Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

June 25, 2026 updated by: University of Florida
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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
70

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

  • Name: Alison A McMurray, M.A.M.C.
  • Phone Number: 3526275016
  • Email: amcmurra@ufl.edu

Study Locations

  • United States
    • Florida
      • Gainesville, Florida, United States, 32610
        • Recruiting
        • University of Florida
        • Contact:
        • Principal Investigator:
          • Michael D Weiss, MD
        • Principal Investigator:
          • Giuseppe Buonocore, MD
        • Sub-Investigator:
          • Candace Rossignol, Sr. Lab Tech
        • Sub-Investigator:
          • Ronald Hayes, MD
        • Sub-Investigator:
          • Kristine Boykin, BSN
        • Principal Investigator:
          • Rajan Wadhawan, MD
        • Sub-Investigator:
          • Nicole Copenhaver, BA, ASN
        • Sub-Investigator:
          • Ganna Zalevska, BS, RRT
        • Contact:
          • Alison A McMurray, M.A.M.C.
          • Phone Number: 352-627-5016
          • Email: amcmurra@ufl.edu
      • Orlando, Florida, United States, 32803
        • Recruiting
        • Florida Hospital for Children
        • Principal Investigator:
          • Rajan Wadhawan, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

No older than 6 hours (Child)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Participants 1-10

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
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.
Other: Magnetic Resonance Imaging
All participants will receive an MRI between 7-12 days of age.
Other Names:
  • MRI
Other: Pharmacokinetics
All participants will receive pharmacokinetics to test the amount of melatonin in the blood.
Behavioral: Neurological Outcome Assessment
All participants will receive the Bayley-III Scores and Subsets for neurological outcome assessments.
Experimental: Participants 11-20

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
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.
Other: Magnetic Resonance Imaging
All participants will receive an MRI between 7-12 days of age.
Other Names:
  • MRI
Other: Pharmacokinetics
All participants will receive pharmacokinetics to test the amount of melatonin in the blood.
Behavioral: Neurological Outcome Assessment
All participants will receive the Bayley-III Scores and Subsets for neurological outcome assessments.
Experimental: Participants 21-30

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
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.
Other: Magnetic Resonance Imaging
All participants will receive an MRI between 7-12 days of age.
Other Names:
  • MRI
Other: Pharmacokinetics
All participants will receive pharmacokinetics to test the amount of melatonin in the blood.
Behavioral: Neurological Outcome Assessment
All participants will receive the Bayley-III Scores and Subsets for neurological outcome assessments.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
To identify the maximum tolerated dose of Melatonin
Time Frame: 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
Changes in Baseline to day 3
Bayley-III Index Scores (Cognitive, Language, and Motor) will be used for neurological outcome assessment
Time Frame: 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".
Approximately 18 - 20 Months
Peak Plasma Concentration (Cmax) of Melatonin 0.5 mg/kg.
Time Frame: 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.
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.
Time Frame: 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
Baseline ongoing to Day 14
Peak Plasma Concentration (Cmax) of Melatonin 3 mg/kg.
Time Frame: 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.
0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
Peak Plasma Concentration (Cmax) of Melatonin 5 mg/kg.
Time Frame: 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.
0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment
Time Frame: 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".
Approximately 18 - 20 Months
Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI)
Time Frame: 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).
Approximately 7 - 12 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Florida

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Thrasher Research Fund

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Michael D Weiss, MD, University of Florida

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 9, 2016

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 1, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 19, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 1, 2015

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 4, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 29, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 25, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IRB201500886

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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