A 52-Week, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate the Safety and Tolerability of GSK573719/GW642444 and GSK573719 in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

A 52 Week Study to Evaluate the Safety and Tolerability of GSK573719/GW642444 125mcg Once-daily Alone and in Combination With GW642444 25mcg Once-daily Via Novel Dry Powder Inhaler (nDPI) in Subjects With Chronic Obstructive Pulmonary Disease

The purpose of this 52-week study is to evaluate the long-term safety (in terms of adverse events, COPD exacerbations, laboratory, ECG, and Holter findings, vital signs, use of rescue medication and lung function) of GSK573719/GW642444 Inhalation Powder 125/25mcg in subjects with COPD. The long-term safety of GSK573719 Inhalation Powder 125mcg will also be evaluated. A placebo arm is included to evaluate these products compared to an inactive control.

Several studies have demonstrated the efficacy and safety of combining an individual LABA compound plus an individual LAMA compound in COPD. These studies have shown the combination of these two products to be superior to either agent alone on a variety of outcomes in COPD. The beneficial effects of this combination regimen are likely due to the different mechanisms of action of the two bronchodilators (smooth bronchial muscle relaxation from activation of beta2 receptors from the LABA product and inhibition of acetylcholine-mediated smooth bronchial muscle contraction via blockade of muscarinic receptors from the LAMA product). The availability of a LABA/LAMA combination in one product instead of two individual products is a technical and therapeutic advancement in the pharmacological armamentarium for COPD and may lead to increased patient compliance due to once-daily administration. The purpose of this 52-week study is to evaluate the long-term safety (in terms of adverse events, COPD exacerbations, laboratory, ECG, and Holter findings, vital signs, use of rescue medication, and lung function) of GSK573719/GW642444 Inhalation Powder 125/25mcg in subjects with COPD. The long-term safety of GSK573719 Inhalation Powder 125mcg will also be evaluated. A placebo arm is included to evaluate these products compared to an inactive control. All treatments will be delivered once-daily via the nDPI. This study will establish the long-term safety profile of GSK573719/GW642444 Inhalation Powder 125/25mcg once-daily in subjects with COPD. The safety profile of GSK573719 Inhalation Powder125mcg once-daily will also be evaluated.

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 greater than or equal to 35% and less than or equal to 80% of predicted normal

Exclusion Criteria:

• Pregant or lactating women or women planning to become 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
• abnormal and clinically significant Holter monitor finding at Visit 1
• significantly abnormal finding from laboratory tests at Visit 1
• unable to withhold albuterol/salbutamol and/or ipratropium bromide 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 within 6 weeks of Visit 1
• use of anitbiotics for lower respiratory tract infection within 6 weeks of Visit 1
• use of cytochrome P450 3A4 inhibitors within 6 weeks of Visit 1
• us of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) products if LABA/ICS therapy is discontinued completely within 30 days of Visit 1
• use of ICS at a dose of >10000mcg/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 within 14 days of Visit 1
• use of roflumilast within 14 days of Visit 1
• use of theophyllines within 48 hours of Visit 1
• use of oral leukotriene inhibitors within 48 hours prior to Visit 1
• use of long-acting oral beta-agonists within 48 hours of Visit 1
• use of short-acting oral beta-agonists within 12 hours of Visit 1
• use of inhaled long-acting beta-agonists within 48 hours prior to 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 within 4 hours of Visit 1
• use of inhaled short-acting anticholinergics within 4 hours of Visit 1
• use of inhaled short-acting anticholinergic/short-acting beta2-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) of Visit 1
• long-term oxygen therapy prescribed for >12 hours per day
• regular use of short-acting bronchodilators
• use of CPAP or NIPPV
• participation in the maintenance phase of a pulmonary rehabilitation program
• known or suspected history of alcohol or drug abluse with 2 years prior to Visit 1
• anyone affiliated with the investigator site (e.g., investigator, study coordinator, etc.)
• previous use of GSK573719, GW642444 , GSK573719/GW642444 combination, GSK233705/GW642444 combination, or Fluticasone Furoate/GW642444 combination