A Study of Ferric Citrate to Improve Inflammation and Lipid Levels

Study Overview
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Brief Summary
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The risk of cardiovascular mortality in patients with end stage renal disease on hemodialysis is 10-100 times higher than the normal population. This is due in part to high levels of inflammation and vascular calcification found in these patients. Phosphate binders, particularly non-calcium based phosphate binders, may decrease cardiovascular risk by decreasing inflammation and vascular calcification. Ferric citrate a non-calcium based phosphate binder with approximately 210 mg of ferric iron has recently been approved for patients on hemodialysis. The effect of this phosphate binder on inflammation and lipid levels is unknown but investigators hypothesize that ferric citrate has the potential to improve inflammation and lipid levels in patients on hemodialysis by decreasing intravenous iron requirements and by improving lipid metabolism.

Detailed Description
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In patients with end stage renal disease (ESRD) receiving dialysis, the risk of cardiovascular death has been estimated to be 10-100 times higher than the general population without renal disease. This is due in part to high levels of inflammation and vascular calcification (large deposits of calcium in arteries) found in these patients. Chronic inflammation is particularly common in patients with ESRD. Parenteral iron therapy, which is common in patients on dialysis, may contribute to this inflammation and also a higher cardiovascular risk. Phosphate binders, particularly non-calcium based phosphate binders, may decrease cardiovascular risk by decreasing inflammation and vascular calcification. In a study of 10,044 hemodialysis patients, treatment with a phosphate binder was associated with improved survival. Ferric citrate a non-calcium based phosphate binder with approximately 210 mg of ferric iron has recently been approved for patients on hemodialysis. It has been shown to improve serum phosphorus levels and decrease intravenous iron requirements for patients on hemodialysis. The effect of this phosphate binder on inflammation and lipid levels is unknown but investigators hypothesize that ferric citrate has the potential to improve inflammation and lipid levels in patients on hemodialysis by decreasing intravenous iron requirements and by improving lipid metabolism. Ferric citrate has the potential to decrease cardiovascular risk through multiple mechanisms: acting as a non-calcium based binder to decrease serum phosphorus levels and vascular calcification, decreasing intravenous iron requirements which in turn may decrease inflammation, binding endotoxin (a harmful substance produced by microorganisms) in the gut and improving lipid metabolism. The purpose of this study is to examine the effect of ferric citrate on inflammatory markers and lipid levels.

Official Title
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The Effect of Ferric Citrate on Inflammation and Lipid Levels in Patients on Hemodialysis

Conditions
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End Stage Renal Disease, Hyperphosphatemia, Chronic Inflammation

Intervention / Treatment
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* Drug: Ferric Citrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hemodialysis treatment for ≥ 6 months Phosphate binder treatment for ≥ to 1 month Maintenance iron therapy with no more than 125mg IV iron weekly≥ to 1 month Serum phosphorus levels between 2.5 and 8 at screening Serum phosphorus ≥ to 6.0 mg/dL after a 2 week washout period. Serum ferritin ≥ 200 and < 600ng/ml after a 2 week washout period Serum calcium levels within normal range Predicted survival greater than 6 months Exclusion Criteria: Intact PTH< 70 pg/ml or > 1,000 pg/ml Oral iron use Vitamin C supplement use Parathyroidectomy Active malignancy Hemodialysis via an intravenous catheter or arteriovenous (AV) graft Received > 250mg of IV iron over the two weeks prior to screening Whole blood transfusion within 3 months prior to screening Active bleeding other than from the dialysis access Hospitalization within one month prior to screening current infection Ongoing or uncontrolled inflammatory disorder Liver cirrhosis Likelihood of imminent renal transplantation

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: Other
Intervention Model: Single Group Assignment
Interventional Model Description: This study will be designed as a single arm, prospective, experimental trial of 45 hemodialysis patients. Patients on hemodialysis at least 6 months and receiving a phosphate binder with serum phosphorus levels between 2.5 and 8.0 mg/dL, normal serum calcium levels, and on maintenance iron therapy are potentially eligible. Participants will receive ferric citrate after at least a 2 week washout period from previous phosphate binders if phosphorus is ≥ 5.5 mg/dl, calcium is within the normal range and ferritin ≥ 200 and < 600 ng/ml. Ferric citrate will be titrated to maintain serum phosphorus and calcium within acceptable levels. Inflammatory markers and lipid levels will be tested at 0, 3, and 6 months.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Ferric Citrate<br>Ferric citrate at a starting dose of 2 tablets with each meal will be given to all participants. | Drug: Ferric Citrate<br>* Study participants will receive ferric citrate at a starting dose of 2 tablets with each meal if serum phosphorus levels are ≥ 6.0 mg/dL calcium levels are in the normal range, Tsat ≥ 20 and < 50% and ferritin ≥ 200 and < 500 ng/ml after a 2 week wash out period.<br>* Other names: Auryxia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Total Cholesterol | Percent change in total cholesterol (mg/dl) from Baseline to Month 6. | Baseline, Month 6 | 
| Percent Change in LDL-Cholesterol | Percent change in low-density lipoprotein (LDL) cholesterol (mg/dl) from baseline to Month 6 | Baseline, Month 6 | 
| Percent Change in HDL Cholesterol | Percent change in high-density lipoprotein (HDL) cholesterol (mg/dl) from baseline to Month 6. | Baseline, Month 6 | 
| Percent Change in Triglycerides | Percent change in triglycerides (mg/dl) from baseline to Month 6. | Baseline, Month 6 | 
| Percent Change in TNF-alpha | Percent change in tumor necrosis factor (TNF)-alpha (pg/ml) from Baseline to Month 6. | Baseline, Month 6 | 
| Percent Change in IL-6 | Percent change in interleukin 6 (IL-6) (pg/ml) from baseline to Month 6 | Baseline, Month 6 | 
| Percent Change in IL-8 | Percent change in interleukin 8 (IL-8) (pg/ml) from baseline to Month 6. | Baseline, Month 6 | 
| Percent Change in Ferritin | Percent change in ferritin (ng/ml) from baseline to Month 6. | Baseline, Month 6 | 
| Percent Change in C-reactive Protein | Percent change in C-reactive Protein (mg/L) from baseline to Month 6. | Baseline, Month 6 | 
| Percent Change in Homocysteine | Percent change in homocysteine (micromol/L) from baseline to Month 6. | Baseline, Month 6 | 
| Change in Intravenous Iron Use | Change in intravenous iron use (mg) from Baseline to Month 6. | Baseline, Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Calcium | Percent change in calcium (mg/dL) from baseline to Month 6. | Baseline, Month 6 | 
| Percent Change in Phosphorus | Percent change in phosphorus (md/dl) from baseline to Month 6. | Baseline, Month 6 | 
| Percent Change in Parathyroid Hormone (PTH) | Percent change in PTH (pg/ml) from baseline to Month 6. | Baseline, Month 6 |