Efficacy of Intravenous Levetiracetam in Neonatal Seizures (NEOLEV2)

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ClinicalTrials.gov Identifier: NCT01720667

Recruitment Status : Completed

First Posted : November 2, 2012

Results First Posted : August 21, 2019

Last Update Posted : August 21, 2019

Sponsor:

Collaborators:

University of California, San Diego

Rady Children's Hospital, San Diego

Auckland City Hospital

Sharp Mary Birch Hospital for Women & Newborns

UCSF Benioff Children’s Hospital Oakland

Food and Drug Administration (FDA)

Information provided by (Responsible Party):

Richard H. Haas, University of California, San Diego

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Neonatal Seizures	Drug: Intravenous levetiracetam Drug: Intravenous phenobarbital	Phase 1 Phase 2

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:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	280 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	March 2013
Actual Primary Completion Date :	October 31, 2017
Actual Study Completion Date :	July 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Seizures

Drug Information available for: Phenobarbital Phenobarbital sodium Levetiracetam

U.S. FDA Resources

Arms and Interventions

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 Name: 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 Name: phenobarbitone

Outcome Measures

Primary Outcome Measures :

Neonates With Seizure Cessation When Given Levetiracetam (40-60 mg/kg) as First Line Therapy Compared to Phenobarbital (20-40mg/kg) [ Time Frame: 24 hours ]
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.

Secondary Outcome Measures :

Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital at 48 Hours After Treatment [ Time Frame: 48 hours ]
A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures.
Number of Neonates With Seizure Termination at 1 Hour After Treatment [ Time Frame: 1 hour ]
A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures.
LEV Dose Escalation Component [ Time Frame: 24 hours ]
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.
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 [ Time Frame: 24 hours ]

Other Outcome Measures:

Pharmacokinetic Data [ Time Frame: 48 hours ]
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.
Feasibility of Continuous Internet EEG Monitoring [ Time Frame: Subject study duration ]
Feasibility of centralized remote access to continuous video EEG monitoring in the NICU via the internet
Evaluation of the Accuracy of Neonatal Seizure Detection Algorithm [ Time Frame: 48 Hours ]
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.
Gather Safety Information on IV Levetiracetam [ Time Frame: 5 days ]
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.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	up to 14 Days (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01720667

Locations

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

Sponsors and Collaborators

Richard H. Haas

University of California, San Diego

Rady Children's Hospital, San Diego

Auckland City Hospital

Sharp Mary Birch Hospital for Women & Newborns

UCSF Benioff Children’s Hospital Oakland

Food and Drug Administration (FDA)

Investigators

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Principal Investigator:	Richard H Haas, MD	University of California, San Diego

Study Documents (Full-Text)

Documents provided by Richard H. Haas, University of California, San Diego:

Statistical Analysis Plan [PDF] September 14, 2018

Study Protocol [PDF] April 13, 2018

More Information

Publications of Results:

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.

Other 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.

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Responsible Party:	Richard H. Haas, Professor, University of California, San Diego
ClinicalTrials.gov Identifier:	NCT01720667 History of Changes
Other Study ID Numbers:	NoGA - R01 FD004147-01A1 Haas 1R01FD004147-01A1 ( U.S. FDA Grant/Contract )
First Posted:	November 2, 2012 Key Record Dates
Results First Posted:	August 21, 2019
Last Update Posted:	August 21, 2019
Last Verified:	August 2019

Keywords provided by Richard H. Haas, University of California, San Diego:


Seizures Neonates Anticonvulsants	Treatment Levetiracetam Phenobarbital

Additional relevant MeSH terms:

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Seizures Neurologic Manifestations Nervous System Diseases Signs and Symptoms Levetiracetam Phenobarbital Anticonvulsants Nootropic Agents Hypnotics and Sedatives Central Nervous System Depressants	Physiological Effects of Drugs Excitatory Amino Acid Antagonists Excitatory Amino Acid Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action GABA Modulators GABA Agents Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 Enzyme Inducers Cytochrome P-450 CYP3A Inducers

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