Use of Melatonin for Neuroprotection in Asphyxiated Newborns

Study Overview
=================
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.

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.

Official Title
-----------------
Use of Melatonin for Neuroprotection in Term Infants With Hypoxic-ischaemic Encephalopathy

Conditions
-----------------
Hypoxic-Ischemic Encephalopathy, Cell Damage, Asphyxia Perinatal

Intervention / Treatment
-----------------
* Dietary Supplement: Melatonin
* Other: PLACEBO group


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 1 Hour
Maximum Age: 6 Hours

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HYPOTHERMIA / MELATONIN group<br>HIE infants who will receive melatonin in addition to the routine cooling treatment | Dietary Supplement: Melatonin<br>* 5 daily enteral doses of melatonin 10 mg/kg. (=2 ml/kg)<br>* Other names: Buona Circadiem;|
| Experimental: HYPOTHERMIA / PLACEBO group<br>HIE infants who will not receive melatonin in addition to the routine cooling treatment | Other: PLACEBO group<br>* 5 daily enteral doses of placebo 2 ml/kg<br>* Other names: placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bayley III scale | 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. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| brain MRI | to evaluate the presence of deep grey matter, PLIC, white matter, brainstem and hippocampus lesions | between the 5th and 7th days of life | 
| continuous aEEG | 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) | Continuous monitoring for the first 72 hours and for the rewarmed | 
| Plasma Concentration of Melatonin | UPLC-Massa Acquity-Xevo TQD (Waters) will be used to measure melatonin concentrations in the plasma | at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life | 
| ATG5 Plasma concentration | ELISA test will be used to measure plasma levels of ATG5 | at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
autophagy, neuroprotection, melatonin, Hypoxic-Ischemic Encephalopathy, hypothermia, newborn, neurological outcome, perinatal asphyxia