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

NCT ID: NCT02395783

Last Updated: 2018-03-02

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-31
• Study Completion Date: 2018-02-28

Brief Summary

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

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

Conditions

Premature Birth

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Melatonin dose1

Melatonin 10 µg

Group Type: ACTIVE_COMPARATOR

Melatonin 10 µg

Intervention Type: DRUG

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

Melatonin dose2

Melatonin 20 µg

Group Type: ACTIVE_COMPARATOR

Melatonin 20 µg

Intervention Type: DRUG

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

Placebo

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

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

Interventions

Melatonin 10 µg

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

Intervention Type: DRUG

Melatonin 20 µg

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

Intervention Type: DRUG

Placebo

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

Intervention Type: OTHER

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Biran Valérie, PHD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Hôpital Robert Debré

Paris, , France

Countries

France

Other Identifiers

P120113

Identifier Type: -

Identifier Source: org_study_id