Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| University of Washington | OTHER |
| Pediatrix | OTHER |
| University of Utah | OTHER |
| Children's National Research Institute |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Erythropoietin | Active Comparator | Erythropoietin 1000 U/kg IV, at about 1, 2, 3, 4, and 7 days of age (i.e., 5 doses) |
|
| Placebo | Placebo Comparator | Normal saline IV (equal volume), at about 1, 2, 3, 4, and 7 days of age |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Normal saline placebo | Drug | Equal volume of normal saline to be used as placebo |
|
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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:
Moderate to severe encephalopathy (based on modified Sarnat exam) present between 1-6 hours after birth
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Yvonne Wu, MD MPH | University of California, San Francisco | Principal Investigator |
| Sandra Juul, MD PHD | University of Washington | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital Los Angeles | Los Angeles | California | United States | |||
| Stanford University |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29514165 | Background | 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. | |
| 33888528 | Background |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | Placebo |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Nov 23, 2020 | Oct 24, 2022 |
Not provided
| OTHER |
| University of Minnesota | OTHER |
| University of Texas | OTHER |
| Washington University School of Medicine | OTHER |
| Indiana University | OTHER |
| Stanford University | OTHER |
| University of Pittsburgh | OTHER |
| Children's Hospital Los Angeles | OTHER |
| Nationwide Children's Hospital | OTHER |
| Boston University | OTHER |
| University of New Mexico | OTHER |
| University of Chicago | OTHER |
| University of North Carolina | OTHER |
| Vanderbilt University | OTHER |
| Children's Hospital Medical Center, Cincinnati | OTHER |
| Johns Hopkins University | OTHER |
| Cook Children's Medical Center | OTHER |
| Children's Hospital of Philadelphia | OTHER |
Not provided
Not provided
Not provided
Not provided
| Erythropoietin | Drug | Epogen drawn from commercially available single dose 4000U/mL vials |
|
|
| 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.
| 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 |
| Through 22-26 months |
| Rates of Epo-related Adverse Events | Through hospital discharge |
| Rates of Epo-related Adverse Events | Through 22-26 months |
| Serial Circulating Biomarkers of Inflammation/Brain Injury | Epo level at baseline, day 2, and day 4. | During first week of life |
| 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). | During first week of life |
| 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 |
| Palo Alto |
| California |
| United States |
| University of California, San Francisco | San Francisco | California | 94158 | United States |
| Children's National Medical Center | Washington D.C. | District of Columbia | 20010 | United States |
| Indiana University | Indianapolis | Indiana | United States |
| Children's Hospitals and Clinics of Minnesota: Minneapolis | Minneapolis | Minnesota | United States |
| Children's Hospitals and Clinics of Minnesota: St. Paul | Saint Paul | Minnesota | United States |
| Washington University | St Louis | Missouri | 63110 | United States |
| Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States |
| Good Samaritan Hospital | Cincinnati | Ohio | United States |
| Nationwide Children's Hospital | Columbus | Ohio | United States |
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States |
| Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania | United States |
| Magee Women's Hospital of UPMC | Pittsburgh | Pennsylvania | United States |
| Vanderbilt University | Nashville | Tennessee | United States |
| UT Southwestern | Dallas | Texas | United States |
| Cook Children's Hospital | Fort Worth | Texas | United States |
| Children's Hospital of San Antonio | San Antonio | Texas | United States |
| Methodist Children's Hospital | San Antonio | Texas | United States |
| Primary Children's Hospital | Salt Lake City | Utah | United States |
| University of Utah | Salt Lake City | Utah | United States |
| Seattle Children's Hospital | Seattle | Washington | 98105 | United States |
| University of Washington Medical Center | Seattle | Washington | 98195 | United States |
| 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. |
| 34144032 | Result | 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. |
| 35830641 | Result | 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. |
| 38984984 | Derived | Lew CO, Calabrese E, Chen JV, Tang F, Chaudhari G, Lee A, Faro J, Juul S, Mathur A, McKinstry RC, Wisnowski JL, Rauschecker A, Wu YW, Li Y. Artificial Intelligence Outcome Prediction in Neonates with Encephalopathy (AI-OPiNE). Radiol Artif Intell. 2024 Sep;6(5):e240076. doi: 10.1148/ryai.240076. |
| 38360261 | Derived | Numis AL, Glass HC, Comstock BA, Gonzalez F, Maitre NL, Massey SL, Mayock DE, Mietzsch U, Natarajan N, Sokol GM, Bonifacio S, Van Meurs K, Thomas C, Ahmad K, Heagerty P, Juul SE, Wu YW, Wusthoff CJ. Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication. J Pediatr. 2024 May;268:113957. doi: 10.1016/j.jpeds.2024.113957. Epub 2024 Feb 13. |
| 38006967 | Derived | Rao R, Comstock BA, Wu TW, Mietzsch U, Mayock DE, Gonzalez FF, Wood TR, Heagerty PJ, Juul SE, Wu YW. Time to Reaching Target Cooling Temperature and 2-year Outcomes in Infants with Hypoxic-Ischemic Encephalopathy. J Pediatr. 2024 Mar;266:113853. doi: 10.1016/j.jpeds.2023.113853. Epub 2023 Nov 23. |
| 37742617 | Derived | Gonzalez FF, Voldal E, Comstock BA, Mayock DE, Goodman AM, Cornet MC, Wu TW, Redline RW, Heagerty P, Juul SE, Wu YW. Placental Histologic Abnormalities and 2-Year Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy. Neonatology. 2023;120(6):760-767. doi: 10.1159/000533652. Epub 2023 Sep 22. |
| 37698478 | Derived | Calabrese E, Wu Y, Scheffler AW, Wisnowski JL, McKinstry RC, Mathur A, Glass HC, Comstock BA, Heagerty PJ, Gillon S, Juul SE, Hess CP, Li Y. Correlating Quantitative MRI-based Apparent Diffusion Coefficient Metrics with 24-month Neurodevelopmental Outcomes in Neonates from the HEAL Trial. Radiology. 2023 Sep;308(3):e223262. doi: 10.1148/radiol.223262. |
| 37418263 | Derived | Juul SE, Voldal E, Comstock BA, Massaro AN, Bammler TK, Mayock DE, Heagerty PJ, Wu YW, Numis AL; HEAL consortium. Association of High-Dose Erythropoietin With Circulating Biomarkers and Neurodevelopmental Outcomes Among Neonates With Hypoxic Ischemic Encephalopathy: A Secondary Analysis of the HEAL Randomized Clinical Trial. JAMA Netw Open. 2023 Jul 3;6(7):e2322131. doi: 10.1001/jamanetworkopen.2023.22131. |
| 37019334 | Derived | Juul SE, Comstock BA, Cornet MC, Gonzalez FF, Mayock DE, Glass HC, Schreiber MD, Heagerty PJ, Wu YW. Safety of High Dose Erythropoietin Used with Therapeutic Hypothermia as Treatment for Newborn Hypoxic-Ischemic Encephalopathy: Secondary Analysis of the HEAL Randomized Controlled Trial. J Pediatr. 2023 Jul;258:113400. doi: 10.1016/j.jpeds.2023.113400. Epub 2023 Apr 4. |
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
| COMPLETED |
|
| NOT COMPLETED |
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||
| Maternal education, high school or less | Count of Participants | Participants |
| ||||||||||||||||
| Parity of 1, including trial infant | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - maternal chorioamnionitis or fever | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - maternal preeclampsia or eclampsia | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - gestational diabetes | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - maternal obesity: body-mass index >30 | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - sentinel event | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - sentinel event (shoulder dystocia) | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - sentinel event (placental abruption) | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - sentinel event (prolapsed cord) | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - sentinel event (uterine rupture) | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - Cesarean section delivery | Count of Participants | Participants |
| ||||||||||||||||
| Pregnancy and delivery complications - outborn delivery | Count of Participants | Participants |
| ||||||||||||||||
| Infant birth weight | Mean | Standard Deviation | grams |
| |||||||||||||||
| Infant gestational age | Mean | Standard Deviation | weeks |
| |||||||||||||||
| Infant 5-minute Apgar score | The Apgar score is a calculated score, with 10 being the maximum score. An infant receives a score of 0, 1, or 2 for each of the following: heart rate, breathing, color, activity, grimace. These sub-scores are added together, and the higher the score, the better the infant appears. This evaluation is typically done at 1, 5, and 10 minutes after birth. | Median | Inter-Quartile Range | score on a scale |
| ||||||||||||||
| Infant 10-minute Apgar score | The Apgar score is a calculated score, with 10 being the maximum score. An infant receives a score of 0, 1, or 2 for each of the following: heart rate, breathing, color, activity, grimace. These sub-scores are added together, and the higher the score, the better the infant appears. This evaluation is typically done at 1, 5, and 10 minutes after birth. | Median | Inter-Quartile Range | score on a scale |
| ||||||||||||||
| Infant - continued resuscitation at 10 minutes | Count of Participants | Participants |
| ||||||||||||||||
| Infant - lowest pH | Mean | Standard Deviation | pH |
| |||||||||||||||
| Infant - severe encephalopathy | Enrolled infants had either moderate or severe encephalopathy, based on the presence of at least 3 of 6 Sarnat criteria present between 1-6 hours after birth. The HEAL study used a modified Sarnat scoring system that assessed: level of consciousness, spontaneous activity, posture, tone, primitive reflexes (suck and moro), and autonomic (pupils and respiration). | Count of Participants | Participants |
| |||||||||||||||
| Infant - age at randomization | Median | Inter-Quartile Range | hours |
| |||||||||||||||
| Infant - age at first treatment | Mean | Standard Deviation | hours |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Posted | Count of Participants | Participants | 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 | 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 | All toddlers evaluated with a neuro exam at 22-26 months | Posted | Count of Participants | Participants | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age |
|
| ||||||||||||||||||||||||||||||
| 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.
| 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. | Posted | Count of Participants | Participants | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age |
| |||||||||||||||||||||||||||||||
| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age |
| ||||||||||||||||||||||||||||||
| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | 22-26 months; For extenuating circumstances, for example, COVID-19 restrictions, may be performed up to 36 months of age |
| ||||||||||||||||||||||||||||||
| Secondary | Number of Participants With Epilepsy | ≥ 2 afebrile, unprovoked seizures | 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. | Posted | Count of Participants | Participants | Prior to 22-26 months |
|
| ||||||||||||||||||||||||||||||
| 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 | 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. | Posted | Count of Participants | Participants | 22-26 months |
|
| ||||||||||||||||||||||||||||||
| 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. | Posted | Count of Participants | Participants | Through 22-26 months |
|
| |||||||||||||||||||||||||||||||
| Other Pre-specified | Rates of Epo-related Adverse Events | Not Posted | Through hospital discharge | Participants | |||||||||||||||||||||||||||||||||||
| Other Pre-specified | Rates of Epo-related Adverse Events | Not Posted | Through 22-26 months | Participants | |||||||||||||||||||||||||||||||||||
| Other Pre-specified | Serial Circulating Biomarkers of Inflammation/Brain Injury | Epo level at baseline, day 2, and day 4. | 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. | Posted | Median | Inter-Quartile Range | mU/ml | During first week of life |
|
| |||||||||||||||||||||||||||||
| 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). | 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. | Posted | Median | Inter-Quartile Range | score on a scale | During first week of life |
| ||||||||||||||||||||||||||||||
| Other Pre-specified | Number of Participants With MR Evidence of Brain Injury - Severity of Brain Injury | 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. | Posted | Count of Participants | Participants | During first week of life |
|
| |||||||||||||||||||||||||||||||
| Other Pre-specified | Number of Participants Experiencing Hearing Impairment Requiring Hearing Aids, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups. | 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. | Posted | Count of Participants | Participants | Through 22-26 months |
|
| |||||||||||||||||||||||||||||||
| Other Pre-specified | Number of Participants Experiencing Cortical Visual Impairment, Per Parent/Caregiver Report, Compared Between the Epo and Placebo Groups. | 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. | Posted | Count of Participants | Participants | Through 22-26 months |
|
|
Adverse Events were collected through hospital discharge from birth, regardless of duration of hospitalization (mean = 21.4 days; median = 14 days; range = 5-187 days). Serious Adverse Events were collected through 30 days of study drug dosing. Death occurring at any time during the neonatal or follow-up period (up to 36 months) was also reported as a Serious Adverse Event.
Adverse Events: anticipated medical complications of hypoxic-ischemic encephalopathy.
Serious Adverse Events: systemic hypertension, polycythemia, disseminated intravascular coagulation, major venous or arterial thrombosis (clot), pulmonary hypertension, intracranial hemorrhage, cardiopulmonary arrest, other unexpected life-threatening event, death.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 | 37 | 257 | 137 | 257 | 254 | 257 |
| EG001 | 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 | 28 | 243 | 106 | 243 | 240 | 243 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | General disorders | Systematic Assessment |
| ||
| Systemic hypertension | Cardiac disorders | Systematic Assessment | Blood pressure elevated enough to require antihypertensive therapy |
| |
| Polycythemia | Blood and lymphatic system disorders | Systematic Assessment | Central hematocrit (Hct) > 65.0%, as measured by a central lab on 2 consecutive free-flowing arterial or venous samples. |
| |
| Major venous or arterial thrombosis | Blood and lymphatic system disorders | Systematic Assessment | Any thrombosis treated with course of anticoagulation. Any venous or arterial thrombosis involving major vessel not related to a central line. Any symptomatic thrombosis involving major vessel (e.g., symptoms such as superior vena cava syndrome). |
| |
| Disseminated intravascular coagulation | Blood and lymphatic system disorders | Systematic Assessment | Clinical bleeding or oozing requiring transfusion of blood products (e.g., fresh frozen plasma, cryoprecipitate, or platelets). |
| |
| Pulmonary hypertension | Cardiac disorders | Systematic Assessment | Elevated pulmonary vascular resistance treated with inhaled nitric oxide or extracorporeal membrane oxygenation (ECMO) therapy |
| |
| Intracranial hemorrhage | Blood and lymphatic system disorders | Systematic Assessment | Intraparenchymal or intraventricular blood visualized by head ultrasound or MRI T1 or T2 sequences. |
| |
| Cardiopulmonary arrest | Cardiac disorders | Systematic Assessment | Clinical code event requiring chest compressions or epinephrine bolus from which the infant recovers (does not lead to death), that is not secondary to endotracheal tube obstruction or other mechanical issue. |
| |
| Other unexpected life threatening event | General disorders | Systematic Assessment | Unexpected for hypoxic-ischemic encephalopathy, or unexpected based on the erythropoietin drug profile. |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Intubated > 7 days | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Ever intubated | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Meconium aspiration system | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Hypotension warranting inotropes | Cardiac disorders | Systematic Assessment |
| ||
| Dysrhythmia | Cardiac disorders | Systematic Assessment |
| ||
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
| ||
| Acute liver injury | Hepatobiliary disorders | Systematic Assessment |
| ||
| Seizure: clinical or electrographic | Nervous system disorders | Systematic Assessment |
| ||
| Discharged alive - abnormal neurologic examination | Nervous system disorders | Systematic Assessment |
| ||
| Discharged alive - nasal cannula oxygen | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Discharged alive - tracheostomy or ventilation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Discharged alive - nasogastric tube feeding | Gastrointestinal disorders | Systematic Assessment |
| ||
| Discharged alive - gastrostomy tube feeding | Gastrointestinal disorders | Systematic Assessment |
| ||
| Discharged alive - failed hearing screening | Ear and labyrinth disorders | Systematic Assessment |
|
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Yvonne W. Wu, MD, MPH | University of California, San Francisco | (415) 353-2400 | Yvonne.Wu@ucsf.edu |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 15, 2022 | Oct 24, 2022 | SAP_001.pdf |
| ID | Term |
|---|---|
| D001238 | Asphyxia Neonatorum |
| ID | Term |
|---|---|
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
Not provided
Not provided
| ID | Term |
|---|---|
| D004921 | Erythropoietin |
| D000068817 | Epoetin Alfa |
| ID | Term |
|---|---|
| D003115 | Colony-Stimulating Factors |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D016298 | Hematopoietic Cell Growth Factors |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
Not provided
Not provided
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
|
| OG001 | 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 |
|
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
|
| Participants |
|
|
|
|
|
|
|
|
|