Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study
Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study
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DOI：
10.1016/s1474-4422(14)70128-0
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发表时间：
2014-09-01
期刊：
影响因子：
48
通讯作者：
Grayzel, David S.
中科院分区：
文献类型：
--
作者：
Dodick, David W.;Goadsby, Peter J.;Grayzel, David S.
背景偏头痛的治疗仍然很差，几乎没有有效的预防药物。我们评估的安全性和有效性LY 2951742，降钙素基因相关肽的完全人源化的单克隆抗体，偏头痛prevention.Methods我们做了一个随机，双盲，安慰剂对照，2期概念验证研究在美国的35个中心。年龄在18-65岁，每月偏头痛天数在4 - 14天的患者通过计算机随机化方案随机分配（1：1）至LY 2951742或安慰剂组。LY 2951742（150 mg）或安慰剂皮下注射，每2周一次，持续12周。主要终点是在9-12周时评估的每28天偏头痛天数的平均变化。在24周内评估安全性，包括12周治疗期和研究药物给药后的后续12周。患者和治疗研究者对治疗分配设盲。采用重复测量的混合效应模型进行分析，包括患者基线值、治疗、访视和治疗-访视相互作用作为固定效应，患者作为随机效应。根据接受的治疗分析安全性指标。该研究已经完成，并在ClinicalTrials.gov注册，NCT 01625988。结果在2012年7月31日至2013年9月18日期间，218名患者被随机分配到LY 2951742组（n=108，但1名患者在治疗前退出）或安慰剂组（n=110）。LY 2951742组偏头痛天数自基线至第12周的平均变化为-4.2（SD 3.1;减少62.5%），而安慰剂组为-3.0（SD 3.0;减少42.3%）（最小二乘均值差为-1.2，90%CI为-1.9至-0.6; p=0.0030）。LY 2951742组发生频率高于安慰剂组的不良事件包括注射部位疼痛、红斑或两者（21/107 [20%] vs 7/110 [6%]）、上呼吸道感染（18 [17%] vs 10 [9%]）和腹痛（6 [6%] vs 3 [3%]）。有两个严重的不良事件报告的治疗组和安慰剂组中的四个，没有一个被认为是与研究drug.Interpretation这些结果提供了初步的证据表明，LY 2951742可能是有益的偏头痛预防和降钙素基因相关肽在偏头痛的发病机制中的作用提供支持。需要进一步的对照研究来评估降钙素基因相关肽单克隆抗体预防性治疗偏头痛的安全性和有效性。
Background Migraine remains poorly treated, with few effective preventive drugs available. We assessed the safety and efficacy of LY2951742, a fully humanised monoclonal antibody to calcitonin gene-related peptide, for migraine prevention.Methods We did a randomised, double-blind, placebo-controlled, phase 2 proof-of-concept study at 35 centres in the USA. Patients aged 18-65 years with four to 14 migraine headache days per month were randomly assigned (1:1) to LY2951742 or placebo by a computerised randomisation scheme. LY2951742 (150 mg) or placebo were given as a subcutaneous injection once every 2 weeks for 12 weeks. The primary endpoint was the mean change in number of migraine headache days per 28-day period assessed at 9-12 weeks. Safety was assessed over 24 weeks, including the 12-week treatment period and the subsequent 12 weeks after study drug administration. Patients and treating investigators were masked to treatment allocation. Analyses were by intention to treat. A mixed-effects model of repeated measures was used, including patient baseline value, treatment, visit, and treatment-by-visit interaction as fixed effects, and patients as random effects. Safety measures were analysed according to the treatment received. This study has been completed and is registered with ClinicalTrials.gov, NCT01625988.Findings Between July 31, 2012, and Sept 18, 2013, 218 patients were randomly assigned to LY2951742 (n=108, but one patient withdrew before treatment) or placebo (n=110). The mean change from baseline to week 12 in the number of migraine headache days was -4.2 (SD 3.1; 62.5% decrease) in the LY2951742 group compared with -3.0 (SD 3.0; 42.3% decrease) in the placebo group (least-squares mean difference -1.2, 90% CI -1.9 to -0.6; p=0.0030). Adverse events that occurred more frequently with LY2951742 than with placebo included injection site pain, erythema, or both (21 [20%] of 107 vs seven [6%] of 110), upper respiratory tract infections (18 [17%] vs ten [9%]), and abdominal pain (six [6%] vs three [3%]). There were two serious adverse events reported in the treatment arm and four in the placebo arm, none of which were deemed to be related to the study drug.Interpretation These results provide preliminary evidence that LY2951742 might be beneficial in migraine prevention and provide support for the role of calcitonin gene-related peptide in the pathogenesis of migraine. Further controlled studies are needed to assess the safety and efficacy of monoclonal calcitonin gene-related peptide antibodies for the preventive treatment of migraine.