Cooling in Mild Encephalopathy Versus Targeted Normothermia

Study Overview
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Brief Summary
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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: Does whole-body hypothermia to 33.5 ±0.5°C started within 6h of birth and continued for 72h, improve cognitive (thinking ability) development at two years of age after mild hypoxic ischaemic encephalopathy compared with targeted normothermia at 36.5 ±0.5 °C? Does a prospective trial-based economic evaluation support the provision of cooling therapy for mild encephalopathy in the NHS on cost-effective 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
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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 and admitted to the neonatal unit will be screened for eligibility. 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) for continued care at earliest. 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. The duration and depth of cooling will be as per the current standards for babies undergoing hypothermia with moderate or severe HIE in the NHS. After 72 hours of whole-body hypothermia at 33.5±0.5°C, the baby will be rewarmed at 0.5°C per hour to reach 36.5±0.5°C over 8 hours. Two hourly rectal temperature data will be collected for the first 80 hours. For babies randomised to 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. Rectal temperature will be recorded every 2 hours for the first 80 hours. 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 for the recruited babies at 24 (±2) months of age by a central team of 2 to 3 examiners, masked to the allocation. 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 (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) similar to the previous whole-body hypothermia trials. 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). The follow up visit will be scheduled in close consultation with the parents, either at the local hospital or at home. 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 2 years for primary outcome evaluation.

Official Title
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Cooling in Mild Encephalopathy Versus Targeted Normothermia Trial

Conditions
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Neonatal Encephalopathy, Newborn Asphyxia

Intervention / Treatment
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* Procedure: Whole body hypothermia
* Procedure: Targeted normothermia
* Other: Supportive neonatal intensive care
* Diagnostic Test: Follow up assessment at 2 years of age


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 0 Hours
Maximum Age: 6 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Whole body hypothermia<br>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<br>* 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.<br>Other: Supportive neonatal intensive care<br>* Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated<br>Diagnostic Test: Follow up assessment at 2 years of age<br>* 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.<br>|
| Active Comparator: Normothermia<br>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. | Procedure: Targeted normothermia<br>* 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.<br>Other: Supportive neonatal intensive care<br>* Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated<br>Diagnostic Test: Follow up assessment at 2 years of age<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| Duration of intensive care. | Number of days of neonatal intensive care. | During neonatal hospitalisation (Expected average of 2 weeks) | 
| Duration of hospital stay. | Total number of days of inpatient care in a neonatal unit. | During neonatal hospitalisation (Expected average of 2 weeks). | 
| Duration of mechanical ventilation. | Number of hours on invasive ventilation through an endotracheal tube. | During neonatal hospitalisation (Expected average of 2 weeks). | 
| Duration of inotropic support. | 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. | 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. | Prolonged blood coagulation requiring blood products | During neonatal hospitalisation (Expected average of 2 weeks). | 
| Opioid use. | 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. | 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 | Defined as per Rutherford/NICHD staging. | During neonatal hospitalisation (Expected average of 2 weeks). | 
| 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 | 
| 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 |