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
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...
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2025-08-01
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| author | Neil Marlow Adrienne Foran Deirdre M Murray Eleanor J Molloy James P Boardman Atul Malhotra Geraldine Boylan Subhabrata Mitra Nicola J Robertson Karel Allegaert Suzanne L Miller Anne Smits Frances Cowan Joseph F Standing Giles Kendall Rodney W Hunt Hakim-Moulay Dehbi Julie-Clare Becher Linda De Vries Divyen Shah Alyson MacNeil Anvi Wadke Raymand Pang Yusuf Jaami Pamela Tranter Ajit K Mahaveer Kathryn A Martinello Balamurugan Palanisami Brian Walsh |
| author_facet | Neil Marlow Adrienne Foran Deirdre M Murray Eleanor J Molloy James P Boardman Atul Malhotra Geraldine Boylan Subhabrata Mitra Nicola J Robertson Karel Allegaert Suzanne L Miller Anne Smits Frances Cowan Joseph F Standing Giles Kendall Rodney W Hunt Hakim-Moulay Dehbi Julie-Clare Becher Linda De Vries Divyen Shah Alyson MacNeil Anvi Wadke Raymand Pang Yusuf Jaami Pamela Tranter Ajit K Mahaveer Kathryn A Martinello Balamurugan Palanisami Brian Walsh |
| collection | DOAJ |
| description | 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 |
| format | Article |
| id | doaj-art-915f386b1f5945f3ae3d9e5f08e73d8c |
| institution | Kabale University |
| issn | 2044-6055 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open |
| spelling | doaj-art-915f386b1f5945f3ae3d9e5f08e73d8c2025-08-26T04:10:18ZengBMJ Publishing GroupBMJ Open2044-60552025-08-0115810.1136/bmjopen-2025-107083Acute 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 Neil Marlow0Adrienne ForanDeirdre M MurrayEleanor J MolloyJames P BoardmanAtul MalhotraGeraldine BoylanSubhabrata MitraNicola J Robertson1Karel AllegaertSuzanne L MillerAnne SmitsFrances CowanJoseph F Standing2Giles KendallRodney W HuntHakim-Moulay Dehbi3Julie-Clare BecherLinda De VriesDivyen ShahAlyson MacNeil4Anvi Wadke5Raymand Pang6Yusuf Jaami7Pamela Tranter8Ajit K MahaveerKathryn A MartinelloBalamurugan PalanisamiBrian Walsh1 EGA Institute for Women’s Health, University College London, London, UK1 EGA Institute for Women’s Health, University College London, London, UK4 Great Ormond Street Institute of Child Health, University College London, London, UK2 Comprehensive Clinical Trials Unit, University College London, London, UK2 Comprehensive Clinical Trials Unit, University College London, London, UK2 Comprehensive Clinical Trials Unit, University College London, London, UK1 EGA Institute for Women’s Health, University College London, London, UK3 Joint Research Office, University College London Hospitals/University College London, London, UK5 Translational Research Office, University College London, London, UKIntroduction 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 2025https://bmjopen.bmj.com/content/15/8/e107083.full |
| spellingShingle | Neil Marlow Adrienne Foran Deirdre M Murray Eleanor J Molloy James P Boardman Atul Malhotra Geraldine Boylan Subhabrata Mitra Nicola J Robertson Karel Allegaert Suzanne L Miller Anne Smits Frances Cowan Joseph F Standing Giles Kendall Rodney W Hunt Hakim-Moulay Dehbi Julie-Clare Becher Linda De Vries Divyen Shah Alyson MacNeil Anvi Wadke Raymand Pang Yusuf Jaami Pamela Tranter Ajit K Mahaveer Kathryn A Martinello Balamurugan Palanisami Brian Walsh 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 BMJ Open |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://bmjopen.bmj.com/content/15/8/e107083.full |
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