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

Primary Purpose

Neonatal Seizures

Status
Unknown status
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Intravenous Levetiracetam
Sponsored by
University Hospital, Tours
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neonatal Seizures focused on measuring seizures, neonates, anticonvulsant treatment, levetiracetam, hypoxic-ischemic encephalopathy, electroencephalography

Eligibility Criteria

36 Weeks - 43 Weeks (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Service de réanimation néonataleRecruiting
  • Service de réanimation néonataleRecruiting
  • Service de réanimation et service néonatale
  • Service de réanimation néonatale et pédiatrique
  • Service de réanimation néonatale
  • NéonatologieRecruiting
  • Service de Pédiatrie néonatale et réanimationRecruiting
  • Service de NéonatologieRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intravenous levetiracetam

Arm Description

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.

Outcomes

Primary Outcome Measures

Levetiracetam Efficacy on EEG recording
Efficacy has been defined as an 80% reduction of seizure burden on EEG recording.
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.
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.

Secondary Outcome Measures

Levetiracetam Elimination Clearance
The mean values of the elimination clearance and their respective interindividual variability will be estimated.
Levetiracetam Distribution Volume
The mean values of distribution volumes and their respective interindividual variability will be estimated.
Plasmatic Levetiracetam Maximal Concentration
Plasmatic Peak Value of Levetiracetam Loading dose will be assessed.
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.
Levetiracetam Entire Treatment Area Under Curve
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
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
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.

Full Information

First Posted
August 27, 2014
Last Updated
November 3, 2020
Sponsor
University Hospital, Tours
Collaborators
Assistance Publique - Hôpitaux de Paris, Rennes University Hospital, Amiens University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02229123
Brief Title
Levetiracetam Treatment of Neonatal Seizures: Safety and Efficacy Phase II Study
Acronym
LEVNEONAT-1
Official Title
Levetiracetam Efficacy and Safety as First-line Treatment of Neonatal Seizures Occuring in Hypoxic-ischemic Encephalopathy Context
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Unknown status
Study Start Date
February 27, 2018 (Actual)
Primary Completion Date
February 27, 2022 (Anticipated)
Study Completion Date
March 1, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Tours
Collaborators
Assistance Publique - Hôpitaux de Paris, Rennes University Hospital, Amiens University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neonatal Seizures
Keywords
seizures, neonates, anticonvulsant treatment, levetiracetam, hypoxic-ischemic encephalopathy, electroencephalography

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
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)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Intravenous levetiracetam
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Intravenous Levetiracetam
Intervention Description
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.
Primary Outcome Measure Information:
Title
Levetiracetam Efficacy on EEG recording
Description
Efficacy has been defined as an 80% reduction of seizure burden 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)
Title
Levetiracetam Short-Term Toxicity
Description
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.
Time Frame
6 days from the loading dose
Title
Levetiracetam Long-Term Toxicity
Description
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.
Time Frame
30 days from the loading dose
Secondary Outcome Measure Information:
Title
Levetiracetam Elimination Clearance
Description
The mean values of the elimination clearance and their respective interindividual variability will be estimated.
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.
Title
Levetiracetam Distribution Volume
Description
The mean values of distribution volumes and their respective interindividual variability will be estimated.
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.
Title
Plasmatic Levetiracetam Maximal Concentration
Description
Plasmatic Peak Value of Levetiracetam Loading dose will be assessed.
Time Frame
30 min, 4 hours and 7 hours after the end of Levetiracetam loading dose infusion
Title
Levetiracetam Loading Dose Area under Curve
Description
ndividual PK parameters will be estimated and used to calculated the AUC corresponding to the loading dose, after the first maintenance dose.
Time Frame
30 min, 4 hours and 7 hours after the end of Levetiracetam loading dose infusion
Title
Levetiracetam Entire Treatment Area Under Curve
Description
Individual PK parameters will be estimated and used to calculated the cumulative AUC of the entire treatment.
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.
Title
Seizure recurrence from the Efficacy criteria completion to day 6
Description
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.
Time Frame
from 4h15 after the loading dose to 6 days
Title
Levetiracetam Efficacy according to the seizure burden intensity prior to loading dose
Description
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.
Time Frame
after the complete recruting period

10. Eligibility

Sex
All
Minimum Age & Unit of Time
36 Weeks
Maximum Age & Unit of Time
43 Weeks
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Geraldine Favrais, Dr
Phone
0247474749
Email
g.favrais@chu-tours.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Estelle Boivin
Phone
0247474620
Email
e.boivin@chu-tours.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Geraldine Favrais, Dr
Organizational Affiliation
University Hospital of Tours
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Geraldine FAVRAIS, Dr
Organizational Affiliation
University hospital of Tours
Official's Role
Principal Investigator
Facility Information:
Facility Name
Service de réanimation néonatale
City
Angers
ZIP/Postal Code
49000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stephane Le Bouedec, Dr
Email
StLeBouedec@chu-angers.fr
First Name & Middle Initial & Last Name & Degree
Geraldine Gascoin, Pr
Email
GeGascoin@chu-angers.fr
Facility Name
Service de réanimation néonatale
City
Lille
ZIP/Postal Code
59037
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Florence Flamein, Dr
Email
Florence.flamein@chru-lille.fr
First Name & Middle Initial & Last Name & Degree
Laurent Storme, Pr
Email
laurent.storme@chru-lille.fr
First Name & Middle Initial & Last Name & Degree
Florence Flamein, Dr
Facility Name
Service de réanimation et service néonatale
City
Orleans
ZIP/Postal Code
45100
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bérengère KIRECHE, PH
Email
berengere.kireche@chr-orleans.fr
First Name & Middle Initial & Last Name & Degree
Evelyne WERNER, PH
Email
evelyne.werner@chr-orleans.fr
Facility Name
Service de réanimation néonatale et pédiatrique
City
Paris
ZIP/Postal Code
75012
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Isabelle GUELLEC, PH
Email
isabelle.guellec@aphp.fr
First Name & Middle Initial & Last Name & Degree
Pierre_Louis LEGER, PH
Email
pierre-louis.leger@aphp.fr
Facility Name
Service de réanimation néonatale
City
Reims
ZIP/Postal Code
51092
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nathalie BEDNAREK, PU-PH
Email
nbednarek@chu-reims.fr
Facility Name
Néonatologie
City
Rennes
ZIP/Postal Code
35000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Patrick Pladys, Pr
Email
patrick.pladys@chu-rennes.fr
First Name & Middle Initial & Last Name & Degree
Alain Beuchee, Pr
Email
alain.beuchee@chu-rennes.fr
First Name & Middle Initial & Last Name & Degree
Patrick Pladys, Pr
Facility Name
Service de Pédiatrie néonatale et réanimation
City
Rouen
ZIP/Postal Code
76031
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alexandra Chadie, Dr
Email
alexandra.chadie@chu-rouen.fr
First Name & Middle Initial & Last Name & Degree
Stephane Marret, Pr
Email
stephane.marret@chu-rouen.fr
First Name & Middle Initial & Last Name & Degree
Alexandra Chadie, Dr
Facility Name
Service de Néonatologie
City
Tours
ZIP/Postal Code
37 000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Geraldine Favrais, Dr
Phone
0247474749
Email
g.favrais@chu-tours.fr
First Name & Middle Initial & Last Name & Degree
Estelle Boivin
Phone
0247474620
Email
e.boivin@chu-tours.fr
First Name & Middle Initial & Last Name & Degree
Geraldine Favrais, Dr

12. IPD Sharing Statement

Citations:
PubMed Identifier
30679288
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.
Results Reference
derived

Learn more about this trial

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

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