Disorder of Fetus or Newborn, Seizures
Conditions
Keywords
Neonatal seizures
Brief summary
The hypothesis is that a loading dose of 20 mg/kg and a maintenance dose of 5 mg/kg of Levetiracetam is going to be safe and effective in the treatment of seizures in neonates.
Detailed description
In adults, drug clearance is less than half of the glomerular filtration rate and the drug half-life is 6-8 hours. Renal function in infants at birth is characterized by immature glomerular filtration and is only 20% that of older children. The specific esterase responsible for levetiracetam hydrolysis has not been identified and its expression in newborn infants is unknown. Depending on its activity, the expected infant total levetiracetam clearance will likely be between 15-45% of older populations. However, due to immaturity in levetiracetam clearance in infants, accumulation with multiple dosing is possible. Therefore the maintenance dose is reduced compared to older children according to the anticipated impaired clearance. These anticipated differences in levetiracetam clearance and volume of distribution, will likely result in a prolonged drug half-life of 10-30 hours in infants. This prolonged elimination will require longer sampling to adequately characterize levetiracetam pharmacodynamics in this population. The primary intent of the data analysis is to determine levetiracetam pharmacokinetics in newborn infants and predict the dosage necessary to maintain concentrations similar to those seen with effective therapy in other populations. Graphs of serum concentration vs. time will be plotted for levetiracetam for each infant. Mean serum drug concentration vs. time curves will also be constructed. Summary statistics (i.e., n, mean, standard deviation, minimum, maximum, and coefficient of variation) will be calculated for serum concentrations for each time point and each dose level.
Interventions
20 mg/kg loading dose; 5 mg/kg daily for 7 days.
DRUGHigh dose levetiracetam
40 mg/kg IV load; 10 mg/kg/day maintenance
Sponsors
Thrasher Research Fund
Richard H. Haas
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Minutes to 14 Days
Healthy volunteers
No
Inclusion criteria
* Newborns admitted to the UCSD, Children's Hospital or Sharp Mary Birch NICUs with seizures. * Term infants (gestational age greater than or equal to 37 weeks. * \> 2500 grams (max blood for study 6mL =3%). * Postnatal age 14 days or less. * Serum creatinine less than 1.2 at time of enrollment. * Received loading dose of phenobarbital 20mg/kg. * Are still experiencing either clinical or electroencephalographic seizures despite this therapy. * For whom parental consent to participate in the study is obtained.
Exclusion criteria
* Biochemical abnormality - hypoglycemia, hypocalcemia-that when treated result in seizure cessation. * Severe hypoxic ischemic injury likely to result in imminent death * The only significant exclusions that will be made in recruitment and enrollment will be the exclusion of infants who are judged by the attending neonatologist to be so critically ill that death is imminent and benefit from neonatal intensive care is very unlikely. * No rule-based criteria, (using lab or clinical parameters) adequately capture the complete nature of this clinical assessment. * In general any child receiving active treatment with head cooling will not be excluded. * Mechanical ventilation and/or the use of inotropic agents to support blood pressure will not be
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Drug Clearance | Day 1 and Day 7 |
| Drug Half Life | Day 1 and Day 7 |
Secondary
| Measure | Time frame |
|---|---|
| Levetiracetam Treated Number of Participants With Serious Adverse Events | 7 Days |
Countries
United States
Participant flow
Recruitment details
Recruitment over 2 years from neonatal intensive care units
Participants by arm
| Arm | Count |
|---|---|
| Levetiracetam Dose Escalation Escalation of dose after 6 patients treated to 40 mg/kg IV load and 10mg/kg/day maintenance
levetiracetam : 20 mg/kg loading dose; 5 mg/kg daily for 7 days.
levetiracetam : 40 mg/kg IV load; 10 mg/kg/day maintenance | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Levetiracetam Dose Escalation |
|---|---|
| Age, Categorical <=18 years | 18 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 2.44 Days STANDARD_DEVIATION 1.38 |
| Region of Enrollment New Zealand | 5 participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 7 / 18 |
| serious Total, serious adverse events | 1 / 18 |
Outcome results
Primary
Drug Clearance
Time frame: Day 1 and Day 7
Population: Subjects were grouped together to improve the reliability of the analysis. The publication of these results reported a grouped analysis because of the small number of subjects in the low dose group, The groups were not analyzed individually.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Drug Clearance | Day 1 | 0.71 ml/min/kg | Standard Deviation 0.27 |
| All Participants | Drug Clearance | Day 7 | 1.31 ml/min/kg | Standard Deviation 0.35 |
Primary
Drug Half Life
Time frame: Day 1 and Day 7
Population: Subjects were grouped together to improve the reliability of the analysis. The publication of these results reported a grouped analysis because of the small number of subjects in the low dose group, The groups were not analyzed individually.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Drug Half Life | Day 1 | 18.5 hr | Standard Deviation 7.1 |
| All Participants | Drug Half Life | Day 7 | 9.1 hr | Standard Deviation 2 |
Secondary
Levetiracetam Treated Number of Participants With Serious Adverse Events
Time frame: 7 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Levetiracetam Treated Number of Participants With Serious Adverse Events | 0 Participants |
| Levetiracetam High Dose | Levetiracetam Treated Number of Participants With Serious Adverse Events | 1 Participants |