Office of Pediatric Therapeutics, Office of Commissioner, US Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA.
JAMA Pediatr. 2013 Mar 1;167(3):243-9. doi: 10.1001/jamapediatrics.2013.872.
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.
对提交给美国食品和药物管理局（FDA）的试验数据进行系统回顾和分析，以确定导致曲坦类药物治疗儿童偏头痛试验失败的可能原因。
FDA 药物信息网站和已发表的文献。
1999 年 1 月 1 日至 2011 年 12 月 31 日期间，所有用于偏头痛发作治疗的药物的儿科疗效和药代动力学试验数据均提交给 FDA。
患者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在药物产品之间进行分析和比较。
我们分析了琥珀酸舒马普坦鼻喷雾剂和佐米曲普坦、依来曲普坦氢溴酸盐、阿莫曲坦马来酸盐和苯甲酸利扎曲普坦片的数据。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，要求患者具有至少持续 4 小时的偏头痛发作史。所有试验中均观察到高安慰剂反应率，2 小时时疼痛缓解率为 53%至 57.5%。2011 年的利扎曲普坦试验采用了早期安慰剂反应设计的患者非随机分组。与 1999 年进行的利扎曲普坦试验相比，由于研究设计，2011 年利扎曲普坦试验将 2 小时治疗后终点头痛无发作的安慰剂反应率降低了 6%。青少年和成人之间的药代动力学特征在统计学上相似。
所有试验中高安慰剂反应率一致，这可能是儿童偏头痛发作治疗药物试验的主要挑战。通过选择持续时间较长的偏头痛发作患者进行富集，不足以克服高安慰剂反应率。另一种富集策略，即对早期安慰剂反应患者进行非随机分组，成功降低了利扎曲普坦的高安慰剂反应率，是一种应考虑用于未来儿童偏头痛治疗药物发作试验的试验设计。
