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期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2314192

摘要内容如下：

背景

经批准的遗传性血管性水肿发作的按需治疗需要胃肠外给药，这是一种与治疗延迟或停止治疗相关的给药途径。

方法

在这项3期、双盲、三向交叉试验中，我们将至少12岁的1型或2型遗传性血管性水肿患者随机分为两组，一组口服两剂Sebetralstat（300 mg或600 mg），另一组口服安慰剂治疗血管性水肿发作。在时间-事件分析中评估的主要终点是症状缓解的开始，定义为在首次给予试验药物后12小时内的两个或多个连续时间点，患者总体印象变化量表（评分范围从“非常差”到“非常好”）中的“稍好”评级。在时间-事件分析中评估的关键次要终点是12小时内两个或两个以上连续时间点的发作严重程度降低（患者总体严重程度印象[PGI-S]量表评级改善，评级范围为“无”至“非常严重”）和24小时内发作完全消退（PGI-S量表评级为“无”）。

结果

共有136名参与者被分配到六个试验序列中的一个，其中110人治疗了264次发作。300mg剂量组和600mg剂量组症状开始缓解的时间比安慰剂组快（两项比较分别为P<0.001和P=0.001），中位时间分别为1.61小时（四分位间距，0.78至7.04）、1.79小时（1.02至3.79）和6.72小时（1.34至>12）。与安慰剂相比，300 mg剂量和600 mg剂量降低发作严重程度的时间更快（p=0.004和p=0.003），中位时间为9.27小时（四分位间距为1.53至>12）、7.75小时（2.19至>12）和12小时以上（6.23至>12）。与安慰剂相比，300 mg和600 mg剂量组的完全缓解时间更快（P=0.002和P<0.001）。在24小时内完全缓解的发作百分比，300mg剂量组为42.5%，600mg剂量组为49.5%，安慰剂组为27.4%。Sebetralstat和安慰剂具有相似的安全性特征；未报告与试验药物相关的严重不良事件。

结论

与安慰剂相比，口服SeBetralstat可更快地开始缓解症状、降低发作严重程度并完全缓解发作。（由Kalvista制药公司资助；Konfident ClinicalTrials.gov编号，NCT05259917；Eudract编号:2021-001226-21。）

英文原文如下：

Abstracts

BACKGROUND  Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy.

METHODS  In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours.

RESULTS  A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported.

CONCLUSIONS  Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).

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