1 Introduction
Iron deficiency (ID) and ID anemia (IDA) are significant global health issues, with the former being the leading cause of anemia [
1,
2]. Women of reproductive age (pregnant and non-pregnant) and children have the highest prevalence of anemia [
3]. Additionally, patients with chronic diseases, such as chronic kidney disease, chronic heart failure (CHF), or inflammatory bowel disease are more susceptible to ID/IDA. Notably, ID alone is an independent risk factor for mortality in patients with CHF [
4–
10]. In China, the prevalence of IDA varies from 19.9% to 28.9%, depending on the population studied, and is considered a moderate public health concern [
11]. The reported prevalence of ID without anemia in China ranges from 9.1% to 44.7% in children [
12–
14], 34.4% in premenopausal non-pregnant women, and 42.6% in pregnant women [
15]. The recommended treatment for ID/IDA [
16–
19] is iron supplementation unless iron depletion is therapeutically necessary [
20] or considered protective against parasitic infestation [
21]. Prevention and correction of mild IDA often involve oral iron supplementation through iron-rich foods or oral iron medication. However, oral iron is generally ineffective in populations with underlying chronic diseases that may impede intestinal iron absorption [
22]. Moreover, oral iron salts, such as ferrous sulfate, are associated with significant gastrointestinal side effects and low treatment adherence [
23,
24]. Thus, intravenous (IV) iron is the preferred treatment for patients with ID/IDA who require rapid iron repletion, large total iron doses or do not tolerate or respond to oral iron [
16,
19,
25]. Newer iron formulations, such as ferric carboxymaltose (FCM), allow for higher doses with fewer infusions compared with formulations, such as iron sucrose (IS) or ferric gluconate [
26]. Although the efficacy and safety of FCM have been studied in various populations and conditions, this study is the first to focus solely on subjects and sites in China to evaluate the non-inferiority of FCM compared with IS in correcting IDA.
2 Materials and methods
2.1 Design and setting
The study was a multicenter trial conducted at 19 study sites in China, designed as an open-label, randomized, controlled trial to assess the non-inferiority of IV FCM (Ferinject®; Vifor Pharma; Glattbrugg, Switzerland [
27]) compared with IS (Venofer®, Vifor Pharma, Glattbrugg, Switzerland [
28]) in improving Hb levels in patients with IDA. The study was funded and designed by Vifor International Inc and conducted by Tigermed Consulting Co Ltd. The study protocol underwent review and approval by the relevant regulatory authorities and ethics committees (Table S1) in accordance with local regulations. It was registered at ClinicalTrials.gov (NCT03591406) and conducted in compliance with the
Declaration of Helsinki of 1975, as revised in 2000, and the International Council for Harmonisation Guidelines for Good Clinical Practice, as well as local and country-specific requirements. Prior to inclusion in the study, all participants provided written informed consent.
2.2 Study population
Subjects who presented with IDA and provided signed and dated informed consent underwent screening within 7 days before the initial treatment administration. Eligible subjects were aged 18 years or older and met the following criteria: Hb levels < 11 g/dL for females or < 12 g/dL for males, microcytic hypochromic anemia (mean corpuscular Hb concentration < 320 g/L, mean corpuscular volume (MCV) < 80 fL, mean corpuscular Hb (MCH) < 27 pg), transferrin saturation (TSAT) < 16%, and serum ferritin < 100 µg/L in the presence of underlying inflammatory conditions, as indicated by high-sensitivity C-reactive protein (hsCRP) above the normal range (1–3 mg/L), or serum ferritin < 15 µg/L in the absence of inflammatory conditions (hsCRP within the normal range). Exclusion criteria included known hypersensitivities to the administered products, history of iron storage diseases, history or clinical findings of iron utilization disorders or hematuria, hemoglobinopathies, vitamin B12 or folic acid deficiency at the time of the study, allergic predispositions, planned surgery with anticipated blood loss resulting in an estimated Hb drop > 2 g/dL within 3 months post-randomization, known malignancies (except basal or squamous cell carcinoma of the skin or cervical-epithelial neoplasia), current or planned hemodialysis within 3 months, history of IV iron therapy, erythropoiesis-stimulating agent therapy, and/or blood transfusion within 4 weeks before baseline, use of oral iron or iron-containing products, including herbal medicines for iron supplementation (> 75 mg iron/day), within 7 days before baseline, body weight < 35 kg, chronic liver disease, screening aspartate aminotransferase (ALT) or alanine aminotransferase (AST) greater than three times the upper limit of normal, ongoing infections, pregnancy or lactation, unwillingness to use adequate contraceptive methods in female subjects during the study and up to one month after the last dose, and males planning to father a child within 7 days of the last drug administration. Additionally, any disorder or disability that compromised the ability to consent to and/or comply with study procedures was also an exclusion criterion.
2.3 Randomization and intervention
At the baseline visit, eligible subjects were randomized in a 1:1 ratio after an initial screening period of up to 7 days. Randomization was done according to a predefined computer-generated randomization list using an interactive response technology (IRT) system. Block randomization (block size 4), and stratification was performed by site, allowing a maximum of 15 blocks per site. Subjects were assigned to receive either FCM or IS based on the randomization. The dosing of FCM was determined based on the subject’s Hb and body weight (BW) at screening (Tab.1). FCM was administered as undiluted injections or diluted infusions. For the 500 mg dose, FCM was diluted in 100 mL saline and administered over at least 5 minutes. For the 1000 mg dose, FCM was diluted in 250 mL saline and administered over at least 15 minutes. The IS dosage regimen was determined based on the individual iron deficit calculated using the Ganzoni formula. The total iron dose = （BW × (target Hb – actual Hb)） × 2.4 + iron storage depot
, considering a target Hb of 15 g/dL and an iron storage depot of 500 mg [
29]. The calculated value was rounded to the nearest 200 mg, and IS was administered as single 200 mg iron doses, with a maximum of three doses per week and up to a total of 11 injections. IS was administered either via slow IV push injection at a rate of 1 mL undiluted solution per minute (not exceeding 60 minutes) or as a drip infusion of diluted product (with a maximum of 10 mL per 200 mL saline) for at least 30 minutes (not exceeding 60 minutes). The first post-dose blood samples were collected two weeks after the administration of the first dose, followed by subsequent samples every two weeks until the eighth week.
2.4 Outcomes and follow-up
The primary efficacy endpoint for this study was the percentage of subjects who achieved an increase in Hb of ≥ 2 g/dL from baseline at any visit up to Week 8. Secondary efficacy endpoints included the percentage of subjects who achieved an increase in Hb and the change in Hb, TSAT, and serum ferritin from baseline to Weeks 2, 4, 6, and 8. Safety assessment involved monitoring changes in vital signs (e.g., blood pressure, temperature, and heart rate), laboratory parameters (e.g., iron status, hematology), clinical chemistry including serum phosphate levels, at each visit. Electrocardiograms (ECG) and physical examinations were conducted at screening and at either Week 4 or Week 8, respectively. Treatment-emergent adverse events (TEAE), defined as adverse events (AEs) that occurred or increased in severity after the first dose of the study drug, were monitored at each visit. The intensity/severity of AEs were categorized as “mild”, “moderate”, or “severe” by the investigators, and events were classified as either “related” or “unrelated” to the study drug.
2.5 Statistical analysis
The sample size estimation was conducted to demonstrate the non-inferiority of the difference in the proportion of subjects achieving an increase in Hb of ≥ 2 g/dL at any time up to Week 8 between the FCM and IS groups. With a 1-sided alpha level of 2.5%, a non-inferiority margin of −15% and an anticipated responder proportion of 70% for IS, a sample size of 147 subjects per group was estimated to yield 80% power to establish the non-inferiority of FCM to IS. To account for an estimated 20% dropout rate, the total planned sample size was set at 368 subjects, with 184 subjects per group. Three analysis sets were reported. The safety set (SS) included all randomized subjects who received at least one dose of study medication. The full analysis set (FAS) comprised subjects who were randomized to a treatment group, received at least one dose of study treatment, and had at least one baseline and post-baseline value (e.g., Hb, ferritin, TSAT). The per-protocol set (PPS) consisted of subjects who completed the study, adhered to the study drug compliance of 80%–120%, and had no major protocol violations.
Non-inferiority of FCM compared to IS was assessed by analyzing the difference in the proportion of subjects in the PPS who achieved the primary endpoint. The analysis was conducted using the one-sided Wilson score test with a 97.5% confidence interval (CI) and a −15% non-inferiority margin. The non-inferiority margin was set to ensure that the treatment effect of FCM (70 − 15 = 55) was greater than 1.5 times the upper limit of the 95% CI of responders to Standard Medical Care (SMC) in a previous study (1VIT07017) comparing FCM to SMC in subjects with IDA due to heavy uterine bleeding or post-partum (where Hb increase ≥ 2 g/dL at Day 30 was observed in 22% of patients (95% CI 11%–33%); → upper CI limit × 1.5 = 49.5) [
30]. To compare the ID correction at Week 2 between the treatment groups, logistic regression was performed, including the covariates of baseline ferritin, baseline TSAT, and site. The calculation of
P values for differences in AE rates between the treatment groups was done using a two-sided Fisher Exact test.
A sensitivity analysis was performed on the FAS. Secondary efficacy endpoints were analyzed using the FAS and the PPS. All statistical tests were two-sided with a significance level of 5% and a 95% CI. Analysis of variance or covariance models were used for continuous secondary endpoints, and the repeated measure procedures was used when necessary. Descriptive statistics included the mean and standard deviation (SD) or median with interquartile range (Q1, Q3). All summary statistics and statistical analyses were performed using SAS® Version 9.2 or later (SAS Institute, Cary, NC, USA).
3 Results
3.1 Subject disposition and baseline characteristics
Out of the initial 569 screened subjects, a total of 371 subjects were enrolled and randomly assigned to receive either FCM or IS (Fig.1). Prior to treatment, four subjects (two in each group) withdrew their consent, resulting in 367 subjects who received treatment (PPS: FCM 177, IS 178; SS: FCM 187, IS 180; FAS: FCM 185, IS 180). The trial was successfully completed by 95.7% of the subjects, with a completion rate of 96.3% in the FCM group and 95.1% in the IS group. No subjects were lost to follow-up. Demographic data and baseline characteristics, including Hb, serum ferritin, TSAT and hsCRP, were representative of a study population with IDA and were comparable between the FCM and IS groups (Tab.2). The majority of subjects (93.2%) were female, and the mean (SD) age of the participants was 39.4 (9.3) years. Menorrhagia, inadequate diet, gastrointestinal disorders, and IDA of unknown origin were the most frequent causes of IDA among the subjects. Unspecified herbal and traditional medicines were the most commonly reported concomitant or prior medications used by subjects in both treatment groups, followed by antibacterial medications for systemic use. The use of concomitant medications was slightly higher in the FCM group (Tab.2).
3.2 Hb response rate at any time until Week 8: primary end point
In the PPS, the percentage of subjects who achieved an increase in Hb of at least 2 g/dL from baseline was 99.4% (176 subjects) in the FCM group and 98.3% (175 subjects) in the IS group. The difference in response rates was 1.12% (95% CI –2.15, 4.71), with the lower limit of the 95% CI being greater than the pre-defined non-inferiority margin of –15%. This finding confirms the non-inferiority of FCM compared to IS in terms of Hb response (PPS). The non-inferiority of FCM versus IS was also confirmed in the FAS (Tab.3).
3.3 Hematological response and iron status
The percentage of subjects who achieved an increase in Hb levels of at least 2 g/dL was similar between the FCM and IS groups at Week 8 (FCM 98.9%, IS 98.8%). However, statistically significant differences were observed at earlier time points, with the largest difference seen at Week 2 (FCM 85.2%, IS 73.2%; difference 12.06% (3.31, 20.65)) (Tab.4). Hb levels continued to increase until Week 8 in the FCM (12.83 ± 1.17 g/dL) and IS (12.93 ± 1.07 g/dL) groups (Fig.2). Repeated measures analysis demonstrated that FCM-treated subjects had a significantly higher likelihood of achieving an increase in Hb levels from baseline by Week 2 compared to IS-treated subjects (P < 0.001; Fig.3). TSAT levels exhibited a sharp increase by Week 2 (FCM 34.87 ± 12.05%; IS 24.94 ± 19.44%) in both groups and remained within the range of 25%–35% until Week 8 (FCM 30.26 ± 11.28%, IS 25.55 ± 7.81%; Fig.2). The change in TSAT from baseline was significantly greater in the FCM group compared to the IS group at each follow-up visit, up until Week 8 (P < 0.001; Fig.3). Serum ferritin levels showed a rapid increase by Week 2 (FCM 757 ± 329 µg/L; IS 388 ± 158 µg/L) and a subsequent overall decrease in both treatment groups until Week 8 (FCM 205 ± 148 µg/L; IS 146 ± 90 µg/L; Fig.2). The mean change in serum ferritin levels from baseline was significantly greater in the FCM group at each visit (P < 0.001; Fig.3). Logistic regression analysis of ID correction demonstrated that subjects in the FCM treatment group had a higher likelihood of achieving ID correction at Week 2 compared to the IS treatment group (98.4% vs. 79.1%, P < 0.001; Tab.5). Similar results were observed in the PPS for all parameters analyzed.
3.4 Drug exposure
The cumulative iron dose administered was comparable between the FCM and IS treatment groups (FCM 1521 ± 231 mg; IS 1464 ± 325 mg). However, the duration of drug exposure differed, with the FCM group having a shorter exposure period (8.2 ± 2.94 days) compared with the IS group (15.6 ± 4.28 days). In the FCM group, the maximum number of injections or infusions administered was 3, whereas in the IS group, it was 11. More than 90% of subjects in the FCM group received one or two injections/infusions, while over 90% of subjects in the IS group required at least six injections/infusions.
3.5 Tolerability
Overall, no new or unexpected treatment-emergent adverse events (TEAEs) were observed in this study. The incidence of TEAEs was slightly higher in the FCM group, with 66.3% of subjects experiencing TEAEs (302 TEAEs), compared to 56.1% of subjects in the IS group (190 TEAEs) (Tab.6). A total of 24 TEAEs resulted in modification or discontinuation of the study drug, with 4.3% of subjects in the FCM group (20 TEAEs) and 1.7% in the IS group (4 TEAEs) being affected. Most of these TEAEs were of mild intensity (18 out of 24) and were considered related to the treatment. All TEAEs resolved by the end of the study. No relevant changes in vital signs or any deaths were reported in either treatment group. Furthermore, the ECG data did not reveal any clinically significant changes in either group.
The most frequently reported TEAEs included decreased urine phosphorus, hypophosphatemia, and abnormal hepatic function. The majority of TEAEs were categorized as mild (56.1% in the FCM group, 47.8% in the IS group) or moderate (8.0% in the FCM group, 7.8% in the IS group). The frequency of TEAEs was similar between the two treatment groups, except for hypophosphatemia, decreased blood phosphorus, and pyrexia, which are known side effects of FCM (Tab.6). At Week 2, mean phosphorus levels decreased to 0.59 ± 0.19 mmol/L in the FCM group and 0.93 ± 0.23 mmol/L in the IS group. Four subjects (2.1%) in the FCM group had phosphorus levels below 0.3 mmol/L, which is categorized as severe hypophosphatemia. However, none of these subjects required medical intervention for this condition, and phosphorus levels started to increase towards the end of the study for all affected subjects.
Three subjects in the study reported serious treatment-related TEAEs, with one subject in the FCM group and two subjects in the IS group (Tab.6). In both treatment groups, one subject experienced a TEAE of anaphylactic reaction, which led to drug interruption, withdrawal, and early termination of the study. In the FCM group, a female subject who received a 1000 mg iron infusion on Day 1 developed a moderate intensity anaphylactic reaction, which was assessed as probably related to the study drug. The reaction occurred three hours after the infusion. The subject received treatment with huoxiangzhengqi (a traditional Chinese medicine), dexamethasone, calcium gluconate, acetaminophen, and loratadine, and recovered on Day 5. In the IS group, a female subject who received a 100 mg iron infusion on Day 1 experienced an anaphylactic shock of moderate intensity, which was assessed as probably related to the study drug. No specific treatment was reported, but the subject recovered from the anaphylactic shock. Another female subject in the IS group had a serious TEAE of moderate intensity pyrexia on Day 1, along with a serious unrelated TEAE of urinary tract infection. The pyrexia was considered possibly related to the study drug. The subject received oral paracetamol for the pyrexia on Day 1 and IV moxifloxacin for the urinary tract infection. The subject recovered on Day 2 and 3, respectively.
4 Discussion
The present study provides evidence that supports the non-inferior efficacy and safety of FCM compared to IS in Chinese subjects. The response rate of Hb (≥ 2 g/dL) at Week 8 was comparable between the FCM and IS groups. However, FCM-treated subjects exhibited a significantly higher response rate as early as Week 2 compared to those in the IS group. Furthermore, FCM-treated subjects were more likely to achieve ID correction within the first two weeks, as indicated by transferrin saturation (TSAT) levels of ≥ 16% and serum ferritin levels of ≥ 15 or ≥ 100 µg/L depending on the presence or absence of underlying inflammatory conditions. The increases in TSAT and ferritin levels from baseline were statistically significantly greater in the FCM group compared to the IS group across all visits.
The observed higher early response rates in the FCM group are consistent with findings from previous studies conducted in non-Chinese populations [
31–
33]. The faster response and higher serum ferritin levels at Week 2 in the FCM group can be attributed to the higher single iron dose that can be administered with FCM (1000 mg) compared to IS (200 mg). Consequently, the majority of FCM-treated subjects required only one to two infusions/injections, while most IS-treated subjects needed six or more. However, it is difficult to determine whether this difference in response rate is due to faster uptake into the bone marrow or improved erythropoietic bioavailability of FCM [
34,
35].
In general, Hb response rates were higher compared to studies conducted on predominantly non-Asian patient populations that investigated the efficacy of FCM and IS [
36]. This difference in response rates may be attributed to the relatively low baseline Hb levels of the subjects in this study. Previous research has shown a positive correlation between lower Hb levels and a higher number of responders [
37,
38]. Interestingly, a separate study conducted on an Asian population (Japanese patients with heavy menstrual bleeding) reported similarly high response rates, even though their baseline Hb levels were higher than those in the present study [
39].
The occurrence of adverse events in this study aligns with findings from previous studies, and no new or unexpected events were reported [
40,
41]. The number of treatment-related TEAEs leading to study discontinuation was equal in both treatment groups. The incidence of commonly reported treatment-related TEAEs was generally similar between the two groups, except for decreased blood phosphorus, hypophosphatemia, and pyrexia, which are known side effects of FCM treatment [
42,
43]. However, the frequency of hypophosphatemia in the FCM group in this study was within the lower range of what has been reported in literature reviews and meta-analyses [
44,
45]. Most cases of hypophosphatemia observed in this study were transient and did not have a significant impact on clinical outcomes. It is important to note that short-term acute hypophosphatemia typically does not have clinical implications, whereas severe hypophosphatemia can lead to complications involving hematologic, neuromuscular, and cardiovascular dysfunction [
46]. Interestingly, a retrospective analysis conducted on a stable, unselected patient cohort in an outpatient gastroenterology setting suggested a correlation between an increase in plasma ferritin levels and a reduction in phosphate levels [
47]. Also, FCM may elevate fibroblast growth factor 23 signaling, resulting in increased phosphate secretion [
48]. However, no significant differences in urinary phosphate levels were observed between the FCM and IS groups in this study.
Potential limitations to consider in this study, include the unbalanced distribution of gender within the study population and the open-label design. The inclusion of a high proportion of females (93.2%) and a significant percentage of individuals with menorrhagia as the cause of IDA (55.0%) limits the generalizability of the results. However, previous studies with a more balanced distribution of sexes have not reported any significant differences in the efficacy of FCM based on sex or gender [
36,
49,
50]. The open-label design, necessitated by the different dosing regimens of FCM and IS, may also be considered a limitation. However, the study endpoints primarily relied on objective laboratory values rather than subjective scores that could have been influenced by participants’ awareness of the treatment received.
Although an economic analysis that compares FCM and IS has not been performed, former cost evaluations in different European countries suggested cost savings for a 1000 mg total iron dose of FCM compared with IS [
10], mainly due the significantly lower number of administrations.
5 Conclusions
The study conducted on a Chinese population reveals that FCM is an efficacious treatment for IDA. It demonstrates a similar efficacy and safety profile as IS. FCM, with its faster Hb response and correction of ID requiring fewer infusions or injections compared to IS, reduces hospital visits, improves patient compliance, and has the potential to decrease direct or indirect medical costs.
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