Neurocognitive, Neuroprotective, Neonatal, Neurodevelopmental Impairment
Conditions
Brief summary
Study Hypothesis: Preterm infants administered weekly Darbe during the neonatal period will have improved neurocognitive outcome at 22-26 months compared to placebo
Detailed description
Advances in neonatal care have led to significant improvements in the survival of the nearly 60,000 very low birth weight (VLBW) infants born each year in the U.S. Improving neurodevelopmental outcomes for these preterm infants continues to be a major goal for neonatal care providers. A subset of these infants sustain a grade 3 or 4 intraventricular hemorrhage (IVH) resulting in an increase in the incidence of developmental delay. Moreover, almost one third of preterm infants with normal head ultrasounds also develop cognitive delay. Although a variety of neuroprotective treatment strategies have been evaluated, no specific treatment has been identified to reduce or prevent brain injury in these most vulnerable preterm infants. A potential neuroprotective therapy involves administering erythropoiesis stimulating agents (ESAs) such as erythropoietin (Epo) and Darbepoetin (Darbe, a longer acting ESA). In addition to stimulating erythropoiesis, ESAs have been shown to be protective in the developing brain in animal models, making it possibly beneficial for very premature infants who are at risk for intraventricular hemorrhage, hypoxic-ischemic injury, and developmental delay. The neuroprotective mechanisms of ESAs include increased neurogenesis, decreased neuronal susceptibility to glutamate toxicity, decreased neuronal apoptosis, decreased inflammation, decreased nitric oxide-mediated injury, increased antioxidant response, decreased axonal degeneration, and increased protective effects on glia. This is a randomized, masked, placebo controlled clinical study in which enrolled infants will receive weekly Darbe or placebo (sham) dosing. Extended follow-up: Subjects will be seen for follow-up at 4-5 years (i.e., 4 years - 4 years 11 months) corrected age and 6-7 years (i.e., 6 years - 6 years 11 months) corrected age to characterize the functional, behavioral and neurological outcomes of the extremely low birth weight (ELBW) population at school age based on treatment with darbepoetin versus placebo in the neonatal period.
Interventions
DRUGDarbepoetin
Darbepoetin 10 micrograms/kg/once every week (IV or SC). Infants will be treated until 35 completed weeks gestation, discharge, or transfer to another hospital.
DRUGPlacebo
normal saline for IV administration, or sham dosing. Infants will be treated until 35 completed weeks gestation, discharge, or transfer to another hospital.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
NICHD Neonatal Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Primary providers and bedside caregivers will be blinded to randomization group. If the dose will be administered IV, the study drug will be administered slow IV push by the bedside nurse. If the dose will be administered subcutaneously, the study drug will be brought to the bedside in a closed container, and injections will be shielded behind screens and out of earshot from caregivers and parents. An adhesive bandage (or 2x2 gauze) will be placed over the true and sham injection sites and either taped or held in place until no evidence of the injection is visible. The parents, medical providers, data collection staff and neurodevelopmental follow up personnel will be masked to the treatment arm.
Intervention model description
Randomized, masked, placebo-controlled trial
Eligibility
Sex/Gender
ALL
Age
1 Hours to 24 Hours
Healthy volunteers
No
Inclusion criteria
* Inborn and outborn preterm infants * 23 0/7-28 6/7 weeks gestational age * ≤24 hours postnatal age
Exclusion criteria
* Hematocrit \> 60% * Infants with known congenital or chromosomal anomalies, including congenital heart disease and known brain anomalies * Hemorrhagic or hemolytic disease * EEG- confirmed seizures * Congenital thrombotic disease * Systolic blood pressures \>100 mm Hg while not on pressor support * Receiving Epo or Darbe clinically, or planning to receive Epo or Darbe during hospitalization * Infants in whom no aggressive therapy is planned * Family will NOT be available for follow-up at 22-26 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bayley III Composite Cognitive Score | 22-26 months corrected age (a median of 25 months corrected age, which corresponds to a median of 29 months calendar age in the analysis population), unless the subject died earlier | Bayley Scale of Infant and Toddler Development (BSID)-III composite cognitive score, where subjects who died prior to the follow-up assessment are assigned the lowest possible score of 54. This is a standardized scale where a score that is more than 1 normative standard deviation from the normative mean of 100 signifies mild developmental delay (score \< 85); 2 standard deviations below the mean, moderate delay (score \< 70); and 3 standard deviations below the mean, severe delay (score \< 55). This self-standing scale comprises the primary outcome for the Darbe study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Volume of Transfusions Per Infant | Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks) | The total volume of transfusions for the infant if ever transfused |
| Number of Donor Exposures Per Infant | Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks) | The number of donor exposures recorded during the study, up to 35 completed weeks gestational age |
| Hematocrit | at 2 and at 7 weeks in the study | Hematocrit adjusted for center, gestational age group, and familial clustering |
| Red Cell Mass | at 2 and at 7 weeks in the study | Red Cell Mass (Circulating Erythrocyte Volume), adjusted for center, gestational age group, and familial clustering |
| Necrotizing Enterocolitis, Bells Stage >=2 With Surgery | Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days) | This is measured as Yes if experienced necrotizing enterocolitis, Bells stage \>=2 with surgery; Otherwise, No. |
| Bronchopulmonary Dysplasia Grades 2 or 3 | At 36 weeks postmenstrual age | This is measured as Yes if infant is on invasive mechanical ventilation, nasal cannula \>2 L/min or noninvasive positive airway pressure at 36 weeks of postmenstrual age; Otherwise, No. |
| Number of Transfusions Per Infant | Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks) | The number of transfusions recorded during the study, up to 35 completed weeks gestational age |
| Intraventricular Hemorrhage Grade I+ | Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days) | This is measured as Yes if experienced Grade I+ Intraventricular Hemorrhage; Otherwise, No. |
| Length of Hospital Stay | At initial hospital discharge or at death if it occurs earlier (a median of 94 days), assessed up to one year of life. | This is measured as the length of stay up to hospital discharge or death, whichever occurred first. |
| Death | Birth, through the 22-26 months corrected age follow-up window, which corresponds to a median of 29 months calendar age in the analysis population | This is measured as Yes if an infant died between birth and 22-26 months corrected age; Otherwise, No. |
| Neurodevelopmental Impairment | At 22-26 months corrected age (a median of 25 months corrected age) | This is a 4-level outcome, where Severe NDI denotes a BSID III cognitive score less than 70, a Gross Motor Functional (GMF) level of 3-5 (where higher scores indicate worse outcomes), blindness (less than 20/200 vision), and/or profound hearing loss, Moderate NDI denotes a BSID III cognitive score from 70-84 and either a GMF level of 2 or limited blindness / moderate hearing loss, Mild NDI denotes a BSID III cognitive score from 70-84, or a cognitive score \>=85 with a GMF level of 1 and/or mild hearing loss, and No NDI denotes a cognitive score \>= 85 and an absence of neurosensory deficits. |
| Any Cerebral Palsy | At 22-26 months corrected age (a median of 25 months corrected age) | This is measured as Yes if the child has been deemed by the medical examiner as having Cerebral Palsy; Otherwise, No. |
| Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days) | This is measured as Yes if experienced Retinopathy of prematurity stage \>=3 or treatment for that condition received; Otherwise, No. Higher stages of ROP indicate a worse outcome; the stages range from 1 for mild disease, to 5 for severe disease. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Darbepoetin Darbepoetin (Amgen, Thousand Oaks, CA), 10 mcg per kg, administered once weekly from 36 hours of birth through 35 weeks PMA, intravenously when the infant had intravenous access, otherwise subcutaneou | 322 |
| Placebo Normal saline, 0.4 mL/kg, administered once weekly from 36 hours of birth through 35 weeks postmenstrual age as a sham subcutaneous dose | 328 |
| Total | 650 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Data withdrawn prior to hospital discharge | 3 | 1 |
| Overall Study | Incomplete Follow-up | 10 | 15 |
| Overall Study | Lost to Follow-up | 18 | 20 |
Baseline characteristics
| Characteristic | Darbepoetin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 26.2 weeks STANDARD_DEVIATION 1.7 | 26.2 weeks STANDARD_DEVIATION 1.6 | 26.2 weeks STANDARD_DEVIATION 1.7 |
| Birth weight, Continuous | 838.2 grams STANDARD_DEVIATION 252.9 | 822.1 grams STANDARD_DEVIATION 238.5 | 830.1 grams STANDARD_DEVIATION 245.7 |
| Race, Customized American Indian or Alaska Native | 7 Participants | 11 Participants | 18 Participants |
| Race, Customized Asian, Native Hawaiian, or Other Pacific Islander | 15 Participants | 7 Participants | 22 Participants |
| Race, Customized Black or African American | 96 Participants | 102 Participants | 198 Participants |
| Race, Customized More Than One Race | 7 Participants | 2 Participants | 9 Participants |
| Race, Customized Unknown or Not Reported | 7 Participants | 9 Participants | 16 Participants |
| Race, Customized White | 190 Participants | 197 Participants | 387 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 54 Participants | 56 Participants | 110 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 263 Participants | 265 Participants | 528 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 5 Participants | 7 Participants | 12 Participants |
| Sex/Gender, Customized Female | 166 Participants | 162 Participants | 328 Participants |
| Sex/Gender, Customized Male | 156 Participants | 166 Participants | 322 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 52 / 319 | 53 / 327 |
| other Total, other adverse events | 16 / 316 | 21 / 325 |
| serious Total, serious adverse events | 85 / 316 | 92 / 325 |
Outcome results
Primary
Bayley III Composite Cognitive Score
Bayley Scale of Infant and Toddler Development (BSID)-III composite cognitive score, where subjects who died prior to the follow-up assessment are assigned the lowest possible score of 54. This is a standardized scale where a score that is more than 1 normative standard deviation from the normative mean of 100 signifies mild developmental delay (score \< 85); 2 standard deviations below the mean, moderate delay (score \< 70); and 3 standard deviations below the mean, severe delay (score \< 55). This self-standing scale comprises the primary outcome for the Darbe study.
Time frame: 22-26 months corrected age (a median of 25 months corrected age, which corresponds to a median of 29 months calendar age in the analysis population), unless the subject died earlier
Population: The analysis population includes all randomized infants with available data up to the two-year followup.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Darbepoetin | Bayley III Composite Cognitive Score | 80.7 score on a scale | Standard Deviation 19.5 |
| Placebo | Bayley III Composite Cognitive Score | 80.1 score on a scale | Standard Deviation 18.7 |
Comparison: Null hypothesis: Weekly administration of Darbepoetin during the neonatal period will not impact neurocognitive outcomes at 22-26 months compared to Placebo in premature infants 23 to 28 weeks gestation.p-value: 0.8895% CI: [-3.09, 2.64]Mixed Models Analysis
Secondary
Any Cerebral Palsy
This is measured as Yes if the child has been deemed by the medical examiner as having Cerebral Palsy; Otherwise, No.
Time frame: At 22-26 months corrected age (a median of 25 months corrected age)
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darbepoetin | Any Cerebral Palsy | Any Cerebral Palsy | 40 Participants |
| Darbepoetin | Any Cerebral Palsy | No Cerebral Palsy | 204 Participants |
| Placebo | Any Cerebral Palsy | Any Cerebral Palsy | 38 Participants |
| Placebo | Any Cerebral Palsy | No Cerebral Palsy | 209 Participants |
Secondary
Bronchopulmonary Dysplasia Grades 2 or 3
This is measured as Yes if infant is on invasive mechanical ventilation, nasal cannula \>2 L/min or noninvasive positive airway pressure at 36 weeks of postmenstrual age; Otherwise, No.
Time frame: At 36 weeks postmenstrual age
Population: The analysis population includes all randomized infants with available data during the initial hospitalization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darbepoetin | Bronchopulmonary Dysplasia Grades 2 or 3 | Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age | 91 Participants |
| Darbepoetin | Bronchopulmonary Dysplasia Grades 2 or 3 | No Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age | 170 Participants |
| Placebo | Bronchopulmonary Dysplasia Grades 2 or 3 | Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age | 128 Participants |
| Placebo | Bronchopulmonary Dysplasia Grades 2 or 3 | No Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age | 149 Participants |
Secondary
Death
This is measured as Yes if an infant died between birth and 22-26 months corrected age; Otherwise, No.
Time frame: Birth, through the 22-26 months corrected age follow-up window, which corresponds to a median of 29 months calendar age in the analysis population
Population: The analysis population includes all randomized infants with available data up to the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darbepoetin | Death | No Death | 267 Participants |
| Darbepoetin | Death | Death | 52 Participants |
| Placebo | Death | No Death | 274 Participants |
| Placebo | Death | Death | 53 Participants |
Secondary
Hematocrit
Hematocrit adjusted for center, gestational age group, and familial clustering
Time frame: at 2 and at 7 weeks in the study
Population: The analysis population includes all randomized infants with available data during the initial hospitalization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Darbepoetin | Hematocrit | week 2 | 36.84 Percent of blood volume made up of RBCs |
| Darbepoetin | Hematocrit | week 7 | 37.02 Percent of blood volume made up of RBCs |
| Placebo | Hematocrit | week 2 | 33.88 Percent of blood volume made up of RBCs |
| Placebo | Hematocrit | week 7 | 31.78 Percent of blood volume made up of RBCs |
Secondary
Intraventricular Hemorrhage Grade I+
This is measured as Yes if experienced Grade I+ Intraventricular Hemorrhage; Otherwise, No.
Time frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)
Population: The analysis population includes all randomized infants with available data during the initial hospitalization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darbepoetin | Intraventricular Hemorrhage Grade I+ | Grade 1+ Intraventricular Hemorrhage | 108 Participants |
| Darbepoetin | Intraventricular Hemorrhage Grade I+ | No Intraventricular Hemorrhage | 207 Participants |
| Placebo | Intraventricular Hemorrhage Grade I+ | Grade 1+ Intraventricular Hemorrhage | 98 Participants |
| Placebo | Intraventricular Hemorrhage Grade I+ | No Intraventricular Hemorrhage | 220 Participants |
Secondary
Length of Hospital Stay
This is measured as the length of stay up to hospital discharge or death, whichever occurred first.
Time frame: At initial hospital discharge or at death if it occurs earlier (a median of 94 days), assessed up to one year of life.
Population: The analysis population includes all randomized infants with available data during the initial hospitalization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Darbepoetin | Length of Hospital Stay | 96.2 Days | Standard Deviation 58.5 |
| Placebo | Length of Hospital Stay | 104.8 Days | Standard Deviation 67.3 |
Secondary
Necrotizing Enterocolitis, Bells Stage >=2 With Surgery
This is measured as Yes if experienced necrotizing enterocolitis, Bells stage \>=2 with surgery; Otherwise, No.
Time frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)
Population: The analysis population includes all randomized infants with available data during the initial hospitalization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darbepoetin | Necrotizing Enterocolitis, Bells Stage >=2 With Surgery | Necrotizing Enterocolitis with Surgery | 14 Participants |
| Darbepoetin | Necrotizing Enterocolitis, Bells Stage >=2 With Surgery | No Necrotizing Enterocolitis with Surgery | 305 Participants |
| Placebo | Necrotizing Enterocolitis, Bells Stage >=2 With Surgery | Necrotizing Enterocolitis with Surgery | 13 Participants |
| Placebo | Necrotizing Enterocolitis, Bells Stage >=2 With Surgery | No Necrotizing Enterocolitis with Surgery | 314 Participants |
Secondary
Neurodevelopmental Impairment
This is a 4-level outcome, where Severe NDI denotes a BSID III cognitive score less than 70, a Gross Motor Functional (GMF) level of 3-5 (where higher scores indicate worse outcomes), blindness (less than 20/200 vision), and/or profound hearing loss, Moderate NDI denotes a BSID III cognitive score from 70-84 and either a GMF level of 2 or limited blindness / moderate hearing loss, Mild NDI denotes a BSID III cognitive score from 70-84, or a cognitive score \>=85 with a GMF level of 1 and/or mild hearing loss, and No NDI denotes a cognitive score \>= 85 and an absence of neurosensory deficits.
Time frame: At 22-26 months corrected age (a median of 25 months corrected age)
Population: The analysis population includes all randomized infants with available data at the two-year followup.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darbepoetin | Neurodevelopmental Impairment | Mild | 72 Participants |
| Darbepoetin | Neurodevelopmental Impairment | Moderate | 1 Participants |
| Darbepoetin | Neurodevelopmental Impairment | None | 121 Participants |
| Darbepoetin | Neurodevelopmental Impairment | Severe/profound | 37 Participants |
| Placebo | Neurodevelopmental Impairment | None | 124 Participants |
| Placebo | Neurodevelopmental Impairment | Mild | 68 Participants |
| Placebo | Neurodevelopmental Impairment | Severe/profound | 42 Participants |
| Placebo | Neurodevelopmental Impairment | Moderate | 3 Participants |
Secondary
Number of Donor Exposures Per Infant
The number of donor exposures recorded during the study, up to 35 completed weeks gestational age
Time frame: Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)
Population: The analysis population includes all randomized infants with available data during the initial hospitalization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Darbepoetin | Number of Donor Exposures Per Infant | 1.6 Donors | Standard Deviation 2.3 |
| Placebo | Number of Donor Exposures Per Infant | 2.2 Donors | Standard Deviation 2.3 |
Secondary
Number of Transfusions Per Infant
The number of transfusions recorded during the study, up to 35 completed weeks gestational age
Time frame: Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)
Population: The analysis population includes all randomized infants with available data during the initial hospitalization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Darbepoetin | Number of Transfusions Per Infant | 2.3 Transfusions | Standard Deviation 3.1 |
| Placebo | Number of Transfusions Per Infant | 3.3 Transfusions | Standard Deviation 3.5 |
Secondary
Red Cell Mass
Red Cell Mass (Circulating Erythrocyte Volume), adjusted for center, gestational age group, and familial clustering
Time frame: at 2 and at 7 weeks in the study
Population: The analysis population includes all randomized infants with available data during the initial hospitalization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Darbepoetin | Red Cell Mass | week 7 | 42.78 mL |
| Darbepoetin | Red Cell Mass | week 2 | 28.35 mL |
| Placebo | Red Cell Mass | week 2 | 24.74 mL |
| Placebo | Red Cell Mass | week 7 | 36.01 mL |
Secondary
Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received
This is measured as Yes if experienced Retinopathy of prematurity stage \>=3 or treatment for that condition received; Otherwise, No. Higher stages of ROP indicate a worse outcome; the stages range from 1 for mild disease, to 5 for severe disease.
Time frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)
Population: The analysis population includes all randomized infants with available data during the initial hospitalization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Darbepoetin | Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | No Retinopathy of Prematurity Stage At least stage 3 or Treatment for That Condition Received | 238 Participants |
| Darbepoetin | Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | Retinopathy of Prematurity At least stage 3 or Treatment for That Condition Received | 35 Participants |
| Placebo | Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | No Retinopathy of Prematurity Stage At least stage 3 or Treatment for That Condition Received | 234 Participants |
| Placebo | Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received | Retinopathy of Prematurity At least stage 3 or Treatment for That Condition Received | 45 Participants |
Secondary
Total Volume of Transfusions Per Infant
The total volume of transfusions for the infant if ever transfused
Time frame: Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)
Population: The analysis population includes all randomized infants that were ever transfused.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Darbepoetin | Total Volume of Transfusions Per Infant | 54.5 mL | Standard Deviation 51.9 |
| Placebo | Total Volume of Transfusions Per Infant | 69.0 mL | Standard Deviation 51 |