Safety and efficacy of eslicarbazepine acetate for seizure prevention in patients with stroke at high risk of developing post-stroke epilepsy: a proof-of-concept, phase 2a, randomised, double-blind, placebo-controlled antiepileptogenesis trial.

BACKGROUND: Eslicarbazepine acetate is an antiseizure medication that has shown potential antiepileptogenic effects in preclinical models of epilepsy. We aimed to investigate whether eslicarbazepine acetate could prevent or reduce the incidence of unprovoked seizures after acute ischaemic stroke or acute intracerebral haemorrhage.

METHODS: Study BIA-2093-213 was an exploratory, proof-of-concept, phase 2a, double-blind, randomised, placebo-controlled trial conducted in adults (aged ≥18 years) after an acute ischaemic stroke or acute intracerebral haemorrhage, who were considered at high risk of developing unprovoked seizures based on a severity of stroke, large artery atherosclerosis, early seizure, cortical involvement, and territory of the middle cerebral artery (SeLECT) score of 5 or greater or a cortical involvement of intracerebral haemorrhage, age, volume, and early seizure after intracerebral haemorrhage (CAVE) score of 2 or greater. Patients were recruited from 19 university hospitals across Austria, Germany, Italy, Israel, Portugal, Spain, Sweden, and the UK, and eligible for inclusion if randomisation was planned within 96 h since the known time of stroke, or last time seen well (prolonged to 120 h to allow detection of acute seizures within 5 days post-stroke following a protocol modification implemented early in recruitment). Participants were randomly assigned (1:1) to receive eslicarbazepine acetate 800 mg/day or placebo, administered orally, for 30 days and followed up for 17 additional months. All patients who received one dose of study drug were included in safety and efficacy analyses. The primary endpoint was the proportion of patients who had a first unprovoked seizure, died, or discontinued (for any reason) within the first 6 months after randomisation. This trial is registered on the EudraCT database (EudraCT 2018-002747-29).

FINDINGS: Between May 29, 2019, and Feb 28, 2022, 129 patients were screened and 125 were randomly assigned (62 to eslicarbazepine acetate and 63 to placebo). The between-group difference for the primary endpoint (17 [28%] of 61 with eslicarbazepine acetate vs 23 [37%] of 62 with placebo) was not significant (odds ratio 0·66 [95% CI 0·31-1·40]; p=0·37). Treatment-emergent adverse events were reported with similar frequency in both eslicarbazepine acetate and placebo groups (50 [82%] of 61 vs 51 [82%] of 62). The most common treatment-emergent adverse events were hyponatraemia (five [8%] of 61 in the eslicarbazepine acetate group vs one [2%] of 62 in the placebo group), dizziness (three [5%] vs none). Serious treatment-emergent adverse events were reported in 12 (20%) patients in the eslicarbazepine acetate group and 13 (21%) in the placebo group. Three serious related treatment-emergent adverse events occurred in the eslicarbazepine acetate group (none in the placebo group): nodal arrhythmia, hepatic failure, and hyponatraemia (one patient each). Five patients died after randomisation (all in the eslicarbazepine acetate group), but deaths were deemed unrelated or unlikely to be related to the study drug.

INTERPRETATION: The proportion of patients who had a first unprovoked seizure, died, or discontinued at 6 months did not differ significantly between the eslicarbazepine acetate and placebo groups. However, the trial was underpowered owing to slow recruitment and the COVID-19 pandemic, producing wide confidence intervals. The findings indicate that antiepileptogenesis studies are feasible, and guide the design of adequately powered trials with clinically meaningful endpoints.

FUNDING: BIAL.