Greater response to placebo in children than in adults: A systematic review and meta-analysis in drug-resistant partial epilepsy
Greater response to placebo in children than in adults: A systematic review and meta-analysis in drug-resistant partial epilepsy
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DOI：
10.1371/journal.pmed.0050166
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发表时间：
2008-08-01
期刊：
影响因子：
15.8
通讯作者：
Ryvlin, Philippe
中科院分区：
文献类型：
--
作者：
Rheims, Sylvain;Cucherat, Michel;Ryvlin, Philippe
背景尽管指南确立了执行全面的儿科药物开发计划的必要性，但癫痫儿童的关键试验大多已在第四阶段完成，作为成人数据的批准后复制。然而，已有研究表明，儿童的治疗反应可能与成人不同。目前还没有研究成人和儿童在治疗耐药部分性癫痫方面是否存在药物疗效的差异，尽管这种差异可能会对儿科随机对照试验(RCT)的设计和结果产生实质性影响。方法和发现搜索三个电子数据库，调查儿童和成人在附加治疗耐药部分性癫痫时是否使用任何抗癫痫药物(AED)。采用有效AEDs治疗组和安慰剂组有效应答率为50%的相对危险度(RR)比和Meta回归分析比较两个年龄组之间的治疗效果。用Logistic回归分析安慰剂和积极治疗的反应差异。采用一种可比较的方法分析次级终点，包括无癫痫发生率、与不良事件有关的总戒断率和不良事件相关的戒断率以及癫痫加重的戒断率。在32个随机对照试验中，对成人和儿童耐药部分性癫痫患者的5种抗癫痫药物进行了评估。儿童组疗效明显低于成人组(RR比：0.67[95%可信区间(CI)0.51~0.89]；Meta回归分析p=0.02)。这种差异与年龄相关的安慰剂反应变化有关，儿童的发生率高于成人(19%比9.9%，p<；0.001)，而对积极治疗的反应没有显著差异(37.2%比30.4%，p 0.364)。儿童的总戒断率的相对风险也显著低于成人(RR比：0.65[95%CI0.43-0.98]，经Meta回归分析，p=0.004)，这是因为儿童癫痫加重的戒断率(5.6%)高于接受安慰剂的成人(0.7%)(p<；0.001)。结论：在双盲随机对照试验中，接受安慰剂治疗的难治性部分性癫痫儿童的有效率显著高于成人，这可能反映了安慰剂的增加和向平均效果的回归。儿科临床试验设计应考虑这些与年龄相关的对安慰剂反应的变化，以减少样本大小被低估的风险，这可能导致假阴性试验。
BackgroundDespite guidelines establishing the need to perform comprehensive paediatric drug development programs, pivotal trials in children with epilepsy have been completed mostly in Phase IV as a postapproval replication of adult data. However, it has been shown that the treatment response in children can differ from that in adults. It has not been investigated whether differences in drug effect between adults and children might occur in the treatment of drug-resistant partial epilepsy, although such differences may have a substantial impact on the design and results of paediatric randomised controlled trials (RCTs).Methods and FindingsThree electronic databases were searched for RCTs investigating any antiepileptic drug (AED) in the add-on treatment of drug-resistant partial epilepsy in both children and adults. The treatment effect was compared between the two age groups using the ratio of the relative risk (RR) of the 50% responder rate between active AEDs treatment and placebo groups, as well as meta-regression. Differences in the response to placebo and to active treatment were searched using logistic regression. A comparable approach was used for analysing secondary endpoints, including seizure-free rate, total and adverse events-related withdrawal rates, and withdrawal rate for seizure aggravation. Five AEDs were evaluated in both adults and children with drug-resistant partial epilepsy in 32 RCTs. The treatment effect was significantly lower in children than in adults (RR ratio: 0.67 [95% confidence interval (CI) 0.51-0.89]; p=0.02 by metaregression). This difference was related to an age-dependent variation in the response to placebo, with a higher rate in children than in adults (19% versus 9.9%, p < 0.001), whereas no significant difference was observed in the response to active treatment (37.2% versus 30.4%, p 0.364). The relative risk of the total withdrawal rate was also significantly lower in children than in adults (RR ratio: 0.65 [95% CI 0.43-0.98], p=0.004 by metaregression), due to higher withdrawal rate for seizure aggravation in children (5.6%) than in adults (0.7%) receiving placebo (p < 0.001). Finally, there was no significant difference in the seizure-free rate between adult and paediatric studies.ConclusionsChildren with drug-resistant partial epilepsy receiving placebo in double-blind RCTs demonstrated significantly greater 50% responder rate than adults, probably reflecting increased placebo and regression to the mean effects. Paediatric clinical trial designs should account for these age-dependent variations of the response to placebo to reduce the risk of an underestimated sample size that could result in falsely negative trials.