Epilepsy Center Kork, Kehl, Germany.
UCB Pharma, Monheim am Rhein, Germany.
Epilepsia Open. 2022 Dec;7(4):588-597. doi: 10.1002/epi4.12628. Epub 2022 Aug 4.
Despite introduction of several antiseizure medications over the past two decades, treatment options for childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) remain limited. We report the innovative adaptive design of an ongoing phase 2/3 trial to evaluate efficacy, safety, and tolerability of brivaracetam (BRV) monotherapy in patients 2-25 years of age with CAE or JAE.
N01269 (ClinicalTrials.gov: NCT04666610; start: July 2021; expected completion: 2024) is a randomized, dose-finding and confirmatory, double-blind, placebo-controlled, parallel-group, multicenter trial. The trial consists of a dose-selection and assessment for futility stage, followed by an optimal-dose stage after interim analysis. Both stages include an up to 2-week screening period, a 2-week placebo-controlled period, and an 11-week active treatment period (10 weeks of initial treatment followed by a 24-hour electroencephalogram [EEG] and an additional week of active treatment for 24-hour EEG assessment). Patients who are absence seizure-free will enter an up to 4-week randomized withdrawal period. Efficacy assessments will be based on 24-hour EEG and seizure diaries.
This two-stage adaptive trial design allows investigation of two potentially efficacious BRV doses, where one dose is dropped in favor of the other dose with a better benefit-risk profile. This allows for a combined phase 2 dose-finding and phase 3 confirmatory efficacy trial, which reduces the number of patients needed to be recruited and reduces trial duration. A randomized withdrawal period is included to evaluate sustainability of treatment effect over time and to allow for placebo control while minimizing placebo exposure. Use of EEG capture in addition to seizure diaries offers a robust mechanism of detecting seizure activity and measuring treatment effect. Positive efficacy and safety/tolerability data may support the use of BRV as monotherapy for CAE or JAE, providing another treatment option and representing long-delayed progress in the treatment of absence seizures in these populations.
尽管在过去的二十年中引入了几种抗癫痫药物，但儿童失神癫痫（CAE）和青少年失神癫痫（JAE）的治疗选择仍然有限。我们报告了一项正在进行的 2/3 期试验的创新适应性设计，以评估 2-25 岁 CAE 或 JAE 患者使用布里瓦卡坦（BRV）单药治疗的疗效、安全性和耐受性。
N01269（ClinicalTrials.gov：NCT04666610；开始：2021 年 7 月；预计完成：2024 年）是一项随机、剂量发现和确证性、双盲、安慰剂对照、平行组、多中心试验。该试验包括一个剂量选择和无效性评估阶段，随后在中期分析后进行一个最佳剂量阶段。两个阶段都包括一个长达 2 周的筛选期、一个 2 周的安慰剂对照期和一个 11 周的活性治疗期（10 周的初始治疗，随后进行 24 小时脑电图[EEG]和另外一周的活性治疗，用于 24 小时 EEG 评估）。无失神发作的患者将进入长达 4 周的随机停药期。疗效评估将基于 24 小时 EEG 和癫痫发作日记。
这种两阶段适应性试验设计允许研究两种潜在有效的 BRV 剂量，其中一种剂量因具有更好的获益风险特征而被另一种剂量取代。这允许进行一个联合的 2 期剂量发现和 3 期确证性疗效试验，从而减少了需要招募的患者数量，并缩短了试验持续时间。包括一个随机停药期，以评估治疗效果随时间的可持续性，并允许进行安慰剂对照，同时最大限度地减少安慰剂暴露。除了癫痫发作日记外，使用 EEG 捕获提供了一种强大的机制来检测癫痫发作活动和测量治疗效果。阳性疗效和安全性/耐受性数据可能支持将 BRV 作为 CAE 或 JAE 的单药治疗，提供另一种治疗选择，并代表这些人群中失神发作治疗的长期延迟进展。
