Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial

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 firstline 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.WHAT'S KNOWN ON THIS SUBJECT: In 1999, a randomized controlled trial comparing phenobarbital and phenytoin in neonates revealed that each drug had 45% efficacy. These treatments remain the standard of care for neonatal seizures. Levetiracetam has a better safety profile; however, its efficacy is unproven in neonates.WHAT THIS STUDY ADDS: In this study conducted in the hypothermia era and with near real-time response to continuous video EEG monitoring, phenobarbital was more effective than levetiracetam in achieving seizure cessation. Dose-finding studies and phase III trials with long-term outcomes are needed.

A Pilot Randomized, Controlled, Double‐Blind Trial of Bumetanide to Treat Neonatal Seizures

“…Importantly, phenobarbital doses and levels at randomization were not different between groups in this trial, so differences in seizure reduction between treatment and control groups could be attributed to bumetanide. Comparing the additive effect of bumetanide with phenobarbital to phenobarbital alone is particularly important in light of new trial data showing the high efficacy of phenobarbital as first-line therapy, 10 compared with older data. 1 A significant challenge in analyzing bumetanide response in this trial was the high variability in seizure severity among treatment groups, which occurred by chance.…”

“…either have employed an open label design 8,9 ; have allowed subjects to cross over, 1,10 limiting evaluation of drug safety and efficacy; or were retrospective studies with historical controls. 11,12 There is increasing interest in conducting anticonvulsant trials, [13][14][15] motivated also by elucidation of unique characteristics of neonatal neurons that facilitate seizures.…”

Recent Advances in the Diagnosis and Treatment of Neonatal Seizures

“…50 Sharpe et al compared PHB and LEV as a first-line AED in a multicenter, randomized, blinded, controlled phase IIb trial (NEOLEV-2). 32 Approximately 80% neonates (< 2 weeks old, 36-46 weeks' gestation) in the PHB group (24 out of 30) were responders (achieving and maintaining seizure freedom for 24 hours) compared with only 28% in the LEV group (15 of 53; p < 0.001). The similar higher efficacy of PHB compared with LEV was noted when the efficacy was calculated at 1 and 48 hours after the infusion.…”

Cannabidiol antiseizure activity and its interactions with clobazam: “It’s déjà vu all over again” Yogi Berra

“…When studies are funded by independent funding agencies, we get head-to-head comparisons of medications, which answer questions relevant to patient management, for example: The United Kingdom Infantile Spasm Study study on Infantile Spasms; 4 Ethosuximide, valproate or lamotrigine for Absence epilepsy; 5 Levetiracetam vs Phenobarbital for neonatal seizures. 6 The Children's Oncology Group is a prime example of clinical questions being objectively answered using proper scientific methods with no vested interests. Sadly, most studies of medications for the treatment of epilepsy have not made any headway in addressing the concerns of Sinclair Lewis or Dr Relman.…”