Levetiracetam Treatment of Neonatal Seizures: Safety and Efficacy Phase II Study (LEVNEONAT-1)

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

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.

Study Overview

• Status: Completed
• Conditions: Neonatal Seizures
• Intervention / Treatment: Drug: Intravenous Levetiracetam

Detailed Description

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
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Geraldine Favrais, Dr; Phone Number: 0247474749; Email: g.favrais@chu-tours.fr
• Study Contact Backup: Name: Estelle Boivin; Phone Number: 0247474620; Email: e.boivin@chu-tours.fr

Study Locations

• France
  • Angers, France, 49000
    • Service de réanimation néonatale
  • Lille, France, 59037
    • Service de réanimation néonatale
  • Orleans, France, 45100
    • Service de réanimation et service néonatale
  • Paris, France, 75012
    • Service de réanimation néonatale et pédiatrique
  • Reims, France, 51092
    • Service de réanimation néonatale
  • Rennes, France, 35000
    • Néonatologie
  • Rouen, France, 76031
    • Service de Pédiatrie néonatale et réanimation
  • Tours, France, 37 000
    • Service de Néonatologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 months to 9 months (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous levetiracetam; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Collaborators: Assistance Publique - Hôpitaux de Paris; Rennes University Hospital; Amiens University Hospital
• Investigators: Study Chair: Geraldine Favrais, Dr, University Hospital of Tours; Principal Investigator: Geraldine FAVRAIS, Dr, University Hospital of Tours

Publications and helpful links

General Publications

• Favrais G, Ursino M, Mouchel C, Boivin E, Jullien V, Zohar S, Saliba E. Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial. BMJ Open. 2019 Jan 24;9(1):e022739. doi: 10.1136/bmjopen-2018-022739.

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2018
• Primary Completion (Actual): February 23, 2022
• Study Completion (Actual): February 23, 2022

Study Registration Dates

• First Submitted: August 27, 2014
• First Submitted That Met QC Criteria: August 28, 2014
• First Posted (Estimated): August 29, 2014

Study Record Updates

• Last Update Posted (Actual): February 5, 2024
• Last Update Submitted That Met QC Criteria: February 2, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: neonates; seizures; electroencephalography; levetiracetam; hypoxic-ischemic encephalopathy; anticonvulsant treatment
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms, Respiratory; Brain Ischemia; Hypoxia; Hypoxia, Brain; Seizures; Hypoxia-Ischemia, Brain; Anticonvulsants; Nootropic Agents; Levetiracetam
• Other Study ID Numbers: 2014-000791-26

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No