Hypoxic Ischemic Encephalopathy
Conditions
Brief summary
Hypoxic-Ischemic Encephalopathy (HIE) occurs in 20 per 1000 births. Only 47% of neonates treated with the state of the art therapy (induced systemic hypothermia) have normal outcomes. Therefore, other promising therapies that potentially work in synergy with hypothermia to improve neurologic outcomes need to be tested. One potential agent is melatonin. Melatonin is a naturally occurring substance produced mainly from the pineal gland. Melatonin is widely known for its role in regulating the circadian rhythm, but it has many other effects that may benefit infants with HI injury. Melatonin serves as a free radical scavenger, decreases inflammatory cytokines, and stimulates anti-oxidant enzymes. Therefore, melatonin may interrupt several key components in the pathophysiology of HIE, in turn minimizing cell death and improving outcomes. The research study will evaluate the neuroprotective properties and appropriate dose of Melatonin to give to infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.
Detailed description
Thirty subjects will be enrolled in a dose escalation study. Subjects 1-10 will receive melatonin (0.5 mg/kg). If that dose proves to be safe, subjects 11-20 will receive an increased dose of melatonin (3 mg/kg). Subjects 21-30 will receive a dose increased to the targeted projected therapeutic dose (5 mg/kg). The serum concentration of melatonin and capture adverse event reports during this dose escalation study in neonates undergoing hypothermia and the long-term safety and potential efficacy via developmental follow-up performed at 18-22 months of age. In addition, this study will determine the effect of melatonin on the inflammatory cascade, oxidative stress, free radical production, and serum biomarkers of brain injury in neonates undergoing hypothermia.
Interventions
DRUGMelatonin
Participants 1-10 will receive a 0.5 mg/kg enteral dose of Melatonin. Participants 11-20 will receive Melatonin dose of 3 mg/kg enteral. Participants 21-30 will receive Melatonin dose of 5 mg/kg enterally.
OTHERMagnetic Resonance Imaging
All participants will receive an MRI between 7-12 days of age.
OTHERPharmacokinetics
All participants will receive pharmacokinetics to test the amount of melatonin in the blood.
BEHAVIORALNeurological Outcome Assessment
All participants will receive the Bayley-III Scores and Subsets for neurological outcome assessments.
Sponsors
University of Florida
Thrasher Research Fund
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Years
Healthy volunteers
No
Inclusion criteria
* Eligible infants are \>36 0/7th weeks gestation, * pH (cord or neonatal) \<7.0, * base deficit \>16 mEq/L, * no available blood gas, * a cord blood/first hour of life blood gas with pH \> 7.0 and \< 7.15, * base deficit between 10 and 15.9 mEq/L, * infants must have a history of an acute perinatal event, * either a 10-minute Apgar \< 5 or a continued need for ventilation, * All infants must have signs of encephalopathy within 6 hours of age using the modified Sarnat scoring system, * neonates cooled within 6 hours of birth will be included in the study.
Exclusion criteria
* suspected inborn errors of metabolism (elevated ammonia) and hypoglycemia, * clinical signs and symptoms consistent with meningitis detected upon sepsis evaluation, * a diagnosis of congenital abdominal surgical problems along with multiple congenital anomalies and/or chromosomal abnormalities.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To identify the maximum tolerated dose of Melatonin | Changes in Baseline to day 3 | The maximum tolerated dose (MTD) is defined as the highest dose level without adverse events in no more than 1 out of 6 patients |
| Bayley-III Index Scores (Cognitive, Language, and Motor) will be used for neurological outcome assessment | Approximately 18 - 20 Months | All raw scores will be transformed into norm-referenced standard scores (scale mean = 100 with s.d. = 15) using the Bayley-III scoring software published with the test. To dichotomize "good" and "poor" outcomes for statistical analysis, standardized scores that are at or greater than one standard deviation below the normative sample mean published with the test (i.e., standard scores \< 85) will be classified as "poor outcome" while higher scores will be classified as "good outcome". |
| Peak Plasma Concentration (Cmax) of Melatonin 0.5 mg/kg. | 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample) | HPLC-ESI/MS/MS will be used to measure melatonin concentrations in the serum samples. The two-way ANOVA (treatments are dose level and timepoint) framework for testing. Testing will be done using a likelihood ratio test, either using large-sample theory approximation or using bootstrap. |
| Number of participants with treatment-related adverse events as assessed by MedDRA ??? This is something the PI/Team needs to agree on which one to use. | Baseline ongoing to Day 14 | Incidence/Grade of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), laboratory abnormalities Percentage and number of subjects who discontinued for adverse event |
| Peak Plasma Concentration (Cmax) of Melatonin 3 mg/kg. | 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample) | HPLC-ESI/MS/MS will be used to measure melatonin concentrations in the serum. The two-way ANOVA (treatments are dose level and timepoint) framework for testing. Testing will be done using a likelihood ratio test, either using large-sample theory approximation or using bootstrap. |
| Peak Plasma Concentration (Cmax) of Melatonin 5 mg/kg. | 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample) | HPLC-ESI/MS/MS will be used to measure melatonin concentrations in the serum samples. The two-way ANOVA (treatments are dose level and timepoint) framework for testing. Testing will be done using a likelihood ratio test, either using large-sample theory approximation or using bootstrap. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment | Approximately 18 - 20 Months | The four performance-based subscales of the Bayley-III Index Scores (Receptive and Expressive Language, Fine and Gross Motor) and two parent-reported scales (Social-Emotional and Adaptive Behavior) will be collected. All raw scores will be transformed into norm-referenced standard scores (scale mean = 100 with s.d. = 15) using the Bayley-III scoring software published with the test. To dichotomize "good" and "poor" outcomes for statistical analysis, standardized scores that are at or greater than one standard deviation below the normative sample mean published with the test (i.e., standard scores \< 85) will be classified as "poor outcome" while higher scores will be classified as "good outcome". |
| Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI) | Approximately 7 - 12 days | The MRI study scores of neonates treated with hypothermia plus melatonin will be compared with historical controls that have matched Sarnat exams (exam of HIE severity at the time of admission). |
Countries
United States
Contacts
CONTACTAlison A McMurray, M.A.M.C.
CONTACTKristine Boykin, BSN
PRINCIPAL_INVESTIGATORMichael D Weiss, MD
University of Florida
Outcome results
None listed