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Cooling in Mild Encephalopathy (COMET)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05889507
Recruitment Status : Not yet recruiting
First Posted : June 5, 2023
Last Update Posted : March 20, 2024
Sponsor:
Information provided by (Responsible Party):
Imperial College London

Study Description
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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.


Condition or disease Intervention/treatment Phase
Neonatal Encephalopathy Newborn Asphyxia Procedure: Whole body hypothermia Procedure: Targeted normothermia Other: Supportive neonatal intensive care Diagnostic Test: Follow up assessment at 2 years of age Not Applicable

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 426 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Masking Description: Administration of cooling therapy cannot be masked. The 24 (±2) months of age assessments will be performed by a central team of 2 to 3 examiners, masked to the allocation.
Primary Purpose: Treatment
Official Title: Whole-body Hypothermia Versus Normothermia in Mild Neonatal Encephalopathy: A Multicentre Randomised Controlled Trial
Estimated Study Start Date : May 1, 2024
Estimated Primary Completion Date : March 30, 2029
Estimated Study Completion Date : March 30, 2029

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hypothermia

Arms and Interventions
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Arm Intervention/treatment
Experimental: Whole body hypothermia
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
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.

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.
Active Comparator: 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.
 Procedure: 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.


Outcome Measures
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Primary Outcome Measures :
  1. Mean Cognitive Composite Scale score from the Bayley IV examination [ Time Frame: 22 to 26 months ]
    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.


Secondary Outcome Measures :
  1. Neonatal seizures [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks) ]
    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.

  2. Duration of intensive care. [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks) ]
    Number of days of neonatal intensive care.

  3. Duration of hospital stay. [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks). ]
    Total number of days of inpatient care in a neonatal unit.

  4. Duration of mechanical ventilation. [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks). ]
    Number of hours on invasive ventilation through an endotracheal tube.

  5. Duration of inotropic support. [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks). ]
    Total number of hours on inotropic support.

  6. Number of babies with bloodstream or cerebrospinal fluid positive infection. [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks). ]
    Isolation of a pathogenic organism from blood or cerebrospinal fluid along with a clinical diagnosis of sepsis, at any time during neonatal hospitalisation.

  7. Number of babies with thrombocytopenia or coagulopathy requiring transfusion of blood products. [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks). ]
    Prolonged blood coagulation requiring blood products

  8. Opioid use. [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks). ]
    Total cumulative dose of morphine per kilogram of body weight.

  9. Number of babies exclusively breastfeeding at hospital discharge. [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks). ]
    Defined as the newborn receiving only breast milk the last feedings before discharge.

  10. Brain injury scores on conventional magnetic resonance imaging [ Time Frame: During neonatal hospitalisation (Expected average of 2 weeks). ]
    Defined as per Rutherford/NICHD staging.

  11. Survival without any neurological impairment. [ Time Frame: 22 to 26 months ]
    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.

  12. Preschool Child Behaviour Checklist (CBCL 1½-5) [ Time Frame: 22 to 26 months ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   0 Hours to 6 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05889507


Contacts
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Contact: Sudhin Thayyil, MD, PhD 02033132473 s.thayyil@imperial.ac.uk
Contact: Reema Garegrat, MD, DNB, MRCPCH 02033132473 r.garegrat@imperial.ac.uk

Locations
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Sponsors and Collaborators
Imperial College London
Investigators
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Principal Investigator: Sudhin Thayyil, PhD Imperial College London
Principal Investigator: Seetha Shankaran, MD Wayne State University
More Information
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Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT05889507    
Other Study ID Numbers: 326176
First Posted: June 5, 2023    Key Record Dates
Last Update Posted: March 20, 2024
Last Verified: March 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Protocol, SAP and consent forms will be shared midway through the trial recruitment following appropriate requests
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Brain Diseases
Asphyxia Neonatorum
Asphyxia
Central Nervous System Diseases
Nervous System Diseases
 Death
Pathologic Processes
Wounds and Injuries
Infant, Newborn, Diseases