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Title: Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial.
Austin Authors: Sullivan, Joseph;Lagae, Lieven;Cross, J Helen;Devinsky, Orrin;Guerrini, Renzo;Knupp, Kelly G;Laux, Linda;Nikanorova, Marina;Polster, Tilman;Talwar, Dinesh;Ceulemans, Berten;Nabbout, Rima;Farfel, Gail M;Galer, Bradley S;Gammaitoni, Arnold R;Lock, Michael;Agarwal, Anupam;Scheffer, Ingrid E 
Affiliation: University of California San Francisco, San Francisco, CA, USA.
Department of Paediatric Neurology, University of Leuven, Leuven, Belgium.
UCL NIHR BRC Great Ormond Street Institute of Child Health, London, UK.
NYU Langone Medical Center, New York, NY, USA.
Children's Hospital Meyer IRCCS, Florence, Italy.
University of Colorado, Children's Hospital Colorado, Aurora, CO, USA.
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Danish Epilepsy Centre, Dianalund, Denmark.
Department of Epileptology (Krankenhaus Mara, Bethel Epilepsy Center), Bielefeld University Medical School, Bielefeld, Germany.
University of Arizona Health Sciences Center, Tucson, AZ, USA.
Department of Paediatric Neurology, University of Antwerp, Edegem, Belgium.
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.
Zogenix, Inc., Emeryville, CA, USA.
UCB, Brussels, Belgium.
Consultant biostatistician based in Haiku, HI, USA.
Zogenix, Inc., Emeryville, CA, USA.
University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.;UCB, Brussels, Belgium.
Austin Health
Issue Date: 6-Aug-2023
Date: 2023
Publication information: Epilepsia 2023-08-06
Abstract: To assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2 to 18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine 0.2 mg/kg/day, or fenfluramine 0.7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose, 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure (MCSF) frequency during baseline and during the combined titration-maintenance period in patients given fenfluramine 0.7 mg/kg/day vs. patients given placebo. 169 patients were screened and 143 were randomized to treatment. Mean age was 9.3±4.7 years (±SD), 51% were male, and median baseline MCSF in the 3 groups ranged from 12.7-18.0 per 28 days. Patients treated with fenfluramine 0.7 mg/kg/day demonstrated a 64.8% (95% CI, 51.8%-74.2%) greater reduction in MCSF compared with placebo (P<0.0001). Following fenfluramine 0.7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% of the placebo group (P<0.0001). The median longest seizure-free interval was 30 days in the fenfluramine 0.7 mg/kg/day group compared with 10 days in the placebo group (P<0.0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the anti-seizure response of fenfluramine in children with Dravet syndrome.
DOI: 10.1111/epi.17737
ORCID: 0000-0002-7118-0139
Journal: Epilepsia
PubMed URL: 37543865
ISSN: 1528-1167
Type: Journal Article
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