Brain Imaging and Developmental Follow up of Infants Treated With Erythropoietin (BRITE)

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.

Study Overview

• Status: Completed
• Conditions: Prematurity

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.

• Study Type: Observational
• Enrollment (Actual): 77

Contacts and Locations

Study Locations

• United States
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • UNM
    • Albuquerque, New Mexico, United States, 87131
      • Mind Research Network
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 3 years (Child)
• Accepts Healthy Volunteers: Yes

• 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.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
preterm ESA recipients; Former preterm infants 500-1250 grams who received erythropoietin (400 units/kg 3x/week) or darbepoetin (10 micrograms/kg 1x/week), from the first week of life through 35 weeks corrected gestation
preterm controls; Former preterm infants 500-1250 grams who received placebo (sham dosing), from first week of life through 35 weeks corrected gestation
term controls; Former term infants with normal delivery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Full Scale IQ, Performance IQ, Verbal IQ, Executive Function	Infants who received ESAs during their initial hospitalization will perform significantly better on measures of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) full scale IQ, performance IQ, verbal IQ, and executive function. Scores are standardized, 100 is an average score with a standard deviation of 15. Higher scores are better. Test scores range from 41 to 160.	42-48 months and 66-72 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain imaging	Compared to former VLBW children who did not receive ESA therapy, VLBW children who did receive ESA therapy will demonstrate lower total cerebral gray/white ratios as determined by morphometric MR analysis, reduced regional cerebral blood flow in the right dorsolateral frontal cortex as determined by arterial spin labeling (ASL), and increased glutamate/glutamine (Glx) in the anterior cingulate gyrus with increased creatine in the left frontal white matter as measured by magnetic resonance spectroscopy	42-48 months and 66-72 months

Collaborators and Investigators

• Sponsor: University of New Mexico
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Robin K Ohls, MD, University of Utah

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): December 31, 2016
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: September 21, 2010
• First Submitted That Met QC Criteria: September 21, 2010
• First Posted (Estimated): September 23, 2010

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: July 17, 2023
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: MRI; brain; erythropoietin; neuroprotection; development
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth
• Other Study ID Numbers: 10-153; R01HD059856 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Plan to submit data if possible for meta analyses

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No