Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials

Abstract

Importance: Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23-mediated hypophosphatemia.

Objective: To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose.

Design, setting, and participants: Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B.

Interventions: Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7.

Main outcomes and measures: The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35.

Results: In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, -67.0% {95% CI, -77.4% to -51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, -65.8% {95% CI, -76.6% to -49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117).

Conclusions and relevance: In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference.

Trial registration: ClinicalTrials.gov Identifiers: NCT03238911 and NCT03237065.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Wolf reported receiving personal fees from Pharmacosmos A/S during the conduct of the study and personal fees from AMAG Pharmaceuticals, Amgen, Akebia, Ardelyx, Keryx, and Luitpold Inc outside the submitted work. Dr Rubin reported receiving personal fees from Pharmacosmos A/S during the conduct of the study. Dr Achebe reported serving as a consultant to Pharmacosmos A/S and AMAG Pharmaceuticals during the conduct of the study and serving as a scientific advisory board member for Global Blood Therapeutics and Fulcrum Therapeutics and receiving personal fees from Bluebird Bio outside the submitted work. Dr Econs reported receiving personal fees from Pharmacosmos A/S during the conduct of the study. Dr Peacock reported receiving personal fees from Pharmacosmos A/S and Ultragenyx during the conduct of the study. Dr Imel reported receiving personal fees from Pharmacosmos A/S during the conduct of the study for consulting and personal fees from American Regent Inc outside the submitted work for consulting. Dr Thomsen reported being an employee of Pharmacosmos A/S and being a coinventor on pending patents related to iron isomatoside. Dr Carpenter reported receiving personal fees from Pharmacosmos A/S during the conduct of the study. Dr Weber reported receiving personal fees from Pharmacosmos A/S during the conduct of the study and grants and personal fees from Ultragenyx outside the submitted work. Dr Brandenburg reported receiving grants and personal fees from Pharmacosmos A/S and Vifor Pharma outside the submitted work. Dr Zoller reported receiving grants, personal fees, and nonfinancial support from Pharmacosmos A/S and Vifor Pharma during the conduct of the study and grants, personal fees, and nonfinancial support from Abbvie and Gilead; personal fees from Merck; personal fees and nonfinancial support from Bayer; grants from Merck Sharp & Dohme; and honoraria for lecturing from Bristol-Myers Squibb, Merz, Medice, Novartis, Pharmacosmos A/S, and Vifor Pharma outside the submitted work.

Figures

Figure 1.. Participant Flow in Trial A and Trial B Assessing the Effect of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Patients With Iron-Deficiency Anemia

aSome potential study participants had more than 1 reason for exclusion. bOne patient randomized to ferric carboxymaltose was erroneously treated with iron isomaltoside and included in the iron isomaltoside safety analysis set. cThree patients randomized to ferric carboxymaltose were not treated and not included in the safety analysis set.

Figure 2.. Hypophosphatemia in Trial A and Trial B

The leftmost columns correspond to the primary outcome of incident hypophosphatemia at any time during the trial. The remaining columns correspond to the proportions of patients with serum phosphate level less than 2.0 mg/dL at each individual time point in the safety analysis set.

Figure 3.. Changes From Baseline in Biomarkers of Mineral and Bone Homeostasis According to Iron Treatment: Pooled Data for Trial A and Trial B

Tukey box plots indicate the interquartile range (25th, 75th percentiles) as vertical boxes, medians as horizontal lines within the boxes, and observations within 1.5 times above and below the interquartile range as vertical whiskers. Outliers are not shown. P values correspond to the treatment group-by-time interaction terms from the mixed models for repeated measures analyses of change from baseline in biomarkers, as described in the Methods section. FCM indicates ferric carboxymaltose; FGF23, fibroblast growth factor 23; and IIM, iron isomaltoside 1000 (now called ferric derisomaltose).

Figure 4.. Changes From Baseline in Biomarkers of Mineral and Bone Homeostasis According to Iron Treatment: Pooled Data for Trial A and Trial B

See the Figure 3 legend for descriptions of the data markers and analysis. FCM indicates ferric carboxymaltose; FGF23, fibroblast growth factor 23; and IIM, iron isomaltoside 1000 (now called ferric derisomaltose).