Cynthia Sharpe1,2, Gail E Reiner2, Suzanne L Davis1, Mark Nespeca2, Jeffrey J Gold2, Maynard Rasmussen3, Rachel Kuperman4, Mary Jo Harbert5, David Michelson6, Priscilla Joe7, Sonya Wang2, Neggy Rismanchi2, Ngoc Minh Le8, Andrew Mower9, Jae Kim10, Malcolm R Battin11, Brian Lane12, Jose Honold12, Ellen Knodel12, Kathy Arnell8, Renee Bridge10, Lilly Lee13, Karin Ernstrom14, Rema Raman14, Richard H Haas15. 1. Department of Paediatric Neurology, Starship Children's Health, Auckland, New Zealand. 2. Department of Neurosciences, School of Medicine, University of California, San Diego and Rady Children's Hospital-San Diego, San Diego, California. 3. San Diego Neonatology Inc and. 4. Pediatric Neurology, University of California, San Francisco Benioff Children's Hospital Oakland, Oakland, California. 5. Department of Neurosciences, School of Medicine, University of California, San Diego and Sharp Mary Birch Hospital for Women & Newborns, San Diego, California. 6. Division of Pediatric Neurology, Department of Pediatrics, Loma Linda University Children's Hospital, Loma Linda, California. 7. Division of Neonatology, Departments of Pediatrics and. 8. Neonatal Research Institute, Sharp Mary Birch Hospital for Women & Newborns, San Diego, California. 9. Department of Neurology, Children's Hospital of Orange County, Orange, California. 10. Division of NeoNatology, Departments of Pediatrics and. 11. Department of Neonatology, Auckland District Health Board, Auckland, New Zealand; and. 12. Division of Neonatology, Departments of Pediatrics, University of California, San Diego and Rady Children's Hospital San Diego, San Diego, California. 13. Neurosciences, School of Medicine, University of California, San Diego, San Diego, California. 14. Alzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, California. 15. Department of Neurosciences, School of Medicine, University of California, San Diego and Rady Children's Hospital-San Diego, San Diego, California; rhaas@health.ucsd.edu.
Abstract
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.
RCT Entities:
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.
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