Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough

Eur Respir J. 2022 Jun 2;59(6):2100725. doi: 10.1183/13993003.00725-2021. Print 2022 Jun.


Background: The purinoceptor subtype P2X3 has been shown to have significant involvement in the cough reflex; the heterotrimer version of the purinoceptor (P2X2/3) has been implicated in taste disturbance. The most advanced clinical candidate antagonist gefapixant has low selectivity among P2X3 receptors and induced taste disturbance, whereas newly developed sivopixant has high selectivity towards P2X3 versus P2X2/3.

Methods: In a phase 2a, randomised, double-blind, placebo-controlled, crossover, multicentre study, adult patients with refractory or unexplained chronic cough received oral sivopixant 150 mg or placebo once daily for 2 weeks, followed by a 2-3-week washout period, and then crossed over to placebo or sivopixant for 2 weeks. Efficacy and safety of sivopixant were evaluated.

Results: Of 31 randomised patients, 15 in the sivopixant-first group and 15 in the placebo-first group completed the study. After 2 weeks of treatment, the placebo-adjusted ratios of the average hourly number of coughs to baseline during daytime (primary end-point) and over 24 h (secondary end-point) were -31.6% (p=0.0546) and -30.9% (p=0.0386), respectively. Sivopixant also improved health-related quality of life. Treatment-related adverse events occurred in 12.9% and 3.2% of patients during sivopixant and placebo administration, respectively. Mild taste disturbance occurred in two patients (6.5%) during sivopixant administration.

Conclusions: Sivopixant reduced objective cough frequency and improved health-related quality of life, with a low incidence of taste disturbance, among patients with refractory or unexplained chronic cough.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Chronic Disease
  • Cough* / chemically induced
  • Cough* / drug therapy
  • Double-Blind Method
  • Graft vs Host Disease* / drug therapy
  • Humans
  • Purinergic P2X Receptor Antagonists / therapeutic use*
  • Pyrimidines / therapeutic use
  • Quality of Life
  • Sulfonamides / therapeutic use
  • Treatment Outcome


  • Purinergic P2X Receptor Antagonists
  • Pyrimidines
  • Sulfonamides
  • Gefapixant