Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens A Randomized Clinical Trial
Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens A Randomized Clinical Trial
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DOI：
10.1001/jamaneurol.2019.4113
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发表时间：
2020-03-01
期刊：
影响因子：
29
通讯作者：
Auvin, Stephane
中科院分区：
文献类型：
--
作者：
Nabbout, Rima;Mistry, Arun;Auvin, Stephane
重要性：芬氟拉明治疗可降低Dravet综合征患者的月惊厥发作频率，这些患者目前使用含斯利戊醇的抗癫痫药物治疗方案癫痫发作控制不佳。目的探讨芬氟拉明与安慰剂相比，是否能降低服用含斯利戊醇方案的Dravet综合征患者的月惊厥发作频率。设计、环境和参与者本双盲、安慰剂对照、平行组随机临床试验在多个中心进行。符合条件的患者是2至18岁的儿童，临床诊断为Dravet综合征，正在接受稳定的、含司立戊醇的抗癫痫药物治疗方案。干预措施在6周基线期发生6次或6次以上惊厥发作的患者被随机分配接受芬氟拉明，0.4 mg/kg/d（最大17 mg/d），或安慰剂。滴定（3周）后，患者的指定剂量维持12周。护理人员通过每日电子日记记录癫痫发作情况。主要结局和测量主要疗效终点是芬氟拉明和安慰剂在联合滴定和维持期间相对于基线的月平均惊厥发作频率的变化。结果共筛选出115例符合条件的患者；其中，87例患者（平均[SD]，年龄9.1[4.8]岁；50例男性患者[57%]；平均基线癫痫发作频率，每月约25次惊厥发作）被纳入研究，随机分为芬氟拉明、0.4 mg/kg/d （n = 43）或安慰剂（n = 44）。接受芬氟拉明治疗的患者比接受安慰剂治疗的患者平均每月惊厥发作频率降低54.0% （95% CI, 35.6%-67.2%; P < 0.001）。使用芬氟拉明，54%的患者表现出有临床意义的月惊厥发作频率减少（>= 50%），而安慰剂组为5% （P < 0.001）。芬氟拉明组最长无癫痫发作间隔的中位数（范围）为22（3.0-105.0）天，安慰剂组为13（1.0-40.0）天（P = 0.004）。最常见的不良事件是食欲下降（服用芬氟拉明19例[44%]vs安慰剂5例[11%]）、疲劳（11例[26%]vs 2例[5%]）、腹泻（10例[23%]vs 3例[7%]）和发热（11例[26%]vs 4例[9%]）。心脏监测未显示有瓣膜病或肺动脉高压的临床或超声心动图证据。结论及相关性芬氟拉明可显著改善包括司替戊醇在内的抗癫痫药物治疗方案控制不足的Dravet综合征患者的月惊厥发作频率。芬氟拉明一般耐受良好。芬氟拉明可能是治疗德拉韦综合征的一种新选择。
Importance Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients' assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (>= 50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. Conclusions and Relevance Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome.