Evaluation of a single dose of ferric carboxymaltose in fatigued, iron-deficient women--PREFER a randomized, placebo-controlled study

Abstract

Background: Unexplained fatigue is often left untreated or treated with antidepressants. This randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of single-dose intravenous ferric carboxymaltose (FCM) in iron-deficient, premenopausal women with symptomatic, unexplained fatigue.

Methods: Fatigued women (Piper Fatigue Scale [PFS] score ≥5) with iron deficiency (ferritin <50 µg/L and transferrin saturation <20%, or ferritin <15 µg/L) and normal or borderline hemoglobin (≥115 g/L) were enrolled in 21 sites in Austria, Germany, Sweden and Switzerland, blinded to the study drug and randomized (computer-generated randomization sequence) to a single FCM (1000 mg iron) or saline (placebo) infusion. Primary endpoint was the proportion of patients with reduced fatigue (≥1 point decrease in PFS score from baseline to Day 56).

Results: The full analysis included 290 women (FCM 144, placebo 146). Fatigue was reduced in 65.3% (FCM) and 52.7% (placebo) of patients (OR 1.68, 95%CI 1.05-2.70; p = 0.03). A 50% reduction of PFS score was achieved in 33.3% FCM- vs. 16.4% placebo-treated patients (p<0.001). At Day 56, all FCM-treated patients had hemoglobin levels ≥120 g/L (vs. 87% at baseline); with placebo, the proportion decreased from 86% to 81%. Mental quality-of-life (SF-12) and the cognitive function scores improved better with FCM. 'Power of attention' improved better in FCM-treated patients with ferritin <15 µg/L. Treatment-emergent adverse events (placebo 114, FCM 209; most frequently headache, nasopharyngitis, pyrexia and nausea) were mainly mild or moderate.

Conclusion: A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function and erythropoiesis in iron-deficient women with normal or borderline hemoglobin. Although more side effects were reported compared to placebo, FCM can be an effective alternative in patients who cannot tolerate or use oral iron, the common treatment of iron deficiency. Overall, the results support the hypothesis that iron deficiency can affect women's health, and a normal iron status should be maintained independent of hemoglobin levels.

Trial registration: ClinicalTrials.gov NCT01110356.

Conflict of interest statement

Competing Interests: The authors have read the journal’s policy and have the following conflicts: BF received study grants and lecture/consultant fees from Vifor Pharma Ltd. and Pierre Fabre Médicament; CG received speaker/consultant honoraria from Vifor Pharma Ltd., Fresenius Medical Care, Pharmacosmos A/S and Renapharma, as well as study grants from Vifor Pharma Ltd. and Janssen & Cilag; MH received speaker/consultant honoraria from Vifor Pharma Ltd.; CB received lecture and consultant fees from Vifor Pharma Ltd.; TK is managing director of ACOMED statistic and received consultant fees from Vifor Pharma Ltd.; AM is employee of Vifor Pharma Ltd.; Medical writing support was funded by Vifor Pharma Ltd. This did not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Study flow diagram.

The most common major protocol deviations were ‘disallowed concurrent medications’ (15 patients in the placebo and 19 patients in the FCM group) and ‘selection criteria not met’ (5 patients in the placebo and 8 patients in the FCM group).

Figure 2. Treatment effects of FCM vs. placebo in fatigued, iron-deficient, non-anemic women (ITT; error bars SD).

(A) Proportion of patients with ≥1 point reduction in PFS (primary endpoint). (B) Improvement of mean PFS total score in FCM- vs. placebo-treated patients throughout the study (Mean differences ± SD vs. baseline: Day 7: −1.2±1.8 vs. −0.8±1.5 points; Day 28: −1.8±2.1 vs. 1.2±2.0 points; Day 56: −2.2±2.1 vs. −1.4±2.0 points). P-values given for intergroup differences. (C) Mean change (Δ) in PFS total score and subscale scores from baseline to Day 56. *P≤0.01 for all scales. (D) Mean change (Δ) in self-rated alertness, contentment and calmness (computer-based VAS scales). *P

Figure 3. Mean changes (Δ) in reticulocyte counts, Hb levels, MCV and TSAT (error bars SD).

The rapid increase of reticulocyte counts in the FCM group is in line with early FCM-associated improvement of the fatigue total score (fig. 2B). The significantly higher increase in reticulocyte counts in the FCM group at Days 7 and 28 (A) translated into higher increases of Hb and MCV at Days 28 and 56 (B,C). The early FCM-associated increase in reticulocyte counts remained significantly higher compared to placebo when analysing the subgroup of patients with Hb≥120 g/L (P