https://orcid.org/0000-0002-9394-091X
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Abstract
Background
Although long-acting muscarinic receptor antagonists are central to the management of chronic obstructive pulmonary disease (COPD), inhaled medicines may have technical difficulty in some patients and adherence barriers.
Methods
A multicenter, randomized, double-blind, placebo-controlled 3×3 crossover Phase II trial was performed to evaluate the efficacy and safety of oral administration of the antimuscarinic agent imidafenacin in patients with COPD. Twenty-seven male COPD patients with % forced expiratory volume in 1 s (FEV1) ≥30% and <80% predicted were randomized to single oral dose of imidafenacin 0.1 mg, imidafenacin 0.2 mg, or placebo.
Results
Maximum change in FEV1 with both doses of imidafenacin significantly improved from baseline to 24 hrs after administration when compared with a placebo. Area under the curve in FEV1 during 24 hrs after administration with 0.2 mg, but not 0.1 mg dose, was significantly improved when compared with a placebo, and the improvement was significantly based on dose-dependent manners. Plasma imidafenacin level was positively correlated with change in FEV1. All subjects with both doses of imidafenacin completed without moderate nor severe adverse events.
Conclusion
A single oral dose of imidafenacin 0.1 mg or imidafenacin 0.2 mg may contribute to the improvement of pulmonary function with excellent safety and tolerability in patients with COPD.
Trial registration
JapicCTI-121760 (Japan Pharmaceutical Information Center – Clinical Trials Information [JapicCTI]; http://www.clinicaltrials.jp/user/cteSearch_e.jsp).
Acknowledgments
Funding for this study was provided by Ono Pharmaceutical Co., Ltd., Osaka, Japan. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank the investigators, health care providers, research staff, and patients who participated in this study. A complete list of the investigators is provided in the Supplementary Appendix.
Abbreviations
AEs, adverse events; ANCOVA, analysis of covariance; AUC, area under the curve; AUC24h, AUC from baseline to 24 hrs; AUCinf, AUC from time 0 to infinity; CL/F, clearance; Cmax, maximum plasma concentration of analyte; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; FAS, full analysis set; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; MedDRA, Medical Dictionary for Regulatory Activities; MMF, mid-maximum flow; PEF, peak expiratory flow; PPS, per protocol set; RND, randomized patients; SAF, safety analysis set; SD, standard deviation; T1/2, elimination half-life; Tmax, time to reach Cmax; V25, 25% vital capacity; V50, 50% vital capacity.
Ethics Approval And Consent To Participate
The study was approved by the Ethics Committee of each of the participating institutions and all subjects gave written informed consent.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Author Contributions
Dr. Machida, Dr. Kawayama, Dr. Kinoshita, Dr. Tsuda, Dr. Takata, Dr. Koto, Dr. Yoshida, Dr. Ashihara, and Dr. Inoue were investigators for this study. Dr. Ichinose was the medical advisor for this study. All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Disclosure
Dr. Kinoshita received honoraria from GlaxoSmithKline K.K., Daiichi Sankyo Co. Ltd., Novartis Pharma K.K., Takeda Pharmaceutical Co. Ltd., and Astellas Pharma Inc. Dr. Tsuda received honoraria from Novartis Pharma K.K., Pfizer Japan Inc., and Nippon Boehringer Ingelheim Co. Ltd. Mr. Kawashima and Dr. Suna are full-time employees of Ono Pharmaceutical Co. Ltd., Japan. Dr. Inoue received research grants from Asahi Kasei Corporation, Astellas Pharma Inc., Nippon Boehringer Ingelheim Co. Ltd., Chugai Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Eisai Co. Ltd., MSD K.K., Nippon Kayaku Co. Ltd., Shionogi & Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., and Teijin Pharma Ltd.; gave lectures and acted on advisory committees for Asahi Kasei Corporation, Astellas Pharma Inc., AstraZeneca K.K., Nippon Boehringer Ingelheim Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., GlaxoSmithKline K.K., Eli Lilly Japan K.K., Kyorin Pharmaceutical Co. Ltd., MSD K.K., Meiji Seika Pharma Co. Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., Shionogi & Co. Ltd., Taisho Pharmaceutical Co. Ltd., and Teijin Pharma Ltd. The authors report no other conflicts of interest in this work.