Oral Melatonin as Neuroprotectant in Preterm Infants

Sponsor

Francesca Garofoli (Other)

Overall Status

Recruiting

CT.gov ID

NCT04235673

Collaborator

IRCCS National Neurological Institute "C. Mondino" Foundation (Other), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (Other)

Enrollment

Locations

Arms

27.2

Anticipated Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Malondialdehyde Melatonin	Dietary Supplement: melatonin Drug: placebo	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Supportive Care

Official Title:

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

Actual Study Start Date :

May 25, 2020

Anticipated Primary Completion Date :

Dec 1, 2021

Anticipated Study Completion Date :

Sep 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: melatonin melatonin oral drops; 3 mg/kg/day for 15 days	Dietary Supplement: melatonin orally administered drops Other Names: not reported
Placebo Comparator: placebo oral drops manufactured to mimic melatonin	Drug: placebo orally administered drops Other Names: not reported

Arm

Intervention/Treatment

Experimental: melatonin

melatonin oral drops; 3 mg/kg/day for 15 days

Dietary Supplement: melatonin

orally administered drops

Other Names:

not reported

Placebo Comparator: placebo

oral drops manufactured to mimic melatonin

Drug: placebo

orally administered drops

Other Names:

not reported

Outcome Measures

Primary Outcome Measures

Malondialdehyde [15 days]
plasmatic concentration pg/ml
Melatonin [15 days]
plasmatic concentration pg/ml

Secondary Outcome Measures

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
Auditory brain stem evoked response (ABR) Assessments [up to 40 weeks]
Identify and score auditory diseases

Other Outcome Measures

Fagan Test of Infant Intelligence (FTII) [up to 24 months]
Measure the time ( minutes) to recognize unfamiliar versus familiar human faces to gauge visual-spatial encoding, attention, and working memory in infants.
Griffiths Mental Developmental Scales'Revised (GMDS-R) [up to 24 months]
The scales rate infant development across 5 main areas (locomotor, personal and social skills, hearing and language, eye and hand co-ordination, and performance), providing a general developmental quotient (DQ) of infants' abilities and 5 subscale quotients (SQ).
Child Behavior Checklist (CBCL) scales. [up to 24 months]
A self-rating scale to evaluate emotional, social, and behavioral problems in infants, according to the parents' evaluation.

Eligibility Criteria

Criteria

Ages Eligible for Study:

25 Weeks to 30 Weeks

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Child and Adolescence Neuropsychiatry Unit, Children's Hospital "Spedali Civili" of Brescia, 25123 Brescia, Italy.	Brescia	BS	Italy	25123
2	Neonatal Intensive Care Unit, Children's Hospital, University Hospital "Spedali Civili" Brescia, 25123 Brescia, Italy.	Brescia	BS	Italy	25123
3	Fondazione IRCCS Mondino	Pavia	PV	Italy	27100
4	Neonatal Unit and NICU, Radiology, Clinical Chemistry Lab., Fondazione IRCCS Policlinico S. Matteo.	Pavia	PV	Italy	27100