Ferric citrate hydrate for the treatment of hyperphosphatemia in nondialysis-dependent CKD

Abstract

Background and objectives: Ferric citrate hydrate is a novel iron-based phosphate binder being developed for hyperphosphatemia in patients with CKD.

Design, setting, participants, & measurements: A phase 3, multicenter, randomized, double blind, placebo-controlled study investigated the efficacy and safety of ferric citrate hydrate in nondialysis-dependent patients with CKD. Starting in April of 2011, 90 CKD patients (eGFR=9.21±5.72 ml/min per 1.73 m(2)) with a serum phosphate≥5.0 mg/dl were randomized 2:1 to ferric citrate hydrate or placebo for 12 weeks. The primary end point was change in serum phosphate from baseline to the end of treatment. Secondary end points included the percentage of patients achieving target serum phosphate levels (2.5-4.5 mg/dl) and change in fibroblast growth factor-23 at the end of treatment.

Results: The mean change in serum phosphate was -1.29 mg/dl (95% confidence interval, -1.63 to -0.96 mg/dl) in the ferric citrate hydrate group and 0.06 mg/dl (95% confidence interval, -0.20 to 0.31 mg/dl) in the placebo group (P<0.001 for difference between groups). The percentage of patients achieving target serum phosphate levels was 64.9% in the ferric citrate hydrate group and 6.9% in the placebo group (P<0.001). Fibroblast growth factor-23 concentrations were significantly lower in patients treated with ferric citrate hydrate versus placebo (change from baseline [median], -142.0 versus 67.0 pg/ml; P<0.001). Ferric citrate hydrate significantly increased serum iron, ferritin, and transferrin saturation compared with placebo (P=0.001 or P<0.001). Five patients discontinued active treatment because of treatment-emergent adverse events with ferric citrate hydrate treatment versus one patient with placebo. Overall, adverse drug reactions were similar in patients receiving ferric citrate hydrate or placebo, with gastrointestinal disorders occurring in 30.0% of ferric citrate hydrate patients and 26.7% of patients receiving placebo.

Conclusion: In patients with nondialysis-dependent CKD, 12-week treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and fibroblast growth factor-23 while simultaneously increasing serum iron parameters.

Figure 1.

90 patients were randomized in the ratio of 2:1 (JTT-751:placebo), and 69 patients completed the 12-week treatment. Four patients were withdrawn from the study without assessment at week 2 and excluded from full analysis set population. IC, informed consent; JTT-751, ferric citrate hydrate; P, serum phosphate.

Figure 2.

Serum phosphate levels decreased during 12-week treatment with JTT-751, but were unchanged in the placebo group. Data are expressed as mean±SD. EOT, end of treatment (week 12 or the observation day at the time of discontinuation); Scr, the initial screening date.

Figure 3.

Urinary phosphate excretion reduced by 50% during 12-week treatment with JTT-751. Data are expressed as median (25th or 75th percentile interval). Pre, before treatment (week −2 to the day of the start of treatment).

Figure 4.

The levels of fibroblast growth factor-23 (FGF-23) decreased during 12-week treatment with JTT-751, but increased in the placebo group. Data are expressed as median (25th or 75th percentile interval).