Study Results
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Basic Information
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RECRUITING
PHASE3
426 participants
INTERVENTIONAL
2024-03-15
2030-01-01
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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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).
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.
Supportive neonatal intensive care
Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated
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.
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.
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.
Supportive neonatal intensive care
Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated
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.
Interventions
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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.
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.
Supportive neonatal intensive care
Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated
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.
Eligibility Criteria
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Inclusion Criteria
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 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.
1 Hour
6 Hours
ALL
No
Sponsors
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Imperial College London
OTHER
Responsible Party
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Principal Investigators
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Sudhin Thayyil, PhD
Role: PRINCIPAL_INVESTIGATOR
Imperial College London
Seetha Shankaran, MD
Role: PRINCIPAL_INVESTIGATOR
Wayne State University
Locations
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Bradford Royal Infirmary
Bradford, , United Kingdom
Neonatal Unit, Università degli Studi della Campania "Luigi Vanvitelli"
Naples, , Italy
William Harvey Hospital
Ashford, , United Kingdom
St Peters Hosptial
Ashford, , United Kingdom
Birmingham Heartlands
Birmingham, , United Kingdom
Royal Bolton Hosptial
Bolton, , United Kingdom
Royal Sussex County Hospital
Brighton, , United Kingdom
St Michael's Hospital
Bristol, , United Kingdom
Southmead Hosptial
Bristol, , United Kingdom
Rosie Maternity Hosptial, Addenbrookes
Cambridge, , United Kingdom
University Hospital Coventry
Coventry, , United Kingdom
Darent Valley Hospital
Dartford, , United Kingdom
Simpson Centre for Reproductive Health NHS Lothian
Edinburgh, , United Kingdom
Royal Devon and Exeter Hospital
Exeter, , United Kingdom
Medway Maritime Hospital
Gillingham, , United Kingdom
Princess Royal Hospital
Haywards Heath, , United Kingdom
Leeds centre for Newborn Care (Leeds General Infirmary)
Leeds, , United Kingdom
Leicester Royal Infirmary
Leicester, , United Kingdom
Liverpool Women's Hospital
Liverpool, , United Kingdom
Homerton University Hospital
London, , United Kingdom
Imperial College Healthcare NHS FT
London, , United Kingdom
Newham General Hosptial
London, , United Kingdom
Northwick Park Hospital
London, , United Kingdom
Queen's Hospital, Barking
London, , United Kingdom
Royal London Hospital
London, , United Kingdom
St Thomas Hospital
London, , United Kingdom
Whipps Cross Hospital
London, , United Kingdom
Luton and Dunstable Hospital
Luton, , United Kingdom
St Mary's Hospital
Manchester, , United Kingdom
Wythenshawe Hosptial
Manchester, , United Kingdom
Royal Victoria Infirmary
Newcastle upon Tyne, , United Kingdom
Queens Medical Centre Nottingham
Nottingham, , United Kingdom
John Radcliffe Hospital
Oxford, , United Kingdom
Derriford Hosptial
Plymouth, , United Kingdom
Turnbridge Wells Hospital
Royal Tunbridge Wells, , United Kingdom
University Hospital of Wales
Wales, , United Kingdom
Whiston Hospital
Whiston, , United Kingdom
Royal Albert Edward Infirmary
Wigan, , United Kingdom
Worthing Hospital
Worthing, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
Other Identifiers
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326176
Identifier Type: -
Identifier Source: org_study_id
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