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Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

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ClinicalTrials.gov Identifier: NCT00513240
Recruitment Status : Active, not recruiting
First Posted : August 8, 2007
Results First Posted : May 19, 2014
Last Update Posted : January 6, 2017
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The Dana Foundation
Texas Children's Hospital
Information provided by (Responsible Party):
Dean Andropoulos, Baylor College of Medicine

August 7, 2007
August 8, 2007
January 24, 2014
May 19, 2014
January 6, 2017
September 2006
September 2012   (Final data collection date for primary outcome measure)
  • MRI Severity of Injury Score [ Time Frame: 7 days postoperatively. ]
    MRI severity of injury score change from preoperative brain MRI to 7 day postoperative MRI(decrease by 25%). Scoring of infarction, hemorrhage, white matter injury, cerebral venous sinus thrombosis, or increased lactate on MR spectroscopy.
  • 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.
  • 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. ]
Complete list of historical versions of study NCT00513240 on ClinicalTrials.gov Archive Site
  • 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. ]
Same as current
Not Provided
Not Provided
 
Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
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.

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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
  • Congenital Heart Disease
  • Hypoplastic Left Heart Syndrome
  • Transposition of the Great Arteries
  • Aortic Arch Hypoplasia or Interruption
  • 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
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
62
240
January 2017
September 2012   (Final data collection date for primary outcome measure)

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).
Sexes Eligible for Study: All
up to 30 Days   (Child)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00513240
R21HD5550101
FDA IND #100011
Baylor GCRC #0942
Yes
Not Provided
Not Provided
Dean Andropoulos, Baylor College of Medicine
Baylor College of Medicine
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • The Dana Foundation
  • Texas Children's Hospital
Principal Investigator: Dean B. Andropoulos, M.D. Baylor College of Medicine/Texas Children's Hospital
Baylor College of Medicine
November 2016

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