A Randomized Noninferiority Trial of Intravenous Iron Isomaltoside versus Oral Iron Sulfate in Patients with Nonmyeloid Malignancies and Anemia Receiving Chemotherapy: The PROFOUND Trial

Abstract

Study objective: A safe alternative to erythropoiesis-stimulating agents to treat anemia is warranted in patients with cancer and anemia; thus the objective of this trial was to compare the efficacy and safety of intravenous (IV) iron isomaltoside with oral iron in patients with cancer and anemia by testing the noninferiority of IV versus oral iron.

Design: Phase III, prospective, open-label, comparative, randomized, noninferiority, multicenter trial.

Setting: Forty-seven hospitals or private cancer clinics in Asia, the United States, and Europe.

Patients: A total of 350 patients with cancer and anemia.

Intervention: Patients were randomized in a 2:1 ratio to either intravenous iron isomaltoside or oral iron sulfate. Patients in the iron isomaltoside group were then randomized into an infusion subgroup (single intravenous infusions of a maximum dose of 1000 mg over 15 min) or a bolus injection subgroup (bolus injections of 500 mg over 2 min).

Measurements and main results: The primary efficacy outcome was change in hemoglobin concentration from baseline to week 4. Changes in other relevant hematology variables, effect on quality of life, and safety outcomes were also assessed. The primary efficacy outcome was tested for noninferiority, whereas the remaining outcomes were tested for superiority. Iron isomaltoside was noninferior to oral iron in change in hemoglobin concentration from baseline to week 4 (difference estimate 0.016, 95% confidence interval -0.26 to 0.29, p<0.001). A faster onset of the hemoglobin response was observed with infusion of iron isomaltoside (superiority test: p=0.03 at week 1), and a sustained effect on hemoglobin level was shown in both the iron isomaltoside and oral iron treatment groups until week 24. A significant mean decrease in fatigue score was observed from baseline to week 12 in the iron isomaltoside group (p<0.001) but not in the oral iron group (p=0.057). A higher proportion of patients treated with oral iron experienced adverse drug reactions (18.8% vs 6.6%, p<0.001) and discontinued the trial due to intolerance (8.0% vs 0.9%, p=0.001). Transient hypophosphatemia (phosphate level less than 2 mg/dl) was reported at similar low frequencies among the groups: 7.1% in the iron isomaltoside infusion subgroup versus 8.5% in the iron isomaltoside bolus injection subgroup versus 5.4% in the oral iron group.

Conclusion: This trial demonstrated comparable sustained increases in hemoglobin concentration over time with both iron isomaltoside and oral iron. Iron isomaltoside was better tolerated than oral iron, and fatigue was significantly decreased with iron isomaltoside. Low rates of clinically insignificant hypophosphatemia were reported in patients receiving both treatments.

Trial registration: ClinicalTrials.gov NCT01145638.

Keywords: anemia; cancer; iron isomaltoside; iron treatment.

Figure 1

Schematic of the disposition of the study patients. FAS = full analysis set; Hb = hemoglobin; PP = per protocol.

Figure 2

Hemoglobin level, serum ferritin level, transferrin saturation, and total iron‐binding capacity over time by treatment group. Data are least‐square means (95% confidence interval [CI]) from a repeated measures analysis with strata and country as factors, treatment × week interaction, and baseline value as the covariate. The change from baseline within the treatment group is statistically significant different from 0 if the 95% CI does not include 0. *p<0.05; **p=0.001–0.01, ***p<0.001 for the comparison of iron isomaltoside versus iron sulfate.

Figure 3

Change in hemoglobin concentration by transferrin saturation subgroups (more than 20% vs 20–50%). Data are estimates (mean and 95% confidence interval) from a mixed model with repeated measures with week and strata as factors and baseline value as the covariate. BL = baseline.

Figure 4

Change in hemoglobin concentration by the two serum ferritin level subgroups (lower than 30 vs 30 μg/L or higher and lower than 100 vs 100 μg/L or higher). Data are estimates (mean and 95% confidence interval) from a mixed model with repeated measures with week, strata, and country as factors and baseline value as the covariate.