Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease

Despite a potential link between the pathogenetic mechanisms involved in Chronic Obstructive
Pulmonary Disease (COPD) and atherosclerotic cardiovascular disease, there are no currently
approved therapies for patients with COPD that have clearly shown an additional beneficial
effect in patients with cardiovascular comorbidities. The TOwards a Revolution in COPD Health
(TORCH) study assessed the impact of the inhaled corticosteroid (ICS) fluticasone propionate
(FP) in combination with the long-acting beta agonist (LABA), salmeterol (SAL), in reducing
all-cause mortality. TORCH demonstrated a 17.5% reduction on all-cause mortality with
salmeterol-fluticasone propionate combination (SFC) compared with placebo (HR=0.825, 95% CI
(0.681, 1.002), p=0.052) in the entire COPD population with disease severity form moderate to
very severe. A post hoc analysis of the data restricted to those subjects with an forced
expiratory volume in 1 second (FEV1) >=50% predicted with an apparent history of
cardiovascular co-morbidities (defined as use at baseline of beta-blockers, angiotensin
converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), HMG CoA reductase
inhibitors (i.e. statins) or a prior MI recorded at baseline) demonstrated a 49% reduction in
the risk of dying within 96 weeks for the comparison of SFC with placebo. These post hoc data
suggest the possibility of an ICS/LABA combination product to be of substantial benefit in
COPD subjects with less severe airflow obstruction yet with increased cardiovascular risk.

The mechanism by which SFC appears to be associated with a greater reduction in mortality in
these less severe COPD subjects with concomitant cardiovascular comorbidities is speculative
at present, but could potentially in part be related to a lessening of the degree of
inflammation in the systemic circulation, potential plaque stabilization and/or amelioration
of arterial stiffness.

ICS/LABA combinations that are currently available require twice daily administration. A once
daily ICS/LABA combination has the potential to improve patient compliance and as a result,
overall disease management.

The purpose of this study is to prospectively evaluate the effect of the once daily ICS/LABA
combination Fluticasone Furoate (FF)/Vilanterol (VI) on survival in subjects with moderate
COPD (>=50 and =<70 % predicted FEV1 ) and a history of, or at increased risk for
cardiovascular disease.

Inclusion Criteria:

- Type of subject: outpatient.

- Informed consent: Subjects must give their signed and dated written informed consent
to participate.

- Gender: Male or female. Female subjects must be post-menopausal or using a highly
effective method for avoidance of pregnancy. The decision to include or exclude women
of childbearing potential may be made at the discretion of the investigator in
accordance with local practice in relation to adequate contraception.

- Age: >=40 and <=80 years of age at Screening (Visit 1).

- Tobacco use: Subjects with a current or prior history of >=10 pack-years of cigarette
smoking at screening (Visit 1). Previous smokers are defined as those who have stopped
smoking for at least 6 months prior to Visit 1.

- Airflow Obstruction:

Subjects with a measured post-albuterol/salbutamol forced expiratory volume in 1 second
(FEV1)/(forced vital capacity)FVC ratio of <=0.70 at Screening (Visit 1).

Subjects with a measured post-albuterol/salbutamol FEV1 >=50 and <=70% of predicted normal
values calculated using NHANES III reference equations [Hankinson, 1999; Hankinson, 2010]
at Screening (Visit 1).

Post-bronchodilator spirometry will be performed approximately 15 minutes after the subject
has self-administered 4 inhalations (i.e., total 400mcg) of albuterol/salbutamol via a
metered dose inhaler (MDI )with a valved-holding chamber. The FEV1/FVC ratio and FEV1
percent predicted values will be calculated.

- Symptoms of COPD: Subjects must score 2 or higher on the modified Medical Research
Council Dyspnea scale (Visit 1)

- Cardiovascular disease:

For patients >= 40 years of age: any one 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 disease (PVD)
Previous stroke Previous MI Diabetes mellitus with target organ disease OR

For patients >=60 years of age: any 2 of the following:

Being treated for hypercholesterolemia Being treated for hypertension Being treated for
diabetes mellitus Being treated for peripheral vascular disease

Exclusion Criteria:

- Pregnancy: Women who are pregnant or lactating.

- Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of
asthma are eligible if they also have a current diagnosis of COPD).

- alpha 1-antitrypsin deficiency: Subjects with known alpha-1 antitrypsin deficiency as
the underlying cause of COPD.

- Other respiratory disorders: Subjects with active tuberculosis, lung cancer,
bronchiectasis, sarcoidosis, pulmonary fibrosis, pulmonary hypertension, interstitial
lung diseases or other active pulmonary diseases.

- Lung resection or transplantation: Subjects with lung volume reduction surgery within
the 12 months prior to Screening or having had a lung transplant.

- A moderate/severe COPD exacerbation that has not resolved at least 14 days prior to
Visit 1 and at least 30 days following the last dose of oral corticosteroids (if
applicable).

- Current severe heart failure (New York Heart Association class IV). Subjects will also
be excluded if they have a known ejection fraction of <30% or if they have an
implantable cardioverter defibrillator (ICD).

- Other diseases/abnormalities: Any life-threatening condition with life expectancy <3
years, other than vascular disease or COPD, that might prevent the subject from
completing the study.

- End stage chronic renal disease: Subjects will be excluded if on renal replacement
therapy (hemodialysis or peritoneal).

- Drug/food allergy: Subjects with a history of hypersensitivity to any of the study
medications (e.g. beta-agonists, corticosteroid) or components of the inhalation
powder (e.g. lactose, magnesium stearate). In addition, patients with a history of
severe milk protein allergy that, in the opinion of the study physician,
contraindicates the subject's participation will also be excluded.

- Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug
abuse within the last 2 years.

- Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or
nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use
(i.e. <=12 hours per day) is not exclusionary.

- Questionable validity of consent: Subjects with a history of psychiatric disease,
intellectual deficiency, poor motivation or other conditions that will limit the
validity of informed consent to participate in the study or the potential compliance
to study procedures.

- Affiliation with investigator site: Study investigators, sub-investigators, study
coordinators, employees of a participating investigator or immediate family members of
the aforementioned are excluded from participating in this study.

- Additional medication: Use of the following medications within the following time
intervals prior to Visit 1 or during the study (unless otherwise specified):

Medication No use within the following time intervals prior to Screening or thereafter at
any time during the study (unless otherwise specified) Inhaled Long acting beta-agonists
(LABA) 48 hours ICS/LABA combination products 48 hours Inhaled corticosteroids 48 hours
Tiotropium 1 week Systemic, Oral, parenteral, intra-articular corticosteroids 30 days (oral
and systemic corticosteroids may be used to treat COPD exacerbations during the study)
Cytochrome P450 3A4 strong inhibitors including but not limited to antiretrovirals
(protease inhibitors) (e.g.Indinavir, Nelfinavir, Ritonavir, Saquinavir); Imidazole and
Triazole anti-fungals (e.g. Ketaconazole, Itraconazole); Clarithromycin, Telithromycin,
Amiodarone, and Nefazodone 6 weeks Grapefruit is allowed up to Visit 1, then limited to no
more than one glass of grapefruit juice (250 mL/ 8 ounces) or one grapefruit per day Any
other investigational drug 30 days or 5 half lives whichever is longer.