Efficacy and safety of eslicarbazepine acetate as adjunctive therapy for refractory focal-onset seizures in children: a double-blind, randomized, placebo-controlled, parallel-group, multicenter, phase-III clinical trial

Abstract

Purpose: this was a phase-III, randomized, double-blind, placebo-controlled study aimed to evaluate efficacy and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in pediatric patients with refractory focal-onset seizures (FOS).

Methods: children (2–18 years old) with FOS, receiving 1–2 antiepileptic drugs, were randomized to ESL or placebo. Treatment was started at 10 mg/kg/day, up-titrated up to 20–30 mg/kg/day, and maintained for 12 weeks, followed by one-year open-label follow-up. Primary efficacy endpoints were relative reduction in standardized seizure frequency (SSF) and proportion of responders (≥ 50% SSF reduction) from baseline. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs).

Results: the intention-to-treat (ITT) set included 134 patients randomized to ESL and 129 to placebo; 89.6% and 91.5%, respectively, completed the trial. An unbalanced number of seizures at baseline were observed between groups. Least square (LS) mean relative change in SSF from baseline was higher in the ESL group (− 18.1%) than in placebo (− 8.6%). Proportion of responders between ESL and placebo groups was not statistically different. A post hoc analysis showed greater relative reduction in SSF in patients above 6 years old treated with ESL 20 or 30 mg/kg/day compared with placebo; this was significant in patients above 6 years old treated with ESL 30 mg/kg/day (LS mean difference: 31.9%; p = 0.0478). The observed safety profile in children was consistent with that established in adult studies.

Conclusions: adjunctive ESL treatment was well-tolerated, but this trial failed to demonstrate that ESL was more effective than placebo in the predefined efficacy endpoints; factors that may have contributed to this outcome, affecting particularly the young age group, include etiological heterogeneity, difficulty in recognizing simple partial seizures, high seizure frequency with risk of imbalance, and underestimation of the efficacious dose range.

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