Efficacy of Aclidinium Bromide 400 μg Twice Daily Compared With Placebo and Tiotropium in Patients With Moderate to Severe COPD

Rainard Fuhr, MD, PhD; Helgo Magnussen, MD; Kristina Sarem, MD; Anna Ribera Llovera, PharmD, PhD; Anne-Marie Kirsten, MD; Meritxell Falqués, MS; Cynthia F. Caracta, MD, FCCP; Esther Garcia Gil, MD

Disclosures

CHEST. 2012;141(3):745-752. 

In This Article

Abstract and Introduction

Abstract

Background: The efficacy and safety of aclidinium bromide bid, a novel, long-acting, muscarinic antagonist, was assessed in patients with moderate to severe COPD.
Methods: In this phase IIa randomized, double-blind, double-dummy, crossover trial, patients with moderate to severe COPD received aclidinium 400 μg bid, tiotropium 8 μg once daily, and placebo for 15 days, with a 9− to 15-day washout between treatment periods. Treatments were administered through the Genuair or HandiHaler dry powder inhalers. The primary end point was mean change from baseline in FEV1 AUC 0–12/12h (area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [eg, 0–12 h postdose divided by 12 h]) on day 15. Secondary end points were changes from baseline in FEV1 AUC 12–24/12h, FEV1 AUC 0–24/24h, morning predose FEV1, peak FEV1, and COPD symptom scores.
Results: Thirty patients with COPD were randomized, and 27 completed the study. Mean change from baseline in FEV1 AUC 0–12/12h at day 15 was significantly greater for aclidinium and tiotropium over placebo ( P < .0001). Mean changes from baseline in FEV1 AUC 12–24/12h, FEV1 AUC 0–24/24h, morning predose FEV1, and peak FEV1 at day 15 were significantly greater for aclidinium and tiotropium over placebo ( P < .0001 for all except P < .001 for FEV1 AUC 12–24/12h tiotropium vs placebo). Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV1 as well as on day 15 for FEV1 AUC 12–24/12h ( P < .05 for all). COPD symptoms were significantly improved from baseline with aclidinium vs placebo ( P < .05) but not with tiotropium.
Conclusions: In patients with COPD, aclidinium 400 μg bid compared with placebo provided clinically meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 μg daily but with significant differences in favor of aclidinium observed in the average nighttime period. Larger studies with longer treatment duration are ongoing to confirm the efficacy of aclidinium 400 μg bid on bronchodilation and COPD symptoms.

Introduction

COPD is a major cause of morbidity worldwide,[1–4] characterized by a gradual loss of lung function and increased cholinergic tone.[1] GOLD (Global Initiative for Chronic Obstructive Lung Disease) recommends long-acting bronchodilators as an effective COPD treatment,[1] and daily tiotropium bromide is currently the only available long-acting anticholinergic drug.[5,6] Aclidinium bromide is a new, long-acting, muscarinic antagonist currently under review with the US Food and Drug Administration and European Medicines Agency for the bid maintenance treatment of COPD. Aclidinium is rapidly hydrolyzed in human plasma to two major inactive metabolites,[7–9] suggesting that aclidinium may have a reduced potential for systemic side effects and a wider safety margin than the currently available inhaled anticholinergic treatments. The purpose of this study was to assess the bronchodilator efficacy and safety of inhaled aclidinium 400 μg bid vs a morning dosing regimen of tiotropium 18 μg daily and placebo in patients with moderate to severe COPD.

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