Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial

Sunil Bhandari, Philip A Kalra, Mario Berkowitz, Diogo Belo, Lars L Thomsen, Myles Wolf, Sunil Bhandari, Philip A Kalra, Mario Berkowitz, Diogo Belo, Lars L Thomsen, Myles Wolf

Abstract

Background: The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia.

Methods: In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs).

Results: A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: -0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met.

Conclusions: Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs.

Trial registration: ClinicalTrials.gov NCT02940860.

Keywords: ferric derisomaltose; iron deficiency anaemia; iron isomaltoside 1000; iron treatment.

© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.

Figures

Graphical abstract
Graphical abstract
FIGURE 1
FIGURE 1
Patient disposition.
FIGURE 2
FIGURE 2
Kaplan–Meier plot of time to first adjudicated and confirmed composite cardiovascular AE (safety analysis set).
FIGURE 3
FIGURE 3
Change in Hb (g/dL), serum ferritin (ng/mL) and TSAT (%) from baseline to Weeks 1, 2, 4 and 8 (intention-to-treat analysis set). Estimated (LS mean and SE) from a mixed model with repeated measures with treatment, strata and time as factors, treatment × time and baseline value × time interactions and baseline value as covariate. *P

References

    1. St Peter WL, Guo H, Kabadi S. et al. Prevalence, treatment patterns, and healthcare resource utilization in Medicare and commercially insured non-dialysis-dependent chronic kidney disease patients with and without anemia in the United States. BMC Nephrol 2018; 19: 67.
    1. Mehdi U, Toto RD.. Anemia, diabetes, and chronic kidney disease. Diabetes Care 2009; 32: 1320–1326
    1. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl 2012; 2: 279–335
    1. National Collaborating Centre for Chronic Conditions, Royal College of Physicians. Guideline on anaemia management in chronic kidney disease. 2015. National Institute for Clinical Excellence. Available at (21 January 2020, date last accessed)
    1. Anker SD, Comin Colet J, Filippatos G. et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361: 2436–2448
    1. Ponikowski P, van Veldhuisen DJ, Comin-Colet J. et al. CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015; 36: 657–668
    1. Jankowska EA, Tkaczyszyn M, Suchocki T. et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail 2016; 18: 786–795
    1. Hildebrandt PR, Bruun NE, Nielsen OW. et al. Effects of administration of iron isomaltoside 1000 in patients with chronic heart failure. A pilot study. Transfus Altern Transfus Med 2010; 11: 131–137
    1. Wikstrom B, Bhandari S, Barany P. et al. Iron isomaltoside 1000: a new intravenous iron for treating iron deficiency in chronic kidney disease. J Nephrol 2011; 24: 589–596
    1. Reinisch W, Altorjay I, Zsigmond F. et al. A 1-year trial of repeated high-dose intravenous iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease. Scand J Gastroenterol 2015; 50: 1226–1233
    1. Reinisch W, Staun M, Tandon RK. et al. A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED). Am J Gastroenterol 2013; 108: 1877–1888
    1. Johansson PI, Rasmussen AS, Thomsen LL.. Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial). Vox Sang 2015; 109: 257–266
    1. Bhandari S, Kalra PA, Kothari J. et al. A randomized, open-label trial of iron isomaltoside 1000 (Monofer®) compared with iron sucrose (Venofer®) as maintenance therapy in haemodialysis patients. Nephrol Dial Transplant 2015; 30: 1577–1589
    1. Kalra PA, Bhandari S, Saxena S. et al. A randomized trial of iron isomaltoside 1000 versus oral iron in non-dialysis-dependent chronic kidney disease patients with anaemia. Nephrol Dial Transplant 2016; 31: 646–655
    1. Birgegård G, Henry D, Glaspy J. et al. A randomized, noninferiority trial of intravenous iron isomaltoside versus oral iron sulfate in patients with nonmyeloid malignancies and anemia receiving chemotherapy, the PROFOUND trial. Pharmacotherapy 2016; 36: 402–414
    1. Dahlerup JF, Jacobsen BA, van der Woude J. et al. High-dose fast infusion of parenteral iron isomaltoside is efficacious in inflammatory bowel disease patients with iron-deficiency anaemia without profound changes in phosphate or fibroblast growth factor 23. Scand J Gastroenterol 2016; 51: 1332–1338
    1. Holm C, Thomsen LL, Norgaard A. et al. Single-dose intravenous iron infusion or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled trial. Vox Sang 2017; 112: 219–228
    1. Holm C, Thomsen LL, Norgaard A. et al. Single-dose intravenous iron infusion versus red blood cell transfusion for the treatment of severe postpartum anaemia: a randomized controlled pilot study. Vox Sang 2017; 112: 122–131
    1. Gybel-Brask M, Seeberg J, Thomsen LL, Johansson PI.. Intravenous iron isomaltoside improves hemoglobin concentration and iron stores in female iron-deficient blood donors: a randomized double-blind placebo-controlled clinical trial. Transfusion 2018; 58: 974–981
    1. Derman R, Roman E, Modiano MR. et al. A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia. Am J Hematol 2017; 92: 286–291
    1. Kalra PA, Bhandari S.. Safety of intravenous iron use in chronic kidney disease. Curr Opin Nephrol Hypertens 2016; 25: 529–535
    1. Agarwal R, Kusek JW, Pappas MK.. A randomized trial of intravenous and oral iron in chronic kidney disease. Kidney Int 2015; 88: 905–914
    1. Macdougall IC, White C, Anker SD. et al. Intravenous iron in patients undergoing maintenance hemodialysis. N Engl J Med 2019; 380: 447–458
    1. Charles-Edwards G, Amaral N, Sleigh A. et al. Effect of iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency. Circulation 2019; 139: 2386–2398
    1. Hoes MF, Grote Beverborg N, Kijlstra JD. et al. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail 2018; 20: 910–919
    1. Jahn MR, Andreasen HB, Futterer S. et al. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer®), a new intravenous iron preparation and its clinical implications. Eur J Pharm Biopharm 2011; 78: 480–491
    1. Haase M, Bellomo R, Haase-Fielitz A.. Novel biomarkers, oxidative stress, and the role of labile iron toxicity in cardiopulmonary bypass-associated acute kidney injury. J Am Coll Cardiol 2010; 55: 2024–2033
    1. Panth N, Paudel KR, Parajuli K.. Reactive oxygen species: a key hallmark of cardiovascular disease. Adv Med 2016; 2016: 1–12
    1. Nuhu F, Bhandari S.. Oxidative stress and cardiovascular complications in chronic kidney disease, the impact of anaemia. Pharmaceuticals (Basel) 2018; 11: 103
    1. Roger SD, Gaillard CA, Bock AH. et al. FIND-CKD Study Investigators. Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial. Nephrol Dial Transplant 2017; 32: 1530–1539
    1. Bhandari S, Kalra PA, Coyne DW.. Data confusion. Kidney Int 2015; 88: 1445
    1. Macdougall IC, Roger SD.. New data on the safety of IV iron-but why the discrepancy with FIND-CKD? Kidney Int 2015; 88: 1445–1446
    1. Agarwal R. The author replies. Kidney Int 2015; 88: 1446–1447
    1. Van Wyck DB, Mangione A, Morrison J. et al. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion 2009; 49: 2719–2728

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する