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Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00513240
Recruitment Status : Completed
First Posted : August 8, 2007
Results First Posted : May 19, 2014
Last Update Posted : February 7, 2020
Sponsor:
Collaborators:
The Dana Foundation
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Dean Andropoulos, Baylor College of Medicine

Tracking Information
First Submitted Date  ICMJE August 7, 2007
First Posted Date  ICMJE August 8, 2007
Results First Submitted Date  ICMJE January 24, 2014
Results First Posted Date  ICMJE May 19, 2014
Last Update Posted Date February 7, 2020
Study Start Date  ICMJE September 2006
Actual Primary Completion Date September 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 28, 2020)
  • Relative Difference in Total Maturity Score (TMS) From Preoperative Brain MRI to 7 Day Postoperative MRI [ Time Frame: 7 days postoperatively. ]
    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.
  • Scores on Bayley Scales of Infant Development III at Age 1 Years. [ Time Frame: 1 year postoperatively ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 7, 2007)
  • MRI severity of injury score change from preoperative brain MRI to 7 day postoperative MRI(decrease by 25%). Scoring of infarction, hemorrhage, periventricular leukomalacia, cerebral venous sinus thrombosis, or increased lactate on MR spectroscopy. [ Time Frame: 7 days postoperatively. ]
  • Scores on Bayley Scales of Infant Development III at age 3 years. [ Time Frame: 3 years postoperatively. ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2020)
  • EEG Seizure Burden in the First 72 Postoperative Hours. (Total Minutes of EEG Seizures). [ Time Frame: 72 hours postoperatively. ]
  • Pharmacokinetics of High Dose Erythropoetin: 7 Erythropoetin Levels in First 24 Hours After First Dose (Maximum EPO Plasma Concentration) [ Time Frame: 24 hours after first EPO dose. ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 7, 2007)
  • EEG Seizure Burden in the First 72 Postoperative Hours. (Total Minutes of EEG Seizures). [ Time Frame: 72 hours postoperatively. ]
  • Pharmacokinetics of High Dose Erythropoetin: 7 Erythropoetin Levels in First 24 Hours After First Dose. [ Time Frame: 24 hours after first EPO dose. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
Official Title  ICMJE Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
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.
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:

  1. 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.
  2. To determine EPO tolerability and safety with short term administration.
  3. To determine EPO pharmacokinetics in this population.
  4. 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Congenital Heart Disease
  • Hypoplastic Left Heart Syndrome
  • Transposition of the Great Arteries
  • Aortic Arch Hypoplasia or Interruption
Intervention  ICMJE
  • Drug: Erythropoetin
    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
    Other Names:
    • Procrit
    • Epoetin alpha
  • Drug: Normal saline

    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.

    .

    Other Name: Saline placebo
Study Arms  ICMJE
  • Experimental: EPO group
    Patients randomized to receive the 3 doses of erythropoetin.
    Intervention: Drug: Erythropoetin
  • Placebo Comparator: Control group.
    Patients randomized to receive 3 doses of normal saline control.
    Intervention: Drug: Normal saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 17, 2014)
62
Original Estimated Enrollment  ICMJE
 (submitted: August 7, 2007)
240
Actual Study Completion Date  ICMJE September 2015
Actual Primary Completion Date September 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Neonates (<30 days) undergoing cardiac surgery with cardiopulmonary bypass will be enrolled.
  • Inclusion criteria include patients with:

    • 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.

Exclusion Criteria:

  • 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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 30 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00513240
Other Study ID Numbers  ICMJE R21HD5550101
IND #100011 ( Other Identifier: FDA )
0942 ( Other Grant/Funding Number: Baylor College of Medicine General Clinical Research Center )
1R21HD055501-01 ( U.S. NIH Grant/Contract )
Not Assigned ( Other Grant/Funding Number: Charles A. Dana Foundation Brain and Immuno-Imaging Grant )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dean Andropoulos, Baylor College of Medicine
Study Sponsor  ICMJE Baylor College of Medicine
Collaborators  ICMJE
  • The Dana Foundation
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators  ICMJE
Principal Investigator: Dean B. Andropoulos, M.D. Baylor College of Medicine/Texas Children's Hospital
PRS Account Baylor College of Medicine
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP