Andermann Eva, Biton Victor, Benbadis Selim R, Shneker Bassel, Shah Aashit K, Carreño Mar, Trinka Eugen, Ben-Menachem Elinor, Biraben Arnaud, Rocha Francisco, Gama Helena, Cheng Hailong, Blum David
Neurogenetics Unit and Epilepsy Research Group, Montreal Neurological Institute and Hospital, 3801 University Street, Suite 127, Montreal, QC H3A 2B4, Canada; Department of Neurology and Neurosurgery, Department of Human Genetics, McGill University, Montreal, QC, Canada.
Arkansas Epilepsy Program, Clinical Trials Inc., 2 Lile Court, Suite 100, Little Rock, AR 72205, USA.
Epilepsy Behav. 2018 May;82:119-127. doi: 10.1016/j.yebeh.2017.12.017. Epub 2018 Mar 28.
To evaluate the nature and incidence of psychiatric and cognitive adverse events (AEs) reported with eslicarbazepine acetate (ESL) used as adjunctive treatment for refractory partial-onset seizures (POS) in adults.
This was a post-hoc analysis of data pooled from three randomized double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients received placebo or adjunctive ESL 400mg (studies 301 and 302 only), 800mg, or 1200mg once daily (QD) for 14weeks (2-week titration period, 12-week maintenance period). Psychiatric and cognitive AEs were identified from individual patient data. Suicidality was also evaluated using the Columbia-Classification Algorithm of Suicide Assessment (C-CASA), or the Columbia-Suicide Severity Rating Scale (C-SSRS). P-values were obtained using the chi-square test of independence or Fisher's exact test, without correcting for multiplicity.
The analysis population included 1447 patients (ESL, n=1021; placebo, n = 426). Psychiatric treatment-emergent AEs (TEAEs) occurred in 10.8% of patients receiving ESL, and in a comparable proportion (10.3%) of patients receiving placebo (p=0.802). The incidence of depression and suicidality-related TEAEs was higher for ESL (7.4%) vs. placebo (3.8%) (p=0.009). The occurrence of these TEAEs differed between treatment groups (p = 0.010), but there was no notable trend between increasing ESL dose and increasing incidence of depression and suicidality-related TEAEs. Aggression/hostility-related TEAEs occurred in <0.1% of patients taking ESL vs. 0.9% taking placebo. The incidence of cognitive TEAEs was higher for ESL (7.1%) vs. placebo (4.0%) (p=0.023); incidences of memory impairment, attention disturbance, apathy, and aphasia were higher for ESL 1200mg than for other treatment groups. Incidences of psychiatric and cognitive serious AEs (SAEs) were 0.6% and 0.2% with ESL, and 0.5% and 0% with placebo, respectively. Psychiatric and cognitive TEAEs leading to discontinuation occurred in 1.9% and 1.4% of patients taking ESL, and 0.7% and 0.5% taking placebo, respectively.
In phase III clinical trials of adjunctive ESL for treatment-refractory POS, psychiatric and cognitive TEAEs were reported infrequently with ESL and placebo. The incidences of depression and suicidality-related TEAEs and of cognitive TEAEs were higher for patients taking ESL vs. placebo. Incidences of psychiatric and cognitive SAEs, and TEAEs leading to discontinuation, were low with ESL and placebo.
评估醋酸艾司利卡西平（ESL）作为成人难治性部分性发作（POS）辅助治疗药物时报告的精神和认知不良事件（AE）的性质及发生率。
这是一项对三项随机双盲、安慰剂对照试验（BIA - 2093 - 301、- 302、- 304）汇总数据的事后分析。在为期8周的基线期后，患者接受安慰剂或辅助性ESL，剂量为400mg（仅研究301和302）、800mg或1200mg，每日一次（QD），持续14周（2周滴定期，12周维持期）。从个体患者数据中识别精神和认知AE。还使用哥伦比亚自杀评估分类算法（C - CASA）或哥伦比亚自杀严重程度评定量表（C - SSRS）评估自杀倾向。使用独立性卡方检验或Fisher精确检验获得P值，未进行多重性校正。
分析人群包括1447例患者（ESL组，n = 1021；安慰剂组，n = 426）。接受ESL治疗的患者中，10.8%发生了精神性治疗中出现的不良事件（TEAE），接受安慰剂治疗的患者中这一比例相当（10.3%）（p = 0.802）。ESL组抑郁和自杀倾向相关TEAE的发生率（7.4%）高于安慰剂组（3.8%）（p = 0.009）。这些TEAE在治疗组之间的发生情况有所不同（p = 0.010），但在ESL剂量增加与抑郁和自杀倾向相关TEAE发生率增加之间没有明显趋势。服用ESL的患者中与攻击/敌意相关的TEAE发生率<0.1%，而服用安慰剂的患者中为0.9%。ESL组认知TEAE的发生率（7.1%）高于安慰剂组（4.0%）（p = 0.023）；1200mg ESL组的记忆损害、注意力障碍、淡漠和失语的发生率高于其他治疗组。ESL组精神和认知严重不良事件（SAE）的发生率分别为0.6%和0.2%，安慰剂组分别为0.5%和0%。导致停药的精神和认知TEAE在服用ESL的患者中发生率分别为1.9%和1.4%，服用安慰剂的患者中分别为0.7%和0.5%。
在ESL辅助治疗难治性POS的III期临床试验中，ESL和安慰剂报告的精神和认知TEAE均不常见。服用ESL的患者中抑郁和自杀倾向相关TEAE以及认知TEAE的发生率高于服用安慰剂的患者。ESL和安慰剂的精神和认知SAE以及导致停药的TEAE发生率均较低。
