Greater response to placebo in children than in adults: a systematic review and meta-analysis in drug-resistant partial epilepsy

Abstract

Background: Despite 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 findings: Three 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.

Conclusions: Children 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.

Figure 1. Flow Diagrams of Trials

Figure 2. Proportion of 50% Responders in Each Trial

I², point estimates of Higgins I² with confidence interval; p Het, value of the heterogeneity test; p TE, value of the treatment effect test.

Figure 3. Analysis of the 50% Responder Rate Including All Dosages

(A) RR of 50% responder rate in adult and paediatric trials and comparison of RR of 50% responder rate in children and adults. (B) Mean 50% responder rate with placebo and with AED in adult and paediatric trials. * p < 0.001 (logistic regression). I², point estimates of Higgins I² with confidence interval; k, total number of trials; n, total number of patients; p Het, value of the heterogeneity test; p TE, value of the treatment effect test.

Figure 4. Analysis of the Seizure-Free Rate

(A) RR of seizure-free rate in adult and paediatric trials and comparison of RR of seizure-free rate in children and adults. (B) Mean seizure-free rate with placebo and with AED in adult and paediatric trials. I², point estimates of Higgins I² with confidence interval; k, total number of trials; n, total number of patients; p Het, value of the heterogeneity test; p TE, value of the treatment effect test.

Figure 5. Analysis of the Withdrawal Rates

(A) RR of withdrawal for any reason in adult and paediatric trials and comparison of RR of the total withdrawal rate in children and adults. (B) Comparison of RR of the adverse events withdrawal rate in children and adults. (C) Comparison of RR of the withdrawal rate related to seizure aggravation in children and adults. (D) Mean withdrawal rate for either any reasons, adverse events or seizure aggravation with placebo and with AED in adult and paediatric trials. * p < 0.001 (logistic regression). I², point estimates of Higgins I² with confidence interval; k, total number of trials; n, total number of patients; p Het, value of the heterogeneity test; p TE, value of the treatment effect test.