Hyperphosphatemia, Kidney Failure
Conditions
Keywords
ESRD, end-stage renal disease, dialysis, hemodialysis, peritoneal dialysis, hemodialysis (HD), peritoneal dialysis (PD), chronic renal insufficiency, phosphate binder, kidney failure, renal failure
Brief summary
This is up to a 58 week study comparing ferric citrate to active control for 52 weeks in ESRD dialysis patients, and subsequently comparing ferric citrate to placebo for 4 weeks.
Detailed description
This trial is a three-period, multicenter, safety and efficacy clinical trial. The first period is a two-week Washout Period, the second period is a 52-week randomized, open-label, active control Safety Assessment Period, and the third period is a four-week, randomized, open-label, placebo-controlled Efficacy Assessment Period in only the patients who were randomized to treatment with ferric citrate during the Safety Assessment Period. The primary objectives of this trial are to determine the long-term safety over 52 weeks of up to twelve (12) caplets/day of KRX-0502 (ferric citrate) in patients with ESRD undergoing either hemodialysis or peritoneal dialysis and to determine the efficacy of KRX-0502 (ferric citrate) in the four-week, randomized, open-label, placebo-controlled Efficacy Assessment Period.
Interventions
DRUGferric citrate, ca acetate, sevelamer carbonate, placebo
All intervention doses will be based on serum phosphorus levels and/or drug label requirements
Sponsors
Keryx Biopharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males or non-pregnant, non-breast-feeding females 2. Age ≥18 years 3. On thrice-weekly hemodialysis or on peritoneal dialysis for at least the previous three months prior to Screening 4. Serum phosphorus ≥6.0 mg/dL for study entry 5. Taking less than 3-18 pills/day of current phosphate binder 6. Willing to be discontinued from current phosphate binder(s) and initiated on ferric citrate 7. Willing and able to give informed consent 8. Life expectancy \>1 year
Exclusion criteria
1. Parathyroidectomy within six months prior to Screening 2. Actively symptomatic gastrointestinal bleeding or inflammatory bowel disease 3. History of multiple drug allergies or intolerances 4. History of malignancy in the last five years (treated cervical or non-melanomatous skin cancer may be permitted if approved by CCC) 5. Previous intolerance to oral ferric citrate 6. Intolerance to oral iron-containing products 7. Psychiatric disorder that interferes with the patient's ability to comply with the study protocol 8. Inability to tolerate oral drug intake 9. Intolerance to calcium acetate and sevelamer carbonate 10. Any other medical condition that renders the patient unable to or unlikely to complete the trial or that would interfere with optimal participation in the trial or produce significant risk to the patient 11. Receipt of any investigational drug within 30 days of Screening Visit (Visit 0) 12. Inability to cooperate with study personnel or history of noncompliance 13. Unsuitable for this trial per Investigator's clinical judgment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Serum Phosphorus From Baseline (Week 52) to the End of the Efficacy Assessment Period (EAP; Week 56) | 4 weeks | Patients who completed the 52-week Safety Assessment Period (SAP) on KRX-0502 (ferric citrate) were randomized in a 1:1 ratio to receive either KRX-0502 (ferric citrate) or Placebo for 4 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Serum Ferritin From Baseline to Week 52 | 52 weeks | — |
| Change in Mean Serum Transferrin Saturation (TSAT) From Baseline to the End of the Safety Assessment Period (Week 52) | 52 weeks | — |
| IV Iron Analysis | 52 weeks | Full Analysis Population, cumulative IV Iron administration from Baseline to the end of the Safety Assessment Period (Week 52) |
| ESA Analysis | 52 weeks | Full analysis population, cumulative Erythropoiesis-stimulating agent (ESA) administration from baseline to the end of the Safety Assessment Period (Week 52) |
Countries
Israel, Puerto Rico, United States
Participant flow
Pre-assignment details
1. Only subjects that completed the SAP on KRX-0502 were eligible to be included in the EAP 2. in the EAP, subjects received only Placebo or KRX-0502-EAP 3. 3 Subjects switched from 'Active Control' to KRX-0502 during the SAP and were randomized into the EAP 4. In the 'Active Control' group, a combination of phosphate binders was allowed
Participants by arm
| Arm | Count |
|---|---|
| Active Control-SAP Patients received either PhosLo (calcium acetate), Renvela (sevelamer carbonate), or a combination of these treatments during a 52-week Safety Assessment Period. | 146 |
| KRX-0502 (Ferric Citrate)-SAP Patients received KRX-0502 (ferric citrate) during a 52-week Safety Assessment Period.
Patients that completed the 52-week Safety Assessment Period were randomized to continue to receive KRX-0502 (ferric citrate) or placebo for a 4-week Efficacy Assessment Period. | 281 |
| Placebo-EAP Patients that completed the 52-week Safety Assessment Period on KRX-0502 were randomized 1:1 to continue to receive KRX-0502 (ferric citrate) or placebo for a 4-week Efficacy Assessment Period. | 91 |
| KRX-0502 (Ferric Citrate)-EAP Patients that completed the 52-week Safety Assessment Period on KRX-0502 were randomized 1:1 to continue to receive KRX-0502 (ferric citrate) or placebo for a 4-week Efficacy Assessment Period. | 91 |
| Total | 609 |
Baseline characteristics
| Characteristic | Active Control-SAP | Total | KRX-0502 (Ferric Citrate)-EAP | Placebo-EAP | KRX-0502 (Ferric Citrate)-SAP |
|---|---|---|---|---|---|
| Age, Customized Age <65 years (EAP) | 0 participants | 150 participants | 73 participants | 77 participants | 0 participants |
| Age, Customized Age >= 65 years (EAP) | 0 participants | 32 participants | 18 participants | 14 participants | 0 participants |
| Age, Customized Age <65 years (SAP) | 118 participants | 341 participants | 0 participants | 0 participants | 223 participants |
| Age, Customized Age >= 65 years (SAP) | 28 participants | 86 participants | 0 participants | 0 participants | 58 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native (EAP) | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native (SAP) | 1 participants | 3 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Asian (EAP) | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian (SAP) | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American (EAP) | 0 participants | 107 participants | 59 participants | 48 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American (SAP) | 77 participants | 230 participants | 0 participants | 0 participants | 153 participants |
| Race/Ethnicity, Customized Hispanic or Latino (EAP) | 0 participants | 23 participants | 9 participants | 14 participants | 0 participants |
| Race/Ethnicity, Customized Hispanic or Latino (SAP) | 23 participants | 64 participants | 0 participants | 0 participants | 41 participants |
| Race/Ethnicity, Customized More Than One Race (EAP) | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized More Than One Race (SAP) | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander (EAP) | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander (SAP) | 2 participants | 2 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino (EAP) | 0 participants | 159 participants | 82 participants | 77 participants | 0 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino (SAP) | 123 participants | 362 participants | 0 participants | 0 participants | 239 participants |
| Race/Ethnicity, Customized Unknown or not reported (EAP) | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Unknown or Not Reported (EAP) | 0 participants | 6 participants | 4 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Unknown or not reported (SAP) | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Unknown or Not Reported (SAP) | 4 participants | 15 participants | 0 participants | 0 participants | 11 participants |
| Race/Ethnicity, Customized White (EAP) | 0 participants | 67 participants | 28 participants | 39 participants | 0 participants |
| Race/Ethnicity, Customized White (SAP) | 61 participants | 175 participants | 0 participants | 0 participants | 114 participants |
| Sex/Gender, Customized Female (EAP) | 0 participants | 150 participants | 73 participants | 77 participants | 0 participants |
| Sex/Gender, Customized Female (SAP) | 62 participants | 168 participants | 0 participants | 0 participants | 106 participants |
| Sex/Gender, Customized Male (EAP) | 0 participants | 32 participants | 18 participants | 14 participants | 0 participants |
| Sex/Gender, Customized Male (SAP) | 84 participants | 259 participants | 0 participants | 0 participants | 175 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 211 / 289 | 88 / 149 | 5 / 95 | 0 / 95 |
| serious Total, serious adverse events | 114 / 289 | 73 / 149 | 11 / 95 | 17 / 95 |
Outcome results
Primary
Change in Mean Serum Phosphorus From Baseline (Week 52) to the End of the Efficacy Assessment Period (EAP; Week 56)
Patients who completed the 52-week Safety Assessment Period (SAP) on KRX-0502 (ferric citrate) were randomized in a 1:1 ratio to receive either KRX-0502 (ferric citrate) or Placebo for 4 weeks.
Time frame: 4 weeks
Population: Full Analysis Population (LOCF)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo-EAP | Change in Mean Serum Phosphorus From Baseline (Week 52) to the End of the Efficacy Assessment Period (EAP; Week 56) | Baseline (Week 52) | 5.44 mg/dL | Standard Deviation 1.459 |
| Placebo-EAP | Change in Mean Serum Phosphorus From Baseline (Week 52) to the End of the Efficacy Assessment Period (EAP; Week 56) | End of EAP (Week 56) | 7.23 mg/dL | Standard Deviation 1.784 |
| KRX-0502 (Ferric Citrate)-EAP | Change in Mean Serum Phosphorus From Baseline (Week 52) to the End of the Efficacy Assessment Period (EAP; Week 56) | Baseline (Week 52) | 5.12 mg/dL | Standard Deviation 1.189 |
| KRX-0502 (Ferric Citrate)-EAP | Change in Mean Serum Phosphorus From Baseline (Week 52) to the End of the Efficacy Assessment Period (EAP; Week 56) | End of EAP (Week 56) | 4.89 mg/dL | Standard Deviation 1.291 |
p-value: <0.0001ANCOVA
Secondary
Change in Mean Serum Ferritin From Baseline to Week 52
Time frame: 52 weeks
Population: Full Analysis Population (LOCF)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control-SAP | Change in Mean Serum Ferritin From Baseline to Week 52 | End of SAP (Week 52) | 631.87 ng/mL | Standard Deviation 368.919 |
| Active Control-SAP | Change in Mean Serum Ferritin From Baseline to Week 52 | Baseline | 609.50 ng/mL | Standard Deviation 307.689 |
| KRX-0502 (Ferric Citrate)-SAP | Change in Mean Serum Ferritin From Baseline to Week 52 | Baseline | 592.80 ng/mL | Standard Deviation 292.863 |
| KRX-0502 (Ferric Citrate)-SAP | Change in Mean Serum Ferritin From Baseline to Week 52 | End of SAP (Week 52) | 894.88 ng/mL | Standard Deviation 481.788 |
p-value: <0.0001ANCOVA
Secondary
Change in Mean Serum Transferrin Saturation (TSAT) From Baseline to the End of the Safety Assessment Period (Week 52)
Time frame: 52 weeks
Population: Full Analysis Population (LOCF)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Control-SAP | Change in Mean Serum Transferrin Saturation (TSAT) From Baseline to the End of the Safety Assessment Period (Week 52) | Baseline | 30.8 % Saturation | Standard Deviation 11.57 |
| Active Control-SAP | Change in Mean Serum Transferrin Saturation (TSAT) From Baseline to the End of the Safety Assessment Period (Week 52) | End of SAP (Week 52) | 29.7 % Saturation | Standard Deviation 11.43 |
| KRX-0502 (Ferric Citrate)-SAP | Change in Mean Serum Transferrin Saturation (TSAT) From Baseline to the End of the Safety Assessment Period (Week 52) | Baseline | 31.3 % Saturation | Standard Deviation 11.21 |
| KRX-0502 (Ferric Citrate)-SAP | Change in Mean Serum Transferrin Saturation (TSAT) From Baseline to the End of the Safety Assessment Period (Week 52) | End of SAP (Week 52) | 39.2 % Saturation | Standard Deviation 16.78 |
p-value: <0.0001ANCOVA
Secondary
ESA Analysis
Full analysis population, cumulative Erythropoiesis-stimulating agent (ESA) administration from baseline to the end of the Safety Assessment Period (Week 52)
Time frame: 52 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Control-SAP | ESA Analysis | 993.46 Units/Day |
| KRX-0502 (Ferric Citrate)-SAP | ESA Analysis | 755.80 Units/Day |
p-value: <0.05Wilcoxon (Mann-Whitney)
Secondary
IV Iron Analysis
Full Analysis Population, cumulative IV Iron administration from Baseline to the end of the Safety Assessment Period (Week 52)
Time frame: 52 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Control-SAP | IV Iron Analysis | 3.83 mg/day |
| KRX-0502 (Ferric Citrate)-SAP | IV Iron Analysis | 1.87 mg/day |
p-value: <0.0001Wilcoxon (Mann-Whitney)