Cooling in Mild Encephalopathy

NCT05889507 | Recruiting Phase 3 DMC

• 1 other identifier: 326176
• Study Type: interventional
• Target: 426
• Locations: 2 countries
• Sites: 39

Brief Summary

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:

• 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.

Conditions

Neonatal Encephalopathy; Newborn Asphyxia

Keywords

therapeutic hypothermia

Outcome Measures

Primary Outcomes (1)

• Mean Cognitive Composite Scale score from the Bayley IV examination

  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 Outcomes (12)

• Neonatal seizures

  During neonatal hospitalisation (Expected average of 2 weeks)

• Duration of intensive care.

  During neonatal hospitalisation (Expected average of 2 weeks)

• Duration of hospital stay.

  During neonatal hospitalisation (Expected average of 2 weeks).

• Duration of mechanical ventilation.

  During neonatal hospitalisation (Expected average of 2 weeks).

• Duration of inotropic support.

  During neonatal hospitalisation (Expected average of 2 weeks).

Study Arms (2)

Whole body hypothermia

EXPERIMENTAL

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).

Procedure: Whole body hypothermia; Other: Supportive neonatal intensive care; Diagnostic Test: Follow up assessment at 2 years of age

Normothermia

ACTIVE COMPARATOR

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.

Procedure: Targeted normothermia; Other: Supportive neonatal intensive care; Diagnostic Test: Follow up assessment at 2 years of age

Interventions

Whole body hypothermia PROCEDURE

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.

Whole body hypothermia

Targeted normothermia PROCEDURE

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.

Normothermia

Supportive neonatal intensive care OTHER

Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated

Normothermia; Whole body hypothermia

Follow up assessment at 2 years of age DIAGNOSTIC_TEST

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.

Normothermia; Whole body hypothermia

Eligibility Criteria

• Age: 1 Hour - 6 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Imperial College London: lead

Study Sites (39)

Neonatal Unit, Università degli Studi della Campania "Luigi Vanvitelli"

Naples, Italy

RECRUITING

William Harvey Hospital

Ashford, TN24 0LZ, United Kingdom

RECRUITING

St Peters Hosptial

Ashford, United Kingdom

RECRUITING

Birmingham Heartlands

Birmingham, United Kingdom

RECRUITING

Royal Bolton Hosptial

Bolton, United Kingdom

RECRUITING

Bradford Royal Infirmary

Bradford, United Kingdom

RECRUITING

Royal Sussex County Hospital

Brighton, BN2 5BE, United Kingdom

RECRUITING

St Michael's Hospital

Bristol, BS2 8EG, United Kingdom

RECRUITING

Southmead Hosptial

Bristol, United Kingdom

RECRUITING

Rosie Maternity Hosptial, Addenbrookes

Cambridge, United Kingdom

RECRUITING

University Hospital Coventry

Coventry, United Kingdom

RECRUITING

Darent Valley Hospital

Dartford, DA2 8DA, United Kingdom

RECRUITING

Simpson Centre for Reproductive Health NHS Lothian

Edinburgh, United Kingdom

RECRUITING

Royal Devon and Exeter Hospital

Exeter, United Kingdom

RECRUITING

Medway Maritime Hospital

Gillingham, United Kingdom

RECRUITING

Princess Royal Hospital

Haywards Heath, RH16 4EX, United Kingdom

RECRUITING

Leeds centre for Newborn Care (Leeds General Infirmary)

Leeds, United Kingdom

RECRUITING

Leicester Royal Infirmary

Leicester, United Kingdom

RECRUITING

Liverpool Women's Hospital

Liverpool, United Kingdom

RECRUITING

Homerton University Hospital

London, United Kingdom

RECRUITING

Imperial College Healthcare NHS FT

London, United Kingdom

RECRUITING

Newham General Hosptial

London, United Kingdom

RECRUITING

Northwick Park Hospital

London, United Kingdom

RECRUITING

Queen's Hospital, Barking

London, United Kingdom

RECRUITING

Royal London Hospital

London, United Kingdom

RECRUITING

St Thomas Hospital

London, United Kingdom

RECRUITING

Whipps Cross Hospital

London, United Kingdom

RECRUITING

Luton and Dunstable Hospital

Luton, United Kingdom

RECRUITING

St Mary's Hospital

Manchester, United Kingdom

RECRUITING

Wythenshawe Hosptial

Manchester, United Kingdom

RECRUITING

Royal Victoria Infirmary

Newcastle upon Tyne, United Kingdom

RECRUITING

Queens Medical Centre Nottingham

Nottingham, United Kingdom

RECRUITING

John Radcliffe Hospital

Oxford, OX3 9DU, United Kingdom

RECRUITING

Derriford Hosptial

Plymouth, United Kingdom

RECRUITING

Turnbridge Wells Hospital

Royal Tunbridge Wells, TN2 4QJ, United Kingdom

RECRUITING

University Hospital of Wales

Wales, United Kingdom

RECRUITING

Whiston Hospital

Whiston, United Kingdom

RECRUITING

Royal Albert Edward Infirmary

Wigan, United Kingdom

RECRUITING

Worthing Hospital

Worthing, United Kingdom

RECRUITING

Related Publications (2)

• Montaldo P, Cirillo M, Burgod C, Caredda E, Ascione S, Carpentieri M, Puzone S, D'Amico A, Garegrat R, Lanza M, Moreno Morales M, Atreja G, Shivamurthappa V, Kariholu U, Aladangady N, Fleming P, Mathews A, Palanisami B, Windrow J, Harvey K, Soe A, Pattnayak S, Sashikumar P, Harigopal S, Pressler R, Wilson M, De Vita E, Shankaran S, Thayyil S; COMET Trial Group. Whole-Body Hypothermia vs Targeted Normothermia for Neonates With Mild Encephalopathy: A Multicenter Pilot Randomized Clinical Trial. JAMA Netw Open. 2024 May 1;7(5):e249119. doi: 10.1001/jamanetworkopen.2024.9119.

  PMID: 38709535 BACKGROUND

• Garegrat R, Montaldo P, Burgod C, Pant S, Mazlan M, Palanisami B, Chakkarapani E, Woolfall K, Johnson S, Grant PE, Land S, Mahmoud M, Brady T, Cornelius V, Adams E, Dorling J, Aladangadi N, Fleming P, Pressler R, Shennan A, Petrou S, Soe A, Basset P, Shankaran S, Thayyil S. Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomised controlled trial. BMC Pediatr. 2024 Jul 18;24(1):460. doi: 10.1186/s12887-024-04935-4.

  PMID: 39026197 DERIVED

MeSH Terms

Conditions

Asphyxia Neonatorum

Interventions

Aging

Condition Hierarchy (Ancestors)

Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Growth and Development; Physiological Phenomena

Study Officials

• Sudhin Thayyil, PhD

  Imperial College London

  PRINCIPAL INVESTIGATOR

• Seetha Shankaran, MD

  Wayne State University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sudhin Thayyil, MD, PhD

CONTACT

02033132473; s.thayyil@imperial.ac.uk

Reema Garegrat, MD, DNB, MRCPCH

CONTACT

02033132473; r.garegrat@imperial.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Administration of cooling therapy cannot be masked. The 24 (±2) months of age assessments will be performed by a central team of 2 to 3 examiners, masked to the allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2023
• First Posted: June 5, 2023
• Study Start: March 15, 2024
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2030
• Last Updated: February 6, 2026

Record last verified: 2026-02

Locations

GB (38); IT (1)