Clinical trial NCT03409770: Optimising the Duration of Cooling in Mild Encephalopathy
Official title: Optimising the Duration of Cooling Therapy in Mild Neonatal Encephalopathy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Neonatal Encephalopathy
Hypothermia Neonatal
Magnetic Resonance Spectroscopy
Lead sponsor: Thayyil, Sudhin
Sponsor class: INDIV
Collaborators: name: Wayne State University
First posted: 2018-01-24
Enrollment: 140
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Therapeutic hypothermia (33 to 34 C) for 2 different durations (48, or 72 h) and usual care (normothermia)
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Thalamic N-acetyl aspartate level
timeFrame: 4 to 14 days after birth
Secondary outcomes:
measure: Brain injury on conventional MR imaging
timeFrame: 4 to 14 days after birth
measure: Hospital stay
timeFrame: Upto 30 days after birth
Other outcomes:
Locations:
city: Michigan Center
country: United States
facility: Wayne State University
state: Michigan
city: Naples
country: Italy
facility: Luigi Vanvitelli Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Womens Hospital
city: Gillingham
country: United Kingdom
facility: Medway NHS Foundation Trust
city: Liverpool
country: United Kingdom
facility: Liverpool Womens Hospital
city: London
country: United Kingdom
facility: Homerton University Hospital
city: London
country: United Kingdom
facility: Imperial College London
city: Newcastle
country: United Kingdom
facility: The Newcastle Upon Tyne NHS Foundation Trust
Study officials:
affiliation: Imperial College London
name: Sudhin Thayyil, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.