A 3-period Crossover Study With GSK573719 as Monotherapy in Adult Subjects With Asthma

Asthma, a reversible obstructive disease of the airways, is defined as a chronic
inflammatory disorder of the airways in which many of the cells and cellular mediators play
a role. The chronic inflammation is associated with airway hyper-responsiveness that leads
to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing,
particularly at night or early in the morning. These episodes are usually associated with
widespread, but variable airflow obstruction within the lung that is often reversible either
spontaneously or with treatment (NIH 2007, GINA, 2010,). Guidelines recommend a stepwise
approach to the management of asthma. For many patients with mild disease, asthma symptoms
can be adequately relieved by 'on demand' use of a short acting beta-2 -agonist (SABA)
alone. A long-acting, inhaled, muscarinic receptor antagonist (LAMA) exerts its effects via
distinct and complementary bronchodilator mechanisms on large and small airways through
antagonism of the endogenous agonist acetylcholine at the muscarinic receptors leading to
smooth muscle relaxation and bronchodilation. However, most experience with older
anti-cholinergics has been with acute use and little is known about their effect in chronic
use or as maintenance in asthma.

Newer more selective muscarinic receptor antagonists are being developed for chronic use
which appear to have a better adverse event profile compared with older anti-cholinergics in
the treatment of asthma [Moulton 2011]. A once daily long-acting, inhaled, muscarinic
receptor antagonist (LAMA) bronchodilator, GSK573719, may offer an alternative treatment
option to patients with asthma.

The proposed study is a multi-national, randomized, double-blind, 3-period crossover,
incomplete block study in outpatient subjects with mild asthma and who are not using inhaled
corticosteroids (ICS) for symptom control. The primary objective of this study is to
evaluate the dose response, efficacy and safety of five once-daily doses of GSK573719
compared with placebo, over a 14-day treatment period, in patients with asthma. A placebo
arm will be included to determine an absolute treatment effect over placebo for each
GSK573719 dose regimen.

Each eligible subject will be randomized to receive 3 out of 8 potential treatments in
sequence over a total of three 14-day treatment periods. There will be 12 clinic visits
including a safety follow-up visit at the end of the study. All subjects will be provided
with albuterol (salbutamol) for use on an 'as-needed' basis throughout the run-in, treatment
and washout periods. A sub-group (approximately 30%) of the study population will comprise
subjects from selected sites. These subjects will have additional assessments at the start
and end of each treatment period, including serial spirometry, serial ECGs, 24 hour Holter
monitoring, and samples of blood and urine for pharmacokinetic analysis. Other safety
parameters include the incidence of adverse events, vital signs, clinical laboratory
parameters, ECGs and spirometry, including twice daily peak expiratory flow, asthma
exacerbation assessment. and use of salbutamol.

Inclusion Criteria:

- Written informed consent

- Outpatient (sub-group will have 3 overnight stays at clinic)

- Diagnosis of asthma (NIH 2007) for at least 6 months

- Male or Eligible female (females of child-bearing potential must use acceptable
method of birth control)

- A best AM pre-bronchodilator FEV1 of 60% to 85% of predicted normal value at
Screening

- Reversibility of disease demonstrated by at least 12% and 200mL increase in FEV1 .

- Subjects must have been prescribed a non-corticosteroid controller at least 3 months
preceding Visit 1, and/or a short-acting beta 2 agonist, without the use of inhaled
corticosteroids in the 4 weeks prior to Visit 1

- Subjects must be able to replace their current short-acting Beta-2-agonist with
albuterol/salbutamol aerosol inhaler for the duration of the study

- Subjects must be judged capable of withholding albuterol/salbutamol for at least 4
hours prior to study visits

Exclusion Criteria:

- History of life threatening asthma

- Severe asthma exacerbation

- Respiratory infection within expected to affect subject's ability to participate

- Concurrent respiratory disease

- Current smoker or smoking history of 10 pack years or more

- Diseases preventing use of anticholinergics

- Other clinically significant, uncontrolled condition or disease which would pose a
safety risk to the patient, or confound interpretation of study results

- Drug allergy to any Beta-2-agonist, sympathomimetic drug, intranasal, inhaled or
systemic corticosteroid therapy

- Known or suspected sensitivity to the constituents of the Novel DPI (ie lactose)

- History of severe milk protein allergy

- Administration of prescription or over-the-counter medication that would
significantly affect the course of asthma, or interact with the study drug

- Any infirmity, disability or disease of a child or family member likely to impair
compliance

- Alcohol or substance abuse history

- Viral hepatitis B surface antigen or Hepatitis C antibody

- Known HIV-positive history.

- Affiliation with investigator or site staff