Birth Asphyxia, Hypoxic-ischemic Encephalopathy, Neonatal Encephalopathy
Conditions
Keywords
erythropoietin, therapeutic hypothermia
Brief summary
Hypoxic-ischemic encephalopathy (HIE), a condition of reduced blood and oxygen flow to a baby's brain near the time of birth, may cause death or neurologic disability. Cooling therapy (hypothermia) provides some protection, but about half of affected infants still have a poor outcome. This clinical trial will determine if the drug erythropoietin, given with hypothermia, is safe to use as a treatment that may further reduce the risk of neurologic deficits after HIE.
Detailed description
This phase I/II clinical trial is designed to demonstrate: 1. The feasibility of recruiting, enrolling and following 50 patients with moderate to severe HIE at 5 sites, while meeting specified recruitment and follow-up target goals. 2. The safety of high-dose Epo therapy in neonates with HIE with respect to systemic organ function and general growth parameters. 3. The value of brain MRI/MRS performed at 4-7 days of age as a biomarker of motor function at 12 months of age.
Interventions
DRUGErythropoietin
1000 U/kg/dose IV x 5 doses
DRUGNormal saline
placebo: NS IV x 5 doses
Sponsors
Thrasher Research Fund
Seattle Children's Hospital
Arkansas Children's Hospital Research Institute
Washington University School of Medicine
Children's National Research Institute
Stanford University
Kaiser Permanente
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
30 Minutes to 24 Hours
Healthy volunteers
No
Inclusion criteria
* Newborns ≥ 36 weeks gestation, \< 23 hours of age at time of consent, must meet all 3 Inclusion Criteria to be eligible for the study: 1. Perinatal depression = at least one of the following: a) Apgar ≤5 at 10 min or b) required resuscitation (endotracheal or mask ventilation, or chest compressions) at 10 min or c) pH \< 7.0 or base deficit ≥15 in cord, arterial, or venous blood obtained at \<60 min of age; 2. Moderate to severe encephalopathy = at least 3 of 6 modified Sarnat criteria present between 1-6 h of birth: a) reduced level of consciousness; b) decreased spontaneous activity; c) hypotonia; d) decreased suck; e) decreased Moro reflex; or f) respiratory distress including periodic breathing or apnea; and 3. Hypothermia = passive or active cooling begun by 6 hours of age.
Exclusion criteria
* Intrauterine growth restriction (BW \<1800 g); * Major congenital malformation; suspected genetic syndrome, metabolic disorder or TORCH infection; * Head circumference \< 2 SD for gestation; * Infant for whom withdrawal of supportive care is being considered; or * Anticipated inability to collect primary endpoint at 12 months of age.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Markers of Organ Function | Participants will be followed for the duration of hospital stay, an expected average of 2 weeks | The investigators will monitor organ function and adverse events until hospital discharge from the neonatal intensive care unit |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alberta Infant Motor Scale (AIMS) | 12 months | The AIMS consists of 58 items, including 4 positions: prone (21 items), supine (9 items), sitting (12 items), & standing (16 items). Each item is scored as 'observed' or 'not observed'. Total score range is 0-58, scored as percentile ranks after a raw score is obtained and plotted against age at testing, based on validated norms. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Warner Initial Developmental Evaluation (WIDEA) | 12 months | A 43-item questionnaire developed and standardized to assess the functional domains of self-care, motor function, communication and social cognition in young children. Self care sub-scale score range 17-68. Mobility score range is 9-36. Communication score range is 13-52. Social Cognition score range is 11-44. Total scale range is 50-200. Higher scores mean higher functioning. Lower scores mean lower functioning. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Erythropoietin Erythropoietin: 1000 U/kg/dose IV x 5 doses | 24 |
| Normal Saline Normal saline: placebo: NS IV x 5 doses | 26 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 5 |
| Overall Study | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Erythropoietin | Normal Saline |
|---|---|---|---|
| 10 minute Apgar 0-3 | 12 Participants | 5 Participants | 7 Participants |
| 10 minute Apgar 4-6 | 24 Participants | 13 Participants | 11 Participants |
| 10 minute Apgar 7-10 | 10 Participants | 3 Participants | 7 Participants |
| 5 minute Apgar 0-3 (critically low) | 25 Participants | 11 Participants | 14 Participants |
| 5 minute Apgar 4-6 (below normal) | 20 Participants | 10 Participants | 10 Participants |
| 5 minute Apgar 7-10 (normal) | 3 Participants | 2 Participants | 1 Participants |
| aEEG severe abnormal background | 14 Participants | 7 Participants | 7 Participants |
| Age at 1st study drug (hours) | 16.5 hours STANDARD_DEVIATION 5.9 | 15.6 hours STANDARD_DEVIATION 5.7 | 17.2 hours STANDARD_DEVIATION 6.1 |
| Age at randomization (hours) | 13.9 hours STANDARD_DEVIATION 6.1 | 13.3 hours STANDARD_DEVIATION 6.1 | 14.6 hours STANDARD_DEVIATION 6.1 |
| Age, Continuous | 29.5 years STANDARD_DEVIATION 6.8 | 29.4 years STANDARD_DEVIATION 7.2 | 29.7 years STANDARD_DEVIATION 6.6 |
| Birth weight (g) | 3393 grams STANDARD_DEVIATION 581 | 3556 grams STANDARD_DEVIATION 618 | 3243 grams STANDARD_DEVIATION 512 |
| Chest compressions | 19 Participants | 8 Participants | 11 Participants |
| Delivery mode Elective cesarean | 1 Participants | 1 Participants | 0 Participants |
| Delivery mode Emergency cesarean | 32 Participants | 17 Participants | 15 Participants |
| Delivery mode Spontaneous vaginal | 14 Participants | 5 Participants | 9 Participants |
| Delivery mode Vacuum or forceps | 3 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 5 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 19 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gestational age (weeks) | 38.7 weeks STANDARD_DEVIATION 1.7 | 38.7 weeks STANDARD_DEVIATION 1.9 | 38.7 weeks STANDARD_DEVIATION 1.6 |
| Large for gestational age | 7 Participants | 6 Participants | 1 Participants |
| Lowest pH | 6.9 pH STANDARD_DEVIATION 0.2 | 6.9 pH STANDARD_DEVIATION 0.2 | 7.0 pH STANDARD_DEVIATION 0.2 |
| Maternal chorioamnionitis | 7 Participants | 4 Participants | 3 Participants |
| Maternal education College graduate, or post-grad | 13 Participants | 6 Participants | 7 Participants |
| Maternal education High school or less | 20 Participants | 10 Participants | 10 Participants |
| Maternal education Some college or university | 12 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 32 Participants | 14 Participants | 18 Participants |
| Resuscitation > 10 minutes | 42 Participants | 21 Participants | 21 Participants |
| Sentinel event | 14 Participants | 7 Participants | 7 Participants |
| Severe Sarnat encephalopathy | 9 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Female | 24 Participants | 14 Participants | 10 Participants |
| Sex: Female, Male Male | 26 Participants | 10 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 24 | 5 / 26 |
| other Total, other adverse events | 17 / 24 | 16 / 26 |
| serious Total, serious adverse events | 3 / 24 | 6 / 26 |
Outcome results
Primary
Markers of Organ Function
The investigators will monitor organ function and adverse events until hospital discharge from the neonatal intensive care unit
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 2 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Erythropoietin | Markers of Organ Function | Renal dysfunction (creatinine > 1.5) | 4 participants |
| Erythropoietin | Markers of Organ Function | Hypertension (requiring anti-hypertensive) | 1 participants |
| Erythropoietin | Markers of Organ Function | Polycythemia (requiring intervention) | 0 participants |
| Erythropoietin | Markers of Organ Function | Persistent pulmonary hypertension | 5 participants |
| Erythropoietin | Markers of Organ Function | Death during birth hospitalization | 2 participants |
| Erythropoietin | Markers of Organ Function | Liver dysfunction (ALT >100 IU/L) | 10 participants |
| Erythropoietin | Markers of Organ Function | Cardiopulmonary collapse within 2 hours of drug | 1 participants |
| Erythropoietin | Markers of Organ Function | Disseminated intravascular coagulation | 3 participants |
| Erythropoietin | Markers of Organ Function | Thrombosis of major vessel | 1 participants |
| Erythropoietin | Markers of Organ Function | Thrombocytopenia (platelet < 100,000 per uL) | 6 participants |
| Erythropoietin | Markers of Organ Function | Unexpected event related to study drug | 0 participants |
| Erythropoietin | Markers of Organ Function | Sepsis (positive blood culture and antibiotics >=7 | 0 participants |
| Erythropoietin | Markers of Organ Function | Hypotension (requiring inotrope or vasopressor) | 9 participants |
| Normal Saline | Markers of Organ Function | Hypertension (requiring anti-hypertensive) | 0 participants |
| Normal Saline | Markers of Organ Function | Liver dysfunction (ALT >100 IU/L) | 6 participants |
| Normal Saline | Markers of Organ Function | Hypotension (requiring inotrope or vasopressor) | 12 participants |
| Normal Saline | Markers of Organ Function | Thrombocytopenia (platelet < 100,000 per uL) | 10 participants |
| Normal Saline | Markers of Organ Function | Persistent pulmonary hypertension | 4 participants |
| Normal Saline | Markers of Organ Function | Disseminated intravascular coagulation | 5 participants |
| Normal Saline | Markers of Organ Function | Sepsis (positive blood culture and antibiotics >=7 | 5 participants |
| Normal Saline | Markers of Organ Function | Polycythemia (requiring intervention) | 0 participants |
| Normal Saline | Markers of Organ Function | Death during birth hospitalization | 5 participants |
| Normal Saline | Markers of Organ Function | Cardiopulmonary collapse within 2 hours of drug | 0 participants |
| Normal Saline | Markers of Organ Function | Thrombosis of major vessel | 1 participants |
| Normal Saline | Markers of Organ Function | Unexpected event related to study drug | 0 participants |
| Normal Saline | Markers of Organ Function | Renal dysfunction (creatinine > 1.5) | 5 participants |
Secondary
Alberta Infant Motor Scale (AIMS)
The AIMS consists of 58 items, including 4 positions: prone (21 items), supine (9 items), sitting (12 items), & standing (16 items). Each item is scored as 'observed' or 'not observed'. Total score range is 0-58, scored as percentile ranks after a raw score is obtained and plotted against age at testing, based on validated norms.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythropoietin | Alberta Infant Motor Scale (AIMS) | 53.5 percentile | Standard Deviation 5.2 |
| Normal Saline | Alberta Infant Motor Scale (AIMS) | 42.8 percentile | Standard Deviation 19.3 |
Post Hoc
Brain Injury, as Determined by Neonatal Brain MRI
Time frame: neonatal hospitalization
Population: For subjects randomized to Erythropoietin, age at MRI was 5.6 days (SD 2.8) and subjects received 3.7 (SD 0.8) doses before MRI.~For subjects randomized to placebo (normal saline), age at MRI was 4.9 days (SD 1.4) and subjects received 3.4 (SD 0.8) doses before MRI.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: >=2 regions injured | 7 participants |
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Global brain injury score: Mild (1-11) | 14 participants |
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Global brain injury score: Moderate (12-31) | 0 participants |
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Global brain injury score: Severe (>=32) | 1 participants |
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: Subcortical | 7 participants |
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: Cortical | 4 participants |
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: White matter | 12 participants |
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: Brainstem | 1 participants |
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: Cerebellar | 0 participants |
| Erythropoietin | Brain Injury, as Determined by Neonatal Brain MRI | Global brain injury score: None (0) | 8 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: Brainstem | 4 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Global brain injury score: None (0) | 3 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: Cortical | 9 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Global brain injury score: Mild (1-11) | 11 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: >=2 regions injured | 14 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Global brain injury score: Moderate (12-31) | 6 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: White matter | 15 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Global brain injury score: Severe (>=32) | 5 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: Cerebellar | 5 participants |
| Normal Saline | Brain Injury, as Determined by Neonatal Brain MRI | Presence of brain injury: Subcortical | 17 participants |
Post Hoc
Growth Parameters: Head Circumference
Time frame: 12-months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythropoietin | Growth Parameters: Head Circumference | 45.7 cm | Standard Deviation 1.6 |
| Normal Saline | Growth Parameters: Head Circumference | 45.5 cm | Standard Deviation 2.1 |
Post Hoc
Growth Parameters: Height
Time frame: 12-months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythropoietin | Growth Parameters: Height | 74.3 cm | Standard Deviation 3.2 |
| Normal Saline | Growth Parameters: Height | 71.7 cm | Standard Deviation 6.2 |
Post Hoc
Growth Parameters: Weight
Time frame: 12-months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythropoietin | Growth Parameters: Weight | 9.9 kg | Standard Deviation 1.4 |
| Normal Saline | Growth Parameters: Weight | 9.7 kg | Standard Deviation 1.2 |
Post Hoc
Moderate to Severe Neurodevelopmental Impairment
Moderate to severe neurodevelopmental impairment at 12 months was defined as AIMS less than 5th percentile for age, or WIDEA more than 2 standard deviations below the mean based on normative data from typically developing infants at 12.9 months of age.
Time frame: 12-months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erythropoietin | Moderate to Severe Neurodevelopmental Impairment | 2 Participants |
| Normal Saline | Moderate to Severe Neurodevelopmental Impairment | 5 Participants |
Other Pre-specified
Warner Initial Developmental Evaluation (WIDEA)
A 43-item questionnaire developed and standardized to assess the functional domains of self-care, motor function, communication and social cognition in young children. Self care sub-scale score range 17-68. Mobility score range is 9-36. Communication score range is 13-52. Social Cognition score range is 11-44. Total scale range is 50-200. Higher scores mean higher functioning. Lower scores mean lower functioning.
Time frame: 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) | Self-care (17-68) | 36.7 units on a scale | Standard Deviation 5.1 |
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) | Social Cognition (11-44) | 28.8 units on a scale | Standard Deviation 6.4 |
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) | Communication (13-52) | 28.2 units on a scale | Standard Deviation 5.1 |
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) | Mobility (9-36) | 28.6 units on a scale | Standard Deviation 3.8 |
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) | Total score (50-200) | 122 units on a scale | Standard Deviation 14 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) | Mobility (9-36) | 23.8 units on a scale | Standard Deviation 8.9 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) | Total score (50-200) | 110 units on a scale | Standard Deviation 31 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) | Self-care (17-68) | 33.8 units on a scale | Standard Deviation 7.7 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) | Communication (13-52) | 25.5 units on a scale | Standard Deviation 8.8 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) | Social Cognition (11-44) | 26.9 units on a scale | Standard Deviation 8.9 |
Post Hoc
Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age
A 43-item questionnaire developed and standardized to assess the functional domains of self-care, motor function, communication and social cognition in young children. Self care score range 7-28. Mobility score range is 9-36. Communication score range is 13-52. Social Cognition score range is 11-44. Higher the score means higher functioning. Lower scores means lower functioning.
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Self-care (7-28) | 28.1 units on a scale | Standard Deviation 4.2 |
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Communication (13-52) | 16.4 units on a scale | Standard Deviation 3.2 |
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Mobility (9-36) | 14.1 units on a scale | Standard Deviation 2.7 |
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Social Cognition (11-44) | 16.7 units on a scale | Standard Deviation 4.5 |
| Erythropoietin | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Total score (50-200) | 75.3 units on a scale | Standard Deviation 9.1 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Social Cognition (11-44) | 14.9 units on a scale | Standard Deviation 3.2 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Total score (50-200) | 68.8 units on a scale | Standard Deviation 10.7 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Self-care (7-28) | 26.1 units on a scale | Standard Deviation 4.7 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Mobility (9-36) | 12.4 units on a scale | Standard Deviation 2.7 |
| Normal Saline | Warner Initial Developmental Evaluation (WIDEA) at 6 Months of Age | Communication (13-52) | 15.3 units on a scale | Standard Deviation 2.8 |