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

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

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

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.

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