24-week Trial Comparing GSK573719/GW642444 With GSK573719 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, GSK573719 125mcg, 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