Clinical trial NCT01207778: Brain Imaging and Developmental Follow up of Infants Treated With Erythropoietin
Official title: Brain Imaging and Developmental Follow up of Infants Treated With Erythropoietin
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Prematurity
Keywords: brain
development
erythropoietin
neuroprotection
MRI
Lead sponsor: University of New Mexico
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2010-09-23
Enrollment: 77
Sex: ALL
Minimum age (years): 36
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All infants previously enrolled in NCT00334737, a randomized masked study of darbepoetin administration in preterm infants, are eligible for the study. In addition we will enroll term infants matched for age, gender and ethnicity to the preterm group to serve as healthy controls.

Brief summary: Approximately 60,000 premature infants are born each year who weigh less than 1,500 grams,many of whom sustain brain damage because of their prematurity. This study is designed to evaluate the long-term developmental effects of one promising neuroprotective treatment,erythropoietin (Epo), when given in the neonatal period. Using detailed neurodevelopmental testing and state-of-the-art brain imaging, we hope to determine whether this is an effective treatment to prevent brain injury associated with prematurity, and to lay the groundwork for further studies to improve the developmental outcome of infants delivered prematurely.

Detailed description: Over twelve percent of infants born less than 1,500 grams (VLBW) sustain brain injury with subsequent developmental delay. Although various neuroprotective strategies have been evaluated, none have been successful. One promising intervention is the use of recombinant erythropoietin (Epo, also known as an erythropoiesis stimulating agent, or ESA). In addition to stimulating red cell production, Epo has been shown to be protective in the developing brain in animal models. We have preliminary data suggesting its efficacy when used in VLBW infants, who are at risk of requiring transfusions, and who are also at risk for brain hemorrhage, hypoxicischemic brain injury, and developmental delay. We are currently performing a multicentered study evaluating hematopoietic and short term developmental effects of ESAs in preterm infants randomized to receive Epo, Darbepoetin alfa (a longer acting ESA), or placebo/ control for the first 10 weeks of age (NCT00334737). The first enrolled infants will reach 42-48 months in January, 2010. While that study evaluates the safety and general short-term developmental effects of ESAs, there is an unprecedented opportunity to study long term effects of ESA in significant detail, including evaluating the long term developmental effects and the underlying mechanism of neurologic improvement with state of the art neuroimaging. This proposal seeks to evaluate longitudinal, long-term developmental effects and underlying neurologic mechanisms of ESAs administered to VLBW infants in the first 10 weeks of life. Our specific hypotheses are:

1) ESAs administered to preterm infants during the neonatal period improve long-term neurodevelopmental outcome, 2) ESAs affect regional brain structure, neurochemistry and neurologic organization as reflected in magnetic resonance (MR) imaging, and 3) the blood level of ESA correlates with MR imaging and neurodevelopmental outcome. To test these hypotheses, neurodevelopmental outcome will be assessed through a comprehensive neurodevelopmental assessment at two time points: 42-48 months, and 66-72 months (WPSSI III, Early Child Assessment, Executive Categorization Battery). Brain imaging will be performed concurrent with developmental assessments and includes measures of volume (high resolution volumetric analysis), neurochemistry (magnetic resonance spectroscopy) and regional cerebral blood flow (arterial spin labeling). This study is highly clinically relevant due to the long-term developmental and imaging follow up studies that are part of the design, significantly increasing our ability to determine if developmental, functional and anatomical differences exist in infants randomized to ESAs, a relatively new interventional strategy used in preterm infants. This proposal addresses our long-term goal of developing effective treatment strategies for disorders associated with prematurity through an improved understanding of brain-behavioral relationships.

Eligibility criteria: Inclusion Criteria (preterm):

* birth weight 500-1,250 grams, gestational age ≤32 weeks
* hematocrit ≤55%
* ≤48 hours of age
* expected to survive greater than 72 hours
* consent signed by parent or guardian

Inclusion Criteria (term):

Former term born infants will be eligible if they have not experienced any episodes of hypoxia, hypoglycemia, hyperbilirubinemia, prenatal drug exposure, or sepsis.

Exclusion Criteria (former preterms):

* hemorrhagic or hemolytic disease
* major congenital anomalies (such as trisomy 13, 18 or 21)
* major neurologic abnormality such as hydrocephalus or meningomyelocele
* complex congenital heart disease
* receiving Epo or are enrolled in an Epo study
* evidence of disseminated intravascular coagulation
* clinical seizures are present
* congenital thrombotic disease is suspected
* systolic blood pressures \>100 mm Hg (while not on pressor support) Infants with minor anomalies such as clinodactyly, single umbilical vessel or patent ductus are not excluded

Exclusion criteria (term):

hypoxia, hypoglycemia, hyperbilirubinemia, prenatal drug exposure, or sepsis

Primary outcomes:
measure: Full Scale IQ, Performance IQ, Verbal IQ, Executive Function
timeFrame: 42-48 months and 66-72 months
Secondary outcomes:
Other outcomes:
Locations:
city: Albuquerque
country: United States
facility: MIND Research Network
state: New Mexico
city: Albuquerque
country: United States
facility: UNM
state: New Mexico
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of Utah
name: Robin K Ohls, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lowe JR, Rieger RE, Moss NC, Yeo RA, Winter S, Patel S, Phillips J, Campbell R, Baker S, Gonzales S, Ohls RK. Impact of Erythropoiesis-Stimulating Agents on Behavioral Measures in Children Born Preterm. J Pediatr. 2017 May;184:75-80.e1. doi: 10.1016/j.jpeds.2017.01.020. Epub 2017 Feb 6.
citation: Ohls RK, Cannon DC, Phillips J, Caprihan A, Patel S, Winter S, Steffen M, Yeo RA, Campbell R, Wiedmeier S, Baker S, Gonzales S, Lowe J. Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin. Pediatrics. 2016 Mar;137(3):e20153859. doi: 10.1542/peds.2015-3859. Epub 2016 Feb 15.