An Early Phase 1 interventional study of Melatonin and Magnetic Resonance Imaging in Hypoxic Ischemic Encephalopathy, sponsored by University of Florida. Recruiting at 2 sites in United States. Open to participants aged Up to 6 Hours. Per ClinicalTrials.gov, last updated 2026-06-29.
Sponsored by University of Florida · Early Phase 1, Interventional, and Treatment
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.
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.
234 studies on the registry are indexed under Hypoxia-Ischemia, Brain; 83 are open to participants now.
This study's planned enrollment of 70 is above the median of 50 across 135 interventional studies indexed under Hypoxia-Ischemia, Brain.
Browse Hypoxia-Ischemia, Brain studies →University of Florida is the lead sponsor of 1,254 studies on the registry; 201 are open to participants now.
Of its 170 completed or terminated interventional studies of FDA-regulated products, 136 (80%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
This group will receive a 0.5 mg/kg enteral dose of Melatonin. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.
Drug: Melatonin · Other: Magnetic Resonance Imaging · Other: Pharmacokinetics · Behavioral: Neurological Outcome Assessment
This group will the Melatonin dose of 3 mg/kg enteral, only if the group Participants 1-10 has meet the safety goals. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.
Drug: Melatonin · Other: Magnetic Resonance Imaging · Other: Pharmacokinetics · Behavioral: Neurological Outcome Assessment
This group will receive Melatonin dose of 5 mg/kg enterally, only if the group Participants 11-20 has meet the safety goals. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.
Drug: Melatonin · Other: Magnetic Resonance Imaging · Other: Pharmacokinetics · Behavioral: Neurological Outcome Assessment
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.
All participants will receive an MRI between 7-12 days of age.
Also known as: MRI
All participants will receive pharmacokinetics to test the amount of melatonin in the blood.
All participants will receive the Bayley-III Scores and Subsets for neurological outcome assessments.
To identify the maximum tolerated dose of Melatonin
The maximum tolerated dose (MTD) is defined as the highest dose level without adverse events in no more than 1 out of 6 patients
Time frame: Changes in Baseline to day 3
Bayley-III Index Scores (Cognitive, Language, and Motor) will be used for neurological outcome assessment
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".
Time frame: Approximately 18 - 20 Months
Peak Plasma Concentration (Cmax) of Melatonin 0.5 mg/kg.
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.
Time frame: 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
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.
Incidence/Grade of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), laboratory abnormalities Percentage and number of subjects who discontinued for adverse event
Time frame: Baseline ongoing to Day 14
Peak Plasma Concentration (Cmax) of Melatonin 3 mg/kg.
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.
Time frame: 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
Peak Plasma Concentration (Cmax) of Melatonin 5 mg/kg.
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.
Time frame: 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment
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".
Time frame: Approximately 18 - 20 Months
Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI)
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).
Time frame: Approximately 7 - 12 days
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
Contact study teamGet an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
University of Florida