Gefapixant（一种P2X3拮抗剂）对咳嗽反射敏感性的作用：一项随机安慰剂对照研究
2020/07/13
摘要
我们评估gefapixant对诱导咳嗽激发的咳嗽反射敏感性的影响。在这个2期双盲2阶段实验中，慢性咳嗽患者（CC）与健康志愿者（HV）被通过交叉模式随机分配到gefapixant 100mg单剂量治疗组或安慰剂治疗组。在给药后第1,3,5小时，使用ATP、柠檬酸、辣椒素及蒸馏水进行后续的吸入激发实验（咳嗽诱导实验）。给药后诱发≥2及≥5次咳嗽的平均浓度（与基线相比）为共同主要结果。在CC中评估24小时的客观咳嗽频率（咳嗽/小时）及咳嗽严重程度视觉模拟评分（VAS）。监测不良事件（AE）发生情况。24名CC及12名HV接受随机分组（平均年龄分别为61岁及38岁）。在慢性咳嗽患者中，与安慰剂治疗组相比，gefapixant治疗组的ATP诱导咳嗽的阈值增加了4.7倍（C2，P≤0.001）、3.7倍（C5，P=0.007）；在健康志愿者中，C2及C5均增加了2.4倍（C2，P=0.113; C5，P=0.003）。在慢性咳嗽患者中，蒸馏水的C2及C5明显增加（P＜0.001），分别增加1.4倍及1.3倍。Gefapixant对辣椒素或柠檬酸诱导咳嗽的阈值无影响。在慢性咳嗽患者中，与安慰剂治疗组相比，Gefapixant治疗组患者的中位咳嗽频率降低了42%，并且最小二乘法平均咳嗽敏感性VAS降低了18mm。味觉障碍是最常见的不良事件（HV:75% VS CC：67%）。Gefapixant（100mg）能明显抑制ATP诱发的咳嗽，表明外周靶点参与该过程。慢性咳嗽患者的咳嗽次数及严重程度降低。蒸馏水也许也能通过一种嘌呤通路诱发咳嗽。
The Effect of Gefapixant, a P2X3 Antagonist, on Cough Reflex Sensitivity: A Randomised Placebo-Controlled Study
Alyn H Morice, Michael M Kitt, Anthony P Ford , Andrew M Tershakovec , Wen-Chi Wu, Kayleigh Brindle , Rachel Thompson , Susannah Thackray-Nocera , Caroline Wright
Abstract
We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking ≥2 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h-1) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p≤0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0 mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients).ATP-evoked cough was significantly inhibited by gefapixant 100 mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway.
我们评估gefapixant对诱导咳嗽激发的咳嗽反射敏感性的影响。在这个2期双盲2阶段实验中，慢性咳嗽患者（CC）与健康志愿者（HV）被通过交叉模式随机分配到gefapixant 100mg单剂量治疗组或安慰剂治疗组。在给药后第1,3,5小时，使用ATP、柠檬酸、辣椒素及蒸馏水进行后续的吸入激发实验（咳嗽诱导实验）。给药后诱发≥2及≥5次咳嗽的平均浓度（与基线相比）为共同主要结果。在CC中评估24小时的客观咳嗽频率（咳嗽/小时）及咳嗽严重程度视觉模拟评分（VAS）。监测不良事件（AE）发生情况。24名CC及12名HV接受随机分组（平均年龄分别为61岁及38岁）。在慢性咳嗽患者中，与安慰剂治疗组相比，gefapixant治疗组的ATP诱导咳嗽的阈值增加了4.7倍（C2，P≤0.001）、3.7倍（C5，P=0.007）；在健康志愿者中，C2及C5均增加了2.4倍（C2，P=0.113; C5，P=0.003）。在慢性咳嗽患者中，蒸馏水的C2及C5明显增加（P＜0.001），分别增加1.4倍及1.3倍。Gefapixant对辣椒素或柠檬酸诱导咳嗽的阈值无影响。在慢性咳嗽患者中，与安慰剂治疗组相比，Gefapixant治疗组患者的中位咳嗽频率降低了42%，并且最小二乘法平均咳嗽敏感性VAS降低了18mm。味觉障碍是最常见的不良事件（HV:75% VS CC：67%）。Gefapixant（100mg）能明显抑制ATP诱发的咳嗽，表明外周靶点参与该过程。慢性咳嗽患者的咳嗽次数及严重程度降低。蒸馏水也许也能通过一种嘌呤通路诱发咳嗽。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(Eur Respir J. 2019 Jul 4;54(1):1900439.doi: 10.1183/13993003.00439-2019.)
(Eur Respir J. 2019 Jul 4;54(1):1900439.doi: 10.1183/13993003.00439-2019.)
The Effect of Gefapixant, a P2X3 Antagonist, on Cough Reflex Sensitivity: A Randomised Placebo-Controlled Study
Alyn H Morice, Michael M Kitt, Anthony P Ford , Andrew M Tershakovec , Wen-Chi Wu, Kayleigh Brindle , Rachel Thompson , Susannah Thackray-Nocera , Caroline Wright
Abstract
We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking ≥2 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h-1) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p≤0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0 mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients).ATP-evoked cough was significantly inhibited by gefapixant 100 mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway.
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