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Sullivan J, Specchio N, Devinsky O, et al. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis. Epilepsia. 2021;63(1):130-138doi: 10.1111/epi.17106.
Sullivan, J., Specchio, N., Devinsky, O., Auvin, S., Perry, M. S., Strzelczyk, A., Gil-Nagel, A., Dai, D., Galer, B. S., & Gammaitoni, A. R. (2022). Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis. Epilepsia, 63(1), 130-138. https://doi.org/10.1111/epi.17106
Sullivan, Joseph, et al. "Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis." Epilepsia vol. 63,1 (2022): 130-138. doi: https://doi.org/10.1111/epi.17106
Sullivan J, Specchio N, Devinsky O, Auvin S, Perry MS, Strzelczyk A, Gil-Nagel A, Dai D, Galer BS, Gammaitoni AR. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis. Epilepsia. 2022 Jan;63(1):130-138. doi: 10.1111/epi.17106. Epub 2021 Oct 22. PMID: 34676542.
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Epilepsia. 2022 Jan;63(1):130-138. doi: 10.1111/epi.17106. Epub 2021 Oct 22.

Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis.

Epilepsia

Joseph Sullivan, Nicola Specchio, Orrin Devinsky, Stéphane Auvin, M Scott Perry, Adam Strzelczyk, Antonio Gil-Nagel, David Dai, Bradley S Galer, Arnold R Gammaitoni

Affiliations

  1. University of California, San Francisco, San Francisco, California, USA.
  2. Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care (IRCCS), Rome, Italy.
  3. New York University Langone Medical Center, New York, New York, USA.
  4. Robert Debré Children's Hospital, Public Hospital Network of Paris (APHP), University of Paris, Paris, France.
  5. University Institute of France (IUF), Paris, France.
  6. Cook Children's Medical Center, Fort Worth, Texas, USA.
  7. Goethe University Frankfurt, Frankfurt am Main, Germany.
  8. Ruber International Hospital, Madrid, Spain.
  9. Syneos Health, Morrisville, North Carolina, USA.
  10. Zogenix, Emeryville, California, USA.

PMID: 34676542 DOI: 10.1111/epi.17106

Abstract

OBJECTIVE: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications.

METHODS: We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time-to-nth seizure), using a post hoc time-to-event (TTE) analysis of data from two Phase 3 placebo-controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2-19 years were randomized to placebo or adjunctive fenfluramine (Study 1: .7 mg/kg/day or .2 mg/kg/day; Study 2: .4 mg/kg/day with stiripentol). Data were analyzed by Kaplan-Meier TTE curves and waterfall plots.

RESULTS: The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7 mg/kg/day, 60%; fenfluramine .2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine .4 mg/kg/day, 58%; placebo, 2%). Median time-to-nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7 mg/kg/day, 13 weeks; .2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine .4 mg/kg/day, 13 weeks; placebo, 5 weeks; p < .001). Longest duration of convulsive seizure-free days was increased in active groups versus the placebo group (Study 1: fenfluramine .7 and .2 mg/kg/day, 25.0 and 15.0 days; placebo, 9.5 days [p = .0001; p = .0352]; Study 2: fenfluramine .4 mg/kg/day, 22.0 days; placebo, 13.0 days [p = .004]). The most common adverse events included decreased appetite, pyrexia, upper respiratory tract infection, diarrhea, and fatigue.

SIGNIFICANCE: These data demonstrate that fenfluramine can significantly reduce day-to-day seizure burden in patients with DS, providing prolonged periods of convulsive seizure-free days, which may help reduce the physical and emotional disease toll while improving health-related QOL for patients and caregivers.

© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Keywords: Dravet syndrome; fenfluramine; seizure-free days; time-to-event analysis

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