Darbepoetin Trial to Improve Red Cell Mass and Neuroprotection in Preterm Infants
- Conditions
- NeurocognitiveNeonatalNeuroprotectiveNeurodevelopmental Impairment
- Interventions
- Drug: Placebo
- Registration Number
- NCT03169881
- Lead Sponsor
- NICHD Neonatal Research Network
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 650
- Inborn and outborn preterm infants
- 23 0/7-28 6/7 weeks gestational age
- ≤24 hours postnatal age
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Equal volume normal saline for IV administration, or sham dosing Darbepoetin Darbepoetin Darbepoetin 10 micrograms/kg/once every week (IV or SC)
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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
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.
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.
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.
Trial Locations
- Locations (16)
Stanford University
🇺🇸Palo Alto, California, United States
Case Western Reserve University, Rainbow Babies and Children's Hospital
🇺🇸Cleveland, Ohio, United States
University of Texas Southwestern Medical Center at Dallas
🇺🇸Dallas, Texas, United States
University of Texas Health Science Center at Houston
🇺🇸Houston, Texas, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Duke University
🇺🇸Durham, North Carolina, United States
RTI International
🇺🇸Durham, North Carolina, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Cincinnati Children's Medical Center
🇺🇸Cincinnati, Ohio, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Emory University
🇺🇸Atlanta, Georgia, United States
University of New Mexico
🇺🇸Albuquerque, New Mexico, United States
Research Institute at Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Univeristy of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University of Rochester
🇺🇸Rochester, New York, United States
Brown University - Women and Infants Hospital of Rhode Island
🇺🇸Providence, Rhode Island, United States