléd
Hungary	Nycomed Investigational Site	Csorna
Hungary	Nycomed Investigational Site	Deszk
Hungary	Nycomed Investigational Site	Erd
Hungary	Nycomed Investigational Site	Miskolc
Hungary	Nycomed Investigational Site	Nyíregyháza
Hungary	Nycomed Investigational Site	Pécs
Hungary	Nycomed Investigational Site	Siófok
Hungary	Nycomed Investigational Site	Sopron
Hungary	Nycomed Investigational Site	Szombathely
Hungary	Nycomed Investigational Site	Törökbálint
Israel	Nycomed Investigational Site	Ashkelon
Israel	Nycomed Investigational Site	Beer Sheva
Israel	Nycomed Investigational Site	Haifa
Israel	Nycomed Investigational Site	Haifa
Israel	Nycomed Investigational Site	Holon
Israel	Nycomed Investigational Site	Jerusalem
Israel	Nycomed Investigational Site	Jerusalm
Israel	Nycomed Investigational Site	Kfar Saba
Israel	Nycomed Investigational Site	Petach Tikva
Israel	Nycomed Investigational Site	Rehovot
Israel	Nycomed Investigational Site	Tel Aviv
Israel	Nycomed Investigational Site	Tel Hashomer
Israel	Nycomed Investigational Site	Tel-Aviv
Italy	Nycomed Investigational Site	Ferrara
Italy	Nycomed Investigational Site	Genova
Italy	Nycomed Investigational Site	Milano
Italy	Nycomed Investigational Site	Milano
Italy	Nycomed Investigational Site	Modena
Italy	Nycomed Investigational Site	Monza
Italy	Nycomed Investigational Site	Pordenone
Italy	Nycomed Investigational Site	Roma
Korea, Republic of	Nycomed Investigational Site	Anyang
Korea, Republic of	Nycomed Investigational Site	Cheongju
Korea, Republic of	Nycomed Investigational Site	Daegu
Korea, Republic of	Nycomed Investigational Site	Seoul
Korea, Republic of	Nycomed Investigational Site	Seoul
Korea, Republic of	Nycomed Investigational Site	Seoul
Korea, Republic of	Nycomed Investigational Site	Wonju
Netherlands	Nycomed Investigational Site	's Hertogenbosch
Netherlands	Nycomed Investigational Site	Amersfoort
Netherlands	Nycomed Investigational Site	Arnhem
Netherlands	Nycomed Investigational Site	Enschede
Netherlands	Nycomed Investigational Site	Heerlen
Netherlands	Nycomed Investigational Site	Hoorn
Poland	Nycomed Investigational Site	Bialystok
Poland	Nycomed Investigational Site	Bydgoszcz
Poland	Nycomed Investigational Site	Gliwice
Poland	Nycomed Investigational Site	Katowice
Poland	Nycomed Investigational Site	Lodz
Poland	Nycomed Investigational Site	Lodz
Poland	Nycomed Investigational Site	Lodz
Poland	Nycomed Investigational Site	Lublin
Poland	Nycomed Investigational Site	Olesnica
Poland	Nycomed Investigational Site	Ostrow Wielkopolski
Poland	Nycomed Investigational Site	Tarnow
Poland	Nycomed Investigational Site	Warszawa
Poland	Nycomed Investigational Site	Wroclaw
Poland	Nycomed Investigational Site	Wroclaw
Poland	Nycomed Investigational Site	Zawadzkie
Russian Federation	Nycomed Investigational Site	Chelyabinsk
Russian Federation	Nycomed Investigational Site	Kazan
Russian Federation	Nycomed Investigational Site	Kemerovo
Russian Federation	Nycomed Investigational Site	Moscow
Russian Federation	Nycomed Investigational Site	Moscow
Russian Federation	Nycomed Investigational Site	Moscow
Russian Federation	Nycomed Investigational Site	Moscow
Russian Federation	Nycomed Investigational Site	Nizhniy Novgorod
Russian Federation	Nycomed Investigational Site	Novosibirsk
Russian Federation	Nycomed Investigational Site	Novosibirsk
Russian Federation	Nycomed Investigational Site	Samara
Russian Federation	Nycomed Investigational Site	Saratov
Russian Federation	Nycomed Investigational Site	Smolensk
Russian Federation	Nycomed Investigational Site	St Petersburg
Russian Federation	Nycomed Investigational Site	St. Petersburg
Russian Federation	Nycomed Investigational Site	St. Petersburg
Russian Federation	Nycomed Investigational Site	Volgograd
Russian Federation	Nycomed Investigational Site	Vsevolozhsk
Russian Federation	Nycomed Investigational Site	Yaroslavl
Slovakia	Nycomed Investigational Site	Banska Bystrica
Slovakia	Nycomed Investigational Site	Bardejov
Slovakia	Nycomed Investigational Site	Bratislava
Slovakia	Nycomed Investigational Site	Bratislava
Slovakia	Nycomed Investigational Site	Kosice
Slovakia	Nycomed Investigational Site	Martin
Slovakia	Nycomed Investigational Site	Nitra
Slovakia	Nycomed Investigational Site	Nove Zamky
Slovakia	Nycomed Investigational Site	Spisska Nova Ves
South Africa	Nycomed Investigational Site	Auckland Park, Johannesburg Gauteng
South Africa	Nycomed Investigational Site	Benoni Gauteng
South Africa	Nycomed Investigational Site	Bloemfontein Free State
South Africa	Nycomed Investigational Site	Cape Town Western Cape
South Africa	Nycomed Investigational Site	Durban Kwazulu-Natal
South Africa	Nycomed Investigational Site	Johannesburg
South Africa	Nycomed Investigational Site	Morningside, Johannesburg Gauteng
South Africa	Nycomed Investigational Site	Thabazimbi Limpopo
South Africa	Nycomed Investigational Site	Umkomaas Kwazulu-Natal
South Africa	Nycomed Investigational Site	Witbank Mpumalanga
Spain	Nycomed Investigational Site	Barcelona
Spain	Nycomed Investigational Site	Guadalajara
Spain	Nycomed Investigational Site	Madrid
Spain	Nycomed Investigational Site	Pozuelo de Alarcon
Spain	Nycomed Investigational Site	Santander
Spain	Nycomed Investigational Site	Terrassa
Spain	Nycomed Investigational Site	Valencia
Turkey	Nycomed Investigational Site	Ankara
Turkey	Nycomed Investigational Site	Canakkale
Turkey	Nycomed Investigational Site	Istanbul
Turkey	Nycomed Investigational Site	Izmir
Turkey	Nycomed Investigational Site	Kocaeli
Turkey	Nycomed Investigational Site	Konya
Turkey	Nycomed Investigational Site	Mersin
United Kingdom	Nycomed Investigational Site	Edinburgh
United Kingdom	Nycomed Investigational Site	Glasgow
United Kingdom	Nycomed Investigational Site	Liverpool
United Kingdom	Nycomed Investigational Site	London
United Kingdom	Nycomed Investigational Site	London
United Kingdom	Nycomed Investigational Site	Norwich

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  Brazil,  Canada,  Denmark,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Russian Federation,  Slovakia,  South Africa,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as follows: Severe=Requiring hospitalization and/or leading to death; Moderate=Requiring oral or parenteral glucocorticosteroid therapy. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.	52 weeks	No
Secondary	Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)	Pulmonary function testing was performed using centralised spirometry. FEV1 is the maximum amount of air that can be forcefully exhaled in one second. Least-squares means is from Analysis of Covariance (ANCOVA) including treatment by time interaction. A positive change from Baseline indicates improvement.	Baseline and Week 52	No
Secondary	Rate of Severe COPD Exacerbations Per Patient Per Year	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. Severe COPD exacerbations were categorized as requiring hospitalization and/or leading to death. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.	52 weeks	No
Secondary	Rate of COPD Exacerbations Per Patient Per Year All Categories	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as follows: Severe=Requiring hospitalization and/or leading to death; Moderate=Requiring oral or parenteral glucocorticosteroid therapy. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.	52 weeks	No
Secondary	Percentage of Participants Experiencing at Least 1 COPD Exacerbation	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.	52 weeks	No
Secondary	Time to First COPD Exacerbation All Categories	Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day for all events: mild, moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.	52 Weeks	No
Secondary	Time to Second Moderate or Severe COPD Exacerbation	Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day for events: moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)	No
Secondary	Time to Third Moderate or Severe COPD Exacerbation	Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day for events: moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.	52 Weeks	No
Secondary	Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived From Exacerbation Per Patient Per Year	The number needed to treat (NNT) analysis is a simple, concise method to quantify directly the benefits that alternative treatment options have on disease outcomes in terms of the number of patients who need to be treated before a benefit is observed. Risk reduction: Rate(Placebo)— Rate (Roflumilast 500 µg), Number needed to treat for benefit (NNTB): 1/(Risk reduction). A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.	52 Weeks	No
Secondary	Number of Moderate or Severe COPD Exacerbation Days	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. The number of exacerbation days per patient is the sum of durations (stop date of exacerbation — start date of exacerbation + 1) of all exacerbations within the category.	52 Weeks	No
Secondary	Duration of Moderate or Severe COPD Exacerbations Per Participant	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.	52 Weeks	No
Secondary	Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)	Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Least-squares means was from ANCOVA including treatment by time interaction. A positive change from Baseline indicates improvement.	52 weeks	No
Secondary	Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)	Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry. Least-squares means was from ANCOVA including treatment by time interaction. A positive change from Baseline indicates improvement.	52 weeks	No
Secondary	Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6)	FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first six seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry. A positive change from Baseline indicates improvement.	52 weeks	No
Secondary	Change From Baseline in Post-Bronchodilator FEV1/FVC	The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry. A positive change from Baseline indicates improvement.	52 weeks	No
Secondary	Change From Baseline in Use of Rescue Medication From Daily Diary	Salbutamol metered dose inhaler was available as rescue medication during the study. The participant recorded the use of rescue medication in a daily diary. A negative change from Baseline indicates an improvement.	Baseline and Week 52	No
Secondary	Change From Baseline in COPD Symptom Score From Daily Diary	Participants recorded COPD symptoms cough and sputum production in a daily diary. Cough was assessed using a 4-point scale where 0=No cough to 3=severe cough and sputum was assessed using a 4-point scale where 0=no sputum production to 3=severe sputum production. Least-squares means from ANCOVA including treatment by time interaction. A negative change from Baseline indicates improvement. Total symptom score is the sum of cough and sputum scores, ranging from 0 (best possible outcome) to 6 (worst possible outcome).	52 weeks	No
Secondary	Percentage of Symptom-Free Days	Symptoms of COPD (cough, sputum) were recorded in a daily diary. The percentage of days without symptoms is reported.	52 Weeks	No
Secondary	Percentage of Rescue Medication-Free Days	Participants recorded their use of rescue medication in a daily diary. The percentage of days without rescue medication use.	52 Weeks	No
Secondary	Change From Baseline in COPD Assessment Test (CAT) Total Score	Participants completed the CAT questionnaire at Baseline and after 52 Weeks of Treatment. The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. A negative change from Baseline indicates improvement. Least-squares means from ANCOVA including treatment by time interaction.	Baseline and Week 52	No
Secondary	Percentage of Participants With Improvement in CAT	Participants completed the CAT questionnaire at Baseline and after 52 Weeks of treatment. The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. Improvement was defined as a CAT Total Score reduction from Baseline > 1.6.	Baseline and Week 52	No
Secondary	Time to Mortality Due to Any Reason During the Treatment Period Score	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)	No
Secondary	Time to Mortality Due to COPD Exacerbation During the Treatment Period	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.	52 Weeks	No
Secondary	Time to Withdrawal During the Treatment Period	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)	No
Secondary	Time to Withdrawal Due to COPD Exacerbation During the Treatment Period	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)	No
Secondary	Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period	Composite MACE is a combined endpoint (cardiovascular death [including death due to undetermined cause], nonfatal myocardial infarction, and nonfatal stroke).	52 Weeks	No
Secondary	Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period	Composite MACE is a combined endpoint(cardiovascular death [including death due to undetermined cause], nonfatal myocardial infarction, and nonfatal stroke). Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)	No
Secondary	Percentage of Participant With All-Cause Hospitalisation During the Treatment Period	Percentage of patients with at least one hospital admission due to any cause.	52 Weeks	No
Secondary	Time to First Hospitalisation Due to Any Cause During the Treatment Period	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)	No
Secondary	Time to Trial Withdrawal Due to an Adverse Event	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)	No
Secondary	Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE)	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.	52 Weeks	Yes
Secondary	Change From Baseline in Body Weight	Least Square Means was from an ANCOVA model including Last Observation Carried Forward (LOCF).	Baseline and Week 52	Yes
Secondary	Change From Baseline in Body Mass Index (BMI)	Body mass index (BMI) is a measure of body fat based on height and weight. Least Square Means was from an ANCOVA model including LOCF.	Baseline and Week 52	Yes