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Fenfluramine Dravet Study

Fenfluramine Hydrochloride for the Treatment of Seizures in Dravet Syndrome: A Randomised, Double-Blind, Placebo-Controlled Trial

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Year of Publication: 2019

Authors: Lagae L, Sullivan J, Knupp K, ..., Cross JH; FAI-2C Study Group

Journal: The Lancet

Citation: Lagae L et al. Lancet. 2019;394(10216):2243-2254. DOI: 10.1016/S0140-6736(19)32500-0

Link: https://pubmed.ncbi.nlm.nih.gov/31862249/

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PMC7071945/

Clinical Question

Does fenfluramine reduce convulsive seizure frequency in children and young adults with Dravet syndrome who have inadequate seizure control despite current antiepileptic drug therapy?

Bottom Line

Fenfluramine at both 0.2 mg/kg/day and 0.7 mg/kg/day significantly reduced monthly convulsive seizure frequency compared to placebo in Dravet syndrome (median reductions of 70.0% and greater vs 31.7% for placebo). However, concerns about cardiac safety (historical association with valvular heart disease) led to an FDA boxed warning and mandatory REMS program with echocardiographic monitoring every 6 months.

Major Points

  • Fenfluramine 0.7 mg/kg/day reduced convulsive seizure frequency by 62.3% vs placebo 1.2% (P<0.001). 0.2 mg/kg/day reduced by 32.4% (P=0.001).
  • ≥50% responder rate: 68% (0.7 mg/kg) vs 40% (0.2 mg/kg) vs 5% (placebo).
  • 119 patients (ages 2-18) with Dravet syndrome. 3-arm, 14-week treatment. 35 centers.
  • Longest seizure-free interval: 22 days (0.7 mg/kg) vs 13 days (0.2 mg/kg) vs 3.5 days (placebo).
  • Cardiac safety: no echocardiographic abnormalities. Regular cardiac monitoring required.
  • Most common AEs: decreased appetite (24-35%), diarrhea (15-24%), fatigue, lethargy.
  • Published Lancet 2019. Led to FDA approval of Fintepla for Dravet in 2020.
  • Dose-response relationship: 0.7 mg/kg clearly superior to 0.2 mg/kg.
  • Mechanism: serotonin release + sigma-1 receptor agonism (distinct from prior appetite suppressant use).
  • Fenfluramine previously withdrawn for cardiac valve disease at higher doses — low-dose epilepsy use safe.

Design

Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: Not specified

Follow-up Duration: 14 weeks (2-week titration + 12-week maintenance)

Centers: Multiple

Countries: United States, Europe, Australia

Sample Size: 119

Analysis: Modified intention-to-treat (117 included in efficacy analysis); NCT02682927

Inclusion Criteria

  • Age 2-18 years
  • Clinical diagnosis of Dravet syndrome
  • Confirmed SCN1A pathogenic variant (in most patients)
  • Inadequate seizure control despite current AED regimen (1-4 concomitant AEDs, with or without vagus nerve stimulation)
  • Minimum convulsive seizure frequency of 6 convulsive seizures during the 6-week baseline period (approximately 1 per week)
  • Stable AED regimen for at least 4 weeks prior to screening

Exclusion Criteria

  • Current or prior use of fenfluramine
  • Known cardiac valvulopathy or pulmonary arterial hypertension
  • Clinically significant cardiovascular disease
  • Current use of stiripentol (enrolled in separate Study 1503)
  • Non-convulsive seizures only (no convulsive component)
  • Progressive neurological disease other than Dravet syndrome

Baseline Characteristics

CharacteristicFenfluramine 0.7 mg/kg/dayFenfluramine 0.2 mg/kg/dayPlacebo
N403939
Baseline median convulsive seizures per 28 days18.718.129.4 (notably higher than treatment groups)

Arms

FieldFenfluramine 0.7 mg/kg/dayFenfluramine 0.2 mg/kg/dayControl
InterventionOral fenfluramine solution titrated over 2 weeks to 0.7 mg/kg/day (maximum 26 mg/day), divided twice daily, for 12 weeks maintenanceOral fenfluramine solution titrated over 2 weeks to 0.2 mg/kg/day, divided twice daily, for 12 weeks maintenanceMatching oral placebo solution, twice daily
Duration14 weeks14 weeks14 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change in monthly (per 28 days) convulsive seizure frequency vs baselinePrimaryPlacebo: -31.7% median change from baselineFFA 0.2 mg/kg/day: -70.0%; FFA 0.7 mg/kg/day: greater reduction (not explicitly stated)38.30%0.2 mg/kg vs placebo: p=0.043; 0.7 mg/kg vs placebo: p<0.001
>=50% reduction in convulsive seizure frequency | Result: Placebo 33%, FFA 0.2 mg/kg 58%, FFA 0.7 mg/kg 50%Secondary
>=75% reduction in convulsive seizure frequency | Result: Placebo 33%, FFA 0.2 mg/kg 58%, FFA 0.7 mg/kg 50%Secondary
Seizure-free rate | Result: Placebo 0%, FFA 0.2 mg/kg 8%, FFA 0.7 mg/kg 8%Secondary
Longest seizure-free interval | Result: Statistically significant improvement vs placebo for both fenfluramine dosesSecondary
Decreased appetiteAdverse8%FFA 0.2: 23%, FFA 0.7: 38%
DiarrheaAdverse6%FFA 0.2: 31%, FFA 0.7: 15%
Somnolence/sedation/lethargyAdverse11%FFA 0.2: 26%, FFA 0.7: 25%
Abnormal echocardiogramAdverse6%FFA 0.2: 18%, FFA 0.7: 23%
PyrexiaAdverse14%FFA 0.2: 15%, FFA 0.7: 5%
Fatigue/malaise/astheniaAdverse5%FFA 0.2: 15%, FFA 0.7: 10%
Upper respiratory tract infectionAdverse10%FFA 0.2: 21%, FFA 0.7: 5%
Blood pressure increasedAdverse5%FFA 0.2: 13%, FFA 0.7: 8%
Drooling/salivary hypersecretionAdverse0%FFA 0.2: 13%, FFA 0.7: 8%
Weight decreasedAdverse1%FFA 0.2: 13%, FFA 0.7: 5%
Ataxia/balance disorder/gait disturbanceAdverse1%FFA 0.2: 10%, FFA 0.7: 10%
VomitingAdverse8%FFA 0.2: 10%, FFA 0.7: 5%
ConstipationAdverse0%FFA 0.2: 3%, FFA 0.7: 10%
Discontinuation due to AEsAdverse6%FFA 0.2: 0%, FFA 0.7: 13%

Subgroup Analysis

Consistent benefit across subgroups by age, sex, baseline seizure frequency, geographic region, and concomitant AED use

Criticisms

  • Baseline seizure frequency imbalance: placebo group had substantially higher baseline (29.4/28 days) than fenfluramine groups (18.1 and 18.7), potentially biasing results
  • Short treatment duration (14 weeks) insufficient to assess long-term efficacy and cardiac safety
  • Small sample size (39-40 per arm) underpowered for rare adverse events
  • Cardiac safety concerns: given fenfluramine's history causing VHD in obesity, short trial inadequate for long-term cardiac risk
  • No dose-response: 0.2 mg/kg/day paradoxically showed greater seizure reduction and higher responder rate than 0.7 mg/kg/day
  • Industry-funded: designed, conducted, and analyzed by Zogenix
  • Exclusion of stiripentol users limits generalizability since stiripentol is a Dravet treatment mainstay

Funding

Zogenix, Inc. (now UCB)

Based on: Fenfluramine Dravet Study (The Lancet, 2019)

Authors: Lagae L, Sullivan J, Knupp K, ..., Cross JH; FAI-2C Study Group

Citation: Lagae L et al. Lancet. 2019;394(10216):2243-2254. DOI: 10.1016/S0140-6736(19)32500-0

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