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HEAL: High-dose Erythropoietin for Asphyxia and Encephalopathy

Sponsor
University of California, San Francisco (Other)
Overall Status
Completed
CT.gov ID
NCT02811263
Collaborator
University of Washington (Other), Mednax Center for Research, Education, Quality and Safety (Other), University of Utah (Other), Children's National Research Institute (Other), University of Minnesota (Other), University of Texas (Other), Washington University School of Medicine (Other), Indiana University (Other), Stanford University (Other), University of Pittsburgh (Other), Children's Hospital Los Angeles (Other), Nationwide Children's Hospital (Other), Boston University (Other), University of New Mexico (Other), University of Chicago (Other), University of North Carolina (Other), Vanderbilt University (Other), Children's Hospital Medical Center, Cincinnati (Other), Johns Hopkins University (Other), Cook Children's Medical Center (Other), Children's Hospital of Philadelphia (Other)
501
Enrollment
23
Locations
2
Arms
62.9
Actual Duration (Months)
21.8
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

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

Study Type:
Interventional
Actual Enrollment :
501 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
High-dose Erythropoietin for Asphyxia and Encephalopathy
Actual Study Start Date :
Jan 1, 2017
Actual Primary Completion Date :
Oct 1, 2021
Actual Study Completion Date :
Apr 1, 2022

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Death or neurodevelopmental impairment [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

    Secondary Outcome Measures

    1. Presence and 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]

      Neurologic diagnoses: no CP, diparetic CP, hemiparetic CP, quadriparetic CP

    2. 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]

    3. Bayley III cognitive and language scores [22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age]

    4. Presence of epilepsy [Prior to 22-26 months]

      ≥ 2 afebrile, unprovoked seizures

    5. Behavioral abnormalities determined by the externalizing score of the Child Behavior Checklist [22-26 months]

    Other Outcome Measures

    1. 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]

      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.

    2. Rates of Epo-related adverse events [Through hospital discharge]

    3. Rates of Epo-related adverse events [Through 22-26 months]

    4. Serial circulating biomarkers of inflammation/brain injury [During first week of life]

    5. MR evidence of brain injury [During first week of life]

    6. Number of subjects experiencing hearing impairment requiring hearing aids and/or cortical visual impairment, per parent/caregiver report, compared between the Epo and Placebo groups. [Through 22-26 months]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 24 Hours
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital Los Angeles Los Angeles California United States
    2 Stanford University Palo Alto California United States
    3 University of California, San Francisco San Francisco California United States 94158
    4 Children's National Medical Center Washington District of Columbia United States 20010
    5 Indiana University Indianapolis Indiana United States
    6 Children's Hospitals and Clinics of Minnesota: Minneapolis Minneapolis Minnesota United States
    7 Children's Hospitals and Clinics of Minnesota: St. Paul Saint Paul Minnesota United States
    8 Washington University Saint Louis Missouri United States 63110
    9 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States
    10 Good Samaritan Hospital Cincinnati Ohio United States
    11 Nationwide Children's Hospital Columbus Ohio United States
    12 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States
    13 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States
    14 Magee Women's Hospital of UPMC Pittsburgh Pennsylvania United States
    15 Vanderbilt University Nashville Tennessee United States
    16 UT Southwestern Dallas Texas United States
    17 Cook Children's Hospital Fort Worth Texas United States
    18 Children's Hospital of San Antonio San Antonio Texas United States
    19 Methodist Children's Hospital San Antonio Texas United States
    20 Primary Children's Hospital Salt Lake City Utah United States
    21 University of Utah Salt Lake City Utah United States
    22 Seattle Children's Hospital Seattle Washington United States 98105
    23 University of Washington Medical Center Seattle Washington United States 98195

    Sponsors and Collaborators

    • University of California, San Francisco
    • University of Washington
    • Mednax Center for Research, Education, Quality and Safety
    • 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

    Investigators

    • Principal Investigator: Yvonne Wu, MD MPH, University of California, San Francisco
    • Principal Investigator: Sandra Juul, MD PHD, University of Washington

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Yvonne Wu, Professor of Neurology and Pediatrics, University of California, San Francisco
    ClinicalTrials.gov Identifier:
    NCT02811263
    Other Study ID Numbers:
    • P0511976
    First Posted:
    Jun 23, 2016
    Last Update Posted:
    May 3, 2022
    Last Verified:
    May 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:
    Brain Diseases
    Asphyxia Neonatorum
    Asphyxia
    Epoetin Alfa

    Study Results

    No Results Posted as of May 3, 2022