Neonatal Seizures
Conditions
Keywords
phenobarbital, neonate, antiepileptic drugs, neurodevelopmental outcome, seizure
Brief summary
The treatment of infants with medications after their seizures have stopped is very variable. No one knows if continuing treatment with phenobarbital for up to several months is helpful or harmful. This clinical trial is designed to help answer that question and provide data that will help determine standard of care for these children.
Detailed description
The treatment of infants with antiepileptic medications after the resolution of neonatal seizures is highly variable and controversial. Infants are commonly treated with phenobarbital after their seizures have resolved to prevent recurrence. Data to support this practice are lacking but animal models suggest that the neonatal brain is vulnerable to repeated seizures. Yet exposure of the developing brain to phenobarbital for prolonged periods may have deleterious consequences. We are proposing a multi-center, randomized, clinical trial (RCT) to determine if continued treatment with phenobarbital reduces seizure recurrence without adversely affecting neurodevelopmental outcome or if infants' outcomes are improved if no prophylactic medication is given. We will identify infants with seizures beginning in the first week that resolve within 7 days and randomize them to receive phenobarbital or placebo daily for four months. Via visits and frequent telephone contacts over the first six months, we will determine the rate of seizure recurrence. The primary outcome, neurodevelopmental status, will be assessed at 18-22 months using the Bayley Scales of Infant Development. Additional subgroup analyses are planned to determine the contribution of seizure etiology to outcome and predictive value of initial EEG classification. The trial will be conducted at 18 - 20 sites, chosen for their experience and proven track record for enrollment and retention in this specific population. The trial will be coordinated by the Clinical Trials Coordination Center at the University of Rochester and overseen by a Steering Committee composed of experienced trialists representing neonatology and pediatric neurology, biostatistics, and clinical trial administration. Extrapolation from the results of an RCT of phenobarbital prophylaxis after febrile seizures in children suggests that phenobarbital may adversely affect brain development and may be ineffective in preventing seizures. Based on this previous RCT that resulted in near universal change in practice (the elimination of prolonged use of phenobarbital after simple febrile seizures), we anticipate that the data we generate may have a similar impact on standard of care for infants with neonatal seizures.
Interventions
DRUGphenobarbital
Phenobarbital, 4-5 mg/kg/d, by mouth, for 4 months
DRUGplacebo
Matched placebo, same volume as active drug, by mouth daily for 4 months
Sponsors
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Days to 2 Weeks
Healthy volunteers
No
Inclusion criteria
* Birth at \> 34 weeks' gestation * Neonatal seizures (clinical, electrographic or both), with onset in the first 120 hours after birth and resolution within 7 days of onset * Parental informed consent
Exclusion criteria
* Birth at \< 34 weeks' gestation * If the attending neonatologist attributes the seizures solely to a transient abnormality, easily correctable and unlikely to recur (eg, transient electrolyte abnormalities). If the attending neonatologist cannot be contacted, the site PI will be asked to review the available information and judge whether the infant is eligible. * If the infant has been diagnosed with or there is a strong suspicion of an inborn error of metabolism, significant brain malformation, microcephaly (\< 3 %ile), or a chromosomal abnormality which, in the absence of seizures, is known to be independently associated with an increased likelihood of cognitive impairment * If the infant has been diagnosed with an intrauterine viral infection * If the infant is not expected to survive to discharge
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Bayley Scales of Infant Development (BSID) Score - Cognitive | 18-22 months | The Bayley Scales of Infant Development (BSID) measure the mental and motor development and test the behavior of infants from one to 42 months of age. The test is intended to measure a child's level of development in three domains: cognitive, motor, and behavioral. The primary outcome is the Bayley assessment of development at 2 years of age. This is a standardized developmental exam that is normalized to the age of the child in months. The mean adjusted score is 100 with a standard deviation of 15 (higher being better) - very similar to the more familiar IQ score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Bayley Scales of Infant Development (BSID) Score - Motor | 18-22 months | This part of the BSID assesses the degree of body control, large muscle coordination, finer manipulatory skills of the hands and fingers, dynamic movement, postural imitation, and the ability to recognize objects by sense of touch. |
| Number of Participants With One or More Seizures | 18-22 months | Any clinical or electrographic seizures occurring between study entry and all follow-up examinations and contacts. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phenobarbital Phenobarbital, 4-5 mg/kg/day, for 4 months
phenobarbital: Phenobarbital, 4-5 mg/kg/d, by mouth, for 4 months | 8 |
| Placebo Placebo in a volume equivalent to active drug for 4 months
placebo: Matched placebo, same volume as active drug, by mouth daily for 4 months | 5 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Phenobarbital | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 8 Participants | 5 Participants | 13 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 8 participants | 5 participants | 13 participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 8 | 5 / 5 |
| serious Total, serious adverse events | 1 / 8 | 1 / 5 |
Outcome results
Primary
Mean Bayley Scales of Infant Development (BSID) Score - Cognitive
The Bayley Scales of Infant Development (BSID) measure the mental and motor development and test the behavior of infants from one to 42 months of age. The test is intended to measure a child's level of development in three domains: cognitive, motor, and behavioral. The primary outcome is the Bayley assessment of development at 2 years of age. This is a standardized developmental exam that is normalized to the age of the child in months. The mean adjusted score is 100 with a standard deviation of 15 (higher being better) - very similar to the more familiar IQ score.
Time frame: 18-22 months
Population: Due to low enrollment, there was limited data available for analysis and therefore insufficient power to provide meaningful results for our primary or secondary analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phenobarbital | Mean Bayley Scales of Infant Development (BSID) Score - Cognitive | 87.50 units on a scale | Standard Deviation 11.9 |
| Placebo | Mean Bayley Scales of Infant Development (BSID) Score - Cognitive | 92.50 units on a scale | Standard Deviation 26.61 |
Secondary
Mean Bayley Scales of Infant Development (BSID) Score - Motor
This part of the BSID assesses the degree of body control, large muscle coordination, finer manipulatory skills of the hands and fingers, dynamic movement, postural imitation, and the ability to recognize objects by sense of touch.
Time frame: 18-22 months
Population: Due to low enrollment, there was limited data available for analysis and therefore insufficient power to provide meaningful results for our primary or secondary analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phenobarbital | Mean Bayley Scales of Infant Development (BSID) Score - Motor | 82.80 units on a scale | Standard Deviation 24.59 |
| Placebo | Mean Bayley Scales of Infant Development (BSID) Score - Motor | 83.75 units on a scale | Standard Deviation 20.65 |
Secondary
Number of Participants With One or More Seizures
Any clinical or electrographic seizures occurring between study entry and all follow-up examinations and contacts.
Time frame: 18-22 months
Population: Due to low enrollment, there was limited data available for analysis and therefore insufficient power to provide meaningful results for our primary or secondary analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenobarbital | Number of Participants With One or More Seizures | 2 participants |
| Placebo | Number of Participants With One or More Seizures | 1 participants |