Melatonin as a novel neuroprotectant in preterm infants
Lead Research Organisation:
Imperial College London
Department Name: Institute of Clinical Sciences
Abstract
Premature babies have a very high risk of growing up with cerebral palsy or other handicaps. We now want to use advanced brain imaging to test a possible treatment to reduce brain damage. Melatonin, a substance produced naturally by the brain and taken by many people to combat jet-lag seems to protect the immature brain from damage due to shortages of oxygen or infection. We want to see if it prevents brain damage in premature infants.
Technical Summary
Preterm brain injury is a major cause of neurodevelopmental imairment. There currently are no treatments, and proof-of-concept trials have previously been limited by potential toxicity of therapeutics and the time and expense of using prolonged neurodevelopmental follow-up as an outcome. Neuroimaging now offers a validated surrogate outcome for rapid and effective proof-of-concept studies, and there are strong pre-clinical data showing the neuroprotective and growth promoting properties of melatonin, an endogenous mediator with very a favourable pharmacological and toxicological profile.
This study thus addresses the question: Does melatonin reduce brain damage in infants born before 30 weeks gestation? It aims to: establish proof-of-concept that prematurity-related brain injury can be ameliorated by administration of a neuroprotective therapy; define melatonin pharmacokinetics in the preterm by a preliminary dosing study; allow planning for a definitive double-blind randomised controlled trial of melatonin.
The study will be in two parts. First, a dosing study recruiting infants from both Hammersmith Hospital, London and Hopital Robert Debre, Paris. Second, a single centre randomised double-blind placebo-controlled proof-of-concept surrogate outcome experimental study to test the hypothesis that melatonin administration achieving peak adult blood levels twice a day for 7 days after preterm delivery reduces cerebral white matter disease defined by diffusion weighted imaging at term. This will use the 3.0T MR system installed within the intensive care unit of the Hammersmith Hospital, a unique research facility.
Infants born at less than 30 weeks gestation without major congenital malformation, will be eligible. After randomisation treatment will begin within 24 hours of birth. Brain injury is known to be affected by increasing gestation and particular brain lesions, and established major tissue distruction is unlikely to respond, therefore: groups will be randomized in blocks with similar gestational age; infants with severe brain destruction established prior to recruitment will be excluded; and MR imaging during the first week will detect other significant but potentially treatable lesions to allow the analysis to account for potential confounding by non-random allocation of cerebral lesions. The primary end-point will be detection of white matter disease using diffusion weighted imaging, and secondary outcomes will address brain growth and development. Power calculations show 2n=72 for primary and 2n=86 for secondary outcomes. The use of surrogate outcomes will allow the project to be completed within 30 months.
This study thus addresses the question: Does melatonin reduce brain damage in infants born before 30 weeks gestation? It aims to: establish proof-of-concept that prematurity-related brain injury can be ameliorated by administration of a neuroprotective therapy; define melatonin pharmacokinetics in the preterm by a preliminary dosing study; allow planning for a definitive double-blind randomised controlled trial of melatonin.
The study will be in two parts. First, a dosing study recruiting infants from both Hammersmith Hospital, London and Hopital Robert Debre, Paris. Second, a single centre randomised double-blind placebo-controlled proof-of-concept surrogate outcome experimental study to test the hypothesis that melatonin administration achieving peak adult blood levels twice a day for 7 days after preterm delivery reduces cerebral white matter disease defined by diffusion weighted imaging at term. This will use the 3.0T MR system installed within the intensive care unit of the Hammersmith Hospital, a unique research facility.
Infants born at less than 30 weeks gestation without major congenital malformation, will be eligible. After randomisation treatment will begin within 24 hours of birth. Brain injury is known to be affected by increasing gestation and particular brain lesions, and established major tissue distruction is unlikely to respond, therefore: groups will be randomized in blocks with similar gestational age; infants with severe brain destruction established prior to recruitment will be excluded; and MR imaging during the first week will detect other significant but potentially treatable lesions to allow the analysis to account for potential confounding by non-random allocation of cerebral lesions. The primary end-point will be detection of white matter disease using diffusion weighted imaging, and secondary outcomes will address brain growth and development. Power calculations show 2n=72 for primary and 2n=86 for secondary outcomes. The use of surrogate outcomes will allow the project to be completed within 30 months.