Clinical trial NCT02395783: Therapeutic Effects of Maternal Melatonin Administration on Brain Injury and White Matter Disease
Official title: Therapeutic Effects of Maternal Melatonin Administration on Brain Injury and White Matter Disease in Very Preterm Infants
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Premature Birth
Keywords: Preterm infants
diagnosis of cerebral white matter injury
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2015-03-24
Enrollment: 14
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Primary outcomes:
measure: TBSS analysis
timeFrame: 40 weeks
Secondary outcomes:
measure: measurement of plasma melatonin levels
timeFrame: before injection of the drug, 5 minutes, 1 hour, 3 hours, 4 hours and 5 hours after injection of the drug
measure: Plasma melatonin level
timeFrame: Day 1
measure: Neurological evaluation (revised Brunet-test)
timeFrame: 2 years
measure: Mortality
timeFrame: 28 days of life
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Robert Debré
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Biran Valérie, PHD
role: PRINCIPAL_INVESTIGATOR
References: