Abstracts

Rationale: Theoretically, antiepileptic drug (AED) combinations with the same mechanism of action may be less adequate than targeting different mechanisms of action. It remains unclear whether AEDs with different mechanisms of action are more likely to interact synergistically than AEDs with similar mechanisms. The aim of this exploratory post hoc analysis was to evaluate efficacy and safety of eslicarbazepine acetate (ESL) as adjuvant therapy to concomitant carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or GABA mimetic AEDs (phenobarbital, lorazepam and clonazepam). Methods: BIA-2093-301, -302, -303, -304 were double-blind, randomized, placebo-controlled trials that evaluated efficacy and safety of ESL as add-on treatment in adult patients with focal onset seizures. After an 8-week baseline period, adults with ≥4 focal seizures/month, taking 1–3 AEDs were randomized to placebo, ESL 400 mg, ESL 800 mg or ESL 1200 mg QD (2-week titration; 12-week maintenance). Data from patients treated with concomitant CBZ, LTG, LEV, or GABA mimetic AEDs were pooled. Efficacy (responder rate: ≥50% reduction in seizure frequency) and safety [incidence of treatment emergent adverse events at least possibly related (TEAE); discontinuation due to TEAE] were evaluated in subgroups of patients (not mutually exclusive) treated with concomitant CBZ, LTG, LEV, or GABA mimetic AEDs. Results: Efficacy and safety population included 1389 and 1699 patients, respectively. At baseline, most patients were treated with 1 or 2 AEDs; concomitant CBZ in 682 (49.1%), LTG in 308 (22.2%), LEV in 277 (19.9%) and GABA mimetic AEDs in 201 (14.5%). In the overall population, responder rate was 22.2%, 33.8%, 43.1% for placebo, ESL 800 mg, 1200 mg, respectively. In the analysis by concomitant AED, ESL was associated with higher responder rate (vs. placebo) as add-on to CBZ (Relative Risk, RR: ESL 800 mg, 1.66; ESL 1200 mg, 2.10); LTG (ESL 1200 mg, 2.39); LEV (RR: ESL 1200 mg, 2.40); GABA mimetic AEDs (RR: ESL 1200 mg: 1.87). ESL 1200 mg and concomitant LEV and LTG had the highest association with responder rate (Table 1). Overall, most frequent TEAE were dizziness (20.7%), somnolence (12.9%), nausea (8.3%); most frequent TEAE leading to discontinuation were dizziness (5.6%), nausea (3.1%), vomiting (2.8%; Table 2). ESL as add-on to treatment regimens containing LEV had the lowest frequency of TEAE such as dizziness (13%), somnolence (8.7%), nausea (6.3%), diplopia (3.9%), blurred vision (4.3%), ataxia (1.4%), vertigo (0,5%); lowest frequency of discontinuation due to TEAE such as dizziness (2.9%), nausea (1.4%), ataxia (1.4%), blurred vision, vertigo, vomiting (0%). ESL as add-on to treatment regimens containing CBZ had the highest frequency of TEAE and discontinuation due to TEAE. Conclusions: In this exploratory post hoc pooled analysis of four double-blind, pivotal phase III studies, ESL was efficacious and well tolerated as add-on treatment to CBZ, LTG, LEV and GABA mimetic AEDs in adult patients with focal seizures. ESL as add-on to treatment regimens containing LEV appeared to be associated with lower incidences of some TEAEs. These results should be interpreted with caution due to the exploratory nature of the analysis and because analysis categories were not mutually exclusive. Funding: Studies funded by BIAL and Sunovion Pharmaceuticals Inc.; analyses funded by BIAL