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High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL)

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ClinicalTrials.gov Identifier: NCT02811263
Recruitment Status : Active, not recruiting
First Posted : June 23, 2016
Last Update Posted : October 18, 2019
Sponsor:
Collaborators:
University of Washington
Mednax Center for Research, Education, Quality and Safety
University of Utah
Children's Research Institute
University of Minnesota - Clinical and Translational Science Institute
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
Information provided by (Responsible Party):
Yvonne Wu, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE June 17, 2016
First Posted Date  ICMJE June 23, 2016
Last Update Posted Date October 18, 2019
Actual Study Start Date  ICMJE January 2017
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 16, 2018)
Death or neurodevelopmental impairment [ Time Frame: Prior to final outcome assessment at 22-26 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
Original Primary Outcome Measures  ICMJE
 (submitted: June 20, 2016)
  • Death (component of primary outcome) [ Time Frame: Prior to final outcome assessment at 22-26 months of age ]
  • Cerebral palsy (component of primary outcome) [ Time Frame: 22-26 months of age ]
    Based on standardized neurologic exam (Kuban K)
  • Gross Motor Function Classification Scale (GMFCS) (component of primary outcome) [ Time Frame: 22-26 months ]
    Palisano (0 = normal, 1-5 = abnormal)
  • Bayley III cognitive score (component of primary outcome [ Time Frame: 22-26 months ]
    Categories of abnormality: severe ≤ 70; moderate > 70 and ≤ 85; mild > 85 and ≤ 90; normal > 90)
  • Primary Outcome = death or moderate to severe neurodevelopmental impairment [ Time Frame: 22-26 months ]
    1) Death or 2) cerebral palsy or 3) GMFCS > 0 or 4) Bayley III cognitive score ≤ 85
Change History Complete list of historical versions of study NCT02811263 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 28, 2016)
  • Presence and type of cerebral palsy (CP) determined using a standardized neurologic examination [ Time Frame: 22-26 months ]
    Neurologic diagnoses: no CP, diparetic CP, hemiparetic CP, quadriparetic CP
  • Level of gross motor function determined using the GMFCS [ Time Frame: 22-26 months ]
  • Bayley III cognitive and language scores [ Time Frame: 22-26 months ]
  • Presence of epilepsy [ Time Frame: Prior to 22-26 months ]
    ≥ 2 afebrile, unprovoked seizures
  • Behavioral abnormalities determined by the externalizing score of the Child Behavior Checklist [ Time Frame: 22-26 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2016)
  • Bayley III language score [ Time Frame: 22-26 months of age ]
    Continuous score
  • Epilepsy [ Time Frame: 22-26 months ]
    prescribed anticonvulsant medications to prevent seizures
  • Child Behavior Checklist (CBC-L) [ Time Frame: 22-26 months ]
    continuous score
  • Weight [ Time Frame: 22-26 months ]
    in kilograms
  • Height [ Time Frame: 22-26 months ]
    in centimeters
  • Head circumference [ Time Frame: 22-26 months ]
    in centimeters
  • Cortical visual impairment [ Time Frame: 22-26 months ]
    Diagnosed by an opthalmologist
  • Hearing impairment requiring hearing aids [ Time Frame: 22-26 months ]
    Prescribed hearing aids
Current Other Pre-specified Outcome Measures
 (submitted: December 28, 2016)
  • Rates of Epo-related adverse events [ Time Frame: Through hospital discharge ]
  • Rates of Epo-related adverse events [ Time Frame: Through 22-26 months ]
  • Serial circulating biomarkers of inflammation/brain injury [ Time Frame: During first week of life ]
  • MR evidence of brain injury [ Time Frame: During first week of life ]
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE High-dose Erythropoietin for Asphyxia and Encephalopathy
Official Title  ICMJE High-dose Erythropoietin for Asphyxia and Encephalopathy
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Neonatal Encephalopathy
  • Birth Asphyxia
Intervention  ICMJE
  • Drug: Normal saline placebo
    Equal volume of normal saline to be used as placebo
    Other Name: NS
  • Drug: Erythropoietin
    Epogen drawn from commercially available single dose 4000U/mL vials
    Other Name: Epogen
Study Arms  ICMJE
  • Active Comparator: Erythropoietin
    Erythropoietin 1000 U/kg IV, at about 1, 2, 3, 4, and 7 days of age (i.e., 5 doses)
    Intervention: Drug: Erythropoietin
  • Placebo Comparator: Placebo
    Normal saline IV (equal volume), at about 1, 2, 3, 4, and 7 days of age
    Intervention: Drug: Normal saline placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 16, 2019)
501
Original Estimated Enrollment  ICMJE
 (submitted: June 20, 2016)
500
Estimated Study Completion Date  ICMJE September 2022
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 24 Hours   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02811263
Other Study ID Numbers  ICMJE P0511976
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Yvonne Wu, University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE
  • University of Washington
  • Mednax Center for Research, Education, Quality and Safety
  • University of Utah
  • Children's Research Institute
  • University of Minnesota - Clinical and Translational Science Institute
  • 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  ICMJE
Principal Investigator: Yvonne Wu, MD MPH University of California, San Francisco
Principal Investigator: Sandra Juul, MD PHD University of Washington
PRS Account University of California, San Francisco
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP