Efficacy of Intravenous Levetiracetam in Neonatal Seizures (NEOLEV2)

• 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: Richard H. Haas
• 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

Tracking Information

• First Submitted Date: October 22, 2012
• First Posted Date: November 2, 2012
• Results First Submitted Date: July 3, 2019
• Results First Posted Date: August 21, 2019
• Last Update Posted Date: August 21, 2019
• Actual Study Start Date: March 2013
• Actual Primary Completion Date: October 31, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 12, 2019)

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.

Original Primary Outcome Measures (submitted: October 31, 2012)

To determine the efficacy of intravenous LEV in terminating neonatal seizures when given as first line therapy compared to phenobarbital [ 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. Seizure burden will be assessed by duration and frequency of seizure events.

Current Secondary Outcome Measures (submitted: August 12, 2019)

• 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 ]

Original Secondary Outcome Measures (submitted: October 31, 2012)

• To obtain dose escalation data by studying the additional efficacy of a further dose in non responders. [ Time Frame: 48 hours ]
  Determine the efficacy of higher dose levetiracetam compared to phenobarbital in reducing seizure burden.
• To evaluate the benefit of remote EEG monitoring [ Time Frame: 48 hours ]
  To prove the feasibility of centralized remote monitoring of continuous EEG monitoring in the NICU via the internet by documentation of remote accessibility of EEG recordings.
• 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.

Current Other Pre-specified Outcome Measures (submitted: August 12, 2019)

• 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.

Original Other Pre-specified Outcome Measures (submitted: October 31, 2012)

• 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.
• Gather safety information on IV levetiracetam [ Time Frame: 48 Hours ]
  Safety information to be collected includes any adverse events and blood parameter monitoring with Complete Blood Count and Comprehensive Chemistry panels after 48 hours of treatment.

Descriptive Information

• Brief Title: Efficacy of Intravenous Levetiracetam in Neonatal Seizures
• 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

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.

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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Neonatal Seizures

Intervention

• Drug: Intravenous levetiracetam
  Intravenous load of levetiracetam (40 to 60 mg/kg) following identification of EEG confirmed neonatal seizure.
  Other Name: Keppra
• Drug: Intravenous phenobarbital
  Intravenous load of phenobarbital (20 to 40 mg/kg) following EEG confirmation of seizure activity load.
  Other Name: phenobarbitone

Study Arms

• Experimental: Intravenous levetiracetam
  Intravenous levetiracetam 40 to 60 mg/kg loading dose. 10 mg/kg 8 hourly maintenance
  Intervention: Drug: Intravenous levetiracetam
• Active Comparator: Intravenous phenobarbital
  Intravenous phenobarbital 20 to 40 mg/kg load. 1.5 mg/kg 8 hourly maintenance
  Intervention: Drug: Intravenous phenobarbital

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 9, 2018): 280
• Original Estimated Enrollment (submitted: October 31, 2012): 100
• Actual Study Completion Date: July 31, 2019
• Actual Primary Completion Date: October 31, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Minutes to 14 Days (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01720667
• Other Study ID Numbers: NoGA - R01 FD004147-01A1 Haas; 1R01FD004147-01A1 ( U.S. FDA Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Richard H. Haas, University of California, San Diego
• Original Responsible Party: Same as current
• Current Study Sponsor: Richard H. Haas
• Original Study Sponsor: Same as current

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)

Investigators

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

• PRS Account: University of California, San Diego
• Verification Date: August 2019