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Use of Melatonin for Neuroprotection in Asphyxiated Newborns (MELPRO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03806816
Recruitment Status : Recruiting
First Posted : January 16, 2019
Last Update Posted : October 11, 2019
AUSL Romagna Rimini
Information provided by (Responsible Party):
Anna Tarocco, University Hospital of Ferrara

Brief Summary:

Protection of brain development is a major aim in the Neonatal Intensive Care Unit. Hypoxic-Ischemic Encephalopathy (HIE) occurs in 3-5 per 1000 births. Only 47% of neonates have normal outcomes. The neurodevelopmental consequences of brain injury for asphyxiated term infants include cerebral palsy, severe intellectual disabilities and also a number of minor behavioural and cognitive deficits. However, there are very few therapeutic strategies for the prevention or treatment of brain damage. The gold standard is hypothermic treatment but, according to the literature, melatonin potentially acts in synergy with hypothermia for neuroprotection and to improve neurologic outcomes. Melatonin appears to be a good candidate because of its different protective effects including reactive oxygen species scavenging, excitotoxic cascade blockade, modulation of neuroinflammatory pathways.

The research study will evaluate the neuroprotective properties and the effects of Melatonin in association with therapeutic hypothermia for hypoxic ischemic encephalopathy.

Condition or disease Intervention/treatment Phase
Hypoxic-Ischemic Encephalopathy Cell Damage Asphyxia Perinatal Dietary Supplement: Melatonin Other: PLACEBO group Not Applicable

Detailed Description:

It is a randomized double blind, placebo controlled trial on 100 neonates with moderate to moderately to severe hypoxic ischemic encephalopathy (HIE) . HIE infants are randomized into two groups: Whole body cooling group (N = 50 receive 72 hours of whole body hypothermia) and melatonin/ hypothermia group (N = 50; receive hypothermia and 5 daily enteral doses of melatonin 10 mg/kg). Serum melatonin and autophagy levels are measured at enrollment, daily during the hypothermic treatment, at day 5 and 7 for the two HIE groups.

aEEG will be performed for 72 hrs during the hypothermic treatment and the re-warming. MRI and Spectroscopy analysis will be performed between day 5 and 7 of. After hospital discharge the infants will enter a follow-up program consisting in periodic clinical and developmental assessments until 2 years of age corrected for prematurity. An expert psychologist and a neonatologist will assess neurodevelopmental outcome using the Bayley Scales III at 6-12-24 months of corrected age.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Use of Melatonin for Neuroprotection in Term Infants With Hypoxic-ischaemic Encephalopathy
Actual Study Start Date : December 13, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Melatonin

Arm Intervention/treatment
Experimental: HYPOTHERMIA / MELATONIN group
HIE infants who will receive melatonin in addition to the routine cooling treatment
Dietary Supplement: Melatonin
5 daily enteral doses of melatonin 10 mg/kg. (=2 ml/kg)
Other Name: Buona Circadiem

Experimental: HYPOTHERMIA / PLACEBO group
HIE infants who will not receive melatonin in addition to the routine cooling treatment
Other: PLACEBO group
5 daily enteral doses of placebo 2 ml/kg
Other Name: placebo

Primary Outcome Measures :
  1. Bayley III scale [ Time Frame: 12 months ]

    Bayley scale of infant and toddler development. It measures developmental skills reached by infant and young children between 1 month and 42 months The scale is subdivided into 5 subscales Cognitive,Receptive communication,Expressive communication,Fine motor ,Gross motor.Receptive and expressive communication have a composite in language score So as fine and gross motor in motor score For all subtests raw scores correspond to scaled scores ranging from 1 to 19 with a mean of 10 and SD of 3 The composite scores are given by the sum of the corresponding subtests scaled scores.

    Two parent-reported scales (Social-Emotional and Adaptive Behavior) will be collected.

Secondary Outcome Measures :
  1. brain MRI [ Time Frame: between the 5th and 7th days of life ]
    to evaluate the presence of deep grey matter, PLIC, white matter, brainstem and hippocampus lesions

  2. continuous aEEG [ Time Frame: Continuous monitoring for the first 72 hours and for the rewarmed ]
    Al Naqueeb classification for aEEG will be used.Background voltage pattern will be scored in NORMAL (Lower margin >5μV,Upper margin >10μV The activity is continuous), MODERATELY ABORMAL (Lower margin <5μV, upper margin >10μV,The activity is moderately discontinuous)SEVERELY ABNORMAL/ SUPPRESSED (Lower margin <5μV, upper margin <10μV)

  3. Plasma Concentration of Melatonin [ Time Frame: at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life ]
    UPLC-Massa Acquity-Xevo TQD (Waters) will be used to measure melatonin concentrations in the plasma

  4. ATG5 Plasma concentration [ Time Frame: at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life ]
    ELISA test will be used to measure plasma levels of ATG5

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

Inclusion Criteria:

  • gestational age > 35 weeks and weight > 1800 gr
  • Apgar score < 5 at 10 minutes o need for cardiopulmonary resuscitation at 10 minutes or evidence of base excess > 12 mmol/L or pH < 7,0 at initial blood gas analyses
  • evidence of moderate or severa encephalopathy graded according to Sarnat&Sarnat neurological evaluation
  • abnormal amplitude integrated electroencephalography

Exclusion Criteria:

  • suspected inborn errors of metabolism
  • major chromosomal congenital defects

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 identifier (NCT number): NCT03806816

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Contact: Anna Tarocco, MD +390532236014
Contact: Paolo Pinton, Professor +390532455802

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Holy See (Vatican City State)
Ospedale Pediatrico Bambin Gesù Recruiting
Vatican City, Holy See (Vatican City State)
Contact: Immacolata Savarese, MD         
Contact: Andrea Dotta, MD         
ospdale di Bolzano Recruiting
Bolzano, Italy
Contact: Elisabetta Chiodin, MD         
Contact: Alex Staffler, MD         
Bufalini Hospital Cesena Recruiting
Cesena, Italy
Contact: MARCELLO Stella   
Contact: Elisa Mariani   
University Hospital "Sant'Anna" of Ferrara Recruiting
Ferrara, Italy, 44124
Contact: Anna Tarocco, MD    +390532236014   
Contact: Paolo Pinton, Prof    +390532455802   
ospedale San Salvatore Recruiting
L'Aquila, Italy
Contact: Eugenia Maranella, MD         
Contact: Sandra Di Fabio, MD         
Infermi Hospital Rimini Recruiting
Rimini, Italy, 47923
Contact: Gina Ancora, MD PhD    +390541705445   
Contact: Miria Natile, MD    +390541705445   
Sponsors and Collaborators
University Hospital of Ferrara
AUSL Romagna Rimini
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Principal Investigator: Anna Tarocco, MD University Hospital of Ferrara
Publications of Results:

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Responsible Party: Anna Tarocco, Medical Doctor, Principal Investigator, University Hospital of Ferrara Identifier: NCT03806816    
Other Study ID Numbers: 23/2018/SPER/AOUFE
First Posted: January 16, 2019    Key Record Dates
Last Update Posted: October 11, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Anna Tarocco, University Hospital of Ferrara:
Hypoxic-Ischemic Encephalopathy
neurological outcome
perinatal asphyxia
Additional relevant MeSH terms:
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Brain Diseases
Brain Ischemia
Hypoxia-Ischemia, Brain
Pathologic Processes
Central Nervous System Diseases
Nervous System Diseases
Signs and Symptoms, Respiratory
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Hypoxia, Brain
Wounds and Injuries
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Central Nervous System Depressants