High-dose Erythropoietin for Asphyxia and Encephalopathy

Neonatal Encephalopathy Clinical Trial

— HEAL  

Official title:

High-dose Erythropoietin for Asphyxia and Encephalopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02811263
• Other study ID #: P0511976
• Status: Completed
• Phase: Phase 3
• Start date: January 2017
• Est. completion date: April 2022

Study information

• Verified date: January 2023
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 500
• Est. completion date: April 2022
• Est. primary completion date: October 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 24 Hours

Eligibility

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)

Related Conditions & MeSH terms

• Asphyxia
• Asphyxia Neonatorum
• Birth Asphyxia
• Brain Diseases
• Neonatal Encephalopathy

Intervention

Drug:
• Normal saline placebo
Equal volume of normal saline to be used as placebo
• Erythropoietin
Epogen drawn from commercially available single dose 4000U/mL vials

Locations

Country	Name	City	State
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	UT Southwestern	Dallas	Texas
United States	Cook Children's Hospital	Fort Worth	Texas
United States	Indiana University	Indianapolis	Indiana
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Children's Hospitals and Clinics of Minnesota: Minneapolis	Minneapolis	Minnesota
United States	Vanderbilt University	Nashville	Tennessee
United States	Stanford University	Palo Alto	California
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	Washington University	Saint Louis	Missouri
United States	Children's Hospitals and Clinics of Minnesota: St. Paul	Saint Paul	Minnesota
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	University of Utah	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital	San Antonio	Texas
United States	University of California, San Francisco	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (22)

Lead Sponsor

Collaborator

University of California, San Francisco

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

Country where clinical trial is conducted

United States, 

References & Publications (4)

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, Poindexte — View Citation

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. — View Citation

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. — View Citation

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, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Rates of Epo-related Adverse Events		Through hospital discharge
Other	Rates of Epo-related Adverse Events		Through 22-26 months
Other	Serial Circulating Biomarkers of Inflammation/Brain Injury	Epo level at baseline, day 2, and day 4.	During first week of life
Other	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
Other	Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury		During first week of life
Other	Number of Participants Experiencing Hearing Impairment Requiring Hearing Aids, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.		Through 22-26 months
Other	Number of Participants Experiencing Cortical Visual Impairment, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.		Through 22-26 months
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of Participants With Epilepsy	= 2 afebrile, unprovoked seizures	Prior to 22-26 months
Secondary	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