Follow-up of Inflammatory Responses and Multiorgan Outcomes FoLlowing Neonatal Brain injurY

Neonatal Encephalopathy Clinical Trial

— FIREFLY  

Official title:

Follow-up of Inflammatory Responses and Multiorgan Outcomes FoLlowing Neonatal Brain injurY

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04816331
• Other study ID #: ILP-POR-2019-086
• Status: Enrolling by invitation
• Start date: August 4, 2020
• Est. completion date: September 30, 2022

Study information

• Verified date: March 2021
• Source: University of Dublin, Trinity College
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Babies who have brain injury also frequently have involvement of their kidneys, lung and heart. Although clinical care in the neonatal period is well defined there are few guidelines and evidence for developmental, heart and kidney followup in childhood. The investigators aim to develop and implement guidelines for health care workers and families on Followup after Neonatal Brain Injury. Inflammation is an important factor in brain injury of newborns and also affects their heart lungs and other parts of their body. The investigators will use tests from the newborn period to predict outcome and help parents with planning health needs for their baby rather than waiting until any issues arise later on. By understanding inflammation the investigators can find methods to decrease the negative effects and improve outcomes in the future for babies and families.

Description:

Neonatal brain injury is an important cause of neonatal death and disability such as cerebral palsy. Perinatal global hypoxic ischemic associated with Neonatal Encephalopathy (NE) results in multi-organ dysfunction which may persist in later childhood. In addition perinatal inflammation has been associated with neonatal brain injury and implicated in adult neuropsychiatric conditions. The investigators aim to examine multi-organ dysfunction in early childhood in children who had NE by examining detailed cardiac, renal, neurological, haematological and neurodevelopmental outcomes. The investigators have previously defined detailed multi organ dysfunction (MOD) in this cohort in the neonatal period in infants with NE including organ outcomes as well as serum, urine and cerebrospinal fluid (CSF) biomarkers. They are now age-appropriate for detailed neurocognitive assessment and correlation with these biomarkers and the investigators plan to compare with age- matched controls. Immunological markers such as the inflammasome and microRNAs are altered in the neonatal period and may persist in early childhood. The investigators will modify negative inflammatory responses in vitro with specific antagonists as well as correlating these immune biomarkers with outcomes. Quantifying multiorgan dysfunction in the neonatal period to ensure appropriate follow-up of all organs is merited. This would help in advanced clinical planning and long term follow up. In addition, understanding, the immune response in these children with NE and exploring systemic inflammation holds promise for future development of immunomodulatory adjunctive therapies and biomarkers to predict outcomes.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 200
• Est. completion date: September 30, 2022
• Est. primary completion date: June 30, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 2 Years to 3 Years

Eligibility

Inclusion Criteria:

• Children at 2-3 years
• With diagnosis of Neonatal Encephalopathy
• Required Therapeutic Hypothermia Exclusion Criteria: -

Related Conditions & MeSH terms

• Brain Diseases
• Brain Injuries
• Neonatal Encephalopathy

Intervention

Other:
• Medical records and clinical measurements
Medical records and clinical measurements: Detailed antenatal, birth, resuscitation, oxygen requirements throughout inpatient stay and detailed neonatal intensive care management will be collected. Therapeutic Hypothermia treatment including initiation, duration and clinical examination, and investigations such as scans. In addition, clinical data will include medication, neurological (paediatric developmental psychologist assessment and Bayley Scales of Infant and Toddler Development) and multiorgan examination. Questionnaires for caregivers to assess social-emotional and adaptive domains. Tissue samples analysis and processing: Samples of blood, urine and saliva will be used for laboratory testing. Biomarker correlation with Multiorgan outcomes using statistical analysis: Data collected from medical records, clinical measurements, questionnaires, and tissue processing will be analysed using SPSS software for statistical analysis and modelling.

Locations

Country	Name	City	State
Ireland	The Coombe Women & Infants University Hospital	Dublin
Ireland	The National Maternity Hospital, or Holles Street Hospital	Dublin
Ireland	The Rotunda Hospital	Dublin
Ireland	The Tallaght University Hospital	Dublin
Ireland	Trinity College Dublin, The University of Dublin	Dublin

Sponsors (2)

Lead Sponsor	Collaborator
University of Dublin, Trinity College	Health Research Board, Ireland

Country where clinical trial is conducted

Ireland, 

References & Publications (25)

Armstrong K, Franklin O, Sweetman D, Molloy EJ. Cardiovascular dysfunction in infants with neonatal encephalopathy. Arch Dis Child. 2012 Apr;97(4):372-5. doi: 10.1136/adc.2011.214205. Epub 2011 Jul 27. Review. — View Citation

Aslam S, Molloy EJ. Biomarkers of multiorgan injury in neonatal encephalopathy. Biomark Med. 2015;9(3):267-75. doi: 10.2217/bmm.14.116. Review. — View Citation

Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. doi: 10.1056/NEJMoa0900854. Erratum in: N Engl J Med. 2010 Mar 18;362(11):1056. — View Citation

Barkovich AJ, Hajnal BL, Vigneron D, Sola A, Partridge JC, Allen F, Ferriero DM. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol. 1998 Jan;19(1):143-9. — View Citation

Buck BH, Liebeskind DS, Saver JL, Bang OY, Yun SW, Starkman S, Ali LK, Kim D, Villablanca JP, Salamon N, Razinia T, Ovbiagele B. Early neutrophilia is associated with volume of ischemic tissue in acute stroke. Stroke. 2008 Feb;39(2):355-60. Epub 2007 Dec 27. — View Citation

Chalak LF, Nguyen KA, Prempunpong C, Heyne R, Thayyil S, Shankaran S, Laptook AR, Rollins N, Pappas A, Koclas L, Shah B, Montaldo P, Techasaensiri B, Sánchez PJ, Sant'Anna G. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months. Pediatr Res. 2018 Dec;84(6):861-868. doi: 10.1038/s41390-018-0174-x. Epub 2018 Sep 13. — View Citation

Chevin M, Guiraut C, Sébire G. Effect of hypothermia on interleukin-1 receptor antagonist pharmacodynamics in inflammatory-sensitized hypoxic-ischemic encephalopathy of term newborns. J Neuroinflammation. 2018 Jul 30;15(1):214. doi: 10.1186/s12974-018-1258-6. — View Citation

Dammann O, Durum S, Leviton A. Do white cells matter in white matter damage? Trends Neurosci. 2001 Jun;24(6):320-4. Review. — View Citation

Eliwan HO, Watson RW, Aslam S, Regan I, Philbin B, O'Hare FM, O'Neill A, Preston R, Blanco A, Grant T, Nolan B, Smith O, Molloy EJ. Neonatal brain injury and systemic inflammation: modulation by activated protein C ex vivo. Clin Exp Immunol. 2015 Mar;179(3):477-84. doi: 10.1111/cei.12453. — View Citation

Fleiss B, Gressens P. Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy? Lancet Neurol. 2012 Jun;11(6):556-66. doi: 10.1016/S1474-4422(12)70058-3. Epub 2012 May 16. Review. — View Citation

Hedtjärn M, Mallard C, Iwakura Y, Hagberg H. Combined deficiency of IL-1beta18, but not IL-1alphabeta, reduces susceptibility to hypoxia-ischemia in the immature brain. Dev Neurosci. 2005 Mar-Aug;27(2-4):143-8. — View Citation

Jenkins DD, Rollins LG, Perkel JK, Wagner CL, Katikaneni LP, Bass WT, Kaufman DA, Horgan MJ, Languani S, Givelichian L, Sankaran K, Yager JY, Martin RH. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab. 2012 Oct;32(10):1888-96. doi: 10.1038/jcbfm.2012.83. Epub 2012 Jul 18. — View Citation

Kirkley MJ, Boohaker L, Griffin R, Soranno DE, Gien J, Askenazi D, Gist KM; Neonatal Kidney Collaborative (NKC). Acute kidney injury in neonatal encephalopathy: an evaluation of the AWAKEN database. Pediatr Nephrol. 2019 Jan;34(1):169-176. doi: 10.1007/s00467-018-4068-2. Epub 2018 Aug 28. Erratum in: Pediatr Nephrol. 2018 Oct 12;:. — View Citation

Lawn JE, Lee AC, Kinney M, Sibley L, Carlo WA, Paul VK, Pattinson R, Darmstadt GL. Two million intrapartum-related stillbirths and neonatal deaths: where, why, and what can be done? Int J Gynaecol Obstet. 2009 Oct;107 Suppl 1:S5-18, S19. doi: 10.1016/j.ijgo.2009.07.016. Review. — View Citation

Lin CY, Chang YC, Wang ST, Lee TY, Lin CF, Huang CC. Altered inflammatory responses in preterm children with cerebral palsy. Ann Neurol. 2010 Aug;68(2):204-12. doi: 10.1002/ana.22049. — View Citation

Looney AM, O'Sullivan MP, Ahearne CE, Finder M, Felderhoff-Mueser U, Boylan GB, Hallberg B, Murray DM. Altered Expression of Umbilical Cord Blood Levels of miR-181b and Its Downstream Target mUCH-L1 in Infants with Moderate and Severe Neonatal Hypoxic-Ischaemic Encephalopathy. Mol Neurobiol. 2019 May;56(5):3657-3663. doi: 10.1007/s12035-018-1321-4. Epub 2018 Sep 3. — View Citation

Morkos AA, Hopper AO, Deming DD, Yellon SM, Wycliffe N, Ashwal S, Sowers LC, Peverini RL, Angeles DM. Elevated total peripheral leukocyte count may identify risk for neurological disability in asphyxiated term neonates. J Perinatol. 2007 Jun;27(6):365-70. Epub 2007 Apr 19. — View Citation

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 Oct;138(4). pii: e20160659. Epub 2016 Sep 20. — View Citation

O'Hare FM, Watson RW, O'Neill A, Blanco A, Donoghue V, Molloy EJ. Persistent systemic monocyte and neutrophil activation in neonatal encephalopathy. J Matern Fetal Neonatal Med. 2016;29(4):582-9. doi: 10.3109/14767058.2015.1012060. Epub 2015 Feb 19. — View Citation

O'Hare FM, Watson RW, O'Neill A, Segurado R, Sweetman D, Downey P, Mooney E, Murphy J, Donoghue V, Molloy EJ. Serial cytokine alterations and abnormal neuroimaging in newborn infants with encephalopathy. Acta Paediatr. 2017 Apr;106(4):561-567. doi: 10.1111/apa.13745. Epub 2017 Feb 16. — View Citation

Ozaki E, Campbell M, Doyle SL. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives. J Inflamm Res. 2015 Jan 16;8:15-27. doi: 10.2147/JIR.S51250. eCollection 2015. Review. — View Citation

Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976 Oct;33(10):696-705. — View Citation

Singh Y, Roehr CC, Tissot C, Rogerson S, Gupta S, Bohlin K, Breindahl M, El-Khuffash A, de Boode WP; European Special Interest Group 'Neonatologist Performed Echocardiography' (NPE). Education, training, and accreditation of Neonatologist Performed Echocardiography in Europe-framework for practice. Pediatr Res. 2018 Jul;84(Suppl 1):13-17. doi: 10.1038/s41390-018-0078-9. Review. — View Citation

Sweetman DU, Onwuneme C, Watson WR, Murphy JF, Molloy EJ. Perinatal Asphyxia and Erythropoietin and VEGF: Serial Serum and Cerebrospinal Fluid Responses. Neonatology. 2017;111(3):253-259. doi: 10.1159/000448702. Epub 2016 Dec 1. — View Citation

Yang Z, Zhong L, Xian R, Yuan B. MicroRNA-223 regulates inflammation and brain injury via feedback to NLRP3 inflammasome after intracerebral hemorrhage. Mol Immunol. 2015 Jun;65(2):267-76. doi: 10.1016/j.molimm.2014.12.018. Epub 2015 Feb 21. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with cardiovascular dysfunction in childhood	It will be determined by normal or abnormal echocardiography using Tissue doppler and functional imaging.	Children at 2-3 years of age
Primary	Number of participants with renal dysfunction in childhood	It will be assessed using renal scoring systems such as the Kidney disease Improving Global Outcomes (KDIGO) Acute Kidney injury score (scores 1 to 3, being 3 worse outcome) and measuring the concentration of urinary biomarkers (in mg/L) such as albumin, B2 microglobulin, Cystatin c, EGF, NGAL, OPN and UMOD. Deviations of the reference range values for the scores and urinary biomarkers will indicate renal dysfunction. Results will be reported as number of patients with renal dysfunction in childhood.	Children at 2-3 years of age
Primary	Number of participants with haematological anomalies persisting in childhood	Number of patients with signs of coagulopathy will be defined using three indicators: APTT/PT (units per seconds), fibrinogen (mg/dL) and Leukocyte/neutrophil (percentage and units per Liter). Deviations of the reference range values for the three indicators will point to haematological anomalies. Results will be reported as number of patients with signs of coagulopathy.	Children at 2-3 years of age
Primary	Number of participants with neurological outcomes	Presence or absence of seizures, motor and sensory dysfunction will be evaluated using Serial Cranial ultrasounds.	Children at 2-3 years of age
Secondary	Number and identity of miRNAs upregulated or downregulated in blood of participants.	Between 350 and 800 miRNAs will be assessed in serum from patients and controls.	Children at 2-3 years of age
Secondary	Fold change of inflammasome components (NLRP3 and ASC) in RNA isolated from blood of participants.	Using RNA extracted from whole blood of patients and controls, the fold change RNA expression of inflammasome components (NLRP3 and ASC) will be evaluated.	Children at 2-3 years of age
Secondary	Concentration level in pg/mL of multicytokines in serum of participants.	Multiplex cytokine analysis will be performed and reported in pg/mL in serum. Cytokines to be included: Interleukin-1 alpha (IL-1a), Interleukin-1 beta (IL- 1ß), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Tumour Necrosis Factor-alpha (TNF-a), Interferon-gamma (IFN-d), Vascular Endothelial Growth Factor (VEGF), Granulocyte Colony Stimulating Factor (G-CSF) and Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF), Erythropoietin, Neuronal glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1 and S100B.	Children at 2-3 years of age
Secondary	Bayley Scales of Infant and Toddler development (BSID III) scores of participants.	Bayley Scales of Infant and Toddler development (BSID III) score is an assessment instrument designed to measure motor, cognitive, language, social-emotional, and adaptive behavior development in babies and young children. Composite scores are derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15, and range of 40 to 160. Scores lower than 85 indicating mild impairment, and lower than 70 indicating moderate or severe impairment. Scores equal or higher than 85 indicate normal development.	Children at 2-3 years of age