Oral Melatonin as Neuroprotectant in Preterm Infants

Not Applicable

Completed

• Conditions: Malondialdehyde; Melatonin
• Interventions: Dietary Supplement: melatonin; Drug: placebo

• Registration Number: NCT04235673
• Lead Sponsor: Francesca Garofoli

Brief Summary

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

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 test"eye tracking, ophthalmological, auditory brain stem evoked response (ABR), neurological/cognitive child assessments. Monitoring parental distress, which can influence the neurodevelopmental outcome in preterms.

Study Timeline

• Study First Submitted: 2019-05-23
• Study First Submitted QC: 2020-01-16
• Study First Posted: 2020-01-22
• Study Start: 2020-05-25
• Status Verified: 2022-10
• Primary Completion: 2022-10-01
• Study Completion: 2022-10-11
• Last Update Submitted: 2024-07-23
• Last Update Posted: 2024-07-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

Not provided

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
melatonin	melatonin	melatonin oral drops; 3 mg/kg/day for 15 days
placebo	placebo	oral drops manufactured to mimic melatonin

Primary Outcome Measures

Name	Time	Method
Malondialdehyde	15 days	plasmatic concentration pg/ml
Melatonin	15 days	plasmatic concentration pg/ml

Secondary Outcome Measures

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

Trial Locations

Locations (4)

Fondazione IRCCS Mondino; 🇮🇹 Pavia, PV, Italy

Child and Adolescence Neuropsychiatry Unit, Children's Hospital "Spedali Civili" of Brescia, 25123 Brescia, Italy.; 🇮🇹 Brescia, BS, Italy

Neonatal Intensive Care Unit, Children's Hospital, University Hospital "Spedali Civili" Brescia, 25123 Brescia, Italy.; 🇮🇹 Brescia, BS, Italy

Neonatal Unit and NICU, Radiology, Clinical Chemistry Lab., Fondazione IRCCS Policlinico S. Matteo.; 🇮🇹 Pavia, PV, Italy