Moderate to severe hypoxic-ischaemic encephalopathy (HIE) in newborn infants Neonatal Diseases
Conditions
Interventions
The intervention is a novel formulation of melatonin in ethanol 50 mg/ml solution for infusion administered to newborn babies with moderate-severe HIE to augment therapeutic hypothermia (HT). HT will
Sponsors
The Comprehensive Clinical Trials Unit at University College London
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Baby admitted to the Neonatal Intensive Care Unit (NICU) with moderate-severe hypoxic-ischaemic encephalopathy (HIE) meeting eligibility criteria for therapeutic hypothermia (HT) (in accordance with local guidelines) and: 1.1. Born at =36 completed weeks gestation 1.2. Clinically stable* at the time of IMP administration 1.3. Invasive blood pressure monitoring in situ prior the administration of the IMP loading dose 2. All participants will undergo a further assessment of HIE grade as determined by amplitude-integrated EEG (aEEG)/EEG and/or a Modified Sarnat neurological examination prior to IMP administration 2.1. Sentinel Participant Criteria Only: must not meet the criteria for severe HIE 3. Informed consent from parents/guardians/person with legal responsibility *Definition of Clinical Stability: Eligibility of the participant must be rechecked prior to administration of the IMP given the varying clinical status of these infants. Stability will take the following into consideration: 1. Well placed central venous catheter or patent peripheral cannula in situ 2. Mean blood pressure (with or without inotropic support) must be greater than the 5th centile for gestation (see BP centile charts in Appendix 3) within 30 mins prior to IMP administration 3. Clinical or electrical seizures, if present, controlled with anti-seizure medications 4. Clinical observations within acceptable range for an infant undergoing therapeutic hypothermia 5. No clinical stability concerns from the attending neonatologist Updated 14/07/2026: * Definition of Clinical Stability Eligibility of the participant must be rechecked prior to administration of the IMP given the varying clinical status of these infants. Stability will take the following into consideration: 1. Well placed central venous catheter or patent peripheral cannula in situ. 2. Haemodynamic stability within 30 minutes prior to IMP administration: 2.1. Mean blood pressure (without inotropic support) must be greater than the 5th centile for gestation (see BP centile charts in Appendix 3) prior to administration of the loading dose. 2.2. Mean blood pressure (with or without inotropic support) must be greater than the 5th centile for gestation (see BP centile charts in Appendix 3) prior to administration of each maintenance dose. 2.2.1. The participant must not be receiving more than one vasoactive inotrope. 2.2.2. The Vasoactive-Inotropic Score (VIS) must be =10. The VIS score is calculated as VIS = dopamine (µg/kg/min) + dobutamine (µg/kg/min) + [100 x adrenaline (µg/kg/min)] + [100 x noradrenaline (µg/kg/min)] 3. No evidence of acute kidney injury resulting in hyperkalaemia (defined as a serum potassium >6.5 mmol/L) that continues to rise despite stopping potassium-containing infusions and potassium-sparing drugs (based on the most recent available blood test result). 4. No clinical concerns of acute liver failure for the loading dose†. 5. No evidence of ongoing acute liver failure defined as INR>3 (despite administration of parenteral vitamin K or clotting factor replacement) for administration of maintenance doses based on the most recent blood test. 6. Clinical or electrographic seizures, if present, controlled with anti-seizure medications. If there are seizures, these must not be ongoing or uncontrolled despite anti-seizure medications. 7. Clinical observations within acceptable range for an infant undergoing therapeutic hypothermia. 8. No clinical stability concerns from the attending
Exclusion criteria
Exclusion criteria: 1. Baby would be >6 hours of age when IMP administered 2. Initiation of IMP unlikely to be administered within 6 hours of birth 3. Infants born in very poor condition or judged too sick to be included (high risk of mortality) in an experimental first-in-human study, for example, infants that are requiring maximal intensive care therapy or in a condition considered to be life-limiting. 4. Postnatal hypoxic insult without any evidence of HIE at birth. 5. Birth weight less than 2nd centile for gestation on UK-WHO growth charts# 6. Congenital anomalies, i.e., any major antenatal diagnosed congenital abnormalities such as congenital heart disease, suspected or known chromosomal abnormalities 7. Infant is participating or intends to participate in another interventional study during the birth hospitalisation (note: does not include observational studies) 8. Parents/legal guardians unable to give consent due to learning or other difficulties Please note that in the event of multiple births: 1. If one baby has HIE, participation in the trial will be offered 2. If both/multiple babies have HIE, participation in the trial will not be offered # - https://www.rcpch.ac.uk/sites/default/files/Boys_neonatal_and_infant_close_monitoring_growth_chart.pdf https://www.rcpch.ac.uk/sites/default/files/Girls_neonatal_and_infant_close_monitoring_growth_chart.pdf Removed 14/07/2026: 7. Head circumference less than 2nd centile adjusted to sex of the baby on UK-WHO growth charts#
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The overall aim of the study is to identify the Recommended Phase II Dose (RP2D) based on the totality of data and outcomes are listed below. The primary outcomes are: 1. Safety: the safety profile of melatonin across dose levels being studied assessed based on the occurrence of dose-limiting events (DLE): DLEs will be evaluated continuously from the time of first administration of the IMP (T0) until 96 hours post-T0 (T+96 hours). T0 is defined as the time of the first loading dose administration, which must occur within the first six hours of birth. 2. The attainment of putative therapeutic plasma melatonin levels (in the range of 15-30 mg/L) across dose levels being studied: plasma melatonin levels will be evaluated at predefined timepoints during the dosing period up to T+96 hours, with T0 as the starting point. 3. The attainment of putative ethanol safety (BAC levels <0.25 g/L across dose levels being studied: blood alcohol concentration will be monitored and evaluated at predefined intervals during the dosing period, up to T+96 hours from the initial loading dose (T0). | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Pharmacokinetic Model (PK): 1.1. Estimation of population PK parameters of melatonin in the target population. 1.2. Estimation of population PK parameters of ethanol in the target population. PK parameters for melatonin and ethanol will be evaluated using blood samples collected at predefined intervals up to the 96-hour time point (T+96 hours, with T0 being the first dose administered within 6 hours of birth) 2. Establishing a Neonatal Neuroprotection Trial Network in anticipation of a Phase II RCT: 2.1. Successful harmonisation of 3T MRI scanners and acquisition of magnetic resonance spectroscopy (MRS) at days 4 to 10: 2.1.1. Evaluation of pattern and severity of injury using T1/T2 MRI and diffusion-weighted imaging (DWI). 2.1.2. Assessment of HIE severity through baseline lactate/N-acetylaspartate (NAA) statistics to inform the sample size calculation of the Phase II trial. 2.2. Successful (in >90% of enrolled babies) integration and standardising of amplitude-integrated electroencephalography aEEG/EEG monitoring throughout the cooling and rewarming periods at all centres, using recovery of background activity as a proxy for outcome (a more rapid recovery of background voltage is associated with a favourable outcome). aEEG/EEG monitoring will be continuous throughout cooling (0–72 hours) and rewarming (72–96 hours). 2.3. Successful (>90% of enrolled babies) integration of continuous cerebral near-infrared spectroscopy (NIRS) as part of the neurocritical care management for infants with HIE. NIRS data will be collected continuously throughout the same timeframe. 2.4. Successful collection (>90% of enrolled babies) of early surrogate measures of neurodevelopmental outcomes (Hammersmith Infant Neurological Examination (HINE) at 3 months, Hammersmith Neonatal Neurological Examinations (HNNE) at hospital discharge, General Movement Assessment (GMA) at 3 months and ASQ-3). 3. Recruitment: 3.1. Metrics on the acceptability of the study among potential participan | — |
Countries
Australia, England, Ireland, Scotland, United Kingdom
Outcome results
None listed