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

Официальное название

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

Обзор

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 20 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

Подробное описание

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.

Вмешательства

• Препарат 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
• Препарат Phenobarbital Sodium Injection
  Standard of care for neonatal seizures

Первичные конечные точки

• The primary endpoint is the maximum safe and tolerated dose of Levetiracetam [Срок оценки: 4 years]

Вторичные конечные точки (7)

• Levetiracetam CL [Срок оценки: 4 years]
• Levetiracetam Vd [Срок оценки: 4 years]
• Adverse event rates [Срок оценки: 4 years]
• Long-term outcome [Срок оценки: 8 years]
• Seizure burden reduction [Срок оценки: 4 years]
• Seizure freedom rates [Срок оценки: 4 years]
• Estimate of efficacy of higher dose LEV [Срок оценки: 4 years]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Новая Зеландия · 3 центра

• Auckland City Hospital — Auckland
• Middlemore Hospital — Auckland
• Capital and Coast District Health Board, Te Whatu Ora, Health New Zealand — Wellington

США · 2 центра

• University of California, San Diego — San Diego
• University of Minnesota — Minneapolis

Идентификаторы

NCT: NCT05610085 · FD-R-6335

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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