Abstracts

Rationale: Mortality and Sudden Unexplained Death in Epilepsy (SUDEP) are important issues in epilepsy. Risk factors for SUDEP are not fully understood, but may include inadequate seizure control. Adjunctive treatment of refractory epilepsy with efficacious doses of antiepileptic drugs (AEDs) may reduce the incidence of SUDEP compared with placebo (PBO) (Ryvlin P, et al. Lancet Neurol 2011;10[11]:961–8). This exploratory analysis evaluates mortality in adult patients with refractory partial-onset seizures (POS) treated with eslicarbazepine acetate (ESL) in Phase III adjunctive or monotherapy studies. ESL is not approved as monotherapy.Methods: Mortality data from six studies were included: three adjunctive studies, BIA-2093-301, -302 and -304, all of which included open-label extension phases; three monotherapy studies, ‑045 and ‑046, and the related open-label extension, ‑050. Adult (aged ≥16 years) patients with refractory POS (≥4/month) during stable treatment with ≥1 AED received adjunctive ESL at doses of 400 mg, 800 mg and 1200 mg once-daily (QD; patients continued to receive stable doses of baseline AEDs), or ESL monotherapy at 1200 mg or 1600 mg QD (studies -045 and -046; previous AEDs were withdrawn), or 800–2400 mg QD (study -050; flexible dosing schedule, up to two additional, non-oxcarbazepine AEDs allowed).Results: 1021 patients received at least 1 dose of double-blind adjunctive ESL, and 639 patients received at least 1 dose of open-label, adjunctive ESL. In the monotherapy studies, 365 patients received at least 1 dose of double-blind ESL, and 274 patients received at least 1 dose of open-label ESL. Exposure data are shown in Table 1. As of September 22 2014, overall ESL exposure (double-blind and open-label combined) was: adjunctive therapy, 1877.3 patient-years; monotherapy, 627.0 patient years. As of September 22 2014, there were 19 deaths overall during the adjunctive and monotherapy studies: two pre-randomization; 13 during treatment with PBO or ESL (double-blind or open-label); four post-ESL discontinuation. 11/13 on-treatment deaths occurred while patients were receiving ESL, and 2/13 occurred during treatment with PBO. 6/19 deaths were potentially due to SUDEP, three of which occurred while patients were receiving ESL (adjunctive, n=2; monotherapy, n=1). Among patients enrolled in the adjunctive studies (double-blind and open-label phases) the SUDEP rate for patients who were receiving ESL was 0.11 per 100 patient-years (90% confidence interval [CI] upper bound = 0.34). For the adjunctive and monotherapy studies combined, the SUDEP rate for patients who were receiving ESL was 0.12 per 100 patient-years (90% CI upper bound = 0.31).Conclusions: Deaths, including those potentially due to SUDEP, among adult patients with refractory POS who received ESL (as adjunctive or monotherapy) in Phase III studies were rare. Studies sponsored by Sunovion Pharmaceuticals Inc.