A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia

Abstract Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside (also known as ferric derisomaltose) and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open‐label, comparative, multi‐center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase ≥2 g/dL from baseline at any time between weeks 1‐5. Both non‐inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.


| I N T R O D U C T I O N
Iron deficiency anemia (IDA) is a common problem associated with many chronic diseases which include chronic kidney disease (CKD), 1 cancer, 2 infections, 3 chronic heart failure (CHF), 4 inflammatory bowel disease (IBD), 5 and bariatric procedures. 6 It is also common in women who have recently given birth 7 or suffer from heavy menstrual bleeding. 8 International guidelines [9][10][11] recommend IV iron as the preferred option when oral iron was either ineffective or not tolerated, either because of limited absorption, lack of adherence, intolerance, or when the iron need is high. IV iron is considered more effective, better tolerated, and improves quality of life (QoL) to a greater extent than oral iron. Thus, the use of IV iron may result in improved iron correction with better adherence, fewer visits to the medical practitioner, and greater convenience. Iron isomaltoside is one of the newer IV iron formulations available. It was initially launched in Europe in 2010 and consists of iron and a carbohydrate moiety where the iron is tightly bound in a matrix structure. It is the matrix structure that enables a controlled and slow release of iron to iron-binding proteins, avoiding potential toxicity from release of labile iron. 12 Previous published data demonstrate good safety and efficacy of iron isomaltoside in different populations with different comparators. [13][14][15][16][17][18][19][20][21][22] A previous trial compared efficacy of ferric carboxymaltose versus iron sucrose in IBD patients, 23 and iron isomaltoside has been compared with iron sucrose in CKD. 13 This trial is the first head to head trial of iron isomaltoside against iron sucrose outside the realm of CKD. The objective of the present trial was to This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

AJH AJH
Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside (also known as ferric derisomaltose) and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open-label, comparative, multi-center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase ≥2 g/dL from baseline at any time between weeks 1-5.
Both non-inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.
with better adherence, fewer visits to the medical practitioner, and greater convenience. Iron isomaltoside (also known as ferric derisomaltose) is one of the newer IV iron formulations available. It was initially launched in Europe in 2010 and consists of iron and a carbohydrate moiety where the iron is tightly bound in a matrix structure. It is the matrix structure that enables a controlled and slow release of iron to iron-binding proteins, avoiding potential toxicity from release of labile iron. 12 Previous published data demonstrate good safety and efficacy of iron isomaltoside in different populations with different comparators. [13][14][15][16][17][18][19][20][21][22] A previous trial compared efficacy of ferric carboxymaltose versus iron sucrose in IBD patients, 23 and iron isomaltoside has been compared with iron sucrose in CKD. 13 This trial is the first head to head trial of iron isomaltoside against iron sucrose outside the realm of CKD. The objective of the present trial was to compare the efficacy and safety of iron isomaltoside with iron sucrose in patients with IDA over a wide range of different clinical diagnoses.

| Trial design
This was a prospective, comparative, open-label, randomized, non-inferiority multicenter trial incorporating 7-12 visits during a 5-week period. Written informed consent was obtained from all participants.

| Participants
The trial was conducted at 48 sites in the United States. Patients 18 years of age with moderate-to-severe IDA caused by different etiologies, and with a documented history of intolerance of, or unresponsiveness to, oral iron, a Hb <11.0 g/dL, TSAT <20%, and s-ferritin <100 ng/mL were recruited. Inclusion and exclusion criteria are shown in Supporting Information Table SI.

| Objective and endpoints
The trial was designed with the primary objective to evaluate and compare iron isomaltoside with iron sucrose in its ability to increase Hb in patients with IDA when oral iron formulations were ineffective or could not be used or where there was a clinical need to deliver iron rapidly.
The primary efficacy endpoint was the proportion of patients with a Hb increase of 2 g/dL from baseline at any time from weeks 1 to 5.
The secondary efficacy endpoints included time to Hb increase 2 g/ dL, and change in Hb, s-ferritin, TSAT, and s-iron, and total quality of life (QoL) score (Short Form 36 (SF-36) questionnaire). Safety endpoints included the number of patients who experienced any adverse drug reaction (ADR) and safety laboratory assessments (complete hematology, s-sodium, s-potassium, s-calcium, s-phosphate, s-urea, screatinine, s-albumin, s-globulin, s-bilirubin, aspartate aminotransferase, alanine aminotransferase, and C-reactive protein). The primary endpoint was tested for non-inferiority. Additionally, if the 95% confidence interval (CI) was entirely above 0, this was evidence of statistically significant superiority at the 5% level. The p-value associated with a test of superiority was to be calculated. The remaining endpoints were tested for superiority.

| Sample size and randomization
A stratified block randomization methodology was used to assign patients in a 2:1 ratio to receive iron isomaltoside or iron sucrose. The randomization to treatment groups was stratified by screening Hb (Hb < 10.0 g/dL and Hb 10 g/dL) and origin of disease (oncology, gastroenterology, gynecology, and others).
With a 2:1 randomization and a 2-sided significance level of 5%, there would be approximately 90% power to demonstrate noninferiority when using an absolute non-inferiority margin of 12.5%points. As the trial was designed to demonstrate non-inferiority, it was a requirement that the analyses of the full analysis set (FAS) and per protocol (PP) population led to similar conclusions. Thus, both analysis sets needed to be powered properly. It was anticipated that approximately 10% would sustain a major protocol deviation, and therefore a total of 500 had to be randomized.

| Statistical methods
The following data sets were used in the analyses (Supporting Information Figure S1). associated with a test of superiority was calculated. The primary analysis was repeated for the PP analysis set. The primary efficacy data were tabulated using number, mean, standard deviation (SD), minimum, maximum, and 95% confidence interval (CI).

| Change in hemoglobin
The primary analysis (proportion with an increase in Hb 2 g/dL from baseline at any time from week 1 to week 5) was conducted on the FAS (N 5 491) and PP analysis set (N 5 454).
A summary of the primary efficacy analysis in the FAS and PP analysis set is provided in Table 2. There were more responders in the iron isomaltoside group compared with the iron sucrose group, with a risk difference of 16.7%-points in the FAS and 15.9%-points in the PP set.  Since the lower end of the 95% CI for the risk difference was above 212.5%-points in both the FAS and PP analysis set, non-inferiority of iron isomaltoside to iron sucrose could be claimed.
As non-inferiority was proven, the predetermined test for superiority was performed, which also confirmed superiority of iron isomaltoside compared with iron sucrose (p < 0.0001, Table 2).
In the FAS, the largest increase in Hb from baseline to any time The change from baseline in Hb was statistically significantly higher in the iron isomaltoside compared to the iron sucrose group at each time point (p < 0.0001) (Table 2, Figure 2), and similar results were found in the gynecology and gastroenterology subgroups (Supporting Information Figure S2). s-iron was statistically significantly higher in the iron isomaltoside group compared to the iron sucrose group at each time point analyzed (p < 0.0001) and at weeks 1, 2, and 3 (p < 0.0001), respectively (Supporting Information Table SIII, Figure 2).

| Change in quality of life
The change in QoL was assessed the FAS population (N 5 491).
In both treatment groups, the SF-36 scores in the eight health domains as well as for the two composite scores improved from baseline to weeks 2 and 5, and there were no differences between the treatment groups (Supporting Information Figure S3).

| Safety
Safety outcomes were conducted on the safety analysis set (N 5 501).
More skin and subcutaneous tissue disorders were reported in the iron isomaltoside group (7.5%) than in the iron sucrose group (3.0%).
Nervous system disorders and gastrointestinal disorders were reported more frequently in the iron sucrose group than in the iron isomaltoside group. Among the nervous system disorders, dysgeusia was more common in the iron sucrose group (2.4%) than in the iron isomaltoside group (0.6%). With gastrointestinal disorders, more patients in the iron sucrose group than in the iron isomaltoside group reported nausea, vomiting, diarrhea, and dyspepsia. Fatigue was reported by 1.2% in the iron sucrose group and none in the iron isomaltoside group.
Hypophosphatemia was reported as an ADR in 1.5% in the iron isomaltoside group and was not reported in the iron sucrose group.
Serious adverse reactions (SARs) (severe dyspnea and severe pruritic rash in one and moderate syncope in one) were reported by 0.6% of the patients in the iron isomaltoside group. In the iron sucrose group 0.6% also reported SARs (severe anaphylactic reaction).
One patient in the iron isomaltoside group died during the trial.
The event was reported as cardiorespiratory arrest with underlying cardiac disease and was not related to trial drug.

| DISCUSSION
Outside the USA, iron isomaltoside has been approved in more than 30 countries worldwide for treatment of iron deficiency when oral iron formulations are ineffective or cannot be used or when there is a clinical need to deliver iron rapidly. For the primary endpoint, the proportion reaching a Hb increase from baseline of 2 g/dL at any time between week 1 and 5, both non-inferiority and superiority was confirmed for iron isomaltoside compared with iron sucrose. Furthermore, shorter time to Hb increase 2 g/dL was observed with iron isomaltoside compared to iron sucrose, which was most likely because of the fact that iron isomaltoside was given in higher doses within a shorter time period. For all biochemical efficacy parameters measured (Hb, s-ferritin, TSAT, and siron), faster and/or greater improvements were found with iron isomaltoside compared to iron sucrose. These findings are in agreement with previous trials with iron isomaltoside reporting efficacy in significantly increasing iron related parameters. [13][14][15][16][17][18][19][20][21][22] In the present trial, QoL improved in both treatment groups which was expected because of the correction of the iron deficiency. No difference between groups was found.
Treatments with iron isomaltoside and iron sucrose were well tolerated. Compared with iron isomaltoside, the iron is more loosely bound in iron sucrose. 12 This is associated with catalytic/labile iron which has been hypothesized to cause increased oxidative stress with potential consequences on long term toxicity. 28,29 Non-serious ADRs, especially rash and pruritus were more common with iron isomaltoside whereas dysgeusia and gastrointestinal side effects were reported more frequently with iron sucrose. SARs were reported in 0.6% in both treatment groups.
In conclusion, administration of iron isomaltoside resulted in a significantly higher and faster Hb response than did iron sucrose. Iron isomaltoside has an advantage over iron sucrose in requiring fewer administrations. Iron isomaltoside administration was efficacious and well tolerated in a broad population of IDA affected individuals.