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.

We aimed to investigate whether eslicarbazepine acetate could prevent or reduce the incidenceof unprovoked seizures after acute ischaemic stroke or acute intracerebral haemorrhage.

我们旨在研究埃斯利卡贝嗪醋酸酯是否能够预防或减少急性缺血性中风或急性脑出血后无诱因癫痫发作的发生率。

Methods

Study BIA-2093-213 was an exploratory, proof-of-concept, phase 2a, double-blind, randomised, placebo-controlledtrial 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.

BIA-2093-213研究是一项探索性、概念验证性的2a期、双盲、随机、安慰剂对照试验，招募了在急性缺血性中风或急性脑内出血后，基于中风严重程度、大动脉粥样硬化、早期癫痫发作、皮层受累以及中脑动脉（SeLECT）评分≥5或脑内出血的皮层受累、年龄、体积和脑内出血后早期癫痫发作（CAVE）评分≥2，被认为是发展为未诱发癫痫发作高风险的成人（≥18岁）患者。

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).

患者从奥地利、德国、意大利、以色列、葡萄牙、西班牙、瑞典和英国的19所大学医院招募而来，如果计划在已知中风时间或最后良好状态时间的96小时内进行随机分组，则符合纳入标准，或者根据研究早期实施的方案修改，将时间延长至120小时，以便在中风后5天内检测到急性癫痫发作。

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.

参与者被随机分配（1:1）接受每日口服800 mg的奥卡西平乙酸酯或安慰剂，为期30天，并随访额外的17个月。

All patients who received one dose of study drug were included in safety and efficacy analyses.

所有接受至少一次研究药物剂量的患者均被纳入安全性和有效性分析。

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.

主要终点是随机化后前6个月内首次出现未诱发癫痫发作、死亡或因任何原因停药的患者比例。

This trial is registered on the EudraCT database (EudraCT 2018-002747-29).

该试验已在EudraCT数据库注册（EudraCT 2018-002747-29）。

Results

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).

在2019年5月29日至2022年2月28日期间，共有129名患者接受了筛查，其中125名被随机分配（62名接受奥卡西平乙酸酯治疗，63名接受安慰剂治疗）。

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).

主要终点的组间差异不显著（奥卡西平乙酸酯组的17名患者[28%]与安慰剂组的23名患者[37%]），比值比为0.66（95%置信区间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).

治疗相关不良事件在艾司利卡西平组和安慰剂组中以相似的频率报告（61例中有50例[82%]对比62例中有51例[82%]）。

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).

最常见的治疗相关不良事件是低钠血症（艾司利卡西平组61例中有五例[8%]对比安慰剂组62例中有一例[2%]），头晕（三例[5%]对比无）。

Serious treatment-emergent adverse events were reported in 12 (20%) patients in the eslicarbazepine acetate group and 13 (21%) in the placebo group.

在接受乙酰唑胺酯治疗的患者中，有12人（20%）报告了严重的治疗后不良事件，而在安慰剂组中有13人（21%）报告了此类事件。

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).

乙酰唑胺酯组发生了三例严重的相关治疗后不良事件（安慰剂组中无此情况）：结性心律失常、肝功能衰竭和低钠血症（各有一名患者）。

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.

随机分组后有五名患者死亡（全部在奥卡西平组），但死亡被认为与研究药物无关或不太可能与之相关。

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.

在6个月时，首次无诱因癫痫发作、死亡或停药的患者比例在奥卡西平组和安慰剂组之间没有显著差异。

However, the trial was underpowered owing to slow recruitment and the COVID-19 pandemic, producing wide confidence intervals.

然而，由于招募缓慢和COVID-19大流行，该试验的统计功效不足，导致置信区间较宽。

The findings indicate that antiepileptogenesis studies are feasible, and guide the design of adequately powered trials with clinically meaningful endpoints.

研究结果表明，抗癫痫形成研究是可行的，并指导设计具有临床意义终点的充分统计功效试验。

funding

BIAL.

BIAL.（此处未提供足够信息，无法翻译）