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

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). 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

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