Chronic Inflammation, End Stage Renal Disease, Hyperphosphatemia
Conditions
Brief summary
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
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: 1. acting as a non-calcium based binder to decrease serum phosphorus levels and vascular calcification, 2. decreasing intravenous iron requirements which in turn may decrease inflammation, 3. binding endotoxin (a harmful substance produced by microorganisms) in the gut and 4. improving lipid metabolism. The purpose of this study is to examine the effect of ferric citrate on inflammatory markers and lipid levels.
Interventions
DRUGFerric Citrate
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.
Sponsors
Keryx Biopharmaceuticals
Winthrop University Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Intravenous Iron Use | Baseline, Month 6 | Change in intravenous iron use (mg) from Baseline to Month 6. |
| Percent Change in Ferritin | Baseline, Month 6 | Percent change in ferritin (ng/ml) from baseline to Month 6. |
| Percent Change in C-reactive Protein | Baseline, Month 6 | Percent change in C-reactive Protein (mg/L) from baseline to Month 6. |
| Percent Change in Homocysteine | Baseline, Month 6 | Percent change in homocysteine (micromol/L) from baseline to Month 6. |
| Percent Change in Total Cholesterol | Baseline, Month 6 | Percent change in total cholesterol (mg/dl) from Baseline to Month 6. |
| Percent Change in LDL-Cholesterol | Baseline, Month 6 | Percent change in low-density lipoprotein (LDL) cholesterol (mg/dl) from baseline to Month 6 |
| Percent Change in HDL Cholesterol | Baseline, Month 6 | Percent change in high-density lipoprotein (HDL) cholesterol (mg/dl) from baseline to Month 6. |
| Percent Change in Triglycerides | Baseline, Month 6 | Percent change in triglycerides (mg/dl) from baseline to Month 6. |
| Percent Change in TNF-alpha | Baseline, Month 6 | Percent change in tumor necrosis factor (TNF)-alpha (pg/ml) from Baseline to Month 6. |
| Percent Change in IL-6 | Baseline, Month 6 | Percent change in interleukin 6 (IL-6) (pg/ml) from baseline to Month 6 |
| Percent Change in IL-8 | Baseline, Month 6 | Percent change in interleukin 8 (IL-8) (pg/ml) from baseline to Month 6. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Parathyroid Hormone (PTH) | Baseline, Month 6 | Percent change in PTH (pg/ml) from baseline to Month 6. |
| Percent Change in Calcium | Baseline, Month 6 | Percent change in calcium (mg/dL) from baseline to Month 6. |
| Percent Change in Phosphorus | Baseline, Month 6 | Percent change in phosphorus (md/dl) from baseline to Month 6. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ferric Citrate Ferric citrate at a starting dose of 2 tablets with each meal will be given to all participants.
Ferric Citrate: 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. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Failed screening | 2 |
| Overall Study | Kidney Transplant | 1 |
| Overall Study | Transferred Out | 1 |
| Overall Study | Withdrawal by Subject | 3 |
| Overall Study | Withdrawn due to access type | 1 |
| Overall Study | Withdrawn due to allergies | 1 |
| Overall Study | Withdrawn due to non-compliance | 1 |
| Overall Study | Withdrawn due to side effects | 8 |
Baseline characteristics
| Characteristic | Ferric Citrate |
|---|---|
| Age, Continuous | 57.8 years STANDARD_DEVIATION 15.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 38 |
| other Total, other adverse events | 0 / 38 |
| serious Total, serious adverse events | 14 / 38 |
Outcome results
Primary
Change in Intravenous Iron Use
Change in intravenous iron use (mg) from Baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Change in Intravenous Iron Use | -588.8 mg | Standard Deviation 807.8 |
Primary
Percent Change in C-reactive Protein
Percent change in C-reactive Protein (mg/L) from baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in C-reactive Protein | 8.89 percent change | Standard Deviation 35.49 |
Primary
Percent Change in Ferritin
Percent change in ferritin (ng/ml) from baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in Ferritin | 51.11 percent change | Standard Deviation 296.4 |
Primary
Percent Change in HDL Cholesterol
Percent change in high-density lipoprotein (HDL) cholesterol (mg/dl) from baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in HDL Cholesterol | 1.32 percent change | Standard Deviation 6.16 |
Primary
Percent Change in Homocysteine
Percent change in homocysteine (micromol/L) from baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in Homocysteine | 1.35 percent change | Standard Deviation 7.31 |
Primary
Percent Change in IL-6
Percent change in interleukin 6 (IL-6) (pg/ml) from baseline to Month 6
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in IL-6 | -1.78 percent change | Standard Deviation 19.5 |
Primary
Percent Change in IL-8
Percent change in interleukin 8 (IL-8) (pg/ml) from baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in IL-8 | 101.96 Percent change | Standard Deviation 422.8 |
Primary
Percent Change in LDL-Cholesterol
Percent change in low-density lipoprotein (LDL) cholesterol (mg/dl) from baseline to Month 6
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in LDL-Cholesterol | -0.05 Percent change | Standard Deviation 32.47 |
Primary
Percent Change in TNF-alpha
Percent change in tumor necrosis factor (TNF)-alpha (pg/ml) from Baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in TNF-alpha | -0.1 percent change | Standard Deviation 1.77 |
Primary
Percent Change in Total Cholesterol
Percent change in total cholesterol (mg/dl) from Baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in Total Cholesterol | 1.58 Percent change | Standard Deviation 33.77 |
Primary
Percent Change in Triglycerides
Percent change in triglycerides (mg/dl) from baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in Triglycerides | -5.11 Percent change | Standard Deviation 67.69 |
Secondary
Percent Change in Calcium
Percent change in calcium (mg/dL) from baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in Calcium | 0.08 Percent change | Standard Deviation 0.53 |
Secondary
Percent Change in Parathyroid Hormone (PTH)
Percent change in PTH (pg/ml) from baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in Parathyroid Hormone (PTH) | 36.47 Percent change | Standard Deviation 280.3 |
Secondary
Percent Change in Phosphorus
Percent change in phosphorus (md/dl) from baseline to Month 6.
Time frame: Baseline, Month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Citrate | Percent Change in Phosphorus | -1.58 Percent change | Standard Deviation 1.87 |