Efficacy of Intravenous Levetiracetam in Neonatal Seizures (NEOLEV2)

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

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.

Study Overview

• Status: Completed
• Conditions: Neonatal Seizures
• Intervention / Treatment: Drug: Intravenous levetiracetam; Drug: Intravenous phenobarbital

Detailed Description

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:

1. To determine the efficacy of intravenous LEV in terminating neonatal seizures when given as first line therapy.
2. To obtain dose escalation data by studying the additional efficacy of a further dose in non responders.
3. To obtain additional pharmacokinetic data to confirm findings from our previous pharmacokinetic study.
4. To obtain further safety data of LEV in neonates.
5. 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.

• Study Type: Interventional
• Enrollment (Actual): 280
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • University of California, San Diego Medical Center / Neonatal Intensive Care Unit (NICU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 minutes to 2 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Newborns admitted to any of the study sites with electrographic seizures seizures.
2. Term infants gestational age >36 weeks less than 2 weeks of age.
3. Greater than 2200 grams.
4. Infants for whom parental consent to participate in the study is obtained.

Exclusion Criteria:

1. Infants who are already receiving anticonvulsants
2. If serum creatinine is greater than 1.6mM
3. If seizures are due to correctable metabolic abnormalities (i.e. hypoglycaemia, hypocalcemia, hyponatremia)
4. Subjects in whom death seems imminent, as assessed by the neonatologist.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Data	To obtain additional pharmacokinetic data "Area under the plasma concentration versus time curve (AUC) and Peak Plasma Concentration (Cmax)" of intravenous levetiracetam to confirm findings from our previous pharmacokinetic study.	48 hours
Feasibility of Continuous Internet EEG Monitoring	Feasibility of centralized remote access to continuous video EEG monitoring in the NICU via the internet	Subject study duration
Evaluation of the Accuracy of Neonatal Seizure Detection Algorithm	A novel neonatal seizure detection algorithm will be compared to the gold standard of two encephalographers reading 48 hours of neonatal video EEG in the measurement of seizure burden.	48 Hours
Gather Safety Information on IV Levetiracetam	Safety information to be collected includes daily recording of any adverse events during the 5 day treatment protocol. Complete Blood Count and Comprehensive Chemistry panels after 48 hours of treatment collected.	5 days

Collaborators and Investigators

• Sponsor: Richard H. Haas
• Collaborators: University of California, San Diego; Food and Drug Administration (FDA); UCSF Benioff Children's Hospital Oakland; Rady Children's Hospital, San Diego; Auckland City Hospital; Sharp Mary Birch Hospital for Women & Newborns
• Investigators: Principal Investigator: Richard H Haas, MD, University of California, San Diego

Publications and helpful links

General Publications

• Sharpe CM, Capparelli EV, Mower A, Farrell MJ, Soldin SJ, Haas RH. A seven-day study of the pharmacokinetics of intravenous levetiracetam in neonates: marked changes in pharmacokinetics occur during the first week of life. Pediatr Res. 2012 Jul;72(1):43-9. doi: 10.1038/pr.2012.51. Epub 2012 Apr 11.
• Sharpe C, Davis SL, Reiner GE, Lee LI, Gold JJ, Nespeca M, Wang SG, Joe P, Kuperman R, Gardner M, Honold J, Lane B, Knodel E, Rowe D, Battin MR, Bridge R, Goodmar J, Castro B, Rasmussen M, Arnell K, Harbert M, Haas R. Assessing the Feasibility of Providing a Real-Time Response to Seizures Detected With Continuous Long-Term Neonatal Electroencephalography Monitoring. J Clin Neurophysiol. 2019 Jan;36(1):9-13. doi: 10.1097/WNP.0000000000000525.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2013
• Primary Completion (Actual): October 31, 2017
• Study Completion (Actual): July 31, 2019

Study Registration Dates

• First Submitted: October 22, 2012
• First Submitted That Met QC Criteria: October 31, 2012
• First Posted (Estimate): November 2, 2012

Study Record Updates

• Last Update Posted (Actual): August 21, 2019
• Last Update Submitted That Met QC Criteria: August 12, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Treatment; Seizures; Neonates; Levetiracetam; Anticonvulsants; Phenobarbital
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Hypnotics and Sedatives; GABA Modulators; GABA Agents; Anticonvulsants; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Nootropic Agents; Cytochrome P-450 CYP2B6 Inducers; Levetiracetam; Phenobarbital
• Other Study ID Numbers: NoGA - R01 FD004147-01A1 Haas; 1R01FD004147-01A1 (U.S. FDA Grant/Contract)