Optimising the Duration of Cooling in Mild Encephalopathy (COMET)
Primary Purpose
Neonatal Encephalopathy, Hypothermia Neonatal, Magnetic Resonance Spectroscopy
Status
Active
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
Therapeutic hypothermia
Sponsored by
About this trial
This is an interventional treatment trial for Neonatal Encephalopathy
Eligibility Criteria
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
Sites / Locations
- Wayne State University
- Luigi Vanvitelli Hospital
- Birmingham Womens Hospital
- Medway NHS Foundation Trust
- Liverpool Womens Hospital
- Homerton University Hospital
- Imperial College London
- The Newcastle Upon Tyne NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
No Intervention
Experimental
Experimental
Arm Label
Usual care
Therapeutic hypothermia - 48 h
Therapeutic hypothermia - 72 h
Arm Description
Usual care (normothermia) arm
Whole body cooling (33 to 34 C) for 48 hours
Whole body cooling (33 to 34 C) for 72 hours
Outcomes
Primary Outcome Measures
Thalamic N-acetyl aspartate level
Feasibility of obtaining Proton MR spectroscopy thalamic N-acetyl aspartate level
Secondary Outcome Measures
Brain injury on conventional MR imaging
Cortical, white matter or deep nuclei injury
Hospital stay
Duration of hospital stay
Full Information
NCT ID
NCT03409770
First Posted
January 10, 2018
Last Updated
August 2, 2023
Sponsor
Thayyil, Sudhin
Collaborators
Wayne State University
1. Study Identification
Unique Protocol Identification Number
NCT03409770
Brief Title
Optimising the Duration of Cooling in Mild Encephalopathy
Acronym
COMET
Official Title
Optimising the Duration of Cooling Therapy in Mild Neonatal Encephalopathy
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 10, 2019 (Actual)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
August 30, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Thayyil, Sudhin
Collaborators
Wayne State University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neonatal Encephalopathy, Hypothermia Neonatal, Magnetic Resonance Spectroscopy
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Therapeutic hypothermia (33 to 34 C) for 2 different durations (48, or 72 h) and usual care (normothermia)
Masking
Outcomes Assessor
Masking Description
MR spectroscopy analysis will be masked to the allocation
Allocation
Randomized
Enrollment
140 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Usual care
Arm Type
No Intervention
Arm Description
Usual care (normothermia) arm
Arm Title
Therapeutic hypothermia - 48 h
Arm Type
Experimental
Arm Description
Whole body cooling (33 to 34 C) for 48 hours
Arm Title
Therapeutic hypothermia - 72 h
Arm Type
Experimental
Arm Description
Whole body cooling (33 to 34 C) for 72 hours
Intervention Type
Other
Intervention Name(s)
Therapeutic hypothermia
Intervention Description
Whole body cooling using a servo controlled device
Primary Outcome Measure Information:
Title
Thalamic N-acetyl aspartate level
Description
Feasibility of obtaining Proton MR spectroscopy thalamic N-acetyl aspartate level
Time Frame
4 to 14 days after birth
Secondary Outcome Measure Information:
Title
Brain injury on conventional MR imaging
Description
Cortical, white matter or deep nuclei injury
Time Frame
4 to 14 days after birth
Title
Hospital stay
Description
Duration of hospital stay
Time Frame
Upto 30 days after birth
10. Eligibility
Sex
All
Maximum Age & Unit of Time
6 Hours
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sudhin Thayyil, PhD
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Wayne State University
City
Michigan Center
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Luigi Vanvitelli Hospital
City
Naples
Country
Italy
Facility Name
Birmingham Womens Hospital
City
Birmingham
Country
United Kingdom
Facility Name
Medway NHS Foundation Trust
City
Gillingham
Country
United Kingdom
Facility Name
Liverpool Womens Hospital
City
Liverpool
Country
United Kingdom
Facility Name
Homerton University Hospital
City
London
Country
United Kingdom
Facility Name
Imperial College London
City
London
Country
United Kingdom
Facility Name
The Newcastle Upon Tyne NHS Foundation Trust
City
Newcastle
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Data can be shared unconditionally will be made available when scientific manuscripts are published.
Data that cannot be shared publicly (e.g. to protect patient confidentiality) will be by request only. The PI will review each request on case-by-case basis. Upon approval the data requester will be asked to sign a data sharing agreement.
IPD Sharing Time Frame
Data will be available 3 to 6 after the end of the study.
IPD Sharing Access Criteria
Unidentified data will be shared by publication. Request for data that affects patient confidentiality will review by the study PI on a case-by-case basis.
Citations:
PubMed Identifier
29095433
Citation
Prempunpong C, Chalak LF, Garfinkle J, Shah B, Kalra V, Rollins N, Boyle R, Nguyen KA, Mir I, Pappas A, Montaldo P, Thayyil S, Sanchez PJ, Shankaran S, Laptook AR, Sant'Anna G. Prospective research on infants with mild encephalopathy: the PRIME study. J Perinatol. 2018 Jan;38(1):80-85. doi: 10.1038/jp.2017.164. Epub 2017 Nov 2.
Results Reference
background
PubMed Identifier
28942433
Citation
Oliveira V, Singhvi DP, Montaldo P, Lally PJ, Mendoza J, Manerkar S, Shankaran S, Thayyil S. Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK. Arch Dis Child Fetal Neonatal Ed. 2018 Jul;103(4):F388-F390. doi: 10.1136/archdischild-2017-313320. Epub 2017 Sep 23.
Results Reference
background
PubMed Identifier
28935718
Citation
Lally PJ, Montaldo P, Oliveira V, Swamy RS, Soe A, Shankaran S, Thayyil S. Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2018 Jul;103(4):F383-F387. doi: 10.1136/archdischild-2017-313321. Epub 2017 Sep 21.
Results Reference
background
PubMed Identifier
26423856
Citation
Lally PJ, Pauliah S, Montaldo P, Chaban B, Oliveira V, Bainbridge A, Soe A, Pattnayak S, Clarke P, Satodia P, Harigopal S, Abernethy LJ, Turner MA, Huertas-Ceballos A, Shankaran S, Thayyil S. Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study. BMJ Open. 2015 Sep 30;5(9):e008912. doi: 10.1136/bmjopen-2015-008912.
Results Reference
background
PubMed Identifier
25055862
Citation
Robertson NJ, Thayyil S, Cady EB, Raivich G. Magnetic resonance spectroscopy biomarkers in term perinatal asphyxial encephalopathy: from neuropathological correlates to future clinical applications. Curr Pediatr Rev. 2014;10(1):37-47. doi: 10.2174/157339631001140408120613.
Results Reference
background
PubMed Identifier
24505327
Citation
Lally PJ, Price DL, Pauliah SS, Bainbridge A, Kurien J, Sivasamy N, Cowan FM, Balraj G, Ayer M, Satheesan K, Ceebi S, Wade A, Swamy R, Padinjattel S, Hutchon B, Vijayakumar M, Nair M, Padinharath K, Zhang H, Cady EB, Shankaran S, Thayyil S. Neonatal encephalopathic cerebral injury in South India assessed by perinatal magnetic resonance biomarkers and early childhood neurodevelopmental outcome. PLoS One. 2014 Feb 5;9(2):e87874. doi: 10.1371/journal.pone.0087874. eCollection 2014. Erratum In: PLoS One. 2014;9(3):e92526.
Results Reference
background
PubMed Identifier
20083516
Citation
Thayyil S, Chandrasekaran M, Taylor A, Bainbridge A, Cady EB, Chong WK, Murad S, Omar RZ, Robertson NJ. Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis. Pediatrics. 2010 Feb;125(2):e382-95. doi: 10.1542/peds.2009-1046. Epub 2010 Jan 18.
Results Reference
background
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Optimising the Duration of Cooling in Mild Encephalopathy
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