Background <p>Infants born preterm are at high risk of anemia, red blood cell transfusions, and iron deficiency, all of which may negatively influence long-term neurodevelopment. To ameliorate these complications of prematurity, we developed a Phase II trial to determine whether treatment with an erythropoietic-stimulating agent, darbepoetin (Darbe), plus a slow-release intravenous (IV) iron preparation (ferumoxytol (FMX) or low-molecular-weight iron dextran (LMW-ID)) might decrease transfusions while maintaining iron sufficiency.</p> Methods <p>This single-center study is a parallel design, prospective, randomized controlled Phase II trial of 120 infants born 24–0/7 to 31–6/7&#xa0;weeks of gestation cared for in the University of Washington Neonatal Intensive Care Unit. After informed consent, infants less than 72&#xa0;h of age are randomized to one of five treatment groups: (1) Oral iron (standard care), <i>n</i> = 40, or weekly Darbe 10&#xa0;µg/kg/dose IV or SQ plus; (2) FMX — 10&#xa0;mg/kg/dose IV, <i>n</i> = 20; (3) FMX — 20&#xa0;mg/kg/dose IV, <i>n</i> = 20; (4) LMW-ID — 10&#xa0;mg/kg/dose IV, <i>n</i> = 20; or (5) LMW-ID — 20&#xa0;mg/kg/dose IV, <i>n</i> = 20. Infants will be followed to 2-year corrected age with sequential developmental testing. Our primary outcome is ferritin level at 34–36&#xa0;weeks postmenstrual age. Secondary outcomes include other hematologic assessments, drug safety, evaluation of the gut microbiome, and neurodevelopment to 2&#xa0;years corrected age.</p> Discussion <p>This trial will determine whether darbepoetin plus a slow-release IV iron preparation is safe, which iron preparation and dose best maintain iron sufficiency and decrease or eliminate transfusions, whether IV iron will result in a more diverse, less pathogenic microbiome when compared to oral iron supplementation, and, finally, whether these treatments affect neurodevelopment to 2&#xa0;years corrected age.</p> Trial registration <p>National Clinical Trial (NCT) NCT05340465. Registered on March 1, 2022.</p>