An Exercise Endurance Study to Evaluate the Effects of Treatment of Chronic Obstructive Pulmonary Disease (COPD) Patients With a Dual Bronchodilator: GSK573719/GW642444. Study A

This is a phase III multicenter, randomized, double-blind, placebo-controlled, combination and component, two-period, incomplete block design cross-over study using GSK573719/GW642444. The primary objective is to evaluate lung function and exercise endurance time after 12 weeks of once-daily administration of GSK573719/GW642444 Inhalation Powder (125/25mcg and 62.5/25mcg), GSK573719 Inhalation Powder (125mcg and 62.5mcg), GW642444 Inhalation Powder 25 mcg and placebo delivered by a Novel dry powder inhaler (Novel DPI)

Expiratory airflow limitation is the most obvious physiological change associated with chronic obstructive pulmonary disease (COPD). A consequence of airflow limitation is gas trapping as expiration becomes flow limited. This may occur at rest with more severe airway obstruction and is most evident during exercise as lung emptying is reduced and increased ventilation does not allow full expiration. This increased gas trapping or hyperinflation is the cause of much of the increased work of breathing, dyspnea, and exercise intolerance in subjects with COPD (O'Donnell 1997; O'Donnell, 1993). Spirometric measurement of airflow limitation, particularly as assessed by forced expiratory volume in one second (FEV1), is commonly used for the diagnosis of and assessment of response to pharmacotherapeutic intervention in COPD. However, changes in FEV1 may not fully predict symptomatic responses and alternative measures of lung hyperinflation such as exercise tolerance and exertional dyspnea may be more sensitive to therapeutic intervention and/or more clinically relevant than FEV1 \[O'Donnell1999; Bauerle, 1998; O'Donnell, 1998; Officer, 1998\]. GSK573719/GW642444 Inhalation Powder, a combination of the long-acting muscarinic antagonist (LAMA) bronchodilator GSK573719 and the long-acting beta2-agonist (LABA) bronchodilator GW642444, is in development for the maintenance treatment of airflow obstruction associated with COPD. Development of this product is supported by studies showing improvement in lung function with similar safety when use of combinations of long-acting bronchodilators with different mechanisms of action are compared with single bronchodilator therapy \[van Noord 2005; van Noord van Noord 2006; Tashkin 2008\]. Previous studies have demonstrated that treatment with short- and long-acting bronchodilators including ipratropium, tiotropium, and salmeterol reduces resting lung hyperinflation as measured by functional residual capacity (FRC), residual volume (RV), and inspiratory capacity (IC), with associated improvements in exercise endurance time and exertional dyspnoea in subjects with COPD \[Ayers, 2001; O'Donnell 1998; O'Donnell 2004; Pepin 2005; Pepin 2007; Ramirez-Venegas 1997\]. However, the effect of combined LAMA/LABA therapy on these measures is not well characterized.

This is a phase III multicenter, randomized, double-blind, placebo-controlled, combination and component, two-period, incomplete block design cross-over study using GSK573719/GW642444. The primary objective is to evaluate lung function and exercise endurance time after 12 weeks of once-daily administration of GSK573719/GW642444 Inhalation Powder (125/25mcg and 62.5/25mcg), GSK573719 Inhalation Powder (125mcg and 62.5mcg), GW642444 Inhalation Powder 25 mcg and placebo delivered by a Novel dry powder inhaler (Novel DPI) Approximately 312 subjects with moderate/severe chronic obstructive pulmonary disease (COPD) will be randomised in order to achieve 208 subjects completing both treatment periods of 3 months.. There will be a total of 12 study clinic visits conducted on an outpatient basis. Subjects who meet the eligibility criteria at Screening (Visit 1) will complete a 12 to 21 day run-in period followed by two 12-week treatment periods that are separated by a 14 day wash-out. Clinic visits will be conducted at Screening (Visit 1), twice during the run-in period (Visits 2 and 3), at randomization (Visit 4) and three times during the first treatment period, on Treatment Day 2 (Visit 5) and at 6 and 12 weeks (Visits 6 and 7 respectively). During the washout period of 14 days there will be 2 clinic visits (Visits 8 and 9). During the second treatment period there will be 3 clinic visits, on Treatment Day 2 (Visit 10) and at 6 and 12 weeks (Visits 11 and 12 respectively). A Safety Follow-Up assessment (Visit 13) to record adverse events will be conducted by telephone 7 days after the end of the second treatment period or early withdrawal. Efficacy measurements will include pre and post dose FEV1, lung volume measurements and exercise endurance time measured using the endurance shuttle walking test (ESWT). Oxycon mobile measurements will be conducted in a subgroup of approximately 104 patients to investigate cardio respiratory measures during exercise. Safety and tolerability will be assessed by collection of adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), clinical laboratory tests and incidence of COPD exacerbations. Dyspnea will be assessed using the Exercise Dyspnea Scale (EDS), a patient-reported outcome. Blood samples will also be collected for potential pharmacogenetics analysis

Eligibility Criteria:
Inclusion Criteria:

* Type of subject: Outpatient.
* Informed Consent: A signed and dated written informed consent prior to study participation.
* Age: 40 years of age or older at Visit 1.
* Gender: Male or female subjects.
* Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society \[Celli, 2004\]
* Smoking History: Current or former cigarette smokers with a history of cigarette smoking of ≥ 10 pack-years
* Severity of Disease: A post-albuterol/salbutamol FEV1/FVC ratio of \<0.70 and a post-albuterol/salbutamol FEV1 of \>35% and \<70% of predicted normal
* Dyspnea: A score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1
* Resting Lung Volumes: A resting FRC of ≥120% of predicted normal FRC at Visit 1.

Exclusion Criteria:

* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
* Asthma: A current diagnosis of asthma.
* Other Respiratory Disorders: Known respiratory disorders other than COPD including but not limited to alpha-1 antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, and interstitial lung disease. Allergic rhinitis is not exclusionary.
* Other Diseases/Abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for \< 5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. Any physical or mental abnormality which would affect the patient carrying out exercise tests including peripheral vascular disease should be excluded at the investigators discretion.
* Chest X-Ray: A chest X-ray or computed tomography (CT) scan that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at Visit 1 if a chest X-ray or CT scan is not available within 6 months prior to Visit 1. For subjects in Germany, if a chest X-ray (or CT scan) is not available in the 6 months prior to Visit 1 the subject will not be eligible for the study.
* Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic.
* Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
* Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
* 12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1, including the presence of a paced rhythm on a 12-lead electrocardiogram (ECG) which causes the underlying rhythm and ECG to be obscured. Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility.
* Screening Labs: Significantly abnormal finding from clinical chemistry and hematology tests at Visit 1.
* Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
* Medications prior to Screening, including depot,oral corticosteroids, combinations of LABA/ICS, LABA, PDE4 inhibitors.
* Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., \<12 hours per day) is not exclusionary.
* Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy
* Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
* Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
* Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study