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

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.