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Cited by 130Iron Metabolism and DisordersErythropoietin and Anemia TreatmentHemoglobinopathies and Related Disorders

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Evaluation of a Single Dose of Ferric Carboxymaltose in Fatigued, Iron-Deficient Women – PREFER a Randomized, Placebo-Controlled Study

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Favrat, Bernard, Balck, Katharina, Breymann, Christian, Hedenus, Michael, Keller, Thomas, Mezzacasa, Anna, Gasche, Christoph·2014·PLoS ONE
DOI 10.1371/journal.pone.0094217PMC PMC3994001
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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.

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Crossref · 10.1371/journal.pone.0094217

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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 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).CC BY · PubMed Central
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<0.05; †P = 0.055 vs. placebo.
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<0.05; †P = 0.055 vs. placebo.CC BY · PubMed Central
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<0.001 for Days 7 and 28). This suggests that iron deficiency without anaemia affected erythropoiesis in these apparently healthy women and raises doubts whether the currently recommended Hb cut-off level of 120 g/L to diagnose anaemia in premenopausal, menstruating women is appropriate. TSAT remained significantly improved until the end of the 56-day study period (D). *P<0.0001 for difference between FCM and placebo group in reticulocyte counts and Hb levels, respectively.
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<0.001 for Days 7 and 28). This suggests that iron deficiency without anaemia affected erythropoiesis in these apparently healthy women and raises doubts whether the currently recommended Hb cut-off level of 120 g/L to diagnose anaemia in premenopausal, menstruating women is appropriate. TSAT remained significantly improved until the end of the 56-day study period (D). *P<0.0001 for difference between FCM and placebo group in reticulocyte counts and Hb levels, respectively.CC BY · PubMed Central

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Metadata

Authors
Favrat, B., Balck, K., Breymann, C., Hedenus, M., Keller, T., Mezzacasa, A., & Gasche, C.
Affiliations
  • University of Lausanne (CH)
  • University Hospital Zurich (CH)
  • Sundsvall Municipality (SE)
  • Vifor Pharma (Switzerland) (CH)
Corresponding author
Favrat, Bernard
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-04-21
Volume
9
Issue
4
Pages
e94217
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0094217
PMC
PMC3994001
OpenAlex
W2021092349
Cited by
130
References
45
Citations by year
2026: 1 · 2025: 9 · 2024: 7 · 2023: 6 · 2022: 14 · 2021: 13 · 2020: 13 · 2019: 9 · 2018: 17 · 2017: 8 · 2016: 18 · 2015: 11 · 2014: 4
FWCI
9.60
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • IRIS (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • European Hematology Association
  • Les Laboratories Pierre Fabre
  • Fresenius Medical Care North America
  • Vifor Pharma
  • Cilag
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
Keywords
ferric carboxymaltose, iron deficiency, unexplained fatigue, premenopausal women, intravenous iron, Piper Fatigue Scale, psychological quality of life, cognitive function, hemoglobin, erythropoiesis, treatment-emergent adverse events, single-dose infusion, low ferritin
MeSH terms
Iron Deficiencies, Adult, Cognition, Dose-Response Relationship, Drug, Erythrocyte Indices, Fatigue, Female, Ferric Compounds, Hemoglobins, Humans, Maltose, Placebos, Quality of Life, Transferrin, Endpoint Determination, Intention to Treat Analysis

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