Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine
Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine
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DOI：
10.1212/01.wnl.0000286940.29755.61
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发表时间：
2008-04-15
期刊：
影响因子：
9.9
通讯作者：
Rapoport, A. M.
中科院分区：
文献类型：
--
作者：
Ho, T. W.;Mannix, L. K.;Rapoport, A. M.
目的：确定一种新型口服降钙素基因相关肽（CGRP）受体拮抗剂MK-0974用于急性偏头痛治疗的有效和耐受剂量。方法：随机、双盲、平行组、两期、自适应、剂量范围设计的临床试验。患者被分配使用MK-0974（25、50、100、200、300、400或600毫克）、利扎曲坦10毫克或口服安慰剂治疗中度或重度偏头痛发作。主要终点是给药后2小时疼痛缓解（减轻到轻度或无疼痛）。次要终点包括2小时疼痛缓解和24小时持续疼痛缓解。一个预先指定的，盲法的，自动的中期分析被用来停止低有效剂量的随机化。结果：根据适应性研究设计，4个最低剂量的MK-0974组（25、50、100、200 mg）因疗效不足而停用。其余治疗组2小时疼痛缓解率分别为300 mg (n = 38) 68.1%、400 mg (n = 45) 48.2%、600 mg (n = 40) 67.5%、利扎曲坦10 mg (n = 34) 69.5%和安慰剂（n = 115） 46.3%。预先设定的主要疗效假设检验比较了300、400和600 mg MK-0974组与安慰剂组的平均2小时疼痛缓解反应比例，具有显著性（P = 0.015）。其他终点的疗效模式大致相似。MK-0974总体耐受性良好，并且似乎没有随着剂量的增加而增加不良事件。结论：口服降钙素基因相关肽（CGRP）受体拮抗剂MK-0974对偏头痛的急性治疗有效且耐受性良好。
Objective: To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide ( CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine.Methods: Randomized, double-blind, parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 ( 25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief ( reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses.Results: Per the adaptive study design, the four lowest MK-0974 groups ( 25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg ( n = 38) 68.1%, 400 mg ( n = 45) 48.2%, 600 mg ( n = 40) 67.5%, rizatriptan 10 mg ( n = 34) 69.5%, and placebo ( n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant ( P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose.Conclusions: The novel, orally administered calcitonin gene-related peptide ( CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.