英国曼彻斯特大学Jaclyn A Smith团队研究了P2X3受体拮抗剂Gefapixant治疗难治性慢性咳嗽和不明原因慢性咳嗽的疗效和安全性。2022年3月5日出版的《柳叶刀》杂志发表了这项成果。

Gefapixant是一种口服P2X3受体拮抗剂，此前已在难治性慢性咳嗽和不明原因慢性咳嗽中显示出有效性和安全性。该研究旨在确认gefapixant治疗难治性慢性咳嗽和不明原因慢性咳嗽患者3期临床试验的有效性和安全性。

咳嗽-1试验和咳嗽-2试验均为双盲、随机、平行组、安慰剂对照的3期临床试验。咳嗽-1试验在17个国家的156个机构进行，咳嗽-2试验在20个国家的175个机构进行。研究组招募18岁及以上的参与者，他们被诊断为难治性慢性咳嗽或持续1年或更长时间的原因不明的慢性咳嗽。在筛选和基线检查时，要求参与者的咳嗽严重程度视觉模拟量表评分为40mm及以上。

将符合条件的参与者随机分为三组，分别接受安慰剂、gefapixant 15mg/天每日两次或gefapixant 45mg/天每日两次治疗。所有研究治疗均为口服。咳嗽-1试验的参与者在12周主要研究期间接受治疗，咳嗽-2试验的参与者在24周主要研究期间接受治疗；两项试验治疗的延长期共长达52周。主要结局是咳嗽-1试验和咳嗽-2试验分别在12周和24周时，经安慰剂校正的24小时咳嗽频率的平均变化。

从2018年3月14日到2019年7月26日，咳嗽-1试验共招募了732名患者，咳嗽-2试验招募了1317名。咳嗽-1试验共随机分配了730名参与者，其中安慰剂组243名，gefapixant 15mg组244名，gefapixant 45mg组243名；咳嗽-1试验共随机分配了1314名参与者，其中安慰剂组435名，gefapixant 15mg组440名，gefapixant 45mg组439名。

参与者大多为女性，其中咳嗽-1试验730人中有542人，咳嗽-2试验1314人中有984人。咳嗽-1试验患者的平均年龄为59岁，咳嗽-2试验患者为58岁；咳嗽-1试验患者的平均咳嗽持续时间为11.6年，咳嗽-2试验患者为11.2年。与安慰剂组相比，咳嗽-1试验患者在第12周、咳嗽-2试验患者在24周，gefapixant 45mg组患者的24小时咳嗽频率显著降低。

在这两项研究中，与安慰剂组相比，gefapixant 15mg组患者的咳嗽频率并没有显著降低。最常见的不良事件与味觉紊乱有关：味觉消失（咳嗽-1试验中有4.9%的患者，咳嗽-2试验有6.5%）、味觉障碍（咳嗽-1试验中有16.2%，咳嗽-2试验有21.1%）、味觉过敏（咳嗽-1试验中有0.4%，咳嗽-2试验有0.5%）、味觉减退（咳嗽-1试验中有2.6%，咳嗽-2试验有6.1%）和味觉失调（咳嗽-1试验中有3.8%，咳嗽-2试验有3.5%）。

研究结果表明，对于难治性慢性咳嗽或原因不明的慢性咳嗽，每天两次45mg gefapixant安全有效。

附：英文原文

Title: 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

Author: Lorcan P McGarvey, Surinder S Birring, Alyn H Morice, Peter V Dicpinigaitis, Ian D Pavord, Jonathan Schelfhout, Allison Martin Nguyen, Qing Li, Anjela Tzontcheva, Beata Iskold, Stuart A Green, Carmen La Rosa, David R Muccino, Jaclyn A Smith

Issue&Volume: 2022/03/05

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.

DOI: 10.1016/S0140-6736(21)02348-5

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02348-5/fulltext