Optimising the Duration of Cooling in Mild Encephalopathy

NCT ID: NCT03409770

Last Updated: 2023-08-04

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-10
• Study Completion Date: 2024-08-30

Brief Summary

Phase II randomised control trial of whole body cooling in mild neonatal encephalopathy.

Detailed Description

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

1. 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)

2. 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.

Conditions

Neonatal Encephalopathy; Hypothermia Neonatal; Magnetic Resonance Spectroscopy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Usual care

Usual care (normothermia) arm

Group Type: NO_INTERVENTION

No interventions assigned to this group

Therapeutic hypothermia - 48 h

Whole body cooling (33 to 34 C) for 48 hours

Group Type: EXPERIMENTAL

Therapeutic hypothermia

Intervention Type: OTHER

Whole body cooling using a servo controlled device

Therapeutic hypothermia - 72 h

Whole body cooling (33 to 34 C) for 72 hours

Group Type: EXPERIMENTAL

Therapeutic hypothermia

Intervention Type: OTHER

Whole body cooling using a servo controlled device

Interventions

Therapeutic hypothermia

Whole body cooling using a servo controlled device

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

All of the following three criteria should be met:

1. Age less than six hours. AND

2. Evidence of acute perinatal asphyxia

1. Metabolic acidosis (pH <7.0 and/or BE >-16) in cord gas or a blood gas within one of birth.

OR

2. 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

3. 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

1. Babies without encephalopathy

2. Babies with moderate or severe encephalopathy who meet the current NICE/AAP guidelines for cooling therapy.

3. Babies with seizures (clinical and/or aEEG/EEG)

4. Babies with moderate or severe abnormalities on aEEG voltage criteria.

5. Babies with life threatening congenital malformations

• Maximum Eligible Age: 6 Hours
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Wayne State University

OTHER

Sponsor Role: collaborator

Thayyil, Sudhin

INDIV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sudhin Thayyil, PhD

Role: PRINCIPAL_INVESTIGATOR

Imperial College London

Locations

Wayne State University

Michigan Center, Michigan, United States

Luigi Vanvitelli Hospital

Naples, , Italy

Birmingham Womens Hospital

Birmingham, , United Kingdom

Medway NHS Foundation Trust

Gillingham, , United Kingdom

Liverpool Womens Hospital

Liverpool, , United Kingdom

Homerton University Hospital

London, , United Kingdom

Imperial College London

London, , United Kingdom

The Newcastle Upon Tyne NHS Foundation Trust

Newcastle, , United Kingdom

Countries

United States; Italy; United Kingdom

References

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Reference Type: BACKGROUND

PMID: 29095433 (View on PubMed)

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Montaldo P, Cirillo M, Burgod C, Caredda E, Ascione S, Carpentieri M, Puzone S, D'Amico A, Garegrat R, Lanza M, Moreno Morales M, Atreja G, Shivamurthappa V, Kariholu U, Aladangady N, Fleming P, Mathews A, Palanisami B, Windrow J, Harvey K, Soe A, Pattnayak S, Sashikumar P, Harigopal S, Pressler R, Wilson M, De Vita E, Shankaran S, Thayyil S; COMET Trial Group. Whole-Body Hypothermia vs Targeted Normothermia for Neonates With Mild Encephalopathy: A Multicenter Pilot Randomized Clinical Trial. JAMA Netw Open. 2024 May 1;7(5):e249119. doi: 10.1001/jamanetworkopen.2024.9119.

Reference Type: DERIVED

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Other Identifiers

37318

Identifier Type: REGISTRY

Identifier Source: secondary_id

241031

Identifier Type: -

Identifier Source: org_study_id