Acute High Dose Melatonin for Encephalopathy of the Newborn (ACUMEN) Study: a protocol for a multicentre phase 1 safety trial of melatonin to augment therapeutic hypothermia for moderate/severe hypoxic ischaemic encephalopathy

Abstract

Introduction: Neonatal death and later disability remain common sequelae of hypoxic-ischaemic encephalopathy (HIE) despite the now standard use of therapeutic hypothermia (HT). New therapeutic approaches to brain protection are required. Melatonin is an indolamine hormone with free-radical scavenging, antiapoptotic, anti-inflammatory and gene regulatory neuroprotective properties, which has extensive preclinical evidence of safety and efficacy. Pharmacokinetic (PK) data suggest it is necessary to reach melatonin levels of 15-30 mg/L within 6-8 hours of hypoxia-ischaemia for brain protection. We developed a novel Good Manufacturing Practice (GMP) grade melatonin in ethanol 50 mg/mL solution for intravenous use. In preclinical studies, ethanol is an adjuvant excipient with additional neuroprotective benefit; optimised dosing protocols can achieve therapeutic melatonin levels while limiting blood alcohol concentrations (BACs).

Methods and analysis: The Acute High Dose Melatonin for Encephalopathy of the Newborn (ACUMEN) Study is a first-in-human, international, multicentre, phase 1 safety study of intravenous melatonin in babies with moderate/severe HIE receiving HT. Sixty babies will be studied over two phases: a dose escalation study including four dose levels to establish the recommended phase 2 dose (RP2D), followed by a 6-month cohort expansion study of RP2D to further characterise PKs and affirm safety. Participants will receive a 2-hour intravenous infusion of melatonin within 6 hours of birth, followed by five maintenance doses every 12 hours to cover the period of HT. Plasma melatonin and BACs will be monitored. The RP2D will be based on the attainment of therapeutic melatonin levels while limiting BACs and the frequency of dose-limiting events (DLEs). A Bayesian Escalation with Overdose Control approach will be used to estimate the risk of DLE per dose level, with a target level of <33%. ACUMEN will establish a network of centres with standardised neurocritical care and harmonised MRI systems for the analysis of the primary outcome-magnetic resonance spectroscopy (MRS) lactate to N-acetylaspartate peak area ratio localised to the basal ganglia and thalamus and include a nested blood biomarker study to explore early disease severity indicators.

Ethics and dissemination: Approval has been given by the London Central National Health Service Health Research Authority Ethics Committee (25/LO/0170) and UK Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency. Separate approvals have been sought in Ireland and Australia. Dissemination will be via peer-reviewed journals, conference presentations, public registries and plain language summaries for parent/legal guardian(s), in accordance with national requirements.

Trial registration number: ISRCTN61218504.

Eu ct: 2025-520538-49-00.

Protocol version: Publication based on the UK protocol V.3.0, 08 May 2025.

Keywords: Brain Injuries; Clinical Trial; Hypoxia; Neonatology.

Figure 1. Melatonin and ethanol levels in 13 newborn piglets. Piglets received a loading of 20 mg/kg of melatonin over 2 hours (arrow) followed by four maintenance doses of 10 mg/kg over 2 hours every 12 hours from 24 hours. Target melatonin level (15–30 mg/L) (A) and BAC <0.25 g/L shaded (B).

Figure 2. Melatonin dosing regimen and timing of pharmacokinetic (PK) blood sampling (A) and illustration of the principles of the dose escalation study design (B). Four dose levels will be assessed with a sentinel baby (red circle) at each dose level to ensure levels of melatonin (<33.5 mg/L), ethanol (<0.25 g/L) and acetaldehyde (<2.2 mg/L) are within safety thresholds after the loading dose. Subsequently, a further two babies at each dose level will be recruited prior to review of safety and PK data by the DSMB. Recommendations by the DSMB to the Trial Steering Committee to either (1) Dose escalate (2) Continue the same dose level for a further cohort of three babies, or (3) Reduce the dose (from dose level 2). The DSMB will also be called for review if there are any dose-limiting events. The figure is an illustration of one possible path of dose escalation in ACUMEN. Other paths, including with dose de-escalation or repeats of dose levels, are possible. Created in BioRender. Pang R (2025) https://BioRender.com/xlkdsdd. MRS, magnetic resonance spectroscopy.

Figure 3. Exploratory Biomarker Study in the Acute High Dose Melatonin for Encephalopathy of the Newborn (ACUMEN) Study. The optional exploratory biomarker study aims to use the next generation of novel technology to identify promising biomarkers of hypoxic-ischaemic encephalopathy (HIE) severity. This includes validating rapid POCT UCH-L1 and GFAP test for HIE. Plasma will also be assessed using NUcleic acid Linked Immuno-Sandwich Assay (NULISA), a novel, proteomic liquid biopsy platform with high attomolar sensitivity and high multiplexing to profile over 120 disease markers, metabolomics, microRNA and assessment of renal injury. Created in BioRender. Pang R (2025) https://BioRender.com/ka7nocl.