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1、511ORIGINAL RESEARCHEffi cacy and Safety of Aclidinium Bromide Compared with Placebo and Tiotropium in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease: Results from a 6-week, Randomized, Controlled Phase IIIb StudyJutta Beier,1 Anne-Marie Kirsten,2 Robert Mrz,3 Rosa Segarra,4
2、Ferran Chuecos,4 Cynthia Caracta,5 and Esther Garcia Gil41 insaf Respiratory Research Institute, Wiesbaden, Germany2 Pulmonary Research Institute at Hospital Grosshansdorf, Grosshansdorf, Germany3 ISPL Centrum Medyczne and Department of Lung Diseases and Tuberculosis, Medical University of Bialystok
3、, Bia ystok, Poland4 Almirall, Barcelona, Spain5 Forest Research Institute, Jersey City, New Jersey, USAAbstract Background: This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to
4、-severe chronic obstructive pulmonary disease (COPD). Methods: Patients received aclidinium 400 g twice daily (morning and evening), tiotropium 18 g once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curv
5、e for the 24-hour period post-morning dose (FEV1 AUC024) at week 6. Secondary and additional endpoints included FEV1 AUC1224, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms E-RS total score and additional symptoms questionnaire), and safety. Results: Overall, 414
6、 patients were randomized and treated (FEV1 1.63 L 55.8% predicted). Compared with placebo, FEV1 AUC024 and FEV1 AUC1224 were significantly increased from baseline with aclidinium ( = 150 mL and 160 mL, respectively; p 0.0001) and tiotropium ( = 140 mL and 123 mL, respectively; p 0.0001) at week 6.
7、Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p 0.0001) than tiotropium (p 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus
8、 placebo (p 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (1.5%) or serious AEs (3%) occurred in any group. Conclusions: Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after
9、6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated. COPD, 10:511522, 2013ISSN: 1541-2555 print / 1541-2563 onlineCopyright Informa Healthcare USA, Inc.DOI: 10.3109/15412555.2013.814626IntroductionCir
10、cadian variation in lung function, driven in part by changes in cho-linergic tone, has been documented in patients with chronic obstructive pulmonary disease (COPD) (13). Variation in COPD daily symptoms has also been reported, with the most severe symptoms generally experienced in the mor ning foll
11、owed by during the nighttime (4, 5). Consequently, the importance of identifying and managing early-morning symptoms is gener-ally accepted. However, unlike in asthma where variation in lung function Keywords: 24-hour, bronchodilation, long-acting muscarinic antagonist, nighttime, symptomsClinical t
12、rial registration: This trial was registered on clinicaltrials.gov (NCT01462929).Correspondence to: Dr Jutta Beier, insaf Respiratory Research Institute, Biebricher Allee 34, 65187, Wiesbaden, Germany, phone: +49 611 985 4410, email: j.beierinsaf-wi.deLCPD_A_814626.indd 511LCPD_A_814626.indd 5117/19
13、/13 2:31:18 PM7/19/13 2:31:18 PMCopyright 2013 Informa Healthcare USA, Inc512 Beier et al. and symptoms has been better characterized, the clini-cal relevance of nighttime symptoms can sometimes be underestimated in COPD and a lack of routine assess-ment means they can be under-reported (6). As symp
14、-toms throughout the day impact on patient quality of life (5), maintaining signifi cant bronchodilation and symptom control over 24 hours should be an impor-tant goal of therapy. Inhaled bronchodilatory therapies, including long-acting 2-agonists and long-acting muscarinic antago-nists (LAMAs), are
15、 central to COPD management (7); however, until recently, tiotropium bromide was the only available agent in the LAMA class (2, 8). Aclidinium bromide is a LAMA that has recently been approved as a maintenance bronchodilator treatment for patients with COPD (9, 10). In a Phase IIa study, twice-daily
16、 (BID) treatment with aclidinium 400 g was demonstrated to provide signifi cant improvements in 24-hour bron-chodilation versus placebo that were generally similar to once-daily (QD) treatment with tiotropium 18 g after 2 weeks, although signifi cant diff erences in favor of acli-dinium were observed for the nighttime period (11). Th e Phase IIIb study reported in this paper was con-ducted to confi rm the 24-hour bronchodilatory effi cacy of aclidinium versus placebo and tiotropium over a longer
