Design and rationale of two phase 3 randomised controlled trials (COUGH-1 and COUGH-2) of gefapixant, a P2X3 receptor antagonist, in refractory or unexplained chronic cough

Abstract

BackgroundWe present study designs, dose selection and preliminary patient characteristics from two phase 3 clinical trials of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough (RCC) or unexplained chronic cough (UCC).MethodsCOUGH-1 (NCT03449134) and COUGH-2 (NCT03449147) are randomised, placebo-controlled, double-blind, parallel-group trials in subjects with RCC or UCC (age ≥18 years; cough duration ≥1 year; Cough Severity Visual Analogue Scale score ≥40 mm). The primary efficacy study periods are 12 weeks (40-week extension; COUGH-1) and 24 weeks (28-week extension; COUGH-2). Interventions include placebo, gefapixant 15 mg and gefapixant 45 mg (1:1:1 ratio). The primary efficacy endpoints are average 24-h cough frequency at Week 12 (COUGH-1) and Week 24 (COUGH-2). Awake cough frequency, patient-reported outcomes and responder analyses are secondary endpoints.ResultsThe doses of 45 mg (to provide maximal efficacy and acceptable tolerability) and 15 mg (to provide acceptable efficacy and improved tolerability) were selected based on phase 1 and 2 studies. In COUGH-1, 730 participants have been randomised and treated; 74% are female with mean age of 59 years (39% over 65 years), and mean baseline duration of cough of 11.5 years. In COUGH-2, 1314 participants have been randomised and treated; 75% are female with mean age of 58 years (33% over 65 years), and mean baseline duration of cough of 11.1 years.ConclusionsThese global studies include participants with baseline characteristics consistent with previous RCC and UCC studies and will inform the efficacy and safety profile of gefapixant in the treatment of patients with RCC and UCC.

Gender Difference in Chronic Cough: Are Women More Likely to Cough?

“…In a national-wide multi-center study, except for a eastern region (Shanghai), chronic cough patients presented an approximately equal gender distribution in western, southern, northern, and northeastern regions of China (Lai et al, 2013;Lai and Long, 2020). What's more, a female predominance among patients with refractory or unexplained chronic cough has been reported (Ryan et al, 2012;Muccino et al, 2020;Smith et al, 2020) (more specific details about sex distribution are shown in Table 1).…”

P2X3 Receptor Ligands: Structural Features and Potential Therapeutic Applications

“…The loss of taste response seems to be due to its unselective block of P2X3 and P2X2/3Rs. Although these side effects, the medical need for patients suffering of this pathology, encouraged Merck to continue the development of gefapixant, which has recently completed two Phase III clinical trials (called COUGH-1 and COUGH-2; NCT03449134, 2020; NCT03449147, 2020) for refractory or unexplained chronic cough (Muccino et al, 2020). In these studies, gefapixant at the dose of 45 mg twice daily induced a significant reduction in 24-h cough frequency with mild to moderate alteration of taste sensitivity (Merck News release, 2020).…”

P2X Receptors: Potential Therapeutic Targets for Symptoms Associated With Lung Cancer — A Mini Review

“…In light of published and ongoing promising data with at least four clinical programs involving P2X3 receptor-antagonists in treating chronic refractory cough (90)(91)(92)(93)(94)(95)(96)(97)(98), and with extracellular ATP and its receptors having been shown to modulate tumor development, invasion progression, and tumor microenvironment, P2X receptor antagonists may be expected also to exert an antitussive effect in lung cancerrelated cough. Further studies in this area are eagerly awaited.…”

“…Furthermore, gefapixant showed a significant reduction in cough frequency, as assessed by randomized, double-blind, placebo-controlled Phase 2 trials ( 92 , 93 ). Recently, two Phase 3 randomized controlled trials (COUGH-1 and COUGH-2) of gefapixant in refractory chronic cough and unexplained chronic cough, evaluating more than 2000 patients, have been completed ( 94 ). Compared to placebo, treatment with 45 mg gefapixant demonstrated a significant reduction in 24-h cough frequency in patients ( 95 ).…”