Clinical trial NCT05610085: A Dose Escalation Study of Levetiracetam in the Treatment of Neonatal Seizures
Official title: A Phase IIb Dose Escalation Study of Levetiracetam for the Treatment of Neonatal Seizures
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Neonatal Seizure
Neonatal Encephalopathy
Hypoxic-Ischemic Encephalopathy
Seizure Newborn
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: University of Minnesota
name: Rady Children's Hospital, San Diego
name: Auckland City Hospital
name: University of Auckland, New Zealand
name: Middlemore Hospital, New Zealand
First posted: 2022-11-09
Enrollment: 133
Sex: ALL
Maximum age (years): 1
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: If seizures persist or recur after 60 mg/kg LEV patients will be randomized to receive either dose escalation of levetiracetam or phenobarbital. Randomization will occur in a 3:1 ratio LEv: PHB stratified by site.
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The primary endpoint is the maximum safe and tolerated dose of Levetiracetam
timeFrame: 4 years
Secondary outcomes:
measure: Levetiracetam CL
timeFrame: 4 years
measure: Levetiracetam Vd
timeFrame: 4 years
measure: Adverse event rates
timeFrame: 4 years
measure: Long-term outcome
timeFrame: 8 years
measure: Seizure burden reduction
timeFrame: 4 years
measure: Seizure freedom rates
timeFrame: 4 years
measure: Estimate of efficacy of higher dose LEV
timeFrame: 4 years
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Auckland
country: New Zealand
facility: Middlemore Hospital
Study officials:
affiliation: University of Minnesota
name: Sonya G Wang, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Auckland City Hospital
name: Cynthia M Sharpe, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Jeff J Gold, M.D. PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Richard H Haas, MBBChir
role: PRINCIPAL_INVESTIGATOR
References: