A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD

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• 作者：James F. Donohue<sup>asup><sup> ; sup><sup>james_donohue@med.unc.edusup> ; Antonio Anzueto<sup>bsup><sup> ; sup><sup>Anzueto@uthscsa.edusup> ; Jean Brooks<sup>csup><sup> ; sup><sup>jean.2.brooks@gsk.comsup> ; Rashmi Mehta<sup>dsup><sup> ; sup><sup>rashmi.s.mehta@gsk.comsup> ; Christopher Kalberg<sup>dsup><sup> ; sup><sup>chris.j.kalberg@gsk.comsup> ; Glenn Crater<sup>dsup><sup> ; sup><sup>glenn.d.crater@gsk.comsup>
• 关键词：Long-acting muscarinic receptor antagonist ; Long-acting bronchodilator ; Anticholinergic ; Chronic obstructive pulmonary disease ; GSK573719
• 刊名：Respiratory Medicine
• 出版年：2012
• 期刊代码：273_09546111
• 类别：med
• 出版时间：July, 2012
• 卷：106
• 期：7
• 页码：970-979
• 文件大小：989 K

摘要

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ss="h3">Summary

ss="h4">Background

This study evaluated the dose-response and dosing interval of the novel long-acting muscarinic receptor antagonist (LAMA) GSK573719 in patients with COPD.

ss="h4">Methods

This randomized, double-blind, placebo-controlled, 3-way cross-over, incomplete block study evaluated 5 once-daily doses of GSK573719 (62.5-1000聽渭g), 3 twice-daily doses (62.5-250聽渭g), and open-label tiotropium for 14 days in patients (N聽=聽176) with COPD (FEV<sub>1sub> of 35-70%predicted). The primary endpoint was morning trough FEV<sub>1sub> at Day 15. Secondary endpoints included 0-24聽h weighted mean FEV<sub>1sub> and serial FEV<sub>1sub> values over 28聽h. Safety measures and pharmacokinetics were assessed.

ss="h4">Results

All once-daily doses of GSK573719 significantly increased trough FEV<sub>1sub> at Day 15 with improvements ranging from 95 to 186聽mL over placebo (p聽鈮ぢ?.006), from 79 to 172聽mL with twice-daily dosing (p聽鈮ぢ?.03), and 105聽mL with tiotropium (p聽=聽0.003). No clear dose ordering was observed. Once-daily doses significantly (p聽<聽0.001) increased 0-24聽h weighted mean FEV<sub>1sub> at Day 14 by 131-143聽mL over placebo, comparable to increases with the twice-daily doses (120-142聽mL) and tiotropium (127聽mL). Significant reductions in rescue albuterol use and improvements in FVC were also observed with once-daily dosing. Plasma C<sub>maxsub> occurred within 5-15聽min of dosing after which the drug was rapidly cleared and eliminated. GSK573719 was well tolerated, with no apparent treatment-related changes in vital signs, ECG and Holter assessments, or clinical laboratory parameters.

ss="h4">Conclusion

Once-daily dosing with GSK573719 in COPD provides clinically significant and sustained improvement in lung function over 24聽h with similar efficacy to twice-daily dosing.