Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomised controlled trial.
Hypothermia
Magnetic resonance spectroscopy
Mild encephalopathy
Journal
BMC pediatrics
ISSN: 1471-2431
Titre abrégé: BMC Pediatr
Pays: England
ID NLM: 100967804
Informations de publication
Date de publication:
18 Jul 2024
18 Jul 2024
Historique:
received:
07
04
2024
accepted:
08
07
2024
medline:
19
7
2024
pubmed:
19
7
2024
entrez:
18
7
2024
Statut:
epublish
Résumé
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. 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. 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. NCT05889507 June 5, 2023.
Sections du résumé
BACKGROUND
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
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
CONCLUSIONS
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
BACKGROUND
NCT05889507 June 5, 2023.
Identifiants
pubmed: 39026197
doi: 10.1186/s12887-024-04935-4
pii: 10.1186/s12887-024-04935-4
doi:
Banques de données
ClinicalTrials.gov
['NCT05889507']
Types de publication
Journal Article
Clinical Trial Protocol
Multicenter Study
Clinical Trial, Phase III
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
460Subventions
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Organisme : National Institute for Health Research (NIHR) Health Technology Assessment Programme
ID : NIHR152188
Informations de copyright
© 2024. The Author(s).
Références
Gale C, Statnikov Y, Jawad S, Uthaya SN, Modi N. Brain injuries expert working g. neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the national neonatal research database. Arch Dis Child Fetal Neonatal Ed. 2018;103(4):F301–6.
doi: 10.1136/archdischild-2017-313707
pubmed: 29180541
Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia. JAMA Pediatr. 2020;174(1):48–55.
doi: 10.1001/jamapediatrics.2019.4011
pubmed: 31710357
Murray DM, O’Connor CM, Ryan CA, Korotchikova I, Boylan GB. Early EEG Grade and Outcome at 5 years after mild neonatal hypoxic ischemic encephalopathy. Pediatrics. 2016;138(4).
Murray DM, editor. Editor hot debate – cooling in mild encephalopathy: importance of long term followup. Dnver, USA: Pediatric Academic Societies Meeting; 2022.
Chalak LF, Nguyen KA, Prempunpong C, Heyne R, Thayyil S, Shankaran S et al. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18–22 months. Pediatr Res. 2018.
Halpin S, McCusker C, Fogarty L, White J, Cavalière E, Boylan G, Murray D. Long-term neuropsychological and behavioral outcome of mild and moderate hypoxic ischemic encephalopathy. Early Hum Dev. 2022;165:105541.
doi: 10.1016/j.earlhumdev.2022.105541
pubmed: 35065415
Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013;2013(1):Cd003311.
pubmed: 23440789
pmcid: 7003568
Oliveira V, Singhvi DP, Montaldo P, Lally PJ, Mendoza J, Manerkar S, et al. Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK. Arch Dis Child Fetal Neonatal Ed. 2018;103(4):F388–90.
doi: 10.1136/archdischild-2017-313320
pubmed: 28942433
Kariholu U, Montaldo P, Markati T, Lally PJ, Pryce R, Teiserskas J, et al. Therapeutic hypothermia for mild neonatal encephalopathy: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2020;105(2):225–8.
doi: 10.1136/archdischild-2018-315711
pubmed: 30567775
Persson M, Razaz N, Tedroff K, Joseph KS, Cnattingius S. Five and 10 minute Apgar scores and risks of cerebral palsy and epilepsy: population based cohort study in Sweden. BMJ. 2018;360:k207.
doi: 10.1136/bmj.k207
pubmed: 29437691
pmcid: 5802319
Walker YL, Lok O, Ratnavel A. Cooling for transfer: an integrated care pathway for London (cooltrip). Arch Dis Child. 2021;106:A1–514.
Goswami IR, Whyte H, Wintermark P, Mohammad K, Shivananda S, Louis D, et al. Characteristics and short-term outcomes of neonates with mild hypoxic-ischemic encephalopathy treated with hypothermia. J Perinatol. 2020;40(2):275–83.
doi: 10.1038/s41372-019-0551-2
pubmed: 31723237
Yieh L, Lee H, Lu T, Song A, Gong CL, Wu TW, et al. Neonates with mild hypoxic-ischaemic encephalopathy receiving supportive care versus therapeutic hypothermia in California. Arch Dis Child Fetal Neonatal Ed. 2022;107(3):324–8.
doi: 10.1136/archdischild-2021-322250
pubmed: 34462319
Rao R, Mietzsch U, DiGeronimo R, Hamrick SE, Dizon MLV, Lee KS, et al. Utilization of therapeutic hypothermia and neurological Injury in neonates with mild hypoxic-ischemic encephalopathy: a report from children’s hospital neonatal Consortium. Am J Perinatol. 2022;39(3):319–28.
doi: 10.1055/s-0040-1716341
pubmed: 32892328
Massaro AN, Murthy K, Zaniletti I, Cook N, DiGeronimo R, Dizon M, et al. Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the children’s hospitals neonatal Consortium HIE focus group. J Perinatology: Official J Calif Perinat Association. 2015;35(4):290–6.
doi: 10.1038/jp.2014.190
Hage L, Jeyakumaran D, Dorling J, Ojha S, Sharkey D, Longford N, et al. Changing clinical characteristics of infants treated for hypoxic-ischaemic encephalopathy in England, Wales and Scotland: a population-based study using the national neonatal research database. Arch Dis Child Fetal Neonatal Ed. 2021;106(5):501–8.
doi: 10.1136/archdischild-2020-319685
pubmed: 33541916
Collins R, Bowman L, Landray M, Peto R. The magic of randomization versus the myth of real-world evidence. N Engl J Med. 2020;382(7):674–8.
doi: 10.1056/NEJMsb1901642
pubmed: 32053307
Faix RG AL, S S, Bonifacio S.. Randomised trial of targetted temperature management with whole body hypothermia for moderate or severe encephalopathy in premature infants 33 to weeks gestation. Pediatric Academic Soceity Meeting;; Washington20232023.
Thayyil S, Pant S, Montaldo P, Shukla D, Oliveira V, Ivain P et al. Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh. Lancet Glob Health. 2021.
Azzopardi D, Strohm B, Edwards A, Dyet L, Halliday H, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361(14):1349–58.
doi: 10.1056/NEJMoa0900854
pubmed: 19797281
Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicentre randomised trial. Lancet. 2005;365:663–70.
doi: 10.1016/S0140-6736(05)17946-X
pubmed: 15721471
Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353:1574–84.
doi: 10.1056/NEJMcps050929
pubmed: 16221780
BAPM. Therapeutic Hypothermia for Neonatal Encephalopathy 2020 https://www.bapm.org/resources/237-therapeutic-hypothermia-for-neonatal-encephalopathy .
Saw CL, Rakshasbhuvankar A, Rao S, Bulsara M, Patole S. Current practice of therapeutic hypothermia for mild hypoxic ischemic encephalopathy. J Child Neurol. 2019;34(7):402–9.
doi: 10.1177/0883073819828625
pubmed: 30898007
Chawla S, Bates SV, Shankaran S. Is it time for a randomized controlled trial of hypothermia for mild hypoxic-ischemic Encephalopathy? J Pediatr. 2020;220:241–4.
doi: 10.1016/j.jpeds.2019.11.030
pubmed: 31952851
pmcid: 8462395
Natarajan G, Shankaran S, Laptook AR, McDonald SA, Pappas A, Hintz SR, et al. Association between sedation-analgesia and neurodevelopment outcomes in neonatal hypoxic-ischemic encephalopathy. J Perinatol. 2018;38(8):1060–7.
doi: 10.1038/s41372-018-0126-7
pubmed: 29795315
pmcid: 6092226
Montaldo P, Vakharia A, Ivain P, Mendoza J, Oliveira V, Markati T, et al. Pre-emptive opioid sedation during therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2020;105(1):108–9.
doi: 10.1136/archdischild-2019-317050
pubmed: 31072966
Liow N, Lally PJ, Slater R, S S, Thayyil S, editors. Pre-emptive morphine sedation during hypothermic neuroprotection for neonatal encephalopathy is associated with adverse outcomes: an uncontrolled cohort study. Neonatal Soceity Meeting (London); 2018.
Gundersen JK, Chakkarapani E, Jary S, Menassa DA, Scull-Brown E, Frymoyer A, et al. Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment. EClinicalMedicine. 2021;36:100892.
doi: 10.1016/j.eclinm.2021.100892
pubmed: 34308308
pmcid: 8257990
UK National Institute for Health and Care Research. Training and certification on expanded modified Sarnat stage. 2024 [Available from: Accessed March 28, 2024.
Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–84.
doi: 10.1056/NEJMcps050929
pubmed: 16221780
Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, et al. Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic-ischemic encephalopathy: a Randomized Clinical Trial. JAMA. 2017;318(16):1550–60.
doi: 10.1001/jama.2017.14972
pubmed: 29067428
pmcid: 5783566
NICE. NICE health technology evaluations: the manual 2022. 2022.
Regier DA, Petrou S, Henderson J, Eddama O, Patel N, Strohm B, et al. Cost-effectiveness of therapeutic hypothermia to treat neonatal encephalopathy. Value Health. 2010;13(6):695–702.
doi: 10.1111/j.1524-4733.2010.00731.x
pubmed: 20561343
Montaldo PCM, Burgod C, Shankaran S, Thayyil S. Whole-body hypothermia for 48 or 72 hours versus targeted normothermia in mild encephalopathy: a multicenter pilot randomised controlled trial. JAMA Netw Open. 2024.