Melatonin for Hypoxic-ischemic encephalopathy | Moderate-severe hypoxic-ischaemic encephalopathy

Inclusion criteria

• {"criterion_text":"- 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.\n- 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.\n- Informed consent from parents/guardians/person with legal responsibility.\n- 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

• {"criterion_text":"- Baby would be >6 hours of age when IMP administered\n- Initiation of IMP unlikely to be administered within 6 hours of birth\n- 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.\n- Postnatal hypoxic insult without any evidence of HIE at birth.\n- Birth weight less than 2nd centile for gestation on UK-WHO growth charts\n- Congenital anomalies i.e. any major antenatal diagnosed congenital abnormalities such as congenital heart disease, suspected or known chromosomal abnormalities\n- Infant is participating in another interventional study during the birth hospitalisation (note: does not include observational studies)\n- Parents/legal guardians unable to give consent due to learning or other difficulties"}

Primary endpoints

• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Safety assessed by occurrence of dose-limiting events (DLEs) during a 172-hour safety window (from first IMP administration to 100 hours after final dose)."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Plasma melatonin concentration measured at specified timepoints (T0, T0+2h, T0+24h, T0+26h, T0+48h, T0+96h); target range 15-30 mg/L."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Blood alcohol concentration (BAC) measured at specified timepoints (T0, T0+2h, T0+24h, T0+26h, T0+48h, T0+96h); target BAC <0.25 g/L."}

Secondary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Population PK parameters (clearance, Vd, half-life, Cmax, AUC) estimated from plasma samples at T0, T0+2h, T0+24h, T0+26h, T0+48h, T0+96h; interim PK analyses after ≥6 babies (dose level 2) to inform DSMB dose-escalation decisions."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Harmonisation of 3T MRI/MRS across centres; MRI (T1/T2/DWI) and MRS acquisition at days 4–10; evaluation of injury pattern/severity and baseline lactate/NAA metrics."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Integration of aEEG/EEG monitoring during cooling/rewarming at all centres; use recovery of background activity as proxy outcome; success defined as >90% integration."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Integration of cerebral NIRS monitoring during cooling/rewarming at all centres; success >90% of enrolled babies."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Collection of early surrogate neurodevelopmental outcome measures (HINE at discharge; HNNE at day 90; GMA at discharge and day 90; ASQ-3 at day 90); target >90% collection."}
• {"endpoint_text":"- Recruitment: a.\tMetrics 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.\tRates of informed consent obtained within the 6-hour timeframe. c.\tTimelines and initiation of the first dose administration within the specified 6-hour window.","definition_or_measurement_approach":"Metrics captured via screening/enrolment logs (consent rates, reasons for non-consent); measurement of consent rates within 6-hour post-birth window and time to first dose administration within 6 hours."}

Ireland

Earliest CTIS Part Ii Submission Date

08-07-2025

Latest Decision Or Authorization Date

23-12-2025

Processing Time Days

168

Number Of Sites

3

Number Of Participants

17

Primary sponsor

Full Name

University College London

Organisation Type

Educational Institution

Country Of Registered Address

United Kingdom

Contract research organisations

Name

Bioxydyn Limited +442031084255

Responsibilities

MRI/MRS Imaging CRO

Third parties

• {"country":"United Kingdom","full_name":"Bioxydyn Limited +442031084255","duties_or_roles":"MRI/MRS Imaging CRO","organisation_type":"Industry"}
• {"country":"United Kingdom","full_name":"Professor Linda de Vries","duties_or_roles":"Perform clinical safety reads of MRI/MRS images.","organisation_type":"Industry"}
• {"country":"United Kingdom","full_name":"Nervus Limited","duties_or_roles":"Data Management and provision of aEEG/EEG equipment. Setup and training of equipment at study sites.","organisation_type":"Industry"}
• {"country":"Ireland","full_name":"University College Cork","duties_or_roles":"Analysis of laboratory results","organisation_type":"Educational Institution"}
• {"country":"United Kingdom","full_name":"University Of Edinburgh","duties_or_roles":"Diffusion MRI analysis","organisation_type":"Educational Institution"}
• {"country":"Belgium","full_name":"KU Leuven","duties_or_roles":"Population-Based Physiological Pharmacokinetic modelling component of the dose escalation study.","organisation_type":"Educational Institution"}
• {"country":"United Kingdom","full_name":"Professor Frances Cowan","duties_or_roles":"Perform clinical safety reads of MRI/MRS images.","organisation_type":"Industry"}
• {"country":"United States","full_name":"Sapient","duties_or_roles":"Support duties (code 4) as listed","organisation_type":"Industry"}
• {"country":"United Kingdom","full_name":"Analytical Services International (ASI)","duties_or_roles":"Analytical services (code 4)","organisation_type":"Industry"}
• {"country":"Ireland","full_name":"University College Cork (aEEG/EEG analysis)","duties_or_roles":"aEEG/EEG analysis of all participant data across all recruitment sites","organisation_type":"Educational Institution"}