Safety and efficacy of ferric citrate in patients with nondialysis-dependent chronic kidney disease

<div><p>Two randomized, placebo-controlled trials conducted in patients with nondialysis-dependent (NDD) chronic kidney disease (CKD), iron deficiency anemia, and normal or elevated serum phosphorus demonstrated that ferric citrate (FC) significantly increased hemoglobin and decreased serum phosphate concentrations. Pooling these trial results could provide a more robust evaluation of the safety and efficacy of FC in this population. We pooled results of a phase 2 (n = 149) and 3 trial (n = 233) of patients randomized and treated for up to 12 and 16 weeks, respectively. The starting dose in both trials was three 1-g (elemental iron 210 mg) tablets/day with food, up to 12 tablets/day. Doses were titrated in the phase 2 and 3 trials to lower serum phosphate concentrations to a target range (0.97–1.13 mmol/L) and to achieve a ≥10-g/L hemoglobin increase, respectively. Safety was assessed in all patients who received ≥1 dose of FC (n = 190) and placebo (n = 188). Treatment-emergent adverse events (AEs) were reported in 143 of 190 (75.3%) FC-treated and 116 of 188 (61.7%) placebo-treated patients; gastrointestinal AEs were the most frequent (94 [49.5%] vs. 52 [27.7%], respectively). Specific events reported in >5% of patients (FC vs. placebo, respectively) included discolored feces (41 [21.6%] vs. 0 [0.0%]), diarrhea (39 [20.5%] vs. 23 [12.2%]), constipation (35 [18.4%] vs. 19 [10.1%]), and nausea (18 [9.5%] vs. 8 [4.3%]). Twenty FC-treated (10.5%) and 21 placebo-treated patients (11.2%) experienced a serious AE. Two patients (1.1%) died in each group. A pooled efficacy assessment demonstrated a consistent hemoglobin rise and modest serum phosphate decline, with few excursions below the normal range. When used for treatment of patients with NDD-CKD, FC contributes to gastrointestinal AEs at higher rates than placebo, while simultaneously correcting two of the principal metabolic manifestations of CKD (iron deficiency anemia and relative hyperphosphatemia).</p></div

Pooled changes from baseline in (A) Hgb, (B) TSAT, (C) ferritin, and (D) serum phosphate over the 12-week randomized treatment period in the phase 2 trial and the first 12 of 16 weeks of the randomized treatment period in the phase 3 trial.

<p>Changes were analyzed using mixed model for repeated measures with restricted maximum likelihood, with treatment (ferric citrate vs. placebo), study, visit, and treatment-by-visit interaction as fixed effects; baseline as a covariate; and patient as a random effect. Study-by-treatment interaction <i>P</i> value was obtained from the same model with the addition of the study-by-treatment interaction term. Hgb, hemoglobin; LSM, least-squares mean; SE, standard error; TSAT, transferrin saturation.</p

Gastrointestinal adverse events by study week.

<p>Discontinuations because of gastrointestinal treatment-emergent adverse events during the randomized periods (ferric citrate [5.3%] vs. placebo [1.1%]).</p

CONSORT diagram.

<p>^aNine patients were enrolled in both studies; of these, three were randomized to the same treatment in both trials and only their data from the phase 3 trial were included, and six patients who were randomized to different treatments contributed data from each trial but were only counted once in the total number of enrolled subjects.</p

Baseline characteristics (pooled data).

<p>Baseline characteristics (pooled data).</p