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

Product:

CNS Disease Panel 120, Neurology

Topic:

Disease Area:

Encephalopathy

Sample Type:

Plasma

Topic/Product:

CNS Disease Panel 120, Neurology

Disease Area:

Encephalopathy

Sample Type:

Plasma

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.

Authors & Affiliations

Raymand Pang¹, Alyson Macneil², Anvi Wadke², Yusuf Jaami³, Neil Marlow¹, Joseph F. Standing⁴, Hakim-Moulay Dehbi², Pamela Tranter⁵, Nicola J. Robertson¹, on behalf of the ACUMEN Consortium

¹ EGA Institute for Women’s Health, University College London, London, UK
² Comprehensive Clinical Trials Unit, University College London, London, UK
³ Joint Research Office, University College London Hospitals / University College London, London, UK
⁴ Great Ormond Street Institute of Child Health, University College London, London, UK
⁵ Translational Research Office, University College London, London, UK

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.