Treatment with the P2X3-Receptor Antagonist Gefapixant for Acute Cough in Induced Viral Upper Respiratory Tract Infection: A Phase 2a, Randomized, Placebo-Controlled Trial

Jaclyn A Smith, Michael M Kitt, Alan Bell, Nicolas Noulin, Anjela Tzontcheva, Megan McGratty Seng, Susan Lu, Jaclyn A Smith, Michael M Kitt, Alan Bell, Nicolas Noulin, Anjela Tzontcheva, Megan McGratty Seng, Susan Lu

Abstract

Introduction: Available therapies for acute cough, a condition frequently caused by a viral upper respiratory tract infection (URTI), have shown limited evidence of efficacy. Gefapixant, a P2X3-receptor antagonist, has demonstrated efficacy and safety in studies of the treatment of refractory or unexplained chronic cough, but its efficacy for treating acute cough has not been previously studied.

Methods: This was a phase 2a, randomized, double-blind, placebo-controlled, parallel-group, pilot study. Healthy volunteers were randomized 1:1 to receive twice-daily gefapixant 45 mg or placebo and inoculated with human rhinovirus 16 to induce URTI and cough. Participants were observed while quarantined for 7 days after the start of treatment. The primary endpoint was awake cough frequency on day 3, which was objectively measured with a cough-recording device. Secondary endpoints included change from baseline to day 3 in subjective cough severity measures (cough severity visual analog scale, Cough Severity Diary) and cough-specific quality of life (Leicester Cough Questionnaire-acute).

Results: Of the 46 participants who met inclusion criteria [mean (standard deviation, SD) age, 24.6 (6.5) years; females, n = 8], 40 completed the study (gefapixant, n = 21; placebo, n = 19). There was no significant difference in awake cough frequency on day 3 between the gefapixant and placebo groups [least squares means, 2.4 versus 2.7 coughs per hour, respectively; mean difference (95% confidence interval, CI), -0.3 (-2.3, 1.7); P = 0.75]. There were no significant between-group differences for any of the secondary endpoints. Peak cough frequency was low and occurred later in the study than expected (days 4-5). The safety profile was consistent with that of previous studies of gefapixant.

Conclusion: Compared with placebo, gefapixant did not reduce the frequency or severity of acute cough secondary to induced URTI. Induced viral URTI produced mild symptoms, including lower cough frequency than observed in previous studies of patients selected for acute cough associated with naturally occurring URTI.

Trial registration: ClinicalTrials.gov, NCT03569033; EudraCT, 2017-000472-28; protocol number, MK-7264-013.

Keywords: Acute cough; Antitussives; Common cold; Cough frequency; P2X3-receptor antagonists; URTI.

© 2022. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, N.J., U.S.A., Jaclyn A. Smith, Michael Kitt, Alan Bell, Nicolas Noulin 2022.

Figures

Fig. 1
Fig. 1
CONSORT diagram. BID twice daily, HRV-16 human rhinovirus 16. aParticipants were not successfully infected with HRV-16, as evidenced by a negative nasal swab for HRV-16 at the 72-h timepoint after inoculation, and were discontinued from treatment
Fig. 2
Fig. 2
Awake cough frequency over time. Error bars represent standard error (SE). BID twice daily, LS least squares
Fig. 3
Fig. 3
Post hoc analyses over treatment period of a 24-h cough frequency, b change from baseline in cough severity VAS scores, c change from baseline in CSD scores, and d change from baseline in LCQ-acute scores. Error bars represent SE (panel A) and SD (panels B–D). BID twice daily, CSD Cough Severity Diary, LCQ Leicester Cough Questionnaire, LS least squares, VAS visual analog scale
Fig. 4
Fig. 4
Post hoc analyses of WURSS-24 changes from baseline by individual symptoms for a cough, b runny nose, c plugged nose, and d sneezing. Error bars represent SD. BID twice daily, WURSS-24 24-item Wisconsin Upper Respiratory Symptom Survey

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