Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial
Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial
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DOI：
10.1016/s1474-4422(16)00019-3
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发表时间：
2016-04-01
期刊：
影响因子：
48
通讯作者：
Lenz, Robert
中科院分区：
文献类型：
--
作者：
Sun, Hong;Dodick, David W.;Lenz, Robert
降钙素基因相关肽（CGRP）途径是偏头痛患者预防治疗的一个有希望的靶点。我们评估了AMG 334（一种针对CGRP受体的全人源单克隆抗体）预防偏头痛的安全性和有效性。方法在这个多中心、随机、双盲、安慰剂对照,第二阶段试验,偏头痛患者年龄在18 - 60岁之间的年4至14天每月登记在59头痛和临床研究中心在北美和欧洲,和随机分配3:2:2:2比例每月皮下安慰剂,AMG 334 7毫克,AMG 334 21毫克,或AMG 334 70毫克使用sponsor-generated随机序列集中执行交互式语音应答或交互式web反应系统。研究现场人员、患者和赞助研究人员对治疗分配保密。主要终点是从基线到12周双盲治疗期最后4周每月偏头痛天数的变化。主要终点是使用重复测量的广义线性混合效应模型中每个时间点的最小二乘平均值来计算的。安全终点为不良事件、临床实验室值、生命体征和抗amg 334抗体。该研究已在ClinicalTrials.gov注册，编号NCT01952574。长达256周的开放标签延长阶段正在进行中，将评估AMG 334的长期安全性。从2013年8月6日至2014年6月30日，483例患者被随机分配到安慰剂组（n=160）、AMG 334 7 mg组（n=108）、AMG 334 21 mg组（n=108）和AMG 334 70 mg组（n=107）。第12周时，AMG 33470 mg组每月偏头痛天数的平均变化为-3.4 （SE 0.4）天，而安慰剂组为-2.3（0.3）天（差异为-1.1天[95% CI -2.1至-0.2],p=0.021）。7毫克（-2.2 [SE 0.4]）和21毫克（-2.4 [SE 0.4]）剂量组每月偏头痛天数的平均减少与安慰剂组没有显著差异。有82例（54%）安慰剂组患者、54例（50%）AMG 334 7 mg组患者、54例（51%）AMG 334 21 mg组患者和57例（54%）AMG 334 70 mg组患者记录了不良事件。最常见的不良反应是鼻咽炎、疲劳和头痛。AMG 334 7 mg组报告了1例严重不良事件（卵巢囊肿破裂）和AMG 334 70 mg组1例患者（偏头痛和眩晕）；这些事件被认为与AMG 334治疗无关。317例患者中有9例（3%）有中和抗体。抗amg 334抗体阳性患者与不良事件之间无明显关联。没有临床显著的生命体征、实验室或心电图发现记录。这些结果表明AMG 334 70mg可能是一种潜在的治疗偏头痛的药物，并支持AMG 334在更大规模的3期试验中进一步研究。
Background The calcitonin gene-related peptide (CGRP) pathway is a promising target for preventive therapies in patients with migraine. We assessed the safety and efficacy of AMG 334, a fully human monoclonal antibody against the CGRP receptor, for migraine prevention.Methods In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients aged 18-60 years with 4 to 14 migraine days per month were enrolled at 59 headache and clinical research centres in North America and Europe, and randomly assigned in a 3:2:2:2 ratio to monthly subcutaneous placebo, AMG 334 7 mg, AMG 334 21 mg, or AMG 334 70 mg using a sponsor-generated randomisation sequence centrally executed by an interactive voice response or interactive web response system. Study site personnel, patients, and the sponsor study personnel were masked to the treatment assignment. The primary endpoint was the change in monthly migraine days from baseline to the last 4 weeks of the 12-week double-blind treatment phase. The primary endpoint was calculated using the least squares mean at each timepoint from a generalised linear mixed-effect model for repeated measures. Safety endpoints were adverse events, clinical laboratory values, vital signs, and anti-AMG 334 antibodies. The study is registered with ClinicalTrials.gov, number NCT01952574. An open-label extension phase of up to 256 weeks is ongoing and will assess the long-term safety of AMG 334.Findings From Aug 6, 2013, to June 30, 2014, 483 patients were randomly assigned to placebo (n=160), AMG 334 7 mg (n=108), AMG 334 21 mg (n=108), or AMG 334 70 mg (n=107). The mean change in monthly migraine days at week 12 was -3.4 (SE 0.4) days with AMG 334 70 mg versus -2.3 (0.3) days with placebo (difference -1.1 days [95% CI -2.1 to -0.2], p=0.021). The mean reductions in monthly migraine days with the 7 mg (-2.2 [SE 0.4]) and the 21 mg (-2.4 [0.4]) doses were not significantly different from that with placebo. Adverse events were recorded in 82 (54%) patients who received placebo, 54 (50%) patients in the AMG 334 7 mg group, 54 (51%) patients in the AMG 334 21 mg group, and 57 (54%) patients in the AMG 334 70 mg group. The most frequently reported adverse events were nasopharyngitis, fatigue, and headache. Serious adverse events were reported for one patient in the AMG 334 7 mg group (ruptured ovarian cyst) and one patient in the AMG 334 70 mg group (migraine and vertigo); these events were judged to be unrelated to AMG 334 treatment. Nine (3%) of 317 patients had neutralising antibodies. No apparent association was recorded between patients with positive anti-AMG 334 antibodies and adverse events. No clinically significant vital signs, laboratory, or electrocardiogram findings were recorded.Interpretation These results suggest that AMG 334 70 mg might be a potential therapy for migraine prevention in patients with episodic migraine and support further investigation of AMG 334 in larger phase 3 trials.