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The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study.
- Source :
-
The European respiratory journal [Eur Respir J] 2019 Jul 04; Vol. 54 (1). Date of Electronic Publication: 2019 Jul 04 (Print Publication: 2019). - Publication Year :
- 2019
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Abstract
- We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a 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 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h <superscript>-1</superscript> ) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The 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 patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0 mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients).ATP-evoked cough was significantly inhibited by gefapixant 100 mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway.<br />Competing Interests: Conflict of interest: A.H. Morice has received consulting fees from Afferent, Merck Sharp & Dohme, Boehringer Ingelheim, Pfizer, and Proctor & Gamble; lecture fees from Boehringer Ingelheim and AstraZeneca; and grant support from Proctor & Gamble. Conflict of interest: M.M. Kitt is a former employee of Afferent Pharmaceuticals and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock in the company. Conflict of interest: A.P. Ford is a former employee of Afferent Pharmaceuticals and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock in the company. Conflict of interest: A.M. Tershakovec is a former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock in the company. Conflict of interest: W-C. Wu was an employee of Merck Sharp & Dohme, Corp, during the conduct of the study. Conflict of interest: K. Brindle has nothing to disclose. Conflict of interest: R. Thompson has nothing to disclose. Conflict of interest: S. Thackray-Nocera has nothing to disclose. Conflict of interest: C. Wright has nothing to disclose.<br /> (Copyright ©ERS 2019.)
- Subjects :
- Adult
Aged
Antitussive Agents adverse effects
Antitussive Agents therapeutic use
Bronchial Provocation Tests
Chronic Disease
Cross-Over Studies
Double-Blind Method
Female
Humans
Male
Middle Aged
Purinergic P2X Receptor Antagonists adverse effects
Pyrimidines adverse effects
Sulfonamides adverse effects
United Kingdom
Visual Analog Scale
Cough drug therapy
Cough physiopathology
Purinergic P2X Receptor Antagonists therapeutic use
Pyrimidines therapeutic use
Sulfonamides therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1399-3003
- Volume :
- 54
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The European respiratory journal
- Publication Type :
- Academic Journal
- Accession number :
- 31023843
- Full Text :
- https://doi.org/10.1183/13993003.00439-2019