A 24-week Evaluation of GSK573719/Vilanterol (62.5/25mcg) and Components in COPD
A 24-week Evaluation of GSK573719/Vilanterol (62.5/25mcg) and Components in COPD
This is a phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group
 study to evaluate the efficacy and safety of GSK573719/GW642444 Inhalation Powder, GSK573719
 Inhalation Powder, GW642444 Inhalation Powder and Placebo when administered once-daily via a
 Novel Dry Powder Inhaler over a 24-week treatment period in subjects with COPD. Subjects who
 meet eligibility criteria at Screening (Visit 1) will complete a 7 to14 day run-in period
 followed by a randomization visit (Visit 2) then a 24-week treatment period. There will be a
 total of 9 clinic study visits. A follow-up phone contact for adverse event assessment will
 be conducted approximately one week after the last study visit (Visit 9 or Early Withdrawal).
 The total duration of subject participation in the study will be approximately 27 weeks. A
 subset of subjects at selected sites will also perform 24-hour serial spirometry and Holter
 monitoring during the study and provide serial blood samples for pharmacokinetic analysis.
 Sparse pharmacokinetic sampling for population pharmacokinetic analyses will be obtained from
 non-subset subjects. The primary measure of efficacy is clinic visit trough
 (pre-bronchodilator and pre-dose) FEV1 on Treatment Day 169. Safety will be assessed by
 adverse events, 12-lead ECGs, vital signs, clinical laboratory tests, and 24 hour Holter
 monitoring (subset only).
This is a 24-week, phase III multicenter, randomized, double-blind, placebo-controlled,
 parallel-group study.

 Eligible subjects will be randomized to GSK573719/GW642444 125/25mcg, GSK573719 125mcg,
 GW642444 25mcg, and placebo treatment groups in a 3:3:3:2 ratio such that of the planned 1463
 total number of randomized subjects approximately 399 subjects will be randomized to each
 active treatment group and 266 subjects will be randomized to placebo. All treatments will be
 administered once-daily in the morning by inhalation using a Novel Dry Powder Inhaler (Novel
 DPI).

 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 14 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 27 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/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, 4, 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 evening throughout the run-in and treatment periods. Subjects will use the eDiary to
 record 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. Disease specific health status will be
 evaluated using the subject-completed St. George's Respiratory Questionnaire (SGRQ). The SGRQ
 will be completed at Visits 2, 4, 6, and 8. Administration of the SGRQ and BDI/TDI should be
 done prior to spirometry testing.

 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. Blood samples for population pharmacokinetic analyses will be
 obtained.

 At selected study sites, a subset of approximately 198 subjects will perform 24-hour serial
 spirometry during the study for evaluation of lung function over the dosing period. In
 conjunction with the serial spirometry, this subset of subjects will also perform 24 hour
 Holter monitoring and provide blood samples for PK analysis.
Inclusion Criteria:

 -  Diagnosis of COPD

 -  10 pack-year or greater history of cigarette smoking

 -  Post-bronchodilator FEV1/FVC of <0.7

 -  Predicted FEV1 of 70% of normal or less

 -  Modified Medical Research Council (mMRC) dyspnea score of 2 or greater

 Exclusion Criteria:

 -  Women who are pregnant, lactating, or planning to become pregnant

 -  Respiratory disorders other than COPD, including a current diagnosis of asthma

 -  Clinically significant non-respiratory diseases or abnormalities that are not adequate
 controlled

 -  Significant allergy or hypersensitivity to anticholinergics, beta-agonist, or the
 excipients of magnesium stereate or lactose used in the inhaler delivery device

 -  Hospitalization for COPD or pneumonia within 12 weeks prior to screening

 -  Lung volume reduction surgery within 12 weeks prior to screening

 -  Abnormal and clinically significant ECG findings at screening

 -  Clinically significant laboratory findings at screening

 -  Use of systemic corticosteroids, antibiotics for respiratory tract infections, strong
 cytochrome P450 3A4 inhibitors, high dose inhaled steroids (>1000mcg fluticasone
 propionate or equivalent), PDE4 inhibitors, tiotropium, oral beta2-agoinists, short-
 and long-acting inhaled beta2-agonists, ipratropium, inhaled sodium cromoglycate or
 nedocromil sodium, or investigational medicines for defined time periods prior to the
 screening visit

 -  Use of long-term oxygen therapy (12 hours or greater per day)

 -  Regular use of nebulized treatment with short-acting bronchodilators

 -  Participation in the acute phase of a pulmonary rehabilitation program

 -  A know or suspected history of alcohol or drug abuse

 -  Affiliation with the investigational site

 -  Previous use of GSK573719 or GW642444 alone or in combination, including the
 combination of fluticasone furoate and GW64244