Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients

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Abstract

Background

This study evaluated the dose–response of the new long-acting muscarinic antagonist umeclidinium (GSK573719) in patients with COPD.

Methods

This randomized, double-blind, placebo-controlled, parallel-group study evaluated three once-daily doses of umeclidinium (125, 250 and 500 μg) for 28 days in 285 patients with COPD having FEV1 of 35–70% predicted (mean (SD) age = 61.4 (8.41); mean (SD) post-bronchodilator FEV1 = 1.577 (0.450)). The primary endpoint was morning trough FEV1 at Day 29. Secondary endpoints included 0–6 h weighted mean FEV1 and serial FEV1 measured over 6 h post-dose and at trough. Safety and pharmacokinetics were also assessed.

Results

All doses of umeclidinium significantly increased trough FEV1 over placebo from 150 to 168 mL (p < 0.001), 0–6 h weighted mean FEV1 from 113 to 211 mL (p < 0.001), and serial FEV1 at each point in time over 24 h. Reductions in salbutamol use and improvements in FVC were noted for all doses. Umeclidinium was well tolerated with no apparent treatment-related changes in vital signs.

Conclusion

Once-daily umeclidinium provides clinically significant, sustained improvement in lung function and is well tolerated.

Highlights

► New inhaled long-acting muscarinic antagonist (LAMA). ► Randomized, double-blind placebo controlled study. ► Significant increases in trough FEV1 ranging from 150 to 168 mL. ► Significant increases in 0–6 h weighted mean FEV1 ranging 113–211 mL.

Introduction

Bronchodilators remain the mainstay in the treatment of chronic obstructive pulmonary disease (COPD) (GOLD, 2011). Umeclidinium (GSK573719) is a new quinuclidine-based quaternary ammonium inhaled long-acting muscarinic antagonist (LAMA), in development for the once-daily treatment of COPD as a monotherapy and in combination with the long-acting β2-agonist vilanterol.

LAMAs such as tiotropium bromide have previously been shown to provide effective bronchodilation in COPD patients (Casaburi et al., 2002, Vincken et al., 2002) conferring clinically meaningful improvements on trough forced expiratory volume1 (FEV1) and post-bronchodilator FEV1 (Tashkin et al., 2008, Littner et al., 2000). This agent has been shown to improve health-related quality of life to a clinically meaningful extent (Casaburi et al., 2002, Vincken et al., 2002, Tashkin et al., 2008) increase exercise tolerance and reduce exacerbation and hospitalization rate relative to placebo (Tashkin et al., 2008, Niewoehner et al., 2005, Dusser et al., 2006). Tiotropium dissociates more slowly from the M1 and M3 muscarinic receptors than from M2 receptors, such that a prolonged action is obtained (Lipson, 2006).

Previous clinical studies have demonstrated that single and repeat dose administration of the LAMA umeclidinium for up to 14 days is safe and well tolerated in healthy volunteers and patients with COPD (Donohue et al., 2012) with low systemic exposure. The extended residence time of umeclidinium at airway smooth muscle muscarinic receptors leads to sustained bronchodilation over 24 h, meaning that it is suitable for once-daily treatment of COPD (Laine et al., 2011).

The present study was designed to further evaluate the dose–response, safety and pharmacokinetics of umeclidinium in patients with COPD over a greater period of time and in a larger cohort of patients than in previous studies.

Section snippets

Patients and methods (inclusion, exclusion, meds)

Patients were recruited between December 2009 and July 2010 at 21 centres worldwide. All patients gave written informed consent prior to any study related procedures and the protocol was approved by the appropriate institutional review boards and conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki. We recruited men and women aged 40–80 years with a clinical history of COPD (Celli and Macnee, 2004) a smoking history of ≥10 pack years, a

Study population

A total of 421 patients were screened to randomize 288 patients, 285 of whom received at least one dose of study treatment (Fig. 2). Of those included, 264 patients completed the treatment period, as 7% of subjects were withdrawn while receiving treatment. The primary reasons for withdrawal during treatment were AE (1%), COPD exacerbation (3%), protocol deviation (1%), withdrew consent (1%), and met study stopping criteria (<1%). The demographics and baseline characteristics of treatment groups

Discussion

The present data demonstrate that umeclidinium, a new long-acting muscarinic antagonist, provides long-acting bronchodilation in patients with moderate to very severe COPD. No evidence of a dose–response effect was seen. Umeclidinium was well tolerated with no treatment-related serious AEs and low incidence of anticholinergic side effects. These data support the potency of umeclidinium as a bronchodilator, with a duration of action consistent with once-daily dosing; a corresponding reduction in

Conflict of interest

Marc Decramer has been part of Advisory Board for Boehringer-Pfizer, GSK, Nycomed, Altana Novartis and Vectura. He has performed consulting work for Boehringer-Pfizer, GSK, AstraZeneca and Dompé. He also received lecture fees from these companies. All of the above amounted to less than 10,000 euro per annum. He received a research grant of 45,000 euro/year from AstraZeneca.

François Maltais has no conflict of interest to disclose.

Gregory Feldman has received funds as the Principal Investigator in

Acknowledgements

The authors would like to thank the study participants and the participating study personnel. All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Statistical support was additionally provided by Lisa Willits at GlaxoSmithKline. Editorial support in the form of editorial suggestions to draft versions of this paper, assembling tables and figures, collating author comments, referencing and graphic services was provided by Cheryl

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