Navafenterol (AZD8871) in patients with COPD: a randomized, double-blind, phase I study evaluating safety and pharmacody
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RESEARCH
Open Access
Navafenterol (AZD8871) in patients with COPD: a randomized, double-blind, phase I study evaluating safety and pharmacodynamics of single doses of this novel, inhaled, longacting, dual-pharmacology bronchodilator Dave Singh1*, Victor Balaguer2, Carol Astbury2, Ulrika Wählby-Hamrén3, Eulalia Jimenez4, Beatriz Seoane5, Cristina Villarroel6, Alejhandra Lei7, Ajay Aggarwal8 and Ioannis Psallidas9
Abstract Background: Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β2−agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD). The pharmacodynamics, safety and tolerability of single doses of navafenterol were investigated in patients with moderate to severe COPD. Methods: This was a randomized, five-way complete cross-over study. Patients received single doses of navafenterol 400 μg, navafenterol 1800 μg and placebo (all double-blind) and indacaterol 150 μg and tiotropium 18 μg (both open-label active comparators). The primary pharmacodynamic endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 2. Safety and tolerability were monitored throughout. Results: Thirty-eight patients were randomized and 28 (73.7%) completed the study. Navafenterol 400 μg and 1800 μg demonstrated statistically significant improvements vs placebo in change from baseline in trough FEV1 (least squares mean [95% confidence interval]: 0.111 [0.059, 0.163] L and 0.210 [0.156, 0.264] L, respectively, both P < .0001). The changes were significantly greater with navafenterol 1800 μg vs the active comparators (least squares mean treatment difference: 0.065–0.069 L, both P < .05). The frequency of treatment-emergent adverse events was similar for placebo and the active comparators (range 34.4–37.5%), slightly higher for navafenterol 400 μg (52.9%), and lowest for navafenterol 1800 μg (22.6%). Conclusions: Both doses of navafenterol demonstrated sustained bronchodilation over 24 h. Navafenterol was well tolerated and no safety concerns were raised. Trial registry: ClinicalTrials.gov; No.: NCT02573155; URL: www.clinicaltrials.gov. Registered 9th October, 2015. Keywords: Bronchodilator, COPD, MABA, Dual-pharmacology muscarinic receptor antagonist β2-adrenoceptor agonist, Safety, Pharmacokinetics
* Correspondence: [email protected] 1 The Medicines Evaluation Unit, Centre for Respiratory and Allergy Medicine, University of Manchester, University Hospital of South Manchester NHS Foundation Trust, M23 9QZ, Manchester, UK Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in
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