Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

Hypoxic Ischemic Encephalopathy Clinical Trial

Official title:

Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02621944
• Other study ID #: IRB201500886
• Status: Recruiting
• Phase: Early Phase 1
• Start date: November 2016
• Est. completion date: March 2025

Study information

• Verified date: May 2023
• Source: University of Florida
• Contact: Livia Sura, MPH, CPH
• Phone: 3522738706
• Email: livia.sura[@]peds.ufl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: March 2025
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 6 Hours

Eligibility

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.

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Hypothermia
• Hypoxia-Ischemia, Brain
• Hypoxic Ischemic Encephalopathy

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	University of Florida	Gainesville	Florida
United States	Florida Hospital for Children	Orlando	Florida

Sponsors (2)

Lead Sponsor	Collaborator
University of Florida	Thrasher Research Fund

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Changes in Baseline to day 3
Primary	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".	Approximately 18 - 20 Months
Primary	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.	0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
Primary	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	Baseline ongoing to Day 14
Primary	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.	0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
Primary	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.	0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
Secondary	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".	Approximately 18 - 20 Months
Secondary	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).	Approximately 7 - 12 days