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. FUNDING Zogenix.

中文翻译：

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盐酸芬氟拉明用于治疗Dravet综合征的癫痫发作：一项随机，双盲，安慰剂对照试验。

背景技术Dravet综合征是一种罕见的，对治疗有抵抗力的发育性癫痫性脑病，其特征在于多种类型的频繁的致残性癫痫发作。据报道，在光敏性癫痫和Dravet综合征的观察研究中，芬氟拉明具有抗癫痫活性。本研究的目的是评估芬氟拉明在Dravet综合征患者中的疗效和安全性。方法在这项随机，双盲，安慰剂对照的临床试验中，我们招募了患有Dravet综合征的儿童和青少年。在为期6周的观察期后，确定基线每月惊厥发作频率（MCSF；惊厥发作的定义为半殖民地，强直性，阵挛性，强直性-强直性，全身性强直性-阵挛性和局灶性，可清楚观察到运动征象），患者通过互动式网络反应系统以1：1：1：1的比例随机分配给安慰剂，芬氟拉明每天0·2 mg / kg或芬氟拉明每天0·7 mg / kg，并添加到现有的抗癫痫药中持续14周。主要结局是每天0×7 mg / kg组与安慰剂组相比，治疗期间惊厥性癫痫发作的平均每月频率与基线相比的变化；与安慰剂相比，每天0·2 mg / kg被评估为关键的次要结局。通过修改意向进行分析。安全性分析包括接受至少一剂研究药物的所有参与者。该试验已在ClinicalTrials.gov上以两个相同的协议NCT02682927和NCT02826863注册。结果在2016年1月15日至2017年8月14日之间，我们评估了173例患者，其中119例（平均年龄9·0岁，随机分配64名[54％]男性）每天接受fenfluramine 0·2 mg / kg（39），每天fenfluramine 0·7 mg / kg（40）或安慰剂（40）。在治疗期间，芬氟拉明0·7 mg / kg组的癫痫发作频率中位数降低为74·9％（从每28天20例7癫痫发作至每28天4例7次癫痫发作），芬氟拉明0·2 mg / kg组（从每28天中位数17·5次发作至每28天12·6次癫痫发作）和安慰剂组的19·2％（从每28天中位数27·3次发作至22/0每次发作） 28天）。该研究达到了其主要疗效终点，与氟哌拉明相比，每天服用0.7 mg / kg的氟氟拉明，与安慰剂相比，平均MCSF降低了62.3％（95％CI 47·7-72·8，p <0·0001） ; 与安慰剂（95％CI 6·2-52·3，p = 0·0209）相比，芬氟拉明0·2 mg / kg /天显示出平均MCSF降低了32·4％。最常见的不良事件（发生在至少10％的患者中，在芬氟拉明组中更频繁地发生）是食欲下降，腹泻，疲劳，嗜睡，嗜睡和体重减轻。超声心动图检查显示试验期间所有患者的瓣膜功能均在正常生理范围内，并且没有肺动脉高压的迹象。解释在Dravet综合征中，与安慰剂相比，芬氟拉明可显着降低惊厥发作频率，并且一般耐受性良好，未观察到瓣膜性心脏病或肺动脉高压。芬氟拉明可能是Dravet综合征患者的重要新治疗选择。资助Zogenix。嗜睡，嗜睡和体重减轻。超声心动图检查显示试验期间所有患者的瓣膜功能均在正常生理范围内，没有肺动脉高压的迹象。解释在Dravet综合征中，与安慰剂相比，芬氟拉明可显着降低惊厥发作频率，并且一般耐受性良好，未观察到瓣膜性心脏病或肺动脉高压。芬氟拉明可能是Dravet综合征患者的重要新治疗选择。资助Zogenix。嗜睡，嗜睡和体重减轻。超声心动图检查显示试验期间所有患者的瓣膜功能均在正常生理范围内，并且没有肺动脉高压的迹象。解释在Dravet综合征中，与安慰剂相比，芬氟拉明可显着降低惊厥发作频率，并且一般耐受性良好，未观察到瓣膜性心脏病或肺动脉高压。芬氟拉明可能是Dravet综合征患者的重要新治疗选择。资助Zogenix。与安慰剂相比，芬氟拉明可显着降低惊厥发作频率，并且一般耐受性良好，未观察到瓣膜性心脏病或肺动脉高压。芬氟拉明可能是Dravet综合征患者的重要新治疗选择。资助Zogenix。与安慰剂相比，芬氟拉明可显着降低惊厥发作频率，并且一般耐受性良好，未观察到瓣膜性心脏病或肺动脉高压。芬氟拉明可能是Dravet综合征患者的重要新治疗选择。资助Zogenix。