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.

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.

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.

Infants born at less than 31 weeks gestation and less than 7 days after birth

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