Moseley Brian D, Dimova Svetlana, Elmoufti Sami, Laloyaux Cédric, Asadi-Pooya Ali A
Department of Neurology & Rehabilitation Medicine, University of Cincinnati, 260 Stetson Street, Suite 2300, Cincinnati, OH, 45267-0525, USA.
UCB Pharma, Allée de la Recherche 60, B-1070, Brussels, Belgium.
Epilepsy Res. 2021 Oct;176:106694. doi: 10.1016/j.eplepsyres.2021.106694. Epub 2021 Jun 24.
This post hoc analysis was conducted to evaluate the efficacy, tolerability, and health-related quality of life during long-term adjunctive brivaracetam (BRV) treatment in adult patients with focal to bilateral tonic-clonic seizures (FBTCS). Patients (≥ 16 years) were included in this post hoc analysis if they were randomized to BRV or placebo in double-blind, placebo-controlled (N01252 [NCT00490035], N01253 [NCT00464269], N01358 [NCT01261325]; core) trials, and received adjunctive BRV in the corresponding long-term follow-up (N01125 [NCT00175916], N01199 [NCT00150800], N01379 [NCT01339559]) trials, and reported FBTCS during the 8-week prospective baseline (core trial). Efficacy (concomitant levetiracetam excluded) and tolerability (concomitant levetiracetam included) were assessed from the first day of BRV in patients who initiated BRV at 50-200 mg/day. Two hundred and eighty-four patients reported FBTCS during baseline (core trials) and were included in the Efficacy Set. Patients (mean age of 37.0 years; 51.8% male; mean epilepsy duration of 22.4 years; median baseline frequency of 2.8 FBTCS per 28 days) received BRV for a median treatment duration of 2.5 years (range< 0.1-11.3) at a median modal dose of 150 mg/day. BRV was discontinued by 175 (61.6%) patients, most commonly (≥ 10% of patients) due to adverse event (18.3%), lack of efficacy (18.3%), and consent withdrawn (11.6%); the median time to discontinuation of BRV due to any reason was 358.5 days. The Kaplan-Meier (KM)-estimated retention on BRV at 1, 3, and 5 years, were 69.3%, 48.2%, and 37.3%, respectively. The KM-estimated proportion of patients not discontinuing BRV due to lack of efficacy or adverse event were 80.0%, 63.9%, and 57.2% at 1, 3, and 5 years, respectively. Overall, the median percentage reduction in FBTCS frequency from baseline was 76.2%, and the 50% and 75% responder rates for FBTCS were 68.7% and 50.7%, respectively, which were sustained over time across completer cohorts. Sustained 50%, 75%, and 100% response in FBTCS from day 1 of adjunctive BRV treatment during the entire first year was estimated for 32.5%, 21.1%, and 15.0% of patients, respectively (KM analysis), and showed maintenance or improvement in the response to BRV over time. For patients with ≥ 1 year of BRV exposure, 51.3% were free from FBTCS for ≥ 1 year during any time of the treatment period, and 22.8% of patients did not report FBTCS during the first year from the first day of treatment. Clinically meaningful improvements in total Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score were reported by 43.6% and 46.4% of patients after 1 and 2 years of treatment, respectively. The largest improvements in the QOLIE-31-P score, with > 50% of patients reporting a clinically meaningful improvement, were observed in the seizure worry and daily activities/social functioning subscales after 1 and 2 years of BRV treatment. Overall, 278/313 (88.8%; Safety Set) patients reported at least one treatment-emergent adverse event (TEAE), 170 (54.3%) had a drug-related TEAE, 88 (28.1%) had a serious TEAE, and 55 (17.6%) discontinued BRV due to a TEAE. Overall, long-term adjunctive BRV was generally well tolerated and reduced the frequency of FBTCS in adults, with 22.8% of patients (who completed ≥ 1 year of treatment) not reporting any FBTCS during the first year from the first day of BRV treatment.
本事后分析旨在评估长期辅助使用布瓦西坦（BRV）治疗局灶性至双侧强直阵挛性发作（FBTCS）成年患者期间的疗效、耐受性及与健康相关的生活质量。如果患者（≥16岁）在双盲、安慰剂对照试验（N01252 [NCT00490035]、N01253 [NCT00464269]、N01358 [NCT01261325]；核心试验）中被随机分配至BRV或安慰剂组，并在相应的长期随访试验（N01125 [NCT00175916]、N01199 [NCT00150800]、N01379 [NCT01339559]）中接受辅助BRV治疗，且在8周前瞻性基线期（核心试验）报告有FBTCS，则纳入本事后分析。从开始以50 - 200 mg/天剂量服用BRV的患者中，自服用BRV的第一天起评估疗效（不包括同时服用左乙拉西坦）和耐受性（包括同时服用左乙拉西坦）。284例患者在基线期（核心试验）报告有FBTCS，被纳入疗效集。患者（平均年龄37.0岁；51.8%为男性；平均癫痫病程22.4年；基线期每28天FBTCS的中位数频率为2.8次）接受BRV治疗的中位持续时间为2.5年（范围<0.1 - 11.3年），中位模式剂量为150 mg/天。175例（61.6%）患者停用BRV，最常见的原因（≥10%的患者）是不良事件（18.3%）、缺乏疗效（18.3%）和撤回同意（11.6%）；因任何原因停用BRV的中位时间为358.5天。采用Kaplan - Meier（KM）法估计，1年、3年和5年时BRV的保留率分别为69.3%、48.2%和37.3%。采用KM法估计，1年、3年和5年时因缺乏疗效或不良事件而未停用BRV的患者比例分别为80.0%、63.9%和57.2%。总体而言，FBTCS频率较基线期的中位数降低百分比为76.2%，FBTCS的50%和75%缓解率分别为68.7%和50.7%，在整个完整队列中随时间持续保持。在辅助BRV治疗的第1年，估计分别有32.5%、21.1%和15.0%的患者从第1天起FBTCS持续有50%、75%和100%的缓解（KM分析），且随时间推移对BRV的反应保持或改善。对于接受BRV治疗≥1年的患者，51.3%在治疗期的任何时间有≥1年无FBTCS，22.8%的患者从治疗第1天起第1年未报告FBTCS。治疗1年和2年后，分别有43.6%和46.4%的患者报告癫痫患者生活质量量表 - 31项简表（QOLIE - 31 - P）总分有临床意义的改善。在BRV治疗1年和2年后，癫痫担忧和日常活动/社会功能子量表中观察到QOLIE - 31 - P评分改善最大，>50%的患者报告有临床意义的改善。总体而言，278/313例（88.8%；安全集）患者报告至少1次治疗中出现的不良事件（TEAE），170例（54.3%）有与药物相关的TEAE，88例（28.1%）有严重TEAE，55例（17.6%）因TEAE停用BRV。总体而言，长期辅助使用BRV通常耐受性良好，可降低成年患者FBTCS的频率，22.8%的患者（完成≥1年治疗）从BRV治疗第1天起第1年未报告任何FBTCS。
