Levetiracetam Treatment of Neonatal Seizures: Safety and Efficacy Phase II Study
- Registration Number
- NCT02229123
- Lead Sponsor
- University Hospital, Tours
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 18
Not provided
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Intravenous levetiracetam 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.
- Primary Outcome Measures
Name Time Method Levetiracetam Short-Term Toxicity 6 days from the loading dose 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.
Levetiracetam Efficacy 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) Efficacy has been defined as an 80% reduction of seizure burden on EEG recording.
Levetiracetam Long-Term Toxicity 30 days from the loading dose 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.
- Secondary Outcome Measures
Name Time Method Levetiracetam Distribution Volume 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. The mean values of distribution volumes and their respective interindividual variability will be estimated.
Levetiracetam Elimination Clearance 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. The mean values of the elimination clearance and their respective interindividual variability will be estimated.
Plasmatic Levetiracetam Maximal Concentration 30 min, 4 hours and 7 hours after the end of Levetiracetam loading dose infusion Plasmatic Peak Value of Levetiracetam Loading dose will be assessed.
Levetiracetam Entire Treatment Area Under Curve 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. Individual PK parameters will be estimated and used to calculated the cumulative AUC of the entire treatment.
Levetiracetam Loading Dose Area under Curve 30 min, 4 hours and 7 hours after the end of Levetiracetam loading dose infusion ndividual PK parameters will be estimated and used to calculated the AUC corresponding to the loading dose, after the first maintenance dose.
Seizure recurrence from the Efficacy criteria completion to day 6 from 4h15 after the loading dose to 6 days 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.
Levetiracetam Efficacy according to the seizure burden intensity prior to loading dose after the complete recruting period 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.
Trial Locations
- Locations (6)
Service de Pédiatrie néonatale et réanimation
🇫🇷Rouen, France
Service de réanimation néonatale et pédiatrique
🇫🇷Paris, France
Service de réanimation néonatale
🇫🇷Reims, France
Néonatologie
🇫🇷Rennes, France
Service de réanimation et service néonatale
🇫🇷Orleans, France
Service de Néonatologie
🇫🇷Tours, France