Abstracts

Rationale: Despite guidelines establishing the necessity to perform comprehensive paediatric drug development programs, pivotal trials in children with epilepsy remain mostly completed in phase 4 as a post-approval replication of adult data. However, it has been shown that treatment response in children can differ from that in adults. Whether such age difference effect might occur in the treatment of drug-resistant partial epilepsy has never been investigated, although it may have a significant impact on the design and results of paediatric randomised controlled trials (RCTs). Methods: Three electronic databases were searched for RCTs investigating any 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, as well as withdrawal rate for seizure aggravation. Results: Five AEDs were evaluated in both adults and children with drug-resistant partial epilepsy in 32 RCTs (Figure 1). Treatment effect was significantly lower in children than in adults (RR ratio: 0.67 (95% CI 0.51-0.89); p=0.02 by meta-regression, Figure 2). This difference was related to an age-dependent variation of the response to placebo, with higher rate in children than in adults (19% vs 9.9%, p<0.001), while no significant difference was observed for the response to active treatment (37.2% vs 30.4%, p=0.364, Figure 2). The relative risk of the total withdrawal rate was also significantly lower in children than in adults (RR ratio: 0.65 (0.43-0.98), p=0.004 by meta-regression), 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. Conclusions: Children with drug resistant partial epilepsy receiving placebo in double blind RCTs demonstrate significantly greater 50% responder rate than adults, probably reflecting increased placebo and regression to the mean effects. Paediatric trials design should consider these age-dependant variation of the response to placebo to reduce the risk of an underestimated sample size that could result in falsely negative trials. Based on our findings, we would recommend to calculate paediatric RCTs statistical power on the premise of a 50% responder rate comparable to that observed in adults for the active treatment group, and of either 20%, or twice that observed in the adult RCTs, for placebo group.