Trial of Darbepoetin plus slow-release intravenous iron to decrease transfusions and improve iron status and neurodevelopment in preterm infants

达贝泊汀联合缓释静脉铁剂减少输血、改善早产儿铁状态和神经发育的试验

• 批准号: 10340574
• 负责人: Sandra E Juul
• 金额: $ 49.23万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10340574
• 关键词: 2 year old; Academy; Adherence; Adult; Adverse event; Aftercare; Age; American; Anemia; Auditory Brainstem Responses; Birth; Blood Transfusion; Blood Volume; Brain; Carbohydrates; Combined Modality Therapy; Development; Dose; Enrollment; Erythrocytes; Erythropoiesis; Erythropoietin; Evaluation; FDA approved; Ferritin; Ferrous Sulfate; Formulation; Goals; Growth; Guidelines; Hematocrit procedure; Hospitalization; Hospitals; Infant; Infant Development; Intestines; Intravenous; Iron; Iron Overload; Iron-Dextran Complex; Lead; Liver; Long-Term Effects; Longevity; Malabsorption Syndromes; Molecular Weight; Monitor; Movement; Neurotransmitters; Oral; Outcome; Pathway interactions; Pediatrics; Pharmaceutical Preparations; Pregnancy; Pregnant Women; Premature Infant; Preparation; Process; Production; Safety; Supplementation; Testing; Therapeutic; Tissues; Transfusion; Venous blood sampling; absorption; dosage; experience; falls; ferryl iron; ferumoxytol; fetal; gastrointestinal; gut inflammation; gut microbiome; gut microbiota; high risk; immune function; improved; infant outcome; iron deficiency; iron supplement; iron supplementation; metabolic rate; microbiome; myelination; neonate; neurodevelopment; oral supplementation; oxidative damage; phase 2 study; postnatal; premature; prevent; primary outcome; saccharated ferric oxide; skills; standard care; stool sample

Preterm infants are at high risk for both transfusions and iron deficiency, both of which may independently contribute to poor neurodevelopmental outcomes. On average, infants less than 1000 gm require 4 to 5 blood transfusions during their initial hospitalization. Darbepoetin (Darbe) can increase the number of infants who remain transfusion-free, and for those who do require transfusions, can decrease the number of transfusions, cumulative volume of blood transfused, and unique donor exposures. However, the use of Darbe increases iron utilization, and treated infants may become progressively iron deficient with oral iron supplementation alone. When iron supply does not meet the iron demand of the rapidly expanding RBC mass, first iron stores in the liver and then non-storage iron in other tissues (including brain) will be compromised. This is of particular concern for preterm infants since iron is required for normal brain development, including such processes as myelination, dendritogenesis, production and degradation of neurotransmitters, and to sustain the brain’s high metabolic rate. Thus, iron deficiency during fetal and early postnatal months can result in irreversible neurodevelopmental abnormalities despite later iron repletion. Our overarching goal is to develop a therapeutic pathway to minimize transfusions while maintaining iron sufficiency, thereby optimizing developmental outcomes. We hypothesize that combined treatment of infants < 32 completed weeks of gestation with Darbe plus one of two slow-release intravenous (IV) iron preparations, ferumoxytol (FMX) or low molecular weight iron dextran (LMW-ID) will 1) be safe, 2) decrease or eliminate transfusions, 3) increase hematocrit, 4) maintain iron sufficiency, and 5) improve neurodevelopment. We further hypothesize that when compared to oral iron supplementation (standard care), IV iron will be better tolerated, with less effect on the gut microbiome. An advantage of using these slow-release IV iron preparations is that fewer, higher doses of iron are needed to prevent or treat iron deficiency. For example, an anemic iron deficient pregnant woman can be treated with a single dose of 1000 mg IV compared to 5 IV doses of iron sucrose. Because FMX and LMW-ID have not been tested in neonates, in Aim 1 we will compare these two drugs and evaluate total dosage needed to maintain iron sufficiency while being treated with Darbe. Starting doses will be 10 mg/kg and 20 mg/kg, repeated as needed to maintain ferritin >75 mcg/L. In Aim 2 we will compare the safety, efficacy and tolerance of the combined approach of using Darbe + IV iron (N=80) with standard care (oral iron supplements up to 12 mg/kg/day, N=40). Evaluation will include safety, gastrointestinal tolerance, and efficacy. The effect of oral compared to IV iron on the microbiome will be evaluated. The primary outcome will be hematocrit, transfusion burden and iron status at hospital discharge. In Aim 3, the long-term neurodevelopmental outcome of the 3 groups (Darbe + FMX, Darbe + LMW-ID, oral iron only) will be evaluated up to 2 years of age. We anticipate demonstrating the feasibility and potential benefit of Darbe plus slow-release IV iron to decrease transfusions, maintain iron sufficiency and improve neurodevelopmental outcomes.

早产儿输血和缺铁的风险都很高，这两种情况都可能独立存在