Welcome to HEAL

Mission: to improve the brain development and neurologic function of term infants with hypoxic-ischemic encephalopathy (HIE).


The HEAL Trial is a randomized, double-blinded, multi-center, placebo-controlled trial designed to test the efficacy of high dose erythropoietin (Epo) for neuroprotection in term infants with hypoxic-ischemic encephalopathy (HIE). HIE is sometimes referred to as neonatal encephalopathy, or birth asphyxia.


The aim of this NINDS funded trial is to assess whether multiple high doses of Epo during the first week of age will reduce the rate of death or moderate/severe motor and cognitive impairment in infants born with HIE. 500 term and near-term infants with HIE will be enrolled at over 15 centers across the U.S. Infants will be assessed at 2 years of age to see whether Epo treatment improved neurodevelopmental outcomes.


Principal Investigators, Clinical Coordinating Center: Yvonne Wu, MD MPH and Sandra Juul, MD, PhD
Principal Investigator, Data Coordinating Center: Patrick Heagerty, PhD
Funding: NINDS 1U01NS092764 and U01 NS092553
ClinicalTrials.gov Identifier: NCT# 02811263

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About HIE

About HIE

Hypoxic-ischemic encephalopathy (HIE) occurs when a baby experiences reduced blood flow and oxygen delivery to the brain near the time of birth. HIE is also referred to as neonatal encephalopathy, or birth asphyxia. When the amount of blood and oxygen supplied to the brain is less than normal, there is a possibility that the baby may sustain injury to the brain. Not all newborn babies suffer brain damage under these circumstances. However, if brain injury occurs, there is a high risk for death or neurologic disabilities including cerebral palsy, cognitive impairment (mental retardation), epilepsy, and visual impairment.

HIE affects 9,000-12,000 newborns each year in the U.S. The standard treatment for HIE is therapeutic hypothermia, or cooling therapy. Cooling the baby's body temperature for 3 days reduces the risk of brain injury after HIE. However, cooling therapy only helps about 1 in 7 infants with HIE. Therefore, additional treatments are needed to further improve brain function and brain recovery after HIE.


Erythropoietin

What is Erythropoietin (Epo)?

  • A hormone produced in the liver during fetal life, and by the kidneys after birth
  • Required for survival
  • Epo stimulates the formation of red blood cells (hematopoiesis)
  • Recombinant human Epo is an FDA approved drug used to treat or prevent anemia

Epo and Anemia

  • Epo works to prevent or treat anemia by promoting the survival and maturation of red blood cell precursors
  • It is used to treat adults and children with kidney failure and anemia
  • It is also used to treat anemia (low red blood cell counts) in premature infants

Epo and the Brain

  • Epo enhances brain regeneration and repair in preclinical models of brain injury
  • Epo is made by cells in the brain (astrocytes)
  • Epo receptors are present on many cell types in the brain (neurons and oligodendrocytes)
  • Epo is an important hormone that helps brain development during fetal life
  • Epo decreases brain damage after an injury has occurred in preclinical models
  • Clinical trials to test the neuroprotective effects of Epo are ongoing

Protective Effects of Epo in the Brain

Protective Growth Factor
↓Neuronal apoptosis ↑Brain derived neurotrophic factor (BDNF)
↓Oligodendrocyte injury ↑Neurogenesis
↓Inflammation ↑Oligodendrogenesis
↓Oxidative Injury ↑Oligodendrocyte maturation
↓Nitric oxide toxicity ↑Angiogenesis
↓Glutamate toxicity
↓Iron utilization

Risks of Epo

In adults with kidney failure, longterm Epo treatment has been associated with the following side effects. These risks have NOT been associated with Epo treatment in newborns.

  • Polycythemia (too high a red blood cell count)
  • Hypertension (high blood pressure)
  • Clotting
  • Seizures
  • Rash
  • Death (rarely)

About This Study

About The HIE / HEAL Study

We hypothesize that high-dose Epo given to cooled infants with moderate/severe HIE will reduce the primary outcome of death or neurodevelopmental impairment at age 24 months from 49% to 33%. We further hypothesize that neonatal Epo will be safe, will decrease brain injury severity on neonatal MRI, and will decrease serial inflammatory cytokines and biomarkers of brain injury.

Primary outcome is the composite of death or moderate/severe neurodevelopmental impairment. Moderate/severe neurodevelopmental impairment is based on standardized testing of motor and cognitive abilities at 2 years of age. Impairment is defined as any of the following:

  • Gross Motor Function Classification System (GMFCS) level = 2, or
  • GMFCS = 1 and presence of any cerebral palsy, or
  • GMFCS = 0 or 0.5 and presence of quadriparetic cerebral palsy, or
  • Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley III) Cognitive Score

Secondary outcomes at 2 years of age include presence of cerebral palsy, severity of motor impairment, Bayley III cognitive and language scores, epilepsy, and behavioral abnormalities (e.g., attention problems or aggressive behavior).

Inclusion Criteria

  1. Newborns = 36 weeks gestational age
  2. Receiving active or passive whole body cooling/hypothermia since = 6 hours of age
  3. Perinatal depression based on at least one of the following:
    • Apgar score
    • Need for resuscitation at 10 minutes (i.e., endotracheal or mask ventilation, or chest compressions), or
    • pH
    • Base deficit = 15 mmol/L in cord, arterial, or venous blood
  4. Moderate to severe encephalopathy, based on presence of at least 3 of 6 Sarnat criteria present between 1-6 hours after birth:
    • Reduced consciousness
    • Decreased spontaneous activity
    • Posture
    • Tone
    • Primitive reflexes (suck and Moro)
    • Autonomic abnormality (pupils and respirations)

Exclusion Criteria

  1. Study drug unlikely to be administered within 26 hours of birth
  2. Infant has living twin (or higher order multiple) who is also being cooled.
  3. Birth weight < 1800 g (e.g., intrauterine growth restriction)
  4. Genetic or congenital condition that affects neurodevelopment or requires multiple surgeries (e.g., congenital viral infection, hydrops, complex congenital heart disease, severe dysmorphic features, etc.)
  5. Head circumference < 30 cm
  6. Redirection of care is being considered due to moribund condition
  7. Patient anticipated to be unavailable for evaluation at age 2
  8. Polycythemia (hematocrit > 65%)
  9. Parents with diminished capacity or autonomy
  10. .Infant is participating in another interventional study (note: does not include observational studies)

Contacts

Clinical Coordinating Center (CCC)

Multi-Principal Investigators

Yvonne Wu, MD MPH, University of California, San Francisco, San Francisco, CA
Sandra Juul, MD PhD, University of Washington, Seattle, WA

Email: HEALtrial@uw.edu

HEAL Trial Operations / Central Coordination

Project Director

Amy Goodman, PhD, University of California, San Francisco, San Francisco, CA
amy.goodman@ucsf.edu

Lead Central Clinical Coordinator

Stephanie Hauge, MS, University of Washington, Seattle, WA
shauge@uw.edu

Data Coordinating Center (DCC)

Principal Investigator
Patrick Heagerty, Ph.D.

Biostatistician
Bryan Comstock, MS