Neonatal Seizures
Conditions
Keywords
Seizures, Neonates, Anticonvulsants, Treatment, Levetiracetam, Phenobarbital
Brief summary
A new anticonvulsant, levetiracetam will be studied to treat seizures in newborn infants. Current treatments for the brain damaging complication of neonatal seizures are unsatisfactory. Monitoring for seizure detection will be tested at five (5) US sites and one (1) international site using the internet.
Detailed description
This project aims to improve the treatment of neonatal seizures. Current treatments are poorly effective and have significant side effects. Levetiracetam (LEV) has great potential as a treatment for neonatal seizures but is not approved for use in children less than 2 years of age. This study aims to obtain essential data regarding the efficacy and safety of LEV in this vulnerable and under researched population and simultaneously to develop EEG monitoring systems that facilitate seizure detection and research. Specific aims are: 1. To determine the efficacy of intravenous LEV in terminating neonatal seizures when given as first line therapy. 2. To obtain dose escalation data by studying the additional efficacy of a further dose in non responders. 3. To obtain additional pharmacokinetic data to confirm findings from our previous pharmacokinetic study. 4. To obtain further safety data of LEV in neonates. 5. To prove the feasibility of centralized remote monitoring of continuous EEG monitoring in the Neonatal Intensive Care Unit (NICU) via the internet and test a promising automated neonatal seizure detection algorithm. The study design is a phase 2b randomized blinded controlled study.
Interventions
Intravenous load of levetiracetam (40 to 60 mg/kg) following identification of EEG confirmed neonatal seizure.
Intravenous load of phenobarbital (20 to 40 mg/kg) following EEG confirmation of seizure activity load.
Sponsors
University of California, San Diego
Rady Children's Hospital, San Diego
Auckland City Hospital
Sharp Mary Birch Hospital for Women & Newborns
UCSF Benioff Children's Hospital Oakland
Food and Drug Administration (FDA)
Richard H. Haas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
15 Minutes to 14 Days
Healthy volunteers
No
Inclusion criteria
1. Newborns admitted to any of the study sites with electrographic seizures seizures. 2. Term infants gestational age \>36 weeks less than 2 weeks of age. 3. Greater than 2200 grams. 4. Infants for whom parental consent to participate in the study is obtained.
Exclusion criteria
1. Infants who are already receiving anticonvulsants 2. If serum creatinine is greater than 1.6mM 3. If seizures are due to correctable metabolic abnormalities (i.e. hypoglycaemia, hypocalcemia, hyponatremia) 4. Subjects in whom death seems imminent, as assessed by the neonatologist.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neonates With Seizure Cessation When Given Levetiracetam (40-60 mg/kg) as First Line Therapy Compared to Phenobarbital (20-40mg/kg) | 24 hours | A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures. Seizure cessation from 15 minutes after completion of infusion for 24 hours as assessed by continuous EEG reviewed by neurophysiologists. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital at 48 Hours After Treatment | 48 hours | A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures. |
| Number of Neonates With Seizure Termination at 1 Hour After Treatment | 1 hour | A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures. |
| LEV Dose Escalation Component | 24 hours | Number of babies with seizure control at levetiracetam (60 mg/Kg load) who had not responded to 40 mg/kg load and number of babies with seizure control at 40 mg/kg who had not responded to 20 mg/kg. |
| Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital Within the Hypoxic Ischemic Encephalopathy (HIE) Population and Treated With Hypothermia | 24 hours | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of Continuous Internet EEG Monitoring | Subject study duration | Feasibility of centralized remote access to continuous video EEG monitoring in the NICU via the internet |
| Evaluation of the Accuracy of Neonatal Seizure Detection Algorithm | 48 Hours | A novel neonatal seizure detection algorithm will be compared to the gold standard of two encephalographers reading 48 hours of neonatal video EEG in the measurement of seizure burden. |
| Gather Safety Information on IV Levetiracetam | 5 days | Safety information to be collected includes daily recording of any adverse events during the 5 day treatment protocol. Complete Blood Count and Comprehensive Chemistry panels after 48 hours of treatment collected. |
| Pharmacokinetic Data | 48 hours | To obtain additional pharmacokinetic data Area under the plasma concentration versus time curve (AUC) and Peak Plasma Concentration (Cmax) of intravenous levetiracetam to confirm findings from our previous pharmacokinetic study. |
Countries
United States
Participant flow
Pre-assignment details
280 were enrolled to EEG monitoring and of these 106 were randomized to treatment as neonatal seizures were thought to have occurred. 174 excluded as they did not have electrographic seizures; from 6 participants only verbal not written consent obtained.
Participants by arm
| Arm | Count |
|---|---|
| Intravenous Levetiracetam Intravenous levetiracetam 40 to 60 mg/kg loading dose. 10 mg/kg 8 hourly maintenance
Intravenous levetiracetam: Intravenous load of levetiracetam (40 to 60 mg/kg) following identification of EEG confirmed neonatal seizure. | 64 |
| Intravenous Phenobarbital Intravenous phenobarbital 20 to 40 mg/kg load. 1.5 mg/kg 8 hourly maintenance
Intravenous phenobarbital: Intravenous load of phenobarbital (20 to 40 mg/kg) following EEG confirmation of seizure activity load. | 42 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Intravenous Levetiracetam | Intravenous Phenobarbital | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 64 Participants | 42 Participants | 106 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 10 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 25 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 7 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 7 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 10 Participants | 23 Participants |
| Race (NIH/OMB) White | 34 Participants | 25 Participants | 59 Participants |
| Region of Enrollment New Zealand | 19 participants | 12 participants | 28 participants |
| Region of Enrollment United States | 45 participants | 30 participants | 53 participants |
| Sex: Female, Male Female | 33 Participants | 18 Participants | 51 Participants |
| Sex: Female, Male Male | 31 Participants | 24 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 42 | 2 / 64 |
| other Total, other adverse events | 13 / 42 | 12 / 64 |
| serious Total, serious adverse events | 5 / 42 | 1 / 64 |
Outcome results
Primary
Neonates With Seizure Cessation When Given Levetiracetam (40-60 mg/kg) as First Line Therapy Compared to Phenobarbital (20-40mg/kg)
A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures. Seizure cessation from 15 minutes after completion of infusion for 24 hours as assessed by continuous EEG reviewed by neurophysiologists.
Time frame: 24 hours
Population: Treated participants with available primary outcome measure- EEG to 24 hours confirming seizure cessation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Levetiracetam | Neonates With Seizure Cessation When Given Levetiracetam (40-60 mg/kg) as First Line Therapy Compared to Phenobarbital (20-40mg/kg) | 15 Participants |
| Intravenous Phenobarbital | Neonates With Seizure Cessation When Given Levetiracetam (40-60 mg/kg) as First Line Therapy Compared to Phenobarbital (20-40mg/kg) | 24 Participants |
Comparison: Comparison of 24 hour seizure termination rates using a Fisher's exact test.p-value: <0.001Fisher Exact
Secondary
LEV Dose Escalation Component
Number of babies with seizure control at levetiracetam (60 mg/Kg load) who had not responded to 40 mg/kg load and number of babies with seizure control at 40 mg/kg who had not responded to 20 mg/kg.
Time frame: 24 hours
Population: Babies who received any treatment of either phenobarbital or levetiracetam within the modified intent to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Levetiracetam | LEV Dose Escalation Component | 4 Participants |
| Intravenous Phenobarbital | LEV Dose Escalation Component | 3 Participants |
Secondary
Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital at 48 Hours After Treatment
A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures.
Time frame: 48 hours
Population: Participants with evaluable data with 48 hours of seizure monitoring
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Levetiracetam | Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital at 48 Hours After Treatment | 8 Participants |
| Intravenous Phenobarbital | Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital at 48 Hours After Treatment | 18 Participants |
Comparison: Comparison of seizure cessation at 48 hours using Fisher's exact testp-value: <0.001Fisher Exact
Secondary
Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital Within the Hypoxic Ischemic Encephalopathy (HIE) Population and Treated With Hypothermia
Time frame: 24 hours
Population: HIE participants with hypothermia treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Levetiracetam | Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital Within the Hypoxic Ischemic Encephalopathy (HIE) Population and Treated With Hypothermia | 6 Participants |
| Intravenous Phenobarbital | Neonates With Seizure Cessation When Given Levetiracetam as First Line Therapy Compared to Phenobarbital Within the Hypoxic Ischemic Encephalopathy (HIE) Population and Treated With Hypothermia | 9 Participants |
Secondary
Number of Neonates With Seizure Termination at 1 Hour After Treatment
A head to head comparison of the efficacy of intravenous levetiracetam versus phenobarbital in the treatment of EEG proven neonatal seizures.
Time frame: 1 hour
Population: Includes 1 participant in each arm who did not have data available for the primary end point at 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Levetiracetam | Number of Neonates With Seizure Termination at 1 Hour After Treatment | 26 Participants |
| Intravenous Phenobarbital | Number of Neonates With Seizure Termination at 1 Hour After Treatment | 28 Participants |
Other Pre-specified
Evaluation of the Accuracy of Neonatal Seizure Detection Algorithm
A novel neonatal seizure detection algorithm will be compared to the gold standard of two encephalographers reading 48 hours of neonatal video EEG in the measurement of seizure burden.
Time frame: 48 Hours
Other Pre-specified
Feasibility of Continuous Internet EEG Monitoring
Feasibility of centralized remote access to continuous video EEG monitoring in the NICU via the internet
Time frame: Subject study duration
Other Pre-specified
Gather Safety Information on IV Levetiracetam
Safety information to be collected includes daily recording of any adverse events during the 5 day treatment protocol. Complete Blood Count and Comprehensive Chemistry panels after 48 hours of treatment collected.
Time frame: 5 days
Post Hoc
Imputation Sensitivity Analysis
Analysis of missing data impact on the outcome measures
Time frame: 48 hours
Other Pre-specified
Pharmacokinetic Data
To obtain additional pharmacokinetic data Area under the plasma concentration versus time curve (AUC) and Peak Plasma Concentration (Cmax) of intravenous levetiracetam to confirm findings from our previous pharmacokinetic study.
Time frame: 48 hours