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Efficacy and safety of intravenous ferric carboxymaltose compared with oral iron for the treatment of iron deficiency anaemia in women after childbirth in Tanzania: a parallel-group, open-label, randomised controlled phase 3 trial.
Vanobberghen, F, Lweno, O, Kuemmerle, A, Mwebi, KD, Asilia, P, Issa, A, Simon, B, Mswata, S, Schmidlin, S, Glass, TR, et al
The Lancet. Global health. 2021;(2):e189-e198
Abstract
BACKGROUND Iron deficiency anaemia is of major concern in low-income settings, especially for women of childbearing age. Oral iron substitution efficacy is limited by poor compliance and iron depletion severity. We aimed to assess the efficacy and safety of intravenous ferric carboxymaltose versus oral iron substitution following childbirth in women with iron deficiency anaemia in Tanzania. METHODS This parallel-group, open-label, randomised controlled phase 3 trial was done at Bagamoyo District Hospital and Mwananyamala Hospital, Tanzania. Eligible participants were close to delivery and had iron deficiency anaemia defined as a haemoglobin concentration of less than 110 g/L and a ferritin concentration of less than 50 μg/L measured within 14 days before childbirth. Participants were randomly assigned 1:1 to receive intravenous ferric carboxymaltose or oral iron, stratified by haemoglobin concentration and site. Intravenous ferric carboxymaltose was administered at a dose determined by the haemoglobin concentration and bodyweight (bodyweight 35 kg to <70 kg and haemoglobin ≥100 g/L: 1000 mg in one dose; bodyweight 35 kg to <70 kg and haemoglobin <100 g/L, or bodyweight ≥70 kg and haemoglobin ≥100 g/L: 1500 mg in two doses at least 7 days apart; bodyweight ≥70 kg and haemoglobin <100 g/L: 2000 mg in two doses at least 7 days apart). Oral iron treatment consisted of three dried ferrous sulphate tablets of 200 mg containing 60 mg of elementary iron and 5 mg of folic acid every morning. Oral treatment was to be taken for 3 months after haemoglobin normalisation. The primary outcome was haemoglobin normalisation (>115 g/L) at 6 weeks. Follow-up visits were at 6 weeks, and 3, 6, and 12 months. Analyses were done in the modified intention-to-treat population of participants who had a 6-week haemoglobin concentration result, using logistic and linear regression models for binary and continuous outcomes, adjusted for baseline haemoglobin concentration and site. This trial is registered with ClinicalTrials.gov, NCT02541708. FINDINGS Between Oct 8, 2015, and March 14, 2017, 533 individuals were screened and 230 were enrolled and randomly assigned to a study group (114 to intravenous iron, 116 to oral iron). At 6 weeks, 94 (82%) participants in the intravenous iron group and 92 (79%) in the oral iron group were assessed for the primary outcome. 75 (80%) participants in the intravenous iron group and 47 (51%) in the oral iron group had normalised haemoglobin (odds ratio 4·65, 95% CI 2·33-9·27). There were two mild to moderate infusion-related adverse events; and five serious adverse events (three in the intravenous iron group, two in the oral iron group), unrelated to the study medication. INTERPRETATION Intravenous iron substitution with ferric carboxymaltose was safe and yielded a better haemoglobin response than oral iron. To our knowledge, this is the first study to provide evidence of the benefits and safety of intravenous iron substitution in a low-income setting. FUNDING Vifor Pharma, R Geigy-Stiftung, Freiwillige Akademische Gesellschaft, and Swiss Tropical and Public Health Institute.
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Effects of sucroferric oxyhydroxide and sevelamer carbonate on chronic kidney disease-mineral bone disorder parameters in dialysis patients.
Ketteler, M, Sprague, SM, Covic, AC, Rastogi, A, Spinowitz, B, Rakov, V, Walpen, S, Floege, J
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(7):1163-1170
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BACKGROUND Treatment of hyperphosphataemia is the primary goal of chronic kidney disease-mineral and bone disorder (CKD-MBD) management. This post hoc analysis of a randomized, Phase 3 study evaluated the effects of 1-year treatment with the phosphate binders sucroferric oxyhydroxide or sevelamer carbonate ('sevelamer') on CKD-MBD indices among dialysis patients with hyperphosphataemia. METHODS After a 2- to 4-week washout from previous phosphate binders, 1059 patients were randomized 2:1 to sucroferric oxyhydroxide 1.0-3.0 g/day (n = 710) or sevelamer 2.4-14.4 g/day (n = 349) for up to 24 weeks. Eligible patients enrolled in a 28-week extension. This post hoc analysis was performed for patients who completed ≥1 year of continuous treatment (n = 549). As the treatment groups showed similar CKD-MBD outcomes, the data were pooled for this analysis. RESULTS Phosphate-binder therapy was associated with significant and sustained 30% reductions in serum phosphorus (P < 0.001). Median intact fibroblast growth factor-23 (FGF-23) also significantly decreased (P < 0.001) by 64% over 1 year. Intact parathyroid hormone decreased significantly after 24 weeks (P < 0.001), but levels returned to near baseline values by Week 52; minimal changes in serum calcium were observed. Of the bone resorption markers evaluated, tartrate-resistant acid phosphatase 5b (TRAP5b) decreased significantly (P < 0.001), whereas CTx increased transiently but returned to baseline levels by Week 52. The bone formation markers bone-specific alkaline phosphatase and osteocalcin both increased over 1 year of treatment. CONCLUSIONS Overall, 1 year of sucroferric oxyhydroxide or sevelamer treatment significantly reduced serum FGF-23, which has been associated with clinical benefit in patients with CKD. The trend towards increased bone formation marker levels indicates a beneficial effect on bone metabolism.
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Effect of preoperative injection of superparamagnetic iron oxide particles on rates of sentinel lymph node dissection in women undergoing surgery for ductal carcinoma in situ (SentiNot study).
Karakatsanis, A, Hersi, AF, Pistiolis, L, Olofsson Bagge, R, Lykoudis, PM, Eriksson, S, Wärnberg, F, ,
The British journal of surgery. 2019;(6):720-728
Abstract
BACKGROUND One-fifth of patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS) have invasive breast cancer (IBC) on definitive histology. Sentinel lymph node dissection (SLND) is performed in almost half of women having surgery for DCIS in Sweden. The aim of the present study was to try to minimize unnecessary SLND by injecting superparamagnetic iron oxide (SPIO) nanoparticles at the time of primary breast surgery, enabling SLND to be performed later, if IBC is found in the primary specimen. METHODS Women with DCIS at high risk for the presence of invasion undergoing breast conservation, and patients with DCIS undergoing mastectomy were included. The primary outcome was whether this technique could reduce SLND. Secondary outcomes were number of SLNDs avoided, detection rate and procedure-related costs. RESULTS This was a preplanned interim analysis of 189 procedures. IBC was found in 47 and a secondary SLND was performed in 41 women. Thus, 78·3 per cent of patients avoided SLND (P < 0·001). At reoperation, SPIO plus blue dye outperformed isotope and blue dye in detection of the sentinel node (40 of 40 versus 26 of 40 women; P < 0·001). Costs were reduced by a mean of 24·5 per cent in women without IBC (€3990 versus 5286; P < 0·001). CONCLUSION Marking the sentinel node with SPIO in women having surgery for DCIS was effective at avoiding unnecessary SLND in this study. Registration number: ISRCTN18430240 (http://www.isrctn.com).
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A controlled study of the effects of ferric carboxymaltose on bone and haematinic biomarkers in chronic kidney disease and pregnancy.
Huang, LL, Lee, D, Troster, SM, Kent, AB, Roberts, MA, Macdougall, IC, McMahon, LP
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2018;(9):1628-1635
Abstract
BACKGROUND Intravenous (IV) iron can modulate fibroblast growth factor 23 (FGF23) concentrations and cause transient but significant hypophosphataemia. However, it is unknown what other markers might be involved, especially in different patient groups. This study aimed to determine changes in bone and haematinic biomarkers following IV ferric carboxymaltose (FCM) and to identify risk factors for hypophosphataemia in pregnant subjects and those with chronic kidney disease (CKD). METHODS Changes in bone [serum FGF23, fractional excretion of phosphate urinary fractional excretion of phosphate (FEPi), serum phosphate and serum vitamin D derivatives] and haematinic [plasma hepcidin, serum ferritin and transferrin saturation (TSAT)] biomarkers after 1 g of IV FCM were followed in iron-deficient pregnant and CKD patients and compared with controls (estimated glomerular filtration rate > 60 mL/min/1.73 m2). Data were collected at baseline and up to 42 days after infusion. Risk factors for post-FCM hypophosphataemia were also assessed. RESULTS Sixty-five subjects completed the study (control, n = 20; pregnant, n = 20; CKD, n = 25). A uniform but variable increase across groups was seen in intact FGF23 (peak Day 2), whereas c-terminal FGF23 varied markedly. Trough serum phosphate timed with the peak FEPi at Day 7, recovering by Day 21 in the pregnant group and Day 42 in other groups. Independent predictors of a low phosphate nadir included baseline phosphate, FEPi and weight-adjusted FCM dose. All groups showed an early and marked increase in plasma hepcidin (peak Day 2), serum ferritin and TSAT (peak Day 7 for both). CONCLUSIONS Changes in bone and haematinic biomarkers differ between patient groups following IV FCM. For patients with lower serum phosphate concentrations, limiting the dose and measuring levels 7 days after administration may mitigate clinically significant hypophosphataemia.
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Simplifying Logistics and Avoiding the Unnecessary in Patients With Breast Cancer Undergoing Sentinel Node Biopsy. A Prospective Feasibility Trial of the Preoperative Injection of Super Paramagnetic Iron Oxide Nanoparticles.
Karakatsanis, A, Olofsson, H, Stålberg, P, Bergkvist, L, Abdsaleh, S, Wärnberg, F
Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society. 2018;(2):130-137
Abstract
PURPOSE Sentinel node is routinely localized with the intraoperative use of a radioactive tracer, involving challenging logistics. Super paramagnetic iron oxide nanoparticle is a non-radioactive tracer with comparable performance that could allow for preoperative localization, would simplify the procedure, and possibly be of value in axillary mapping before neoadjuvant treatment. The current trial aimed to determine the a priori hypothesis that the injection of super paramagnetic iron oxide nanoparticles in the preoperative period for the localization of the sentinel node is feasible. METHODS This is a prospective feasibility trial, conducted from 9 September 2014 to 22 October 2014 at Uppsala University Hospital. In all, 12 consecutive patients with primary breast cancer planned for resection of the primary and sentinel node biopsy were recruited. Super paramagnetic iron oxide nanoparticles were injected in the preoperative visit in the outpatient clinic. The radioactive tracer (99mTc) and the blue dye were injected perioperatively in standard fashion. A volunteer was injected with super paramagnetic iron oxide nanoparticles to follow the decline in the magnetic signal in the sentinel node over time. The primary outcome was successful sentinel node detection. RESULTS Super paramagnetic iron oxide nanoparticles' detection after preoperative injection (3-15 days) was successful in all cases (100%). In the volunteer, axillary signal was presented for 4 weeks. No adverse effects were noted. Conclusion and relevance: Preoperative super paramagnetic iron oxide nanoparticles' injection is feasible and leads to successful detection of the sentinel node. That may lead to simplified logistics as well as the identification, sampling, and marking of the sentinel node in patients planned for neoadjuvant treatment.
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Long-Term Assessment of the Safety and Efficacy of PA21 (Sucroferric Oxyhydroxide) in Japanese Hemodialysis Patients With Hyperphosphatemia: An Open-Label, Multicenter, Phase III Study.
Koiwa, F, Yokoyama, K, Fukagawa, M, Akizawa, T
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2017;(5):346-354
Abstract
OBJECTIVE The objective of this article was to assess the safety and efficacy of long-term administration of PA21. DESIGN AND METHODS Phase III, open-label, long-term study in 15 sites in Japan. SUBJECTS Japanese hemodialysis patients (N = 161) with hyperphosphatemia aged ≥20 years undergoing stable maintenance hemodialysis 3 times weekly, for ≥12 weeks. INTERVENTION After a 2-week observation period with their previous hyperphosphatemia therapy, patients began the 52-week treatment with PA21, which was administered orally at an initial dose of 250 mg, 3 times daily, immediately before every meal (dosing range between 750 and 3,000 mg/day). MAIN OUTCOME MEASURE Safety was evaluated based on the development of adverse events and adverse drug reactions (ADRs). Efficacy was evaluated according to serum phosphorus concentration, corrected serum calcium concentration, and serum intact-parathyroid hormone concentration. RESULTS The mean serum phosphorus concentration decreased from 5.46 ± 1.06 mg/dL at baseline to 5.00 ± 1.17 mg/dL at end of treatment. The serum phosphorus concentration was maintained within the target range (3.5-6.0 mg/dL) throughout the 52 weeks of the study period with a mean of 3.3 tablets per day of PA21. Most ADRs were mild, transient, and developed early during treatment, and the incidence was not shown to increase with long-term treatment. The most frequently reported ADR was diarrhea (22.4%). CONCLUSION Treatment with PA21 was effective in lowering and maintaining target serum phosphorus concentrations in Japanese hemodialysis patients with hyperphosphatemia over 52 weeks. PA21 was generally well tolerated in the long term.
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The Ferumoxytol for Anemia of CKD Trial (FACT)-a randomized controlled trial of repeated doses of ferumoxytol or iron sucrose in patients on hemodialysis: background and rationale.
Macdougall, IC, Dahl, NV, Bernard, K, Li, Z, Batycky, A, Strauss, WE
BMC nephrology. 2017;(1):117
Abstract
BACKGROUND Iron deficiency anemia (IDA) is a common manifestation of chronic kidney disease (CKD), affecting most patients on hemodialysis and imposing a substantial clinical burden. Treatment with iron supplementation increases hemoglobin levels and can reduce the severity of anemia in patients with CKD. While correcting anemia in these patients is an important therapeutic goal, there is a lack of long-term trials directly comparing intravenous iron therapies in patients with CKD receiving hemodialysis. METHODS/DESIGN The Ferumoxytol for Anemia of CKD Trial (FACT) is a 13-month, open-label, randomized, multicenter, international, prospective study with 2 substudies. Entry criteria for the main study include adults with IDA (defined as hemoglobin <11.5 g/dL [<115.0 g/L] and a transferrin saturation <30%), serum ferritin <800 ng/mL (<1798 pmol/L), and receiving hemodialysis for ≥3 months. Patients are randomized to receive ferumoxytol (1.02 g over 2 doses) or iron sucrose (1.0 g over 10 doses) during the initial 5-week treatment period. Those with persistent/recurrent IDA over the 11-month observation period will receive additional 5-week treatment periods, as appropriate. The primary efficacy endpoint of the main study is the mean change in hemoglobin from Baseline to Week 5 for each treatment period. The secondary efficacy endpoints include the mean change in transferrin saturation from Baseline to Week 5 and the proportion of patients with a hemoglobin increase of ≥1.0 g/dL at any time from Baseline to Week 5. Safety will be assessed through an examination of the adverse event profile over the course of the study. An "oxidative stress" substudy in approximately 100 patients will assess the effects of treatment on biomarkers of oxidative stress/inflammation during the initial 5-week treatment period, and a magnetic resonance imaging substudy in approximately 70 patients will assess the potential for iron deposition in target tissues over 24 months. DISCUSSION FACT fulfills the need for a long-term comparative trial in patients with IDA and CKD receiving hemodialysis. The efficacy and safety results will provide useful information for guiding therapy in this population. Two hundred ninety-six patients have been enrolled, and completion of the main study is expected soon. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01227616 (registered October 22, 2010); EudraCT number: 2010-022133-28.
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Iron-related parameters in dialysis patients treated with sucroferric oxyhydroxide.
Covic, AC, Floege, J, Ketteler, M, Sprague, SM, Lisk, L, Rakov, V, Rastogi, A
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(8):1330-1338
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BACKGROUND Sucroferric oxyhydroxide is a non-calcium, iron-based phosphate binder indicated for the treatment of hyperphosphataemia in adult dialysis patients. This post hoc analysis of a randomized, 24-week Phase 3 study and its 28-week extension was performed to evaluate the long-term effect of sucroferric oxyhydroxide on iron parameters. METHODS A total of 1059 patients were randomized to sucroferric oxyhydroxide 1.0-3.0 g/day (n = 710) or sevelamer carbonate ('sevelamer') 2.4-14.4 g/day (n = 349) for up to 52 weeks. The current analysis only included patients who completed 52 weeks of continuous treatment (n = 549). Changes in iron-related parameters and anti-anaemic product use during the study were measured. RESULTS Some changes in iron-related parameters across both treatment groups were observed during the first 24 weeks of the study, and to a lesser extent with longer-term treatment. There were small, but significantly greater increases in mean transferrin saturation (TSAT) and haemoglobin levels with sucroferric oxyhydroxide versus sevelamer during the first 24 weeks (change in TSAT +4.6% versus +0.6%, P = 0.003; change in haemoglobin: +1.6 g/L versus -1.1 g/L, P = 0.037). Mean serum ferritin concentrations also increased from Weeks 0 to 24 with sucroferric oxyhydroxide and sevelamer (+119 ng/mL and +56.2 ng/mL respectively; no statistically significant difference between groups). In both treatment groups, ferritin concentrations increased to a greater extent in the overall study population [>70% of whom received concomitant intravenous (IV) iron], compared with the subset of patients who did not receive IV iron therapy during the study. The pattern of anti-anaemic product use was similar in both treatment groups, with a trend towards higher use of IV iron and erythropoiesis-stimulating agents with sevelamer. CONCLUSIONS Initial increases in some iron-related parameters were observed in both treatment groups but were more pronounced with sucroferric oxyhydroxide. These differences between treatment groups with respect to changes in iron parameters are likely due to minimal iron absorption from sucroferric oxyhydroxide.
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Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial.
Trenkwalder, C, Winkelmann, J, Oertel, W, Virgin, G, Roubert, B, Mezzacasa, A, ,
Movement disorders : official journal of the Movement Disorder Society. 2017;(10):1478-1482
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BACKGROUND Compromised iron status is important in restless legs syndrome pathophysiology. We compared the efficacy and tolerability of ferric carboxymaltose (single intravenous dose) versus placebo for restless legs syndrome treatment in iron-deficient nonanemic patients. METHODS Patients with moderate to severe restless legs syndrome and serum ferritin < 75 μg/L (or serum ferritin 75-300 μg/L and transferrin saturation < 20%) were randomized to ferric carboxymaltose (1000 mg iron) or placebo. Mean change difference between ferric carboxymaltose and placebo in International Restless Legs Syndrome Severity Scale score from baseline to week 4 was the primary end point; week 12 was a secondary end point. RESULTS Ferric carboxymaltose treatment (n = 59) led to nonsignificant improvement over placebo (n = 51) in International Restless Legs Syndrome Severity Scale score at week 4 (difference [95% confidence interval], -2.5 [-5.93 to 1.02], P = 0.163), reaching significance by week 12 (-4.66 [-8.59 to -0.73], P = 0.021). CONCLUSIONS In patients who responded to treatment, ferric carboxymaltose may require more time to stabilize restless legs syndrome than previously assumed. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency.
van Veldhuisen, DJ, Ponikowski, P, van der Meer, P, Metra, M, Böhm, M, Doletsky, A, Voors, AA, Macdougall, IC, Anker, SD, Roubert, B, et al
Circulation. 2017;(15):1374-1383
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BACKGROUND Iron deficiency is common in patients with heart failure (HF) and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO2], an objective measure of exercise intolerance in HF, has not been examined. METHODS We studied patients with systolic HF (left ventricular ejection fraction ≤45%) and mild to moderate symptoms despite optimal HF medication. Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary end point was the change in peak VO2 from baseline to 24 weeks. Secondary end points included the effect on hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of 0 imputed for 24-week peak VO2. Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data. RESULTS A total of 172 patients with HF were studied and received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well matched; mean age was 64 years, 75% were male, mean left ventricular ejection fraction was 32%, and peak VO2 was 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO2 had decreased in the control group (least square means -1.19±0.389 mL/min/kg) but was maintained on FCM (-0.16±0.387 mL/min/kg; P=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO2 at 24 weeks decreased by -0.63±0.375 mL/min/kg in the control group and by -0.16±0.373 mL/min/kg in the FCM group; P=0.23 between groups). Patients' global assessment and functional class as assessed by the New York Heart Association improved on FCM versus standard of care. CONCLUSIONS Treatment with intravenous FCM in patients with HF and iron deficiency improves iron stores. Although a favorable effect on peak VO2 was observed on FCM, compared with standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01394562.