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Randomized Controlled Trial
. 2023 Feb;201(1):25-35.
doi: 10.1007/s00408-022-00592-5. Epub 2022 Dec 13.

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 2b Trial of P2X3 Receptor Antagonist Sivopixant for Refractory or Unexplained Chronic Cough

Lorcan McGarvey  1 , Jaclyn A Smith  2 , Alyn Morice  3 , Surinder S Birring  4 , Kian Fan Chung  5 , Peter V Dicpinigaitis  6 , Akio Niimi  7 , Michael S Benninger  8 , Mandel Sher  9 , Yuko Matsunaga #  10 , Sayaka Miyazaki  11 , Mitsuaki Machida  11 , Hiroyuki Ishihara  11 , Adnan Mahmood  12 , Juan-Carlos Gomez  13
Affiliations
Randomized Controlled Trial

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 2b Trial of P2X3 Receptor Antagonist Sivopixant for Refractory or Unexplained Chronic Cough

Lorcan McGarvey et al. Lung. 2023 Feb.

Abstract

Introduction: To determine the optimal dose of sivopixant, a highly selective P2X3 receptor antagonist, for refractory or unexplained chronic cough (RCC/UCC).

Methods: In this phase 2b, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, patients received sivopixant 50, 150, or 300 mg or placebo once daily for 4 weeks. The primary endpoint was a change from baseline in 24-h cough frequency (coughs/h) with sivopixant vs placebo.

Results: Overall, 390/406 randomized patients completed the study. Placebo-adjusted changes in hourly cough count over 24 h were 13.17% (P = 0.3532), - 1.77% (P = 0.8935), and - 12.47% (P = 0.3241) and in cough severity (visual analog scale) were 1.75 mm (P = 0.5854), - 1.21 mm (P = 0.7056), and - 6.55 mm (P = 0.0433) with sivopixant 50, 150, and 300 mg, respectively. Placebo-adjusted changes from baseline in Leicester Cough Questionnaire total scores were - 0.37 (P = 0.4207), - 0.07 (P = 0.8806), and 0.69 (P = 0.1473) with sivopixant 50, 150, and 300 mg, respectively. Additionally, 61.3%, 78.3%, 86.8%, and 71.4% of patients receiving sivopixant 50, 150, and 300 mg and placebo, respectively, reported any improvements in Patient Global Impression of Change. The incidence of treatment-emergent adverse events (TEAEs) was 25.7%, 32.0%, 49.0%, and 20.6% in sivopixant 50, 150, and 300 mg and placebo groups, respectively; all TEAEs in the sivopixant group were mild-to-moderate.

Conclusion: Sivopixant did not demonstrate a statistically significant difference vs placebo in change from baseline in 24-h cough frequency. The dose of 300 mg has potential for RCC/UCC, showing the greatest improvements in cough frequency and patient-reported outcomes and dose-related mild to moderate reversible taste disturbance, although further trials are needed.

Clinical trial registration: ClinicalTrials.gov identifier NCT04110054; registered September 26, 2019.

Keywords: Chronic cough; Cough frequency; P2X3 receptor antagonist; Phase 2b trial; Sivopixant.

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Conflict of interest statement

LMG has received grants or contracts and consulting fees from Shionogi Inc., Bayer, Merck, Bellus Health, and Chiesi; consulting fees from AstraZeneca, Nocion, Trevi Therapeutics, Reckitt Benckiser Health Limited, NeRRe Therapeutics, and Bionorica; payment or honoraria from Merck, Chiesi, Bellus, Bionorica, GSK, and Shionogi Inc. and participated on a Data Safety Monitoring Board or the Advisory Board for Applied Clinical Intelligence. JAS has served as a consultant and helped in the setup of clinical studies for Shionogi; received grants or contracts from Wellcome Trust investigator award and NIHR Manchester Biomedical Research Centre; her hospital has received royalties from Vitalograph Ltd.; received consulting fee from Bellus Health, Axalbion, Merck, Bayer, Algernon, Nocion, Chiesi, Boehringer Ingelheim, and AstraZeneca; received honoraria from Merck and Boehringer Ingelheim; has a patent issued for cough monitoring; and received equipment supply from Vitalograph Ltd. AMo has received funding from Shionogi; received payment or honoraria from Merck, Bayer, and NeRRe; participated on a Data Safety Monitoring Board or an Advisory Board for Merck, Bayer, NeRRe, Shionogi, and Bellus; and served as the task force chair for the European Respiratory Society. SSB has received personal fees from Shionogi Inc., Merck, Bellus, Bayer, and Nocion. KFC has speaking engagements for Novartis and AstraZeneca; has participated on Advisory Boards for Roche, Merck, Reckitt Benckiser, and Shionogi & Co., Ltd., on asthma, COPD, and chronic cough; serves on Data Safety Monitoring Board for Nocion; and has received grants including MRC grant on Precision Medicine for severe asthma, an EPSRC grant on air pollution and asthma, and a GSK grant on mepolizumab and eosinophils in asthma. PVD has served as a consultant to Bayer, Bellus, Chiesi, Merck, and Shionogi Inc. and is the editor-in-chief of Lung. MSB has served as a consultant for Merck (2020) and Shionogi Inc. (2020) and received research funding from Merck. MS has served on the Medical Advisory Board and as a principal investigator for Bayer, Bellus, Merck, NeRRe, and Shionogi Inc.; serves on the Medical Advisory Board and Data Safety Monitoring Board for Nocion; and is a consultant for Soundable Health. YM is a former employee of Shionogi Inc. SM, MM, and HI are employees of Shionogi & Co. Ltd. JCG is an employee of Shionogi B.V. AMa is a medical consultant for Shionogi B.V. AN has no disclosures.

Figures

Fig. 1
Fig. 1
Study CONSORT flow diagram. For the analyzed population: invalid cough count recording is postbaseline. Invalid cough count: cough count recording was considered to have failed for any reason. CONSORT Consolidated Standards of Reporting Trials, COVID-19 coronavirus disease 2019
Fig. 2
Fig. 2
Geometric mean of percent change in hourly cough counts in 24 h from baseline to weeks 1 to 4 (FAS). Treatment effects and their 95% CIs plotted are based on a mixed-effects model for the log-transformed ratio of the number of coughs/h in 24 h at Weeks 1, 3 and 4, with treatment group, week, and interaction between treatment group and week as fixed effects; patient as random effect; and region and the log-transformed coughs/h in 24 h at baseline as covariates. Modeled estimates are presented as geometric mean of percent change from baseline. CI confidence interval, FAS full analysis set
Fig. 3
Fig. 3
Change from baseline in a weekly cough severity (VAS) and b LCQ total score (FAS). Change from baseline in a weekly cough severity (VAS) and b LCQ total score (FAS). Treatment effects and their 95% CIs plotted are based on a mixed-effects model for the change from baseline in a VAS and b LCQ total score at Weeks 1, 3 and 4, with treatment group, week, and interaction between treatment group and week as fixed effects; patient as random effect; and region and the weekly cough severity on VAS/LCQ total score at baseline as covariates. Modeled estimates are presented as percent change from baseline. CI confidence interval, FAS full analysis set, LCQ Leicester Cough Questionnaire, VAS visual analog scale
Fig. 4
Fig. 4
Percent change relative to placebo in hourly cough count in 24 h at Week 4: patients with a cough count of ≥ 10 at Visit 2 in the FAS. Treatment effects and their 95% CIs plotted are based on a mixed-effects model for the log-transformed ratio of the number of coughs/h in 24 h after 4 weeks of treatment, with treatment, week, and treatment by week as fixed effects; patient as random effect; and region and the log-transformed coughs/h in 24 h at baseline as covariates. Modeled estimates are presented as percent change relative to placebo from Visit 2. CC cough count, CI confidence interval, FAS full analysis set
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