Sabtu , 22 Mei 2021 13:00:09
The Effect of Gefapixant, a P2X3 antagonist, on Cough Reflex Sensitivity: A randomised placebo-controlled study


Abstract

Introduction We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.

Methods In this Phase 2, double-blind, 2-period study, chronic cough subjects (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin, and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking ≥2 (C2) and ≥5 (C5) coughs post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·hr−1) over 24 h, and Cough Severity Visual Analogue Scale (VAS) were assessed in CC. Adverse events (AE) were monitored.

Results 24 CC and 12 HV were randomised (mean age 61 and 38 years, respectively). Cough challenge threshold increased for ATP by 4.7-fold (C2, p=<0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). Distilled water C2 and C5 were increased significantly (p<0.001), by a factor of 1.4 and 1.3, respectively, in CC. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and least-squares (LS) mean Cough Severity VAS was 18.0 mm lower for gefapixant versus placebo in CC subjects. Dysgeusia was the most frequent AE (75% HV and 67% CC).

Conclusions ATP-evoked cough was significantly inhibited by gefapixant 100 mg demonstrating peripheral target engagement. Cough count and severity were reduced in CC. Distilled water may also evoke cough through a purinergic pathway.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Morice reports personal fees from Afferent, grants and personal fees from Merck, during the conduct of the study.

Conflict of interest: Dr. Kitt reports other from Merck/Afferent, during the conduct of the study; other from Merck/Afferent, outside the submitted work.

Conflict of interest: Dr. Ford has nothing to disclose.

Conflict of interest: Dr. Tershakovec reports personal fees and other from Merck, during the conduct of the study.

Conflict of interest: Dr. Wu reports that she was an employee of Merck Sharp &amp; Dohme, Corp, during the conduct of the study.

Conflict of interest: Dr. Brindle has nothing to disclose.

Conflict of interest: Dr. Thompson has nothing to disclose.

Conflict of interest: Ms. Thackray-Nocera has nothing to disclose.

Conflict of interest: Dr. Wright has nothing to disclose.

This is a PDF-only article. Please click on the PDF link above to read it.

sumber : https://erj.ersjournals.com/content/early/2019/04/05/13993003.00439-2019?utm_source=TrendMD&utm_medium=cpc&utm_campaign=European_Respiratory_Journal_TrendMD_0