A 4-week Dose-Ranging, Dose-Interval, Efficacy, Safety and Tolerability Study of GSK961081 in Subjects with COPD.

COPD is a disorder characterized by airflow obstruction and reduced maximum
expiratory flow from the lungs that is not fully reversible. Previous clinical
research has indicated that combining an inhaled muscarinic antagonist with a
beta2-agonist is more effective than the individual components in managing
stable COPD to improve lung function. Therefore, the development of a novel
chemical entity which combines both pharmacological approaches in a single
bifunctional molecule (i.e. a dual pharmacophore) affords clear advantages.
GSK961081 is a bifunctional molecule that demonstrates both anti-muscarinic
receptor activity and beta-adrenergic agonist activity in both pre-clinical and
clinical studies. In previous studies, inhaled GSK961081 has been administered
as a dry powder either as the edisylate or succinate salt. GSK961081 has been
safe and well tolerated and demonstrated bronchodilatory activity in these
studies. In this and future studies, GSK961081 dry powder formulations will
contain the succinate salt. This study is primarily designed to assess the
dose response, dose interval, efficacy and safety of 3 once daily and 3 twice
daily doses for 28 days in subjects with moderate/severe COPD versus placebo.
Salmeterol 50mcg BID is included in the study as an active comparator.

The primary objective of this study is to evaluate the dose response, dose
interval, efficacy, and safety of GSK961081 by studying three QD doses and
three BID doses in subjects with COPD.
The study will also evaluate the population PK, systemic PK-PD, dose-response
and dose-time-response FEV1 profile of GSK961081, and collect blood samples for
a pharmacogenetic study.

Multicenter randomized double blind phase IIb parallel group study en active
and placebo control.
Randomisation (1:1) to treatment with:
1. GSK961081 100 mcg QD
2. GSK961081 400 mcg QD
3. GSK961081 800 mcg QD
4. GSK961081 100 mcg BID
5. GSK961081 200 mcg BID
6. GSK961081 400 mcg BID
7. Salmeterol 50 mcg BID
8. Placebo.
Administration as inhaled dry powder formulation.
Startification according to reversibility (salbutamol) and steroid use.
Treatmnent duration 4 weeks.
Approx 425 patients, 35 in NL.

Treatment with GSK961081, salmeterol or placebo.

Risk: Adverse effects of study medication.
Burden: 6 visits in 6 weeks. Duration 4-14 h ( 2 long measurement days of
approx. 14 h). Fasting required for 2 visits.
Pulmonary function tests: 1x incl. reversibility. During 5 visits serial
measurements (3 visits: 2 tests in 2 h, 2 visits: 10 tests in 13 h).
Blood tests during 4 visits (thereof on 2 occasions 4 draws), 100 ml in total ,
pregnancy test (if relevant) 3x, ECGs during 4 vistis (thereof on 2 occasions 4
recordings).
Daily completion of diary.
Chest X-ray only if not performed in the past 6 months.
Optional blood sample for pharmacogentic research (10 ml).