High-dose Erythropoietin for Asphyxia and Encephalopathy

Study Overview
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Brief Summary
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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
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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.

Official Title
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High-dose Erythropoietin for Asphyxia and Encephalopathy

Conditions
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Neonatal Encephalopathy, Birth Asphyxia

Intervention / Treatment
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* Drug: Normal saline placebo
* Drug: Erythropoietin


Participation Criteria
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Eligibility Criteria
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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: Apgar score < 5 at 10 minutes, or Need for resuscitation at 10 minutes (i.e., chest compressions, or positive pressure respiratory support including endotracheal, mask ventilation, or CPAP), or pH < 7.00 in cord gas (arterial or venous) or in an infant gas (arterial or venous) obtained at < 60 minutes of age, or 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)

Ages Eligible for Study
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Maximum Age: 24 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Erythropoietin<br>Erythropoietin 1000 U/kg IV, at about 1, 2, 3, 4, and 7 days of age (i.e., 5 doses) | Drug: Erythropoietin<br>* Epogen drawn from commercially available single dose 4000U/mL vials<br>* Other names: Epogen;|
| Placebo Comparator: Placebo<br>Normal saline IV (equal volume), at about 1, 2, 3, 4, and 7 days of age | Drug: Normal saline placebo<br>* Equal volume of normal saline to be used as placebo<br>* Other names: NS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Death or Neurodevelopmental Impairment | 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 | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | Neurologic diagnoses: no CP, diparetic CP, hemiparetic CP, quadriparetic CP | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age | 
| Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | Gross Motor Function Scale (GMFCS) is a scale from 0-5, with higher values representing worse outcomes. Level 0: Walks 10 steps independently with symmetrical gait Level 0.5: Walks 10 steps independently without symmetrical gait Level 1: Sits. Hands free for play, and creeps or crawls on hands and knees, pulls to stand; cruises or walks with hands held Level 2: Uses hands for sitting support; creeps on stomach or crawls, may cruise/pull to stand Level 3: Sits with external support for lower trunk; rolls, creeps on stomach Level 4: Good head control in supported sitting; can roll to supine, may roll to prone Level 5: Unable to maintain anti-gravity head and trunk postures in prone or sitting; little or no voluntary movement. | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age | 
| Bayley III Cognitive Score | The Bayley III cognitive score is a population normed score. 100 indicates the population mean with a standard deviation of 15; higher scores indicate a higher level of development. | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age | 
| Bayley III Language Score | The Bayley III language score is a population normed score. 100 indicates the population mean with a standard deviation of 15; higher scores indicate a higher level of development. | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age | 
| Number of Participants With Epilepsy | ≥ 2 afebrile, unprovoked seizures | Prior to 22-26 months | 
| Number of Participants With Behavioral Abnormalities Determined by the Externalizing Score of the Child Behavior Checklist | Score for externalizing problems on Childhood Behavior Checklist of >= 65 | 22-26 months |