P2X3受体拮抗剂吉法匹生治疗难治性慢性咳嗽及不明原因慢性咳嗽的有效性与安全性评价（COUGH-1、COUGH-2）：两
2022/03/17
P2X3受体拮抗剂吉法匹生治疗难治性慢性咳嗽及不明原因慢性咳嗽的有效性与安全性评价（COUGH-1、COUGH-2）：两项双盲随机平行组安慰剂对照III期临床试验
摘要
背景：既往研究已显示，口服P2X3受体拮抗剂吉法匹生在治疗难治性慢性咳嗽和不明原因慢性咳嗽方面具有一定的有效性和安全性。据此，本研究旨在证实吉法匹生治疗难治性慢性咳嗽和不明原因慢性咳嗽的有效性和安全性。
方法：临床试验COUGH-1和 COUGH-2均为双盲、随机、平行组、安慰剂对照、III 期试验。 COUGH-1在 17个国家 156 个地点开展，COUGH-2 在20个国家175个地点开展。本研究招募受试者为18岁及以上、确诊难治性慢性咳嗽或不明原因慢性咳嗽持续1年及以上。同时要求受试者的咳嗽严重程度视觉模拟量表评分在筛查期和基线期达 40 mm及以上。符合条件的受试者采用计算机生成分配表随机分为3个治疗组（1:1:1）：安慰剂组、吉法匹生15 mg 每天两次组和吉法匹生45 mg 每天两次组。本研究中所有治疗均为口服给药。COUGH-1 中受试者接受治疗的主要研究期为12 周，COUGH-2则为 24 周，随后均延长治疗至总治疗周期达52 周。主要研究终点为COUGH-1 在 12 周和 COUGH-2在 24 周时安慰剂校正24 小时咳嗽频率的平均变化。两项研究均在 ClinicalTrials.gov上注册登记，编号分别为NCT03449134 (COUGH-1) 、 NCT03449147 (COUGH-2) 。
结果：从 2018 年 3 月 14 日（筛选第一位受试者）到 2019 年 7 月 26 日（筛选最后一位受试者），COUGH-1 共招募732 例患者，COUGH-2共招募1317 名例患者。 COUGH-1 中共有730例受试者接受随机分组及治疗，（其中244例 [33.3%] 接受安慰剂治疗，244例 [33.4%]接受吉法匹生15 mg 每天两次治疗，243 例 [33.3%] 接受吉法匹生45 mg 每天两次治疗）；COUGH-2 中共有1314例受试者接受随机分组及治疗，（其中435例 [33.1%] 接受安慰剂治疗，440例 [33.5%]接受吉法匹生15 mg 每天两次治疗，439例[33.4%] 接受吉法匹生45 mg 每天两次治疗）。
受试者大多为女性（COUGH-1中为542/730 [74.2%]， COUGH-2中为984/1314 [74.9%]）。 COUGH-1中受试者的平均年龄为 59.0±12.6 岁，COUGH-2为 58.1±12.1 岁；COUGH-1的平均咳嗽持续时间为 11.6±9.5 年，COUGH-2 为11.2±9.8年。在COUGH-1研究第12周和COUGH-2研究第24周，吉法匹生45mg每天两次组的咳嗽频率较安慰剂组显著降低（分别降低18.5% [95%CI 32.9-0.9]，p=0.041；14.6% [26.1-1.4]，p=0.031）。两项研究中吉法匹生15mg每天两次组的咳嗽频率较安慰剂组无明显降下降。
最常见的不良事件与味觉功能障碍相关：味觉缺失（COUGH-1 中为36/730 [4.9%]，COUGH-2中为86/1314 [6.5%]）、味觉倒错（COUGH-1中118 [16.2%]例，COUGH-2 中277 [21.1%]例）、味觉过敏（COUGH-1 中 3 [0.4%] 和 COUGH-2 中 6 [0.5%]）、味觉减退（COUGH-1中19 [2.6%]例， COUGH-2 中 80 [6.1%]例）以及味觉紊乱 (COUGH-1 中 28 [3.8%]例，COUGH-2 中 46 [3.5%]例）。
结论：在难治性慢性咳嗽或不明原因慢性咳嗽的III期临床试验中，吉法匹生45 mg 每天两次是首个在可接受安全性范围内显示出有效性的治疗方案。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Lancet. 2022 Mar 5;399(10328):909-923. doi: 10.1016/S0140-6736(21)02348-5.)
(Lancet. 2022 Mar 5;399(10328):909-923. doi: 10.1016/S0140-6736(21)02348-5.)
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
McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, Nguyen AM, Li Q, Tzontcheva A, Iskold B, Green SA, Rosa C, Muccino DR, Smith JA; COUGH-1 and COUGH-2 Investigators.
Summary
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.
