Study to Evaluate the 24-Hour Pulmonary Function Profile of Fluticasone Furoate/Vilanterol (FF/VI) Inhalation Powder 100/25mcg Once Daily Compared With Tiotropium Bromide Inhalation Powder 18mcg Once Daily in Subjects With COPD Who Have or Are At Risk for Co-morbid Cardiovascular Disease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the 24-hour spirometry effect (FEV1) of Fluticasone Furoate/Vilanterol Inhalation Powder 100/25mcg once daily compared with tiotropium bromide inhalation powder 18mcg once daily over a 12-week treatment period in subjects with COPD who have or are at risk for co-morbid cardiovascular disease

Detailed Description
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This is a randomized, double-blind, double-dummy, multi-center, parallel-group study. Subjects who meet the eligibility criteria at Screening and at the end of a 2-week Run-In Period will enter a 12-week Treatment Period. There will be a 7-day Follow-up Period after the Treatment Period.

Official Title
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A 12-Week Study to Evaluate the 24-Hour Pulmonary Function Profile of Fluticasone Furoate /Vilanterol (FF/VI) Inhalation Powder 100/25mcg Once-Daily Via a Novel Dry Powder Inhaler Compared With Tiotropium Bromide Inhalation Powder 18mcg Delivered Once-Daily Via the HandiHaler in Subjects With Chronic Obstructive Pulmonary Disease (COPD) Who Have or Are at Risk for Co-morbid Cardiovascular Disease

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: fluticasone furoate/vilanterol 100/25mcg
* Drug: tiotropium bromide 18mcg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent Male or females ≥ 40 years of age Females must be post-menopausal or using a highly effective method for avoidance of pregnancy Established clinical history of COPD by ATS/ERS definition Post-albuterol spirometry criteria: FEV1/FVC ratio ≤ 0.70 and FEV1 ≥30 to ≤ 70% of predicted normal (NHANES III) Former or current smoker ≥10 pack years A history of diagnosed cardiovascular disease or a prior cardiovascular event including any of the following: Established (i.e., by clinical signs or imaging studies) coronary artery disease (CAD) Established (i.e., by clinical signs or imaging studies) peripheral vascular (i.e., arterial) disease (PVD) Previous stroke Objectively confirmed transient ischemic attack (TIA) (i.e., transient neurological deficit documented by a health-care professional) Previous myocardial infarction (MI) (Note: An MI within 6 months prior to Visit 1 is exclusionary) OR Presence of one of the following cardiovascular risk factors (in addition to being a former/current smoker): Current diagnosis of hypertension Current diagnosis of hypercholesterolemia Diabetes mellitus treated with pharmacotherapy Exclusion Criteria: Current diagnosis of asthma Subjects with other respiratory disorders including α1-antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis (Note: focal bronchiectasis is not exclusionary), sarcoidosis, pulmonary fibrosis (Note: focal fibrotic pulmonary lesions are not exclusionary), pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases Lung volume reduction surgery within previous 12 months Clinically significant abnormalities not due to COPD by chest X-ray or CT scan Hospitalized for poorly controlled COPD within 12 weeks of Screening Poorly controlled COPD 6 weeks prior to Screening, defined as acute worsening of COPD that is managed by the subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician Lower respiratory infection requiring antibiotics 6 weeks prior to Screening A moderate or severe COPD exacerbation and/or a lower respiratory tract infection (including pnuemonia) during the Run-In Period An abnormal, clinically significant finding in any liver chemistry, biochemical, or haematology tests at Screening (Visit 1) or upon repeat prior to randomization An abnormal, clinically significant ECG finding at Screening (Visit 1) or upon repeat prior to randomization An abnormal, clinically significant Holter finding at Screening (Visit 1) or upon repeat prior to randomization (sub-set of subjects) Historical or current evidence of clinically significant (in opinion of the Investigator) and unstable disease such as cardiovascular (e.g., patients requiring ICD, pacemaker requiring a ventricular pace rate set at >60 bpm, uncontrolled hypertension, New York Heart Association Class IV (New York Heart Association,1994), known left ventricular ejection fraction <30%), neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease), peptic ulcer disease, or haematological abnormalities Carcinoma not in complete remission for at least 5 years History of allergy or hypersensitivity to any of the study medications (e.g., anticholinergic/muscarinic receptor antagonist, beta2-agonist, corticosteroid) or components of the inhalation powder (e.g., lactose, magnesium stearate) or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic. In addition, subjects with a history of severe milk protein allergy that, in the opinion of the Investigator, contraindicates the subject's participation will also be excluded Known/suspected history of alcohol or drug abuse in the last 2 years Women who are pregnant or lactating or plan to become pregnant Subjects medically unable to withhold albuterol /salbutamol for 4 hours prior to spirometry testing at each study visit Use of certain medications such as bronchodilators and corticosteroids for the protocol-specific times prior to Visit 1 (the Investigator will discuss the specific medications) Long Term Oxygen Therapy (LTOT) or nocturnal oxygen therapy >12 hours a day Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Screening or during the study Failure to demonstrate adequate compliance defined as completion of the Diary Card (completed all diary entries on at least 4 of the last 7 consecutive days), the ability to withhold COPD medications and to keep clinic visit appointments Non-compliance or inability to comply with study procedures or scheduled visits History of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study Affiliation with investigator site Women who are pregnant or lactating or are planning on becoming pregnant during the study

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: fluticasone furoate/vilanterol<br>inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) | Drug: fluticasone furoate/vilanterol 100/25mcg<br>* inhalation powder<br>|
| Active Comparator: tiotropium bromide<br>anticholinergic | Drug: tiotropium bromide 18mcg<br>* inhalation powder<br>* Other names: Spiriva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Trough in 24-hour Weighted Mean FEV1 on Treatment Day 84 | Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. The weighted mean was calculated from the pre-dose FEV1 and post-dose FEV1 measurements at 5, 15, 30 minutes and 1, 2, 4, 6, 8, 12, 13, 14, 16, 20, and 24 hours on Treatment Day 84. Baseline trough FEV1 was the mean of the two assessments made 30 and 5 minutes pre-dose on Treatment Day 1. Change from Baseline (BL) was calculated as the average of the Day 84 values minus the Baseline value. Analysis was performed using an analysis of covariance (ANCOVA) model with covariates of BL FEV1, exacerbation history and reversibility stratum, smoking status at screening, country, and treatment group. | Baseline and Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset on Treatment Day 1 | Time to onset on Treatment Day 1 is defined as the time to an increase of 100 milliliters (mL) from Baseline in FEV1. Time of onset was calculated over 0 to 4 hours (5 minutes (min), 15 min, 30 min, 60 min, 120 min, and 240 min) post-dose. Time to onset was analyzed using a log-rank test, stratified by exacerbation history and reversibility stratum. | Baseline and Day 1 | 
| Change From Baseline in Trough FEV1 at Treatment Day 84 | Pulmonary function was measured by FEV1. Trough FEV1 was defined as the 24-hour FEV1 assessment, which was obtained on Day 84. Baseline is defined as the mean of the two assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1.Change from Baseline was calculated as the average of the Day 84 values minus the Baseline value. Analysis was performed using an ANCOVA model with covariates of BL FEV1, exacerbation history and reversibility stratum, smoking status at screening, country, and treatment group. | Baseline and Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular event, Cardiovascular disease