Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study
Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study
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DOI：
10.1016/s1474-4422(15)00245-8
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发表时间：
2015-11-01
期刊：
影响因子：
48
通讯作者：
Silberstein, Stephen D.
中科院分区：
文献类型：
--
作者：
Bigal, Marcelo E.;Edvinsson, Lars;Silberstein, Stephen D.
降钙素基因相关肽（CGRP）抑制剂对慢性偏头痛的疗效尚未确定。在这里，我们评估的安全性，耐受性和疗效的两个剂量的TEV-48125，单克隆抗CGRP抗体，在预防性治疗慢性偏头痛。方法在这个多中心，随机，双盲，双模拟，安慰剂对照，平行组2b期研究，我们招募了男性和女性（年龄18-65岁）从62个网站在美国谁有慢性偏头痛。使用由中央计算机化系统和交互式网络应答系统生成的随机化列表，我们将患者（1：1：1，按性别和合并预防药物的使用分层）随机分配至皮下注射TEV-48125 675/225 mg（第一个治疗周期675 mg，第二和第三个治疗周期225 mg）、TEV-48125 900 mg（所有三个治疗周期900 mg）或安慰剂的三个28天治疗周期。研究者、患者和资助者对治疗分配不知情。使用电子日记记录每日头痛信息。主要终点是第三个治疗周期（第9-12周）头痛小时数较基线的变化以及研究期间的安全性和耐受性。次要终点是第9-12周中度或重度头痛天数相对于基线的变化。分析意向治疗人群的疗效终点。使用描述性统计分析安全性和耐受性。在2014年1月8日至2014年8月27日期间，我们招募了264名参与者：89名随机分配接受安慰剂，88名接受675/225 mg TEV-48125，87名接受900 mg TEV-48125。ClinicalTrials.gov第9-12周期间，675/225 mg组头痛小时数较基线的平均变化为-59.84 h（SD 80.38），900 mg组为-67.51 h（79.37），安慰剂组为-37.10 h（79.44）。安慰剂和675/225 mg剂量组之间头痛-小时减少的最小二乘平均差异为-22.74 h（95% CI -44.28至-1.21; p=0.0386），而安慰剂和900 mg剂量组之间的差异为-30.41 h（-51.88至-8.95; p=0.0057）。安慰剂组36例（40%）患者、675/225 mg剂量组47例（53%）患者和900 mg剂量组41例（47%）患者报告了不良事件，而分别有15例（17%）、25例（29%）和28例（32%）患者记录了治疗相关不良事件。最常见的不良反应是轻度注射部位疼痛和瘙痒。4例（1%）患者发生严重非治疗相关不良事件（安慰剂组1例，675/225 mg组1例，900 mg组2例）;没有严重的治疗相关不良事件，血压或其他生命体征也没有相关变化。通过皮下注射每28天给予TEV-48125似乎是可耐受的和有效的，因此支持在3期试验中进一步开发TEV-48125用于预防性治疗慢性偏头痛。
Background Benefits of calcitonin-gene related peptide (CGRP) inhibition have not been established in chronic migraine. Here we assess the safety, tolerability, and efficacy of two doses of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of chronic migraine.Methods In this multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had chronic migraine. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1, stratified by sex and use of concomitant preventive drugs) to three 28-day treatment cycles of subcutaneous TEV-48125 675/225 mg (675 mg in the first treatment cycle and 225 mg in the second and third treatment cycles), TEV-48125 900 mg (900 mg in all three treatment cycles), or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Daily headache information was captured using an electronic diary. Primary endpoints were change from baseline in the number of headache-hours during the third treatment cycle (weeks 9-12) and safety and tolerability during the study. Secondary endpoint was change in the number of moderate or severe headache-days in weeks 9-12 relative to baseline. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered with ClinicalTrials.gov, number, NCT02021773.Findings Between Jan 8, 2014, and Aug 27, 2014, we enrolled 264 participants: 89 were randomly assigned to receive placebo, 88 to receive 675/225 mg TEV-48125, and 87 to receive 900 mg TEV-48125. The mean change from baseline in number of headache-hours during weeks 9-12 was -59.84 h (SD 80.38) in the 675/225 mg group and -67.51 h (79.37) in the 900 mg group, compared with -37.10 h (79.44) in the placebo group. The least square mean difference in the reduction of headache-hours between the placebo and 675/225 mg dose groups was -22.74 h (95% CI -44.28 to -1.21; p=0.0386), whereas the difference between placebo and 900 mg dose groups was -30.41 h (-51.88 to -8.95; p=0.0057). Adverse events were reported by 36 (40%) patients in the placebo group, 47 (53%) patients in the 675/225 mg dose group, and 41 (47%) patients in the 900 mg dose group, whereas treatment-related adverse events were recorded in 15 (17%) patients, 25 (29%) patients, and 28 (32%) patients, respectively. The most common adverse events were mild injection-site pain and pruritus. Four (1%) patients had serious non-treatment-related adverse events (one patient in the placebo group, one patient in the 675/225 mg group, and two patients in the 900 mg group); no treatment-related adverse events were serious and there were no relevant changes in blood pressure or other vital signs.Interpretation TEV-48125 given by subcutaneous injection every 28 days seems to be tolerable and effective, thus supporting the further development of TEV-48125 for the preventive treatment of chronic migraine in a phase 3 trial.