A randomized, controlled, open label non-inferiority trial of intravenous ferric carboxymaltose versus iron sucrose in patients with iron deficiency anemia in China

Abstract

Iron deficiency (ID) and ID anemia (IDA) pose significant public health concerns in China. Although iron sucrose (IS) treatment is well-established in the country, ferric carboxymaltose (FCM) offers the advantage of higher doses and fewer infusions. This open label, randomized, controlled, non-inferiority trial was conducted at multiple sites in China to compare the outcomes of FCM (maximum of 2 doses, 500 or 1000 mg iron) and IS (up to 11 infusions, 200 mg iron) treatments in subjects with IDA. The primary endpoint was the achievement of hemoglobin (Hb) response (an increase of ≥2 g/dL from baseline) within 8 weeks, whereas secondary endpoints included changes in Hb, transferrin saturation, and serum ferritin levels. Among the 371 randomized subjects, a similar percentage of subjects treated with FCM and IS achieved Hb-response (FCM 99.4%, IS 98.3%), thereby confirming the non-inferiority of FCM compared with IS (difference 1.12 (−2.15, 4.71; 95% confidence interval (CI))). Furthermore, a significantly higher proportion of FCM-treated subjects achieved early Hb-response at Week 2 (FCM 85.2%, IS 73.2%; difference 12.1 (3.31, 20.65; 95% CI)). Additionally, the increase in TSAT and serum ferritin levels from baseline was significantly greater at all time points for FCM-treated subjects. The safety profiles of FCM and IS were comparable, with the exception of transient hypophosphatemia and pyrexia, which are consistent with FCM’s known safety profile. In conclusion, FCM proves to be an efficacious treatment for IDA, providing faster Hb-response and correction of ID with fewer administrations than IS.

Keywords

iron deficiency / anemia / intravenous iron / ferric carboxymaltose / iron sucrose / Hb response / early response

References

[1] Kassebaum NJ; GBD 2013 Anemia Collaborators. The global burden of anemia. Hematol Oncol Clin North Am 2016; 30(2): 247–308

[2] GBD 2019 Diseases, Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020; 396(10258): 1204–1222

[3] WorldHealth Organization. Iron deficiency anaemia assessment, prevention and control. A guide for programme managers. 2001. Available at the website of WHO

[4] Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn’s disease. Aliment Pharmacol Ther 2006; 24(11–12): 1507–1523

[5] Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleve Clin J Med 2006; 73(3): 289–297

[6] Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, Borodulin-Nadzieja L, Banasiak W, Polonski L, Filippatos G, McMurray JJ, Anker SD, Ponikowski P. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 2010; 31(15): 1872–1880

[7] Aapro M, Österborg A, Gascón P, Ludwig H, Beguin Y. Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of i.v.iron. Ann Oncol 2012; 23(8): 1954–1962

[8] Lopes MB, Tu C, Zee J, Guedes M, Pisoni RL, Robinson BM, Foote B, Hedman K, James G, Lopes AA, Massy Z, Reichel H, Sloand J, Waechter S, Wong MMY, Pecoits-Filho R. A real-world longitudinal study of anemia management in non-dialysis-dependent chronic kidney disease patients: a multinational analysis of CKDopps. Sci Rep 2021; 11(1): 1784

[9] Beguin Y, Jaspers A. Iron sucrose—characteristics, efficacy and regulatory aspects of an established treatment of iron deficiency and iron-deficiency anemia in a broad range of therapeutic areas. Expert Opin Pharmacother 2014; 15(14): 2087–2103

[10] Muñoz M, Martín-Montañez E. Ferric carboxymaltose for the treatment of iron-deficiency anemia. [corrected]. Expert Opin Pharmacother 2012; 13(6): 907–921

[11] WorldHealth Organization. The global prevalence of anaemia in 2011. 2015. Available at the website of WHO

[12] ZhuYPLiao QK; Collaborative Study Group for “The Epidemiological Survey of Iron Deficiency in Children in China”. Prevalence of iron deficiency in children aged 7 months to 7 years in China. Chin J Pediatr (Zhonghua Er Ke Za Zhi) 2004; 42(12): 886–891 (in Chinese)

[13] WangLSun JHuangJLiHLiJ TangYPiao WChenDHuoJ. Iron status of first-year junior high school students in rural boarding school among nine provinces in China. J Hyg Res (Wei Sheng Yan Jiu) 2016; 45(6): 911–937 (in Chinese)

[14] ZhanJYZheng SSDongWWShaoJ. Predictive values of routine blood test results for iron deficiency in children. Chin J Pediatr (Zhonghua Er Ke Za Zhi) 2020; 58(3): 201–205 (in Chinese)

[15] LiaoQK; Chinese ChildrenPregnantWomen & Premenopausal Women Iron Deficiency Epidemiological Survey Group. Prevalence of iron deficiency in pregnant and premenopausal women in China: a nationwide epidemiological survey. Chin J Hematol (Zhonghua Xue Ye Xue Za Zhi) 2004; 25(11): 653–657 (in Chinese)

[16] Dignass AU, Gasche C, Bettenworth D, Birgegård G, Danese S, Gisbert JP, Gomollon F, Iqbal T, Katsanos K, Koutroubakis I, Magro F, Savoye G, Stein J, Vavricka S; European Crohn’s, Colitis OrganisationECCO. European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases. J Crohn’s Colitis 2015; 9(3): 211–222

[17] KidneyDisease: Improving Global Outcomes (KDIGO). KDIGO clinical practice guideline for anemia in CKD. Kidney Int 2012; 2 (Suppl 2012)(4): 279–335

[18] NationalComprehensive Cancer Network. Management of cancer- and chemotherapy-induced anemia in hematopoietic growth factors. 2021. Available at the website of National Comprehensive Cancer Network

[19] Pavord S, Daru J, Prasannan N, Robinson S, Stanworth S, Girling J; BSH Committee. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2020; 188(6): 819–830

[20] Sharma R, Stanek JR, Koch TL, Grooms L, O’Brien SH. Intravenous iron therapy in non-anemic iron-deficient menstruating adolescent females with fatigue. Am J Hematol 2016; 91(10): 973–977

[21] Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, Dhingra U, Kabole I, Deb S, Othman MK, Kabole FM. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 2006; 367(9505): 133–143

[22] Ganz T. Anemia of inflammation. N Engl J Med 2019; 381(12): 1148–1157

[23] Lyseng-Williamson KA, Keating GM. Ferric carboxymaltose: a review of its use in iron-deficiency anaemia. Drugs 2009; 69(6): 739–756

[24] Vaucher P, Druais PL, Waldvogel S, Favrat B. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. CMAJ 2012; 184(11): 1247–1254

[25] Nowak A, Angelillo-Scherrer A, Betticher D, Dickenmann M, Guessous I, Juillerat P, Korte W, Neuner-Jehle S, Pfister O, Surbek D, Battegay E, Steurer J. Swiss Delphi study on iron deficiency. Swiss Med Wkly 2019; 149: w20097

[26] Martin-Malo A, Borchard G, Flühmann B, Mori C, Silverberg D, Jankowska EA. Differences between intravenous iron products: focus on treatment of iron deficiency in chronic heart failure patients. ESC Heart Fail 2019; 6(2): 241–253

[27] ViforPharma. SmPC Ferinject (ferric carboxymaltose). 2021. Available at the related website

[28] ViforPharma. SmPC Venofer (iron sucrose). 2020. Available at the related website

[29] GanzoniAM. Intravenous iron-dextran: therapeutic and experimental possibilities. Schweiz Med Wochenschr 1970; 100(7): 301–303 (in German)

[30] Seid MH, Butcher AD, Chatwani A. Ferric carboxymaltose as treatment in women with iron-deficiency anemia. Anemia 2017; 2017: 9642027

[31] Onken JE, Bregman DB, Harrington RA, Morris D, Buerkert J, Hamerski D, Iftikhar H, Mangoo-Karim R, Martin ER, Martinez CO, Newman GE, Qunibi WY, Ross DL, Singh B, Smith MT, Butcher A, Koch TA, Goodnough LT. Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial. Nephrol Dial Transplant 2014; 29(4): 833–842

[32] Naqash A, Ara R, Bader GN. Effectiveness and safety of ferric carboxymaltose compared to iron sucrose in women with iron deficiency anemia: phase IV clinical trials. BMC Womens Health 2018; 18(1): 6

[33] Jose A, Mahey R, Sharma JB, Bhatla N, Saxena R, Kalaivani M, Kriplani A. Comparison of ferric carboxymaltose and iron sucrose complex for treatment of iron deficiency anemia in pregnancy—randomised controlled trial. BMC Pregnancy Childbirth 2019; 19(1): 54

[34] Beshara S, Sörensen J, Lubberink M, Tolmachev V, Långström B, Antoni G, Danielson BG, Lundqvist H. Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose in anaemic patients using positron emission tomography. Br J Haematol 2003; 120(5): 853–859

[35] Bailie GR. Efficacy and safety of ferric carboxymaltose in correcting iron-deficiency anemia: a review of randomized controlled trials across different indications. Arzneimittelforschung 2010; 60(6a): 386–398

[36] Evstatiev R, Marteau P, Iqbal T, Khalif IL, Stein J, Bokemeyer B, Chopey IV, Gutzwiller FS, Riopel L, Gasche C; FERGI Study Group. FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology 2011; 141(3): 846–853. e1–2

[37] Rozen-Zvi B, Gafter-Gvili A, Zingerman B, Levy-Drummer RS, Levy L, Mor E, Gafter U, Rahamimov R. Intravenous iron supplementation after kidney transplantation. Clin Transplant 2012; 26(4): 608–614

[38] Okam MM, Koch TA, Tran MH. Iron supplementation, response in iron-deficiency anemia: analysis of five trials. Am J Med 2017; 130(8): 991.e1–991.e8

[39] Ikuta K, Hanashi H, Hirai K, Ota Y, Matsuyama Y, Shimura A, Terauchi M, Momoeda M. Comparison of efficacy and safety between intravenous ferric carboxymaltose and saccharated ferric oxide in Japanese patients with iron-deficiency anemia due to hypermenorrhea: a multi-center, randomized, open-label noninferiority study. Int J Hematol 2019; 109(1): 41–49

[40] Koduru P, Abraham BP. The role of ferric carboxymaltose in the treatment of iron deficiency anemia in patients with gastrointestinal disease. Therap Adv Gastroenterol 2016; 9(1): 76–85

[41] Scott LJ. Ferric carboxymaltose: a review in iron deficiency. Drugs 2018; 78(4): 479–493

[42] Favrat B, Balck K, Breymann C, Hedenus M, Keller T, Mezzacasa A, Gasche C. Evaluation of a single dose of ferric carboxymaltose in fatigued, iron-deficient women—PREFER a randomized, placebo-controlled study. PLoS One 2014; 9(4): e94217

[43] Hardy S, Vandemergel X. Intravenous iron administration and hypophosphatemia in clinical practice. Int J Rheumatol 2015; 2015: 468675

[44] Bellos I, Frountzas M, Pergialiotis V. Comparative risk of hypophosphatemia following the administration of intravenous iron formulations: a network meta-analysis. Transfus Med Rev 2020; 34(3): 188–194

[45] Glaspy JA, Lim-Watson MZ, Libre MA, Karkare SS, Hadker N, Bajic-Lucas A, Strauss WE, Dahl NV. Hypophosphatemia associated with intravenous iron therapies for iron deficiency anemia: a systematic literature review. Ther Clin Risk Manag 2020; 16: 245–259

[46] Subramanian R, Khardori R. Severe hypophosphatemia. Pathophysiologic implications, clinical presentations, and treatment. Medicine (Baltimore) 2000; 79(1): 1–8

[47] Bager P, Hvas CL, Dahlerup JF. Drug-specific hypophosphatemia and hypersensitivity reactions following different intravenous iron infusions. Br J Clin Pharmacol 2017; 83(5): 1118–1125

[48] Wolf M, Chertow GM, Macdougall IC, Kaper R, Krop J, Strauss W. Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight 2018; 3(23): e124486

[49] Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Lüscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361(25): 2436–2448

[50] Qunibi WY, Martinez C, Smith M, Benjamin J, Mangione A, Roger SD. A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients. Nephrol Dial Transplant 2011; 26(5): 1599–1607

Acknowledgements

We express our gratitude to all principal investigators at the participating sites (Table S2) and acknowledge the contributions of the entire study staff. The funding for medical writing support was provided by Vifor Pharma, Glattbrugg, Switzerland.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1001-2 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Emanuele Noseda, Bernard Roubert, Matthieu Marty, Anna Mezzacasa, and Udo Michael Göring are employees of Vifor Pharma, Glattbrugg, Switzerland. Jie Jin and Zhihua Ran declare no conflicts of interest.

The study was approved by the appropriate institutional and/or national research ethics committee (see Table S1 for names of the ethics committees) and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for their inclusion in the study.

RIGHTS & PERMISSIONS

2023 Higher Education Press