Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials

COUGH-1 and COUGH-2 Investigators

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Abstract

Background: Gefapixant is an oral P2X3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough. 

Methods: COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2). 

Findings: From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 [33×3%] with placebo, 244 [33×4%] with gefapixant 15 mg twice per day, and 243 [33×3%] with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 [33×1%] with placebo, 440 [33×5%] with gefapixant 15 mg twice per day, and 439 [33×4%] with gefapixant 45 mg twice per day). Participants were mostly female (542 [74×2%] of 730 in COUGH-1 and 984 [74×9%] of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% [95% CI 32·9–0·9]; p=0·041) and at week 24 in COUGH-2 (14·6% [26·1–1·4]; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 [4·9%] of 730 in COUGH-1 and 86 [6·5%] of 1314 in COUGH-2), dysgeusia (118 [16·2%] in COUGH-1 and 277 [21·1%] in COUGH-2), hypergeusia (3 [0·4%] in COUGH-1 and 6 [0×5%] in COUGH-2), hypogeusia (19 [2·6%] in COUGH-1 and 80 [6·1%] in COUGH-2), and taste disorder (28 [3·8%] in COUGH-1 and 46 [3·5%] in COUGH-2). 

Interpretation: Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough. 


Original languageEnglish
Pages (from-to)909-923
Number of pages15
JournalThe Lancet
Volume399
Issue number10328
DOIs
Publication statusPublished - 05 Mar 2022

Bibliographical note

Funding Information:
LPM has received grants and personal fees from Afferent Pharmaceuticals and Merck Sharp & Dohme; personal fees from Applied Clinical Intelligence; grants from Asthma UK, Northern Ireland Chest Heart and Stroke, NC3Rs, British Heart Foundation, and Chiesi; travel and subsistence for attendance at scientific meetings from Boehringer Ingelheim, GlaxoSmithKline, and Chiesi; and advisory board or consultancy fees from Almirall, NAPP, GlaxoSmithKline, and Boehringer Ingelheim. SSB has received scientific advisory board or consultancy fees from Merck Sharp & Dohme, Bayer, Bellus, Shionogi, Nocion, Nerre, and Boehringer Ingelheim. AHM has received grants and personal fees from Afferent Pharmaceuticals and Merck Sharp & Dohme; and is a consultant to Bayer, Bellus, Shionogi, and Nocion. PVD is a consultant to Merck Sharp & Dohme, Bayer, Bellus, and Shionogi. IDP has received research grants, speaker's honoraria, travel expenses, and advisory board fees from AstraZeneca and Chiesi; speaker's honoraria, travel expenses, advisory boards from GlaxoSmithKline, Boehringer Ingelheim, and Teva; advisory board fees from Sanofi and Regeneron, Merck Sharp & Dohme, Novartis, Knopp, and Roche and Genentech; and speaker fees from Cirassia and Mundipharma. JS, AMN, QL, AT, BI, SAG, CLR, and DRM are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, and own stock in the company. JAS has received grants and personal fees from Afferent Pharmaceuticals and Merck Sharp & Dohme; grants and personal fees from Ario Pharma, GlaxoSmithKline, NeRRe Theraputics, Menlo, and Bayer; personal fees from Boehringer Ingelheim, Genentech, and Neomed; non-financial support from Vitalograph; and personal fees from Chiesi. JAS is funded by the National Institute of Health Research (NIHR) Manchester Biomedical Research Centre and a Wellcome Investigator Award, and is an NIHR senior investigator. Additionally, JAS is a named inventor on a patent describing detection of cough from sound recordings. The patent is owned by University Hospital of South Manchester and licensed to Vitalograph.

Funding Information:
This study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. This study was supported by the Northern Ireland Clinical Research Network and by the UK National Institute of Health Research (NIHR) Clinical Research Facilities and Clinical Research Network staff. Support was also provided by NIHR Manchester Biomedical Research Centre and the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. Medical writing support was provided by Anish Mehta (Merck & Co). We thank Jennifer Pawlowski (Merck & Co) for additional editorial and administrative support.

Funding Information:
This study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. This study was supported by the Northern Ireland Clinical Research Network and by the UK National Institute of Health Research (NIHR) Clinical Research Facilities and Clinical Research Network staff. Support was also provided by NIHR Manchester Biomedical Research Centre and the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. Medical writing support was provided by Anish Mehta (Merck & Co). We thank Jennifer Pawlowski (Merck & Co) for additional editorial and administrative support.

Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. All rights reserved.

ASJC Scopus subject areas

  • Medicine(all)

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