A Dose Escalation Study of Levetiracetam in the Treatment of Neonatal Seizures

Aims/Hypotheses:

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

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 loading dose (90 mg/kg, 120 mg/kg, or 180 mg/kg (in increments) 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.

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 20 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.