Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial

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; Arnold R. Gammaitoni; Michael Lock; Anupam Agarwal; Ingrid E. Scheffer

doi:10.1111/epi.17737

Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial

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, Arnold R. Gammaitoni, Michael Lock, Anupam Agarwal, Ingrid E. Scheffer^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Objective: This study was undertaken 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 2–18 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.2 mg/kg/day, or fenfluramine.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 frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine.7 mg/kg/day versus patients given placebo. Results: A total of 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 three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine.7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo (p <.0001). Following fenfluramine.7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p <.0001). The median longest seizure-free interval was 30 days in the fenfluramine.7 mg/kg/day group compared with 10 days in the placebo group (p <.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 antiseizure response of fenfluramine in children with Dravet syndrome.

Original language	English (US)
Pages (from-to)	2653-2666
Number of pages	14
Journal	Epilepsia
Volume	64
Issue number	10
DOIs	https://doi.org/10.1111/epi.17737
State	Published - Oct 2023

Funding

This study was funded by Zogenix, now a part of UCB. Role of the sponsor: Zogenix, in collaboration with study investigators and contract research organizations (InVentiv Health and Syneos Health), was responsible for the design and conduct of the study; manufacture of the active treatment and placebo; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Additional contributions: The authors received professional medical writing and editing assistance from Edward Weselcouch, PhD, and Barbara Schwedel, MS, ELS (PharmaWrite, Princeton, NJ), which was funded by Zogenix. Open access publishing facilitated by The University of Melbourne, as part of the Wiley ‐ The University of Melbourne agreement via the Council of Australian University Librarians. This study was funded by Zogenix, now a part of UCB. Role of the sponsor: Zogenix, in collaboration with study investigators and contract research organizations (InVentiv Health and Syneos Health), was responsible for the design and conduct of the study; manufacture of the active treatment and placebo; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Additional contributions: The authors received professional medical writing and editing assistance from Edward Weselcouch, PhD, and Barbara Schwedel, MS, ELS (PharmaWrite, Princeton, NJ), which was funded by Zogenix. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.

Keywords

clinical pharmacology
encephalopathy
epilepsy
seizure

ASJC Scopus subject areas

Neurology
Clinical Neurology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/epi.17737

Cite this

Sullivan, J., Lagae, L., Cross, J. H., Devinsky, O., Guerrini, R., Knupp, K. G., Laux, L., Nikanorova, M., Polster, T., Talwar, D., Ceulemans, B., Nabbout, R., Farfel, G. M., Galer, B. S., Gammaitoni, A. R., Lock, M., Agarwal, A., & Scheffer, I. E. (2023). Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial. Epilepsia, 64(10), 2653-2666. https://doi.org/10.1111/epi.17737

@article{1f7696ded0b146399641d73aabc3c98f,

title = "Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial",

abstract = "Objective: This study was undertaken 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 2–18 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.2 mg/kg/day, or fenfluramine.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 frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine.7 mg/kg/day versus patients given placebo. Results: A total of 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 three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine.7 mg/kg/day demonstrated a 64.8\% (95\% confidence interval = 51.8\%–74.2\%) greater reduction in MCSF compared with placebo (p <.0001). Following fenfluramine.7 mg/kg/day, 72.9\% of patients had a ≥50\% reduction in MCSF compared with 6.3\% in the placebo group (p <.0001). The median longest seizure-free interval was 30 days in the fenfluramine.7 mg/kg/day group compared with 10 days in the placebo group (p <.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 antiseizure response of fenfluramine in children with Dravet syndrome.",

keywords = "clinical pharmacology, encephalopathy, epilepsy, seizure",

author = "Joseph Sullivan and Lieven Lagae and Cross, \{J. Helen\} and Orrin Devinsky and Renzo Guerrini and Knupp, \{Kelly G.\} and Linda Laux and Marina Nikanorova and Tilman Polster and Dinesh Talwar and Berten Ceulemans and Rima Nabbout and Farfel, \{Gail M.\} and Galer, \{Bradley S.\} and Gammaitoni, \{Arnold R.\} and Michael Lock and Anupam Agarwal and Scheffer, \{Ingrid E.\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.",

year = "2023",

month = oct,

doi = "10.1111/epi.17737",

language = "English (US)",

volume = "64",

pages = "2653--2666",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "10",

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Sullivan, J, Lagae, L, Cross, JH, Devinsky, O, Guerrini, R, Knupp, KG, Laux, L, Nikanorova, M, Polster, T, Talwar, D, Ceulemans, B, Nabbout, R, Farfel, GM, Galer, BS, Gammaitoni, AR, Lock, M, Agarwal, A & Scheffer, IE 2023, 'Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial', Epilepsia, vol. 64, no. 10, pp. 2653-2666. https://doi.org/10.1111/epi.17737

TY - JOUR

T1 - Fenfluramine in the treatment of Dravet syndrome

T2 - Results of a third randomized, placebo-controlled clinical trial

AU - Sullivan, Joseph

AU - Lagae, Lieven

AU - Cross, J. Helen

AU - Devinsky, Orrin

AU - Guerrini, Renzo

AU - Knupp, Kelly G.

AU - Laux, Linda

AU - Nikanorova, Marina

AU - Polster, Tilman

AU - Talwar, Dinesh

AU - Ceulemans, Berten

AU - Nabbout, Rima

AU - Farfel, Gail M.

AU - Galer, Bradley S.

AU - Gammaitoni, Arnold R.

AU - Lock, Michael

AU - Agarwal, Anupam

AU - Scheffer, Ingrid E.

PY - 2023/10

Y1 - 2023/10

N2 - Objective: This study was undertaken 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 2–18 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.2 mg/kg/day, or fenfluramine.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 frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine.7 mg/kg/day versus patients given placebo. Results: A total of 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 three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine.7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo (p <.0001). Following fenfluramine.7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p <.0001). The median longest seizure-free interval was 30 days in the fenfluramine.7 mg/kg/day group compared with 10 days in the placebo group (p <.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 antiseizure response of fenfluramine in children with Dravet syndrome.

AB - Objective: This study was undertaken 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 2–18 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.2 mg/kg/day, or fenfluramine.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 frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine.7 mg/kg/day versus patients given placebo. Results: A total of 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 three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine.7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo (p <.0001). Following fenfluramine.7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p <.0001). The median longest seizure-free interval was 30 days in the fenfluramine.7 mg/kg/day group compared with 10 days in the placebo group (p <.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 antiseizure response of fenfluramine in children with Dravet syndrome.

KW - clinical pharmacology

KW - encephalopathy

KW - epilepsy

KW - seizure

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Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial

Abstract

Funding

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ASJC Scopus subject areas

UN SDGs

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