PURPOSE: This was a phase IIb dose-ranging study for GSK573719, an inhaled LAMA with sustained 24-hour activity under development as a once-daily therapy alone and in combination with the long-acting beta2 agonist vilanterol for the treatment of COPD. The study objectives were to evaluate the efficacy, dose response, safety and pharmacokinetics of GSK573719 in patients with COPD.
METHODS: This was a multicenter, randomized, double-blind, double-dummy, placebo-controlled, three-way cross-over, incomplete block study evaluating five doses of GSK573719 administered once daily (62.5-1000mcg) and three doses twice daily (62.5-250mcg) via a novel single-step activation dry powder inhaler in patients (N=176) with COPD (FEV1 ≥35 and ≤70% predicted). Tiotropium (18mcg, open-label) was an active control. The primary endpoint was morning trough FEV1 after 14 days of treatment.
RESULTS: All doses of GSK573719 significantly increased trough FEV1 at Day 15 with improvements ranging from 95-186mL over placebo (p≤0.006) with once-daily dosing and from 79-172mL with twice-daily dosing (p≤0.03). A 105mL increase was observed for tiotropium. All once-daily doses of GSK573719 significantly (p<0.001) increased 0-24 hour weighted mean FEV1 at Day 14 by 131-143mL over placebo, similar to increases with twice-daily dosing (120-142mL) and tiotropium (127mL). All doses of GSK573719 significantly reduced rescue albuterol use, except 62.5mcg and 1000mcg once daily. Across all doses, plasma Cmax on Day 14 occurred at a median tmax of 5-15 minutes; steady-state was achieved by Day 7. No correlations between Cmax and heart rate were observed. GSK573719 was well tolerated at all doses, with no apparent treatment-related changes in vital signs, ECG and Holter assessments, or clinical laboratory parameters.
CONCLUSIONS: Once-daily dosing with GSK573719 in patients with COPD provides clinically significant and sustained improvement in lung function over 24 hours with similar efficacy to twice-daily dosing.
CLINICAL IMPLICATIONS: Further development of GSK573719 may provide an alternative to currently available long-acting bronchodilators for the treatment of COPD. Funded by GSK (AC4113073; NCT00950807)
DISCLOSURE: James Donohue: Consultant fee, speaker bureau, advisory committee, etc.: Consultant to: Almiral, Forest Laboratories, BI AZ, GSK , Pfizer, Novartis , Pearl, Elevation Pharm, Dey, Sunovion, Grant monies (from industry related sources): Research grants with BI, Novartis, GSK
Antonio Anzueto: Grant monies (from sources other than industry): NHLBI funding - COPD gene study, Grant monies (from industry related sources): ): Grant for clinical research studies to the University of Texas Health Science Center at San Antonio - GKS, Lilly, Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: GSK, Forest, BI, Astra-Zeneca, Bayer-Schering
Jean Brooks: Shareholder: Holds shares in GSK, Employee: Employee of GSK
Rashmi Mehta: Employee: Employee of GSK, Shareholder: Holds shares in GSK
Chris Kalberg: Employee: Employee of GSK, Shareholder: Holds stocks in GSK
Glenn Crater: Employee: Employee of GSK, Shareholder: Holds shares in GSK
Results from a phase IIb clinical trial of an investigational product GSK573719 for treatment of COPD