利马前列素口崩片治疗中国和韩国偏头痛急性发作的安全性和有效性：一项 3 期、双盲、随机、安慰剂对照试验。

Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trial.

机构信息

Chinese PLA General Hospital, Beijing, China.

Nowon Eulji Medical Center, Seoul, South Korea.

出版信息

Lancet Neurol. 2023 Jun;22(6):476-484. doi: 10.1016/S1474-4422(23)00126-6.

DOI:10.1016/S1474-4422(23)00126-6

PMID:37210098

Abstract

BACKGROUND

No acute treatments targeting calcitonin gene-related peptide (CGRP) have been approved for use in China or South Korea. We aimed to compare the efficacy and safety of rimegepant-an orally administered small molecule CGRP antagonist-with placebo in the acute treatment of migraine among adults in these countries.

METHODS

This double-blind, randomised, placebo-controlled, multicentre phase 3 trial was done at 86 outpatient clinics at hospitals and academic medical centres (73 in China and 13 in South Korea). Participants were adults (≥18 years) with at least a 1-year history of migraine who had two to eight moderate or severe attacks per month and fewer than 15 headache days per month within the 3 months before the screening visit. Participants were randomly assigned (1:1) to 75 mg rimegepant or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use of preventive medication and by country. The allocation sequence was generated and implemented by study personnel using an interactive web-response system accessed online from each study centre. All participants, investigators, and the sponsor were masked to treatment assignment. The coprimary endpoints of freedom from pain and freedom from the most bothersome symptom (nausea, phonophobia, or photophobia) 2 h after dosing were assessed in the modified intention-to-treat (mITT) population (randomly assigned participants who took study medication for a migraine attack of moderate or severe pain intensity, and provided at least one efficacy datapoint after treatment) using Cochran-Mantel Haenszel tests. Safety was assessed in all participants who received rimegepant or placebo. The study is registered with ClinicalTrials.gov, number NCT04574362, and is completed.

FINDINGS

1431 participants were randomly assigned (716 [50%] to rimegepant and 715 [50%] to placebo). 668 (93%) participants in the rimegepant group and 674 (94%) participants in the placebo group received treatment. 1340 participants were included in the mITT analysis (666 [93%] in the rimegepant group and 674 [94%] in the placebo group). 2 h after dosing, rimegepant was superior to placebo for pain freedom (132 [20%] of 666 vs 72 [11%] of 674, risk difference 9·2, 95% CI 5·4-13·0; p<0·0001) and freedom from the most bothersome symptom (336 [50%] of 666 participants vs 241 [36%] of 674 participants, 14·8, 9·6-20·0; p<0·0001). The most common (≥1%) adverse events were protein in urine (8 [1%] of 668 participants in the rimepegant group vs 7 [1%] of 674 participants in the placebo group), nausea (7 [1%] of 668 vs 18 [3%] of 674), and urinary tract infection (5 [1%] of 668 vs 8 [1%] of 674). There were no rimegepant-related serious adverse events.

INTERPRETATION

Among adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population.

FUNDING

BioShin Limited.

TRANSLATIONS

For the Chinese and Korean translations of the abstract see Supplementary Materials section.

摘要

背景

在中、韩两国，尚无针对降钙素基因相关肽（CGRP）的急性治疗药物获批上市。我们旨在比较利马前列素（一种口服小分子 CGRP 拮抗剂）与安慰剂在两国成年偏头痛急性发作患者中的疗效和安全性。

方法

这是一项在 86 家医院和学术医疗中心（中国 73 家，韩国 13 家）的门诊进行的双盲、随机、安慰剂对照、多中心 3 期试验。参与者为年龄≥18 岁、偏头痛病史至少 1 年、每月有 2 至 8 次中度或重度发作且在筛选前 3 个月内每月头痛天数少于 15 天的成年人。参与者以 1:1 的比例随机分配至 75 mg 利马前列素或安慰剂，以治疗中重度疼痛强度的单次偏头痛发作。根据预防性药物的使用情况和国家进行分层随机分组。通过每个研究中心在线访问的交互式网络应答系统生成和实施分配序列。所有参与者、研究者和申办方对治疗分组均设盲。主要疗效终点为治疗 2 h 后无疼痛（改良意向治疗人群[ITT]）和无最困扰症状（恶心、恐声症或畏光症）的比例，使用 Cochran-Mantel-Haenszel 检验评估（随机分配至接受中重度疼痛强度偏头痛发作治疗、且在治疗后至少提供一个疗效数据点的研究药物的参与者）。所有接受利马前列素或安慰剂治疗的参与者均进行安全性评估。本研究在 ClinicalTrials.gov 上注册，编号为 NCT04574362，现已完成。

结果

共纳入 1431 名参与者（716 名[50%]接受利马前列素治疗，715 名[50%]接受安慰剂治疗）。利马前列素组 668 名（93%）和安慰剂组 674 名（94%）参与者接受了治疗。1340 名参与者纳入改良 ITT 分析（利马前列素组 666 名[93%]，安慰剂组 674 名[94%]）。治疗 2 h 后，利马前列素在疼痛缓解方面优于安慰剂（利马前列素组 132 名[20%]，安慰剂组 72 名[11%]，风险差 9.2，95%CI 5.4-13.0；p<0.0001）和最困扰症状缓解（利马前列素组 336 名[50%]，安慰剂组 241 名[36%]，14.8，9.6-20.0；p<0.0001）。最常见（≥1%）的不良事件为蛋白尿（利马前列素组 668 名参与者中 8 名[1%]，安慰剂组 674 名参与者中 7 名[1%]）、恶心（利马前列素组 668 名参与者中 7 名[1%]，安慰剂组 674 名参与者中 18 名[3%]）和尿路感染（利马前列素组 668 名参与者中 5 名[1%]，安慰剂组 674 名参与者中 8 名[1%]）。无利马前列素相关严重不良事件。