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: 10662182
• 负责人: Sandra E Juul
• 金额: $ 56.38万
• 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/10662182
• 关键词: 2 year old; Academy; Adherence; Adult; Adverse event; Aftercare; Age; American; Anemia; Auditory Brainstem Responses; Binding; 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 deficiency anemia; Iron-Dextran Complex; 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; Recommendation; Safety; Supplementation; Testing; Therapeutic; Tissues; Transfusion; Venous blood sampling; absorption; dosage; experience; falls; 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.

早产婴儿对输血和铁缺乏症的风险很高，这两者都可能独立 导致不良神经发育结果。平均而言，婴儿小于1000克需要4至5个血液 他们最初住院期间的输血。 Darbepoetin（Darbe）可以增加婴儿人数 保持无输血，对于确实需要输血的人，可以减少输血数量， 输血的累积量和独特的供体暴露。但是，使用达比增加了铁 仅通过补充口服铁，可以逐步使用治疗的婴儿。 当铁供应不满足迅速扩张的RBC质量的铁需求时，肝脏中的第一座铁储存 然后将损害其他组织中的非存储铁（包括大脑）。这特别关心 早产婴儿由于脑发育正常需要铁，包括髓鞘化等过程 神经递质的树突生成，生产和降解，并维持大脑的高代谢率。 这是胎儿和产后早期的铁缺乏会导致不可逆的神经发育 异常后来替代铁。我们的总体目标是开发一种治疗途径以最小化 在维持铁安全的同时输血，从而优化了发展结果。我们假设 <32个完整的妊娠几周的婴儿的妊娠和两个慢速释放之一 静脉注射（IV）铁制剂，铁氧基二醇（FMX）或低分子量铁葡萄糖（LMW-ID）将1） 安全，2）减少或消除输血，3）增加血细胞比容，4）保持铁足和5）改进 神经发育。我们进一步假设，与口服铁补充（标准护理）相比， 静脉输液将得到更好的耐受性，对肠道微生物组的影响较小。使用这些缓释的优点 IV铁制剂是，预防或治疗铁缺乏需要更少，更高的铁。例如， 与5 iv相比 铁蔗糖剂量。由于FMX和LMW-ID尚未在新生儿中进行测试，因此在AIM 1中，我们将比较 这两种药物并评估了在用Darbe治疗的同时维持铁充足性所需的总剂量。 起始剂量为10 mg/kg和20 mg/kg，根据需要重复维持铁蛋白> 75 mcg/l。在目标2中我们 将比较使用Darbe + IV铁（n = 80）的合并方法的安全性，效率和公差 标准护理（口服铁补充剂最大12 mg/kg/天，n = 40）。评估将包括安全性，胃肠道 宽容和有效性。将评估与静脉铁对微生物组相比的口服作用。主要 结果将是血细胞比容，输血伯恩和医院出院时的铁状态。在AIM 3中，长期 将评估这三组的神经发育结果（Darbe + FMX，Darbe + LMW-ID，口服铁）将被评估 最多2岁。我们预计将证明达尔贝和缓慢发行的可行性和潜在好处 静脉输液以减少输血，保持铁足够并改善神经发育结果。