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. This phase III study evaluated the efficacy and safety of once-daily (QD) ESL as adjunctive therapy for adult patients with refractory POS (NCT00988429).Methods: Patients aged 16 years with 4 POS per month, taking stable doses of 1 2 antiepileptic drugs entered an 8 week baseline (BL) period and were randomized 1:1:1 to placebo (PBO), ESL 800mg, or ESL 1200mg, all QD. A 2-week titration phase was followed by 12 weeks of maintenance treatment. Seizure data were captured by event and daily entry diaries. The primary endpoint was standardized seizure frequency per 28-days during the maintenance phase. Other measures included 50% reduction in seizure frequency from BL, median reduction in seizure frequency from BL and Clinician s Global Impression-Improvement (CGI-I). Adverse events (AEs) were reported at each clinic visit. The primary efficacy analysis used the Analysis of Covariance model (ANCOVA) with treatment as fixed effect, BL seizure frequency and diary version as covariates, with two-stage gatekeeping multiplicity corrections. A sensitivity analysis of the primary endpoint including titration phase observation carried forward (TOCF) for those who discontinued prior to maintenance was also performed. Results: A total of 640 patients comprised the Intention-to-Treat population. Demographic characteristics were similar across groups: mean age was 39 years (SD = 12) with 50% males, and 63% Caucasian. The proportions of study completers were: PBO = 84%; ESL 800 mg = 80% and 1200 mg = 67%. In the primary analysis, the LS mean seizure frequencies were: PBO = 7.88, ESL 800mg = 6.54 (p=0.058 vs PBO), and 1200mg = 6.00 (p=0.004 vs PBO). The TOCF analysis demonstrated benefit for both ESL groups, with LS mean seizure frequency of 6.18 for the 800 mg group and 5.82 for the 1200 mg group compared with 8.12 for placebo (Figure 1). A 50% reduction in seizure frequency from BL was seen for 23.1% of PBO, 30.5% of ESL 800mg (p=0.07 vs PBO) and 42.6% of ESL 1200mg (p<0.001 vs PBO) patients. Median reductions in seizure frequencies were: PBO = -21.8%, ESL 800mg = -29.7% (p=0.249 vs PBO), and ESL 1200mg = -35.6% (p<0.012 vs PBO). Proportions of patients rated much improved and very much improved on the CGI-I were: PBO = 21%; ESL 800mg = 35%, ESL 1200mg = 36%. AEs were dose-related and are reported separately.Conclusions: In this study, ESL was effective and well tolerated as adjunctive treatment of refractory POS. ESL was associated with a reduction in seizure frequency that was statistically significant in the ESL 1200 mg group with a trend towards improvement in the ESL 800 mg group.