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

McGarvey, Lorcan; Smith, Jaclyn A.; Morice, Alyn; Birring, Surinder S.; Chung, Kian Fan; Dicpinigaitis, Peter V.; Niimi, Akio; Benninger, Michael S.; Sher, Mandel; Matsunaga, Yuko; Miyazaki, Sayaka; Machida, Mitsuaki; Ishihara, Hiroyuki; Mahmood, Adnan; Gomez, Juan Carlos

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.

Citation

McGarvey, L., Smith, J. A., Morice, A., Birring, S. S., Chung, K. F., Dicpinigaitis, P. V., Niimi, A., Benninger, M. S., Sher, M., Matsunaga, Y., Miyazaki, S., Machida, M., Ishihara, H., Mahmood, A., & Gomez, J. C. (2022). A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 2b Trial of P2X3 Receptor Antagonist Sivopixant for Refractory or Unexplained Chronic Cough. Lung, https://doi.org/10.1007/s00408-022-00592-5

• Journal Article Type: Article
• Acceptance Date: Dec 7, 2022
• Publication Date: Jan 1, 2022
• Deposit Date: Jul 16, 2023
• Publicly Available Date: Jul 24, 2023
• Journal: Lung
• Print ISSN: 0341-2040
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1007/s00408-022-00592-5
• Public URL: https://hull-repository.worktribe.com/output/4161285