Abstracts

Rationale: Eslicarbazepine acetate (ESL) is an antiepileptic that is converted to eslicarbazepine after oral administration. ESL was approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures (POS), with or without secondary generalization. ESL is not approved in the US. The role of ESL as monotherapy has not been established.Methods: This study adopted the historical control withdrawal to monotherapy design, as described by French et al (Epilepsia 2010;51:1936 43). The trial was a multicenter, randomized, double-blind, historical control study, with gradual conversion to ESL monotherapy, in adults with POS who were not well controlled ( 4 POS in the 8 wks prior to screening with no 4-wk seizure-free period) by current (1 2) anti-epileptic drugs (AEDs). Treatment, in which patients were randomized 2:1 to receive ESL 1600mg or 1200mg QD, comprised a 2-wk titration phase (when ESL was titrated up from starting doses of 600mg and 400mg QD, respectively), a 6-wk tapering or conversion phase (when other AEDs were withdrawn), and a 10-wk ESL monotherapy phase. The primary endpoint was the proportion of patients meeting any of 5 exit criteria (signifying worsening seizure control) post-titration. Treatment was considered effective if the upper limit of the 95% confidence interval (CI) for the exit rate (estimated using Kaplan-Meier methods) was lower than the lower limit of the prespecified prediction interval (i.e. 65.3%), based on the historical controls.Results: Fifty-eight patients (mean age 37.8 yrs; 53.4% male) in the ESL 1200mg arm and 114 (mean age 38.4 yrs; 45.6% male) in the ESL 1600mg arm were randomized and received double-blind treatment; of these patients, 54 and 100 entered the AED tapering phase, respectively. At baseline, mean (standard deviation) maximum 2-day seizure rate was 2.2 (1.8) in the 1200mg arm and 2.5 (1.5) in the 1600mg arm; mean (standard deviation) maximum 28-day seizure rate was 9.2 (6.7) and 11.1 (7.9), respectively. The Kaplan-Meier estimated exit rate (95% CI) was 15.6% (8.1 to 28.7%) in the ESL 1200mg arm and 12.8% (7.5 to 21.5%) in the ESL 1600mg arm (Figure 1). As the upper limits of the 95% CIs for both doses were below the prespecified threshold of 65.3%, ESL monotherapy was shown to be superior to historical controls. There was no statistically significant difference in exit rates between the two arms (log-rank test: p=0.633). In the 1200mg and 1600mg arms, median decrease in seizure frequency from baseline to the monotherapy phase was 45.7% and 52.1%, respectively, and 38.4% and 46.0% of patients had a 50% reduction in seizures. Treatment-emergent adverse events (TEAEs) occurring in 5% of patients are shown in Table 1. During monotherapy, headache was the only TEAE observed in 5% of patients overall (11.6%). Discontinuations due to TEAEs were reported in 1.7% (1/58) of patients in the 1200mg arm and 7.9% (9/114) of those in the 1600mg arm.Conclusions: ESL was superior to historical controls and well-tolerated as conversion to monotherapy in adults with POS.