Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial
Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s0140-6736(19)32500-0
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发表时间：
2019-12-21
期刊：
影响因子：
168.9
通讯作者：
Zupanc, Mary
中科院分区：
文献类型：
--
作者：
Lagae, Lieven;Sullivan, Joseph;Zupanc, Mary
Dravet综合征是一种罕见的难治性发育性癫痫脑病，其特征是多种类型的频繁致残性癫痫发作。在光敏性癫痫和Dravet综合征的观察性研究中，已报告芬氟拉明具有抗癫痫发作活性。本研究的目的是评估芬氟拉明在Dravet syndrome.Methods患者中的疗效和安全性，在这项随机、双盲、安慰剂对照的临床试验中，我们招募了Dravet综合征的儿童和年轻人。经过6周的观察期以确定基线每月惊厥发作频率（MCSF;惊厥发作定义为半阵挛性、强直性、阵挛性、强直-失张力性、全身强直-阵挛性和局灶性，伴有明显可观察到的运动体征）后，患者通过交互式网络应答系统以1：1：1的比例随机分配至安慰剂组、芬氟拉明0.2 mg/kg/天组或芬氟拉明0.7 mg/kg/天组，在现有抗癫痫药物的基础上添加治疗14周。主要结局是0.7 mg/kg/d组与安慰剂组相比，治疗期间惊厥发作的平均每月频率较基线的变化; 0.2 mg/kg/d组与安慰剂组被评估为关键次要结局。安全性分析包括所有接受至少一剂研究药物的参与者。该试验在www.example.com注册ClinicalTrials.gov，有两个相同的方案NCT 02682927和NCT 02826863。结果2016年1月15日至2017年8月14日，我们评估了173例患者，其中119例患者（平均年龄9.0岁，64名[54%]男性）被随机分配接受芬氟拉明0.2 mg/kg/天（39名），芬氟拉明0.7 mg/kg/天（40）或安慰剂（40）。在治疗过程中，芬氟拉明0.7 mg/kg组的癫痫发作频率中位数降低了74.9（从每28天中位20.7次癫痫发作降至每28天4.7次癫痫发作），芬氟拉明0.2 mg/kg组为42.3%（从中位数17.5次癫痫发作/28天到12.6次/28天），安慰剂组为19.2%（从中位数27.3次/28天到22.0次/28天）。该研究达到了主要疗效终点，与安慰剂相比，芬氟拉明0.7 mg/kg/天组MCSF平均值降低62.3%（95%CI 47.7-72.8，p
Background Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome.Methods In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0.2 mg/kg per day, or fenfluramine 0.7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0.7 mg/kg per day group versus placebo; 0.2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863.Findings Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9.0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0.2 mg/kg per day (39), fenfluramine 0.7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74.9% in the fenfluramine 0.7 mg/kg group (from median 20.7 seizures per 28 days to 4.7 seizures per 28 days), 42.3% in the fenfluramine 0.2 mg/kg group ( from median 17.5 seizures per 28 days to 12.6 per 28 days), and 19.2% in the placebo group ( from median 27.3 per 28 days to 22.0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0.7 mg/kg per day showing a 62.3% greater reduction in mean MCSF compared with placebo (95% CI 47.7-72.8, p