Clinical trial NCT02811263: High-dose Erythropoietin for Asphyxia and Encephalopathy
Official title: High-dose Erythropoietin for Asphyxia and Encephalopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neonatal Encephalopathy
Birth Asphyxia
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: University of Washington
name: Pediatrix
name: University of Utah
name: Children's National Research Institute
name: University of Minnesota
name: University of Texas
name: Washington University School of Medicine
name: Indiana University
name: Stanford University
name: University of Pittsburgh
name: Children's Hospital Los Angeles
name: Nationwide Children's Hospital
name: Boston University
name: University of New Mexico
name: University of Chicago
name: University of North Carolina
name: Vanderbilt University
name: Children's Hospital Medical Center, Cincinnati
name: Johns Hopkins University
name: Cook Children's Medical Center
name: Children's Hospital of Philadelphia
First posted: 2016-06-23
Enrollment: 500
Sex: ALL
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Number of Participants With Death or Neurodevelopmental Impairment
timeFrame: 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 outcomes:
measure: Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination
timeFrame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
measure: Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS
timeFrame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
measure: Bayley III Cognitive Score
timeFrame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
measure: Bayley III Language Score
timeFrame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
measure: Number of Participants With Epilepsy
timeFrame: Prior to 22-26 months
measure: Number of Participants With Behavioral Abnormalities Determined by the Externalizing Score of the Child Behavior Checklist
timeFrame: 22-26 months
Other outcomes:
measure: 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.
timeFrame: Through 22-26 months
measure: Rates of Epo-related Adverse Events
timeFrame: Through hospital discharge
measure: Rates of Epo-related Adverse Events
timeFrame: Through 22-26 months
measure: Serial Circulating Biomarkers of Inflammation/Brain Injury
timeFrame: During first week of life
measure: MR Evidence of Brain Injury - Brain Injury Score
timeFrame: During first week of life
measure: Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury
timeFrame: During first week of life
measure: Number of Participants Experiencing Hearing Impairment Requiring Hearing Aids, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.
timeFrame: Through 22-26 months
measure: Number of Participants Experiencing Cortical Visual Impairment, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.
timeFrame: Through 22-26 months
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota: Minneapolis
state: Minnesota
city: Saint Paul
country: United States
facility: Children's Hospitals and Clinics of Minnesota: St. Paul
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cincinnati
country: United States
facility: Good Samaritan Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee Women's Hospital of UPMC
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Hospital
state: Texas
city: San Antonio
country: United States
facility: Children's Hospital of San Antonio
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
Study officials:
affiliation: University of California, San Francisco
name: Yvonne Wu, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Sandra Juul, MD PHD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: 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.
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, 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.