美国Zogenix公司的Arnold Gammaitoni团队近日取得一项新成果。经过不懈努力，他们探索了盐酸芬氟拉明治疗Dravet综合征癫痫的疗效和安全性。2019年12月17日，国际知名学术期刊《柳叶刀》发表了这一成果。

Dravet综合征是一种罕见的、难治性的发育性癫痫脑病，其特点是多种类型的频繁、致残性癫痫发作。芬氟拉明在光敏性癫痫和Dravet综合征的观察研究中具有抗癫痫作用。

为评估芬氟拉明治疗Dravet综合征的有效性和安全性，2016年1月15日至2017年8月14日，研究组进行了一项随机、双盲、安慰剂对照的临床试验，招募了173名患有Dravet综合征的儿童和年轻人。

经过6周的观察期后，最终选定119名患者，平均年龄为9岁，54%为男性。按1：1：1将其随机分为三组，其中39名接受芬氟拉明0.2mg/kg/天进行治疗，40名接受芬氟拉明0.7mg/kg/天进行治疗，40名接受安慰剂治疗。

在治疗期间，芬氟拉明0.7mg/kg组的发作频率平均降低了74.9%，芬氟拉明0.2mg/kg组平均降低了42.3%，安慰剂组平均降低了19.2%。芬氟拉明0.7mg/kg组的每月抽搐发作频率比安慰剂组降低62.3%，芬氟拉明0.2mg/kg组比安慰剂组降低32.4%，差异均具有统计学意义。

大约有10%的患者发生不良反应，而在芬氟拉明组中更为常见，主要包括食欲下降、腹泻、疲劳、嗜睡、困倦和体重下降。超声心动图检查显示试验期间所有患者的心脏瓣膜功能均在正常生理范围内，无肺动脉高压的迹象。

总之，芬氟拉明治疗Dravet综合征，与安慰剂相比，可显著降低癫痫的发作频率，且总体耐受性良好，未观察到瓣膜性心脏病或肺动脉高压。

附：英文原文

Title: Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial

Author: Lieven Lagae, Joseph Sullivan, Kelly Knupp, Linda Laux, Tilman Polster, Marina Nikanorova, Orrin Devinsky, J Helen Cross, Renzo Guerrini, Dinesh Talwar, Ian Miller, Gail Farfel, Bradley S Galer, Arnold Gammaitoni, Arun Mistry, Glenn Morrison, Michael Lock, Anupam Agarwal, Wyman W Lai, Berten Ceulemans

Issue&Volume: December 17, 2019

Abstract: 

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<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2–52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension.

Interpretation

In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome.

DOI: 10.1016/S0140-6736(19)32500-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32500-0/fulltext