A Three-Period, 58-Week Safety and Efficacy Trial of KRX-0502 (ferric citrate) in Patients with End-Stage Renal Disease (ESRD) on Dialysis
This is a three period multicenter trial. It is anticipated that there will be approximately 5 to 10 centers in the United States and approximately 5 to 10 centers in Israel. Up to approximately 775 patients will be screened to randomize approximately 350 patients to the ferric citrate group or active-control group. Each of approximately 25 to 50 sites will be asked to enroll approximately 5 to 15 patients.
Ferric citrate, active control, and placebo will be considered study drugs. Eligible patients with a serum phosphorus level and amp;gt;6.0mg/dL after the Washout Period will be randomized in a 2:1 ratio to the ferric citrate group or the active-control group. For patients randomized to ferric citrate, the starting dose will be 6 caplets/day. The starting dose of phosphate binder will be the last dose that was administered immediately prior to the start of the Washout Period (if the patient remains on the same phosphate binder) or at the discretion of the PI, guided by the package insert, if the patient changes binders. However, for patients whose previous dose of phosphate binder exceeded 12 pills/day, if randomized to the active-control group, their starting dose of active-control drug will be at the discretion of the PI, but will not exceed 12 pills/day. Calcium acetate 667 mg capsules and sevelamer carbonate 800 mg tablets will be used and supplied by Keryx Biopharmaceuticals, Inc. (Keryx).
Serum phosphorus and calcium will be checked at Visit 5 (Week 1), and every two weeks during the first 12 weeks after Visit 4 (Randomization Visit), and monthly for the rest of the Safety Assessment Period. During the Efficacy Assessment Period, serum phosphorus and calcium will be drawn weekly. These values will guide study drug administration. While on study drug, the use of other phosphate binders will not be permitted. Dose adjustments in ferric citrate will be guided by a titration schedule (see Figure 2). The titration of calcium acetate and sevelamer carbonate throughout the 52-week Safety Assessment Period will be according to the current package inserts for these agents and/or at the discretion of the site PI.
* Period 1 (Washout Period). Patients will be washed out from their current phosphate binder for up to approximately two weeks. Patients who do not achieve a serum phosphorus >=6.0 mg/dL during washout will be screen failures.
* Period 2 (Safety Assessment Period). Patients will be randomized 2:1 to either the ferric citrate group or an active-control group of either calcium acetate, sevelamer carbonate, or any combination of calcium acetate and sevelamer carbonate at the discretion of the PI and/or patient and followed on their randomized assignment for safety assessments over 52 weeks. If a patient is and amp;gt; 80% compliant with 12 caplets/day of ferric citrate or 12 pills/day of calcium acetate and/or sevelamer carbonate at least 2 visits in a row, and has a serum phosphorus and amp;gt; 8.0 mg/dL, the patient will be considered a treatment failure and will stop study drug but will continue to complete all trial visits. The ferric citrate or active-control drug will be stopped and the patient will return to the care of their primary nephrologist, but will continue to be followed for all trial visits and outcomes.
* Period 3 (Efficacy Assessment Period). Patients randomized to ferric citrate will enter a four-week, randomized, open-label, placebo-controlled Efficacy Assessment Period. Patients entering the Efficacy Assessment Period will be re-randomized 1:1 to treatment with ferric citrate or placebo.
307 Long-term Extension:
Open-label, 48-wk safety extension with 45-50 centers and up 35 subjects per site totaling 400 subjects. Up to 6 subjects from this site. There will be up to 15 visits, participation could last around 48 wks (or around 56 weeks if there is a gap in time before you start taking ferric citrate).
* Males or non-pregnant, non-breast-feeding females
* Age >= 18 years
* On thrice-weekly hemodialysis or on peritoneal dialysis for at least the previous three months prior to Screening Visit (Visit 0)
* Serum phosphorus levels >=2.5 mg/dL and <=8.0 mg/dL at Screening Visit (Visit 0)
* Serum phosphorus >=6.0 mg/dL during the Washout Period (Visits 2 or 3)
* Taking 3 to 18 pills/day of calcium acetate, calcium carbonate, lanthanum carbonate, and/or sevelamer (carbonate or hydrochloride or equivalent sevelamer powder) or any other agent serving as a phosphate binder, or any combination of these agents as reported by the patient at Screening Visit (Visit 0)
* Serum ferritin <1000 micrograms/L and TSAT < 50% at the Screening Visit (Visit 0)
* Willing to be discontinued from current phosphate binder and randomized to ferric citrate or active-control group.
* Willing and able to give informed consent
* Life expectancy >1 year
307 Long-term Extension: Inclusion
Subjects must meet the following inclusion criteria to be eligible to participate in this trial:
1.Males or non-pregnant, non-breast-feeding females who participated in the Safety Assessment Period, and if eligible, the Efficacy Assessment Period of Study KRX-0502-304 and completed Keryx Study KRX-0502-304
2.Willing and able to give informed consent