Intravenous Iron Carboxymaltose, Isomaltoside and Oral Iron Sulphate for Postpartum Anemia

Sponsor

University Medical Centre Ljubljana (Other)

Overall Status

Completed

CT.gov ID

NCT03957057

Collaborator

(none)

300

Enrollment

Location

Arms

21.1

Actual Duration (Months)

14.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Anemia affects between 20 and 50 % of women in the postpartum period. 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. Postpartum anemia has also been shown to be a major risk factor for postpartum depression and to significantly disrupt maternal-infant interactions. Iron deficiency is the principal cause of anemia after delivery. Oral iron supplementation with ferrous sulfate has been considered the standard of care with blood transfusion reserved for more severe or symptomatic cases. In the last decade, two new intravenous iron compounds have been registered for clinical use: ferric carboxymaltose (Iroprem®) and iron isomaltoside (Monofer®). No study to date compared efficacy of iron carboxymaltose to iron isomaltoside for treatment of postpartum anemia.

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.

Condition or Disease	Intervention/Treatment	Phase
Postpartum Anemia Nos Iron-deficiency	Drug: Iron Carboxymaltose Drug: Iron Isomaltoside Drug: Ferrous sulphate	Phase 3

Detailed Description

RATIONALE Anemia affects between 20 and 50 % of women in the postpartum period. 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. Postpartum anemia has also been shown to be a major risk factor for postpartum depression and to significantly disrupt maternal-infant interactions.

Iron deficiency is the principal cause of anemia after delivery. Oral iron supplementation with ferrous sulfate has been considered the standard of care with blood transfusion reserved for more severe or symptomatic cases. 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. Blood transfusion, on the other hand, is associated with several hazards, including transfusion of the wrong blood type, infection, anaphylaxis and lung injury.

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. 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. 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.

In the last decade, two new intravenous iron compounds have been registered for clinical use:

ferric carboxymaltose (Iroprem®) and iron isomaltoside (Monofer®). 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. 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. 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. 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. 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. 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. They found significant reduction in fatigue within 12 weeks postpartum in women who received iron isomaltoside. Iron isomaltoside treatment was also associated with improved haematological and iron parameters compared to oral ferrous sulfate.

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.

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.

After signed informed consent patients will be allocated randomly in a 1:1:1 fashion into one of three groups:

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 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.
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.
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.

The investigators 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomized Trial Comparing Intravenous Iron Carboxymaltose, Intravenous Iron Isomaltoside and Oral Iron Sulphate for Postpartum Anemia

Actual Study Start Date :

Sep 10, 2020

Actual Primary Completion Date :

Apr 30, 2022

Actual Study Completion Date :

Jun 15, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Iron carboxymaltose group 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.	Drug: Iron Carboxymaltose Intravenous iron carboxymaltose application
Experimental: 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.	Drug: Iron Isomaltoside Inravenous iron isomaltoside application
Active Comparator: Iron sulphate group 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.	Drug: Ferrous sulphate Oral ferrous sulphate application

Arm

Intervention/Treatment

Experimental: Iron carboxymaltose group

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.

Drug: Iron Carboxymaltose

Intravenous iron carboxymaltose application

Experimental: 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.

Drug: Iron Isomaltoside

Inravenous iron isomaltoside application

Active Comparator: Iron sulphate group

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.

Drug: Ferrous sulphate

Oral ferrous sulphate application

Outcome Measures

Primary Outcome Measures

Multidimensional Fatigue Inventory (MFI) score [6 weeks postpartum]
Multidimensional Fatigue Inventory (MFI) score at 6 weeks postpartum. The MFI is a 20-item self-report instrument designed to measure fatigue. Items are scored 1-5, with 10 positively phrased items reverse scored (this concerns following items: 2, 5, 9, 10, 13, 14, 16, 17, 18, 19). For each of the 5 scales (general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue) a total score is calculated by summation of the scores of the individual items. Scores can range from the minimum of 4 to the maximum of 20. Higher scores indicate a higher degree of fatigue.

Secondary Outcome Measures

Edinburgh Postnatal Depression Scale (EPDS) score [6 weeks postpartum]
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. Each answer is given a score of 0 to 3 . The maximum score is 30. Higher scores indicate more depressive symptoms. A score of more than 10 suggests minor or major depression may be present.
hemoglobin [6 weeks postpartum]
Mean hemoglobin level at 6 weeks postpartum
hemoglobin level > 120 g/L [6 weeks postpartum]
Proportion of participants with hemoglobin level > 120 g/L at 6 weeks postpartum
ferritin level > 50 mcg/L at 6 weeks postpartum [6 weeks postpartum]
Proportion of participants with ferritin level > 50 mcg/L
reticulocyte count [6 weeks postpartum]
Mean reticulocyte count
ferritin level [6 weeks postpartum]
Mean ferritin level
transferrin level [6 weeks postpartum]
Mean transferrin level
Costs of medication used in each study arm [6 weeks postpartum]
Costs of treatments
Compliance - proportion of participants receiving treatments as recommended [6 weeks postpartum]
Compliance with oral ferrous sulphate treatment
Side effects - proportion of participants reporting side effects of treatments [6 weeks postpartum]
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)