Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- University of Florida
- Enrollment
- 70
- Locations
- 4
- Primary Endpoint
- To identify the maximum tolerated dose of Melatonin
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- — to 6 Hours (Child)
- Sex
- All
- Accepts 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.
Arms & Interventions
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.
Intervention: Melatonin (Drug)
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.
Intervention: Melatonin (Drug)
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.
Intervention: Melatonin (Drug)
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.
Intervention: Magnetic Resonance Imaging (Other)
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.
Intervention: Pharmacokinetics (Other)
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.
Intervention: Neurological Outcome Assessment (Behavioral)
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.
Intervention: Magnetic Resonance Imaging (Other)
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.
Intervention: Pharmacokinetics (Other)
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.
Intervention: Neurological Outcome Assessment (Behavioral)
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.
Intervention: Magnetic Resonance Imaging (Other)
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.
Intervention: Pharmacokinetics (Other)
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.
Intervention: Neurological Outcome Assessment (Behavioral)
Outcomes
Primary Outcomes
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
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".
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
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.
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.
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.
Secondary Outcomes
- Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment(Approximately 18 - 20 Months)
- Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI)(Approximately 7 - 12 days)