Comparative safety of intravenous Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia: rationale and study design of a randomized double-blind study with a focus on acute hypersensitivity reactions

Abstract

BackgroundIntravenous (IV) iron is often used to treat iron deficiency anemia in patients who are unable to tolerate or are inadequately managed with oral iron. However, IV iron treatment has been associated with acute hypersensitivity reactions. The comparative risk of adverse events (AEs) with IV iron preparations has been assessed by a few randomized controlled trials, which are most often limited by small patient numbers, which lack statistical power to identify differences in low-frequency AE such as hypersensitivity reactions.Materials and methodsFerumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia (FIRM) is a randomized, double-blind, international, multicenter, Phase III study designed to compare the safety of ferumoxytol and ferric carboxymaltose (FCM). The study includes adults with hemoglobin <12.0 g/dL (females) or <14.0 g/dL (males), transferrin saturation ≤20% or ferritin ≤100 ng/mL within 60 days of dosing, and a history of unsatisfactory or nontolerated oral iron therapy or in whom oral iron therapy is inappropriate. Patients are randomized (1:1) to ferumoxytol 510 mg or FCM 750 mg, each given intravenously on days 1 and 8. Primary end points are the incidence of moderate-to-severe hypersensitivity reactions, including anaphylaxis, and moderate-to-severe hypotension. All potential hypersensitivity and hypotensive reactions will be adjudicated by a blinded, independent Clinical Events Committee. A secondary safety end point is the composite frequency of moderate-to-severe hypersensitivity reactions, including anaphylaxis, serious cardiovascular events, and death. Secondary efficacy end points include mean change in hemoglobin and mean change in hemoglobin per milligram of iron administered from baseline to week 5. Urinary excretion of phosphorus and the occurrence of hypophosphatemia after IV iron administration will be examined as well as the mechanisms of such hypophosphatemia in a substudy.ConclusionFIRM will provide data on the comparative safety of ferumoxytol and FCM, two IV iron preparations with similar dosing schedules, focusing on moderate-to-severe hypersensitivity reactions, including anaphylaxis, and moderate-to-severe hypotension. The study plans to enroll 2000 patients and is expected to complete in 2017.

Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial

“…Study IDA‐304 (the FIRM study: a phase 3, randomized, multicenter, double‐blind, safety study of Ferumoxytol compared to ferrIc carboxymaltose [FCM] for the treatment of IDA) was designed to formally investigate these concerns by prospectively adjudicating the rates of HSRs and related adverse events (AEs) in 2 approved and available intravenous iron formulations, ferumoxytol and FCM, using dosing regimens indicated for treatment of IDA. Additionally, although previously considered transient and without clinical sequelae, hypophosphatemia is gaining recognition as potentially important . Therefore, we included an evaluation of hypophosphatemia in this large, phase 3, randomized, double‐blind study.…”

Intravenous iron use in pregnancy: Ironing out the issues and evidence

“…The risk with FCM (Ferinject®) has been reported to be ~0.1%, with several deaths (in the non‐obstetric population) attributed to FCM use . In addition to hypersensitivity reactions/anaphylaxis, other risks associated with IV iron include the potential for inducing iron overload, oxidative stress, infection, and severe hypophosphataemia, among others …”

The Story of Ferumoxytol: Synthesis Production, Current Clinical Applications, and Therapeutic Potential

“…But it is vital to pay close attention to hypersensitivity reactions (HSRs) (such as pruritus, rash, urticaria, and wheezing) and hypotension caused by intravenous administration. [ 19 b, 39 ]…”