Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study
Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study
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DOI：
10.1016/s0140-6736(18)32534-0
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发表时间：
2018-11-24
期刊：
影响因子：
168.9
通讯作者：
Klatt, Jan
中科院分区：
文献类型：
--
作者：
Reuter, Uwe;Goadsby, Peter J.;Klatt, Jan
背景：相当大比例的偏头痛患者对口服预防治疗无反应或不能耐受。Erenumab是一种新型的cgrp受体抗体，具有预防偏头痛的作用。我们评估了其对发作性偏头痛患者的疗效和耐受性，这些患者先前使用2 - 4种偏头痛预防药物治疗无效。LIBERTY是一项为期12周、双盲、安慰剂对照的随机研究，在16个国家的59个试验点进行。符合条件的患者年龄为18-65岁，有或无先兆发作性偏头痛病史至少12个月，在筛查前的3个月内平均每月偏头痛4-14天，接受2 - 4种预防治疗失败（根据疗效或耐受性，或两者兼而有之）。符合条件的参与者被随机分配（1:1）接受erenumab 140 mg（通过两次70 mg注射）或安慰剂，每4周皮下注射12周。随机化是通过互动反应技术进行的，并根据基线阶段偏头痛的每月频率（每月4-7天vs 8-14天）进行分层。Cenduit生成随机列表并将参与者分配到不同组。参与者、调查人员、进行各种评估的人以及研究发起者都对治疗分配进行了掩饰。主要终点是在9-12周期间，每月偏头痛平均天数减少50%或更多的患者比例。在完整的分析集中测量疗效，其中包括所有随机分配的患者，他们开始指定的治疗并完成至少一次基线后每月偏头痛日测量。通过记录不良事件、体格检查、生命体征评估、临床实验室评估和心电图来评估安全性和耐受性。对所有随机分配的接受至少一剂研究药物的患者进行安全性评估。该试验已在ClinicalTrials.gov注册，注册号NCT03096834。该试验对新参与者关闭，但开放标签扩展阶段正在进行中。在2017年3月20日至2017年10月27日期间，246名参与者被随机分配，其中121名被分配到erenumab组，125名被分配到安慰剂组。246名参与者中有95名（39%）曾尝试过两种预防药物，93名（38%）尝试过三种，56名（23%）尝试过四种。在第12周，36例（30%）患者在erenumab组的平均每月偏头痛天数较基线减少了50%或更多，而安慰剂组为17例（14%）（优势比为2.7 [95% CI 1.4-5.2]; p=0.002）。erenumab和安慰剂的耐受性和安全性相似。最常见的治疗不良事件是注射部位疼痛，两组中均有7人（6%）出现。与安慰剂相比，erenumab对发作性偏头痛患者有效，这些患者以前对2到4次偏头痛预防治疗没有反应或耐受。Erenumab可能是难以治疗的偏头痛患者的一个选择，他们有很高的未满足的需求和很少的治疗选择。爱思唯尔有限公司版权所有2018版权所有。
Background A substantial proportion of patients with migraine does not respond to, or cannot tolerate, oral preventive treatments. Erenumab is a novel CGRP-receptor antibody with preventive efficacy in migraine. We assessed its efficacy and tolerability in patients with episodic migraine in whom previous treatment with two-to-four migraine preventives had been unsuccessful.Methods LIBERTY was a 12-week, double-blind, placebo-controlled randomised study at 59 sites in 16 countries. Eligible patients were aged 18-65 years and had a history of episodic migraine with or without aura for at least 12 months, had migraine for an average of 4-14 days per month during the 3 months before screening, and had been treated unsuccessfully (in terms of either efficacy or tolerability, or both) with between two and four preventive treatments. Eligible participants were randomly assigned (1:1) to receive either erenumab 140 mg (via two 70 mg injections) or placebo every 4 weeks subcutaneously for 12 weeks. Randomisation was by interactive response technology and was stratified by monthly frequency of migraine headache (4-7 vs 8-14 migraine days per month) during the baseline phase. Cenduit generated the randomisation list and assigned participants to groups. Participants, investigators, people doing various assessments, and the study sponsor were masked to treatment assignment. The primary endpoint was the proportion of patients achieving a 50% or greater reduction in the mean number of monthly migraine days during weeks 9-12. Efficacy was measured in the full analysis set, which included all randomly assigned patients who started their assigned treatment and completed at least one post-baseline monthly migraine day measurement. Safety and tolerability were assessed by recording adverse events and by physical examination, assessment of vital signs, clinical laboratory assessments, and electrocardiography. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT03096834. The trial is closed to new participants, but the open-label extension phase is ongoing.Findings Between March 20, 2017, and Oct 27, 2017, 246 participants were randomly assigned, 121 to the erenumab group and 125 to the placebo group. 95 of 246 (39%) participants had previously unsuccessfully tried two preventive drugs, 93 (38%) had tried three, and 56 (23%) had tried four. At week 12, 36 (30%) patients in the erenumab had a 50% or greater reduction from baseline in the mean number of monthly migraine days, compared with 17 (14%) in the placebo group (odds ratio 2.7 [95% CI 1.4-5.2]; p=0.002). The tolerability and safety profiles of erenumab and placebo were similar. The most frequent treatment-emergent adverse event was injection site pain, which occurred in seven (6%) participants in both groups.Interpretation Compared with placebo, erenumab was efficacious in patients with episodic migraine who previously did not respond to or tolerate between two and four previous migraine preventive treatments. Erenumab might be an option for patients with difficult-to-treat migraine who have high unmet needs and few treatment options. Copyright (c) 2018 Elsevier Ltd. All rights reserved.