24-week Trial Comparing GSK573719/GW642444 With GW642444 and With Tiotropium in Chronic Obstructive Pulmonary Disease

This is a 24-week, Phase III multicenter, randomized, double-blind, double-dummy,
parallel-group study. Eligible subjects will be randomized to GSK573719/GW642444 125/25mcg,
GSK573719/GW642444 62.5/25mcg, GW642444 25mcg, or tiotropium treatment groups in a 1:1:1:1
ratio. Treatments will be administered once-daily in the morning by inhalation using a Novel
Dry Powder Inhaler (Novel DPI) and HandiHaler. There will be a total of 9 study clinic visits
conducted on an outpatient basis. Subjects who meet the eligibility criteria at Screening
(Visit 1) will complete a 7 to 10 day run-in period followed by a 24-week treatment period.
Clinic visits will be at Screening, Randomization (Day 1), Day 2, after 4, 8, 12, 16, and
24-weeks of treatment, and 1 day after the Week 24 Visit (also referred as Treatment Day
169). A follow-up contact for adverse assessment will be conducted by telephone approximately
7 days after Visit 9 or the Early Withdrawal Visit. The total duration of subject
participation, including follow-up will be approximately 26 weeks. All subjects will be
provided with albuterol/salbutamol for use on an "as-needed" basis throughout the run-in and
study treatment periods. At screening, pre-bronchodilator spirometry testing will be followed
by post-albuterol/salbutamol spirometry testing. Post-albuterol/salbutamol FEV1 and
FEV1/forced vital capacity (FVC) values will be used to determine subject eligibility. To
further characterize bronchodilator responsiveness, post-ipratropium testing will be
conducted following completion of post-albuterol/salbutamol spirometry. Spirometry will be
conducted at each post-randomization clinic visit. Six hour post-dose serial spirometry will
be conducted at Visits 2, 6, and 8. Trough spirometry will be obtained 23 and 24 hours after
the previous day's dose of blinded study medication at Visits 3 to 9. All subjects will be
provided with an electronic diary (eDiary) for completion daily in the morning and the
evening throughout the run-in and treatment periods. Subjects will use the eDiary to record
peak expiratory flow (PEF) each morning, dyspnea scores using the Shortness of Breath with
Daily Activities instrument (SOBDA), daily use of supplemental albuterol/salbutamol as either
puffs/day from a metered-dose inhaler (MDI) and/or nebules used per day, and any healthcare
contacts related to COPD. Additional assessments of dyspnea will be obtained using the
Baseline and Transition Dyspnea Index (BDI/TDI) which is an interviewer based instrument. At
Visit 2, the severity of dyspnea at baseline will be assessed using the BDI. At subsequent
visits (Visits 4, 6, and 8) change from baseline will be assessed using the TDI. General
health status will be evaluated using the subject-completed EQ-5D questionnaire at Visits 2,
4, 6, and 8. Disease specific health status will be evaluated using the subject-completed St.
George's Respiratory Questionnaire (SGRQ) at Visits 2, 4, 6, and 8, and the subject-completed
COPD Assessment Test (CAT) at Visits 2, 6, and 8. The occurrence of adverse events will be
evaluated throughout the study beginning at Visit 2. SAEs will be collected over the same
time period as for AEs. However, any SAEs assessed as related to study participation (e.g.,
study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy)
or related to a GSK concomitant medication, will be recorded from the time a subject consents
to participate in the study up to and including any follow up contact. Additional safety
assessments of vital signs (blood pressure and pulse rate), 12-lead ECGs and standard
clinical laboratory tests (hematology and chemistry) will be obtained at selected clinic
visits.

Inclusion Criteria:

- outpatient

- signed and dated written informed consent

- 40 years of age or older

- male and female subjects

- COPD diagnosis

- at least 10 pack-year smoking history

- post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and post-albuterol/salbutamol FEV1
of less than or equal to 70% predicted normal values

- score of greater than or equal to 2 on the Modified Medical Resarch Council Dyspnea
Scale (mMRC)

Exclusion Criteria:

- women who are pregnant or lactating or are planning on becoming pregnant during the
study

- current diagnosis of asthma

- other respiratory disorders other than COPD

- other diseases/abnormalities that are uncontrolled including cancer not in remission
for at least 5 years

- chest x-ray or CT scan with clinically significant abnormalities not believed to be
due to COPD

- hypersensitivity to anticholinergics, beta-agonists, lactose/milk protein or magnesium
stearate or medical conditions associated with inhaled anticholinergics

- hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1

- lung volume reduction surgery within 12 months prior to Visit 1

- abnormal and clinically significant ECG at Visit 1

- significantly abnormal finding from laboratory tests at Visit 1

- unable to withhold albuterol/salbutamol at least 4 hours prior to spirometry at each
visit

- use of depot corticosteroids within 12 weeks of Visit 1

- use of oral or parenteral corticosteroids, antibiotics for lower respiratory tract
infection, or cytochrome P450 3A4 inhibitors, within 6 weeks of Visit 1

- use of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) product if
LABA/ICS therapy is discontinued withing 30 days of Visit 1

- use of ICS at a dose of >1000mcg/day of fluticasone propionate or equivalent within 30
days of Visit 1

- initiation or discontinuation of ICS within 30 days of Visit 1

- use of tiotropium or roflumilast within 14 days of Visit 1

- use of theophyllines, oral leukotriene inhibitors, long-acting oral beta-agonists, or
inhaled long-acting beta-agonists within 48 hours of Visit 1

- short-acting oral beta-agonists within 12 hours of Visit 1

- use of LABA/ICS combination products only if discontinuing LABA therapy and switching
to ICS monotherapy within 48 hours of Visit 1 for the LABA component

- use of sodium cromoglycate or nedocromil sodium within 24 hours of Visit 1

- use of inhaled short-acting beta-agonists, inhaled short-acting anticholinergics, or
inhaled short-acting anticholinergic/short-acting beta-agonist combination products
within 4 hours of Visit 1

- use of any other investigational medication within 30 days or 5 drug half-lives
(whichever is longer)

- long-term oxygen therapy prescribed for >12 hours per day

- regular use of nebulized short-acting bronchodilators

- participation in acute phase of pulmonary rehabilitation program

- known or suspected history of alcohol or drug abse within 2 years prior to Visit 1

- anyone affiliated with the investigator site (e.g., investigator, sub-investigator,
study coordinator, employee of a participating investigator or study site, or
immediate family member)

- previous exposure to GSK573719, GSK573719/GW642444 combination, GW642444 (vilanterol),
or fluticasone furoate/GW642444 combination