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Clinical Trial
. 2020 Jun;145(6):e20193182.
doi: 10.1542/peds.2019-3182. Epub 2020 May 8.

Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial

Cynthia Sharpe  1   2 , Gail E Reiner  2 , Suzanne L Davis  1 , Mark Nespeca  2 , Jeffrey J Gold  2 , Maynard Rasmussen  3 , Rachel Kuperman  4 , Mary Jo Harbert  5 , David Michelson  6 , Priscilla Joe  7 , Sonya Wang  2 , Neggy Rismanchi  2 , Ngoc Minh Le  8 , Andrew Mower  9 , Jae Kim  10 , Malcolm R Battin  11 , Brian Lane  12 , Jose Honold  12 , Ellen Knodel  12 , Kathy Arnell  8 , Renee Bridge  10 , Lilly Lee  13 , Karin Ernstrom  14 , Rema Raman  14 , Richard H Haas  15 ; NEOLEV2 INVESTIGATORS
Affiliations
Clinical Trial

Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial

Cynthia Sharpe et al. Pediatrics. 2020 Jun.

Erratum in

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.

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Conflict of interest statement

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1
Study protocol and timing. aProgression to the next treatment occurs if electrographic seizures persist 15 minutes after completion of 15-minute infusion or recur within 24 hours.
FIGURE 2
FIGURE 2
Consolidated Standards of Reporting Trials (CONSORT) flow diagram. ECMO, extracorporeal membrane oxygenation; mITT, modified intention-to-treat; PVC, premature ventricular contraction; PP, per protocol; PPA, per protocol analysis.
FIGURE 3
FIGURE 3
Results: Treatment response flowchart.
See this image and copyright information in PMC

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