Cooling in Mild Encephalopathy (COMET)

February 4, 2026 updated by: Imperial College London

Whole-body Hypothermia Versus Normothermia in Mild Neonatal Encephalopathy: A Multicentre Randomised Controlled Trial

The goal of this randomised control trial is to establish the safety and efficacy of whole-body hypothermia for babies with mild hypoxic ischaemic encephalopathy, inform national and international guidelines, and establish uniform practice across the NHS.

The main questions it aims to answer are:

  1. Does whole-body cooling (33.5±0.5°C) initiated within six hours of birth and continued for 72 hours, improve cognitive development at 24 (±2) months of age after mild neonatal encephalopathy compared with normothermia (37±0.5°C)?
  2. Does a prospective trial-based economic evaluation support the provision of cooling therapy for mild encephalopathy in the NHS on cost-effectiveness grounds?

Participants will have the following interventions:

  • Randomisation into one of the following groups

    • Whole body hypothermia group
    • Targeted normothermia group
  • Bayley Scales of Infant and Toddler Development 4th Edition (Bayley-IV) examination at 24 (±2) months of age.

Researchers will compare the mean Cognitive Composite Scale score from the Bayley IV examination between the two groups.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

COMET is a phase III prospective multi-centre open label two-arm randomised controlled trial with an internal pilot and masked outcome assessments. Administration of cooling therapy cannot be masked.

All babies born at or after 36 weeks and requiring prolonged resuscitation at birth (defined as continued resuscitation at 10 minutes after birth or 10-minute Apgar score less than 6) or those with severe birth acidosis (defined as any occurrence of: pH =<7.00 or Base deficit >=16mmol/l in any cord or baby gas sample within 60 minutes of birth) and admitted to the neonatal unit will started on aEEG or EEG as a part of standard clinical care.

Neonatal doctors or advanced nurse practitioners (clinical team) will screen for eligibility using a structured neurological examination performed between 1 to 6 hours after birth.

Once parental consent is obtained, babies will be randomised to whole-body hypothermia or targeted normothermia within 6 hours of birth, using a web-based program. Initial assessment and randomisation (and initiation of whole-body hypothermia or targeted normothermia) will occur at the hospital of birth. The babies in both arms, who are born at a non-cooling centre (LNU or SCBU) will be then transferred to the nearest cooling centre (NICU) within 8 hours of birth for continued care.

Whole-body hypothermia (33.5±0.5°C) will be initiated within 6 hours of birth and continued for 72 hours using a servo-controlled cooling machine at the nearest available neonatal intensive care unit (cooling centre). Passive cooling methods will not be allowed. Whole-body hypothermia to 33.5±0.5°C for 72 hours is the duration and depth of cooling that is standard for babies with moderate or severe HIE in high income countries. To administer this intervention babies will be kept on a cooling mattress or blanket circulating a coolant/water, a rectal temperature probe will be inserted, and overhead radiant warmers will be switched off. The cooling device will be set to hypothermia mode and body temperature will be rapidly reduced to 33.5°C from 37.0°C and maintained within the target range of 33°C to 34°C.

In the Normothermia (Control group), the rectal temperature will be maintained at 37.0±0.5°C for the first 88 hours and any hyperthermia will be treated with a standardised protocol. Four hourly axillary temperature will be recorded during the first 88 hours. Babies in the control group who develop seizures (level 1 or level 2) and progress to moderate HIE between 6 to 24 hours may be treated with whole-body cooling for 72 hours as clinical care, although this is expected to occur in less than 5%.

Conventional MRI using standard 3D T1-weighted and 2D T2-weighted sequences and diffusion weighted imaging will be performed prior to discharge home.

The follow-up assessment will be done when the recruited babies are 24 (±2) months of age. The assessment will be carried out using the Bayley Scales of Infant and Toddler Development IV. It is a validated and standardized scoring system that assesses development in three domains, that is cognition, language, and motor development. In addition, all infants will have a detailed neurological examination, including Gross Motor Function Classification System (GMFCS) for cerebral palsy, vision, and hearing assessment. Babies who die (the mortality rate is expected to be less than 1% in mild HIE) or who cannot be assessed with the Bayley-IV due to severe disability will be allocated a Cognitive Scale Composite score one point below the basal test score (i.e., score of 54). In all infants, PARCA-R (online or face to face) will be completed by the parents immediately prior to the Bayley IV assessments and CBCL (face to face only) after the Bayley IV assessments.

The data will be collected into a paper case report form (CRF) initially and then entered into electronic database at the participating sites. Data will include ante-natal, birth, and neonatal clinical information including gestational age, birth weight, gender, Apgar scores, birth history, delivery room resuscitation to assess the baseline comparability of the groups, core body temperature for assessment of intervention, details of the hospital course, laboratory investigations and MR imaging for safety monitoring, and neurodevelopmental outcomes at 24 (±2) months of age for primary outcome evaluation.

Study Type

Interventional

Enrollment (Estimated)

426

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Naples, Italy
        • Recruiting
        • Neonatal Unit, Università degli Studi della Campania "Luigi Vanvitelli"
        • Contact:
  • United Kingdom
      • Ashford, United Kingdom, TN24 0LZ
        • Recruiting
        • William Harvey Hospital
        • Contact:
      • Ashford, United Kingdom
      • Birmingham, United Kingdom
      • Bolton, United Kingdom
      • Bradford, United Kingdom
        • Recruiting
        • Bradford Royal Infirmary
        • Contact:
      • Brighton, United Kingdom, BN2 5BE
      • Bristol, United Kingdom, BS2 8EG
      • Bristol, United Kingdom
      • Cambridge, United Kingdom
      • Coventry, United Kingdom
      • Dartford, United Kingdom, DA2 8DA
      • Edinburgh, United Kingdom
      • Exeter, United Kingdom
      • Gillingham, United Kingdom
        • Recruiting
        • Medway Maritime Hospital
        • Contact:
      • Haywards Heath, United Kingdom, RH16 4EX
        • Recruiting
        • Princess Royal Hospital
        • Contact:
      • Leeds, United Kingdom
        • Recruiting
        • Leeds centre for Newborn Care (Leeds General Infirmary)
        • Contact:
      • Leicester, United Kingdom
      • Liverpool, United Kingdom
      • London, United Kingdom
        • Recruiting
        • Northwick Park Hospital
        • Contact:
      • London, United Kingdom
      • London, United Kingdom
        • Recruiting
        • Homerton University Hospital
        • Contact:
      • London, United Kingdom
      • London, United Kingdom
      • London, United Kingdom
        • Recruiting
        • Imperial College Healthcare NHS FT
        • Contact:
      • London, United Kingdom
      • London, United Kingdom
      • Luton, United Kingdom
      • Manchester, United Kingdom
      • Manchester, United Kingdom
      • Newcastle upon Tyne, United Kingdom
      • Nottingham, United Kingdom
        • Recruiting
        • Queens Medical Centre Nottingham
        • Contact:
      • Oxford, United Kingdom, OX3 9DU
      • Plymouth, United Kingdom
      • Royal Tunbridge Wells, United Kingdom, TN2 4QJ
        • Recruiting
        • Turnbridge Wells Hospital
        • Contact:
      • Wales, United Kingdom
      • Whiston, United Kingdom
      • Wigan, United Kingdom
      • Worthing, United Kingdom
        • Recruiting
        • Worthing Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

All babies born at or after 36 weeks of gestation with a birth weight of 1800g or more with birth acidosis or requiring resuscitation at birth will be screened for eligibility.

Parents will be approached for consent if the baby meets all the three (A + B + C) criteria below:

A. Evidence of intra-partum hypoxia-ischemia defined as any of - (i) Apgar score of <6 at 10 minutes after birth; (ii) continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth; (iii) severe birth acidosis defined as any occurrence of pH =<7.00 or a Base deficit >=16mmol/l in any cord or baby gas sample within 60 minutes of birth.

B. Evidence of mild hypoxic ischaemic encephalopathy defined as - two or more abnormal findings in any of the six categories of the modified Sarnat examination (level of consciousness, spontaneous activity, posture, tone, primitive reflexes, and autonomic nervous system) but not meeting the diagnosis of moderate or severe hypoxic ischaemic encephalopathy on a standardised examination performed by a certified examiner between 1 to 6 hours of age.

C. Normal amplitude on aEEG performed for at least 30 minutes between 1 to 6 hours of age. Normal amplitude will be defined as upper margin of the aEEG activity more than 10 microvolts and the lower margin more than 5 microvolts on a single channel aEEG.

Exclusion Criteria:

  • Infants who meet the BAPM criteria for whole-body hypothermia
  • Infants without encephalopathy defined as less than two abnormalities on structured neurological examination.
  • Infants with major congenital or chromosomal anomalies identified prior to randomisation.
  • Infants with birthweight <1800g.
  • Infants who have already received sedation, muscle relaxation, or anti-convulsants prior to neurological assessment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Whole body hypothermia
Whole-body hypothermia (33.5±0.5°C) will be initiated within 6 hours of birth and continued for 72 hours using a servo-controlled cooling machine at the nearest available neonatal intensive care unit (cooling centre).
Other: Supportive neonatal intensive care
Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated
Procedure: Whole body hypothermia
Whole-body hypothermia (33.5±0.5°C) initiated within 6 hours of birth and continued for 72 hours. The rectal temperature will be maintained at 33.5±0.5°C using a servo-controlled cooling machine.
Diagnostic test: Follow up assessment at 2 years of age
The assessment will be carried out using the Bayley Scales of Infant and Toddler Development IV. In addition, all infants will have a detailed neurological examination, including Gross Motor Function Classification System (GMFCS) for cerebral palsy, vision, and hearing assessment. Babies who die or who cannot be assessed with the Bayley-IV due to severe disability will be allocated a Cognitive Scale Composite score one point below the basal test score. PARCA-R will be completed by the parents immediately.
Active Comparator: Normothermia
The axillary temperature will be maintained at 37±0.5°C using servo-controlled incubators for the first 80 hours and any hyperthermia will be treated with a standardised protocol.
Other: Supportive neonatal intensive care
Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated
Diagnostic test: Follow up assessment at 2 years of age
The assessment will be carried out using the Bayley Scales of Infant and Toddler Development IV. In addition, all infants will have a detailed neurological examination, including Gross Motor Function Classification System (GMFCS) for cerebral palsy, vision, and hearing assessment. Babies who die or who cannot be assessed with the Bayley-IV due to severe disability will be allocated a Cognitive Scale Composite score one point below the basal test score. PARCA-R will be completed by the parents immediately.
Procedure: Targeted normothermia
The axillary temperature will be maintained at 37±0.5°C for the first 80 hours and any hyperthermia will be treated with a standardised protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean Cognitive Composite Scale score from the Bayley IV examination
Time Frame: 22 to 26 months
The Bayley scales of Infant and toddler development IV is a validated and standardised scoring system that assesses development of three domains, that is cognition, language, and motor development. Babies who die or who cannot be assessed with the Bayley IV due to severe disability will be allocated a Cognitive Scale Composite score one point below the basal test score similar to the previous whole-body hypothermia trials.
22 to 26 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neonatal seizures
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks)
Definite seizures: seizures confirmed on EEG with or without clinical manifestations or Level 2-Probable seizure: clinically assessed focal clonic/ focal tonic seizure or seizures confirmed on aEEG.
During neonatal hospitalisation (Expected average of 2 weeks)
Duration of intensive care.
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks)
Number of days of neonatal intensive care.
During neonatal hospitalisation (Expected average of 2 weeks)
Duration of hospital stay.
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks).
Total number of days of inpatient care in a neonatal unit.
During neonatal hospitalisation (Expected average of 2 weeks).
Duration of mechanical ventilation.
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks).
Number of hours on invasive ventilation through an endotracheal tube.
During neonatal hospitalisation (Expected average of 2 weeks).
Duration of inotropic support.
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks).
Total number of hours on inotropic support.
During neonatal hospitalisation (Expected average of 2 weeks).
Number of babies with bloodstream or cerebrospinal fluid positive infection.
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks).
Isolation of a pathogenic organism from blood or cerebrospinal fluid along with a clinical diagnosis of sepsis, at any time during neonatal hospitalisation.
During neonatal hospitalisation (Expected average of 2 weeks).
Number of babies with thrombocytopenia or coagulopathy requiring transfusion of blood products.
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks).
Prolonged blood coagulation requiring blood products
During neonatal hospitalisation (Expected average of 2 weeks).
Opioid use.
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks).
Total cumulative dose of morphine per kilogram of body weight.
During neonatal hospitalisation (Expected average of 2 weeks).
Number of babies exclusively breastfeeding at hospital discharge.
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks).
Defined as the newborn receiving only breast milk the last feedings before discharge.
During neonatal hospitalisation (Expected average of 2 weeks).
Brain injury scores on conventional magnetic resonance imaging
Time Frame: During neonatal hospitalisation (Expected average of 2 weeks).
Defined as per Rutherford/NICHD staging.
During neonatal hospitalisation (Expected average of 2 weeks).
Survival without any neurological impairment.
Time Frame: 22 to 26 months
Score of >85 in all Bayley-IV domains (motor, language, and cognitive), normal neurological examination with no cerebral palsy (Gross motor function classification system score <1), no hearing or visual impairment (as reported by parents), and no seizure disorder.
22 to 26 months
Preschool Child Behaviour Checklist (CBCL 1½-5)
Time Frame: 22 to 26 months
Completed by parents at the 24-month assessment to provide a standardised measure of children's behavioural outcomes on scales that assess internalizing and externalizing behaviour problems and a Total Problems Scale. Mean standardised T-scores on each scale will be compared between groups. The CBCL checklist will be completed after the Bayley IV assessments.
22 to 26 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Imperial College London

Investigators

  • Principal Investigator: Sudhin Thayyil, PhD, Imperial College London
  • Principal Investigator: Seetha Shankaran, MD, Wayne State University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 15, 2024

Primary Completion (Estimated)

January 1, 2030

Study Completion (Estimated)

January 1, 2030

Study Registration Dates

First Submitted

May 12, 2023

First Submitted That Met QC Criteria

May 25, 2023

First Posted (Actual)

June 5, 2023

Study Record Updates

Last Update Posted (Actual)

February 6, 2026

Last Update Submitted That Met QC Criteria

February 4, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 326176

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Protocol, SAP and consent forms will be shared midway through the trial recruitment following appropriate requests

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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