Levetiracetam Treatment of Neonatal Seizures: Safety and Efficacy Phase II Study

University Hospital, Tours18 enrolled

Overview

LEVNEONAT is a multicentre French clinical trials with the aim to develop new treatment strategies for the treatment of neonatal seizures using Levetiracetam. The purpose of this study is to determine the correct dosing, safety and efficacy for intravenous levetiracetam as first line treatment in term newborn babies with seizures in hypoxic-ischemic encephalopathy context. This new anticonvulsivant drug is a promising treatment for seizures in newborns.

Article Focus * The principal aim of LEVNEONAT-1 is to determine the levetiracetam optimal dose defined as the highest efficient dose under toxicity restrictions for treating neonatal seizures. * LEVNEONAT-1 is an open-label, sequential dose-finding study with 3 increasing dose levels of levetiracetam. Strenghts and limitation of study * For the first time, levetiracetam will be used as the first-line treatment of neonatal seizures and not as an add-on therapy. * Statistical model is designed for a rare clinical situation with a sequential adaptive method updating in real time the dose allocation for next patient by using all available data from previous participants. * The targeted population, i.e. the newborn less than 3 days of life, is particularly sensitive and the written consent of both parents is required before the levetiracetam administration.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Neonatal Seizures

Interventions

Intravenous LevetiracetamDRUG

Open-study. If seizure lasting more than 3 minutes on EEG recording or brief repeated seizures (more or equal to 2 seizures lasting more than 20 seconds on a 1 hour-interval), the loading-dose of LEV allocated to patient is infused followed by the 8 maintenance dose.

Eligibility

Sex: ALLMin age: 36 WeeksMax age: 43 Weeks

Medical Language ↔ Plain English

Eligibility Criteria: 1. Male or female term baby with gestational age of 36-43 weeks and postnatal age \< or= 72 hours 2. One or more of the following : * APGAR score \< 5 at 5 mins * Umbilical cord or arterial blood sample (within one hour after birth): pH \<7.0 or base deficit \> or = 16 mmol/L or lactates \> or equal to 11 mmol/L * Abnormal neurological examination before 6 hours of life 3. Suspected clinical or EEG seizures Inclusion criteria: * A seizure lasting more than 3 minutes or more than 2 seizures lasting more than 20 seconds on a 1 hour-period on standard EEG recording 4 hours before the levetiracetam loading dose * Availability of 8 electrode EEG recording * Written informed consent of both parents or the authorized guardians * Subscription to social security health insurance are required Exclusion Criteria: * Suspected or confirmed brain malformation, inborn error of metabolism, genetic syndrome or major congenital malformation * Congenital (in utero) infection (TORCH) * Babies who have received phenobarbital or any other anticonvulsive medication other than a bolus of midazolam for intubation * Anuria/renal failure defined as serum creatinine \> 150 micromol/L * Seizures secondary to treatable metabolic etiology as hypoglycemia and hypocalcemia * Corrected QT interval (QTc) greater than 450 milliseconds on the electrocardiogram (ECG) prior to inclusion in the presence or absence of a condition that promotes QT prolongation (hypokalemia, maternal treatment during childbirth or treatment of the child with drugs known to prolong QT), * Participation to an interventional research study

Locations (8)

Service de réanimation néonatale

Angers, France

Service de réanimation néonatale

Lille, France

Service de réanimation et service néonatale

Orléans, France

Service de réanimation néonatale et pédiatrique

Paris, France

Outcomes

Primary Outcomes

Levetiracetam Efficacy on EEG recording

Efficacy has been defined as an 80% reduction of seizure burden on EEG recording.

Time frame: the period just before the LEV loading dose (from 20 min to 3 hours) and the 3 hour time-interval from 1 hour 15 min (T11/4) to 4 hours 15 min (T41/4) after the starting of loading dose infusion (T0)

Levetiracetam Short-Term Toxicity

Short-term toxicity focuses on 4 adverse events potentially attributable to LEV occurring in the 6 days following the loading dose: i) Severe apnoea leading to mechanical ventilation during the 4-hour period following the LEV infusion; ii) Anaphylactic shock occurring during the 30 minutes following the LEV infusion; iii) Toxic epidermic necrosis; iv) Stevens-Jonhson Syndrome. Short-term toxicity has been designed to trigger quickly a decreasing dose allocation to the next potential participant through a e-CRF alert.

Time frame: 6 days from the loading dose

Levetiracetam Long-Term Toxicity

Long-term toxicity includes all the adverse events observed and declared to the pharmacovigilance unit up to the hospital discharge or the 30th day of life at the latest.

Time frame: 30 days from the loading dose

Secondary Outcomes

Levetiracetam Elimination Clearance

The mean values of the elimination clearance and their respective interindividual variability will be estimated.

Time frame: at 30 min, 4 hours and 7 hours after the end of loading dose infusion, respectively and at 1 to 3 hours and 12 hours to 18 hours after the last levetiracetam maintenance dose, respectively.

Levetiracetam Distribution Volume

The mean values of distribution volumes and their respective interindividual variability will be estimated.

Data from ClinicalTrials.gov

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