Optimising the Duration of Cooling in Mild Encephalopathy

Study Overview
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Brief Summary
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Phase II randomised control trial of whole body cooling in mild neonatal encephalopathy.

Detailed Description
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Although therapeutic hypothermia for 72 hours reduces brain injury and improves long term neurodevelopmental outcomes after moderate or severe neonatal encephalopathy, the benefits and optimal duration of cooling therapy in mild encephalopathy is not known. Adverse neurodevelopmental outcomes at 2 years occur in 16% of babies with un-treated mild neonatal encephalopathy. In the phase I of the COMET trial, we have shown that it is feasible to identify and randomise babies with mild encephalopathy, and to obtain the primary outcome (proton MR spectroscopy levels of Thalamic N-acetyl Aspartate) accurately. The phase II of the COMET trial will examine the benefits and optimal duration of cooling therapy in babies with mild encephalopathy. Research questions Does whole body cooling initiated within 6 hours of birth and continued for 72 hours increase thalamic MR spectroscopy N-acetyl aspartate levels in babies with mild encephalopathy, when compared with those who are not cooled? (Cohort 1) In babies with mild encephalopathy undergoing cooling therapy as clinical care, does rewarming at 48 hours as opposed to 72 hours result in similar thalamic N-acetyl aspartate levels? (Cohort 2) Study Population Cohort 1: A total of 60 babies with mild encephalopathy (>36 weeks; >2Kg) aged less than 6 hours will be recruited from several tertiary neonatal units in the UK, Europe, USA and Canada, over a 2 year period. The babies will be randomised to usual care (no cooling) or cooling therapy (core temperature 33 to 34 C) for 72 hours within six hours of birth. MR imaging and spectroscopy will be performed between 4 to 14 days after birth. Cohort 2: A total of 80 babies will mild encephalopathy (>36 weeks; >2Kg) aged 24 to 48 hours and undergoing cooling therapy as a part of standard clinical care will be recruited from several UK cooling centres, over a 2 year period. The babies will be randomised to rewarming after 48 hours or 72 hours of cooling therapy. MR imaging and spectroscopy will be performed between 4 to 14 days after birth. The babies recruited to cohort 1 will not be eligible for recruitment to cohort 2. Primary outcome (both cohorts) • Proton MR spectroscopy Thalamic N-acetyl aspartate levels between 4 to 14 days of age. Benefits of the trial These data will inform the national and international guidelines on management of babies with mild neonatal encephalopathy. If a shorter duration of cooling is as good or better than 3 days of cooling, this will reduce the intensive care stays, opioid use and separation from parents.

Official Title
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Optimising the Duration of Cooling Therapy in Mild Neonatal Encephalopathy

Conditions
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Neonatal Encephalopathy, Hypothermia Neonatal, Magnetic Resonance Spectroscopy

Intervention / Treatment
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* Other: Therapeutic hypothermia


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA All of the following three criteria should be met: Age less than six hours. AND Evidence of acute perinatal asphyxia Metabolic acidosis (pH <7.0 and/or BE >-16) in cord gas or a blood gas within one of birth. OR If the pH or BE is borderline (pH<7.15 to 7.0) and/or BE >-10 to -16) in cord and/or blood gas within 1h of birth additional evidence of perinatal asphyxia is required, which includes either an acute obstetric event (e.g. cord prolapse, abruption, shoulder dystocia) OR Need for continued resuscitation or ventilation at 10 minutes and/or a 10 min Apgar score <6 Evidence of mild NE (at-least two abnormalities) on an NICHD neurological examination performed between 1 and 6h of birth. EXCLUSION CRITERIA The following group of babies will be excluded prior to randomisation Babies without encephalopathy Babies with moderate or severe encephalopathy who meet the current NICE/AAP guidelines for cooling therapy. Babies with seizures (clinical and/or aEEG/EEG) Babies with moderate or severe abnormalities on aEEG voltage criteria. Babies with life threatening congenital malformations

Ages Eligible for Study
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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
Interventional Model Description: Therapeutic hypothermia (33 to 34 C) for 2 different durations (48, or 72 h) and usual care (normothermia)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Usual care<br>Usual care (normothermia) arm | |
| Experimental: Therapeutic hypothermia - 48 h<br>Whole body cooling (33 to 34 C) for 48 hours | Other: Therapeutic hypothermia<br>* Whole body cooling using a servo controlled device<br>|
| Experimental: Therapeutic hypothermia - 72 h<br>Whole body cooling (33 to 34 C) for 72 hours | Other: Therapeutic hypothermia<br>* Whole body cooling using a servo controlled device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thalamic N-acetyl aspartate level | Feasibility of obtaining Proton MR spectroscopy thalamic N-acetyl aspartate level | 4 to 14 days after birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain injury on conventional MR imaging | Cortical, white matter or deep nuclei injury | 4 to 14 days after birth | 
| Hospital stay | Duration of hospital stay | Upto 30 days after birth |