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

Study Overview
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Brief Summary
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The main objective of the study is to compare the impact of oral ferric citrate compared to standard of care oral ferrous sulfate on serum iron, percent transferrin saturation, ferritin, hepcidin and hemoglobin levels in individuals with moderate to severe chronic kidney disease (CKD) and absolute iron deficiency.

Detailed Description
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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.

Official Title
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Impact of Ferric Citrate vs Ferrous Sulfate on Iron Parameters and Hemoglobin in Individuals With Moderate to Severe Chronic Kidney Disease (CKD) With Iron Deficiency

Conditions
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Chronic Kidney Disease, Iron Deficiency, Anemia

Intervention / Treatment
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* Drug: ferric citrate
* Drug: ferrous sulfate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ferric citrate<br>Participants randomized to the ferric citrate arm will receive 2 grams of ferric citrate three times a day with each meal. | Drug: ferric citrate<br>* Participants randomized to the ferric citrate arm will take 2 grams of ferric citrate three times a day with meals.<br>* Other names: Auryxia;|
| Active Comparator: ferrous sulfate<br>Participants randomized to the ferrous sulfate arm will receive 325 mg of ferrous sulfate three times a day | Drug: ferrous sulfate<br>* Participants randomized to the ferrous sulfate arm will take 325 mg of ferrous sulfate three times a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ferritin From Baseline to End of Treatment | The change in serum ferritin concentrations from the baseline of the study to the 12 week time point. | Baseline and 12 weeks | 
| Change in Transferrin Saturation From Baseline to End of Treatment | The change in serum transferrin saturation from the baseline to the end of treatment | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hemoglobin From Baseline to End of Treatment | The change in hemoglobin concentrations from the baseline visit to the 12-week time point. | Baseline and 12 weeks | 
| Change in Hepcidin From Baseline to the End of Treatment | The change in hepcidin concentrations from the baseline visit to the 12-week time point. | Baseline and 12 weeks | 
| Change in Fibroblast Growth Factor 23 From Baseline to the End of Treatment | The change in fibroblast growth factor 23 concentrations from the baseline visit to the 12-week time point. | Baseline and 12 weeks |