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Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomised controlled
Reema Garegrat1, Paolo Montaldo2,3, Constance Burgod2
1Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, Du Cane Road, London, W12 0HS, England. r.garegrat@imperial.ac.uk.
Insights
The COMET trial investigates if cooling newborns with mild hypoxic ischemic encephalopathy improves cognitive development. This study aims to determine the safety and effectiveness of therapeutic hypothermia for mild cases, potentially guiding future treatment guidelines.
Area of Science:
- Neonatal neurology
- Pediatric critical care
- Therapeutic hypothermia
Background:
- Mild hypoxic ischemic encephalopathy (HIE) is linked to cognitive deficits and learning issues.
- Whole-body hypothermia is effective for moderate/severe HIE but its use in mild HIE is unproven.
- The Cooling in Mild Encephalopathy (COMET) trial addresses this knowledge gap.
Purpose of the Study:
- To evaluate the efficacy of whole-body hypothermia in improving cognitive development in neonates with mild HIE.
- To establish the safety profile of therapeutic hypothermia for mild HIE.
- To provide an economic assessment of hypothermia therapy in the NHS.
Main Methods:
- Phase III, multicenter, open-label, randomized controlled trial.
- 426 neonates with mild HIE randomized to 72 hours of hypothermia (33.5°C) or normothermia (37°C).
- Neurodevelopmental outcomes assessed at 2 years using Bayley Scales of Infant and Toddler Development, 4th Edition.
Main Results:
- Primary outcome: mean difference in composite cognitive scores.
- Secondary outcomes include safety and resource utilization.
- Central masked assessment of neurodevelopmental outcomes at 2 years.
Conclusions:
- The COMET trial will determine the safety and efficacy of whole-body hypothermia for mild HIE.
- Findings will inform national and international clinical guidelines for mild HIE management.
- Economic evaluation will assess cost-effectiveness in the NHS.
Background:
Mild hypoxic ischemic encephalopathy is associated with sub optimal cognition and learning difficulties at school age. Although whole-body hypothermia reduces death and disability after moderate or severe encephalopathy in high-income countries, the safety and efficacy of hypothermia in mild encephalopathy is not known. The cooling in mild encephalopathy (COMET) trial will examine if whole-body hypothermia improves cognitive development of neonates with mild encephalopathy.
Methods:
The COMET trial is a phase III multicentre open label two-arm randomised controlled trial with masked outcome assessments. A total of 426 neonates with mild encephalopathy will be recruited from 50 to 60 NHS hospitals over 2 ½ years following parental consent. The neonates will be randomised to 72 h of whole-body hypothermia (33.5 ± 0.5 C) or normothermia (37.0 ± 0.5 C) within six hours or age. Prior to the recruitment front line clinical staff will be trained and certified on expanded modified Sarnat staging for encephalopathy. The neurological assessment of all screened and recruited cases will be video recorded and centrally assessed for quality assurance. If recruitment occurs at a non-cooling centre, neonates in both arms will be transferred to a cooling centre for continued care, after randomisation. All neonates will have continuous amplitude integrated electroencephalography (aEEG) at least for the first 48 h to monitor for seizures. Predefined safety outcomes will be documented, and data collected to assess resource utilization of health care. A central team masked to trial group allocation will assess neurodevelopmental outcomes at 2 years of age. The primary outcome is mean difference in composite cognitive scores on Bayley scales of Infant and Toddler development 4th Edition.
Discussion:
The COMET trial will establish the safety and efficacy of whole-body hypothermia for mild hypoxic ischaemic encephalopathy and inform national and international guidelines in high income countries. It will also provide an economic assessment of whole-body hypothermia therapy for mild encephalopathy in the NHS on cost-effectiveness grounds.
Trial Registration Number:
NCT05889507 June 5, 2023.
