Migraine therapeutics in adolescents: a systematic analysis and historic perspectives of triptan trials in adolescents.
Migraine therapeutics in adolescents: a systematic analysis and historic perspectives of triptan trials in adolescents.
复制标题
青少年偏头痛治疗：青少年曲坦类试验的系统分析和历史观点。
作者：
Haihao Sun;E. Bastings;J. Temeck;P. Brian Smith;A. Men;Veneeta Tandon;D. Murphy;W. Rodriguez
对提交给美国食品药品监督管理局（FDA）的试验数据进行系统性审查和分析，以确定曲坦类药物治疗偏头痛的儿科试验失败的可能原因。数据来源FDA网站提供药物信息和已发表文献。资料选择：1999年1月1日至2011年12月31日期间提交给FDA的所有用于偏头痛流产治疗的药物的儿科疗效和药代动力学试验数据。主要观察指标：分析患者的人口统计学基线特征、纳入和排除标准、试验设计、疗效终点和药代动力学特征，并在不同药物产品之间进行比较。结果：我们分析了琥珀酸舒马曲坦鼻喷雾剂和佐米曲坦、氢溴酸依来曲坦、苹果酸阿莫曲坦和苯甲酸利扎曲坦片剂的数据。7项疗效试验采用随机、双盲、安慰剂对照、平行组试验设计。在4项试验中，要求患者有持续至少4小时的偏头痛发作史。在所有试验中均观察到安慰剂的高应答率，2小时疼痛缓解率范围为53%至57.5%。2011年利扎曲普坦试验采用了早期安慰剂反应设计的非随机化患者。与1999年进行的利扎曲普坦试验相比，由于研究设计，2011年利扎曲普坦试验在治疗后2小时终点时头痛缓解率降低了6%。青少年和成人之间的药代动力学特征在统计学上相似。结论：所有试验中安慰剂的高应答率是一致的，这可能代表了偏头痛流产治疗药物儿科试验的主要挑战。通过选择长期偏头痛发作的受试者进行丰富，不足以克服高安慰剂应答率。另一种富集策略，早期安慰剂反应患者的非随机化，成功地降低了利扎曲普坦的高安慰剂反应率，是未来流产偏头痛治疗的儿科试验应考虑的试验设计。
OBJECTIVES To conduct a systematic review and analysis of trial data submitted to the US Food and Drug Administration (FDA) to identify possible causes for the failure of pediatric trials of triptans for treatment of migraines. DATA SOURCE The FDA website for drug information and published literature. STUDY SELECTION All pediatric efficacy and pharmacokinetics trial data of drugs used for abortive treatment of migraine submitted to the FDA from January 1, 1999, through December 31, 2011. MAIN OUTCOME MEASURES Patient demographic baseline characteristics, inclusion and exclusion criteria, trial designs, efficacy end points, and pharmacokinetic profiles were analyzed and compared across drug products. RESULTS We analyzed data for sumatriptan succinate nasal spray and zolmitriptan, eletriptan hydrobromide, almotriptan malate, and rizatriptan benzoate tablets. Seven efficacy trials had a randomized, double-blinded, placebo-controlled, parallel-group trial design. In 4 trials, patients were required to have a history of migraine attacks lasting at least 4 hours. High response rates for placebo were observed in all trials, with pain relief at 2 hours ranging from 53% to 57.5%. Nonrandomization of patients with an early placebo response design was used in the rizatriptan trial in 2011. Compared with the rizatriptan trial conducted in 1999, the 2011 rizatriptan trial reduced the placebo response rate by 6% for headache freedom at the 2-hour posttreatment end point owing to study design. The pharmacokinetic profiles between adolescents and adults were statistically similar. CONCLUSIONS High placebo response rates are consistent across all trials and may represent the principal challenge in pediatric trials of drugs for abortive treatment of migraine. Enrichment with selection of subjects with long-lasting migraine attacks is not sufficient to overcome high placebo response rates. Another enrichment strategy, the nonrandomization of patients with an early placebo response, successfully reduces the high placebo response rate for rizatriptan and is a trial design that should be considered for future pediatric trials of abortive migraine therapeutics.