• Rima Nabbout, Arun Mistry, Sameer Zuberi, Nathalie Villeneuve, Antonio Gil-Nagel, Rocio Sanchez-Carpintero, Ulrich Stephani, Linda Laux, Elaine Wirrell, Kelly Knupp, Catherine Chiron, Gail Farfel, Bradley S Galer, Glenn Morrison, Michael Lock, Anupam Agarwal, Stéphane Auvin, and FAiRE, DS Study Group.
• Hôpital Universitaire Necker-Enfants Malades, Service de Neurologie Pédiatrique Centre de Référence Épilepsies Rares, Imagine Institute, Institut National de la Santé et de la Recherche Médicale, Unite Mixté de Recherche 1163, Paris Descartes University, Paris, France.
• JAMA Neurol. 2020 Mar 1; 77 (3): 300-308.

ImportanceFenfluramine 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.ObjectiveTo 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 ParticipantsThis 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.InterventionsPatients 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 MeasuresThe 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.ResultsA 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 RelevanceFenfluramine 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.Trial RegistrationClinicalTrials.gov identifier: NCT02926898.

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