High-dose Erythropoietin for Asphyxia and Encephalopathy

NCT ID: NCT02811263

Last Updated: 2023-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 500 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-31
• Study Completion Date: 2022-04-30

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Erythropoietin

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

Group Type: ACTIVE_COMPARATOR

Erythropoietin

Intervention Type: DRUG

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

Placebo

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

Group Type: PLACEBO_COMPARATOR

Normal saline placebo

Intervention Type: DRUG

Equal volume of normal saline to be used as placebo

Interventions

Normal saline placebo

Equal volume of normal saline to be used as placebo

Intervention Type: DRUG

Erythropoietin

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

Intervention Type: DRUG

Other Intervention Names

NS; Epogen

Eligibility Criteria

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)

• Maximum Eligible Age: 24 Hours
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Washington

OTHER

Sponsor Role: collaborator

Pediatrix

OTHER

Sponsor Role: collaborator

University of Utah

OTHER

Sponsor Role: collaborator

Children's National Research Institute

OTHER

Sponsor Role: collaborator

University of Minnesota

OTHER

Sponsor Role: collaborator

University of Texas

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Indiana University

OTHER

Sponsor Role: collaborator

Stanford University

OTHER

Sponsor Role: collaborator

University of Pittsburgh

OTHER

Sponsor Role: collaborator

Children's Hospital Los Angeles

OTHER

Sponsor Role: collaborator

Nationwide Children's Hospital

OTHER

Sponsor Role: collaborator

Boston University

OTHER

Sponsor Role: collaborator

University of New Mexico

OTHER

Sponsor Role: collaborator

University of Chicago

OTHER

Sponsor Role: collaborator

University of North Carolina

OTHER

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: collaborator

Children's Hospital Medical Center, Cincinnati

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: collaborator

Cook Children's Medical Center

OTHER

Sponsor Role: collaborator

Children's Hospital of Philadelphia

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Yvonne Wu

Professor of Neurology and Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yvonne Wu, MD MPH

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Sandra Juul, MD PHD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

Stanford University

Palo Alto, California, United States

University of California, San Francisco

San Francisco, California, United States

Children's National Medical Center

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

Indiana University

Indianapolis, Indiana, United States

Children's Hospitals and Clinics of Minnesota: Minneapolis

Minneapolis, Minnesota, United States

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

Saint Paul, Minnesota, United States

Washington University

St Louis, Missouri, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Good Samaritan Hospital

Cincinnati, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Magee Women's Hospital of UPMC

Pittsburgh, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

UT Southwestern

Dallas, Texas, United States

Cook Children's Hospital

Fort Worth, Texas, United States

Children's Hospital of San Antonio

San Antonio, Texas, United States

Methodist Children's Hospital

San Antonio, Texas, United States

Primary Children's Hospital

Salt Lake City, Utah, United States

University of Utah

Salt Lake City, Utah, United States

Seattle Children's Hospital

Seattle, Washington, United States

University of Washington Medical Center

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 29514165 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 33888528 (View on PubMed)

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.

Reference Type: RESULT

PMID: 34144032 (View on PubMed)

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.

Reference Type: RESULT

PMID: 35830641 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38984984 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38006967 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37742617 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37698478 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37418263 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37019334 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

P0511976

Identifier Type: -

Identifier Source: org_study_id