ACUMEN: Acute High Dose Melatonin for Encephalopathy of the Newborn

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University College London

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2025-09-12

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Medical Research Council Developmental Pathway Funding Scheme (UKRI MRC DPFS)

External identifiers

EU CT number

2025-520538-49-00

ISRCTN

ISRCTN61218504

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Dose response, Therapy, Safety

1. Safety Profile Assessment: to assess the safety profile of melatonin across all dose levels being studied based on the occurrence of dose-limiting events (DLE).
2. The attainment of putative therapeutic plasma melatonin levels (in the range of 15-30mg/L) across dose levels being studied.
3. The attainment of putative ethanol safety (BAC levels < 0.25g/L) across dose levels being studied.
4. To identify the recommended Phase 2 dose (RP2D).

Secondary objectives 3

1. Pharmacokinetic (PK) Model: To establish the pharmacokinetic (PK) profile of intravenous melatonin infusion in term infants with moderate to severe hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (HT).
2. Feasibility of Neonatal Neuroprotection Trial Network: To assess the feasibility of developing a neonatal neuroprotection trial network for future Phase 2 randomised controlled trials (RCTs) that will evaluate efficacy.
3. Recruitment Feasibility: to assess the feasibility of recruiting participants within 6 hours of birth.

Conditions and MedDRA coding

Moderate-Severe Hypoxic-Ischaemic Encephalopathy (HIE)

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

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: a) Born at ≥36 completed weeks gestation; b) Clinically stable* at the time of IMP administration; c)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: a) Sentinel Participant Criteria Only: must not meet the criteria for severe HIE.
3. Informed consent from parents/guardians/person with legal responsibility.
4. 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: a. Mean blood pressure (without inotropic support) must be greater than the 5th centile for gestation (see BP centile charts in Appendix 3) prior to administration of the loading dose. b. Mean blood pressure (with or without inotropic support) must be greater than the 5th centile for gestation (see BP centile charts in Appendix 3) prior to administration of each maintenance dose. i. The participant must not be receiving more than one vasoactive inotrope. ii. The Vasoactive-Inotropic Score (VIS) must be ≤10. The VIS score is calculated as: VIS = dopamine (μg/kg/min) + dobutamine (μg/kg/min) + [100 x adrenaline (μg/kg/min)] + [100 x noradrenaline (μg/kg/min)] 3. No evidence of acute kidney injury resulting in hyperkalaemia (defined as a serum potassium >6.5mmol/L) that continues to rise despite stopping potassium containing infusions and potassium sparing drugs (based on the most recent available blood test result). 4. No clinical concerns of acute liver failure for the loading dose†. 5. No evidence of ongoing acute liver failure defined as INR >3 (despite administration of parenteral vitamin K or clotting factor replacement) for administration of maintenance doses based on the most recent blood test. 6. Clinical or electrographic seizures, if present, controlled with anti-seizure medications. If there are seizures, these must not be ongoing or uncontrolled despite anti-seizure medications. 7. Clinical observations within acceptable range for an infant undergoing therapeutic hypothermia. 8. No clinical stability concerns from the attending neonatologist.

Exclusion criteria 8

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 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Safety: Assessment of the safety profile of melatonin across up to four dose levels based on the occurrence of dose-limiting events (DLEs) during the 172-hour safety window (from the first IMP administration to 100 hours after the final dose).
2. The attainment of plasma melatonin levels within the range of 15-30mg/L measured at T0, T0+2h, T0+24h, T0+26h, T0+48h, T0+96h across dose levels being studied.
3. The attainment of plasma blood alcohol concentration (BAC) levels <0.25g/L measured at T0, T0+2h, T0+24h, T0+26h, T0+48h, T0+96h across dose levels being studied.

Secondary endpoints 6

1. Pharmacokinetic Model (PK): Estimation of population PK parameters in the target population (clearance, volume of distribution, half-life, Cmax, AUC) of melatonin and ethanol from plasma samples collected at T0, T0+2h, T0+24h, T0+26h, T0+48h, T0+96h , with interim analyses after recruitment of at least 6 babies (dose level 2), updated with cumulating real-time data prior to every DSMB meeting for dose-escalation decision.
2. 2A) Establishing a Neonatal Neuroprotection Trial Network in anticipation of a Phase II RCT: a) Successful harmonisation of 3T MRI scanners and acquisition of magnetic resonance spectroscopy (MRS) at days 4 to 10: i) Evaluation of pattern and severity of injury using T1/T2 MRI and diffusion-weighted imaging (DWI). ii) Assessment of HIE severity through baseline lactate/N-acetylaspartate (NAA) statistics to inform the sample size calculation of the Phase 2 trial.
3. 2B) Establishing a Neonatal Neuroprotection Trial Network in anticipation of a Phase II RCT: b) Successful (in >90% of enrolled babies) integration of amplitude-integrated electroencephalography aEEG/EEG monitoring throughout the cooling and rewarming periods at all centres, using recovery of background activity as a proxy for outcome (a more rapid recovery of background voltage is associated with a favourable outcome).
4. 2C) Establishing a Neonatal Neuroprotection Trial Network in anticipation of a Phase II RCT: c) Successful (>90% of enrolled babies) integration of cerebral near-infrared spectroscopy (NIRS) as part of the neurocritical care management for infants with HIE throughout the cooling and rewarming periods at all centres using NIRS as standard care.
5. 2D) Successful collection (>90% of enrolled babies) of early surrogate measures of neurodevelopmental outcomes (The Hammersmith Infant Neurological Examination (HINE) at hospital discharge, Hammersmith Neonatal Neurological Examinations (HNNE) at day 90 General Movement Assessment (GMA) at hospital discharge and day 90, and Ages & Stages Questionnaires (ASQ-3) at day 90).
6. Recruitment: a. Metrics on the acceptability of the study among potential participants’ parent/legal guardian(s) assessed through screening and enrolment logs that capture consent rates and reasons for non-consent b. Rates of informed consent obtained within the 6-hour timeframe. c. Timelines and initiation of the first dose administration within the specified 6-hour window.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University College London

Sponsor organisation

University College London

Address

250 Euston Road

City

London

Postcode

NW1 2PG

Country

United Kingdom

Scientific contact point

Organisation

University College London

Contact name

Professor Nikki Robertson

Public contact point

Organisation

University College London

Contact name

Felicia Ikeji

Third parties 11

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Application history

3 submissions — initial application plus substantial / non-substantial modifications