Clinical trial NCT02229123: Levetiracetam Treatment of Neonatal Seizures: Safety and Efficacy Phase II Study
Official title: Levetiracetam Efficacy and Safety as First-line Treatment of Neonatal Seizures Occuring in Hypoxic-ischemic Encephalopathy Context
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neonatal Seizures
Keywords: seizures
neonates
anticonvulsant treatment
levetiracetam
hypoxic-ischemic encephalopathy
electroencephalography
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
Collaborators: name: Assistance Publique - Hôpitaux de Paris
name: Rennes University Hospital
name: Amiens University Hospital
First posted: 2014-08-29
Enrollment: 18
Sex: ALL
Minimum age (years): 36
Maximum age (years): 43
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Levetiracetam Efficacy on EEG recording
timeFrame: 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)
measure: Levetiracetam Short-Term Toxicity
timeFrame: 6 days from the loading dose
measure: Levetiracetam Long-Term Toxicity
timeFrame: 30 days from the loading dose
Secondary outcomes:
measure: Levetiracetam Elimination Clearance
timeFrame: 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.
measure: Levetiracetam Distribution Volume
timeFrame: 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.
measure: Plasmatic Levetiracetam Maximal Concentration
timeFrame: 30 min, 4 hours and 7 hours after the end of Levetiracetam loading dose infusion
measure: Levetiracetam Loading Dose Area under Curve
timeFrame: 30 min, 4 hours and 7 hours after the end of Levetiracetam loading dose infusion
measure: Levetiracetam Entire Treatment Area Under Curve
timeFrame: 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.
measure: Seizure recurrence from the Efficacy criteria completion to day 6
timeFrame: from 4h15 after the loading dose to 6 days
measure: Levetiracetam Efficacy according to the seizure burden intensity prior to loading dose
timeFrame: after the complete recruting period
Other outcomes:
Locations:
city: Angers
country: France
facility: Service de réanimation néonatale
city: Lille
country: France
facility: Service de réanimation néonatale
city: Orleans
country: France
facility: Service de réanimation et service néonatale
city: Paris
country: France
facility: Service de réanimation néonatale et pédiatrique
city: Reims
country: France
facility: Service de réanimation néonatale
city: Rennes
country: France
facility: Néonatologie
city: Rouen
country: France
facility: Service de Pédiatrie néonatale et réanimation
city: Tours
country: France
facility: Service de Néonatologie
Study officials:
affiliation: University Hospital of Tours
name: Geraldine Favrais, Dr
role: STUDY_CHAIR
affiliation: University hospital of Tours
name: Geraldine FAVRAIS, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.