High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL)

• ClinicalTrials.gov Identifier: NCT02811263
• Recruitment Status: Active, not recruiting
• First Posted: June 23, 2016
• Last Update Posted: January 15, 2021
• Sponsor: University of California, San Francisco
• Collaborators: 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
• Information provided by (Responsible Party): Yvonne Wu, University of California, San Francisco

Tracking Information

• First Submitted Date: June 17, 2016
• First Posted Date: June 23, 2016
• Last Update Posted Date: January 15, 2021
• Actual Study Start Date: January 2017
• Estimated Primary Completion Date: January 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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

Current Secondary Outcome Measures (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 (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: High-dose Erythropoietin for Asphyxia and Encephalopathy
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Neonatal Encephalopathy
• Birth Asphyxia

Intervention

• 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

• 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 *

• 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.
• Wu YW, Mathur AM, Chang T, McKinstry RC, Mulkey SB, Mayock DE, Van Meurs KP, Rogers EE, Gonzalez FF, Comstock BA, Juul SE, Msall ME, Bonifacio SL, Glass HC, Massaro AN, Dong L, Tan KW, Heagerty PJ, Ballard RA. High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial. Pediatrics. 2016 Jun;137(6). pii: e20160191. doi: 10.1542/peds.2016-0191. Epub 2016 May 2.
• Wu YW, Bauer LA, Ballard RA, Ferriero DM, Glidden DV, Mayock DE, Chang T, Durand DJ, Song D, Bonifacio SL, Gonzalez FF, Glass HC, Juul SE. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Oct;130(4):683-91. doi: 10.1542/peds.2012-0498. Epub 2012 Sep 24.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 16, 2019): 501
• Original Estimated Enrollment (submitted: June 20, 2016): 500
• Estimated Study Completion Date: September 2022
• Estimated Primary Completion Date: January 2022 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 24 Hours (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02811263
• Other Study ID Numbers: P0511976
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes

• Responsible Party: Yvonne Wu, University of California, San Francisco
• Study Sponsor: University of California, San Francisco

Collaborators

• 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

• PRS Account: University of California, San Francisco
• Verification Date: January 2021