Neonatal EncephalopathyPhase 3HEALNCT02811263
High-dose Erythropoietin for Asphyxia and Encephalopathy
A Phase 3 study testing Erythropoietin in people with Neonatal Encephalopathy and Birth Asphyxia, run by University of California, San Francisco at 23 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages Up to 24 hours
- Conditions the study is for
- Neonatal Encephalopathy, Birth Asphyxia
- What is being tested?
- Erythropoietin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 500 participants
- Where
- 23 sitesUnited States
- Study dates
- Jan 2017to Apr 2022
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 24 hours
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- ≥ 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
Who cannot join
- 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
Show all 12Show fewer
- 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)
Trial locations and contacts
23 sites in 1 country.
23 sites in 1 country
United States23 sites
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio
Good Samaritan Hospital
Cincinnati, Ohio
Nationwide Children's Hospital
Columbus, Ohio
UT Southwestern
Dallas, Texas
Cook Children's Hospital
Fort Worth, Texas
Indiana University
Indianapolis, Indiana
Children's Hospital Los Angeles
Los Angeles, California
Children's Hospitals and Clinics of Minnesota: Minneapolis
Minneapolis, Minnesota
Vanderbilt University
Nashville, Tennessee
Stanford University
Palo Alto, California
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania
Magee Women's Hospital of UPMC
Pittsburgh, Pennsylvania
Children's Hospitals and Clinics of Minnesota: St. Paul
Saint Paul, Minnesota
Primary Children's Hospital
Salt Lake City, Utah
University of Utah
Salt Lake City, Utah
Children's Hospital of San Antonio
San Antonio, Texas
Methodist Children's Hospital
San Antonio, Texas
University of California, San Francisco
San Francisco, California, 94158
Seattle Children's Hospital
Seattle, Washington, 98105
University of Washington Medical Center
Seattle, Washington, 98195
Washington University
St Louis, Missouri, 63110
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
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.
Read the 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.
- Conditions
- Neonatal Encephalopathy, Birth Asphyxia
- Being tested
- Normal saline placebo, Erythropoietin
- Medical subject headings
- Asphyxia Neonatorum
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Normal saline placeboDrug
Also called NS
Equal volume of normal saline to be used as placebo
ErythropoietinDrug
Also called Epogen
Epogen drawn from commercially available single dose 4000U/mL vials
| Study group | Role | What they receive |
|---|---|---|
| Erythropoietin | Active comparator | Erythropoietin 1000 U/kg IV, at about 1, 2, 3, 4, and 7 days of age (i.e., 5 doses) Receives: Drug: Erythropoietin |
| Placebo | Placebo comparator | Normal saline IV (equal volume), at about 1, 2, 3, 4, and 7 days of age Receives: Drug: Normal saline placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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 outcomes (6)
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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 22-26 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jun 2016 (estimated)
- Study startJan 2017
- Primary completionOct 2021
- Study completionApr 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Neonatal EncephalopathyStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 500 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- 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
- Responsible party
- Principal investigator, Yvonne Wu, University of California, San Francisco
- Investigators
- Yvonne Wu, MD MPH, Principal investigator, University of California, San FranciscoSandra Juul, MD PHD, Principal investigator, University of Washington
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02811263
- Sponsor's protocol ID
- P0511976
- Acronym
- HEAL
- Status last verified
- Jan 2023
- First submitted
- 17 Jun 2016
- Last updated
- 30 Jan 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes
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.
PubMed 29514165Wisnowski 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.
PubMed 33888528Chalak 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.
PubMed 34144032Wu 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.
PubMed 35830641Clifford D, Vaughan CL, Costelloe SJ, Walsh BH, Numis A, Juul SE, Murray DM. Blood-Based Biomarkers Predict Cerebral Palsy and Cognitive Delay in Hypoxic-Ischemic Encephalopathy: A Secondary Analysis of the High-Dose Erythropoietin for Asphyxia and Encephalopathy Randomized Controlled Trial. J Pediatr. 2026 Jul 1;297:115216. doi: 10.1016/j.jpeds.2026.115216. Online ahead of print.
PubMed 42386129Lew CO, Calabrese E, Chen JV, Tang F, Chaudhari G, Lee A, Faro J, Juul S, Mathur A, McKinstry RC, Wisnowski JL, Rauschecker A, Wu YW, Li Y. Artificial Intelligence Outcome Prediction in Neonates with Encephalopathy (AI-OPiNE). Radiol Artif Intell. 2024 Sep;6(5):e240076. doi: 10.1148/ryai.240076.
PubMed 38984984Numis AL, Glass HC, Comstock BA, Gonzalez F, Maitre NL, Massey SL, Mayock DE, Mietzsch U, Natarajan N, Sokol GM, Bonifacio S, Van Meurs K, Thomas C, Ahmad K, Heagerty P, Juul SE, Wu YW, Wusthoff CJ. Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication. J Pediatr. 2024 May;268:113957. doi: 10.1016/j.jpeds.2024.113957. Epub 2024 Feb 13.
PubMed 38360261Rao R, Comstock BA, Wu TW, Mietzsch U, Mayock DE, Gonzalez FF, Wood TR, Heagerty PJ, Juul SE, Wu YW. Time to Reaching Target Cooling Temperature and 2-year Outcomes in Infants with Hypoxic-Ischemic Encephalopathy. J Pediatr. 2024 Mar;266:113853. doi: 10.1016/j.jpeds.2023.113853. Epub 2023 Nov 23.
PubMed 38006967Gonzalez FF, Voldal E, Comstock BA, Mayock DE, Goodman AM, Cornet MC, Wu TW, Redline RW, Heagerty P, Juul SE, Wu YW. Placental Histologic Abnormalities and 2-Year Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy. Neonatology. 2023;120(6):760-767. doi: 10.1159/000533652. Epub 2023 Sep 22.
PubMed 37742617Calabrese E, Wu Y, Scheffler AW, Wisnowski JL, McKinstry RC, Mathur A, Glass HC, Comstock BA, Heagerty PJ, Gillon S, Juul SE, Hess CP, Li Y. Correlating Quantitative MRI-based Apparent Diffusion Coefficient Metrics with 24-month Neurodevelopmental Outcomes in Neonates from the HEAL Trial. Radiology. 2023 Sep;308(3):e223262. doi: 10.1148/radiol.223262.
PubMed 37698478Juul SE, Voldal E, Comstock BA, Massaro AN, Bammler TK, Mayock DE, Heagerty PJ, Wu YW, Numis AL; HEAL consortium. Association of High-Dose Erythropoietin With Circulating Biomarkers and Neurodevelopmental Outcomes Among Neonates With Hypoxic Ischemic Encephalopathy: A Secondary Analysis of the HEAL Randomized Clinical Trial. JAMA Netw Open. 2023 Jul 3;6(7):e2322131. doi: 10.1001/jamanetworkopen.2023.22131.
PubMed 37418263Juul SE, Comstock BA, Cornet MC, Gonzalez FF, Mayock DE, Glass HC, Schreiber MD, Heagerty PJ, Wu YW. Safety of High Dose Erythropoietin Used with Therapeutic Hypothermia as Treatment for Newborn Hypoxic-Ischemic Encephalopathy: Secondary Analysis of the HEAL Randomized Controlled Trial. J Pediatr. 2023 Jul;258:113400. doi: 10.1016/j.jpeds.2023.113400. Epub 2023 Apr 4.
PubMed 37019334
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- High-dose Erythropoietin for Asphyxia and Encephalopathy
- ClinicalTrials.gov ID
- NCT02811263
- Acronym / sponsor ID
- HEAL / P0511976
- Conditions
- Neonatal Encephalopathy, Birth Asphyxia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 500 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- 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
- Study start
- Jan 2017 (actual)
- Primary completion
- Oct 2021 (actual)
- Study completion
- Apr 2022 (actual)
- First posted
- 23 Jun 2016 (estimated)
- Results
- Posted 30 Jan 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Erythropoietin | Active comparator | Drug: ErythropoietinErythropoietin 1000 U/kg IV, at about 1, 2, 3, 4, and 7 days of age (i.e., 5 doses) |
| Placebo | Placebo comparator | Drug: Normal saline placeboNormal saline IV (equal volume), at about 1, 2, 3, 4, and 7 days of age |
Who may qualify
- Ages
- Up to 24 hours
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (8 listed)
- ≥ 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:
- Moderate to severe encephalopathy (based on modified Sarnat exam) present between 1-6 hours after birth
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Normal saline placeboAlso: NSEqual volume of normal saline to be used as placebo | Drug | Placebo |
| ErythropoietinAlso: EpogenEpogen drawn from commercially available single dose 4000U/mL vials | Drug | Erythropoietin |
Primary outcome
Number of Participants With Death or Neurodevelopmental Impairment
Time frame: 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
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
6 secondary outcomes
Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination
Time frame: 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
Time frame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
Bayley III Cognitive Score
Time frame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
Bayley III Language Score
Time frame: 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
Time frame: Prior to 22-26 months
Number of Participants With Behavioral Abnormalities Determined by the Externalizing Score of the Child Behavior Checklist
Time frame: 22-26 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 29514165Juul 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.
- Background: PubMed 33888528Wisnowski 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.
- Results publication: PubMed 34144032Chalak 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.
- Results publication: PubMed 35830641Wu 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.
- Derived from this study: PubMed 42386129Clifford D, Vaughan CL, Costelloe SJ, Walsh BH, Numis A, Juul SE, Murray DM. Blood-Based Biomarkers Predict Cerebral Palsy and Cognitive Delay in Hypoxic-Ischemic Encephalopathy: A Secondary Analysis of the High-Dose Erythropoietin for Asphyxia and Encephalopathy Randomized Controlled Trial. J Pediatr. 2026 Jul 1;297:115216. doi: 10.1016/j.jpeds.2026.115216. Online ahead of print.
- Derived from this study: PubMed 38984984Lew CO, Calabrese E, Chen JV, Tang F, Chaudhari G, Lee A, Faro J, Juul S, Mathur A, McKinstry RC, Wisnowski JL, Rauschecker A, Wu YW, Li Y. Artificial Intelligence Outcome Prediction in Neonates with Encephalopathy (AI-OPiNE). Radiol Artif Intell. 2024 Sep;6(5):e240076. doi: 10.1148/ryai.240076.
- Derived from this study: PubMed 38360261Numis AL, Glass HC, Comstock BA, Gonzalez F, Maitre NL, Massey SL, Mayock DE, Mietzsch U, Natarajan N, Sokol GM, Bonifacio S, Van Meurs K, Thomas C, Ahmad K, Heagerty P, Juul SE, Wu YW, Wusthoff CJ. Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication. J Pediatr. 2024 May;268:113957. doi: 10.1016/j.jpeds.2024.113957. Epub 2024 Feb 13.
- Derived from this study: PubMed 38006967Rao R, Comstock BA, Wu TW, Mietzsch U, Mayock DE, Gonzalez FF, Wood TR, Heagerty PJ, Juul SE, Wu YW. Time to Reaching Target Cooling Temperature and 2-year Outcomes in Infants with Hypoxic-Ischemic Encephalopathy. J Pediatr. 2024 Mar;266:113853. doi: 10.1016/j.jpeds.2023.113853. Epub 2023 Nov 23.
- Derived from this study: PubMed 37742617Gonzalez FF, Voldal E, Comstock BA, Mayock DE, Goodman AM, Cornet MC, Wu TW, Redline RW, Heagerty P, Juul SE, Wu YW. Placental Histologic Abnormalities and 2-Year Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy. Neonatology. 2023;120(6):760-767. doi: 10.1159/000533652. Epub 2023 Sep 22.
- Derived from this study: PubMed 37698478Calabrese E, Wu Y, Scheffler AW, Wisnowski JL, McKinstry RC, Mathur A, Glass HC, Comstock BA, Heagerty PJ, Gillon S, Juul SE, Hess CP, Li Y. Correlating Quantitative MRI-based Apparent Diffusion Coefficient Metrics with 24-month Neurodevelopmental Outcomes in Neonates from the HEAL Trial. Radiology. 2023 Sep;308(3):e223262. doi: 10.1148/radiol.223262.
- Derived from this study: PubMed 37418263Juul SE, Voldal E, Comstock BA, Massaro AN, Bammler TK, Mayock DE, Heagerty PJ, Wu YW, Numis AL; HEAL consortium. Association of High-Dose Erythropoietin With Circulating Biomarkers and Neurodevelopmental Outcomes Among Neonates With Hypoxic Ischemic Encephalopathy: A Secondary Analysis of the HEAL Randomized Clinical Trial. JAMA Netw Open. 2023 Jul 3;6(7):e2322131. doi: 10.1001/jamanetworkopen.2023.22131.
- Derived from this study: PubMed 37019334Juul SE, Comstock BA, Cornet MC, Gonzalez FF, Mayock DE, Glass HC, Schreiber MD, Heagerty PJ, Wu YW. Safety of High Dose Erythropoietin Used with Therapeutic Hypothermia as Treatment for Newborn Hypoxic-Ischemic Encephalopathy: Secondary Analysis of the HEAL Randomized Controlled Trial. J Pediatr. 2023 Jul;258:113400. doi: 10.1016/j.jpeds.2023.113400. Epub 2023 Apr 4.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yvonne Wu, MD MPH principal investigator
University of California, San Francisco
Sandra Juul, MD PHD principal investigator
University of Washington
23 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Erythropoietin in people with Neonatal Encephalopathy and Birth Asphyxia, run by University of California, San Francisco at 23 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Jan 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Death or Neurodevelopmental Impairment (time frame: 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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02811263, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2023.