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，这两者都可能独立存在。 会导致不良的神经发育结果。平均而言，小于1000克的婴儿需要4到5个血液。 在他们最初住院期间输血。达贝泊丁(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，可以减少输血次数， 累计输血量和独特的献血者暴露。然而，Darbe的使用增加了铁的含量 单独口服补铁，经治疗的婴儿可能会逐渐缺铁。 当铁供应不能满足迅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。这一点特别值得关注 早产儿，因为铁是正常大脑发育所必需的，包括髓鞘形成等过程， 树突状细胞的形成、神经递质的产生和降解，以及维持大脑的高代谢率。 因此，胎儿和出生后早期的缺铁可导致不可逆转的神经发育。 尽管后来铁补充了，但仍有异常。我们的首要目标是开发一种治疗方法，将 在保持铁充足的同时进行输血，从而优化发育结果。我们假设 这一联合治疗结束了32周的妊娠，达贝和两种缓释剂中的一种。 静脉注射(IV)铁制剂、阿魏酸甘油(FMX)或低分子右旋糖苷铁(LMW-ID)将1) 安全，2)减少或取消输血，3)增加红细胞压积，4)保持铁的充足，5)改善 神经发育。我们进一步假设，与口服铁质补充剂(标准护理)相比， 静脉注射铁的耐受性更好，对肠道微生物群的影响较小。使用这些缓释剂的一个优点是 IV铁制剂是预防或治疗铁缺乏症所需要的更少、更高剂量的铁。例如, 缺铁性贫血的孕妇可以单剂量静脉注射1000毫克，而不是5毫克。 剂量的蔗糖铁。由于FMX和LMW-ID尚未在新生儿中进行测试，在目标1中，我们将比较 这两种药物并评估在使用Darbe治疗的同时保持铁充足所需的总剂量。 起始剂量为10毫克/千克和20毫克/千克，根据需要重复使用，以维持铁蛋白75微克/升。 将使用DarBe+IV铁(N=80)的联合方法的安全性、有效性和耐受性与 标准护理(口服铁补充剂每天最多12毫克/公斤，N=40)。评估将包括安全性、胃肠道 耐受性和有效性。将评估口服铁与静脉注射铁对微生物群的影响。初级阶段 结果将是出院时的红细胞压积、输血负担和铁状态。在目标3中，长期 将评估3组(Darbe+FMX，Darbe+LMW-ID，仅口服铁)的神经发育结果 最大可达2岁。我们期望展示Darbe plus缓释剂的可行性和潜在的益处 IV铁可以减少输血，保持铁的充足，并改善神经发育结果。