Efficacy and safety of the long-acting muscarinic antagonist, GSK233705, delivered once-daily in patients with COPD.
ABSTRACT Introduction: GSK233705 is a recently developed inhaled anticholinergic being investigated for the potential treatment of chronic obstructive pulmonary disease (COPD). Objectives: This dose-ranging, parallel-group, double-blind study compared the bronchodilator efficacy, safety and pharmacokinetics of GSK233705 with placebo in patients with moderate to severe COPD. Methods: Patients were randomised to receive 12.5µg, 25µg, 50µg, 100µg or 200µg of GSK233705 or placebo once-daily for 28 days. The primary endpoint was change from baseline in trough forced expiratory volume in one second (FEV(1) ) on Day 29. Results: The Intent-to-treat population consisted of 576 patients (mean predicted FEV(1) 51%; mean age 62 years). Treatment with GSK233705 produced statistically significant improvements in pulmonary function compared with placebo. Only the 200µg dose exceeded the pre-defined target threshold of 130 mL difference compared with placebo for the primary endpoint of change from baseline in trough FEV(1) on Day 29. No clear pattern of dose response was observed for the other doses. Serial FEV(1) (0-24 hours) showed a peak effect around 2 hours post-dose and tended to decline to clinically insignificant levels compared with placebo at 23 and 24 hours. Each dose of GSK233705 was well tolerated. The incidence of adverse events was low and similar across all treatment groups. There were no clinically significant effects on laboratory parameters, vital signs, or ECGs. Conclusion: All doses of GSK233705 demonstrated bronchodilatory activity and were well tolerated. Although the onset of bronchodilation was rapid, it was not sustained over 24 hours making it unsuitable for once-daily dosing.