A Dose Escalation Study of Levetiracetam in the Treatment of Neonatal Seizures (NEOLEV3)

A Phase IIb Dose Escalation Study of Levetiracetam for the Treatment of Neonatal Seizures

The main purpose of this study is to determine the maximum safe tolerated dose of LEV in the treatment of neonatal seizures. Our hypothesis is that optimal dosing of Levetiracetam (LEV) to treat neonatal seizures is significantly greater than 60mg/kg. This study will be an open label dose-escalation, preliminary safety and efficacy study. There will be a randomized control treatment component. Infants recognized as having neonatal seizures or as being at risk of developing seizures will be recruited and started on continuous video EEG monitoring (CEEG). Eligibility will be confirmed and consent will be obtained. In the first 2 phases of the study, neurologists will identify neonates with mild-moderate seizure burden (less than 8 minutes cumulative seizure activity per hour), appropriate for study with LEV, and exclude patients with higher seizure burden where treatment with PHB is more appropriate. Phase 3 of the dose escalation will only proceed if additional efficacy of LEV has been demonstrated in phases 1 and 2. In Phase 3 we will recruit neonates with seizures of greater severity up to 30 minute seizure burden/hour. This will make the final results of study more generalizable.

If seizures are confirmed, enrolled subjects will receive 60mg/kg of LEV. Subjects whose seizures persist or recur 15 minutes after the first infusion is complete, subjects will then be randomized in the dose escalation study. Patients in the dose escalation study will be randomly assigned to receive either higher dose LEV or treatment with the control drug PHB in a 3:1 allocation ratio, stratified by site.

Funding Source- FDA OOPD

Study Overview

• Status: Recruiting
• Conditions: Hypoxic-Ischemic Encephalopathy; Neonatal Encephalopathy; Neonatal Seizure; Seizure Newborn
• Intervention / Treatment: Drug: Levetiracetam Injection; Drug: Phenobarbital Sodium Injection

Detailed Description

Aims/Hypotheses:

Primary Aim: To determine the recommended maximal safe dose of LEV in the setting of neonatal seizures of mild to moderate severity.

If 60mg/kg LEV does not control seizures, subjects will be randomised to receive either additional LEV or PHB. LEV dose will be escalated in 30mg/kg increments to a maximal dose of 150mg/kg total loading dose. We will use a continual reassessment method to determine the maximal safe and tolerated dose.

Secondary/exploratory aims:

• To study the pharmacokinetics of high dose LEV in neonates with seizures of mild to moderate severity.
• To estimate the additional efficacy of higher doses of LEV in neonates with seizures of mild to moderate severity.
• To improve technologies for the prompt detection of neonatal seizures: We will assess the latest version of Persyst's neonatal seizure detector.

Research Design

This is a Phase IIb, open label dose-escalation, preliminary safety and efficacy study. An active drug treatment control arm (PHB group) is included in the study design. This study is not designed or powered to compare high dose LEV and PHB groups, however, the randomized control group will help with interpretation of adverse events and seizure cessation efficacy seen in the high dose escalation group. This is particularly important because of the high rates of morbidity in neonates with seizures.

24-hour seizure control endpoint: cEEG reviewed by a neurophysiologist will be used for assessing 24-hour seizure control. Treatment will be considered effective in achieving 24-hour seizure control if there is a seizure burden less than 30 seconds in the 24 hours following the dose. Change in seizure burden in 2-hour post treatment period will also be assessed.

Intervention If seizure activity occurs participants will be enrolled and will receive 60mg/kg LEV.

If seizures continue babies will then be randomised to receive either:

• Additional LEV at a higher dose (30 mg/kg, 60 mg/kg, or 90 mg/kg depending on the stage of the study), OR
• PHB at 20-40 mg/kg. Maintenance treatment will continue for 5 days, either IV or orally if baby is tolerating feeds.

LEV discontinuation or addition of PHB: there are multiple criteria for transition to, or addition of, PHB treatment if required for seizure control.

• Study Type: Interventional
• Enrollment (Estimated): 133
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sonya G Wang, M.D.; Phone Number: 612-301-1454; Email: sgwang@umn.edu
• Study Contact Backup: Name: Brittany Faanes, MPH; Phone Number: 612-625-5929; Email: grego318@umn.edu

Study Locations

• New Zealand
  • Auckland
    • Auckland, Auckland, New Zealand, 1023
      • Recruiting
      • Auckland City Hospital
      • Contact: Cynthia Sharpe, MBChB; Phone Number: 021924015; Email: cynthias@adhb.govt.nz
    • Auckland, Auckland, New Zealand, 1050
      • Recruiting
      • Middlemore Hospital
      • Contact: Chris McKinlay, MBChB; Phone Number: +64274725099; Email: c.mckinlay@auckland.ac.nz
      • Contact: Cynthia Sharpe, MBChB; Phone Number: +6421924015; Email: ciasharpe@gmail.com
  • Wellington Region
    • Wellington, Wellington Region, New Zealand, 6021
      • Recruiting
      • Capital and Coast District Health Board, Te Whatu Ora, Health New Zealand
      • Contact: Krishna Raghu, MBBS, DCH, FRACP; Phone Number: +64 22 309 8900; Email: krishna.raghu@ccdhb.org.nz
      • Sub-Investigator: Cynthia Sharpe, MBChB
• United States
  • California
    • San Diego, California, United States, 92093
      • Recruiting
      • University of California, San Diego
      • Contact: Jeff Gold, M.D.; Email: jjgold@health.ucsd.edu
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • University of Minnesota
      • Contact: Brittany Faanes, MPH; Phone Number: 612-625-5929; Email: grego318@umn.edu
      • Contact: Elizabeth Ramey, MS; Email: eramey@umn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• at risk for seizures or suspected to be having seizures;
• all seizure aetiologies except correctable metabolic abnormalities such as hypoglycaemia and hypocalcaemia;
• Term neonates (corrected gestational age between 35 and 44 weeks, postnatal age less than 28 days);
• weight > 2200g.
• Parental ability to comprehend and provide written informed consent

Exclusion Criteria:

• Cumulative seizure burden of 8 minutes/ hour or more in phases 1 and 2, Cumulative seizure burden of 30 minutes/hour or more in phase 3;
• Renal failure defined as anuria in the first 24 hours of life;
• Subjects in whom death seems imminent;
• Seizures caused by correctable metabolic abnormality, such as hypocalcaemia, hypoglycaemia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose escalation with LEV; Additional LEV at a higher dose (30 mg/kg, 60 mg/kg, or 90 mg/kg depending on the stage of the study).	Drug: Levetiracetam Injection; Neonates will be treated with intravenous levetiracetam 60mg/kg for first line management of seizures, and if seizures persist will be randomized to receive higher dose Levetiracetam or standard of care phenobarbital
Active Comparator: Standard of care Phenobarbital; Treatment with Phenobarbital 20mg/kg IV and if needed a further 20mg/kg totalling 40mg/kg	Drug: Phenobarbital Sodium Injection; Standard of care for neonatal seizures

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary endpoint is the maximum safe and tolerated dose of Levetiracetam	A continual reassessment method will be used to determine the maximal safe and tolerated dose	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levetiracetam CL	Population pharmacokinetic parameters for LEV Clearance (CL)will be calculated	4 years
Levetiracetam Vd	Population pharmacokinetic parameters for LEV Volume of distribution (Vd) will be calculated	4 years
Adverse event rates	Rates of adverse events seen with high dose LEV treatment will be reported and compared to rates seen in PHB control arm.	4 years
Long-term outcome	Rates of adverse long-term outcome ( Death or Disability at 24 months) will be compared between treatment arms	8 years
Seizure burden reduction	Number of patients with at least 50% seizure burden reduction post treatment will be compared between randomized treatment arms	4 years
Seizure freedom rates	Number of patients who become seizure free for 24 hours post treatment will be compared between the randomized treatment groups in each stage of the study	4 years
Estimate of efficacy of higher dose LEV	Assuming no dose limiting toxicity is demonstrated and the study proceeds to completion, 50 subjects will be treated at 120mg/kg or higher dosing level. This sample size will give satisfactory power for estimating additional efficacy of higher doses. For example, if we document an additional response rate of 15%, this sample size will provide a 95% confidence interval (0.051, 0.248) around that estimate.	4 years

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: University of Minnesota; Rady Children's Hospital, San Diego; Middlemore Hospital, New Zealand; University of Auckland, New Zealand; Auckland City Hospital
• Investigators: Principal Investigator: Sonya G Wang, M.D., University of Minnesota; Principal Investigator: Cynthia M Sharpe, M.D., Auckland City Hospital; Principal Investigator: Jeff J Gold, M.D. PhD, University of California, San Diego; Principal Investigator: Richard H Haas, MBBChir, University of California, San Diego

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2023
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: October 27, 2022
• First Submitted That Met QC Criteria: November 6, 2022
• First Posted (Actual): November 9, 2022

Study Record Updates

• Last Update Posted (Estimated): October 31, 2025
• Last Update Submitted That Met QC Criteria: October 29, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Brain Ischemia; Signs and Symptoms, Respiratory; Hypoxia, Brain; Hypoxia; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hypoxia-Ischemia, Brain; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Acids, Acyclic; Carboxylic Acids; Amides; Pyrimidines; Pyrimidinones; Pyrrolidines; Acetamides; Acetates; Pyrrolidinones; Barbiturates; Levetiracetam; Phenobarbital
• Other Study ID Numbers: FD-R-6335

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No