Mark Koury, MD
Dr. Koury is a medical monitor and safety committee member for this clinical trial and a consultant for Keryx Biopharmaceuticals, Inc.
Study Title: A Three-Period, 58-Week Safety and Efficacy Trial of KRX-0502 (Ferric Citrate) in Patients With End-Stage Renal Disease (ESRD) on Dialysis
ClinicalTrials.Gov Identifier: NCT01191255
Coordinator: The Collaborative Study Group
Sponsor: Keryx Biopharmaceuticals, Inc.
Participating Centers: 54 medical centers in the United States, two in Israel, and two in Puerto Rico
Accrual goal: 441 subjects randomized; enrollment closed
Study Design: This phase III trial has a two-week washout period of oral phosphate binders in ESRD subjects on hemodialysis or peritoneal dialysis. After washout, subjects are randomized 2:1 to open-label ferric citrate or calcium acetate and/or sevelamer carbonate as their oral phosphate binder for a 52-week safety assessment period. Subjects completing the safety assessment period on ferric citrate are re-randomized 1:1 to receive open-label ferric citrate or calcium acetate and/or sevelamer carbonate for a four-week efficacy assessment period. The primary goal is to determine safety and efficacy of oral ferric citrate as a phosphate binder. A secondary goal is to determine changes in iron status of subjects receiving ferric citrate.
Rationale: Currently available phosphate binders have safety and cost issues. ESRD patients have excessive iron losses due to blood lost with hemodialysis and frequent laboratory tests. In comparisons of oral and intravenous iron therapies (Macdougall IC et al. Kidney Int. 1996; Fudin R et al. Nephron. 1998), oral supplementation with ferrous salts failed to meet erythropoietic demands of hemodialysis patients, especially those treated with erythropoietin. Intravenous iron is routinely given to hemodialysis patients who develop iron deficiency or respond insufficiently to erythropoietin.
Comment: Hemodialysis patients lose 4 to 8 mg iron daily. Fasting, iron-deficient hemodialysis patients were considered capable of absorbing this amount of iron per day from ferrous salt supplements, but gastrointestinal side effects, lack of compliance, and reduced absorption as iron stores are repleted prevented these maximal absorption rates (Skikne BS et al. J Lab Clin Med. 2000).
Daily iron intake is much higher in this ferric citrate trial than in supplementation trials with ferrous preparations. However, negligible iron absorption had been expected because ferric ions must be reduced to ferrous ions for absorption. Furthermore, ferric citrate is given with food to maximize phosphate binding, thereby decreasing iron available for absorption. The wrinkle that arose in phase II trials of ferric citrate in hemodialysis patients was that an increase in serum iron, transferrin saturation, and ferritin was observed. The increased iron absorption was not accompanied by serious gastrointestinal side effects and, in one study, erythropoietin and intravenous iron administration decreased.
This ongoing phase III trial should provide answers about how iron absorption is regulated with long-term ferric citrate use, whether long-term ferric citrate is associated with as few gastrointestinal side effects as were found in the shorter phase II trials, and how much intravenous iron and erythropoietic stimulating agent usages might be reduced in hemodialysis patients taking ferric citrate. If iron absorption is well regulated and not associated with adverse gastrointestinal events in ESRD patients, ferric citrate may be potentially useful in those very common patients without ESRD who have iron deficiency but cannot tolerate oral ferrous supplements.
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