Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

NCT00513240 | Completed Phase 1 Results DMC

• 5 other identifiers: R21HD5550101IND #10001109421R21HD055501-01Not Assigned
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

Brain problems occur in neonatal open heart surgery with a frequency of 20-70%, seen on neurological examination, brain imaging such as magnetic resonance imaging (MRI), or long term development problems such as learning disorders and hyperactivity syndromes. This study aims to determine if erythropoetin, a natural hormone made in the body, protects the brain from damage when given in high doses before and during neonatal open heart surgery. We will use brain MRI, brain wave tests (EEG), neurological examination, and long term developmental outcome testing to see if erythropoetin is better than salt water injection (placebo) in protecting the brain.

Conditions

Congenital Heart Disease; Hypoplastic Left Heart Syndrome; Transposition of the Great Arteries; Aortic Arch Hypoplasia or Interruption

Keywords

erythropoetin; neuroprotection; neonate; cardiac; magnetic resonance imaging; brain magnetic resonance imaging; electroencephalogram

Outcome Measures

Primary Outcomes (2)

• Relative Difference in Total Maturity Score (TMS) From Preoperative Brain MRI to 7 Day Postoperative MRI

  TMS is a measure of developmental maturity of the brain as assessed from T1 and T2-weighted images, grading myelination, cortical infolding, involution of the germinal matrix, and presence of bands of migrating glial cells. The brain MRIs were reviewed for infarction, hemorrhage, white matter injury (WMI), or dural sinovenous thrombosis (DVST). Injuries in each category are scored 0 for none, 1 for mild, 2 for moderate, 3 for severe. The score in each category is then multiplied by a proposed outcome significance multiplier. A total injury score of 0 signifies no injury, 1-5 a mild injury, 6-10 a moderate injury, and \>10 a severe injury. Range of scores is 0 - 51. Lower scores indicate less injury. The results present the relative difference of this score between the pre- and post-operative MRI. This was calculated as ((Post-operative MRI TMS - Pre-operative MRI TMS) / (Absolute(Pre-operative MRI TMS)) ). The proportion is then converted into a percentage.

  7 days postoperatively.

• Scores on Bayley Scales of Infant Development III at Age 1 Years.

  3 domains of the Bayley Scales of Infant Development III: Cognitive, Language and Motor Minimum score = 45, maximum score = 155; Population mean = 100, SD = 15; Higher scores are indicative of better outcomes Language scores are reflective of receptive communication and expressive communication subscales. Motor scores are reflective of fine motor and gross motor subscales.

  1 year postoperatively

Secondary Outcomes (2)

• EEG Seizure Burden in the First 72 Postoperative Hours. (Total Minutes of EEG Seizures).

  72 hours postoperatively.

• Pharmacokinetics of High Dose Erythropoetin: 7 Erythropoetin Levels in First 24 Hours After First Dose (Maximum EPO Plasma Concentration)

  24 hours after first EPO dose.

Study Arms (2)

EPO group

EXPERIMENTAL

Patients randomized to receive the 3 doses of erythropoetin.

Drug: Erythropoetin

Control group.

PLACEBO COMPARATOR

Patients randomized to receive 3 doses of normal saline control.

Drug: Normal saline

Interventions

Erythropoetin DRUG

Erythropoetin 500 units/kg IV x 3 : dose 1. 12-72 hours preoperatively, dose 2. Postoperative day #1, 48 hours after separating from cardiopulmonary bypass, and dose 3. postoperative day #3, 48 hours after dose #2

Also known as: Procrit, Epoetin alpha

EPO group

Normal saline DRUG

Normal saline placebo in 3 doses:dose 1. 12-72 hours preoperatively, dose 2. Postoperative day #1, 48 hours after separating from cardiopulmonary bypass, and dose 3. postoperative day #3, 48 hours after dose #2. .

Also known as: Saline placebo

Control group.

Eligibility Criteria

• Age: 1 Day - 30 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Neonates (\<30 days) undergoing cardiac surgery with cardiopulmonary bypass will be enrolled.
• single ventricle: hypoplastic left heart syndrome or variant undergoing Norwood Stage I or Sano palliation (SV group);
• patients with D-transposition of the great vessels with or without ventricular septal defect (VSD) undergoing arterial switch operation with VSD closure if needed (ASO group); and
• patients with interrupted or hypoplastic aortic arch with intracardiac defects (VSD, ASD, or subaortic stenosis) who are undergoing complete 2- ventricle repair including aortic arch advancement(AAA group), any other 2 ventricle lesion scheduled for complex anatomic repair.

You may not qualify if:

• Gestational age less than 35 weeks at birth
• Weight less than 2 kg
• Known recognizable dysmorphic syndrome
• Surgery not requiring cardiopulmonary bypass
• Preoperative cardiac arrest requiring chest compressions for greater than 3 minutes
• Inability to enroll the patient greater than 12 hours preoperatively
• Aortic crossclamping is not used
• CPB times are anticipated to be less than 60 minutes
• A nadir temperature on bypass greater than 25° C is planned.
• Presence of known contraindications to EPO administration-sustained systolic blood pressure \>100, hemoglobin .18 g/dL, known allergy to EPO or one of its components
• Platelet count \>600,000 per dL, INR \<0.8.
• Maternal history of major vascular thrombosis, or multiple fetal loss (3 or more spontaneous abortions).

Sponsors & Collaborators

• Baylor College of Medicine: lead
• The Dana Foundation: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Related Publications (19)

• Kellert BA, McPherson RJ, Juul SE. A comparison of high-dose recombinant erythropoietin treatment regimens in brain-injured neonatal rats. Pediatr Res. 2007 Apr;61(4):451-5. doi: 10.1203/pdr.0b013e3180332cec.

  PMID: 17515870 BACKGROUND

• McPherson RJ, Demers EJ, Juul SE. Safety of high-dose recombinant erythropoietin in a neonatal rat model. Neonatology. 2007;91(1):36-43. doi: 10.1159/000096969. Epub 2006 Nov 10.

  PMID: 17344650 BACKGROUND

• Galli KK, Zimmerman RA, Jarvik GP, Wernovsky G, Kuypers MK, Clancy RR, Montenegro LM, Mahle WT, Newman MF, Saunders AM, Nicolson SC, Spray TL, Gaynor JW. Periventricular leukomalacia is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg. 2004 Mar;127(3):692-704. doi: 10.1016/j.jtcvs.2003.09.053.

  PMID: 15001897 BACKGROUND

• Andropoulos DB, Stayer SA, Diaz LK, Ramamoorthy C. Neurological monitoring for congenital heart surgery. Anesth Analg. 2004 Nov;99(5):1365-1375. doi: 10.1213/01.ANE.0000134808.52676.4D.

  PMID: 15502032 BACKGROUND

• Andropoulos DB, Stayer SA, McKenzie ED, Fraser CD Jr. Regional low-flow perfusion provides comparable blood flow and oxygenation to both cerebral hemispheres during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg. 2003 Dec;126(6):1712-7. doi: 10.1016/s0022-5223(03)01027-4.

  PMID: 14688677 BACKGROUND

• Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA. 2005 Jan 5;293(1):90-5. doi: 10.1001/jama.293.1.90.

  PMID: 15632341 BACKGROUND

• McQuillen PS, Barkovich AJ, Hamrick SE, Perez M, Ward P, Glidden DV, Azakie A, Karl T, Miller SP. Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke. 2007 Feb;38(2 Suppl):736-41. doi: 10.1161/01.STR.0000247941.41234.90.

  PMID: 17261728 BACKGROUND

• Chang YS, Mu D, Wendland M, Sheldon RA, Vexler ZS, McQuillen PS, Ferriero DM. Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatr Res. 2005 Jul;58(1):106-11. doi: 10.1203/01.PDR.0000163616.89767.69. Epub 2005 May 5.

  PMID: 15879287 BACKGROUND

• Ballweg JA, Wernovsky G, Gaynor JW. Neurodevelopmental outcomes following congenital heart surgery. Pediatr Cardiol. 2007 Mar-Apr;28(2):126-33. doi: 10.1007/s00246-006-1450-9. Epub 2007 Jan 29.

  PMID: 17265108 BACKGROUND

• Karl TR, Hall S, Ford G, Kelly EA, Brizard CP, Mee RB, Weintraub RG, Cochrane AD, Glidden D. Arterial switch with full-flow cardiopulmonary bypass and limited circulatory arrest: neurodevelopmental outcome. J Thorac Cardiovasc Surg. 2004 Jan;127(1):213-22. doi: 10.1016/j.jtcvs.2003.06.001.

  PMID: 14752433 BACKGROUND

• Wypij D, Newburger JW, Rappaport LA, duPlessis AJ, Jonas RA, Wernovsky G, Lin M, Bellinger DC. The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg. 2003 Nov;126(5):1397-403. doi: 10.1016/s0022-5223(03)00940-1.

  PMID: 14666011 BACKGROUND

• Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, Ji L, Guo X, Xiong H, Simbruner G, Blomgren K, Wang X. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009 Aug;124(2):e218-26. doi: 10.1542/peds.2008-3553. Epub 2009 Jul 27.

  PMID: 19651565 BACKGROUND

• Andropoulos DB, Mizrahi EM, Hrachovy RA, Stayer SA, Stark AR, Heinle JS, McKenzie ED, Dickerson HA, Meador MR, Fraser CD Jr. Electroencephalographic seizures after neonatal cardiac surgery with high-flow cardiopulmonary bypass. Anesth Analg. 2010 Jun 1;110(6):1680-5. doi: 10.1213/ANE.0b013e3181dd5a58. Epub 2010 Apr 30.

  PMID: 20435942 BACKGROUND

• Andropoulos DB, Hunter JV, Nelson DP, Stayer SA, Stark AR, McKenzie ED, Heinle JS, Graves DE, Fraser CD Jr. Brain immaturity is associated with brain injury before and after neonatal cardiac surgery with high-flow bypass and cerebral oxygenation monitoring. J Thorac Cardiovasc Surg. 2010 Mar;139(3):543-56. doi: 10.1016/j.jtcvs.2009.08.022. Epub 2009 Nov 11.

  PMID: 19909994 BACKGROUND

• McPherson RJ, Juul SE. Erythropoietin for infants with hypoxic-ischemic encephalopathy. Curr Opin Pediatr. 2010 Apr;22(2):139-45. doi: 10.1097/MOP.0b013e328336eb57.

  PMID: 20090525 BACKGROUND

• Juul SE, McPherson RJ, Bauer LA, Ledbetter KJ, Gleason CA, Mayock DE. A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety. Pediatrics. 2008 Aug;122(2):383-91. doi: 10.1542/peds.2007-2711.

  PMID: 18676557 BACKGROUND

• Fauchere JC, Dame C, Vonthein R, Koller B, Arri S, Wolf M, Bucher HU. An approach to using recombinant erythropoietin for neuroprotection in very preterm infants. Pediatrics. 2008 Aug;122(2):375-82. doi: 10.1542/peds.2007-2591.

  PMID: 18676556 BACKGROUND

• Brown MS, Eichorst D, Lala-Black B, Gonzalez R. Higher cumulative doses of erythropoietin and developmental outcomes in preterm infants. Pediatrics. 2009 Oct;124(4):e681-7. doi: 10.1542/peds.2008-2701. Epub 2009 Sep 28.

  PMID: 19786428 BACKGROUND

• Andropoulos DB, Brady K, Easley RB, Dickerson HA, Voigt RG, Shekerdemian LS, Meador MR, Eisenman CA, Hunter JV, Turcich M, Rivera C, McKenzie ED, Heinle JS, Fraser CD Jr. Erythropoietin neuroprotection in neonatal cardiac surgery: a phase I/II safety and efficacy trial. J Thorac Cardiovasc Surg. 2013 Jul;146(1):124-31. doi: 10.1016/j.jtcvs.2012.09.046. Epub 2012 Oct 23.

  PMID: 23102686 RESULT

Related Links

• Texas Children's Hospital Web Site
• Baylor College of Medicine Web Site
• Congenital Cardiac Anesthesia Society Web Page
• American Heart Association Web Page--Congenital Heart Disease
• National Institutes of Health: National Institute of Child Health and Developement Web Site

MeSH Terms

Conditions

Heart Defects, Congenital; Hypoplastic Left Heart Syndrome; Transposition of Great Vessels

Interventions

Erythropoietin; Epoetin Alfa; Saline Solution

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Dr. Dean B. Andropoulos
• Organization: Baylor College of Medicine

dra@bcm.edu

832-826-5831

Study Officials

• Dean B. Andropoulos, M.D.

  Baylor College of Medicine - Texas Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Chief of Pediatric Anesthesiology

Study Record Dates

• First Submitted: August 7, 2007
• First Posted: August 8, 2007
• Study Start: September 1, 2006
• Primary Completion: September 1, 2012
• Study Completion: September 1, 2015
• Last Updated: February 7, 2020
• Results First Posted: May 19, 2014

Record last verified: 2020-01

Locations

US (1)