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。 导致神经发育不良平均而言，体重低于1000克的婴儿需要4至5份血液 在初次住院期间输血。Darbepopoposide（Darbe）可以增加婴儿的数量， 保持不输血，对于那些确实需要输血的人，可以减少输血的次数， 累计输血量和独特的供体暴露。然而，使用Darbe增加铁 使用，和治疗的婴儿可能会成为渐进的铁缺乏与口服铁补充剂单独。 当铁供应不能满足快速膨胀的红细胞质量的铁需求时，首先铁储存在肝脏中 然后其他组织（包括大脑）中的非储存铁将受到损害。这一点尤其令人关注， 早产儿由于铁是正常脑发育所必需的，包括髓鞘形成等过程， 神经递质的产生和降解，以及维持大脑的高代谢率。 因此，在胎儿和出生后早期几个月内缺铁可导致不可逆的神经发育障碍。 尽管后来铁补充异常。我们的首要目标是开发一种治疗途径， 输血，同时保持铁充足，从而优化发育结果。我们假设 对于小于32周妊娠的婴儿，联合使用Darbe加两种缓释剂之一， 静脉内（IV）铁制剂、ferumoxytol（FMX）或低分子量右旋糖酐铁（LMW-ID）将1） 安全，2）减少或消除输血，3）增加红细胞压积，4）维持铁充足，5）改善 神经发育我们进一步假设，与口服补铁（标准护理）相比， 静脉注射铁的耐受性更好，对肠道微生物组的影响较小。使用这些缓释剂的一个优点是 IV铁制剂是需要更少，更高剂量的铁来预防或治疗铁缺乏症。比如说， 贫血性缺铁孕妇可以用1000 mg IV单次给药治疗， 蔗糖铁的剂量。由于FMX和LMW-ID尚未在新生儿中进行测试，因此在目标1中，我们将比较 这两种药物，并评估总剂量需要保持铁充足，而正在与Darbe治疗。 起始剂量为10 mg/kg和20 mg/kg，根据需要重复，以维持铁蛋白>75 mcg/L。在目标2中， 将比较使用Darbe + IV铁剂（N=80）与 标准治疗（口服铁补充剂高达12 mg/kg/天，N=40）。评价将包括安全性、胃肠道 耐受性和功效。将评价口服铁与IV铁相比对微生物组的影响。主 结果将是出院时的红细胞压积、输血负担和铁状态。目标3：长期 将评价3组（Darbe + FMX、Darbe + LMW-ID、仅口服铁）的神经发育结局 2岁以下。我们期望证明Darbe plus缓释的可行性和潜在益处 静脉铁剂，以减少输血，维持铁充足，改善神经发育结果。