Clinical trial NCT05889507: Cooling in Mild Encephalopathy
Official title: Whole-body Hypothermia Versus Normothermia in Mild Neonatal Encephalopathy: A Multicentre Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Neonatal Encephalopathy
Newborn Asphyxia
Keywords: therapeutic hypothermia
Lead sponsor: Imperial College London
Sponsor class: OTHER
First posted: 2023-06-05
Enrollment: 426
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mean Cognitive Composite Scale score from the Bayley IV examination
timeFrame: 22 to 26 months
Secondary outcomes:
measure: Neonatal seizures
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks)
measure: Duration of intensive care.
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks)
measure: Duration of hospital stay.
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks).
measure: Duration of mechanical ventilation.
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks).
measure: Duration of inotropic support.
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks).
measure: Number of babies with bloodstream or cerebrospinal fluid positive infection.
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks).
measure: Number of babies with thrombocytopenia or coagulopathy requiring transfusion of blood products.
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks).
measure: Opioid use.
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks).
measure: Number of babies exclusively breastfeeding at hospital discharge.
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks).
measure: Brain injury scores on conventional magnetic resonance imaging
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks).
measure: Survival without any neurological impairment.
timeFrame: 22 to 26 months
measure: Preschool Child Behaviour Checklist (CBCL 1½-5)
timeFrame: 22 to 26 months
Other outcomes:
Locations:
city: Naples
country: Italy
facility: Neonatal Unit, Università degli Studi della Campania "Luigi Vanvitelli"
city: Ashford
country: United Kingdom
facility: William Harvey Hospital
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: Bristol
country: United Kingdom
facility: St Michael's Hospital
city: Dartford
country: United Kingdom
facility: Darent Valley Hospital
city: Gillingham
country: United Kingdom
facility: Medway Maritime Hospital
city: Haywards Heath
country: United Kingdom
facility: Princess Royal Hospital
city: Liverpool
country: United Kingdom
facility: Liverpool Women's Hospital
city: London
country: United Kingdom
facility: Homerton University Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS FT
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hosptial
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Tunbridge Wells
country: United Kingdom
facility: Turnbridge Wells Hospital
city: Worthing
country: United Kingdom
facility: Worthing Hospital
Study officials:
affiliation: Imperial College London
name: Sudhin Thayyil, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Seetha Shankaran, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.