Phase I dose escalation and cohort expansion study to affirm the safety of pharmacological doses of a novel formulation of intravenous melatonin in babies with hypoxic-ischaemic encephalopathy (HIE) to augment therapeutic hypothermia (HT) treatment; to reduce the incidence and severity of disability in babies with moderate-severe HIE
Moderate to severe hypoxic-ischaemic encephalopathy (HIE) in newborn infants
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 be started in eligible babies according to local guidelines as soon as possible after birth. Administration of IMP will be provided over 6 infusions: A loading dose administered over 2 hours within 6 hours of birth 5 x maintenance doses every 12h from 24h after initiation of loading dose (administered over 2 hours) ACUMEN is an open-label, non-randomized study, meaning all enrolled participants receive IMP in addition to standard therapeutic hypothermia. The dose levels to be considered as part of this trial are outlined in the table below. Dose Level 1 and Dose Level 2 will be investigated as fixed starting points of the dose-escalation phase. From Dose Level 3 onwards, dose levels may be skipped based on accumulating safety data and population pharmacokinetic (POP-PK) modelling. In total, it is anticipated that 4 dose levels will be explored during the dose-escalation part of the study. Loading doses: Dose Level 1: 5 mg/kg Dose Level 2: 10 mg/kg Dose Level 3: 15 mg/kg Dose Level 4: 20 mg/kg Dose Level 5: 25 mg/kg Dose Level 6: 30 mg/kg Dose Level 7: 35 mg/kg Dose Level 8: 40 mg/kg The ACUMEN study consists of two phases: Dose Escalation Phase: Multiple cohorts of neonates will receive different dose levels of IMP. There are eight predefined dose levels, but only four will be investigated based on accumulating safety data and pharmacokinetic (PK) modelling. Cohort Expansion Phase: Once an optimal dose level is identified, a larger cohort will receive this dose to determine the recommended Phase II dose (RP2D). Participants will be followed up for 3 months as part of the ACUMEN trial.
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 t
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#