Ferric carboxymaltose vs. oral iron in the treatment of pregnant women with iron deficiency anemia: an international, open-label, randomized controlled trial (FER-ASAP)

Participants

Pregnant women aged ≥18 years, in their second or third trimester (gestational weeks 16–33) and with serum ferritin levels ≤20 ng/mL and IDA [defined as hemoglobin (Hb) 8.0–10.4 g/dL for gestation weeks 16–26 or Hb ≤11.0 g/dL for gestation weeks 27–33] were eligible for this study. Women were excluded if they had a significant bleed or surgery within 3 months prior to screening, received a blood transfusion, erythropoietin treatment, oral iron (unless the dose was ≤100 mg iron per day) or parenteral iron treatment during the month prior to screening, or were anticipated to need a blood transfusion during the study period. Other exclusion criteria included anemia that was not caused by iron deficiency (ID) or was related to other acute or ongoing disorders, multiple pregnancies, fetal abnormalities evident on ultrasound, or any serious medical condition that may prevent completion of the trial.

Study design

FER-ASAP was an international, Phase IIIb, open-label study in which pregnant women were randomized 1:1 to receive IV FCM (Ferinject^®; 1000–1500 mg iron) or oral ferrous sulfate (FS; Plastufer^®; 100 mg capsules taken twice daily; total daily dose 200 mg iron) (ClinicalTrials.gov identifier: NCT01131624). FCM dosing regimens were stratified according to body weight (Table 1) in order not to exceed a dose of 15 mg iron per kg of body weight per single dose, with all infusions to be completed by week 3. Oral FS was to be taken daily for 12 weeks. This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and institutional review boards or independent ethics committees of all investigational sites approved the protocol. All study participants provided written informed consent prior to enrollment.

Study objectives and assessments

The primary objective was to compare the efficacy of IV FCM with oral FS as treatment of IDA in pregnant women during their second and third trimesters. Secondary objectives were to determine the safety and tolerability of FCM in pregnant women and their newborns, and to determine the relationship between iron status and women’s quality of life.

Efficacy assessments were performed at baseline, weeks 3, 6, 9, and 12 and/or prior to delivery (whichever came first; samples prior to delivery could be taken at any point after week 3). The primary efficacy endpoint was the change in Hb from baseline to week 3. Secondary efficacy endpoints were change in Hb and other serum iron parameters, the proportion of women who achieved anemia correction (defined as Hb ≥11.0 g/dL), and time to anemia correction. Changes in quality of life were also evaluated: the 36-item short-form (SF-36) health survey was completed at baseline, week 3 and prior to delivery. Safety was monitored throughout and comprised the incidence of treatment-emergent adverse events (TEAEs; defined as an adverse event that occurred or increased in severity after the first dose of medication was administered) and treatment-related TEAEs, coded according to the Medical Dictionary for Regulatory Activities (version 16.1). Changes in routine hematological and biochemical laboratory parameters, physical examinations and vital signs were also evaluated at the same time as efficacy assessments. Apgar scores and other newborn parameters were also assessed. Newborns delivered at hospitals that were not participating in this study were not assessed. Blood samples were taken using standard venipuncture techniques and clinical laboratory parameters [Hb, serum ferritin, total iron binding capacity, serum iron, transferrin saturation (TSAT), soluble transferrin receptor] were assessed by an independent laboratory.

Statistical analysis

A sample size of 120 women per treatment arm was considered sufficiently powered to detect cross-group differences in Hb levels at week 3 versus baseline (α=0.05, two sided; 90% power). The sample size was increased to 125 women per treatment arm to account for low expected discontinuation at week 3; therefore, the total planned study population size was 250.

Efficacy analyses were conducted on the full analysis set (intent to treat), which comprised all randomized women who received at least one dose of study treatment and had at least one efficacy assessment available at baseline and within the study period. The primary efficacy endpoint was analyzed using an analysis of covariance (ANCOVA) model with factors for treatment, pooled countries [South Korea, Russia, rest of the world (Australia, Singapore, Sweden, Switzerland and Turkey)] and baseline Hb level; changes in Hb and other serum iron parameters at weeks 6, 9, and 12 and delivery were also analyzed using this model. Logistic regression, including the same factors accounted for in the primary efficacy analysis, was used to compare the proportions of women achieving anemia correction, and an unstratified log-rank test was used to explore the time to anemia correction. SF-36 domain scores were calculated using the algorithms provided within the SF-36 documentation and analyzed as for the primary efficacy endpoint. Safety data were summarized descriptively; the safety population comprised all women who received at least one dose of study treatment. Data from newborns were also summarized descriptively. For all analyses, missing data were treated as missing – no imputation was performed.

Patients

Between November 2010 and May 2014, 252 pregnant women [median age 31 years (range 27–35)] from 29 centers across seven countries were randomized to IV FCM (n=126) or oral FS (n=126) (Figure 1). The majority of participants (88%) completed the study, with similar withdrawal rates between the treatment arms (Figure 1). Most withdrawals from the study were because of voluntary discontinuation by the participant (8 women treated with FCM and 6 with FS); one woman treated with FCM and seven treated with FS withdrew because of TEAEs (Figure 1). Participant demographics and baseline characteristics were generally balanced between the treatment arms and were representative of the target population (Table 2). Samples for the time point of last visit prior to delivery were taken a median of 14.5 (range 2–93) days before delivery for the FCM group and 15.0 (range 2–85) days before delivery for the FS group. By week 12, many of the participating women had already given birth; as such, there are limited data for the hematological assessments at this time point.

Figure 1:

Participant disposition.

TEAE=treatment-emergent adverse event.

Efficacy

Hb levels improved with both study treatments at each visit throughout the assessment period (Figure 2). Mean changes in Hb for the FCM group were consistently superior to mean changes in Hb for FS (change in Hb at week 3: 1.23±0.95 g/dL vs. 0.96±1.38 g/dL, respectively), although statistical significance was not reached at week 3 [least-squares mean: 1.16 vs. 1.04; difference: 0.12, 95% confidence interval (CI): –0.10, 0.34; P=0.274; repeated-measures model]; therefore, the primary efficacy endpoint was not met at week 3. However, a statistically significant improvement in mean change in Hb levels from baseline was achieved for FCM vs. FS at week 6 (change in Hb: 1.75±1.18 g/dL vs. 1.32±1.54 g/dL; least-squares mean: 1.68 vs. 1.40; difference: 0.28, 95% CI: 0.02, 0.55; P=0.032; repeated-measures model). Pregnant women treated with FCM were twice as likely to achieve anemia correction (Hb ≥11.0 g/dL) than those treated with FS [84% (n=101) vs. 70% (n=80); odds ratio (OR): 2.06, 95% CI: 1.07, 3.97; P=0.031], and the median time to achieving this correction was shorter with FCM treatment (3.4 vs. 4.3 weeks).

Figure 2:

Change in hemoglobin levels.

FCM=ferric carboxymaltose, FS=ferrous sulfate, Hb=hemoglobin, SD=standard deviation.

Comparative analysis of other hematological parameters revealed sustained, significantly greater increases in serum ferritin levels with FCM treatment compared with FS (Figure 3A). Similar TSAT levels between treatment arms were seen up to the week 9 assessment; however, at week 12 and prior to delivery, TSAT levels were significantly greater with FS treatment (Figure 3B). Soluble transferrin receptor levels decreased with both treatments, with significantly greater decreases with FCM treatment at weeks 6 and 9 (Figure 3C).

Figure 3:

Changes in other hematological parameters: (A) serum ferritin; (B) transferrin saturation; (C) soluble transferrin receptor.

FCM=ferric carboxymaltose, FS=ferrous sulfate, SD=standard deviation, SF=serum ferritin, sTfR=soluble transferrin receptor, TSAT=transferrin saturation.

Quality of life

According to the SF-36 health survey, FCM treatment led to significant, clinically relevant improvements over FS in vitality prior to delivery (mean score change±standard deviation: FCM, 6.51±21.90; FS, 2.34±22.09; least-squares mean: 5.67 vs. –0.23; difference: 5.90, 95% CI: 0.75, 11.04; P=0.025) (Figure 4A). Significant improvements in social functioning were also evident prior to delivery following FCM vs. FS treatment (FCM, 3.03±23.61; FS, –2.50±24.55; least-squares mean: 3.28 vs. –2.49; difference: 5.77, 95% CI: 0.01, 11.51; P=0.049) (Figure 4B).

Figure 4:

Changes in SF-36 component scores: (A) vitality; (B) social functioning.

FCM=ferric carboxymaltose, FS=ferrous sulfate, SF-36=36-item short-form health survey.

Safety and tolerability

The median (range) total dose administered was 1000 (2–1500) mg for FCM and 12,300 (200–20,500) mg for FS. One patient received only 2 mg of FCM; administration was interrupted due to bronchospasm and the patient withdrew on day 6. One patient who received only 200 mg of FS withdrew due to nausea on day 4.

The incidence of TEAEs was similar between the treatment arms: in the FCM group, 60 women (49%) experienced 165 TEAEs; in the FS group, 50 women (40%) experienced 105 TEAEs. The majority of events were mild in intensity (Table 3). Overall, the most common TEAEs were nausea (6%), headache (5%) and dyspepsia (4%), and the most common TEAEs according to system organ class were “pregnancy, puerperium and perinatal conditions” in the FCM group [32 events in 26 women (21%)] and “gastrointestinal disorders” in the FS group [42 events in 25 women (20%)]. The most common treatment-related TEAEs were headache with FCM [experienced by 4 women (3%)] and nausea with FS [in 6 women (5%)], and markedly higher rates of gastrointestinal disorders were reported with FS treatment (in 16 women) compared with FCM treatment (3 women) (Table 4). Serious TEAEs occurred in 23 women treated with FCM (26 events) and in 10 women treated with FS (11 events); all were single events, except for “failed trial of labor”, “fetal distress syndrome”, “premature delivery”, “premature rupture of membranes” and “threatened labor”, each of which occurred in two women treated with FCM, and “premature labor”, which occurred in three women treated with FS (pre-eclampsia was also reported to have occurred twice in one woman treated with FS). One serious TEAE, “bronchospasm”, which was treatment related, led to discontinuation of FCM; this event was of moderate intensity and resolved on the same day after withdrawal of study treatment. Seven women discontinued treatment with FS because of gastrointestinal TEAEs (n=5), syncope (n=1) and rash (n=1). No hypophosphatemia TEAEs were reported during this study. Eleven women (FCM, n=10; ferrous sulfate, n=1) recorded phosphate levels below the lower normal range threshold [0.6 mmol/L (2 mg/dL)]; these decreases were largely observed at week 3 and recovered in all the women to within the normal range by the end of the study, indicating no clinical relevance of these findings.

Newborn status

Apgar scoring was similar between treatment groups. The overall mean Apgar score of the newborns at the first minute following birth was 8.3, increasing to 9.1 at 5 min, with all achieving an Apgar score of 10 by 10 min after birth. Other newborn characteristics were also similar between treatments (Table 5). Independent of the mother’s cord serum ferritin levels, all newborns were assessed to have normal serum ferritin levels.