Article Information
Accepted for Publication: March 3, 2022.
Published Online: May 2, 2022. doi:10.1001/jamaneurol.2022.0829
Open Access: This is an open access article distributed under the terms of the
CC-BY-NC-ND License. © 2022 Knupp KG et al.
JAMA Neurology.
Author Contributions: Dr Farfel had full access to all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the data analysis.
Concept and design: Knupp, Ceulemans, Sullivan, Lagae, Zuberi, Shore, Agarwal, Lock, Farfel, Galer, Gil-Nagel.
Acquisition, analysis, or interpretation of data: Knupp, Scheffer, Ceulemans, Nickels, Guerrini, Zuberi, Nabbout, Riney, Shore, Agarwal,
Lock, Farfel, Galer, Gammaitoni, Davis, Gil-Nagel.
Drafting of the manuscript: Knupp, Sullivan, Riney, Galer, Gammaitoni, Gil-Nagel.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Knupp, Shore, Lock, Farfel, Galer, Gammaitoni.
Obtained funding: Knupp, Farfel, Galer.
Administrative, technical, or material support: Riney, Shore, Agarwal, Galer, Gammaitoni, Davis.
Supervision: Knupp, Ceulemans, Sullivan, Lagae, Guerrini, Shore, Agarwal, Farfel, Galer, Gammaitoni,
Gil-Nagel.
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.
Funding/Support: The study was funded by Zogenix Inc.
Role of the Funder/Sponsor: The funder, with input from the investigators, had a role in the design and conduct
of the study. The funder and the contracted clinical research organization (Syneos
Health LLC) had a role in trial management, data collection, site monitoring, data
monitoring and reporting; preparation of placebo and fenfluramine; and statistical
analysis. The funder and the investigators had a role in the interpretation of the
data; preparation, review, or approval of the manuscript; and decision to submit the
manuscript for publication.
Meeting Presentations: A poster of this study was presented at the American Epilepsy Society Annual Meeting;
December 4-8, 2020; virtual meeting.
Additional Contributions: Syneos Health LLC assisted with statistical analysis, with funding from Zogenix Inc.
Danielle Ippolito, PhD, CMPP, MWC, and Scott Bergfeld, PhD, of PharmaWrite LLC, provided
medical writing and editorial assistance, with funding from Zogenix Inc.