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Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

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ClinicalTrials.gov Identifier: NCT02621944
Recruitment Status : Recruiting
First Posted : December 4, 2015
Last Update Posted : February 16, 2018
Sponsor:
Collaborator:
Thrasher Research Fund
Information provided by (Responsible Party):
University of Florida

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.

Condition or disease Intervention/treatment Phase
Hypoxic Ischemic Encephalopathy Drug: Melatonin Other: Magnetic Resonance Imaging Other: Pharmacokinetics Behavioral: Neurological Outcome Assessment Behavioral: Generalized Motor Assessment Early Phase 1

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia
Study Start Date : November 2016
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hypothermia
Drug Information available for: Melatonin

Arm Intervention/treatment
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, Generalized Motor Assessment (GMA), 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 Name: 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.

Behavioral: Generalized Motor Assessment
All participants will receive the GMA assessment.
Other Name: GMA

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, Generalized Motor Assessment (GMA), 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 Name: 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.

Behavioral: Generalized Motor Assessment
All participants will receive the GMA assessment.
Other Name: GMA

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, Generalized Motor Assessment (GMA), 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 Name: 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.

Behavioral: Generalized Motor Assessment
All participants will receive the GMA assessment.
Other Name: GMA




Primary Outcome Measures :
  1. 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

  2. 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".

  3. 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.

  4. 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

  5. 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.

  6. 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.


Secondary Outcome Measures :
  1. 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".

  2. Generalized Motor Assessment (GMA) [ Time Frame: Months 3 and 23 ]
    The GMA has a high sensitivity and specify in predicting the presence of CP at 23 months of age. Subjects will be videotaped at a clinic visit for at least 30 minutes after a feed and several minutes during periods of wakefulness. Movements will be classified using the Prechtl method.

  3. 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 6 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02621944


Contacts
Contact: Livia Sura, MPH, CPH 3522738706 livia.sura@peds.ufl.edu
Contact: Kristine Boykin, BSN 3522738706 kristineboykin@ufl.edu

Locations
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Kristine L Boykin, BSN    352-273-8985    kristineboykin@ufl.edu   
Contact: Michael Weiss, MD    3522738985    weissmd@peds.ufl.edu   
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         
Florida Hospital for Children Recruiting
Orlando, Florida, United States, 32803
Contact: Rajan Wadhawan, M.D.    407-303-2528    Rajan.Wadhawan.MD@flhosp.org   
Principal Investigator: Rajan Wadhawan, MD         
Sponsors and Collaborators
University of Florida
Thrasher Research Fund
Investigators
Principal Investigator: Michael D Weiss, MD University of Florida

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02621944     History of Changes
Other Study ID Numbers: IRB201500886
First Posted: December 4, 2015    Key Record Dates
Last Update Posted: February 16, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Hypothermia
Brain Diseases
Brain Ischemia
Hypoxia-Ischemia, Brain
Body Temperature Changes
Signs and Symptoms
Central Nervous System Diseases
Nervous System Diseases
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Hypoxia, Brain
Melatonin
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Central Nervous System Depressants