Darbepoetin Trial to Improve Red Cell Mass and Neuroprotection in Preterm Infants

Study Overview
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Brief Summary
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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
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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.

Official Title
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Darbepoetin Trial to Improve Red Cell Mass and Neuroprotection in Preterm Infants

Conditions
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Neurocognitive, Neuroprotective, Neonatal, Neurodevelopmental Impairment

Intervention / Treatment
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* Drug: Darbepoetin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inborn and outborn preterm infants 23 0/7-28 6/7 weeks gestation ≤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

Ages Eligible for Study
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Minimum Age: 23 Weeks
Maximum Age: 28 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, masked, placebo-controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darbepoetin<br>Darbepoetin 10 micrograms/kg/once every week (IV or SC) | Drug: Darbepoetin<br>* 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.<br>* Other names: Darbe;|
| Placebo Comparator: Placebo<br>Equal volume normal saline for IV administration, or sham dosing | Drug: Placebo<br>* normal saline for IV administration, or sham dosing. Infants will be treated until 35 completed weeks gestation, discharge, or transfer to another hospital.<br>* Other names: normal saline for IV administration, or sham dosing;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite cognitive score on Bayley Scale of Infant Development III | The primary outcome is the Bayley III cognitive score. Deaths will be assigned a score of 54. | Birth to 26 months corrected age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | Death includes any mortality prior to follow-up at 22-26 months of age | Birth to 26 months corrected age | 
| Cerebral Palsy |  | Follow-up at 26 months corrected age | 
| Length of Hospital Stay | Days in hospital following birth. | Birth to 26 months corrected age | 
| Number of transfusions |  | Birth to 35 completed weeks gestational age | 
| Hematocrit |  | Birth to 35 completed weeks gestational age | 
| Red cell mass |  | Birth to 35 completed weeks gestational age | 
| Volume of transfusions |  | Birth to 35 completed weeks gestational age | 
| Neurodevelopmental impairment (NDI) | Severe NDI will be defined by any of the following: a BSID III cognitive score < 70, Gross Motor Functional (GMF) Level of 3-5, blindness (<20/200 vision) or profound hearing loss (inability to understand commands despite amplification); moderate NDI will be defined as a BSID III cognitive score 70-84 and either a GMF level of 2 or a hearing deficit requiring amplification to understand commands or unilateral blindness; mild NDI will be defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMF level 1 or hearing loss not requiring amplification. Normal (no NDI) will be defined by a cognitive score ≥ 85 and absence of any neurosensory deficits. | 26 months corrected age | 
| Seizures | Documented seizures during hospital course | Up to 120 days of life | 
| Thromboses | Documented thromboses during hospital course | Up to 120 days of life | 
| Hypertension | Documented hypertension during hospital course | Up to 120 days of life | 
| Intra-cranial Hemorrhage (ICH) | Documented ICH during hospital course | Up to 120 days of life | 
| Necrotizing Enterocolitis (NEC) requiring surgery | Documented NEC requiring surgery during hospital course | Up to 120 days of life | 
| Bronchopulmonary dysplasia (BPD) | Documented BPD during hospital course | Up to 120 days of life | 
| Retinopathy of prematurity (ROP) requiring intervention | Documented ROP requiring intervention (to include but not limited to laser, cryotherapy, scleral buckle, vitrectomy, avastin Injection) during hospital course | Up to 120 days of life | 
| Culture positive sepsis | Documented culture positive sepsis during hospital course | Up to 120 days of life |