High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL)

University of California San Francisco (UCSF)

Status and phase: Completed; Phase 3

Conditions: Neonatal Encephalopathy; Birth Asphyxia

Treatments: Drug: Normal saline placebo; Drug: Erythropoietin

Study type: Interventional

Funder types: Other

Identifiers

NCT02811263

P0511976

Details and patient eligibility

About

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.

Full 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.

Enrollment: 500 patients

Sex: All

Ages: Under 24 hours old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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500 participants in 2 patient groups, including a placebo group

Erythropoietin

Active Comparator group

Description:

Erythropoietin 1000 U/kg IV, at about 1, 2, 3, 4, and 7 days of age (i.e., 5 doses)

Treatment:

Drug: Erythropoietin

Placebo

Placebo Comparator group

Description:

Normal saline IV (equal volume), at about 1, 2, 3, 4, and 7 days of age

Treatment:

Drug: Normal saline placebo