BACKGROUND AND OBJECTIVES: There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures.
METHODS: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the EEGs by 2 neurophysiologists.
RESULTS: Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam ( P < .001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant).
CONCLUSIONS: In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.
Bibliographical noteFunding Information:
FUNDING: The NEOLEV2 study was funded by the US Food and Drug Administration Orphan Products Division (1 RO1FD004147). The Research Electronic Data Capture database is supported by National Institutes of Health Cooperative Agreement UL1TR001442. 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 article. 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 article. The authors of this article discuss the use of the automated neonatal seizure detection algorithm created by the Persyst EEG software company, which is not yet US Food and Drug Administration–approved for commercial use. Funded by the National Institutes of Health (NIH).
© 2020 by the American Academy of Pediatrics.
- Anticonvulsants/therapeutic use
- Dose-Response Relationship, Drug
- Double-Blind Method
- Epilepsy, Benign Neonatal/diagnosis
- Infant, Newborn
- Levetiracetam/therapeutic use
- Phenobarbital/therapeutic use
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.
- Randomized Controlled Trial
- Multicenter Study
- Clinical Trial, Phase II
- Journal Article
- Research Support, N.I.H., Extramural
- Comparative Study