Abstracts

Rationale: Eslicarbazepine acetate (ESL) is an oral antiepileptic drug (AED) that 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 U.S. The role of ESL as monotherapy has not been established.Methods: This study adopted the historical control withdrawal to monotherapy design (French et al. Epilepsia 2010). The trial (093-045) 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 1 2 AEDs. Treatment, in which subjects were randomized 2:1 to receive ESL 1600mg or 1200mg QD (high- and low-dose arms), comprised a 2-wk titration phase (when ESL was titrated up from starting doses of 600mg and 400mg QD, respectively), a 6-wk conversion phase (when other AEDs were withdrawn), and a 10-wk ESL monotherapy phase. The primary endpoint was the proportion of subjects meeting any of 5 exit criteria (signifying worsening seizure control) at 16-wks 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 pre-specified prediction interval (i.e. 65.3%), based on the historical controls.Results: Sixty-five subjects (mean age 38.7 yrs; 47.7% male) in the low-dose arm and 128 (mean age 39.9 yrs; 47.7% male) in the high-dose arm were randomized and received double-blind treatment; of these subjects, 60 and 118 entered the conversion phase, respectively. All subjects were recruited in North America. At baseline, mean (standard deviation) maximum 2-day seizure rate was 3.7 (2.8) in the low-dose and 3.8 (2.4) in the high-dose arm; mean maximum 28-day seizure rate was 12.1 (8.3) and 13.8 (9.1), respectively. The Kaplan-Meier estimated exit rate was 44.4% (95% CI: 32.5 to 58.3%) in the low-dose and 28.7% (21.2 to 38.1%) in the high-dose arm. As the upper limits of the 95% CIs for both doses were below the pre-specified threshold of 65.3%, ESL monotherapy was considered superior to historical controls. The trend to lower exit rates in the higher compared to lower dose was not statistically significant (p=0.07). Exit rates were similar for subjects who used or did not use carbamazepine. Treatment-emergent adverse events (TEAEs) occurring in 10% of subjects were dizziness, headache, fatigue, somnolence, nausea and nasopharyngitis and were similar in incidence between the low- and high-dose arms. Discontinuations due to TEAEs were reported in 12.3 and 18.0% of subjects in the low- and high-dose arms, respectively.Conclusions: ESL was superior to historical controls and was well-tolerated as conversion to monotherapy in adults from North America with POS. Exit and AE reporting rates were higher compared to the identically designed 093-046 study (conducted globally, poster at AES 2013).