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).

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

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.

ISRCTN61218504. EU CT: 2025-520538-49-00.

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

Although caesarean sections (CSs) are essential for the management of obstructed labour and other obstetric complications, postoperative pain, delayed recovery and complication risks continue to be significant challenges in perioperative management. Improvements in traditional medications and surgical techniques have helped, yet issues, including medication side effects and extended recovery times, persist. Therefore, it is particularly important to seek non-pharmacological interventions, such as acupoint stimulation, to optimise the perioperative management of CS. The aim of this systematic review protocol is to synthesise the available evidence and assess the effect of acupoint stimulation in the perioperative period of CS.

We plan to search PubMed, Web of Science, EMBASE, Scopus, the Cochrane Library and China National Knowledge Infrastructure, from their inception to August 2025. Primary outcome indicators will include pain, time to first defecation, time to first bowel movement and time to return of bowel sounds. Secondary outcome indicators will include postoperative complications, such as nausea and vomiting, bloating, anxiety and depression, as well as length of hospital stay and morphine consumption. Subgroup analyses, meta-regression and sensitivity analyses will be used to investigate the potential sources of heterogeneity and to test the stability of the results. Trial sequential analysis will be introduced to enhance the reliability of the evidence.

No ethical approval is required as this study synthesises the existing published data. Results will be disseminated through peer-reviewed publications and conference presentations. Any protocol amendments will be documented in PROSPERO and detailed in the final publication.

CRD42024558572.