High-dose Erythropoietin for Asphyxia and Encephalopathy

NCT02811263 | Completed Phase 3 Results DMC

• 1 other identifier: P0511976
• Study Type: interventional
• Target: 500
• Locations: 1 country
• Sites: 23

Brief 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. This clinical trial will determine if the drug erythropoietin (Epo) added to hypothermia (usual therapy) will improve outcomes for infants suffering from HIE.

Conditions

Neonatal Encephalopathy; Birth Asphyxia

Outcome Measures

Primary Outcomes (1)

• 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 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

  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

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

• Bayley III Cognitive Score

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

• Bayley III Language Score

  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

  Prior to 22-26 months

Other Outcomes (8)

• 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.

  Through 22-26 months

• Rates of Epo-related Adverse Events

  Through hospital discharge

• Rates of Epo-related Adverse Events

  Through 22-26 months

Study Arms (2)

Erythropoietin

ACTIVE COMPARATOR

Erythropoietin 1000 U/kg IV, at about 1, 2, 3, 4, and 7 days of age (i.e., 5 doses)

Drug: Erythropoietin

Placebo

PLACEBO COMPARATOR

Normal saline IV (equal volume), at about 1, 2, 3, 4, and 7 days of age

Drug: Normal saline placebo

Interventions

Normal saline placebo DRUG

Equal volume of normal saline to be used as placebo

Also known as: NS

Placebo

Erythropoietin DRUG

Epogen drawn from commercially available single dose 4000U/mL vials

Also known as: Epogen

Erythropoietin

Eligibility Criteria

• Age: Up to 24 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• ≥ 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

You may not qualify if:

• 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)

Sponsors & Collaborators

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

Study Sites (23)

Children's Hospital Los Angeles

Los Angeles, California, United States

Location

Stanford University

Palo Alto, California, United States

Location

University of California, San Francisco

San Francisco, California, 94158, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Indiana University

Indianapolis, Indiana, United States

Location

Children's Hospitals and Clinics of Minnesota: Minneapolis

Minneapolis, Minnesota, United States

Location

Children's Hospitals and Clinics of Minnesota: St. Paul

Saint Paul, Minnesota, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Location

Good Samaritan Hospital

Cincinnati, Ohio, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Location

Magee Women's Hospital of UPMC

Pittsburgh, Pennsylvania, United States

Location

Vanderbilt University

Nashville, Tennessee, United States

Location

UT Southwestern

Dallas, Texas, United States

Location

Cook Children's Hospital

Fort Worth, Texas, United States

Location

Children's Hospital of San Antonio

San Antonio, Texas, United States

Location

Methodist Children's Hospital

San Antonio, Texas, United States

Location

Primary Children's Hospital

Salt Lake City, Utah, United States

Location

University of Utah

Salt Lake City, Utah, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Related Publications (10)

• 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.

  PMID: 29514165 BACKGROUND

• 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.

  PMID: 33888528 BACKGROUND

• 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.

  PMID: 34144032 RESULT

• 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.

  PMID: 35830641 RESULT

• Lew 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.

  PMID: 38984984 DERIVED

• Rao 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.

  PMID: 38006967 DERIVED

• Gonzalez 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.

  PMID: 37742617 DERIVED

• Calabrese 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.

  PMID: 37698478 DERIVED

• Juul 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.

  PMID: 37418263 DERIVED

• Juul 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.

  PMID: 37019334 DERIVED

MeSH Terms

Conditions

Asphyxia Neonatorum

Interventions

Erythropoietin; Epoetin Alfa

Condition Hierarchy (Ancestors)

Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Yvonne W. Wu, MD, MPH
• Organization: University of California, San Francisco

Yvonne.Wu@ucsf.edu

(415) 353-2400

Study Officials

• Yvonne Wu, MD MPH

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Sandra Juul, MD PHD

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology and Pediatrics

Study Record Dates

• First Submitted: June 17, 2016
• First Posted: June 23, 2016
• Study Start: January 1, 2017
• Primary Completion: October 1, 2021
• Study Completion: April 1, 2022
• Last Updated: January 30, 2023
• Results First Posted: January 30, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share

Locations

US (23)