Congenital Heart DiseasePhase 1/2NCT00513240

Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

A Phase 1/2 study testing Erythropoetin and Normal saline in people with Congenital Heart Disease and Hypoplastic Left Heart Syndrome, run by Baylor College of Medicine at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 1 day to 30 days
Conditions the study is for: Congenital Heart Disease, Hypoplastic Left Heart Syndrome, Transposition of the Great Arteries
What is being tested?: Erythropoetin and Normal saline
Type of treatment: Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 62 participants
Where: 1 siteUnited States
Study dates: Sep 2006to Sep 2015
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 1 day to 30 days
All sexes
No healthy volunteers
Child

Who may be able to join

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.

Who cannot join

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

Show all 12Show fewer

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).

Trial locations and contacts

1 site in 1 country.

United States1 site

Texas Children's Hospital
Houston, Texas, 77030

Other trials in United States

About this study

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.

Read the detailed description

Hypothesis: Erythropoetin (EPO) will protect the neonatal brain in the perioperative period for congenital heart surgery.

Using a prospective, randomized, placebo-controlled, double-blinded design, the specific aims of this study are:

To determine the effect of perioperative EPO on short and long term neurological outcomes in neonates undergoing cardiac surgery with an optimized cardiopulmonary bypass strategy.
To determine EPO tolerability and safety with short term administration.
To determine EPO pharmacokinetics in this population.
To determine the relationship of neurological monitoring, specifically NIRS, to neurological outcomes with an optimized cardiopulmonary bypass technique in neonates that avoids deep hypothermic circulatory arrest, and to determine if EPO affects this relationship.

Protocol: Neonates undergoing arterial switch, Norwood, or aortic arch advancement/other complete 2 ventricle repair, >35 weeks gestation and ≥2.0 kg are eligible.

Preop day 1:NIRS for 12-24 hours, neuro exam, and Study drug dose #1: EPO 500 units/kg or saline placebo 12-72 hours before surgery. EPO Pharmacokinetic data for 25-50 consenting patients.

Day of surgery: Brain MRI immediately preop. Anesthesia/CPB per our standard practice (fentanyl 100-200 mcg/kg, midazolam, isoflurane, epsilon-aminocaproic acid, 75 mg/kg IV load to patient and CPB prime, and 75 mg/kg/hr infusion in OR) with ACP guided by TCD, pH stat, hct 30-35, avoid DHCA.

POD #1: Study drug dose #2: EPO 500 units/kg or saline placebo 24 hours after dose #2.

For 72 hours postop, NIRS monitoring. All monitor data collected electronically.

POD #3: Study drug dose #3: EPO 500 units/kg or saline placebo 48 hours after dose #3.

7 days postop: Brain MRI. (pentobarbital IV). Neuro exam before discharge. 3-6 months: Brain MRI immediately before or after 2nd surgery, or as outpatient (IV pentobarb or propofol/midazolam-may use N2O/sevo for induction, cannot intubate if outpatient; OR if cardiac MRI at same time, any indicated anesthetic technique). NIRS x 24h after 2nd surgery.

1,and 3 years: Bayley Scales of Infant Development III. 5 years: Battery of neurodevelopmental tests.

Early primary outcome variable: MRI severity of injury score (decrease by 25%). Late outcome variable Bayley Scales of Infant Development score: improvement by 18% at age 1 years.

Sample size: 60 patients: stratified into 3 groups to give power 0.85, alpha 0.05. Expect to accrue 2-4 patients per month.

Conditions: Congenital Heart Disease, Hypoplastic Left Heart Syndrome, Transposition of the Great Arteries, Aortic Arch Hypoplasia or Interruption
Being tested: Erythropoetin, Normal saline
Keywords: erythropoetin, neuroprotection, neonate, cardiac, magnetic resonance imaging, brain magnetic resonance imaging, electroencephalogram
Medical subject headings: Heart Defects, Congenital, Hypoplastic Left Heart Syndrome, Transposition of Great Vessels

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

ErythropoetinDrug
Also called Procrit, Epoetin alpha
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
Normal salineDrug
Also called Saline placebo
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.
.

Study groups in NCT00513240
Study group	Role	What they receive
EPO group	Experimental	Patients randomized to receive the 3 doses of erythropoetin. Receives: Drug: Erythropoetin
Control group.	Placebo comparator	Patients randomized to receive 3 doses of normal saline control. Receives: Drug: Normal saline

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 1 year postoperatively

Secondary outcomes (2)

EEG Seizure Burden in the First 72 Postoperative Hours. (Total Minutes of EEG Seizures).
Measured: 72 hours postoperatively.
Pharmacokinetics of High Dose Erythropoetin: 7 Erythropoetin Levels in First 24 Hours After First Dose (Maximum EPO Plasma Concentration)
Measured: 24 hours after first EPO dose.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Sep 2006Sep 2015

First posted8 Aug 2007 (estimated)
Study startSep 2006
Primary completionSep 2012
Study completionSep 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (19)Papers the sponsor has linked to this study.
Other trials for Congenital Heart DiseaseStudies of the same condition, open and under way.
More trials run by Baylor College of MedicineThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Care provider, Investigator
Enrolment: 62 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00513240
Sponsor's protocol ID: R21HD5550101
Other IDs: IND #100011, 0942, 1R21HD055501-01, Not Assigned
Status last verified: Jan 2020
First submitted: 7 Aug 2007
Last updated: 7 Feb 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
PubMed 17515870
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.
PubMed 17344650
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.
PubMed 15001897
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.
PubMed 15502032
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.
PubMed 14688677
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.
PubMed 15632341
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.
PubMed 17261728
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.
PubMed 15879287
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.
PubMed 17265108
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.
PubMed 14752433
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.
PubMed 14666011
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.
PubMed 19651565
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.
PubMed 20435942
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.
PubMed 19909994
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.
PubMed 20090525

Want to know more?

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Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 7 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
ClinicalTrials.gov ID: NCT00513240
Acronym / sponsor ID: R21HD5550101
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
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 62 participants (actual)
Lead sponsor: Baylor College of MedicineUniversity, hospital or other
Collaborators: The Dana Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study start: Sep 2006
Primary completion: Sep 2012 (actual)
Study completion: Sep 2015 (actual)
First posted: 8 Aug 2007 (estimated)
Results: Posted 19 May 2014

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Hypothesis: Erythropoetin (EPO) will protect the neonatal brain in the perioperative period for congenital heart surgery.

Using a prospective, randomized, placebo-controlled, double-blinded design, the specific aims of this study are:

To determine the effect of perioperative EPO on short and long term neurological outcomes in neonates undergoing cardiac surgery with an optimized cardiopulmonary bypass strategy.
To determine EPO tolerability and safety with short term administration.
To determine EPO pharmacokinetics in this population.
To determine the relationship of neurological monitoring, specifically NIRS, to neurological outcomes with an optimized cardiopulmonary bypass technique in neonates that avoids deep hypothermic circulatory arrest, and to determine if EPO affects this relationship.