Cooling in Mild Encephalopathy

Neonatal Encephalopathy Clinical Trial

— COMET  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05889507
• Other study ID #: 326176
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 1, 2024
• Est. completion date: March 30, 2029

Study information

• Verified date: March 2024
• Source: Imperial College London
• Contact: Sudhin Thayyil, MD, PhD
• Phone: 02033132473
• Email: s.thayyil[@]imperial.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 the NHS. 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 using servo-controlled incubators for the first 88 hours and any hyperthermia will be treated with a standardised protocol. Rectal temperature will be recorded as in the whole-body hypothermia group. Continuous 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 in all babies 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 426
• Est. completion date: March 30, 2029
• Est. primary completion date: March 30, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Hours to 6 Hours

Eligibility

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.

Related Conditions & MeSH terms

• Asphyxia
• Asphyxia Neonatorum
• Brain Diseases
• Neonatal Encephalopathy

Intervention

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.
• Targeted normothermia
The rectal temperature will be maintained at 36.5±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.

Locations

Country	Name	City	State
United Kingdom	William Harvey Hospital	Ashford
United Kingdom	Royal Sussex County Hospital	Brighton
United Kingdom	St Michaels Hospital	Bristol
United Kingdom	Frimley Park Hospital	Camberley
United Kingdom	Ashford and St Peter's Hospital	Chertsey
United Kingdom	Darent Valley Hospital	Dartford
United Kingdom	Medway NHS Foundation Trust	Gillingham
United Kingdom	Royal Surrey County Hospital	Guildford
United Kingdom	East Sussex Hospital	Hastings
United Kingdom	Princess Royal Hospital	Haywards Heath
United Kingdom	Liverpool Womens NHS Foundation Trust	Liverpool
United Kingdom	Homerton University Hospital	London
United Kingdom	Imperial College London	London
United Kingdom	Queen Elisabeth the Queen Mother Hospital	Margate
United Kingdom	John Radcliffe Hospital	Oxford
United Kingdom	East Surrey Hospital	Redhill
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Turnbridge Wells Hospital	Tunbridge Wells
United Kingdom	Worthing Hospital	Worthing

Sponsors (1)

Lead Sponsor	Collaborator
Imperial College London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Neonatal seizures	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)
Secondary	Duration of intensive care.	Number of days of neonatal intensive care.	During neonatal hospitalisation (Expected average of 2 weeks)
Secondary	Duration of hospital stay.	Total number of days of inpatient care in a neonatal unit.	During neonatal hospitalisation (Expected average of 2 weeks).
Secondary	Duration of mechanical ventilation.	Number of hours on invasive ventilation through an endotracheal tube.	During neonatal hospitalisation (Expected average of 2 weeks).
Secondary	Duration of inotropic support.	Total number of hours on inotropic support.	During neonatal hospitalisation (Expected average of 2 weeks).
Secondary	Number of babies with bloodstream or cerebrospinal fluid positive infection.	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).
Secondary	Number of babies with thrombocytopenia or coagulopathy requiring transfusion of blood products.	Prolonged blood coagulation requiring blood products	During neonatal hospitalisation (Expected average of 2 weeks).
Secondary	Opioid use.	Total cumulative dose of morphine per kilogram of body weight.	During neonatal hospitalisation (Expected average of 2 weeks).
Secondary	Number of babies exclusively breastfeeding at hospital discharge.	Defined as the newborn receiving only breast milk the last feedings before discharge.	During neonatal hospitalisation (Expected average of 2 weeks).
Secondary	Brain injury scores on conventional magnetic resonance imaging	Defined as per Rutherford/NICHD staging.	During neonatal hospitalisation (Expected average of 2 weeks).
Secondary	Survival without any neurological impairment.	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
Secondary	Preschool Child Behaviour Checklist (CBCL 1½-5)	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