Pharmacokinetic and Safety Trial of Intravenous Levetiracetam in the Treatment of Neonatal Seizures (Keppra)

The hypothesis is that a loading dose of 20 mg/kg and a maintenance dose of 5 mg/kg of Levetiracetam is going to be safe and effective in the treatment of seizures in neonates.

Study Overview

• Status: Completed
• Conditions: Seizures; Disorder of Fetus or Newborn
• Intervention / Treatment: Drug: Low dose levetiracetam; Drug: High dose levetiracetam

Detailed Description

In adults, drug clearance is less than half of the glomerular filtration rate and the drug half-life is 6-8 hours. Renal function in infants at birth is characterized by immature glomerular filtration and is only 20% that of older children. The specific esterase responsible for levetiracetam hydrolysis has not been identified and its expression in newborn infants is unknown. Depending on its activity, the expected infant total levetiracetam clearance will likely be between 15-45% of older populations. However, due to immaturity in levetiracetam clearance in infants, accumulation with multiple dosing is possible. Therefore the maintenance dose is reduced compared to older children according to the anticipated impaired clearance.

These anticipated differences in levetiracetam clearance and volume of distribution, will likely result in a prolonged drug half-life of 10-30 hours in infants. This prolonged elimination will require longer sampling to adequately characterize levetiracetam pharmacodynamics in this population.

The primary intent of the data analysis is to determine levetiracetam pharmacokinetics in newborn infants and predict the dosage necessary to maintain concentrations similar to those seen with effective therapy in other populations. Graphs of serum concentration vs. time will be plotted for levetiracetam for each infant. Mean serum drug concentration vs. time curves will also be constructed. Summary statistics (i.e., n, mean, standard deviation, minimum, maximum, and coefficient of variation) will be calculated for serum concentrations for each time point and each dose level.

• Study Type: Interventional
• Enrollment (Actual): 18
• 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: 1 minute to 2 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Newborns admitted to the UCSD, Children's Hospital or Sharp Mary Birch NICUs with seizures.
• Term infants (gestational age greater than or equal to 37 weeks.
• > 2500 grams (max blood for study 6mL =3%).
• Postnatal age 14 days or less.
• Serum creatinine less than 1.2 at time of enrollment.
• Received loading dose of phenobarbital 20mg/kg.
• Are still experiencing either clinical or electroencephalographic seizures despite this therapy.
• For whom parental consent to participate in the study is obtained.

Exclusion Criteria:

• Biochemical abnormality - hypoglycemia, hypocalcemia-that when treated result in seizure cessation.
• Severe hypoxic ischemic injury likely to result in imminent death
• The only significant exclusions that will be made in recruitment and enrollment will be the exclusion of infants who are judged by the attending neonatologist to be so critically ill that death is imminent and benefit from neonatal intensive care is very unlikely.
• No rule-based criteria, (using lab or clinical parameters) adequately capture the complete nature of this clinical assessment.
• In general any child receiving active treatment with head cooling will not be excluded.
• Mechanical ventilation and/or the use of inotropic agents to support blood pressure will not be exclusion criteria.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: levetiracetam dose escalation; 6 Babies in Phase 1-Received Dose 1: 20 mg/kg; 5 mg/kg daily 12 Babies in Phase 2-Received Dose 2: 40 mg/kg; 10 mg/kg/day	Drug: Low dose levetiracetam; 20 mg/kg loading dose; 5 mg/kg daily for 7 days.; Other Names: Keppra; Drug: High dose levetiracetam; 40 mg/kg IV load; 10 mg/kg/day maintenance; Other Names: Keppra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Drug Clearance	Day 1 and Day 7
Drug Half Life	Day 1 and Day 7

Secondary Outcome Measures

Outcome Measure	Time Frame
Levetiracetam Treated Number of Participants With Serious Adverse Events	7 Days

Collaborators and Investigators

• Sponsor: Richard H. Haas
• Collaborators: Thrasher Research Fund
• Investigators: Principal Investigator: Richard Haas, MD, University of Calfornia, 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: April 17, 2009
• First Submitted That Met QC Criteria: April 17, 2009
• First Posted (Estimate): April 20, 2009

Study Record Updates

• Last Update Posted (Actual): March 26, 2020
• Last Update Submitted That Met QC Criteria: March 12, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Neonatal seizures
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Pregnancy Complications; Seizures; Fetal Diseases; Anticonvulsants; Nootropic Agents; Levetiracetam
• Other Study ID Numbers: Thrasher 02825-1