Clinical trial NCT03169881: Darbepoetin Trial to Improve Red Cell Mass and Neuroprotection in Preterm Infants
Official title: Darbepoetin Trial to Improve Red Cell Mass and Neuroprotection in Preterm Infants
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Neurocognitive
Neuroprotective
Neonatal
Neurodevelopmental Impairment
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2017-05-30
Enrollment: 650
Sex: ALL
Minimum age (years): 1
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, masked, placebo-controlled trial
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Bayley III Composite Cognitive Score
timeFrame: 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
Secondary outcomes:
measure: Number of Transfusions Per Infant
timeFrame: Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)
measure: Total Volume of Transfusions Per Infant
timeFrame: Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)
measure: Number of Donor Exposures Per Infant
timeFrame: Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)
measure: Hematocrit
timeFrame: at 2 and at 7 weeks in the study
measure: Red Cell Mass
timeFrame: at 2 and at 7 weeks in the study
measure: Necrotizing Enterocolitis, Bells Stage >=2 With Surgery
timeFrame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)
measure: Bronchopulmonary Dysplasia Grades 2 or 3
timeFrame: At 36 weeks postmenstrual age
measure: Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received
timeFrame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)
measure: Intraventricular Hemorrhage Grade I+
timeFrame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)
measure: Length of Hospital Stay
timeFrame: At initial hospital discharge or at death if it occurs earlier (a median of 94 days), assessed up to one year of life.
measure: Death
timeFrame: 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
measure: Neurodevelopmental Impairment
timeFrame: At 22-26 months corrected age (a median of 25 months corrected age)
measure: Any Cerebral Palsy
timeFrame: At 22-26 months corrected age (a median of 25 months corrected age)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: RTI International
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University, Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Research Institute at Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Univeristy of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: Brown University - Women and Infants Hospital of Rhode Island
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of Utah
name: Robin Ohls, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vu PT, Ohls RK, Mayock DE, German KR, Comstock BA, Heagerty PJ, Juul SE; PENUT Consortium. Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial. Pediatr Res. 2021 Jul;90(1):109-116. doi: 10.1038/s41390-020-01273-w. Epub 2021 Jan 11.