Research Article: Greater Response to Placebo in Children Than in Adults: A Systematic Review and Meta-Analysis in Drug-Resistant Partial Epilepsy

Date Published: August 12, 2008

Publisher: Public Library of Science

Author(s): Sylvain Rheims, Michel Cucherat, Alexis Arzimanoglou, Philippe Ryvlin, Terry Klassen

Abstract: 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 meta-regression). 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.

Partial Text: Epilepsy is a common disorder in children that often requires antiepileptic drug (AED) treatment for many years [1]. However, most AEDs have inadequate paediatric use information [2]. Indeed, AEDs are evaluated primarily in adult patients [3], and only a few randomised controlled trials (RCTs) have been performed in paediatric population [1]. Furthermore, despite reviews and guidelines establishing the importance of comprehensive drug development programs in children [2,4], most pivotal paediatric trials have been completed in Phase IV as a postapproval replication of adult data. Formulations, target doses, and expected effect size—which determines trial design and sample size—have been largely extrapolated from data collected in adult studies. Overall, the typical practice has been to extend the use of AEDs approved for adult epilepsy to children [5].

The initial search for RCTs investigating any AED in the add-on treatment of drug-resistant partial epilepsy yielded 2,122 articles. A review of the abstracts and exclusion of irrelevant and duplicate articles yielded 109 articles (Figure 1). Of the 109 articles examined, we excluded 25 open-label trials or trials with inappropriate blinding methods, seven studies with inappropriate randomization, two studies with a response conditional design, two studies with a period of treatment phase shorter than 8 wk, one monotherapy study, ten studies with inappropriate baseline, five review articles, five studies for which we were unable to determine the 50% responder rate, and two duplicate studies, leaving 50 potentially eligible studies (Figure 1). Among these 50 studies, we excluded 18 that investigated AEDs that have not been evaluated in paediatric populations (Figure 1). Two trials were only published in abstract [33,34]. However, the main data regarding the study design and the 50% responder rate were directly available in these abstracts, and missing information could be retrieved in the corresponding systematic review performed by the Cochrane Collaboration Group [35,36]. No other unpublished RCTs fulfilling our criteria was notified by pharmaceutical companies.

In this meta-analysis, we found that the RR of the 50% responder rate for active AEDs over placebo, one of the main measurements of AED efficacy in drug-resistant partial epilepsy, was significantly lower in paediatric trials than in adult ones. This difference was primarily related to a 2-fold higher placebo responder rate in children than in adults. Such a difference, if ignored, could well result in an underestimation of the placebo response and type II errors in paediatric RCTs.



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