High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL)

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.

Study Overview

• Status: Completed
• Conditions: Neonatal Encephalopathy; Birth Asphyxia
• Intervention / Treatment: Drug: Erythropoietin; Drug: Normal saline placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 500
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States
      • Children's Hospital Los Angeles
    • Palo Alto, California, United States
      • Stanford University
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Indiana
    • Indianapolis, Indiana, United States
      • Indiana University
  • Minnesota
    • Minneapolis, Minnesota, United States
      • Children's Hospitals and Clinics of Minnesota: Minneapolis
    • Saint Paul, Minnesota, United States
      • Children's Hospitals and Clinics of Minnesota: St. Paul
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • Ohio
    • Cincinnati, Ohio, United States
      • Cincinnati Children's Hospital Medical Center
    • Cincinnati, Ohio, United States
      • Good Samaritan Hospital
    • Columbus, Ohio, United States
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States
      • Children's Hospital of Pittsburgh of UPMC
    • Pittsburgh, Pennsylvania, United States
      • Magee Women's Hospital of UPMC
  • Tennessee
    • Nashville, Tennessee, United States
      • Vanderbilt University
  • Texas
    • Dallas, Texas, United States
      • UT Southwestern
    • Fort Worth, Texas, United States
      • Cook Children's Hospital
    • San Antonio, Texas, United States
      • Children's Hospital of San Antonio
    • San Antonio, Texas, United States
      • Methodist Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States
      • University of Utah
    • Salt Lake City, Utah, United States
      • Primary Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 day (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Apgar score < 5 at 10 minutes, or
  2. Need for resuscitation at 10 minutes (i.e., chest compressions, or positive pressure respiratory support including endotracheal, mask ventilation, or CPAP), or
  3. pH < 7.00 in cord gas (arterial or venous) or in an infant gas (arterial or venous) obtained at < 60 minutes of age, or
  4. 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Erythropoietin; Erythropoietin 1000 U/kg IV, at about 1, 2, 3, 4, and 7 days of age (i.e., 5 doses)	Drug: Erythropoietin; Epogen drawn from commercially available single dose 4000U/mL vials; Other Names: Epogen
Placebo Comparator: Placebo; Normal saline IV (equal volume), at about 1, 2, 3, 4, and 7 days of age	Drug: Normal saline placebo; Equal volume of normal saline to be used as placebo; Other Names: NS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Death or Neurodevelopmental Impairment	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination	Neurologic diagnoses: no CP, diparetic CP, hemiparetic CP, quadriparetic CP	22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS	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
Bayley III Cognitive Score	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
Bayley III Language Score	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 Epilepsy	≥ 2 afebrile, unprovoked seizures	Prior to 22-26 months
Number of Participants With Behavioral Abnormalities Determined by the Externalizing Score of the Child Behavior Checklist	Score for externalizing problems on Childhood Behavior Checklist of >= 65	22-26 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Through 22-26 months
Rates of Epo-related Adverse Events		Through hospital discharge
Rates of Epo-related Adverse Events		Through 22-26 months
Serial Circulating Biomarkers of Inflammation/Brain Injury	Epo level at baseline, day 2, and day 4.	During first week of life
MR Evidence of Brain Injury - Brain Injury Score	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).	During first week of life
Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury		During first week of life
Number of Participants Experiencing Hearing Impairment Requiring Hearing Aids, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.		Through 22-26 months
Number of Participants Experiencing Cortical Visual Impairment, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.		Through 22-26 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Boston University; Johns Hopkins University; Children's Hospital of Philadelphia; Washington University School of Medicine; University of Chicago; University of Pittsburgh; University of Washington; Vanderbilt University; Stanford University; University of Minnesota; Nationwide Children's Hospital; Children's Hospital Medical Center, Cincinnati; University of Texas; University of Utah; Indiana University; Children's National Research Institute; Children's Hospital Los Angeles; University of New Mexico; University of North Carolina; Cook Children's Medical Center; Pediatrix
• Investigators: Principal Investigator: Yvonne Wu, MD MPH, University of California, San Francisco; Principal Investigator: Sandra Juul, MD PHD, University of Washington

Publications and helpful links

General Publications

• Juul SE, Comstock BA, Heagerty PJ, Mayock DE, Goodman AM, Hauge S, Gonzalez F, Wu YW. High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL): A Randomized Controlled Trial - Background, Aims, and Study Protocol. Neonatology. 2018;113(4):331-338. doi: 10.1159/000486820. Epub 2018 Mar 7.
• Wisnowski JL, Bluml S, Panigrahy A, Mathur AM, Berman J, Chen PK, Dix J, Flynn T, Fricke S, Friedman SD, Head HW, Ho CY, Kline-Fath B, Oveson M, Patterson R, Pruthi S, Rollins N, Ramos YM, Rampton J, Rusin J, Shaw DW, Smith M, Tkach J, Vasanawala S, Vossough A, Whitehead MT, Xu D, Yeom K, Comstock B, Heagerty PJ, Juul SE, Wu YW, McKinstry RC; HEAL Study Group. Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation. BMJ Open. 2021 Apr 22;11(4):e043852. doi: 10.1136/bmjopen-2020-043852.
• Chalak L, Redline RW, Goodman AM, Juul SE, Chang T, Yanowitz TD, Maitre N, Mayock DE, Lampland AL, Bendel-Stenzel E, Riley D, Mathur AM, Rao R, Van Meurs KP, Wu TW, Gonzalez FF, Flibotte J, Mietzsch U, Sokol GM, Ahmad KA, Baserga M, Weitkamp JH, Poindexter BB, Comstock BA, Wu YW. Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy. J Pediatr. 2021 Oct;237:190-196. doi: 10.1016/j.jpeds.2021.06.023. Epub 2021 Jun 16.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): October 1, 2021
• Study Completion (Actual): April 1, 2022

Study Registration Dates

• First Submitted: June 17, 2016
• First Submitted That Met QC Criteria: June 20, 2016
• First Posted (Estimate): June 23, 2016

Study Record Updates

• Last Update Posted (Estimate): January 30, 2023
• Last Update Submitted That Met QC Criteria: January 4, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Infant, Newborn, Diseases; Death; Brain Diseases; Asphyxia; Asphyxia Neonatorum; Hematinics; Epoetin Alfa
• Other Study ID Numbers: P0511976

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes