Brain Injury, Premature Birth
Conditions
Keywords
Premature Birth, Brain injury, Neuroprotection, Melatonin, Pharmacokinetics
Brief summary
Preterm babies are at risk of brain injury. Melatonin, a naturally occurring hormone, may reduce this risk. The unborn baby receives melatonin from the mother but following premature delivery there maybe a period of prolonged melatonin deficiency. This deficiency may be harmful because studies suggest that melatonin is important in protecting the brain and reducing the risk of brain injury after preterm birth. The purpose of this study is to find the ideal dose of melatonin to give to preterm babies. We intend to study a total of 24 babies less than 31 weeks gestation and who are less than 7 days old.
Detailed description
PURPOSE OF THE STUDY AND OBJECTIVES The overall purpose is to investigate whether melatonin, on achieving adult maternal peak blood levels in preterm infants, will reduce brain injury and white matter disease as defined by specialised magnetic resonance imaging (MRI) at term. Before testing this hypothesis in a clinical trial, the dose of melatonin required to achieve the desired concentration in preterm infants needs to be determined. This data will be used in the clinical double blinded randomised trial for which a separate application will be made to the ethics committee. The principal research objective in this study is to determine the dose required to achieve physiological melatonin blood levels in the preterm infants similar to that of the mother. Secondary objective is to define the pharmacokinetic profile of melatonin in preterm infants. STUDY DESIGN AND METHODOLOGY The proposed clinical trial is a single dose, open label, dose escalation pharmacokinetic study in preterm infants less than 31weeks gestation to achieve adult peak blood concentrations of melatonin (200-250 pmol/L). The trial will be a multi centre study based in the Neonatal Intensive Care Units in UK. TREATMENT A single intravenous infusion of melatonin will be given to each infant over 6 hours once in the first 7 days of life. The starting dose is 0.1 microgram/kg/hr which will be increased or decreased incrementally in subsequent groups of infants until the desired melatonin concentration is achieved. DURATION The duration of treatment will be 6 hours only. INVESTIGATIONS Pharmacokinetic assessment will be performed on the blood and urine samples will be collected 2 hourly at various timepoints. STATISTICAL ANALYSIS Pharmacokinetic assessment will be done using appropriate software.
Interventions
DRUGMelatonin injection
A single intravenous infusion of melatonin will be given to each infant over 6 hours so that successive groups will receive increasing doses until the correct dose for age is found. Based on the pharmacokinetics and clearance of melatonin in adults an approximate dose has been calculated. The starting dose of melatonin will be 0.1 microgram/kg/hr to be given over 6 hours intravenously. The range of expected dose is 0.1-0.5 microgram/kg/hr.
Sponsors
British Medical Research Council
Imperial College London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
23 Weeks to 31 Weeks
Healthy volunteers
No
Inclusion criteria
* Infants born less than 31 weeks gestation who are less than 7 days old, after parental consent for participation will be included in the study.
Exclusion criteria
* Those with major congenital malformation, or cystic periventricular leucomalacia (cPVL) or haemorrhagic parenchymal infarcts (HPI) on cranial ultrasonography prior to enrolment will be excluded from the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To Find the Dose of Melatonin Required to Achieve Physiological Blood Levels in the Preterm Infants Similar to That of the Mother. | 6 months |
Countries
United Kingdom
Participant flow
Recruitment details
We conducted an open label dose ranging study between May 2010 and December 2010 in 3 neonatal intensive care units in the UK.
Pre-assignment details
Infants born less than 31 weeks gestation and less than 7 days old were eligible for the study, although those with: major congenital malformation; or cystic periventricular leucomalacia or haemorrhagic parenchymal infarcts on cranial enrolment were excluded.
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Open label dose finding study in infants born before 31 weeks gestation and less than 7 days of age | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Single Arm |
|---|---|
| Age, Customized Gestation at birth | 26.63 weeks |
| Region of Enrollment United Kingdom | 18 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 0 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
To Find the Dose of Melatonin Required to Achieve Physiological Blood Levels in the Preterm Infants Similar to That of the Mother.
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm | To Find the Dose of Melatonin Required to Achieve Physiological Blood Levels in the Preterm Infants Similar to That of the Mother. | 203.3 pg/ml |