Efficacy of Intravenous Levetiracetam in Neonatal Seizures

Study Overview
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Brief Summary
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A new anticonvulsant, levetiracetam will be studied to treat seizures in newborn infants. Current treatments for the brain damaging complication of neonatal seizures are unsatisfactory. Monitoring for seizure detection will be tested at five (5) US sites and one (1) international site using the internet.

Detailed Description
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This project aims to improve the treatment of neonatal seizures. Current treatments are poorly effective and have significant side effects. Levetiracetam (LEV) has great potential as a treatment for neonatal seizures but is not approved for use in children less than 2 years of age. This study aims to obtain essential data regarding the efficacy and safety of LEV in this vulnerable and under researched population and simultaneously to develop EEG monitoring systems that facilitate seizure detection and research. Specific aims are: To determine the efficacy of intravenous LEV in terminating neonatal seizures when given as first line therapy. To obtain dose escalation data by studying the additional efficacy of a further dose in non responders. To obtain additional pharmacokinetic data to confirm findings from our previous pharmacokinetic study. To obtain further safety data of LEV in neonates. To prove the feasibility of centralized remote monitoring of continuous EEG monitoring in the Neonatal Intensive Care Unit (NICU) via the internet and test a promising automated neonatal seizure detection algorithm. The study design is a phase 2b randomized blinded controlled study.

Official Title
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Efficacy of Intravenous Levetiracetam in Neonatal Seizures: A Phase 2 Randomized Blinded Controlled Study of the Efficacy of Intravenous Levetiracetam (LEV) as First Line Treatment for Neonatal Seizures

Conditions
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Neonatal Seizures

Intervention / Treatment
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* Drug: Intravenous levetiracetam
* Drug: Intravenous phenobarbital


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newborns admitted to any of the study sites with electrographic seizures seizures. Term infants gestational age >36 weeks less than 2 weeks of age. Greater than 2200 grams. Infants for whom parental consent to participate in the study is obtained. Exclusion Criteria: Infants who are already receiving anticonvulsants If serum creatinine is greater than 1.6mM If seizures are due to correctable metabolic abnormalities (i.e. hypoglycaemia, hypocalcemia, hyponatremia) Subjects in whom death seems imminent, as assessed by the neonatologist.

Ages Eligible for Study
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Minimum Age: 15 Minutes
Maximum Age: 14 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous levetiracetam<br>Intravenous levetiracetam 40 to 60 mg/kg loading dose. 10 mg/kg 8 hourly maintenance | Drug: Intravenous levetiracetam<br>* Intravenous load of levetiracetam (40 to 60 mg/kg) following identification of EEG confirmed neonatal seizure.<br>* Other names: Keppra;|
| Active Comparator: Intravenous phenobarbital<br>Intravenous phenobarbital 20 to 40 mg/kg load. 1.5 mg/kg 8 hourly maintenance | Drug: Intravenous phenobarbital<br>* Intravenous load of phenobarbital (20 to 40 mg/kg) following EEG confirmation of seizure activity load.<br>* Other names: phenobarbitone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neonates With Seizure Cessation When Given Levetiracetam (40-60 mg/kg) as First Line Therapy Compared to Phenobarbital (20-40mg/kg) | A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures. Seizure cessation from 15 minutes after completion of infusion for 24 hours as assessed by continuous EEG reviewed by neurophysiologists. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital at 48 Hours After Treatment | A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures. | 48 hours | 
| Number of Neonates With Seizure Termination at 1 Hour After Treatment | A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures. | 1 hour | 
| LEV Dose Escalation Component | Number of babies with seizure control at levetiracetam (60 mg/Kg load) who had not responded to 40 mg/kg load and number of babies with seizure control at 40 mg/kg who had not responded to 20 mg/kg. | 24 hours | 
| Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital Within the Hypoxic Ischemic Encephalopathy (HIE) Population and Treated With Hypothermia |  | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seizures, Neonates, Anticonvulsants, Treatment, Levetiracetam, Phenobarbital