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

Figures & data

Table 1 Comparative safety studies of IV iron

Study	Design	Patients (n)	Comparators (n)	Major safety end points	Results
Kosch et al^Citation28	RCT, OL	59	Iron sucrose (27) Iron gluconate (28)	Hypotension, dizziness, nausea, symptoms suggestive of anaphylactoid reactions	No anaphylactic reactions, hypotension, flushing, dizziness, or nausea
Sheashaa et al^Citation31	RCT, OL	48	Iron saccharate (22) Sodium ferric gluconate (26)	Any change in clinical stress on any allergic manifestations	No changes
Sav et al^Citation30	RCT, OL	60	Iron dextran (30) Iron sucrose (30)	Hypotension, hypertension (∆ in SBP >20 mmHg during infusion), dyspnea, chest pain, flushing, urticaria, pruritus, abdominal pain, nausea, vomiting, swelling, convulsion, others	Hypotension (iron dextran, n=1; iron sucrose, n=2); dyspnea (iron dextran, n=1; iron sucrose, n=1); chest pain (iron dextran, n=1); pruritus (iron dextran, n=1; iron sucrose, n=1); swelling (iron dextran, n=1; iron sucrose, n=1); nausea (iron dextran, n=4; iron sucrose, n=4)
Ganguli et al^Citation26	RCT, OL	370	Iron dextran (122) Sodium ferric gluconate complex (124) Iron sucrose (124)	Anaphylactoid reaction (defined as wheeze, dyspnea, hypotension, urticaria, or angioedema, without any history of sensitization occurring immediately at start or within 4 hours of infusion)	Anaphylactoid reaction (iron dextran, n=3)
Hetzel et al^Citation27	RCT, OL	605	Ferumoxytol (406) Iron sucrose (199)	AEs of special interest: hypotension (moderate to severe day 1 and 48 hours post dose), composite CV end point (predefined nonfatal MI, HF, moderate-to-severe hypertension, or hospitalization due to any CV event)	AEs of special interest (ferumoxytol, n=15; iron sucrose, n=12)
Macdougall et al^Citation29	RCT, OL	162	Ferumoxytol (80) Iron sucrose (82)	AEs of special interest: hypotension, hypersensitivity, or anaphylactic reaction	Hypotension (ferumoxytol, n=3; iron sucrose, n=18), anaphylactic reaction (ferumoxytol, n=1)
Airy et al^Citation32	Retrospective database review (US Renal Data System)	14,206	Ferumoxytol (3752) Iron sucrose or ferric gluconate (10,454)	Risk of all-cause deaths, CV deaths, infectious mortality	Similar risk in ferumoxytol group versus iron sucrose/ferric gluconate group: all-cause deaths (HR, 0.95; 95% CI, 0.85–1.07), CV deaths (HR, 0.99; 95% CI, 0.83–1.19), and infectious mortality (HR, 0.88; 95% CI, 0.61–1.25)
Wang et al^Citation33	Retrospective database review (Medicare Part A and Part B)	688,183	Iron dextran (247,500) Nondextran (ferric gluconate, ferumoxytol, iron sucrose) (440,683)	Risk of anaphylaxis	Risk at first exposure: iron dextran, 85/100,000 persons; ferric gluconate, 47/100,000 persons; ferumoxytol, 34/100,000 persons; iron sucrose, 16/100,000 persons
Wetmore et al^Citation34	Retrospective database review (Medicare 20% random sample)	50,543 (non- CKD: 26,050; NDD-CKD: 24,493)	“Non-CKD + NDD-CKD” Ferumoxytol (11,647) Iron sucrose (20,898) Ferric gluconate (5319) Iron dextran (12,679)	Risk of hypersensitivity symptoms, anaphylaxis, ED encounters, hospitalizations, death	In non-CKD patients: hypersensitivity: HR 1.04 (95% CI, 0.94–1.16); anaphylaxis: HR, 1.0 (95% CI, 0.43–2.34); ED encounters (HR, 0.48; 95% CI, 0.35–0.64); hospitalizations HR, 0.64; 95% CI, 0.46–0.89); death HR, 2.00; 95% CI, 0.33–11.97)

Abbreviations: AEs, adverse events; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; ED, emergency department; HF, heart failure; HR, hazard ratio; IV, intravenous; MI, myocardial infarction; NDD, non-dialysis dependant; OL, open label; RCT, randomized controlled trial; SBP, systolic blood pressure.

Figure 1 Study design.

Abbreviations: FCM, ferric carboxymaltose; Hb, hemoglobin; IV, intravenous; TSAT, transferrin saturation.

Table 2 Key inclusion and exclusion criteria in the FIRM trial

Inclusion criteria

Exclusion criteria

• Males and females aged ≥18 years • IDA in whom iron therapy is indicated  ○ Hemoglobin <12.0 g/dL for females and <14.0 g/dL for males within 60 days of dosing “and”  ○ Transferrin saturation of ≤20% “or” ferritin of ≤100 ng/mL within 60 days of dosing • History of unsatisfactory oral iron therapy or in whom oral iron cannot be tolerated or is considered medically inappropriate • Capable of understanding and complying with the protocol requirements • All patients (male and female) of childbearing potential who are sexually active and agree to routinely use adequate contraception from randomization throughout the duration of the study

• Known hypersensitivity to any component of ferumoxytol or FCM, history of allergy to an IV iron, or history of multiple drug allergies • Dialysis-dependent CKD • Hemoglobin ≤7.0 g/dL • Pregnant, intend to become pregnant, breastfeeding, positive serum/urine pregnancy test, or not willing to use effective contraceptive precautions • Systolic BP of ≤90 mmHg or diastolic BP of ≤60 mmHg • Participation in another investigative clinical study • Weight <50 kg (110 lbs) • Any other condition or patient responsibility that may interfere with participation in the study

Abbreviations: BP, blood pressure; CKD, chronic kidney disease; FIRM, Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia; FCM, ferric carboxymaltose; IDA, iron deficiency anemia; IV, intravenous.

Table 3 Study end pointsa

Main study
Primary end point	• Incidence of moderate-to-severe hypersensitivity reactions, including anaphylaxis, and moderate-to-severe hypotension
Secondary end points	• Incidence of the composite safety end points of moderate-to-severe hypersensitivity reactions, including anaphylaxis, serious cardiovascular events, and death
	• Mean change in hemoglobin from baseline to week 5
	• Mean change in hemoglobin per milligram of iron administered
Exploratory end points	• Proportion of patients reporting treatment-emergent AEs (overall and related to study drug)
	• Proportion of patients reporting treatment-emergent serious AEs (overall and related to study drug)
	• Incidence of treatment-emergent AEs (including clinically significant laboratory results and vital signs)
	• Incidence of serious AEs
	• AEs leading to study drug discontinuation
	• Mean change in blood phosphorus and urinary phosphorus excretion from baseline to week 2
	• Incidence of hypophosphatemia defined as a blood phosphorus level of <2.0 mg/dL (<0.6 mmol/L)
Mechanisms of hypophosphatemia substudy
Exploratory end points	In addition to incidence of hypophosphatemia:
	• Changes in blood and urine markers of phosphate and bone metabolism, including:
	• Blood and urine phosphorus
	• Fractional excretion of phosphate
	• Blood calcium
	• Blood PTH
	• Blood C-terminal FGF-23
	• Blood intact FGF-23
	• Blood 25-hydroxyvitamin D
	• Blood 1,25-dihydroxyvitamin D

Note:

a Incidences of AEs and distributions of biochemical end points will be compared statistically to determine whether the data differ by treatment product.

Abbreviations: AEs, adverse events; FGF-23, fibroblast growth factor 23; PTH, parathyroid hormone.

Table 4 Clinical criteria for anaphylaxis⁷

Anaphylaxis is likely when any one of the three criteria are filleda
(1) Acute onset of an illness (minutes to hours) with involvement of:
• Skin/mucosal tissue (eg, hives, generalized itch/flush, or swollen lips/tongue/uvula)
“and” at least one of the following
• Airway compromise (eg, dyspnea, wheeze/bronchospasm, stridor, or reduced PEF)
“or”
• Reduced BP or associated symptoms (eg, hypotonia or syncope)
(2) Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
• History of severe allergic reaction
• Skin/mucosal tissue (eg, hives, generalized itch/flush, or swollen lips/tongue/uvula)
• Airway compromise (eg, dyspnea, wheeze/bronchospasm, stridor, or reduced PEF)
• Reduced BP or associated symptoms (eg, hypotonia or syncope)
• In suspected food allergy: gastrointestinal symptoms (eg, cramping abdominal pain or vomiting)
(3) Hypotension following exposure to known allergen for that patient (minutes to hours):
• Infants and children: low systolic BP (age-specific) or >30% drop in systolic BP
• Adults: systolic BP of 100 mmHg or >30% drop from their baseline

Note:

a For the FIRM study, only the first criteria were applicable because patients with a prior allergic reaction to either study medication were excluded. FIRM, Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia. Adapted from J Allergy Clin Immunol, 117(2), Sampson HA, Munoz-Furlong A, Campbell RL, et al, Second symposium on the definition and management of anaphylaxis: summary report – Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium, 391–397, Copyright (2006), with permission from Elsevier.⁷

Abbreviations: BP, blood pressure; PEF, peak expiratory flow.

KoschMBahnerUBettgerHMatzkiesFTeschnerMSchaeferRMA randomized, controlled parallel-group trial on efficacy and safety of iron sucrose (Venofer) vs iron gluconate (Ferrlecit) in haemodialysis patients treated with rHuEpoNephrol Dial Transplant20011661239124411390726

 PubMed Web of Science ®Google Scholar

SheashaaHEl-HusseiniASabryAParenteral iron therapy in treatment of anemia in end-stage renal disease patients: a comparative study between iron saccharate and gluconateNephron Clin Pract2005994c97c10115692217

 PubMedGoogle Scholar

SavTTokgozBSipahiogluMHIs there a difference between the allergic potencies of the iron sucrose and low molecular weight iron dextran?Ren Fail200729442342617497463

 PubMed Web of Science ®Google Scholar

GanguliAKohliHSJhaVGuptaKLSakhujaVThe comparative safety of various intravenous iron preparations in chronic kidney disease patientsRen Fail200830662963818661414

 PubMed Web of Science ®Google Scholar

HetzelDStraussWBernardKLiZUrbonieneAAllenLFA phase III, randomized, open-label trial of ferumoxytol compared with iron sucrose for the treatment of iron deficiency anemia in patients with a history of unsatisfactory oral iron therapyAm J Hematol201489664665024639149

 PubMed Web of Science ®Google Scholar

MacdougallICStraussWEMcLaughlinJLiZDellannaFHertelJA randomized comparison of ferumoxytol and iron sucrose for treating iron deficiency anemia in patients with CKDClin J Am Soc Nephrol20149470571224458078

 PubMed Web of Science ®Google Scholar

AiryMMandayamSMitaniAAComparative outcomes of predominant facility-level use of ferumoxytol versus other intravenous iron formulations in incident hemodialysis patientsNephrol Dial Transplant201530122068207526311216

 PubMed Web of Science ®Google Scholar

WangCGrahamDJKaneRCComparative risk of anaphylactic reactions associated with intravenous iron productsJAMA2015314192062206826575062

 PubMed Web of Science ®Google Scholar

WetmoreJBWeinhandlEDZhouJGilbertsonDTRelative incidence of acute adverse events with ferumoxytol compared to other intravenous iron compounds: a matched cohort studyPLoS One2017121e017109828135334

 PubMed Web of Science ®Google Scholar

SampsonHAMunoz-FurlongACampbellRLSecond symposium on the definition and management of anaphylaxis: summary report – Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network SymposiumJ Allergy Clin Immunol2006117239139716461139

 PubMedGoogle Scholar