Levetiracetam Treatment of Neonatal Seizures: Safety and Efficacy Phase II Study (LEVNEONAT-1)
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|ClinicalTrials.gov Identifier: NCT02229123|
Recruitment Status : Recruiting
First Posted : August 29, 2014
Last Update Posted : June 12, 2018
|Condition or disease||Intervention/treatment||Phase|
|Neonatal Seizures||Drug: Intravenous Levetiracetam||Phase 2|
- 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 4 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 (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||LEVNEONAT-1 is an open and sequential dose-finding study with 1 loading dose of 30, 40, 50 and 60 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 50 participants with a minimum of 24 patients or less in case of high rate of toxicity.|
|Masking:||None (Open Label)|
|Official Title:||Levetiracetam Efficacy and Safety as First-line Treatment of Neonatal Seizures Occuring in Hypoxic-ischemic Encephalopathy Context|
|Actual Study Start Date :||February 27, 2018|
|Estimated Primary Completion Date :||March 1, 2020|
|Estimated Study Completion Date :||March 1, 2020|
Experimental: Intravenous levetiracetam
1 loading dose of 30, 40, 50 or 60 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, 12.5 or 15 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.
- Levetiracetam Efficacy 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) ]Efficacy has been defined as an 80% reduction of seizure burden on EEG recording.
- Levetiracetam Short-Term Toxicity [ Time Frame: 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 Long-Term Toxicity [ Time Frame: 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.
- Levetiracetam Elimination Clearance [ 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. ]The mean values of the elimination clearance and their respective interindividual variability will be estimated.
- Levetiracetam Distribution Volume [ 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. ]The mean values of distribution volumes and their respective interindividual variability will be estimated.
- Plasmatic Levetiracetam Maximal Concentration [ Time Frame: 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 Loading Dose Area under Curve [ Time Frame: 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.
- Levetiracetam Entire Treatment Area Under Curve [ 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. ]Individual PK parameters will be estimated and used to calculated the cumulative AUC of the entire treatment.
- Seizure recurrence from the Efficacy criteria completion to day 6 [ Time Frame: 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 [ Time Frame: 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02229123
|Contact: Geraldine Favrais, Drfirstname.lastname@example.org|
|Contact: Estelle Boivinemail@example.com|
|Service de réanimation néonatale||Recruiting|
|Angers, France, 49000|
|Contact: Stephane Le Bouedec, Dr StLeBouedec@chu-angers.fr|
|Contact: Geraldine Gascoin, Pr GeGascoin@chu-angers.fr|
|Service de réanimation néonatale||Recruiting|
|Lille, France, 59037|
|Contact: Florence Flamein, Dr Florence.firstname.lastname@example.org|
|Contact: Laurent Storme, Pr email@example.com|
|Principal Investigator: Florence Flamein, Dr|
|Service de réanimation et service néonatale||Not yet recruiting|
|Orleans, France, 45100|
|Contact: Bérengère KIRECHE, PH firstname.lastname@example.org|
|Contact: Evelyne WERNER, PH email@example.com|
|Service de réanimation néonatale et pédiatrique||Not yet recruiting|
|Paris, France, 75012|
|Contact: Isabelle GUELLEC, PH firstname.lastname@example.org|
|Contact: Pierre_Louis LEGER, PH email@example.com|
|Service de réanimation néonatale||Not yet recruiting|
|Reims, France, 51092|
|Contact: Nathalie BEDNAREK, PU-PH firstname.lastname@example.org|
|Rennes, France, 35000|
|Contact: Patrick Pladys, Pr email@example.com|
|Contact: Alain Beuchee, Pr firstname.lastname@example.org|
|Principal Investigator: Patrick Pladys, Pr|
|Service de Pédiatrie néonatale et réanimation||Recruiting|
|Rouen, France, 76031|
|Contact: Alexandra Chadie, Dr email@example.com|
|Contact: Stephane Marret, Pr firstname.lastname@example.org|
|Principal Investigator: Alexandra Chadie, Dr|
|Service de Néonatologie||Recruiting|
|Tours, France, 37 000|
|Contact: Geraldine Favrais, Dr 0247474749 email@example.com|
|Contact: Estelle Boivin 0247474620 firstname.lastname@example.org|
|Principal Investigator: Geraldine Favrais, Dr|
|Study Chair:||Geraldine Favrais, Dr||University Hospital of Tours|
|Principal Investigator:||Geraldine FAVRAIS, Dr||University hospital of Tours|