Randomized Trial Comparing Intravenous Iron Carboxymaltose, Intravenous Iron Isomaltoside and Oral Iron Sulphate for Postpartum Anemia
Phase: PHASE3
Conditions: Postpartum Anemia Nos, Iron-deficiency
Sponsor: University Medical Centre Ljubljana

Official Title of the Study: 
Randomized Trial Comparing Intravenous Iron Carboxymaltose, Intravenous Iron 
Isomaltoside and Oral Iron Sulphate for Postpartum Anemia 
 
NCT Number:  
Not yet assigned. 
 
Date of the document: 
05/15/2019 
 
 
 
 
 
 
 
 
 
 
 
 

RATIONALE 
Anemia affects between 20 and 50 % of women in the postpartum period (1). It is associated 
with several adverse health consequences, such as impaired physical work capacity, deficits in 
cognitive function and mood, reduced immune function and reduced duration of breastfeeding 
(1-5). Postpartum anemia has also been shown to be a major risk factor for postpartum 
depression and to significantly disrupt maternal–infant interactions (1-3).  
Iron deficiency is the principal cause of anemia after delivery (1).  Oral iron supplementation 
with ferrous sulfate has been considered the standard of care with blood transfusion reserved 
for more severe or symptomatic cases (6,7). However, efficacy of oral iron is limited by 
gastrointestinal side effects, patient non-adherence as well as prolonged time required to treat 
anemia and replenish body iron stores (7-9). Blood transfusion, on the other hand, is 
associated with several hazards, including transfusion of the wrong blood type, infection, 
anaphylaxis and lung injury (7,8,10). 
In last decades, modern formulations of intravenous iron have emerged as safe and effective 
alternatives to oral iron supplementation for iron deficiency anemia management outside 
pregnancy (11). Several studies have also evaluated efficacy of intravenous iron preparations 
for treatment of postpartum anemia. Westad et al. reported no significant difference in 
hemoglobin levels at 4, 8 and 12 weeks postpartum in women receiving intravenous iron 
sucrose (Venofer®) compared to those receiving oral ferrous sulphate, whereas the total 
fatigue score was significantly improved in the intravenous iron supplementation group at 
weeks 4, 8 and 12 (6).  In addition, mean serum ferritin value after 4 weeks was significantly 
higher in the iron sucrose group. Several other authors came to similar conclusion, 
intravenous iron sucrose and oral ferrous sulphate were both effective in correcting 
peripartum anemia, although intravenous iron restored stores faster than oral iron (7,12-14).  
In the last decade, two new intravenous iron compounds have been registered for clinical use: 
ferric carboxymaltose (Iroprem®) and iron isomaltoside (Monofer®) (15-18). These 
treatments were designed to be administered in large doses by rapid intravenous injection. 
They have been demonstrated to be more efficacious than intravenous iron sucrose in patients 
with inflammatory bowel disease and in patients with chronic kidney disease (19-21). In the 
postpartum period, ferric carboxymaltose has been compared to oral iron supplements in four 
randomized trials. All reported a faster rise in hemoglobin levels compared to oral ferrous 

sulphate (15,16,22,23). Pfenninger et al. compared efficacy of intravenous ferric 
carboxymaltose with iron sucrose for the treatment of postpartum anemia in a retrospective 
cohort study.  Both drugs offered rapid normalization of hemoglobin levels after delivery with 
no difference in mean daily hemoglobin increase between the groups up to 8 days after 
treatment (24). Only one randomized study to date compared intravenous ferric carboxylase to 
intravenous iron sucrose and oral ferrous sulphate for treatment of postpartum anemia. 
Radhod et al. found a significantly faster rise in hemoglobin and ferritin levels with ferric 
carboxylase compared to iron sucrose and ferrous sulphate in Indian women presenting with 
anemia after delivery (25). This study, like most randomized trials on efficacy of various iron 
treatments, focused solely on hematological biomarkers. However, iron deficiency, even 
without anemia, contributes significantly to fatigue experienced by women in the puerperium, 
and these women may benefit from iron supplementation as well (1,16,26). Data on patient 
reported outcomes associated with different iron treatments are, therefore, very much needed. 
Holm et al. compared the effects of single-dose intravenous iron isomaltoside to 
oral iron supplementation on physical fatigue in women after postpartum haemorrhage 
(17,18). They found significant reduction in fatigue within 12 weeks postpartum in women 
who received iron isomaltoside (16). Iron isomaltoside treatment was also associated with 
improved haematological and iron parameters compared to oral ferrous sulfate (17,18).  
No study to date, however, compared efficacy of iron carboxymaltose to iron isomaltoside for 
treatment of postpartum anemia. The only head-to-head comparison between these two 
compounds merely examined economic aspects of each treatment, showing potential 
reduction of costs associated with the use of iron isomaltoside vs. iron carboxymaltose (27).  
OBJECTIVE 
The objective of the study is to compare efficacy of intravenous iron carboxymaltose to 
intravenous iron isomaltoside and oral iron sulphate for treatment of postpartum anemia. 
METHODS 
Single-center, randomized, open-label trial.  
Inclusion criteria 

Postpartum patients with a hemoglobin level between 70 g/L and 100 g/L within 48 hours 
after delivery.  
Exclusion criteria 
 Contraindications for any of the study drugs. 
 Anemia due to causes other than iron deficiency. 
 Signs of systemic infection.  
 Renal or hepatic dysfunction. 
 Depression during pregnancy or pre-existing depressive disorders. 
After signed informed consent patients will be allocated randomly in a 1:1:1 fashion into 
one of three groups: 
1. Iron carboxymaltose group. Total dose of intravenous ferric carboxymaltose (Iroprem®) 
needed to correct anemia and replenish iron stores will be calculated using the Ganzoni 
formula (28) modified to include adjustment for baseline iron status: prepregnancy weight 
in kilograms X (15–baseline Hb) X 2.4 + 500. Fifteen is the target Hb in g/dL, 2.4 is a unit 
less conversion constant and 500 is the target iron stores in mg. The maximal dose 
administered in a single day will not exceed 15 mg/kg (current weight) or 1000 mg (for 
participants with body weight > 67 kg). If total calculated dose will exceed 15 mg/kg or 
1000 mg, subsequent doses will be administered weekly until the total calculated dose will 
be reached. 
2. Iron isomaltoside group. Total dose of intravenous iron isomaltoside (Monofer®) needed 
to correct anemia and replenish iron stores will be calculated as described above. The 
maximal dose administered in a single day will not exceed 20 mg/kg (current weight) or 
1500 mg (for participants with body weight > 75 kg). If total calculated dose will exceed 
20 mg/kg or 1500 mg, subsequent doses will be administered weekly until the total 
calculated dose will be reached.  
3. Iron sulphate group. Participants will receive oral ferrous sulphate (Tardyfer®) 160 mg 
daily for 6 weeks with instruction to take two tablets by mouth once daily 1 hour before 
meal. They will receive no additional iron supplementation.  

We will monitor blood pressure and record adverse events in all patients before and after 
administration of IV iron and ask all patients to report any untoward medical event at its 
onset. 
Outcomes 
Primary outcome 
 Multidimensional Fatigue Inventory (MFI) score at 6 weeks postpartum. The MFI 
evaluates five dimensions of fatigue: general fatigue, physical fatigue, reduced 
activity, reduced motivation, and mental fatigue, and consists of 20 statements for 
which the participant indicates, on a five-point scale, the extent to which the particular 
statement applies with regard to aspects of fatigue experienced during the previous 
days. Higher scores indicate a higher degree of fatigue. 
Secondary outcomes 
 Edinburgh Postnatal Depression Scale (EPDS) score at 6 weeks postpartum. EPDA is 
a 10-item questionnaire which evaluates different depression symptoms, such as guilt 
feeling, sleep disturbance, low energy, anhedonia, and suicidal ideation. Overall 
assessment is done by total score, which is determined by adding together the scores 
for each of the 10 items. Higher scores indicate more depressive symptoms. 
 Mean hemoglobin level at 6 weeks postpartum.  
 Proportion of participants with hemoglobin level > 120 g/L at 6 weeks postpartum.  
 Proportion of participants with ferritin level > 50 mcg/L at 6 weeks postpartum.  
 Mean reticulocyte count at 6 weeks postpartum. 
 Mean ferritin level at 6 weeks postpartum. 
 Mean transferrin level at 6 weeks postpartum. 
 Costs of treatments 
 Compliance with oral ferrous sulphate treatment 
 Side effects of all three study treatments in mothers (e.g. constipation, headache, 
infusion site burning) and infants (e.g. constipation, erythema, diarrhea, abdominal 
pain, upper respiratory tract infection) 
Statistical analysis 

The planned sample size of 100 patients per group was based on a 80% power to detect non-
inferiority using a margin of 5 (half the estimated clinically relevant difference in MFI), an α 
of 0.01, and expected standard deviation (SD) of 10, with a 20 % dropout rate. 
All data will be analyzed according to a pre-established statistical plan. Statistical analyses 
will be performed with SPSS software (version 24.0; IBM Corporation, Armonk, New York). 
Data will be entered as numerical or categorical, as appropriate. Shapiro-Wilk test will be 
used to assess normality of distribution. Parametric statistics will be carried out for normally 
distributed variables; for non-normal distribution, we will use nonparametric statistics. Data 
with normal distribution will be described using minimum, maximum, and mean with 
standard deviation. Data with non-normal distribution will be described using minimum, 
maximum, median, and interquartile range (IQR). Comparisons will be carried out between 
the study groups using independent Student’s t test or Mann-Whitney U test for continuous 
and with Chi-square test for categorical variables.  
 
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