Birth Asphyxia, Neonatal Encephalopathy
Conditions
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.
Interventions
DRUGNormal saline placebo
Equal volume of normal saline to be used as placebo
DRUGErythropoietin
Epogen drawn from commercially available single dose 4000U/mL vials
Sponsors
University of Washington
Pediatrix
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
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 24 Hours
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Death or Neurodevelopmental Impairment | 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age | Neurologic diagnoses: no CP, diparetic CP, hemiparetic CP, quadriparetic CP |
| Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age | 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. |
| Bayley III Cognitive Score | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age | 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. |
| Bayley III Language Score | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age | 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. |
| Number of Participants With Epilepsy | Prior to 22-26 months | ≥ 2 afebrile, unprovoked seizures |
| Number of Participants With Behavioral Abnormalities Determined by the Externalizing Score of the Child Behavior Checklist | 22-26 months | Score for externalizing problems on Childhood Behavior Checklist of \>= 65 |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. | Through 22-26 months | Mild impairment: GMFCS=1 and no cerebral palsy, or GMFCS\<=0.5 and hemiplegic or diplegic cerebral palsy. Moderate/severe impairment: GMFCS=1 and cerebral palsy, GMFCS \>=2, quadriplegic cerebral palsy, or Bayley III cognitive score \<85. |
| Rates of Epo-related Adverse Events | Through hospital discharge | — |
| Serial Circulating Biomarkers of Inflammation/Brain Injury | During first week of life | Epo level at baseline, day 2, and day 4. |
| MR Evidence of Brain Injury - Brain Injury Score | During first week of life | Global brain injury scores were calculated using a validated scoring system for HIE. The extent of injury was recorded (i.e., none = 0, \<25% = 1, 25-50% = 2; \>50% = 3) as seen on T1, T2, and apparent diffusion coefficient (ADC) images in 8 regions of the brain: caudate, putamen/globus pallidus, thalamus, posterior limb of t he internal capsule (PLIC), cortex, white matter, brainstem, and cerebellum. The severity of brain injury was determined from the global injury score as follows: none (global injury score = 0), mild (1-11), moderate (12-32), or severe (33-138). |
| Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | During first week of life | — |
| Number of Participants Experiencing Hearing Impairment Requiring Hearing Aids, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups. | Through 22-26 months | — |
| Number of Participants Experiencing Cortical Visual Impairment, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups. | Through 22-26 months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Erythropoietin Erythropoietin 1000 U/kg IV, at about 1, 2, 3, 4, and 7 days of age (i.e., 5 doses)
Erythropoietin: Epogen drawn from commercially available single dose 4000U/mL vials | 257 |
| Placebo Normal saline IV (equal volume), at about 1, 2, 3, 4, and 7 days of age
Normal saline placebo: Equal volume of normal saline to be used as placebo | 243 |
| Total | 500 |
Baseline characteristics
| Characteristic | Placebo | Total | Erythropoietin |
|---|---|---|---|
| Age, Continuous | 30.0 years STANDARD_DEVIATION 6.6 | 29.6 years STANDARD_DEVIATION 6.3 | 29.6 years STANDARD_DEVIATION 6.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 59 Participants | 122 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 184 Participants | 378 Participants | 194 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Infant 10-minute Apgar score | 5 score on a scale | 5 score on a scale | 5 score on a scale |
| Infant 5-minute Apgar score | 3 score on a scale | 3 score on a scale | 3 score on a scale |
| Infant - age at first treatment | 17.6 hours STANDARD_DEVIATION 5.5 | 17.6 hours STANDARD_DEVIATION 5.5 | 17.6 hours STANDARD_DEVIATION 5.5 |
| Infant - age at randomization | 14 hours | 14 hours | 14 hours |
| Infant birth weight | 3414 grams STANDARD_DEVIATION 614 | 3372 grams STANDARD_DEVIATION 594 | 3332 grams STANDARD_DEVIATION 572 |
| Infant - continued resuscitation at 10 minutes | 217 Participants | 460 Participants | 243 Participants |
| Infant gestational age | 39.2 weeks STANDARD_DEVIATION 1.5 | 39.1 weeks STANDARD_DEVIATION 1.5 | 39.1 weeks STANDARD_DEVIATION 1.4 |
| Infant - lowest pH | 6.91 pH STANDARD_DEVIATION 0.17 | 6.93 pH STANDARD_DEVIATION 0.17 | 6.95 pH STANDARD_DEVIATION 0.17 |
| Infant - severe encephalopathy | 54 Participants | 113 Participants | 59 Participants |
| Maternal education, high school or less | 83 Participants | 185 Participants | 102 Participants |
| Parity of 1, including trial infant | 141 Participants | 286 Participants | 145 Participants |
| Pregnancy and delivery complications - Cesarean section delivery | 159 Participants | 329 Participants | 170 Participants |
| Pregnancy and delivery complications - gestational diabetes | 25 Participants | 58 Participants | 33 Participants |
| Pregnancy and delivery complications - maternal chorioamnionitis or fever | 32 Participants | 77 Participants | 45 Participants |
| Pregnancy and delivery complications - maternal obesity: body-mass index >30 | 42 Participants | 89 Participants | 47 Participants |
| Pregnancy and delivery complications - maternal preeclampsia or eclampsia | 23 Participants | 45 Participants | 22 Participants |
| Pregnancy and delivery complications - outborn delivery | 201 Participants | 415 Participants | 214 Participants |
| Pregnancy and delivery complications - sentinel event | 72 Participants | 143 Participants | 71 Participants |
| Pregnancy and delivery complications - sentinel event (placental abruption) | 31 Participants | 71 Participants | 40 Participants |
| Pregnancy and delivery complications - sentinel event (prolapsed cord) | 13 Participants | 23 Participants | 10 Participants |
| Pregnancy and delivery complications - sentinel event (shoulder dystocia) | 18 Participants | 32 Participants | 14 Participants |
| Pregnancy and delivery complications - sentinel event (uterine rupture) | 11 Participants | 24 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 33 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 38 Participants | 66 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 16 Participants | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 29 Participants | 18 Participants |
| Race (NIH/OMB) White | 173 Participants | 356 Participants | 183 Participants |
| Region of Enrollment United States | 243 participants | 500 participants | 257 participants |
| Sex: Female, Male Female | 103 Participants | 225 Participants | 122 Participants |
| Sex: Female, Male Male | 140 Participants | 275 Participants | 135 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 37 / 257 | 28 / 243 |
| other Total, other adverse events | 254 / 257 | 240 / 243 |
| serious Total, serious adverse events | 137 / 257 | 106 / 243 |
Outcome results
Primary
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
Time frame: 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erythropoietin | Number of Participants With Death or Neurodevelopmental Impairment | 126 Participants |
| Placebo | Number of Participants With Death or Neurodevelopmental Impairment | 110 Participants |
Secondary
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.
Time frame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
Population: The analysis population includes participants with Bayley III cognitive score available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) is higher, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythropoietin | Bayley III Cognitive Score | 89.1 score on a scale | Standard Deviation 15.7 |
| Placebo | Bayley III Cognitive Score | 89.5 score on a scale | Standard Deviation 17.5 |
Secondary
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.
Time frame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
Population: The analysis population includes participants with Bayley III language score available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) is higher, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythropoietin | Bayley III Language Score | 87.9 score on a scale | Standard Deviation 20.4 |
| Placebo | Bayley III Language Score | 86.7 score on a scale | Standard Deviation 20.8 |
Secondary
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
Time frame: 22-26 months
Population: The analysis population includes participants with Child Behavior Checklist scores available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) is higher, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erythropoietin | Number of Participants With Behavioral Abnormalities Determined by the Externalizing Score of the Child Behavior Checklist | 15 Participants |
| Placebo | Number of Participants With Behavioral Abnormalities Determined by the Externalizing Score of the Child Behavior Checklist | 3 Participants |
Secondary
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
Time frame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
Population: All toddlers evaluated with a neuro exam at 22-26 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Erythropoietin | Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | No cerebral palsy | 176 Participants |
| Erythropoietin | Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | Diparetic cerebral palsy | 9 Participants |
| Erythropoietin | Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | Hemiparetic cerebral palsy | 3 Participants |
| Erythropoietin | Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | Quadriparetic cerebral palsy | 19 Participants |
| Placebo | Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | Quadriparetic cerebral palsy | 17 Participants |
| Placebo | Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | No cerebral palsy | 173 Participants |
| Placebo | Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | Hemiparetic cerebral palsy | 2 Participants |
| Placebo | Number of Participants With Cerebral Palsy (CP) and Number of Participants With Each Type of Cerebral Palsy (CP), Determined Using a Standardized Neurologic Examination | Diparetic cerebral palsy | 6 Participants |
Secondary
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.
Time frame: 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age
Population: The analysis population includes participants with GMFCS score available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) is higher, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Erythropoietin | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 5 | 6 Participants |
| Erythropoietin | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 0.5 | 6 Participants |
| Erythropoietin | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 1 | 4 Participants |
| Erythropoietin | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 2 | 3 Participants |
| Erythropoietin | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 3 | 2 Participants |
| Erythropoietin | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 4 | 4 Participants |
| Erythropoietin | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 0 | 186 Participants |
| Placebo | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 5 | 7 Participants |
| Placebo | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 0 | 178 Participants |
| Placebo | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 3 | 1 Participants |
| Placebo | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 0.5 | 6 Participants |
| Placebo | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 1 | 6 Participants |
| Placebo | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 4 | 1 Participants |
| Placebo | Number of Participants With Each Level of Gross Motor Function, Determined Using the GMFCS | GMFCS = 2 | 5 Participants |
Secondary
Number of Participants With Epilepsy
≥ 2 afebrile, unprovoked seizures
Time frame: Prior to 22-26 months
Population: The analysis population includes participants with data regarding epilepsy available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) is higher, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erythropoietin | Number of Participants With Epilepsy | 5 Participants |
| Placebo | Number of Participants With Epilepsy | 4 Participants |
Other Pre-specified
MR Evidence of Brain Injury - Brain Injury Score
Global brain injury scores were calculated using a validated scoring system for HIE. The extent of injury was recorded (i.e., none = 0, \<25% = 1, 25-50% = 2; \>50% = 3) as seen on T1, T2, and apparent diffusion coefficient (ADC) images in 8 regions of the brain: caudate, putamen/globus pallidus, thalamus, posterior limb of t he internal capsule (PLIC), cortex, white matter, brainstem, and cerebellum. The severity of brain injury was determined from the global injury score as follows: none (global injury score = 0), mild (1-11), moderate (12-32), or severe (33-138).
Time frame: During first week of life
Population: The analysis population includes participants with brain MRI data from the first week of life available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) differs, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erythropoietin | MR Evidence of Brain Injury - Brain Injury Score | 8 score on a scale |
| Placebo | MR Evidence of Brain Injury - Brain Injury Score | 7 score on a scale |
Other Pre-specified
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.
Mild impairment: GMFCS=1 and no cerebral palsy, or GMFCS\<=0.5 and hemiplegic or diplegic cerebral palsy. Moderate/severe impairment: GMFCS=1 and cerebral palsy, GMFCS \>=2, quadriplegic cerebral palsy, or Bayley III cognitive score \<85.
Time frame: Through 22-26 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Erythropoietin | 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. | Normal | 114 Participants |
| Erythropoietin | 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. | Mild motor and/or cognitive impairment | 26 Participants |
| Erythropoietin | 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. | Moderate/severe impairment | 63 Participants |
| Erythropoietin | 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. | Death | 37 Participants |
| Placebo | 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. | Death | 28 Participants |
| Placebo | 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. | Normal | 112 Participants |
| Placebo | 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. | Moderate/severe impairment | 59 Participants |
| Placebo | 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. | Mild motor and/or cognitive impairment | 23 Participants |
Other Pre-specified
Number of Participants Experiencing Cortical Visual Impairment, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.
Time frame: Through 22-26 months
Population: The analysis population includes participants with visual impairment data available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) differs, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erythropoietin | Number of Participants Experiencing Cortical Visual Impairment, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups. | 19 Participants |
| Placebo | Number of Participants Experiencing Cortical Visual Impairment, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups. | 20 Participants |
Other Pre-specified
Number of Participants Experiencing Hearing Impairment Requiring Hearing Aids, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups.
Time frame: Through 22-26 months
Population: The analysis population includes participants with hearing impairment data available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) differs, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erythropoietin | Number of Participants Experiencing Hearing Impairment Requiring Hearing Aids, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups. | 10 Participants |
| Placebo | Number of Participants Experiencing Hearing Impairment Requiring Hearing Aids, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups. | 13 Participants |
Other Pre-specified
Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury
Time frame: During first week of life
Population: The analysis population includes participants with brain MRI data from the first week of life available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) differs, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Erythropoietin | Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | None | 49 Participants |
| Erythropoietin | Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | Mild | 91 Participants |
| Erythropoietin | Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | Moderate | 46 Participants |
| Erythropoietin | Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | Severe | 56 Participants |
| Placebo | Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | Severe | 43 Participants |
| Placebo | Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | None | 51 Participants |
| Placebo | Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | Moderate | 51 Participants |
| Placebo | Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | Mild | 86 Participants |
Other Pre-specified
Rates of Epo-related Adverse Events
Time frame: Through 22-26 months
Other Pre-specified
Rates of Epo-related Adverse Events
Time frame: Through hospital discharge
Other Pre-specified
Serial Circulating Biomarkers of Inflammation/Brain Injury
Epo level at baseline, day 2, and day 4.
Time frame: During first week of life
Population: The analysis population includes participants with biologic samples available. Total number of participants analyzed in the Participant Flow module (N=240, N=222) differs, as it reflects participants for whom the primary endpoint of death or neurodevelopmental impairment (NDI) could be determined. The primary endpoint can be determined when thresholds are met on either neurologic examination, Bayley III cognitive score, or GMFCS score, or when death occurred.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Erythropoietin | Serial Circulating Biomarkers of Inflammation/Brain Injury | Day 2 | 1530 mU/ml |
| Erythropoietin | Serial Circulating Biomarkers of Inflammation/Brain Injury | Day 4 | 2682 mU/ml |
| Erythropoietin | Serial Circulating Biomarkers of Inflammation/Brain Injury | Baseline | 32.7 mU/ml |
| Placebo | Serial Circulating Biomarkers of Inflammation/Brain Injury | Baseline | 36.0 mU/ml |
| Placebo | Serial Circulating Biomarkers of Inflammation/Brain Injury | Day 2 | 34.4 mU/ml |
| Placebo | Serial Circulating Biomarkers of Inflammation/Brain Injury | Day 4 | 20.5 mU/ml |