High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL)

University of Washington, Pediatrix, University of Utah, Children's National Research Institute, University of Minnesota, University of Texas, Washington University School of Medicine, Indiana University, Stanford University, University of Pittsburgh, Children's Hospital Los Angeles, Nationwide Children's Hospital, Boston University, University of New Mexico, University of Chicago, University of North Carolina, Vanderbilt University, Children's Hospital Medical Center, Cincinnati, Johns Hopkins University, Cook Children's Medical Center, Children's Hospital of Philadelphia

Hypoxic-ischemic encephalopathy (HIE) occurs when a baby gets reduced blood flow and oxygen to the brain near the time of birth. This results in death or neurologic disabilities including cerebral palsy and cognitive impairment in up to half of affected infants. This clinical trial will determine if the drug erythropoietin (Epo) added to hypothermia (usual therapy) will improve outcomes for infants suffering from HIE.

Neonatal hypoxic-ischemic encephalopathy (HIE) refers to brain injury resulting from reduced blood and oxygen flow to a baby's brain near the time of birth. HIE affects up to 12,000 newborns each year in the U.S. Half of affected infants have a bad outcome including death, cerebral palsy and cognitive impairment despite receiving hypothermia, the only available treatment. Erythropoietin (Epo) is a cytokine with remarkable neuroprotective and neuroregenerative effects demonstrated in animal models of neonatal brain injury. In a phase I trial of Epo + hypothermia, the investigators found that Epo 1000 U/Kg/dose best reproduced the pharmacokinetics of neuroprotective dosing in animal models. Long term outcomes were better than expected based on entry criteria and MRI findings. A phase II trial compared 50 cooled infants randomized to receive Epo or placebo. Infants treated with hypothermia + Epo had less brain injury on early MRI, and better 12-month motor development. The investigators hypothesize that Epo given to cooled infants with moderate/severe HIE will reduce the combined primary outcome of death or neurodevelopmental impairment from 49 to 33%. This is a randomized, double-blind, placebo-controlled trial of Epo therapy in 500 infants with HIE undergoing hypothermia. Specific aims are 1) To determine if 5 doses of Epo 1000 U/kg IV reduces the rate of death, motor or cognitive deficits at 2 years; 2) To assess safety of Epo by evaluating clinical toxicity; and 3) To determine whether Epo decreases the severity of neonatal brain injury as evidenced by early MRI and circulating biomarkers of brain injury. The investigators anticipate that Epo will confer improved 2-year neurodevelopmental outcome, will be safe, and will decrease brain injury severity as determined by early biomarkers.

Neurodevelopmental impairment defined as any of the following: a) Gross Motor Function Scale (GMFCS) level ≥ 1, or b) GMFCS = 0 or 0.5 and cerebral palsy (CP) (any type), or c) Bayley III Cognitive Score < 90

Prior to final outcome assessment at 22-26 months of age; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age

Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination

22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age

Gross Motor Function Scale (GMFCS) is a scale from 0-5, with higher values representing worse outcomes. Level 0: Walks 10 steps independently with symmetrical gait Level 0.5: Walks 10 steps independently without symmetrical gait Level 1: Sits. Hands free for play, and creeps or crawls on hands and knees, pulls to stand; cruises or walks with hands held Level 2: Uses hands for sitting support; creeps on stomach or crawls, may cruise/pull to stand Level 3: Sits with external support for lower trunk; rolls, creeps on stomach Level 4: Good head control in supported sitting; can roll to supine, may roll to prone Level 5: Unable to maintain anti-gravity head and trunk postures in prone or sitting; little or no voluntary movement.

22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age

The Bayley III cognitive score is a population normed score. 100 indicates the population mean with a standard deviation of 15; higher scores indicate a higher level of development.

22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age

The Bayley III language score is a population normed score. 100 indicates the population mean with a standard deviation of 15; higher scores indicate a higher level of development.

22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age

Number of Participants With Behavioral Abnormalities Determined by the Externalizing Score of the Child Behavior Checklist

Number of Participants at Each Level of Severity of Impairment [(1) Normal, (2) Mild Motor and/or Cognitive Impairment, (3) Moderate/Severe Motor and or Cognitive Impairment, (4) Death], Compared Between the Epo and Placebo Groups.

Mild impairment: GMFCS=1 and no cerebral palsy, or GMFCS<=0.5 and hemiplegic or diplegic cerebral palsy. Moderate/severe impairment: GMFCS=1 and cerebral palsy, GMFCS >=2, quadriplegic cerebral palsy, or Bayley III cognitive score <85.

Global brain injury scores were calculated using a validated scoring system for HIE. The extent of injury was recorded (i.e., none = 0, <25% = 1, 25-50% = 2; >50% = 3) as seen on T1, T2, and apparent diffusion coefficient (ADC) images in 8 regions of the brain: caudate, putamen/globus pallidus, thalamus, posterior limb of t he internal capsule (PLIC), cortex, white matter, brainstem, and cerebellum. The severity of brain injury was determined from the global injury score as follows: none (global injury score = 0), mild (1-11), moderate (12-32), or severe (33-138).

Number of Participants Experiencing Hearing Impairment Requiring Hearing Aids, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.

Number of Participants Experiencing Cortical Visual Impairment, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.

Inclusion Criteria: ≥ 36 weeks of gestational age Receiving active or passive whole body cooling/hypothermia since < 6 hours of age Perinatal depression based on at least one of the following: Apgar score < 5 at 10 minutes, or Need for resuscitation at 10 minutes (i.e., chest compressions, or positive pressure respiratory support including endotracheal, mask ventilation, or CPAP), or pH < 7.00 in cord gas (arterial or venous) or in an infant gas (arterial or venous) obtained at < 60 minutes of age, or Base deficit ≥ 15 mmol/L in cord gas (arterial or venous) or in an infant gas (arterial or venous) obtained at < 60 minutes of age Moderate to severe encephalopathy (based on modified Sarnat exam) present between 1-6 hours after birth Exclusion Criteria: Study drug unlikely to be administered within 26 hours of birth Infant has living twin (or higher order multiple) who is also being cooled Birth weight < 1800 g (e.g., intrauterine growth restriction) 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.) Head circumference < 30 cm Redirection of care is being considered due to moribund condition Patient anticipated to be unavailable for evaluation at age 2 Polycythemia (hematocrit > 65.0%) Parents/legal guardians with diminished capacity and autonomy Infant is participating or intends to participate in another interventional study during the birth hospitalization (note: does not include observational studies) Sentinel event and encephalopathy occurred only after birth Unable to consent in primary language of parent(s)

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Wu YW, Comstock BA, Gonzalez FF, Mayock DE, Goodman AM, Maitre NL, Chang T, Van Meurs KP, Lampland AL, Bendel-Stenzel E, Mathur AM, Wu TW, Riley D, Mietzsch U, Chalak L, Flibotte J, Weitkamp JH, Ahmad KA, Yanowitz TD, Baserga M, Poindexter BB, Rogers EE, Lowe JR, Kuban KCK, O'Shea TM, Wisnowski JL, McKinstry RC, Bluml S, Bonifacio S, Benninger KL, Rao R, Smyser CD, Sokol GM, Merhar S, Schreiber MD, Glass HC, Heagerty PJ, Juul SE; HEAL Consortium. Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. N Engl J Med. 2022 Jul 14;387(2):148-159. doi: 10.1056/NEJMoa2119660.