Therapeutic Effects of Maternal Melatonin Administration on Brain Injury and White Matter Disease

Study Overview
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Brief Summary
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Neurocognitive sequelae observed in preterm represent a major health problem for which there is no preventive treatment approved to date. These effects are the result of a multifactorial brain damage occurring in developing prenatal and perinatal period. Melatonin, the principal hormone secreted by the pineal gland has neuroprotective properties in various experimental animal models of perinatal brain damage level. This hormone readily crosses the placental barrier, its antenatal administration would have a neuroprotective effect in the case of preventive preterm birth before 28 weeks of amenorrhea. The objective of this study determine the dose of melatonin administered parenterally in prenatal maternal in preterm labor to reduce brain damage in the white matter detected by diffusion tensor imaging (DTI) with statistical spatial analysis (TBSS) to the theoretical term of 40 weeks in children born prematurely.

Detailed Description
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Neurocognitive sequelae observed in preterm represent a major health problem for which there is no preventive treatment approved to date. These effects are the result of a multifactorial brain damage occurring in developing prenatal and perinatal period. Melatonin, the principal hormone secreted by the pineal gland has neuroprotective properties in various experimental animal models of perinatal brain damage level. This hormone readily crosses the placental barrier, its antenatal administration would have a neuroprotective effect in the case of preventive preterm birth before 28 weeks of gestation. The objective of this study determine the dose of melatonin administered parenterally in prenatal maternal in preterm labor to reduce brain damage in the white matter detected by diffusion tensor imaging (DTI) with statistical spatial analysis (TBSS) to the theoretical term of 40 weeks in children born prematurely. Secondary objectives: Determine the pharmacokinetics of melatonin administered intravenously in two dosage regimens and after randomization in pregnant women under 28 weeks Assess the contribution of antenatal injection of melatonin on the incidence of white matter injury detected by conventional brain MRI Assess the contribution of antenatal injection of melatonin on the rate of neurological sequelae at 2 years corrected age, mortality at 28 days of life and at the end of hospitalization. Evaluate the adverse effects of melatonin injection Selection criteria (inclusion and non-inclusion) Inclusion criteria: gestational age between 24 weeks + 0 and 27 weeks + 6 days Delivery imminent spontaneous defined by cervical dilation greater than or equal to 3 cm and regular contractions, painful (greater than or equal to 2 every 10 minutes) or elective caesarean section. maternal age ≥18 years at baseline written consent and Joining a social security scheme mother and holders of parental authority Criteria for non-inclusion Related to the parent criteria: Delivery Outborn Magnesium Sulphate injection in mother Chronic renal and hepatic impairment before pregnancy Circumstances of maternal or fetal distress requiring emergency cesarean eclampsia, placental abruption, placenta previa bleeding. Criteria related to the fetus: diagnosis of antenatal malformation Number of subjects required 60 pregnant women between 24 weeks + 0 and 27 weeks + 6 days Search time, duration of participation of each patient Total study duration: 36 months Inclusion period: 12months Duration of participation for a patient 24 months Number of participating centers: 3 Average number of inclusions per month per center: 3 Methodology Clinical phase Iib, 3-arms, double-blind randomised controlled trial, multicenter Exams required specifically for research (blood, biopsy ...) Treatment: antenatal injection of melatonin ((maximum of 2 doses of 10 mcg or 20 mcg)) against placebo in the delivery room Reviews: Determination of plasma melatonin before, after the injection of melatonin (5 minutes, 1 hour, 3 hours, 4 hours after birth) in the mother Determination of plasma melatonin and serotonin in umbilical cord Brain MRI with diffusion tensor sequence (spatial analysis statistiqueTBSS) at 40 weeks • Primary endpoint and secondary endpoints Primary endpoint: MRI with diffusion tensor sequence (TBSS analysis). Standard (s) Secondary Outcome (s): Pharmacokinetics of melatonin in the mother Determination of plasma melatonin and serotonin in umbilical cord f Brain lesions by conventional MRI Neurological Evaluation at the age of 2 years by the revised Brunet-test skimped Mortality at 28 days of life and at discharge Tolerance of melatonin in pregnant women

Official Title
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Therapeutic Effects of Maternal Melatonin Administration on Brain Injury and White Matter Disease in Very Preterm Infants

Conditions
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Premature Birth

Intervention / Treatment
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* Drug: Melatonin 10 µg
* Drug: Melatonin 20 µg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: gestational age between 24 weeks + 0 and 27 weeks + 6 days Delivery imminent spontaneous defined by cervical dilation greater than or equal to 3 cm and regular contractions, painful (greater than or equal to 2 every 10 minutes) or elective caesarean section. maternal age ≥18 years at baseline written consent and Joining a social security scheme mother and holders of parental authority Exclusion Criteria: Related to the parent criteria: Delivery Outborn Magnesium Sulphate injection in mother Chronic renal and hepatic impairment before pregnancy Circumstances of maternal or fetal distress requiring emergency cesarean eclampsia, placental abruption, placenta previa bleeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Melatonin dose1<br>Melatonin 10 µg | Drug: Melatonin 10 µg<br>* Determine the dose of prenatal administration of melatonin in preterm labor to reduce brain damage in the white matter detected by diffusion tensor imaging (DTI) analysis with spatial statistics (TBSS) to the theoretical term 40 weeks<br>|
| Active Comparator: Melatonin dose2<br>Melatonin 20 µg | Drug: Melatonin 20 µg<br>* Determine the dose of prenatal administration of melatonin in preterm labor to reduce brain damage in the white matter detected by diffusion tensor imaging (DTI) analysis with spatial statistics (TBSS) to the theoretical term 40 weeks<br>|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br>* Determine the dose of prenatal administration of melatonin in preterm labor to reduce brain damage in the white matter detected by diffusion tensor imaging (DTI) analysis with spatial statistics (TBSS) to the theoretical term 40 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TBSS analysis | The primary endpoint will be the analysis of white matter injury (LSB) at 40 weeks corrected by brain MRI with diffusion tensor sequence (TBSS analysis). | 40 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| measurement of plasma melatonin levels | Pharmacokinetics of melatonin in the mother to determine the dose of Melatonin supplementation in pregnant women (between 24 weeks and 27 weeks + 6days) | before injection of the drug, 5 minutes, 1 hour, 3 hours, 4 hours and 5 hours after injection of the drug | 
| Plasma melatonin level | Plasma melatonin level measured in the mother and the newborn at birth (cord blood) | Day 1 | 
| Neurological evaluation (revised Brunet-test) | Neurological evaluation at the age of 2 years by the revised Brunet-test skimped | 2 years | 
| Mortality | Mortality at 28 days of life and at discharge | 28 days of life | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preterm infants, diagnosis of cerebral white matter injury