Oral Melatonin as Neuroprotectant in Preterm Infants

Study Overview
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Brief Summary
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Preterm newborns survival rates are improved, but long-term disabilities are still common. Major destructive focal lesions became less common, the most predominant lesion at present is diffuse white matter (WM damage). Melatonin (ME) serves as a neuroprotectant cerebral ischemia through its potent anti-oxidant/-inflammatory effect. Preclinical studies demonstrated that protects the developing brain by preventing abnormal myelination and inflammatory glial reaction. Clinical studies demonstrated ME ability in reducing brain damage after neonatal Hypoxic Ischemic Encephalopathy (HIE) or preventing neonatal impairments due to antenatal/ post-natal injuries: preeclampsia, IntraUterineGrowthRestriction (IUGR), ventilation, Bronchopulmonary Dysplasia (BPD). ME has a good safety profile with no known adverse effects. This study aims to highlight that ME can prevent brain impairment due to premature birth. ME will be administered orally (3 mg/kg/die for 15 days to neonates born before 29+6 week gestation, in a prospective double blind, randomized vs placebo study, 2 parallel arms. ME and malondialdehyde (MDA), a lipid peroxidation product) levels before and at the end of treatment will be measured . Other outcomes: Cerebral ultrasounds (cUS); cerebral magnetic resonance imaging (cMRI),  Fagan test  eye tracking, ophthalmological, auditory, neurological/cognitive child assessments. Monitoring parental distress, which can influence the neurodevelopmental outcome in preterms.

Detailed Description
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About 552.000 infants are born in Italy each year, 1% of them with gestational age under 30 weeks. Survival rates are improved, but long-term disabilities are still common. Major destructive focal lesions became less common, the most predominant lesion at present is diffuse white matter (WM damage). The prevention of neurodevelopmental impairment is a major public health challenge and efforts are needed to test neuroprotective strategies. Melatonin (ME) serves as a neuroprotectant cerebral ischemia through its potent anti-oxidant/-inflammatory effect. Preclinical studies demonstrated that protects the developing brain by preventing abnormal myelination and inflammatory glial reaction. Clinical studies demonstrated ME ability in reducing brain damage after neonatal Hypoxic Ischemic Encephalopathy (HIE) or preventing neonatal impairments due to antenatal/ post-natal injuries: preeclampsia, IntraUterineGrowthRestriction (IUGR), ventilation, Bronchopulmonary Dysplasia (BPD). Ongoing studies are testing in premature neonates and pregnant women its neuroprotective properties. ME has a good safety profile with no known adverse effects. This study aims to highlight that ME can prevent brain impairment due to premature birth. ME will be administered orally (3 mg/kg/die for 15 days within 96 hours from birth) to neonates born before 29+6 week gestation age (GA), in a prospective double blind, randomized vs placebo study, 2 parallel arms (30 preterm infants each). ME and malondialdehyde (MDA, a lipid peroxidation product) levels will be measured before and at the end of treatment. At birth, within 40 weeks of neonatal age, at 4-6 and at 24 months of age the following examinations are performed: Cerebral ultrasounds (cUS); cerebral magnetic resonance imaging (cMRI), during natural sleep (i.e. adopting sleep deprivation and/or feeding protocols); Fagan testeye tracking, ophthalmological, auditory brain stem evoked response (ABR), neurological/cognitive child assessments. Monitoring parental distress, which can influence the neurodevelopmental outcome in preterms.

Official Title
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Oral Melatonin as Neuroprotectant in Preterm Infants .A Prospective, Double Blind vs Placebo, Parallel Arms Study

Conditions
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Malondialdehyde, Melatonin

Intervention / Treatment
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* Dietary Supplement: melatonin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria preterm newborns gestational age GA < 29+6 weeks + day able to receive min 20ml/kg/day enteral nutrition, within 96 hours from birth written informed consent by both the parents. Exclusion Criteria: preterm newborns GA > 29+6 weeks + days not able to receive enteral nutrition (min 20 ml/kg/die) within 96 hours of life infants with genetic and/or congenital metabolic or chronic diseases intraventricular hemorrhage (IVH) ≥ III, parents refusing to sign a written informed consent

Ages Eligible for Study
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Minimum Age: 25 Weeks
Maximum Age: 30 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: melatonin<br>melatonin oral drops; 3 mg/kg/day for 15 days | Dietary Supplement: melatonin<br>* orally administered drops<br>* Other names: not reported;|
| Placebo Comparator: placebo<br>oral drops manufactured to mimic melatonin | Drug: placebo<br>* orally administered drops<br>* Other names: not reported;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Malondialdehyde | plasmatic concentration pg/ml | 15 days | 
| Melatonin | plasmatic concentration pg/ml | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cranial ultrasound (cUS) Assessment | to identify and score White Matter injuries | up to 40 weeks | 
| Brain Magnetic Resonance Immaging (cMRI) Assessment | Identify and score White Matter injuries | up to 40 weeks | 
| Auditory brain stem evoked response (ABR) Assessments | Identify and score auditory diseases | up to 40 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preterm neonate, Neuroprotection, Malondialdehyde, Melatonin