Impact of Ferric Citrate vs Ferrous Sulfate on Iron Parameters and Hemoglobin in Individuals With CKD and Iron Deficiency

Ferric citrate is an FDA-approved oral phosphorus binder that has been shown to be effective
in reducing serum phosphorus and fibroblast growth factor 23 (FGF23) concentrations and
increasing iron stores and hemoglobin in individuals with non-dialysis-dependent CKD who have
iron-deficiency anemia. This may prove to be advantageous in individuals with pre-dialysis
CKD who require iron supplementation for iron-deficiency anemia. This is because ferric
citrate may not only restore iron stores in individuals who are iron deficient, but by
lowering FGF23 concentrations, ferric citrate may increase local and systemic concentrations
of 1,25-dihydroxyvitamin D, a powerful inhibitor of hepcidin synthesis, potentially
attenuating the increase in hepcidin following oral iron supplementation. When compared to
standard iron supplementation therapies (e.g., oral ferrous sulfate) that powerfully
stimulate hepcidin secretion, this may then allow for greater iron bioavailability by
increasing iron absorption in the gut while also reducing the degree of iron sequestration in
reticuloendothelial system stores. However, little is known about the comparative
effectiveness of treatment with oral ferric citrate vs. oral ferrous sulfate (currently the
standard of care) in increasing iron stores and hemoglobin in iron-deficient CKD patients. If
ferric citrate is shown to not only improve overall iron status, but also partially mitigate
the long-term effects of iron supplementation on hepcidin secretion by increasing
endogenously produced 1,25-dihydroxyvitamin D, this may indicate that ferric citrate can
provide superior short- and long-term effects on iron-restricted erythropoiesis in CKD as
compared to the current standard of care. The main objectives of the study are to compare the
impact of ferric citrate compared to standard of care ferrous sulfate on serum iron, percent
transferrin saturation (TSAT), ferritin, hemoglobin and hepcidin concentrations in
individuals with moderate to severe CKD and absolute iron deficiency.

Inclusion Criteria:

- Age 18 years or greater

- Moderate to severe CKD not requiring dialysis (eGFR 15 - 45 ml/min/1.73 m2 by CKD-EPI)

- Absolute iron deficiency (serum ferritin <300ng/ml and Transferrin Saturation < 30%)

Exclusion Criteria:

- Hemoglobin concentrations > 13 g/dL

- Known disorder of iron homeostasis (e.g., hemochromatosis)

- Known gastrointestinal disorder (irritable bowel disease, inflammatory bowel disease)

- Known liver disease (ALT/AST or bilirubin > 3x normal)

- Serum phosphorus concentrations < 3.0 mg/dL

- Any known cause of anemia other than iron deficiency or CKD (e.g., sickle cell anemia)

- Symptomatic gastrointestinal bleeding within 12 weeks prior to the screening visit.

- Subjects receiving any form of renal replacement therapy including hemodialysis,
peritoneal dialysis, or renal transplant.

- Pregnancy or lactation in female participants

- Severe anemia defined as a hemoglobin < 8.0 g/dL for males or a hemoglobin <7.0 g/dL
for females.

- Receipt of erythropoiesis stimulating agents within 4 weeks of screening.

- Receipt of intravenous iron therapy within 8 weeks of screening.

- Blood transfusion within 4 weeks of screening

- Known allergies or severe adverse reactions to previous oral iron therapy

- Current use of oral phosphorus binders.

- Current use of an active vitamin D analog