End Stage Renal Disease
Conditions
Keywords
End Stage Renal Disease, Hemodialysis, SFP
Brief summary
The purpose of this study is to compare the clinical safety and efficacy of SFP in sparing the need for erythropoiesis stimulating agents (ESAs) required to maintain hemoglobin (hgb) levels in chronic hemodialysis subjects who receive SFP via the dialysate versus subjects who receive conventional dialysate without iron.
Interventions
DRUGSoluble Ferric Pyrophosphate in liquid bicarbonate
Subjects will receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) at every dialysis session, for a total duration of 36 weeks.
DRUGPlacebo: Conventional liquid bicarbonate
Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking SFP at every dialysis session, for a total duration of 36 weeks.
DRUGErythrocyte Stimulating Agent (ESA)
ESA was administered according to the recommendation of a blinded central anemia management center (CAMC) based on the weekly hemoglobin value and its rate of change.
DRUGIntravenous (IV) Iron
Approved IV iron preparations were administered per a protocol driven algorithm when patients serum ferritin value decreased below 200 ug/L.
Sponsors
Rockwell Medical Technologies, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: 1. Male and female subjects ≥ 18 years of age. 2. End-stage renal disease undergoing maintenance hemodialysis 3 to 4 times a week for at least 4 months and expected to remain on this schedule and be able to complete the study. Subjects on a cadaveric transplant list need not be excluded for this reason unless there is an identified donor. 3. Mean Hgb in the range of ≥ 9.5 to ≤ 12.0 g/dL during screening. 4. The difference between the maximum and minimum Hgb values during screening does not exceed 1.0 g/dL. 5. Mean ferritin ≥ 200 to ≤ 1000 µg/L during screening. 6. Mean TSAT ≥ 15% to ≤ 40% during screening. 7. Any and all serum albumin measured during the 2 months preceding randomization must be ≥ 3.0 g/dL. 8. Prescribed ESA dosing remaining in the range of ≥ 4,000 to ≤ 45,000 U/week epoetin or ≥ 12.5 to ≤ 200 µg/week darbepoetin during the 6 weeks preceding randomization. 9. Required IV iron at any time in the 6 months preceding randomization. Main
Exclusion criteria
1. Vascular access for dialysis is a catheter. 2. During the 6 months prior to randomization, infection of the vascular access to be used at the time of randomization. 3. Received a total of \> 600 mg IV iron during the 6 weeks prior to randomization. 4. Received any amount of IV or oral iron during the 2 weeks prior to randomization. 5. Change in prescribed ESA dose: 1. Any change in prescribed ESA dose within 4 weeks prior to randomization. 2. The prescribed ESA dose at the time of randomization is \> 25% higher or lower than the prescribed dose at 6 weeks prior to randomization. 3. Change in prescribed type of ESA (e.g., epoetin vs. darbepoetin) or route of administration within 6 weeks prior to randomization. 6. Actual ESA dosing missed or withheld for a cumulative total of ≥ 1 week for any reason during the 6 weeks prior to randomization. 7. Known cause of anemia other than anemia attributable to renal disease (e.g., sickle cell disease, thalassemia, pure red cell aplasia, hemolytic anemia, myelodysplastic syndrome, etc.) 8. Scheduled kidney transplant or a donor has been identified but the transplant has not been scheduled. 9. Known ongoing inflammatory disorder (other than Chronic Kidney Disease), such as systemic lupus erythematosus, rheumatoid arthritis, other collagen-vascular diseases, etc. 11\. Known active tuberculosis, fungal, viral, or parasitic infection requiring anti-microbial therapy or anticipated to require anti-microbial therapy during the patient's participation in this study. Subjects with hepatitis C, in the absence of cirrhosis, are not excluded from participation in the study if Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are below 2 times the upper limit of normal on a consistent basis during the 2 months preceding randomization. 12\. Occult tuberculosis requiring prophylactic treatment with anti-tubercular drug(s) that overlaps with the patient's participation in this study. 13\. Cirrhosis of the liver based on histological criteria or clinical criteria (e.g., presence of ascites, esophageal varices, spider nevi, or history of hepatic encephalopathy).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percent Change From Baseline in ESA Dose Required to Maintain Hemoglobin in the Target Range, Adjusted for Hgb. | Hemoglobin measured weekly and serum ferritin and Transferrin Saturation (TSAT) determined every other week; ESA dose recorded at each visit for 36 weeks. | The statistical endpoint is the change from baseline between groups at End of Treatment, where the baseline prescribed ESA dose (expressed as U/week epoetin) per subject is defined as the average weekly dose of ESA prescribed for administration over the two-week period of time immediately prior to randomization. The end-of-treatment prescribed ESA dose (expressed as U/week epoetin) per subject is defined as the average weekly dose of ESA prescribed for administration over the last two weeks of the treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose is monitored and recorded at each dialysis session for 36 weeks. | The change from baseline in prescribed ESA dose at end-of-treatment was categorized as being greater than or equal to 25%, 10 to less than 25%, -10 to 10%, greater than -25 to -10% and less than or equal to -25%. The number of subjects in each treatment group that fit each category was compared. |
| Stability of Hemoglobin Over Time (Maintenance of Hemoglobin Between 9.5-11.5 g/dL. | 36 weeks | The number of patients in each treatment group who had maintained their hemoglobin between 95 and 115 grams/liter at the end of treatment was quantified. |
| The Amount of Supplemental Intravenous (IV) Iron Needed During Study Participation. | 36 weeks | The absolute amount of IV iron administered to subjects in each treatment group was divided by the number of weeks on study and the number of subjects per treatment group such that the mean dose of IV iron (mg) per week per subject (for the entire treatment group) was calculated. |
| Comparison of Iron Delivery to the Erythron From Baseline to End of Treatment Between the Treatment Groups. | 36 weeks | Iron delivery to the erythron was estimated by Hgb generation in response to erythropoietin (ERI, calculated as ESA dose/Hgb). In addition, ERI was also divided by body weight in kilograms to obtain a modified ERI (ERI/kg). |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SFP in Liquid Bicarbonate Soluble Ferric Pyrophosphate in liquid bicarbonate: Subjects will be randomized in a 1:1 ratio to receive hemodialysis containing SFP at 2 µM (11 µg iron/dL of dialysate) or conventional solutions lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks. | 54 |
| Placebo: Conventional Liquid Bicarbonate Control concentrate lacking SFP does not contain SFP (total iron = 0)
Subjects will receive hemodialysis containing conventional liquid bicarbonate lacking iron (placebo) at every dialysis session, for a total duration of 36 weeks. | 49 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Death | 2 | 3 |
| Overall Study | peritoneal dialysis, randomized in error | 1 | 3 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | SFP in Liquid Bicarbonate | Placebo: Conventional Liquid Bicarbonate | Total |
|---|---|---|---|
| Age, Continuous | 59.4 years STANDARD_DEVIATION 12.4 | 58.5 years STANDARD_DEVIATION 13.89 | 59 years STANDARD_DEVIATION 13.07 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 21 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 28 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 17 Participants | 39 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 31 Participants | 32 Participants | 63 Participants |
| Sex: Female, Male Female | 23 Participants | 17 Participants | 40 Participants |
| Sex: Female, Male Male | 31 Participants | 32 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 50 / 54 | 46 / 49 |
| serious Total, serious adverse events | 18 / 54 | 20 / 49 |
Outcome results
Primary
The Percent Change From Baseline in ESA Dose Required to Maintain Hemoglobin in the Target Range, Adjusted for Hgb.
The statistical endpoint is the change from baseline between groups at End of Treatment, where the baseline prescribed ESA dose (expressed as U/week epoetin) per subject is defined as the average weekly dose of ESA prescribed for administration over the two-week period of time immediately prior to randomization. The end-of-treatment prescribed ESA dose (expressed as U/week epoetin) per subject is defined as the average weekly dose of ESA prescribed for administration over the last two weeks of the treatment period.
Time frame: Hemoglobin measured weekly and serum ferritin and Transferrin Saturation (TSAT) determined every other week; ESA dose recorded at each visit for 36 weeks.
Population: MITT population: Randomized subjects who received at least one dose of study drug and also received ESA during the treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SFP in Liquid Bicarbonate | The Percent Change From Baseline in ESA Dose Required to Maintain Hemoglobin in the Target Range, Adjusted for Hgb. | 4.9 Percent change | Standard Error 12.07 |
| Placebo: Conventional Liquid Bicarbonate | The Percent Change From Baseline in ESA Dose Required to Maintain Hemoglobin in the Target Range, Adjusted for Hgb. | 39.8 Percent change | Standard Error 12.18 |
p-value: <0.05ANCOVA
Secondary
Comparison of Iron Delivery to the Erythron From Baseline to End of Treatment Between the Treatment Groups.
Iron delivery to the erythron was estimated by Hgb generation in response to erythropoietin (ERI, calculated as ESA dose/Hgb). In addition, ERI was also divided by body weight in kilograms to obtain a modified ERI (ERI/kg).
Time frame: 36 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SFP in Liquid Bicarbonate | Comparison of Iron Delivery to the Erythron From Baseline to End of Treatment Between the Treatment Groups. | baseline | 10.43 Units/kilogram/week/gram/liter | Standard Deviation 6.457 |
| SFP in Liquid Bicarbonate | Comparison of Iron Delivery to the Erythron From Baseline to End of Treatment Between the Treatment Groups. | end of treatment | 11.71 Units/kilogram/week/gram/liter | Standard Deviation 9.808 |
| Placebo: Conventional Liquid Bicarbonate | Comparison of Iron Delivery to the Erythron From Baseline to End of Treatment Between the Treatment Groups. | baseline | 10.38 Units/kilogram/week/gram/liter | Standard Deviation 6.471 |
| Placebo: Conventional Liquid Bicarbonate | Comparison of Iron Delivery to the Erythron From Baseline to End of Treatment Between the Treatment Groups. | end of treatment | 14.67 Units/kilogram/week/gram/liter | Standard Deviation 13.804 |
p-value: 0.361Wilcoxon (Mann-Whitney)
Secondary
Stability of Hemoglobin Over Time (Maintenance of Hemoglobin Between 9.5-11.5 g/dL.
The number of patients in each treatment group who had maintained their hemoglobin between 95 and 115 grams/liter at the end of treatment was quantified.
Time frame: 36 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SFP in Liquid Bicarbonate | Stability of Hemoglobin Over Time (Maintenance of Hemoglobin Between 9.5-11.5 g/dL. | 30 Participants |
| Placebo: Conventional Liquid Bicarbonate | Stability of Hemoglobin Over Time (Maintenance of Hemoglobin Between 9.5-11.5 g/dL. | 30 Participants |
p-value: 0.6714Cochran-Mantel-Haenszel
Secondary
The Amount of Supplemental Intravenous (IV) Iron Needed During Study Participation.
The absolute amount of IV iron administered to subjects in each treatment group was divided by the number of weeks on study and the number of subjects per treatment group such that the mean dose of IV iron (mg) per week per subject (for the entire treatment group) was calculated.
Time frame: 36 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SFP in Liquid Bicarbonate | The Amount of Supplemental Intravenous (IV) Iron Needed During Study Participation. | 23.5 mg per week per subject | Standard Deviation 54.22 |
| Placebo: Conventional Liquid Bicarbonate | The Amount of Supplemental Intravenous (IV) Iron Needed During Study Participation. | 45.6 mg per week per subject | Standard Deviation 62.78 |
p-value: 0.028Wilcoxon (Mann-Whitney)
Secondary
The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms
The change from baseline in prescribed ESA dose at end-of-treatment was categorized as being greater than or equal to 25%, 10 to less than 25%, -10 to 10%, greater than -25 to -10% and less than or equal to -25%. The number of subjects in each treatment group that fit each category was compared.
Time frame: ESA dose is monitored and recorded at each dialysis session for 36 weeks.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SFP in Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change >10 to 25% | 5 Participants |
| SFP in Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change > -25% to -10% | 3 Participants |
| SFP in Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change > -10% to 10% | 12 Participants |
| SFP in Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change < or = to -25% | 16 Participants |
| SFP in Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change > or = to 25% | 16 Participants |
| Placebo: Conventional Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change < or = to -25% | 15 Participants |
| Placebo: Conventional Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change > or = to 25% | 20 Participants |
| Placebo: Conventional Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change >10 to 25% | 4 Participants |
| Placebo: Conventional Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change > -10% to 10% | 9 Participants |
| Placebo: Conventional Liquid Bicarbonate | The Distribution of Changes From Baseline in the Prescribed ESA Dose Between the Two Treatment Arms | ESA dose change > -25% to -10% | 3 Participants |
p-value: 0.915Cochran-Mantel-Haenszel