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Randomized Controlled Trial
. 2022 Jun 1;79(6):554-564.
doi: 10.1001/jamaneurol.2022.0829.

Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial

Kelly G Knupp  1 , Ingrid E Scheffer  2 , Berten Ceulemans  3 , Joseph E Sullivan  4 , Katherine C Nickels  5 , Lieven Lagae  6   7 , Renzo Guerrini  8   9 , Sameer M Zuberi  10 , Rima Nabbout  11 , Kate Riney  12   13 , Svetlana Shore  14   15 , Anupam Agarwal  14 , Michael Lock  14   16 , Gail M Farfel  14 , Bradley S Galer  14 , Arnold R Gammaitoni  14 , Ronald Davis  17 , Antonio Gil-Nagel  18
Affiliations
Randomized Controlled Trial

Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial

Kelly G Knupp et al. JAMA Neurol. .

Abstract

Importance: New treatment options are needed for patients with Lennox-Gastaut syndrome (LGS), a profoundly impairing, treatment-resistant, developmental and epileptic encephalopathy.

Objective: To evaluate the efficacy and safety of fenfluramine in patients with LGS.

Design, setting, and participants: This multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted from November 27, 2017, to October 25, 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia. Included patients were aged 2 to 35 years with confirmed diagnosis of LGS and experienced 2 or more drop seizures per week during the 4-week baseline. Using a modified intent-to-treat method, data analysis was performed from November 27, 2017, to October 25, 2019. The database lock date was January 30, 2020, and the date of final report was September 11, 2021.

Interventions: Patients were randomized to receive either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo. After titration (2-week period), patients were taking their randomized dose for 12 additional weeks.

Main outcomes and measures: Primary efficacy end point was percentage change from baseline in drop seizure frequency in patients who received 0.7 mg/kg/d of fenfluramine vs placebo.

Results: A total of 263 patients (median [range] age, 13 [2-35] years; 146 male patients [56%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n = 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n = 87). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7-mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. The trial met its primary efficacy end point: patients in the 0.7-mg/kg/d fenfluramine group achieved a -19.9 percentage points (95% CI, -31.0 to -8.7 percentage points; P = .001) estimated median difference in drop seizures from baseline vs placebo. More patients in the 0.7-mg/kg/d fenfluramine group achieved a 50% or greater response (22 of 87 [25%]; P = .02) vs placebo (9 of 87 [10%]). Site investigators and caregivers gave a much improved or very much improved rating on the Clinical Global Impression of Improvement scale to more patients in the 0.7-mg/kg/d fenfluramine group than patients in the placebo group (21 [26%] vs 5 [6%]; P = .001). The seizure subtype that appeared most responsive to fenfluramine was generalized tonic-clonic seizure (120 of 263 [46%]), with a decrease in frequency of 45.7% in the 0.7-mg/kg/d fenfluramine group and 58.2% in the 0.2-mg/kg/d fenfluramine group compared with an increase of 3.7% in the placebo group. Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%]). No cases of valvular heart disease or pulmonary arterial hypertension were observed.

Conclusions and relevance: Results of this trial showed that, in patients with LGS, fenfluramine compared with placebo provided a significantly greater reduction in drop seizures and may be a particularly advantageous choice in patients who experience generalized tonic-clonic seizures.

Trial registration: ClinicalTrials.gov Identifier: NCT03355209.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Knupp reported receiving grants from Pediatric Epilepsy Research Fund during the conduct of the study; grants from Zogenix Inc, Stoke, Encoded Therapeutics, Colorado Department of Public Health, and West Therapeutics; consulting fees from Biomarin, Epygenix, and Biocodex; and other support as a Data and Safety Monitoring Board member from Greenwich Pharmaceuticals outside the submitted work. Dr Scheffer reported receiving personal fees and/or other support from Anavex Life Sciences, Atheneum Partners, Biocodex, BioMarin, Care Beyond Diagnosis, Chiesi, GlaxoSmithKline, Eisai, Encoded Therapeutics, GW Pharmaceuticals, Marinus, Ovid Therapeutics, Rogcon Scientific Advisory Board, UCB, Ultragenyx, Zogenix Inc, Knopp Biosciences, Liva Nova, Zynerba Pharmaceuticals, Nutricia, and Xenon Pharmaceuticals outside the submitted work; receiving grants from Health Research Council of New Zealand, National Institutes of Health, Australian National Health and Medical Research Council, Australian Medical Research Future Fund, Australian Epilepsy Research Fund, and Shenzhen Sanming outside the submitted work; and holding a patent for WO/2013/059884, with royalties paid; patent for a molecular diagnostic/therapeutic target for benign familial infantile epilepsy, with royalties paid; pending patent for WO2009/086591; pending patent for Diagnostic and Therapeutic Methods for EFMR (Epilepsy and Mental Retardation Limited to Females), may accrue future revenue; patent for WO/2006/133508, licensed to Bionomics Inc; and patent for SCN1A testing, held by Bionomics Inc and licensed to various diagnostic companies. Dr Ceulemans reported receiving research funding from Brabant and Zogenix Inc; other support from Brabant and Zogenix Inc; holding a patent for ZX008; and potentially benefitting financially from a royalty arrangement that is related to this research if Zogenix Inc is successful in marketing its product, fenfluramine, with the terms of this arrangement reviewed and approved by the co-beneficiary, KU Leuven/Antwerp University Hospital. Dr Sullivan reported receiving research grants from Stoke Therapeutics, Marinus, Zogenix Inc, BioPharm, and Encoded Therapeutics; receiving personal fees and/or other support from Dravet Syndrome Foundation, Epygenix, GW Pharmaceuticals, Asceneuron, Longboard Pharmaceuticals, Knopp Biosciences, Neurocrine, Zogenix Inc, and Epilepsy Study Consortium; and owning stock options in Epygenix. Dr Lagae reported receiving other support from LivaNova, Novartis, Takeda UCB, Shire, Eisai, Brabant, and Ovid outside the submitted work; holding a patent for ZX008 for the treatment of Dravet syndrome and infantile epilepsies, assigned to his institution and licensed to Zogenix Inc; and potentially benefitting financially from a royalty arrangement that is related to this research if Zogenix Inc is successful in marketing its product, andomizede, with the terms of this arrangement reviewed and approved by the co-beneficiary, KU Leuven/Antwerp University Hospital. Dr Guerrini reported receiving personal fees and/or other support from Zogenix Inc, Biocodex, UCB, Angelini, Eisai Inc, Novartis, Biomarin, and GW Pharmaceuticals outside the submitted work. Dr Zuberi reported receiving research support from Epilepsy Research UK, Dravet Syndrome UK, and Zogenix Inc as well as personal fees and/or other support from Zogenix Inc, GW Pharmaceuticals, Encoded Therapeutics, Stoke Therapeutics, Eisai, UCB, Jaguar Gene Therapy, and Arvelle outside the submitted work. Dr Nabbout reported receiving research funding from Eisai, GW Pharmaceuticals, Novartis, Shire, and Zogenix Inc as well as personal fees and/or other support from Eisai, Biogen, GW Pharmaceuticals, Novartis, Shire, and Zogenix Inc, Advicenne, and BioMarin. Dr Riney reported receiving personal fees and/or other support from AFT Pharmaceuticals, Eisai Australia, Janssen-Cilag Pty, LivaNova Australia, Novartis, UCB, and Zogenix International. Dr Shore reported receiving personal fees from, owning stock in, and being an employee of Zogenix Inc, with patents pending, during the conduct of the study as well as being a current employee of Neurocrine Biosciences outside the submitted work. Dr Agarwal reported receiving personal fees from, owning stock in, and being an employee of Zogenix Inc, with patents pending. Dr Lock reported receiving personal fees from, owning stock in, and being an employee of Zogenix Inc, with patents pending, during the conduct of the study as well as being, at the time of publication, an independent consultant for Zogenix Inc. Dr Farfel reported receiving personal fees from, owning stock in, and being an employee of Zogenix Inc, with patents pending. Dr Galer reported receiving personal fees from, owning stock in, and being an employee of Zogenix Inc, with patents pending. Dr Gammaitoni reported receiving personal fees from, owning stock in, and being an employee of Zogenix Inc, with patents pending. Dr Davis reported serving as speaker for LivaNova, Eisai, and Lundbeck as well as serving as an investigator for LivaNova, Eisai, Global Pharmaceuticals, Lundbeck, Pfizer, UCB, and Zogenix Inc. Dr Gil-Nagel reported receiving personal fees and/or other support from Arvelle/Angelini, Bial, Biocodex, Eisai, Esteve, GW Pharmaceuticals, GW Research, PTC Therapeutics, Sanofi, Stoke, UCB, and Zogenix Inc. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Screening exclusion included patients who did not meet at least 1 entry or randomization criteria. A patient who did not meet 2 or more of these criteria may be counted in multiple categories. Seven patients discontinued the first part of the trial early and were allowed to enter the open-label extension (OLE) studies. Two patients who completed the trial did not continue to the OLE studies. CVD indicates cardiovascular disease; LGS, Lennox-Gastaut syndrome.
Figure 2.
Figure 2.. Patient Response to Treatment From Prerandomization During the Combined Titration and Maintenance Period and/or Maintenance Only Period
A, Estimated median difference from placebo was calculated using Hodges-Lehmann estimate. B, The 50%, 25%, and 75% or greater responder levels were included. C, P values were calculated using the Cochran-Mantel-Haenszel test. D, Countable motor seizures included generalized tonic-clonic (GTC) seizure, secondary GTC, tonic seizure, atonic seizure, tonic or atonic seizure, clonic seizure, hemiclonic seizure, and focal seizure. P values were statistically significant for the primary efficacy outcome and the 50% or greater responder rate for the 0.7-mg/kg/d fenfluramine group; all other P values were nominal. Distribution data are presented in eFigure 2 in the Supplement. CGI-I indicates Clinical Global Impression-Improvement scale; NS, not statistically significant.
Figure 3.
Figure 3.. Median Percentage Reduction at Baseline for the Combined Titration and Maintenance Period and Maintenance Only Period, by Seizure Type
P values calculated using pairwise Wilcoxon rank sum test compared percentage changes from baseline between active treatment and placebo groups. All P values were nominal. Distribution data are presented in eFigure 2 in the Supplement. GTC indicates generalized tonic-clonic seizure; NS, not statistically significant.
See this image and copyright information in PMC

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