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

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJAMA neurology
DOIs
StateAccepted/In press - Jan 1 2019

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Myoclonic Epilepsy
Fenfluramine
Seizures
Randomized Controlled Trials
Placebos
Therapeutics
Anticonvulsants
stiripentol
Heart Valve Diseases
Appetite
Pulmonary Hypertension
Caregivers
Fatigue
Diarrhea

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Fenfluramine for Treatment-Resistant Seizures in Patients with Dravet Syndrome Receiving Stiripentol-Inclusive Regimens : A Randomized Clinical Trial. / Nabbout, Rima; Mistry, Arun; Zuberi, Sameer; Villeneuve, Nathalie; Gil-Nagel, Antonio; Sanchez-Carpintero, Rocio; Stephani, Ulrich; Laux, Linda; Wirrell, Elaine; Knupp, Kelly; Chiron, Catherine; Farfel, Gail; Galer, Bradley S.; Morrison, Glenn; Lock, Michael; Agarwal, Anupam; Auvin, Stéphane.

In: JAMA neurology, 01.01.2019.

Research output: Contribution to journalArticle

Nabbout, R, Mistry, A, Zuberi, S, Villeneuve, N, Gil-Nagel, A, Sanchez-Carpintero, R, Stephani, U, Laux, L, Wirrell, E, Knupp, K, Chiron, C, Farfel, G, Galer, BS, Morrison, G, Lock, M, Agarwal, A & Auvin, S 2019, 'Fenfluramine for Treatment-Resistant Seizures in Patients with Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial', JAMA neurology. https://doi.org/10.1001/jamaneurol.2019.4113
Nabbout, Rima ; Mistry, Arun ; Zuberi, Sameer ; Villeneuve, Nathalie ; Gil-Nagel, Antonio ; Sanchez-Carpintero, Rocio ; Stephani, Ulrich ; Laux, Linda ; Wirrell, Elaine ; Knupp, Kelly ; Chiron, Catherine ; Farfel, Gail ; Galer, Bradley S. ; Morrison, Glenn ; Lock, Michael ; Agarwal, Anupam ; Auvin, Stéphane. / Fenfluramine for Treatment-Resistant Seizures in Patients with Dravet Syndrome Receiving Stiripentol-Inclusive Regimens : A Randomized Clinical Trial. In: JAMA neurology. 2019.
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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.",
author = "Rima Nabbout and Arun Mistry and Sameer Zuberi and Nathalie Villeneuve and Antonio Gil-Nagel and Rocio Sanchez-Carpintero and Ulrich Stephani and Linda Laux and Elaine Wirrell and Kelly Knupp and Catherine Chiron and Gail Farfel and Galer, {Bradley S.} and Glenn Morrison and Michael Lock and Anupam Agarwal and St{\'e}phane Auvin",
year = "2019",
month = "1",
day = "1",
doi = "10.1001/jamaneurol.2019.4113",
language = "English (US)",
journal = "JAMA Neurology",
issn = "2168-6149",
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TY - JOUR

T1 - Fenfluramine for Treatment-Resistant Seizures in Patients with Dravet Syndrome Receiving Stiripentol-Inclusive Regimens

T2 - A Randomized Clinical Trial

AU - Nabbout, Rima

AU - Mistry, Arun

AU - Zuberi, Sameer

AU - Villeneuve, Nathalie

AU - Gil-Nagel, Antonio

AU - Sanchez-Carpintero, Rocio

AU - Stephani, Ulrich

AU - Laux, Linda

AU - Wirrell, Elaine

AU - Knupp, Kelly

AU - Chiron, Catherine

AU - Farfel, Gail

AU - Galer, Bradley S.

AU - Morrison, Glenn

AU - Lock, Michael

AU - Agarwal, Anupam

AU - Auvin, Stéphane

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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