Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial | Epilepsy and Seizures | JAMA Neurology | JAMA Network
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    Original Investigation
    December 2, 2019

    Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial

    Author Affiliations
    • 1Hôpital 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
    • 2Zogenix, Inc, Emeryville, California
    • 3Paediatric Neurosciences Research Group, Royal Hospital for Children Glasgow, Glasgow, United Kingdom
    • 4Assistance Publique–Hôpitaux de Marseille, Department of Pediatric Neurology, Hôpital de la Timone, Marseille, France
    • 5Hospital Ruber Internacional, Madrid, Spain
    • 6Pediatric Neurology Unit, Clínica Universidad de Navarra, Pamplona, Spain
    • 7Department of Neuropediatrics, Christian-Albrechts-University, Kiel, Germany
    • 8Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois
    • 9Mayo Clinic, Rochester, Minnesota
    • 10University of Colorado, Children’s Hospital Colorado, Aurora
    • 11Pediatric Neurology, Necker-Enfants Malades Hospital, Institut National de la Santé et de la Recherche Médicale Unite 1141, Paris, France
    • 12Robert Debré University Hospital, Université de Paris, Institut National de la Santé et de la Recherche Médicale Unite 1141, Paris, France
    JAMA Neurol. 2020;77(3):300-308. doi:10.1001/jamaneurol.2019.4113
    Key Points

    Question  Is fenfluramine safe and effective for treating patients with Dravet syndrome who have frequent seizures despite taking a stiripentol-inclusive antiepileptic drug regimen?

    Findings  Oral fenfluramine (0.4 mg/kg/d; maximum 17 mg/d) provided a 54.0% greater reduction in mean monthly convulsive seizure frequency than placebo in patients with Dravet syndrome who were taking stiripentol-containing antiepileptic drug regimens; a significantly greater proportion of patients who were taking fenfluramine (vs placebo) experienced a clinically meaningful (≥50%) or profound (≥75%) reduction in monthly convulsive seizure frequency. The most common adverse events included decreased appetite, pyrexia, fatigue, and diarrhea; no patient developed valvular heart disease or pulmonary hypertension.

    Meaning  Adjunctive fenfluramine may be a safe, effective new treatment option for patients with Dravet syndrome with seizures that are not controlled by a regimen including stiripentol.


    Importance  Fenfluramine 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.

    Objective  To 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 Participants  This 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.

    Interventions  Patients 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 Measures  The 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.

    Results  A 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 Relevance  Fenfluramine 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 Registration  ClinicalTrials.gov identifier: NCT02926898