Iron Delivery Via hemodialysate in ESRD

描述（由申请人提供）：促红细胞生成素（EPO）是治疗终末期肾病（ESRD）贫血的有效药物，几乎用于所有接受长期血液透析的ESRD患者。 促红细胞生成素刺激铁的利用，再加上血液透析中少量但不可避免的额外皮质血的损失，导致几乎所有患者的铁缺乏。 通过口服或胃肠外补充足够的铁递送对于最佳EPO作用是必要的。 由于胃肠道毒性，口服铁剂的依从性较差。 因此，静脉内（i. v.）对50- 75%的血液透析患者施用铁，或者在铁缺乏发展时间歇地施用，或者定期施用以防止铁耗尽。 肠外铁是一种促氧化剂，并且可能通过进一步增强大多数血液透析患者中存在的氧化应激和炎症来增加感染、炎症和动脉粥样硬化的风险。 与静脉注射的大聚合铁复合物不同，焦磷酸铁（FePPi）是一种单体铁盐（745 Da），当加入透析溶液中时，可直接进入循环。 Fe（III）与焦磷酸盐（PPi）紧密络合，从而减少游离铁的解离和释放。 PPi阴离子是一种抗氧化剂，可促进铁直接传递到转铁蛋白，以及铁从转铁蛋白转移到铁蛋白。 FePPi在酸性浓缩物中高度可溶，用FePPi强化的浓缩物可用于生成具有规定浓度的FePPi（Fe-HD）的透析液。 这是一项双盲、随机、对照II期临床试验，旨在确定在ESRD患者血液透析溶液中添加FePPi的安全性和有效性，为期9个月。 在过去2个月内需要静脉注射铁剂的铁充足患者（=30），没有铁过载的证据（转铁蛋白饱和度或TSAT<40%，铁蛋白< 800 lag/L），将入选。 患者将随机接受使用Fe-HD或C-HD的血液透析，每次透析共持续9个月。 如果TSAT为30- 40%，透析液铁的初始剂量为9 lag/dl，如果TSAT <30%，则为11 lag/dl。 将每月监测血清铁参数（TSAT和铁蛋白）。 如果透析前TSAT增加到35- 40%，透析液铁浓度将降低到9 lag/dl，如果TSAT超过40%，透析液铁将保留。 如果TSAT <30%，透析液铁将以11 lag/dl重新开始，如果TSAT为30- 40%，则以9 lag/dl重新开始。 如果TSAT <20%，两组患者将在5个连续透析疗程中接受500 mg静脉注射蔗糖铁（Venezuela（r）），分5次给药。 透析液铁剂组的患者将继续接受透析液铁剂，即使他们需要一个疗程的静脉铁剂。 根据方案，EPO的剂量将每6周调整一次，目标是将血红蛋白维持在11至12 grn/dl之间。 在整个试验期间将仔细监测安全性参数。 主要终点将是铁缺乏的发展（TSAT<20%），需要静脉铁剂治疗和两组患者所需的静脉铁剂量。 次要终点将是铁过载的发展（TSAT> 40%和铁蛋白> 800 lag/L）。 将在研究开始和结束时测量透析液铁对血清催化活性铁水平以及炎症和氧化应激标志物的急性和慢性影响。 这项II期研究将提供通过透析液输注焦磷酸铁的安全性和有效性的初步证据，旨在预防铁缺乏症，并为透析液铁治疗的大型临床试验铺平道路。

DESCRIPTION (provided by applicant): Erythropoietin (EPO) is an effective therapy for anemia of end-stage renal disease (ESRD) and is used in almost all ESRD patients receiving chronic hemodialysis. EPO stimulated iron utilization, coupled with small but unavoidable loss of extra corporeal blood with hemodialysis, leads to iron deficiency in almost all patients. Adequate iron delivery, by oral or parenteral supplementation, is necessary for optimal EPO action. Compliance with oral iron is poor due to gastrointestinal toxicity. Therefore intravenous (i.v.) iron is administered to 50-75 percent of hemodialysis patients, either intermittently when iron deficiency develops or at regular intervals to prevent iron depletion. Parenteral iron is a pro-oxidant, and may increase the risk of infections, inflammation and atherosclerosis by further enhancing oxidative stress and inflammation present in the majority of hemodialysis patients. Unlike the large polymeric iron complexes that are administered i.v., ferric pyrophosphate (FePPi), a monomeric iron salt (745 Da), can be delivered directly into the circulation when added to dialysis solutions. Fe(III) complexes tightly with pyrophosphate (PPi), thereby reducing dissociation and release of free iron. PPi anion is an antioxidant that promotes direct delivery of iron to transferrin, and iron transfer from transferrin to ferritin. FePPi is highly soluble in the acid concentrate and a concentrate fortified with FePPi can be used to generate a dialysate with defmed concentration of FePPi (Fe-HD). This is a double-blinded, randomized, controlled Phase II clinical trial to determine the safety and efficacy of FePPi added to the hemodialysis solutions in ESRD patients over a period of 9 months. Iron replete patients in=30) with no evidence of iron overload (transferrin saturation or TSAT< 40 percent, and ferritin < 800 lag/L), who have needed intravenous iron in the previous 2 months will be enrolled. Patients will be randomized to receive hemodialysis using Fe-HD or C-HD with every dialysis session for a total period of 9 months. The initial dose of dialysate iron will be 9 lag/dl if TSAT is 30-40 percent, and 11 lag/dl if TSAT is < 30 percent. Serum iron parameters (TSAT and ferritin) will be monitored every month. The dialysate iron concentration will be reduced to 9 lag/dl if pre-dialysis TSAT increases to 35-40 percent, and dialysate iron will be held if TSAT exceeds 40 percent. Dialysate iron will be restarted at 11 lag/dl if TSAT is < 30 percent and at 9 lag/dl if TSAT is 30-40 percent. Patients in both groups will receive 500 mg i.v. iron saccharate (Venofer(r)) in 5 divided doses at 5 consecutive dialysis sessions if TSAT is < 20 percent. Patients in the dialysate iron group will continue to receive dialysate iron even if they require a course of i.v. iron. The dose of EPO will be adjusted every 6 weeks, according to a protocol, with the goal of maintaining hemoglobin between 11 to 12 grn/dl. Safety parameters will be carefully monitored throughout the trial. The primary end-points will be the development of iron deficiency (TSAT< 20 percent) that necessitates intravenous iron therapy and the amount of i.v. iron needed by the patients in the two groups. A secondary end-point will be development of iron overload (TSAT> 40 percent and ferritin > 800 lag/L). The acute and chronic effects of dialysate iron on serum levels of catalytically active iron and markers of inflammation and oxidative stress will be measured at the beginning and the end of the study. This Phase II study will provide preliminary evidence of the safety and efficacy of ferric pyrophosphate infusion via the dialysate, with the aim of preventing iron deficiency, and pave the way for a large, clinical trial of dialysate iron therapy.