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

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

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.

Study Overview

• Status: Terminated
• Conditions: Premature Birth
• Intervention / Treatment: Drug: Melatonin 10 µg; Drug: Melatonin 20 µg; Other: Placebo

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

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75019
    • Hopital Robert Debre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: 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
Active Comparator: Melatonin dose1; Melatonin 10 µg	Drug: 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
Active Comparator: Melatonin dose2; Melatonin 20 µg	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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Biran Valérie, PHD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): February 1, 2018

Study Registration Dates

• First Submitted: March 6, 2015
• First Submitted That Met QC Criteria: March 17, 2015
• First Posted (Estimate): March 24, 2015

Study Record Updates

• Last Update Posted (Actual): March 2, 2018
• Last Update Submitted That Met QC Criteria: March 1, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Preterm infants; diagnosis of cerebral white matter injury
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Brain Injuries; Premature Birth; Leukoencephalopathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: P120113