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

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