Importance New treatment options are needed for patients with Lennox-Gastaut syndrome (LGS), a profoundly impairing, treatment-resistant, developmental and epileptic encephalopathy. Objective To evaluate the efficacy and safety of fenfluramine in patients with LGS. Design, Setting, and Participants This multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted from November 27, 2017, to October 25, 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia. Included patients were aged 2 to 35 years with confirmed diagnosis of LGS and experienced 2 or more drop seizures per week during the 4-week baseline. Using a modified intent-to-treat method, data analysis was performed from November 27, 2017, to October 25, 2019. The database lock date was January 30, 2020, and the date of final report was September 11, 2021. Interventions Patients were randomized to receive either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo. After titration (2-week period), patients were taking their randomized dose for 12 additional weeks. Main Outcomes and Measures Primary efficacy end point was percentage change from baseline in drop seizure frequency in patients who received 0.7 mg/kg/d of fenfluramine vs placebo. Results A total of 263 patients (median [range] age, 13 [2-35] years; 146 male patients [56%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n = 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n = 87). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7-mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. The trial met its primary efficacy end point: patients in the 0.7-mg/kg/d fenfluramine group achieved a -19.9 percentage points (95% CI, -31.0 to -8.7 percentage points; P = .001) estimated median difference in drop seizures from baseline vs placebo. More patients in the 0.7-mg/kg/d fenfluramine group achieved a 50% or greater response (22 of 87 [25%]; P = .02) vs placebo (9 of 87 [10%]). Site investigators and caregivers gave a much improved or very much improved rating on the Clinical Global Impression of Improvement scale to more patients in the 0.7-mg/kg/d fenfluramine group than patients in the placebo group (21 [26%] vs 5 [6%]; P = .001). The seizure subtype that appeared most responsive to fenfluramine was generalized tonic-clonic seizure (120 of 263 [46%]), with a decrease in frequency of 45.7% in the 0.7-mg/kg/d fenfluramine group and 58.2% in the 0.2-mg/kg/d fenfluramine group compared with an increase of 3.7% in the placebo group. Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%]). No cases of valvular heart disease or pulmonary arterial hypertension were observed. Conclusions and Relevance Results of this trial showed that, in patients with LGS, fenfluramine compared with placebo provided a significantly greater reduction in drop seizures and may be a particularly advantageous choice in patients who experience generalized tonic-clonic seizures. Trial Registration ClinicalTrials.gov Identifier: NCT03355209.

中文翻译：

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芬氟拉明治疗 Lennox-Gastaut 综合征相关癫痫发作的疗效和安全性：一项随机临床试验。

重要性 Lennox-Gastaut 综合征 (LGS) 患者需要新的治疗选择，这是一种严重损害、治疗抵抗、发育性和癫痫性脑病。目的评价芬氟拉明治疗LGS患者的疗效和安全性。设计、地点和参与者这项多中心、双盲、安慰剂对照、平行组随机临床试验于 2017 年 11 月 27 日至 2019 年 10 月 25 日进行，试验持续时间为 20 周。患者在北美、欧洲和澳大利亚的 65 个研究地点入组。纳入的患者年龄在 2 至 35 岁之间，确诊为 LGS，并且在 4 周的基线期间每周经历 2 次或更多的跌倒性癫痫发作。使用改良的意向治疗方法，从 2017 年 11 月 27 日至 2019 年 10 月 25 日进行数据分析。数据库锁定日期为 2020 年 1 月 30 日，最终报告日期为 2021 年 9 月 11 日。干预 患者随机接受 0.7-mg/kg/d 或 0.2-mg/kg/d（最大 26 d) 芬氟拉明或安慰剂的剂量。滴定后（2 周期），患者服用他们的随机剂量额外 12 周。主要结果和措施 主要疗效终点是接受 0.7 mg/kg/d 芬氟拉明的患者与安慰剂相比，癫痫发作频率与基线相比的百分比变化。结果共有 263 名患者（中位 [范围] 年龄，13 [2-35] 岁；146 名男性患者 [56%]）被随机分配到 0.7-mg/kg/d 芬氟拉明组（n = 87），0.2- mg/kg/d 芬氟拉明组（n = 89）或安慰剂组（n = 87）。跌落发作频率的中位百分比减少为 0.0 的 26.5 个百分点。7-mg/kg/d fenfluramine 组，0.2-mg/kg/d fenfluramine 组为 14.2 个百分点，安慰剂组为 7.6 个百分点。该试验达到了主要疗效终点：0.7-mg/kg/d 芬氟拉明组的患者达到了 -19.9 个百分点（95% CI，-31.0 至 -8.7 个百分点；P = .001）估计的下降中位数差异基线与安慰剂的癫痫发作。在 0.7-mg/kg/d 芬氟拉明组中，更多的患者获得了 50% 或更高的反应（87 人中有 22 人 [25%]；P = .02），而安慰剂组（87 人中有 9 人 [10%]）。现场调查员和护理人员对 0.7-mg/kg/d 芬氟拉明组的患者比安慰剂组的患者更多（21 [26%] vs 5 [[21 [26%] vs 5 [[ 6%]；P = .001)。对芬氟拉明最敏感的癫痫发作亚型是全身强直-阵挛发作（263 例中的 120 例 [46%]），在 0.7-mg/kg/d 芬氟拉明组和 0.2 -mg/kg/d 芬氟拉明组较安慰剂组增加 3.7%。最常见的治疗引起的不良事件包括食欲下降 (59 [22%])、嗜睡 (33 [13%]) 和疲劳 (33 [13%])。没有观察到心脏瓣膜病或肺动脉高压的病例。结论和相关性 该试验的结果表明，在 LGS 患者中，与安慰剂相比，芬氟拉明可显着减少跌倒性癫痫发作，并且对于经历全身强直-阵挛性癫痫发作的患者可能是一个特别有利的选择。试验注册 ClinicalTrials.gov 标识符：