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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Levetiracetam Efficacy and Safety as First-line Treatment of Neonatal Seizures Occuring in Hypoxic-ischemic Encephalopathy Context

Conditions
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Neonatal Seizures

Intervention / Treatment
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* Drug: Intravenous Levetiracetam


Participation Criteria
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Eligibility Criteria
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Eligibility Criteria: Male or female term baby with gestational age of 36-43 weeks and postnatal age < or= 72 hours 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 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

Ages Eligible for Study
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Minimum Age: 36 Weeks
Maximum Age: 43 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: LEVNEONAT-1 is an open and sequential dose-finding study with 1 loading dose of 30, 40 and 50 mg/kg and 8 quarter-loading maintenance doses for a 3-day treatment. The optimal dose will be the one estimated to be associated with a toxicity not exceeding 10% and an efficacy higher than 60%. Efficacy has been defined by a seizure burden reduction of 80% after the loading dose. A 2-patient cohort will be necessary at each dose level to consider an upper dose level assignment with a dynamic consideration of each participant data. The maximal sample size expected is 30 participants patients.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous levetiracetam<br>1 loading dose of 30, 40 or 50 mg/kg administered intra-venously. Maintenance treatment: one intra-venous injection /8h, 8 doses in total for a 3-day treatment. Maintenance dose corresponds to the loading dose quarter i.e. 7.5, 10 or 12.5 mg/kg. | Drug: Intravenous Levetiracetam<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levetiracetam Efficacy on EEG recording | Efficacy has been defined as an 80% reduction of seizure burden on EEG recording. | 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. | 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. | 30 days from the loading dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levetiracetam Elimination Clearance | The mean values of the elimination clearance and their respective interindividual variability will be estimated. | 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. | 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. | 
| Plasmatic Levetiracetam Maximal Concentration | Plasmatic Peak Value of Levetiracetam Loading dose will be assessed. | 30 min, 4 hours and 7 hours after the end of Levetiracetam loading dose infusion | 
| Levetiracetam Loading Dose Area under Curve | ndividual PK parameters will be estimated and used to calculated the AUC corresponding to the loading dose, after the first maintenance dose. | 30 min, 4 hours and 7 hours after the end of Levetiracetam loading dose infusion | 
| Levetiracetam Entire Treatment Area Under Curve | Individual PK parameters will be estimated and used to calculated the cumulative AUC of the entire treatment. | 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. | 
| Seizure recurrence from the Efficacy criteria completion to day 6 | Clinical or electric seizures recurrence after the efficacy criteria assessment and up to the complete levetiracetam elimination (estimated 5 half-life) will be reported by investigator. | from 4h15 after the loading dose to 6 days | 
| Levetiracetam Efficacy according to the seizure burden intensity prior to loading dose | A new analysis will be performed retrospectively by adjusting the efficacy criteria to the seizure burden on the pre-treatment EEG. Two subgroups will be considered according to the seizure burden (SB) intensity on the pre-treatment EEG, i.e equal or above to 50% of the EEG recording duration (high SB group) and strictly under 50% of it (low SB group), respectively. LEV efficacy will be considered positive when a SB reduction of 50% will be observed on the post-treatment EEG recording in the high SB group whereas the reduction of 80% will be still valid for the low SB group. | after the complete recruting period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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levetiracetam, hypoxic-ischemic encephalopathy, electroencephalography, seizures, neonates, anticonvulsant treatment