lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

A Randomized Controlled Trial of Levetiracetam Compared with Phenobarbital in the Treatment of Neonatal Seizures

111 Pages Posted: 20 Jun 2019

See all articles by Cynthia Sharpe

Cynthia Sharpe

Auckland District Health Board - Department of Paediatric Neurology

Gail E. Reiner

University of California, San Diego (UCSD) - Department of Neurosciences

Suzanne L. Davis

Auckland District Health Board - Department of Paediatric Neurology

Mark Nespeca

University of California, San Diego (UCSD) - Department of Neurosciences

Jeffrey J. Gold

University of California, San Diego (UCSD) - Department of Neurosciences

Maynard Rasmussen

San Diego Neonatology Inc.

Rachel Kuperman

University of California, San Francisco (UCSF) - School of Medicine

Mary Jo Harbert

University of California, San Diego (UCSD) - Department of Neurosciences

David Michelson

Loma Linda University

Priscilla Joe

Children's Hospital and Research Center

Sonya Wang

University of California, San Diego (UCSD) - Department of Neurosciences

Neggy Rismanchi

University of California, San Diego (UCSD) - Department of Neurosciences

Minh Le

University of California, San Diego (UCSD) - Department of Neurosciences

Andrew Mower

Children's Hospital Orange County

Jae Kim

University of California, San Diego (UCSD) - Department of Pediatrics

Malcolm R. Battin

Auckland District Health Board

Brian Lane

University of California, San Diego (UCSD) - Department of Pediatrics

Jose Honold

University of California, San Diego (UCSD) - Department of Pediatrics

Ellen Knodel

University of California, San Diego (UCSD) - Department of Pediatrics

Kathy Arnell

University of California, San Diego (UCSD) - School of Medicine

Renee Bridge

University of California, San Diego (UCSD) - Department of Pediatrics

Lilly Lee

University of California, San Diego (UCSD) - Department of Neurosciences

Karin Ernstrom

University of Southern California - Keck School of Medicine

Rema Raman

University of Southern California - Keck School of Medicine

Richard H. Haas

University of California, San Diego (UCSD) - Department of Neurosciences

NEOLEV2 Investigators

More...

Abstract

Background: There are no FDA approved therapies for neonatal seizures. Previous studies demonstrated that phenobarbital (PHB) and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam (LEV) has proven efficacy in children and adults and has an excellent safety profile; therefore, there is great interest in its use in neonates, but randomized studies have not been performed.

Methods: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of LEV compared with PHB in the first-line treatment of neonatal seizures, and including a dose escalation component. The primary outcome measure was complete seizure freedom for 24 hours after medication administration. Efficacy in seizure control was determined by independent review of the video EEGs by two neurophysiologists.

Results: Eighty percent of subjects (24 of 30) randomized to PHB remained seizure free for 24 hours as compared with 28% of subjects (15 of 53) randomized to LEV (p <0.001). There were trends towards more adverse effects in subjects randomized to PHB including hypotension, respiratory suppression and sedation. A 7.5% improvement in efficacy was achieved with dose escalation of LEV from 40mg/kg to 60mg/kg.

Conclusions: In this phase IIb study PHB was more effective than LEV for the treatment of neonatal seizures. Higher rates of adverse effects were seen with PHB treatment.

Trial Registration Number: (NCT01720667).

Funding Statement: The NEOLEV2 study was funded by the FDA 1 RO1FD004147 The Persyst EEG software company worked closely with the authors on the NEOLEV2 study and provided their software to the researchers free of charge but have had no input into this manuscript. The Corticare commercial EEG monitoring company worked closely with the authors on the NEOLEV2 study on a commercial basis. They have had no input into the writing of this manuscript. This manuscript discusses use of the automated neonatal seizure detection algorithm created by the Persyst EEG software company, which is not yet FDA approved for commercial use. The REDCap database is supported by NIH Cooperative Agreement UL1TR001442.

Declaration of Interests: The authors state: "None."

Ethics Approval Statement: The study was approved by the institutional review boards of each institution and written consent was obtained from parents of all subjects. A steering committee and data safety monitoring board guided and monitored the study.

Suggested Citation

Sharpe, Cynthia and Reiner, Gail E. and Davis, Suzanne L. and Nespeca, Mark and Gold, Jeffrey J. and Rasmussen, Maynard and Kuperman, Rachel and Harbert, Mary Jo and Michelson, David and Joe, Priscilla and Wang, Sonya and Rismanchi, Neggy and Le, Minh and Mower, Andrew and Kim, Jae and Battin, Malcolm R. and Lane, Brian and Honold, Jose and Knodel, Ellen and Arnell, Kathy and Bridge, Renee and Lee, Lilly and Ernstrom, Karin and Raman, Rema and Haas, Richard H. and Investigators, NEOLEV2, A Randomized Controlled Trial of Levetiracetam Compared with Phenobarbital in the Treatment of Neonatal Seizures (June 17, 2019). Available at SSRN: https://ssrn.com/abstract=3405581 or http://dx.doi.org/10.2139/ssrn.3405581

Cynthia Sharpe

Auckland District Health Board - Department of Paediatric Neurology ( email )

Auckland
New Zealand

Gail E. Reiner

University of California, San Diego (UCSD) - Department of Neurosciences ( email )

9500 Gilman Dr.
La Jolla, CA 92093
United States

Suzanne L. Davis

Auckland District Health Board - Department of Paediatric Neurology

Auckland
New Zealand

Mark Nespeca

University of California, San Diego (UCSD) - Department of Neurosciences

9500 Gilman Dr.
La Jolla, CA 92093
United States

Jeffrey J. Gold

University of California, San Diego (UCSD) - Department of Neurosciences

9500 Gilman Dr.
La Jolla, CA 92093
United States

Maynard Rasmussen

San Diego Neonatology Inc.

San Diego, CA
United States

Rachel Kuperman

University of California, San Francisco (UCSF) - School of Medicine

513 Parnassus Ave
San Francisco, CA 94143
United States

Mary Jo Harbert

University of California, San Diego (UCSD) - Department of Neurosciences

9500 Gilman Dr.
La Jolla, CA 92093
United States

David Michelson

Loma Linda University

Loma Linda, CA 92350
United States

Priscilla Joe

Children's Hospital and Research Center

Oakland, CA
United States

Sonya Wang

University of California, San Diego (UCSD) - Department of Neurosciences

9500 Gilman Dr.
La Jolla, CA 92093
United States

Neggy Rismanchi

University of California, San Diego (UCSD) - Department of Neurosciences

9500 Gilman Dr.
La Jolla, CA 92093
United States

Minh Le

University of California, San Diego (UCSD) - Department of Neurosciences

9500 Gilman Dr.
La Jolla, CA 92093
United States

Andrew Mower

Children's Hospital Orange County

Orange, CA
United States

Jae Kim

University of California, San Diego (UCSD) - Department of Pediatrics

San Diego, CA 92093
United States

Malcolm R. Battin

Auckland District Health Board

Auckland, Auckland Region
New Zealand

Brian Lane

University of California, San Diego (UCSD) - Department of Pediatrics

San Diego, CA 92093
United States

Jose Honold

University of California, San Diego (UCSD) - Department of Pediatrics

San Diego, CA 92093
United States

Ellen Knodel

University of California, San Diego (UCSD) - Department of Pediatrics

San Diego, CA 92093
United States

Kathy Arnell

University of California, San Diego (UCSD) - School of Medicine

9500 Gilman Drive
MC 0507
La Jolla, CA 92093
United States

Renee Bridge

University of California, San Diego (UCSD) - Department of Pediatrics

San Diego, CA 92093
United States

Lilly Lee

University of California, San Diego (UCSD) - Department of Neurosciences

9500 Gilman Dr.
La Jolla, CA 92093
United States

Karin Ernstrom

University of Southern California - Keck School of Medicine

Los Angeles, CA 90089
United States

Rema Raman

University of Southern California - Keck School of Medicine

Los Angeles, CA 90089
United States

Richard H. Haas (Contact Author)

University of California, San Diego (UCSD) - Department of Neurosciences ( email )

9500 Gilman Dr.
La Jolla, CA 92093
United States

No contact information is available for NEOLEV2 Investigators

Click here to go to TheLancet.com

Paper statistics

Abstract Views
895
Downloads
289