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

Abstract

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.

• Authors: 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, FAiRE, DS Study Group
• Journal: JAMA neurology (JAMA Neurol) Vol. 77 Issue 3 Pg. 300-308 (03 01 2020) ISSN: 2168-6157 [Electronic] United States
• PMID: 31790543 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Dioxolanes
• Serotonin Uptake Inhibitors
• Fenfluramine
• stiripentol

Topics

• Adolescent
• Anticonvulsants (therapeutic use)
• Child
• Child, Preschool
• Dioxolanes (therapeutic use)
• Double-Blind Method
• Drug Resistant Epilepsy (drug therapy, etiology)
• Drug Therapy, Combination (methods)
• Epilepsies, Myoclonic (complications, drug therapy)
• Female
• Fenfluramine (therapeutic use)
• Humans
• Male
• Selective Serotonin Reuptake Inhibitors (therapeutic use)