Joseph Sullivan, Lieven Lagae, J. Helen Cross, Orrin Devinsky, Renzo Guerrini, Kelly G. Knupp, Linda Laux, Marina Nikanorova, Tilman Polster, Dinesh Talwar, Berten Ceulemans, Rima Nabbout, Gail M. Farfel, Bradley S. Galer, Arnaold R. Gammaitoni, Michael Lock, Anupam Agarwal, Ingrid E. Scheffer, The FAiRE DS Study Group
University of California San Francisco. University of Leuven. Great Ormond Street Institute of Child Health. New York University Langone Medical Center. Children’s Hospital Meyer IRCCS. University of Colorado and Children’s Hospital Colorado. Northwestern University Feinberg School of Medicine. Danish Epilepsy Centre. Bielefeld University Medical School. University of Arizona Health Sciences Center. University of Antwerp. Hôpital Universitaire Necker-Enfants Malades. Zogenix, Inc. University of Melbourne and Austin Health and Royal Children’s Hospital.
United States, Belgium, United Kingdom, Italy, Denmark, Germany, France and Australia
Epilepsia
Epilepsia 2023;
DOI: 10.1111/epi.17737
Abstract
Objective: To assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome.
Methods: 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.
Results: 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.
Significance: 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.
Category
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Medical Therapy. Adverse Effects or Lack of Adverse Effects
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
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