Safety and Efficacy of Ferric Carboxymaltose in the Treatment of Iron Deficiency Anaemia in Patients with Inflammatory Bowel Disease, in Routine Daily Practice

Safety and Efficacy of Ferric Carboxymaltose in the Treatment of Iron Deficiency Anaemia in... Abstract Introduction Iron deficiency and iron deficiency anaemia are common complications in inflammatory bowel disease [IBD] patients. Anaemia in IBD is attributable to chronic blood loss and/or impaired iron intake and absorption. International guidelines recommend intravenous iron supplementation in IBD patients, since oral supplements are frequently poorly tolerated and can exacerbate inflammation. Intravenous ferric carboxymaltose [FCM; Ferinject® 50 mg ferric iron[III]/mL suspension] was approved in Europe in 2007 for correction of iron deficiency, and can be administered in single 15-min infusions of up to 1000 mg. Methods A prospective non-interventional post-marketing study was performed in 101 centres in Germany to assess the efficacy, tolerability, and convenience of Ferinject® in clinical practice in a large cohort of IBD patients. Primary endpoints were haemoglobin [Hb] normalisation or increase ≥2 g/dL [responders], and normalisation of serum ferritin [s-ferritin] and transferrin saturation. Adverse events [AEs], clinical signs/symptoms, and disease activity indices were also analysed. Results In all, 224 subjects (127 Crohn’s disease [CD]; 97 ulcerative colitis [UC]) were treated. Mean total iron dose was 1139 mg [range: 100 mg-4800 mg], with 76.7% of doses between 500 mg and 2000 mg; 63.3% of patients responded, and no adverse drug reactions or drug-attributed serious adverse events [SAEs] or deaths occurred. Mean increases of Hb [10.0 to 12.3 g/dL], ferritin [52 μg/L to 103 μg/L], transferrin saturation [TSAT, 15% to 25%], and s-iron [6.1 to 12.4 μmol/L] were significant [p = 0.0001]. Clinical scores and quality of life improved due to the amelioration of anaemia symptoms. Conclusions Ferinject®-therapy was proven to be effective and safe in a large cohort of patients with IBD-associated anaemia in routine practice. Rapid, high-dose application is convenient for physicians and reduces patients’ time lost from work. IBD, iron deficiency anaemia, ferric carboxymaltose 1. Introduction Iron deficiency [ID] and subsequent anaemia are common complications in patients with inflammatory bowel disease [IBD], a set of chronic intestinal conditions including Crohn’s disease [CD] and ulcerative colitis [UC] which share a variety of symptoms including diarrhoea, abdominal pain, and fever, as well as extraintestinal manifestations affecting the joints, skin, and eyes. Anaemia in IBD has multiple causes,1,2 the most prevalent being iron deficiency.6 Iron deficiency occurs in up to 90% of IBD patients,3 often progressively deteriorating to the point of manifest iron deficiency anaemia [IDA], which has a major impact on quality of life in IBD patients.4,5 IDA is largely attributable to chronic blood loss from the ulcerated intestinal mucosa and/or to impairment of iron intake and absorption.6–8 Symptoms of IDA include fatigue, headache, hair loss, and [exertional] dyspnoea. In addition, restless legs syndrome has been shown to occur at an approximately nine-fold higher rate in individuals with IDA than in the overall population.9 The goals of anaemia treatment are to raise haemoglobin, serum ferritin [s-ferritin], and transferrin saturation [TSAT] levels above the lower threshold of normal [LLN], thus not only restoring short-term haematopoietic status but also replenishing iron stores to prevent recurrence of anaemia. Iron supplementation is recommended even if iron deficiency occurs without reduction of haemoglobin concentration.10,11 Oral iron replacement is of limited value, failing to balance continuous iron loss due to inadequate intestinal absorption in the presence of inflammation.2,11 Furthermore, non-absorbed iron has been shown to enhance mucosal inflammation in animal models and increase clinical activity in IBD patients.12,13 In contrast, intravenous [IV] iron has been demonstrated to be safe, effective, and well tolerated in both the correction of IDA and the maintenance of iron stores in patients with IBD.12,14,15 Moreover, intravenous iron replacement not only facilitates the faster correction of ID and repletion of body iron stores, but also effectively avoids gastrointestinal [GI] side effects by bypassing the GI tract. Several intravenous iron preparations are currently available for treatment of IDA. Such formulations differ by complex chemistry and can be grouped into labile, semi-labile, and stable iron complexes.16,17 Of all the IV iron compounds available, by far the largest number of pharmacology studies, phase I to III clinical trials, and controlled clinical trials in IBD patients have been performed with ferric carboxymaltose [FCM].18–21 These trials have proved its efficacy and tolerability in IBD-associated anaemia. No safety concerns have been identified. However, published data concerning routine use in daily practice are still limited. This post-marketing surveillance study was designed and performed to assess the safety and efficacy of FCM in a large cohort of patients under routine daily conditions. 2. Materials and Methods 2.1. Study design This non-interventional study [NIS] was designed as a prospective, multicentre survey without influence on regular treatment of patients by the attending physician in routine medical care. Physicians [hospital gastroenterologists, specialists in internal medicine, and general practitioners] in 101 German treatment centres were recruited to enrol patients and to complete treatment documentation according to the study protocol. Due to the non-interventional character of the study, subjects were treated based on the medical needs of their underlying disease in accordance with therapy requirements published in the German Physicians’ Circular [GPC]. The observation period extended from November 2008 [first patient, first visit] to August 2010 [last patient, last visit]. For each individual subject, the study duration was approximately 12 weeks, and at least two visits were planned: baseline visit [start of treatment with Ferinject®] and last visit [end of therapy or Week 12–14]. 2.2. Patient characteristics and definitions Patients at 101 treatment centres who were due to receive iron replacement therapy with ferric carboxymaltose, based on the indication and therapy requirements according to the GPC and Summary of Product Characteristics [age ≥18 years, iron deficiency anaemia based on chronic IBD, therapeutic necessity for IV iron substitution], were invited to participate in the observational study; 223 patients gave written informed consent and were enrolled in the study. All patients were FCM-naïve. 2.3. Intervention The patients received FCM according to the usual therapeutic procedure of the attending physician and in accordance with the authorised indications of the Summary of Product Characteristics for ferric carboxymaltose. Mean number of infusions given during the observation period was 3.3 [range 1–10]. 2.4. Efficacy and safety analysis The primary efficacy endpoint was response to treatment, defined as correction of anaemia (haemoglobin [[Hb] ≥13 g/dL in men and ≥12 g/dL in women) or Hb increase of 2 g/dL or more. Partial response was defined as Hb increase of 1 g/dL or more but less than 2 g/dL, without anaemia correction. Secondary analyses included normalisation of serum ferritin [s-ferritin] and serum transferrin saturation [TSAT] and predictive values to treatment response according to gender, age, and baseline measurements of iron parameters. For the analysis of efficacy parameters, all available data were used. Clinical signs/symptoms associated with anaemia were analysed according to a self-devised ‘symptom scale’ by shift tables comparing beginning of study [BOS] and end of study [EOS] visits for all patients, and stratified by gender, risk factors, and underlying disease type [CD/UC]. Analyses of demographic data were performed on the total evaluable population comprising 223 patients [entitled: ‘total group’] and additionally for two subpopulations; patients evaluable for effectiveness [n = 150, entitled: ‘efficacy group’] and the safety population [n = 193, entitled: ‘safety group’]. The disposition of patients is shown in Figure 1. Figure 1. View largeDownload slide Disposition of patients. Figure 1. View largeDownload slide Disposition of patients. For the safety analysis, EOS documentations of 193 FCM-treated patients were returned, and from these safety data were extracted. Both paper case report forms CRFs] and electronic CRFs [eCRFs] were screened daily for adverse events [AEs] or suspected adverse drug reactions [ADRs]. In case of doubt, queries were issued in order to clarify the documentation. In addition to primary and secondary endpoints, demographic data and additional laboratory parameters were documented, i.e. C-reactive protein [CRP], serum transferrin [s-transferrin], serum iron [s-Fe], liver enzymes [γ-GT, ALAT, ASAT], lipoproteins [HDL, LDL], triglycerides, and glucose. In addition, disease activity was recorded by means of the Crohn’s Disease Activity Index [CDAI]22 or the Clinical Activity Index for ulcerative colitis [CAI].23 For the analysis of treatment effectiveness in different inflammatory states, patients were divided into the following CRP subgroups: CRP <5 mg/L [no inflammation] and CRP ≥5 mg/L [inflammation]. The latter subgroup was further divided into CRP 5‑10 mg/L [moderate inflammation] and CRP >10 mg/L [severe inflammation]. 2.5. Ethics The study proposal had been submitted to the responsible local ethics commissions as well as the German Federal Institute for Drugs and Medical Devices [BfArM]. The National Association of Statutory Health Insurance Physicians was informed of the names of participating physicians. The study was registered and published according to the recommendations of the VFA [German Association of Research-Based Pharmaceutical Companies] [http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_232]. 2.6. Statistical methods All statistical methods were predefined in the statistical analysis plan, based on the International Conference on Harmonisation [ICH E9] publication: Guidance for Industry on Statistical Principles for Clinical Trials.24 Collected data were analysed and reported by SAS software [Version 9.2]. The analysis was performed in an exploratory manner using descriptive statistical methods. For the valuation of differences, a two-sided Student’s t-test, with α = 0.05, was adopted. Data from premature study termination visits between Weeks 4 and 12 after inclusion were accounted to the visit week in which they actually occurred. Termination visits at Week 12, 13, or 14 were accounted to Week 12. For these patients, changes from baseline to last recorded value were analysed. Other patients were considered not evaluable. 3. Results 3.1 Patients and treatments A total of 101 centres started documentation for 223 patients for this NIS [‘total group’]. For 30 subjects, no end-of-study [EOS] documentation was done, or they did not actually receive Ferinject® infusions. Documentation of the remaining 193 patients [86.5%; n = 223] were returned to the Contract Research Organisation and included in the safety evaluation [‘safety group’]. For 42 patients [18.8%; n = 223] of the safety group, data from their premature termination visit [between Weeks 4 and 14 post inclusion] were not documented. In addition, for one patient [0.4%; n = 223] baseline data were not recorded. The remaining 150 individuals [67.3%; n = 223] met the endpoints and were therefore included in the efficacy analysis [‘efficacy group’]. Gender distribution was comparable in all three groups: 137 patients [61.4 %; n = 223] in the total group, 114 [59.1%; n = 193] within the safety group, and 92 [61.3%; n = 150] in the efficacy group were female. Age characteristics were also very similar in each of these groups: mean [aM] age was approximately 39 years (Standard deviation [SD] ±14) and age distribution range 18 to 83 years, with a median age of 36 years [Table 1]. Table 1. Baseline patient characteristics. All patients Crohn’s disease Ulcerative colitis n [%] n [%] n [%] Patients 193a [100%] 115 [59.9%] 77 [40.1%] Age [years] [mean±SD] 38.7 ± 13.70 39.1 ± 13.98 38.5 ± 14.57 Gender  Male 79 [41%] 43 [37.4%] 36 [46.8%]  Female 114a [59%] 72 [62.6%] 41 [53.2%] CDAI [median, range] - 190 [48–530] - CAI [median, range] - - 8 [0–347] CRP [ mg/L] [median, range] 5.95 [0–108] 6.84 [0–108] 4.62 [0–56.7] Haemoglobin [g/dL] [mean±SD] 10.1 ± 1.41 10.0 ± 1.35 10.2 ± 1.50 Ferritin [μg/L] [median, range] 14.0 [1.0–1000] 13.0 [1.6–1000] 15.5 [1.0–535] TSAT [%] [median, range] 10.0 [0.9–85] 10.0 [1.8–51] 12.2 [0.9–85.0] Medication  Aminosalicylates 89 [46.1%] 55 [47.8%] 34 [44.2%]  Steroids 84 [43.5%] 55 [47.8%] 29 [37.7%]  Immunosuppressants 36 [18.7%] 18 [15.7%] 18 [23.4%]  Biologics 36 [19%] 18 [23%] 18 [16%]  Antibiotics 8 [4.1%] 3 [2.6%] 5 [6.5%]  Antidiarrhoeics 11 [5.7%] 3 [2.6%] 8 [10.4%] All patients Crohn’s disease Ulcerative colitis n [%] n [%] n [%] Patients 193a [100%] 115 [59.9%] 77 [40.1%] Age [years] [mean±SD] 38.7 ± 13.70 39.1 ± 13.98 38.5 ± 14.57 Gender  Male 79 [41%] 43 [37.4%] 36 [46.8%]  Female 114a [59%] 72 [62.6%] 41 [53.2%] CDAI [median, range] - 190 [48–530] - CAI [median, range] - - 8 [0–347] CRP [ mg/L] [median, range] 5.95 [0–108] 6.84 [0–108] 4.62 [0–56.7] Haemoglobin [g/dL] [mean±SD] 10.1 ± 1.41 10.0 ± 1.35 10.2 ± 1.50 Ferritin [μg/L] [median, range] 14.0 [1.0–1000] 13.0 [1.6–1000] 15.5 [1.0–535] TSAT [%] [median, range] 10.0 [0.9–85] 10.0 [1.8–51] 12.2 [0.9–85.0] Medication  Aminosalicylates 89 [46.1%] 55 [47.8%] 34 [44.2%]  Steroids 84 [43.5%] 55 [47.8%] 29 [37.7%]  Immunosuppressants 36 [18.7%] 18 [15.7%] 18 [23.4%]  Biologics 36 [19%] 18 [23%] 18 [16%]  Antibiotics 8 [4.1%] 3 [2.6%] 5 [6.5%]  Antidiarrhoeics 11 [5.7%] 3 [2.6%] 8 [10.4%] SD, standard deviation; CDAI, Crohn’s Disease Activity Index; CAI, Clinical Colitis Activity Index; CRP, C-reactive protein; TSAT, transferrin saturation. aIncluding one patient with indeterminate IBD disease type. View Large Table 1. Baseline patient characteristics. All patients Crohn’s disease Ulcerative colitis n [%] n [%] n [%] Patients 193a [100%] 115 [59.9%] 77 [40.1%] Age [years] [mean±SD] 38.7 ± 13.70 39.1 ± 13.98 38.5 ± 14.57 Gender  Male 79 [41%] 43 [37.4%] 36 [46.8%]  Female 114a [59%] 72 [62.6%] 41 [53.2%] CDAI [median, range] - 190 [48–530] - CAI [median, range] - - 8 [0–347] CRP [ mg/L] [median, range] 5.95 [0–108] 6.84 [0–108] 4.62 [0–56.7] Haemoglobin [g/dL] [mean±SD] 10.1 ± 1.41 10.0 ± 1.35 10.2 ± 1.50 Ferritin [μg/L] [median, range] 14.0 [1.0–1000] 13.0 [1.6–1000] 15.5 [1.0–535] TSAT [%] [median, range] 10.0 [0.9–85] 10.0 [1.8–51] 12.2 [0.9–85.0] Medication  Aminosalicylates 89 [46.1%] 55 [47.8%] 34 [44.2%]  Steroids 84 [43.5%] 55 [47.8%] 29 [37.7%]  Immunosuppressants 36 [18.7%] 18 [15.7%] 18 [23.4%]  Biologics 36 [19%] 18 [23%] 18 [16%]  Antibiotics 8 [4.1%] 3 [2.6%] 5 [6.5%]  Antidiarrhoeics 11 [5.7%] 3 [2.6%] 8 [10.4%] All patients Crohn’s disease Ulcerative colitis n [%] n [%] n [%] Patients 193a [100%] 115 [59.9%] 77 [40.1%] Age [years] [mean±SD] 38.7 ± 13.70 39.1 ± 13.98 38.5 ± 14.57 Gender  Male 79 [41%] 43 [37.4%] 36 [46.8%]  Female 114a [59%] 72 [62.6%] 41 [53.2%] CDAI [median, range] - 190 [48–530] - CAI [median, range] - - 8 [0–347] CRP [ mg/L] [median, range] 5.95 [0–108] 6.84 [0–108] 4.62 [0–56.7] Haemoglobin [g/dL] [mean±SD] 10.1 ± 1.41 10.0 ± 1.35 10.2 ± 1.50 Ferritin [μg/L] [median, range] 14.0 [1.0–1000] 13.0 [1.6–1000] 15.5 [1.0–535] TSAT [%] [median, range] 10.0 [0.9–85] 10.0 [1.8–51] 12.2 [0.9–85.0] Medication  Aminosalicylates 89 [46.1%] 55 [47.8%] 34 [44.2%]  Steroids 84 [43.5%] 55 [47.8%] 29 [37.7%]  Immunosuppressants 36 [18.7%] 18 [15.7%] 18 [23.4%]  Biologics 36 [19%] 18 [23%] 18 [16%]  Antibiotics 8 [4.1%] 3 [2.6%] 5 [6.5%]  Antidiarrhoeics 11 [5.7%] 3 [2.6%] 8 [10.4%] SD, standard deviation; CDAI, Crohn’s Disease Activity Index; CAI, Clinical Colitis Activity Index; CRP, C-reactive protein; TSAT, transferrin saturation. aIncluding one patient with indeterminate IBD disease type. View Large 3.2 Exposure to [dosing of] iron A total of 495 intravenous FCM treatment courses were given to 193 IBD patients. Due to the non-interventional nature of the study, dose calculations and infusion regimens were determined by the treating physicians purely according to the patients’ medical needs and in the context of regular clinical practice. Median total FCM dosage of the 150 patients in the efficacy group was 975 mg, with total doses ranging from 100 mg to 4800 mg. FCM was most commonly administered at cumulative doses of between 500 mg and 2000 mg [76.7%] [7.3% received <500 mg, 9.3% received 2000–3000 mg, and 6.7% received >3000 mg]. The mean minimum single dose per patient was 431 ± 301.65 mg, and the mean maximum single dose was 508 ± 321.01 mg. In the efficacy group, 13 subjects received additional concomitant anti-anaemic treatment with oral iron compounds. The response in patients receiving oral iron was, however, not significantly different from patients treated with Ferinject® only [results not shown]. Concerning number of infusions, 1-10 infusions were applied to the patients in the efficacy group, with a median value of two infusions. The median time period from first to last infusion was 22 days [range 0–96]. Median infusion duration for all evaluable patients was 15 min [range 5 to 75 min]. Infusion times were longest for the lowest [<500 mg], as well as for higher [2000 mg to <3000 mg] dosages. Median dilution of infusion was 250 mL [range 10 mL to 500 mL]. 3.3 Treatment efficacy 3.3.1 Haemoglobin Within the efficacy group, haemoglobin [Hb] values were evaluable in 148 patients. Absolute Hb values were ≥10 g/dL in 86 patients [58.1%], 8 to 10 g/dL [33.1%] in 49 patients, and <8 g/dL in 13 patients [8.8%]. Visit-by-visit changes in Hb levels from BOS to EOS for subgroups according to baseline Hb are shown in Figure 2a. In all subgroups, the mean increase in Hb was statistically significant. In 114 patients [77%], Hb increased by more than 1 g/dL and to a value ≥11 g/dL. In 79 [53.4%] patients, Hb increased by more than 2 g/dL and up to LLN, i.e. ≥12 g/dL in women or ≥13 g/dL in men. The primary efficacy endpoint of Hb normalisation or increase of ≥2 g/dL was reached by 63.3% of patients. Figure 2. View largeDownload slide Visit-by-visit changes in clinical parameters for the two baseline haemoglobin groups. Figure 2. View largeDownload slide Visit-by-visit changes in clinical parameters for the two baseline haemoglobin groups. In subgroups of patients with lower [<10 g/dL] or higher [≥10 g/dL] Hb at baseline, a comparison of the visit-by-visit increments of Hb increase indicates rapid improvement between BOS and the second visit between Weeks 4 and 8 for both groups. Even though only 40 subjects had a visit between these two time points, a greater increase [Δ = 2.5 g/dL] was found in patients with low baseline Hb compared with patients with higher baseline Hb values [Δ = 1.5 g/dL] [data not shown]. These improvements were sustained for the whole observation period and resulted in a greater mean difference of 3.1 g/dL in subjects with low baseline Hb values compared with 1.7 g/dL in subjects with higher baseline Hb [data not shown]. 3.3.2 Serum ferritin and transferrin saturation Mean ferritin level in the efficacy group was 53 [±126] μg/L at BOS, increasing to 110 [±148] μg/L after treatment with FCM. Mean increase in ferritin from BOS to EOS was 58.5 [±160.0] μg/L [p <0.0001]. Figure 2b compares changes of ferritin values in patients with low [<10 g/dL] or higher [≥10 g/dL] Hb at baseline, indicating a rapid improvement between the first and second visits in the low Hb subgroup. Only minor changes in ferritin levels from BOS to EOS were observed in the subgroup with higher baseline Hb. Despite no significant difference in baseline ferritin values, the most substantial increase in ferritin occurred in patients with Hb levels <8 g/dL. Mean TSAT level in patients in the efficacy group increased under FCM treatment from 15.6 [±13.4]% at BOS to 24.2 [±20.2]% at EOS [p <0.001]. Stratification according to baseline Hb showed that mean TSAT was below LLN in all Hb subgroups. Mean TSAT values for Hb <10 g/dL and Hb ≥10 g/dL were 15% and both medians were 10%, and TSAT ranged from approximately 1% to far above the upper threshold of normal [85% vs 50% for the respective subgroups]. In all Hb subgroups, both mean [≈29% vs 23%] and median [25% vs 21%] TSAT values increased considerably, reaching normal range. Differences from EOS to BOS were +11.2% vs +6.7% [p <0.0001]. Changes in TSAT levels during the study are shown in Figure 2c. 3.3.3 Disease activity Although patients [n = 97] with elevated CD or UC activity indices [CDAI ≥150; CAI ≥5] presented with lower mean Hb values at BOS compared with those with normal activity indices, mean Hb levels at EOS were comparable, and changes in Hb from BOS to EOS were statistically significant for both patient groups [data not shown]. Subjects with higher indices also presented with higher mean CRP values at BOS [6.1 mg/L] compared with those with normal activity indices [3.6 mg/L]. Whereas at BOS, mean CRP levels were outside normal range, they were found to decrease during FCM therapy independently of baseline Hb levels [data not shown]. The change in CRP levels from BOS to EOS was statistically significant overall, as well as in patients with high disease activity, in CD and UC patients treated with a total dose of 500 to 1000 mg iron, and in patients who completed therapy. The decrease in disease activity indicated by lower CRP levels was confirmed by a reduction in mean values of the clinical disease activity indices CDAI and CAI [data not shown]. Patients in both CRP subgroups showed increases in Hb, serum ferritin, and TSAT. CRP and the number of symptoms decreased from baseline to end of study [Table 2]. Table 2. Parameters in CRP subgroups (only complete data pairs [BOS/EOS] were taken into account). Mean haemoglobin [g/dL] Mean ferritin [µg/L] Mean TSAT [%] Mean number of symptoms CRP [ mg/L] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] All patients 10.0 ± 1.4 12.3 ± 1.6 *** 53 ± 126 110 ± 148 *** 15.6 ± 13.4 24.2 ± 20.2 *** 4.8 ± 2.0 3.0 ± 2.0 *** 6.6 ± 14.5 4.1 ± 8.3 ** CRP <5 mg/L 9.9 ± 1.4 12.4 ± 1.6 *** 54 ± 122 105 ± 115 *** 17.0 ± 14.2 26.1 ± 14.4 *** 4.9 ± 2.0 3.0 ± 2.1 *** 1.5 ± 1.2 1.3 ± 1.7 CRP ≥5 mg/L 10.4 ± 1.3 12.0 ± 1.7 *** 49 ± 145 126 ± 230 9.8 ± 7.7 16.6 ± 34.5 ** 4.4 ± 1.8 3.1 ± 1.9 *** 22.3 ± 23.8 12.6 ± 13.4 * CRP 5–10 mg/L 10.3 ± 1.7 11.6 ± 2.1 * 25 ± 30 192 ± 339 11.5 ± 9.6 18.6 ± 53.6 4.4 ± 2.1 3.3 ± 2.0 * 7.3 ± 1.9 5.8 ± 3.2 * CRP >10 mg/L 10.5 ± 1.1 12.2 ± 1.3 *** 62 ± 178 89 ± 121 8.7 ± 6.0 15.3 ± 10.5 * 4.4 ± 1.5 3.0 ± 1.9 ** 30.3 ± 26.3 16.4 ± 14.4 * Mean haemoglobin [g/dL] Mean ferritin [µg/L] Mean TSAT [%] Mean number of symptoms CRP [ mg/L] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] All patients 10.0 ± 1.4 12.3 ± 1.6 *** 53 ± 126 110 ± 148 *** 15.6 ± 13.4 24.2 ± 20.2 *** 4.8 ± 2.0 3.0 ± 2.0 *** 6.6 ± 14.5 4.1 ± 8.3 ** CRP <5 mg/L 9.9 ± 1.4 12.4 ± 1.6 *** 54 ± 122 105 ± 115 *** 17.0 ± 14.2 26.1 ± 14.4 *** 4.9 ± 2.0 3.0 ± 2.1 *** 1.5 ± 1.2 1.3 ± 1.7 CRP ≥5 mg/L 10.4 ± 1.3 12.0 ± 1.7 *** 49 ± 145 126 ± 230 9.8 ± 7.7 16.6 ± 34.5 ** 4.4 ± 1.8 3.1 ± 1.9 *** 22.3 ± 23.8 12.6 ± 13.4 * CRP 5–10 mg/L 10.3 ± 1.7 11.6 ± 2.1 * 25 ± 30 192 ± 339 11.5 ± 9.6 18.6 ± 53.6 4.4 ± 2.1 3.3 ± 2.0 * 7.3 ± 1.9 5.8 ± 3.2 * CRP >10 mg/L 10.5 ± 1.1 12.2 ± 1.3 *** 62 ± 178 89 ± 121 8.7 ± 6.0 15.3 ± 10.5 * 4.4 ± 1.5 3.0 ± 1.9 ** 30.3 ± 26.3 16.4 ± 14.4 * CRP, C-reactive protein; BOS, beginning of study; EOS, end of study; p[Δ], p-value of change from BOS to EOS. *p < 0.05; **p < 0.01; ***p < 0.001. View Large Table 2. Parameters in CRP subgroups (only complete data pairs [BOS/EOS] were taken into account). Mean haemoglobin [g/dL] Mean ferritin [µg/L] Mean TSAT [%] Mean number of symptoms CRP [ mg/L] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] All patients 10.0 ± 1.4 12.3 ± 1.6 *** 53 ± 126 110 ± 148 *** 15.6 ± 13.4 24.2 ± 20.2 *** 4.8 ± 2.0 3.0 ± 2.0 *** 6.6 ± 14.5 4.1 ± 8.3 ** CRP <5 mg/L 9.9 ± 1.4 12.4 ± 1.6 *** 54 ± 122 105 ± 115 *** 17.0 ± 14.2 26.1 ± 14.4 *** 4.9 ± 2.0 3.0 ± 2.1 *** 1.5 ± 1.2 1.3 ± 1.7 CRP ≥5 mg/L 10.4 ± 1.3 12.0 ± 1.7 *** 49 ± 145 126 ± 230 9.8 ± 7.7 16.6 ± 34.5 ** 4.4 ± 1.8 3.1 ± 1.9 *** 22.3 ± 23.8 12.6 ± 13.4 * CRP 5–10 mg/L 10.3 ± 1.7 11.6 ± 2.1 * 25 ± 30 192 ± 339 11.5 ± 9.6 18.6 ± 53.6 4.4 ± 2.1 3.3 ± 2.0 * 7.3 ± 1.9 5.8 ± 3.2 * CRP >10 mg/L 10.5 ± 1.1 12.2 ± 1.3 *** 62 ± 178 89 ± 121 8.7 ± 6.0 15.3 ± 10.5 * 4.4 ± 1.5 3.0 ± 1.9 ** 30.3 ± 26.3 16.4 ± 14.4 * Mean haemoglobin [g/dL] Mean ferritin [µg/L] Mean TSAT [%] Mean number of symptoms CRP [ mg/L] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] All patients 10.0 ± 1.4 12.3 ± 1.6 *** 53 ± 126 110 ± 148 *** 15.6 ± 13.4 24.2 ± 20.2 *** 4.8 ± 2.0 3.0 ± 2.0 *** 6.6 ± 14.5 4.1 ± 8.3 ** CRP <5 mg/L 9.9 ± 1.4 12.4 ± 1.6 *** 54 ± 122 105 ± 115 *** 17.0 ± 14.2 26.1 ± 14.4 *** 4.9 ± 2.0 3.0 ± 2.1 *** 1.5 ± 1.2 1.3 ± 1.7 CRP ≥5 mg/L 10.4 ± 1.3 12.0 ± 1.7 *** 49 ± 145 126 ± 230 9.8 ± 7.7 16.6 ± 34.5 ** 4.4 ± 1.8 3.1 ± 1.9 *** 22.3 ± 23.8 12.6 ± 13.4 * CRP 5–10 mg/L 10.3 ± 1.7 11.6 ± 2.1 * 25 ± 30 192 ± 339 11.5 ± 9.6 18.6 ± 53.6 4.4 ± 2.1 3.3 ± 2.0 * 7.3 ± 1.9 5.8 ± 3.2 * CRP >10 mg/L 10.5 ± 1.1 12.2 ± 1.3 *** 62 ± 178 89 ± 121 8.7 ± 6.0 15.3 ± 10.5 * 4.4 ± 1.5 3.0 ± 1.9 ** 30.3 ± 26.3 16.4 ± 14.4 * CRP, C-reactive protein; BOS, beginning of study; EOS, end of study; p[Δ], p-value of change from BOS to EOS. *p < 0.05; **p < 0.01; ***p < 0.001. View Large 3.3.4 Clinical [non-haematological] parameters In order to assess the influence of IV iron treatment on their general well-being, patients were asked at BOS and EOS to evaluate the following anaemia-associated, clinical, non-haematological parameters for intensity, by rating them on a ‘symptom’ scale of 0 for ‘not present’ to 4 for ‘very severe’: fatigue, lack of concentration, headache, paleness of mucous membranes, hair loss, [exertional] dyspnoea, sleeping disorders, and restless legs syndrome. Whereas 146 patients [97%] reported at least one non-haematological symptom at baseline, 14 patients [9.3%] reported all eight symptoms. The average number of symptoms per patient at baseline was 4.7 ± 0.3. At EOS, this figure had significantly declined, with patients reporting an average of 3.0 ± 0.3 symptoms [p <0.001]. Furthermore, 14.7% of patients [22] were symptom-free, with only one patient reporting the presence of all symptoms. The most frequent symptom at baseline was ‘fatigue’, with 93% of patients reporting at least mild symptoms, and the rarest was ‘restless legs syndrome’ with 22%. For each of the symptoms, the number of affected patients decreased from BOS to the EOS, the most evident decreases being associated with paleness of mucous membranes, followed by [exertional] dyspnoea and lack of concentration [Figure 3]. Figure 3. View largeDownload slide Intensity of symptoms. Figure 3. View largeDownload slide Intensity of symptoms. The mean intensity of reported non-haematological symptoms at baseline varied between 1.7 [headache] and 2.3 [fatigue]. At EOS, mean intensity decreased to 0.3-1.2 points on the rating scale, with the biggest decreases observed in fatigue [1.2], headache [1.1], and paleness of mucous membranes [1.0]. 3.3.5 Predictive factors for response to intravenous iron Logistic regression analyses of the current data were performed. However, after removal of excess values and missing data, the sample size was too small to allow the identification of any predictors of response. 3.3.6 Safety Among the 193 patients representing the safety population, only one adverse event was reported, an aggravation of UC. This exacerbation was estimated by both physician and sponsor to be a serious adverse event [SAE], but the treating physician judged it to be unrelated to the drug. Treatment was stopped and the patient recovered without sequelae. To sum up the tolerability of FCM therapy, no treatment-related adverse drug reaction was documented. One SAE occurred in 193 patients during the 12-month observation period, but this was not drug-related. Premature treatment discontinuation was documented in only one patient, but the termination was not due to an AE. No deaths occurred. No clinical changes were documented in vital signs or physical examinations which could be considered an AE. Elevated serum ferritin was observed in one patient at EOS. 4. Discussion Iron deficiency [ID] is the main cause of anaemia in IBD patients. ID arises due to dietary restrictions, malabsorption, intestinal bleeding, and/or undertreatment of anaemia.3 Oral iron replacement is often unsuitable for anaemia therapy in IBD patients because of intolerance to oral iron compounds, abnormal absorption due to inflammation, non-compliance, and large iron deficits, all factors which limit the success of oral iron treatment for anaemia.7,8 The literature indicates that high doses of iron are often required in anaemic patients, with IBD patients requiring up to 3600 mg daily,4 and several international guidelines recommend the administration of intravenous iron formulations in preference to oral iron in the correction of IBD-associated anaemia.10,25,26 Nevertheless, a retrospective analysis of clinical practice in nine European countries in 2011 found that oral iron was administered to 68% of IBD patients with anaemia [with national rates varying from 24% to 83%], but only 32% [16% to 79%] received intravenous iron therapy.27 Our results underline that awareness of international guidelines on anaemia and iron therapy in IBD is still lacking, as evidenced by the very wide total dose range of 100 mg to 4800 mg. Furthermore, the fact that dose duration was longest not only for the largest, but also for the smallest doses [<500 mg] indicates that there is still some trepidation among physicians concerning the application of intravenous iron in general. FCM therapy has been demonstrated to be very effective and convincingly safe in IBD-associated anaemia in a large cohort of patients under daily routine conditions, and has also been shown to sufficiently replenish iron stores. In this NIS, all goals of anaemia treatment were met in the majority of patients: to increase Hb to normal levels or by at least 2 g/dL, and to raise serum ferritin and transferrin saturation above the lower limit of normal. Our results from daily routine practice confirm the results obtained in two pivotal clinical trials with FCM,18,19 covering an equally sized but selective and strictly-defined IBD patient collective. In these controlled trials, median Hb increased from 8.7 to 12.3 g/dL. Increments of Hb increase were found to be greatest at the second [and third] visit. Mean ferritin level in this NIS increased from 52 μg/L to 103 μg/L. Again, the ferritin increase [+51 μg/L] was most pronounced after Visit 2. This evidence of early response [Visit 2] is in agreement with previous FCM trials showing full response after 4–8 weeks.18,19 CRP levels showed a significant decrease during the observation period, falling from 6.4 mg/L to 3.5 mg/L in mean values [median 1.9 to 1.0 mg/L], indicating a general reduction in inflammatory activity. A corresponding decrease of CRP was not described in the two randomized controlled trials [RCTs].18,19 However, a similar reduction in disease activity has previously been shown by Kaltwasser et al. during IV iron sucrose therapy of patients with rheumatoid arthritis and anaemia of chronic disease. The authors observed not only a slight overall reduction in CRP levels during IV iron treatment, but also significant decreases in several clinical disease activity variables.28 In the present study, multivariate analysis was performed in an attempt to assess any relation between intravenous iron therapy and inflammation parameters. However, after removal of excess values and missing data, the sample size was too small to allow a meaningful analysis. Nevertheless, FCM does not appear to prevent drug-induced amelioration of inflammation. Larger, well-designed, prospective studies are needed in order to identify clinical, demographic, or other predictors of response to intravenous iron therapy, and to investigate further the question of whether intravenous iron therapy may influence inflammation parameters. Shifts of clinical parameters during the observation period, particularly regarding fatigue, lack of concentration, and anaemic mucosa, indicated a tendency for clinical improvement during FCM treatment and reflect improvement in quality of life. Accordingly, acceptance of FCM therapy was high: 95% of patients assessed it to be superior to their previous substitution therapy and 79% preferred it to their previous parenteral therapy. Only one participant graded the current therapy to be inferior to the previous one, and the remaining subjects were reported as undetermined. Single doses of 1000 mg FCM were tolerated under routine daily practice conditions by a high proportion [21.3%] of patients without any signs of adverse reactions. This represents a clear advantage of FCM compared with intravenous iron sucrose [Venofer®, Vifor GmbH], which should not exceed 200 mg per infusion and thus often necessitates repeat infusions. FCM is also superior in terms of the short infusion time of 15 min in median [mean 22, maximum 75 min], compared with the longer infusion time of 30 to 210 min for iron sucrose. These considerable advantages of high dosage, high infusion speed, and reduced need for repeat infusions, clearly favour FCM in the daily routine therapy of anaemic IBD patients and minimise time expenditure and effort of physicians and patients. Until now, tolerability data from FCM therapy have been available from selected patient collectives in controlled clinical trials.18–21 About 57% of those patients experienced an AE and 29% an adverse drug reaction. Adverse events assessed to be clearly drug-related were mild erythematous rash, urticaria, and pruritus. However, no immunological reactions were encountered on re-challenge. It may be perceived as a limitation of the present study that no data were collected regarding changes in serum phosphate levels in patients treated with intravenous iron. Although isolated cases of symptomatic hypophosphataemia have been reported in patients receiving long-term FCM, iron polymaltose, and iron sucrose therapy, no serious AEs associated with hypophosphataemia were recorded in any of the large clinical trials of intravenous iron preparations. However, FCM seems to be associated with a higher risk of hypophosphataemia compared to other IV iron products. Although the mechanisms involved are not yet fully understood,29 limited data indicate that FCM-associated hypophosphataemia may be dose-dependent.30 Thus, serum phosphate values should be routinely monitored, especially in patients with low baseline phosphate values or other concomitant risk factors [e.g. vitamin D deficiency, renal tubular defects], and in those receiving long-term or repeated intravenous iron therapy.31 Reporting data from a prospective open non-interventional trial including 394 Swedish IBD patients from 14 centres, Befrits et al. describe 27 [7%] infusion reactions [most commonly pruritus, chest tightness, nausea, and slightly increased temperature] of which, however, only one was considered serious.32 In their recent network meta-analysis comparing efficacy and safety of IV iron compounds based on five trials in IBD patients, Aksan et al. found that 12% of patients reported adverse events in connection with FCM doses of 500-1000 mg, but all but one [pulmonary embolism] were minor and transient in nature.33 In contrast, during the 495 routine FCM applications discussed in this NIS, only one adverse event [0.5%] was monitored. As classified by MedDRA terminology, it was a gastrointestinal disorder [SOC], more precisely the deterioration of ulcerative colitis [PT]. This AE was not related to the therapy in question. Reasons for the obvious difference in tolerability between controlled enquiry and routine application remain unknown, and it is conceivable that some AEs were lost from the analysis due to missing patient data. However, our data have only recently been substantiated by the results of a contemporaneous Spanish trial34 which reports only one severe AE during 88 FCM infusions in 72 patients. Whereas it may be argued that the disparity is a result of more intensive monitoring in clinical trials compared with non-interventional studies, this remains hypothetical. Generally, however, the tolerability of FCM therapy can be described as excellent under regular day-to-day treatment conditions. In addition, data from routine practice provides important information for the advancement of therapeutic treatment strategies and for the updating of guidelines. 5. Summary and Conclusion Ferinject® therapy was proven to be effective and safe in a large cohort of patients with IBD-associated anaemia in routine practice. Rapid, high-dose application is convenient for physicians and reduces patients’ time lost from work. In this retrospective study analysing real-life data from IBD patients treated with FCM, clinical scores and quality of life improved due to the amelioration of anaemia symptoms. Nevertheless, there are still a number of important issues which need to be addressed in future studies, in particular concerning the long-term safety of high doses of intravenous iron and the utility of remission therapy to ensure and sustain normal haemoglobin and ferritin levels and to maintain patient quality of life. Funding This work was funded by Vifor Germany GmbH, Munich, Germany, who also supported the development of the study design. Conflict of Interest No conflicts of interest were disclosed to study participants in the informed consent form. SW-M: employee of Vifor Pharma, Germany. KN: employee of Vifor Pharma, Germany. AD: speaker’s honoraria from Vifor International and Vifor Germany. JS: consultancy and speaker’s honoraria from Vifor International and Vifor Germany. Author Contributions JS: contributed to acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and statistical analysis. AA: contributed to analysis and interpretation of data; critical revision of the manuscript for important intellectual content; statistical analysis; and preparation of the revised version of the manuscript. WK: acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. KN: contributed to analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; and study supervision. SW-M: contributed to analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; and study supervision. AD: contributed to acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript. Acknowledgments An independent clinical research organisation [MedPharm Tec-Services, Germany] conducted the trial and performed the statistical analyses. The authors interpreted the results and made the decision for submission independently. The authors wish to thank all the investigators and study personnel who contributed to the study, and Janet Collins [ICCC Rhein-Main, Frankfurt, Germany] for providing medical writing assistance. A poster publishing data from this study was first presented at the ECCO Congress 2013 in Vienna. References 1. Stein J , Dignass AU . Anaemia in the elderly IBD patient . Curr Treat Options Gastroenterol 2015 ; 13 : 308 – 18 . Google Scholar CrossRef Search ADS PubMed 2. Stein J , Hartmann F , Dignass AU . Diagnosis and management of iron deficiency anemia in patients with IBD . Nat Rev Gastroenterol Hepatol 2010 ; 7 : 599 – 610 . Google Scholar CrossRef Search ADS PubMed 3. Kulnigg S , Gasche C . Systematic review: managing anaemia in Crohn’s disease . Aliment Pharmacol Ther 2006 ; 24 : 1507 – 23 . Google Scholar CrossRef Search ADS PubMed 4. Bager P . Anemia in inflammatory bowel diseases is much more than levels of hemoglobin . J Gastrointestin Liver Dis 2015 ; 24 : 145 – 6 . Google Scholar PubMed 5. Wells CW , Lewis S , Barton JR , Corbett S . Effects of changes in hemoglobin level on quality of life and cognitive function in inflammatory bowel disease patients . Inflamm Bowel Dis 2006 ; 12 : 123 – 30 . Google Scholar CrossRef Search ADS PubMed 6. Semrin G , Fishman DS , Bousvaros A et al. Impaired intestinal iron absorption in Crohn’s disease correlates with disease activity and markers of inflammation . Inflamm Bowel Dis 2006 ; 12 : 1101 – 6 . Google Scholar CrossRef Search ADS PubMed 7. Loitsch SM , Diehl D , Hartmann F et al. Impaired intestinal iron absorption in inflammatory bowel disease correlates with disease activity and markers of inflammation but is independent of disease location . Gastroenterology 2011 ; 140 : S5 . Google Scholar CrossRef Search ADS 8. Martinelli M , Strisciuglio C , Alessandrella A et al. Serum hepcidin and iron absorption in paediatric inflammatory bowel disease . J Crohns Colitis 2016 ; 10 : 566 – 74 . Google Scholar CrossRef Search ADS PubMed 9. Allen RP , Auerbach S , Bahrain H , Auerbach M , Earley CJ . The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia . Am J Hematol 2013 ; 88 : 261 – 4 . Google Scholar CrossRef Search ADS PubMed 10. Dignass AU , Gasche C , Bettenworth D et al. ; European Crohn’s and Colitis Organisation [ECCO] . European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases . J Crohns Colitis 2015 ; 9 : 211 – 22 . Google Scholar CrossRef Search ADS PubMed 11. Martin J , Radeke HH , Dignass A , Stein J . Current evaluation and management of anemia in patients with inflammatory bowel disease . Expert Rev Gastroenterol Hepatol 2017 ; 11 : 19 – 32 . Google Scholar CrossRef Search ADS PubMed 12. Avni T , Bieber A , Steinmetz T , Leibovici L , Gafter-Gvili A . Treatment of anemia in inflammatory bowel disease – systematic review and meta-analysis . PLoS One 2013 ; 8 : e75540 . Google Scholar CrossRef Search ADS PubMed 13. Tolkien Z , Stecher L , Mander AP , Pereira DI , Powell JJ . Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis . PLoS One 2015 ; 10 : e0117383 . Google Scholar CrossRef Search ADS PubMed 14. Avni T , Bieber A , Grossman A , Green H , Leibovici L , Gafter-Gvili A . The safety of intravenous iron preparations: systematic review and meta-analysis . Mayo Clin Proc 2015 ; 90 : 12 – 23 . Google Scholar CrossRef Search ADS PubMed 15. Bonovas S , Fiorino G , Allocca M et al. Intravenous versus oral iron for the treatment of anemia in inflammatory bowel disease: a systematic review and meta-analysis of randomized controlled trials . Medicine 2016 ; 95 : e2308 . Google Scholar CrossRef Search ADS PubMed 16. Geisser P , Burckhardt S . The pharmacokinetics and pharmacodynamics of iron preparations . Pharmaceutics 2011 ; 3 : 12 – 33 . Google Scholar CrossRef Search ADS PubMed 17. Geisser P , Baer M , Schaub E . Structure/histotoxicity relationship of parenteral iron preparations . Arzneimittelforschung 1992 ; 42 : 1439 – 52 . Google Scholar PubMed 18. Kulnigg S , Stoinov S , Simanenkov V et al. A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose [FERINJECT] randomized controlled trial . Am J Gastroenterol 2008 ; 103 : 1182 – 92 . Google Scholar CrossRef Search ADS PubMed 19. Evstatiev R , Marteau P , Iqbal T et al. ; FERGI Study Group . FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease . Gastroenterology 2011 ; 141 : 846 – 53.e1 –2. Google Scholar CrossRef Search ADS PubMed 20. Evstatiev R , Alexeeva O , Bokemeyer B et al. ; FERGI Study Group . Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease . Clin Gastroenterol Hepatol 2013 ; 11 : 269 – 77 . Google Scholar CrossRef Search ADS PubMed 21. Kulnigg-Dabsch S , Schmid W , Howaldt S et al. Iron deficiency generates secondary thrombocytosis and platelet activation in IBD: the randomized, controlled thromboVIT trial . Inflamm Bowel Dis 2013 ; 19 : 1609 – 16 . Google Scholar CrossRef Search ADS PubMed 22. Best WR , Becktel JM , Singleton JW , Kern F Jr . Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study . Gastroenterology 1976 ; 70 : 439 – 44 . Google Scholar PubMed 23. Walmsley RS , Ayres RC , Pounder RE , Allan RN . A simple clinical colitis activity index . Gut 1998 ; 43 : 29 – 32 . Google Scholar CrossRef Search ADS PubMed 24. U.S. Department of Health and Human Services, Food and Drug Administration/Center for Drug Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER) . Guidance for Industry: E9 Statistical Principles for Clinical Trials . ICH; 1998. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073137.pdf. 25. Peyrin-Biroulet L , Williet N , Cacoub P . Guidelines on the diagnosis and treatment of iron deficiency across indications: a systematic review . Am J Clin Nutr 2015 ; 102 : 1585 – 94 . Google Scholar CrossRef Search ADS PubMed 26. Goddard AF , James MW , McIntyre AS , Scott BB ; British Society of Gastroenterology . Guidelines for the management of iron deficiency anaemia . Gut 2011 ; 60 : 1309 – 16 . Google Scholar CrossRef Search ADS PubMed 27. Stein J , Bager P , Befrits R et al. Anaemia management in patients with inflammatory bowel disease: routine practice across nine European countries . Eur J Gastroenterol Hepatol 2013 ; 25 : 1456 – 63 . Google Scholar CrossRef Search ADS PubMed 28. Kaltwasser JP , Kessler U , Gottschalk R , Stucki G , Möller B . Effect of recombinant human erythropoietin and intravenous iron on anemia and disease activity in rheumatoid arthritis . J Rheumatol 2001 ; 28 : 2430 – 6 . Google Scholar PubMed 29. Zoller H , Schaefer B , Glodny B . Iron-induced hypophosphatemia: an emerging complication . Curr Opin Nephrol Hypertens 2017 ; 26 : 266 – 75 . Google Scholar CrossRef Search ADS PubMed 30. Stein J , Aksan A , Farrag K , Dignass A , Radeke HH . Management of inflammatory bowel disease-related anemia and iron deficiency with specific reference to the role of intravenous iron in current practice . Expert Opin Pharmacother 2017 ; 18 : 1721 – 37 . Google Scholar CrossRef Search ADS PubMed 31. Gaasbeek A , Meinders AE . Hypophosphatemia: an update on its etiology and treatment . Am J Med 2005 ; 118 : 1094 – 101 . Google Scholar CrossRef Search ADS PubMed 32. Befrits R , Wikman O , Blomquist L et al. Anemia and iron deficiency in inflammatory bowel disease: an open, prospective, observational study on diagnosis, treatment with ferric carboxymaltose and quality of life . Scand J Gastroenterol 2013 ; 48 : 1027 – 32 . Google Scholar CrossRef Search ADS PubMed 33. Aksan A , Işık H , Radeke HH , Dignass A , Stein J . Systematic review with network meta-analysis: comparative efficacy and tolerability of different intravenous iron formulations for the treatment of iron deficiency anaemia in patients with inflammatory bowel disease . Aliment Pharmacol Ther 2017 ; 45 : 1303 – 18 . Google Scholar CrossRef Search ADS PubMed 34. García-López S , Bocos JM , Gisbert JP et al. High-dose intravenous treatment in iron deficiency anaemia in inflammatory bowel disease: early efficacy and impact on quality of life . Blood Transfus 2016 ; 14 : 199 – 205 . Google Scholar PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Safety and Efficacy of Ferric Carboxymaltose in the Treatment of Iron Deficiency Anaemia in Patients with Inflammatory Bowel Disease, in Routine Daily Practice

Journal of Crohn's and Colitis , Volume Advance Article (7) – May 4, 2018

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Abstract

Abstract Introduction Iron deficiency and iron deficiency anaemia are common complications in inflammatory bowel disease [IBD] patients. Anaemia in IBD is attributable to chronic blood loss and/or impaired iron intake and absorption. International guidelines recommend intravenous iron supplementation in IBD patients, since oral supplements are frequently poorly tolerated and can exacerbate inflammation. Intravenous ferric carboxymaltose [FCM; Ferinject® 50 mg ferric iron[III]/mL suspension] was approved in Europe in 2007 for correction of iron deficiency, and can be administered in single 15-min infusions of up to 1000 mg. Methods A prospective non-interventional post-marketing study was performed in 101 centres in Germany to assess the efficacy, tolerability, and convenience of Ferinject® in clinical practice in a large cohort of IBD patients. Primary endpoints were haemoglobin [Hb] normalisation or increase ≥2 g/dL [responders], and normalisation of serum ferritin [s-ferritin] and transferrin saturation. Adverse events [AEs], clinical signs/symptoms, and disease activity indices were also analysed. Results In all, 224 subjects (127 Crohn’s disease [CD]; 97 ulcerative colitis [UC]) were treated. Mean total iron dose was 1139 mg [range: 100 mg-4800 mg], with 76.7% of doses between 500 mg and 2000 mg; 63.3% of patients responded, and no adverse drug reactions or drug-attributed serious adverse events [SAEs] or deaths occurred. Mean increases of Hb [10.0 to 12.3 g/dL], ferritin [52 μg/L to 103 μg/L], transferrin saturation [TSAT, 15% to 25%], and s-iron [6.1 to 12.4 μmol/L] were significant [p = 0.0001]. Clinical scores and quality of life improved due to the amelioration of anaemia symptoms. Conclusions Ferinject®-therapy was proven to be effective and safe in a large cohort of patients with IBD-associated anaemia in routine practice. Rapid, high-dose application is convenient for physicians and reduces patients’ time lost from work. IBD, iron deficiency anaemia, ferric carboxymaltose 1. Introduction Iron deficiency [ID] and subsequent anaemia are common complications in patients with inflammatory bowel disease [IBD], a set of chronic intestinal conditions including Crohn’s disease [CD] and ulcerative colitis [UC] which share a variety of symptoms including diarrhoea, abdominal pain, and fever, as well as extraintestinal manifestations affecting the joints, skin, and eyes. Anaemia in IBD has multiple causes,1,2 the most prevalent being iron deficiency.6 Iron deficiency occurs in up to 90% of IBD patients,3 often progressively deteriorating to the point of manifest iron deficiency anaemia [IDA], which has a major impact on quality of life in IBD patients.4,5 IDA is largely attributable to chronic blood loss from the ulcerated intestinal mucosa and/or to impairment of iron intake and absorption.6–8 Symptoms of IDA include fatigue, headache, hair loss, and [exertional] dyspnoea. In addition, restless legs syndrome has been shown to occur at an approximately nine-fold higher rate in individuals with IDA than in the overall population.9 The goals of anaemia treatment are to raise haemoglobin, serum ferritin [s-ferritin], and transferrin saturation [TSAT] levels above the lower threshold of normal [LLN], thus not only restoring short-term haematopoietic status but also replenishing iron stores to prevent recurrence of anaemia. Iron supplementation is recommended even if iron deficiency occurs without reduction of haemoglobin concentration.10,11 Oral iron replacement is of limited value, failing to balance continuous iron loss due to inadequate intestinal absorption in the presence of inflammation.2,11 Furthermore, non-absorbed iron has been shown to enhance mucosal inflammation in animal models and increase clinical activity in IBD patients.12,13 In contrast, intravenous [IV] iron has been demonstrated to be safe, effective, and well tolerated in both the correction of IDA and the maintenance of iron stores in patients with IBD.12,14,15 Moreover, intravenous iron replacement not only facilitates the faster correction of ID and repletion of body iron stores, but also effectively avoids gastrointestinal [GI] side effects by bypassing the GI tract. Several intravenous iron preparations are currently available for treatment of IDA. Such formulations differ by complex chemistry and can be grouped into labile, semi-labile, and stable iron complexes.16,17 Of all the IV iron compounds available, by far the largest number of pharmacology studies, phase I to III clinical trials, and controlled clinical trials in IBD patients have been performed with ferric carboxymaltose [FCM].18–21 These trials have proved its efficacy and tolerability in IBD-associated anaemia. No safety concerns have been identified. However, published data concerning routine use in daily practice are still limited. This post-marketing surveillance study was designed and performed to assess the safety and efficacy of FCM in a large cohort of patients under routine daily conditions. 2. Materials and Methods 2.1. Study design This non-interventional study [NIS] was designed as a prospective, multicentre survey without influence on regular treatment of patients by the attending physician in routine medical care. Physicians [hospital gastroenterologists, specialists in internal medicine, and general practitioners] in 101 German treatment centres were recruited to enrol patients and to complete treatment documentation according to the study protocol. Due to the non-interventional character of the study, subjects were treated based on the medical needs of their underlying disease in accordance with therapy requirements published in the German Physicians’ Circular [GPC]. The observation period extended from November 2008 [first patient, first visit] to August 2010 [last patient, last visit]. For each individual subject, the study duration was approximately 12 weeks, and at least two visits were planned: baseline visit [start of treatment with Ferinject®] and last visit [end of therapy or Week 12–14]. 2.2. Patient characteristics and definitions Patients at 101 treatment centres who were due to receive iron replacement therapy with ferric carboxymaltose, based on the indication and therapy requirements according to the GPC and Summary of Product Characteristics [age ≥18 years, iron deficiency anaemia based on chronic IBD, therapeutic necessity for IV iron substitution], were invited to participate in the observational study; 223 patients gave written informed consent and were enrolled in the study. All patients were FCM-naïve. 2.3. Intervention The patients received FCM according to the usual therapeutic procedure of the attending physician and in accordance with the authorised indications of the Summary of Product Characteristics for ferric carboxymaltose. Mean number of infusions given during the observation period was 3.3 [range 1–10]. 2.4. Efficacy and safety analysis The primary efficacy endpoint was response to treatment, defined as correction of anaemia (haemoglobin [[Hb] ≥13 g/dL in men and ≥12 g/dL in women) or Hb increase of 2 g/dL or more. Partial response was defined as Hb increase of 1 g/dL or more but less than 2 g/dL, without anaemia correction. Secondary analyses included normalisation of serum ferritin [s-ferritin] and serum transferrin saturation [TSAT] and predictive values to treatment response according to gender, age, and baseline measurements of iron parameters. For the analysis of efficacy parameters, all available data were used. Clinical signs/symptoms associated with anaemia were analysed according to a self-devised ‘symptom scale’ by shift tables comparing beginning of study [BOS] and end of study [EOS] visits for all patients, and stratified by gender, risk factors, and underlying disease type [CD/UC]. Analyses of demographic data were performed on the total evaluable population comprising 223 patients [entitled: ‘total group’] and additionally for two subpopulations; patients evaluable for effectiveness [n = 150, entitled: ‘efficacy group’] and the safety population [n = 193, entitled: ‘safety group’]. The disposition of patients is shown in Figure 1. Figure 1. View largeDownload slide Disposition of patients. Figure 1. View largeDownload slide Disposition of patients. For the safety analysis, EOS documentations of 193 FCM-treated patients were returned, and from these safety data were extracted. Both paper case report forms CRFs] and electronic CRFs [eCRFs] were screened daily for adverse events [AEs] or suspected adverse drug reactions [ADRs]. In case of doubt, queries were issued in order to clarify the documentation. In addition to primary and secondary endpoints, demographic data and additional laboratory parameters were documented, i.e. C-reactive protein [CRP], serum transferrin [s-transferrin], serum iron [s-Fe], liver enzymes [γ-GT, ALAT, ASAT], lipoproteins [HDL, LDL], triglycerides, and glucose. In addition, disease activity was recorded by means of the Crohn’s Disease Activity Index [CDAI]22 or the Clinical Activity Index for ulcerative colitis [CAI].23 For the analysis of treatment effectiveness in different inflammatory states, patients were divided into the following CRP subgroups: CRP <5 mg/L [no inflammation] and CRP ≥5 mg/L [inflammation]. The latter subgroup was further divided into CRP 5‑10 mg/L [moderate inflammation] and CRP >10 mg/L [severe inflammation]. 2.5. Ethics The study proposal had been submitted to the responsible local ethics commissions as well as the German Federal Institute for Drugs and Medical Devices [BfArM]. The National Association of Statutory Health Insurance Physicians was informed of the names of participating physicians. The study was registered and published according to the recommendations of the VFA [German Association of Research-Based Pharmaceutical Companies] [http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_232]. 2.6. Statistical methods All statistical methods were predefined in the statistical analysis plan, based on the International Conference on Harmonisation [ICH E9] publication: Guidance for Industry on Statistical Principles for Clinical Trials.24 Collected data were analysed and reported by SAS software [Version 9.2]. The analysis was performed in an exploratory manner using descriptive statistical methods. For the valuation of differences, a two-sided Student’s t-test, with α = 0.05, was adopted. Data from premature study termination visits between Weeks 4 and 12 after inclusion were accounted to the visit week in which they actually occurred. Termination visits at Week 12, 13, or 14 were accounted to Week 12. For these patients, changes from baseline to last recorded value were analysed. Other patients were considered not evaluable. 3. Results 3.1 Patients and treatments A total of 101 centres started documentation for 223 patients for this NIS [‘total group’]. For 30 subjects, no end-of-study [EOS] documentation was done, or they did not actually receive Ferinject® infusions. Documentation of the remaining 193 patients [86.5%; n = 223] were returned to the Contract Research Organisation and included in the safety evaluation [‘safety group’]. For 42 patients [18.8%; n = 223] of the safety group, data from their premature termination visit [between Weeks 4 and 14 post inclusion] were not documented. In addition, for one patient [0.4%; n = 223] baseline data were not recorded. The remaining 150 individuals [67.3%; n = 223] met the endpoints and were therefore included in the efficacy analysis [‘efficacy group’]. Gender distribution was comparable in all three groups: 137 patients [61.4 %; n = 223] in the total group, 114 [59.1%; n = 193] within the safety group, and 92 [61.3%; n = 150] in the efficacy group were female. Age characteristics were also very similar in each of these groups: mean [aM] age was approximately 39 years (Standard deviation [SD] ±14) and age distribution range 18 to 83 years, with a median age of 36 years [Table 1]. Table 1. Baseline patient characteristics. All patients Crohn’s disease Ulcerative colitis n [%] n [%] n [%] Patients 193a [100%] 115 [59.9%] 77 [40.1%] Age [years] [mean±SD] 38.7 ± 13.70 39.1 ± 13.98 38.5 ± 14.57 Gender  Male 79 [41%] 43 [37.4%] 36 [46.8%]  Female 114a [59%] 72 [62.6%] 41 [53.2%] CDAI [median, range] - 190 [48–530] - CAI [median, range] - - 8 [0–347] CRP [ mg/L] [median, range] 5.95 [0–108] 6.84 [0–108] 4.62 [0–56.7] Haemoglobin [g/dL] [mean±SD] 10.1 ± 1.41 10.0 ± 1.35 10.2 ± 1.50 Ferritin [μg/L] [median, range] 14.0 [1.0–1000] 13.0 [1.6–1000] 15.5 [1.0–535] TSAT [%] [median, range] 10.0 [0.9–85] 10.0 [1.8–51] 12.2 [0.9–85.0] Medication  Aminosalicylates 89 [46.1%] 55 [47.8%] 34 [44.2%]  Steroids 84 [43.5%] 55 [47.8%] 29 [37.7%]  Immunosuppressants 36 [18.7%] 18 [15.7%] 18 [23.4%]  Biologics 36 [19%] 18 [23%] 18 [16%]  Antibiotics 8 [4.1%] 3 [2.6%] 5 [6.5%]  Antidiarrhoeics 11 [5.7%] 3 [2.6%] 8 [10.4%] All patients Crohn’s disease Ulcerative colitis n [%] n [%] n [%] Patients 193a [100%] 115 [59.9%] 77 [40.1%] Age [years] [mean±SD] 38.7 ± 13.70 39.1 ± 13.98 38.5 ± 14.57 Gender  Male 79 [41%] 43 [37.4%] 36 [46.8%]  Female 114a [59%] 72 [62.6%] 41 [53.2%] CDAI [median, range] - 190 [48–530] - CAI [median, range] - - 8 [0–347] CRP [ mg/L] [median, range] 5.95 [0–108] 6.84 [0–108] 4.62 [0–56.7] Haemoglobin [g/dL] [mean±SD] 10.1 ± 1.41 10.0 ± 1.35 10.2 ± 1.50 Ferritin [μg/L] [median, range] 14.0 [1.0–1000] 13.0 [1.6–1000] 15.5 [1.0–535] TSAT [%] [median, range] 10.0 [0.9–85] 10.0 [1.8–51] 12.2 [0.9–85.0] Medication  Aminosalicylates 89 [46.1%] 55 [47.8%] 34 [44.2%]  Steroids 84 [43.5%] 55 [47.8%] 29 [37.7%]  Immunosuppressants 36 [18.7%] 18 [15.7%] 18 [23.4%]  Biologics 36 [19%] 18 [23%] 18 [16%]  Antibiotics 8 [4.1%] 3 [2.6%] 5 [6.5%]  Antidiarrhoeics 11 [5.7%] 3 [2.6%] 8 [10.4%] SD, standard deviation; CDAI, Crohn’s Disease Activity Index; CAI, Clinical Colitis Activity Index; CRP, C-reactive protein; TSAT, transferrin saturation. aIncluding one patient with indeterminate IBD disease type. View Large Table 1. Baseline patient characteristics. All patients Crohn’s disease Ulcerative colitis n [%] n [%] n [%] Patients 193a [100%] 115 [59.9%] 77 [40.1%] Age [years] [mean±SD] 38.7 ± 13.70 39.1 ± 13.98 38.5 ± 14.57 Gender  Male 79 [41%] 43 [37.4%] 36 [46.8%]  Female 114a [59%] 72 [62.6%] 41 [53.2%] CDAI [median, range] - 190 [48–530] - CAI [median, range] - - 8 [0–347] CRP [ mg/L] [median, range] 5.95 [0–108] 6.84 [0–108] 4.62 [0–56.7] Haemoglobin [g/dL] [mean±SD] 10.1 ± 1.41 10.0 ± 1.35 10.2 ± 1.50 Ferritin [μg/L] [median, range] 14.0 [1.0–1000] 13.0 [1.6–1000] 15.5 [1.0–535] TSAT [%] [median, range] 10.0 [0.9–85] 10.0 [1.8–51] 12.2 [0.9–85.0] Medication  Aminosalicylates 89 [46.1%] 55 [47.8%] 34 [44.2%]  Steroids 84 [43.5%] 55 [47.8%] 29 [37.7%]  Immunosuppressants 36 [18.7%] 18 [15.7%] 18 [23.4%]  Biologics 36 [19%] 18 [23%] 18 [16%]  Antibiotics 8 [4.1%] 3 [2.6%] 5 [6.5%]  Antidiarrhoeics 11 [5.7%] 3 [2.6%] 8 [10.4%] All patients Crohn’s disease Ulcerative colitis n [%] n [%] n [%] Patients 193a [100%] 115 [59.9%] 77 [40.1%] Age [years] [mean±SD] 38.7 ± 13.70 39.1 ± 13.98 38.5 ± 14.57 Gender  Male 79 [41%] 43 [37.4%] 36 [46.8%]  Female 114a [59%] 72 [62.6%] 41 [53.2%] CDAI [median, range] - 190 [48–530] - CAI [median, range] - - 8 [0–347] CRP [ mg/L] [median, range] 5.95 [0–108] 6.84 [0–108] 4.62 [0–56.7] Haemoglobin [g/dL] [mean±SD] 10.1 ± 1.41 10.0 ± 1.35 10.2 ± 1.50 Ferritin [μg/L] [median, range] 14.0 [1.0–1000] 13.0 [1.6–1000] 15.5 [1.0–535] TSAT [%] [median, range] 10.0 [0.9–85] 10.0 [1.8–51] 12.2 [0.9–85.0] Medication  Aminosalicylates 89 [46.1%] 55 [47.8%] 34 [44.2%]  Steroids 84 [43.5%] 55 [47.8%] 29 [37.7%]  Immunosuppressants 36 [18.7%] 18 [15.7%] 18 [23.4%]  Biologics 36 [19%] 18 [23%] 18 [16%]  Antibiotics 8 [4.1%] 3 [2.6%] 5 [6.5%]  Antidiarrhoeics 11 [5.7%] 3 [2.6%] 8 [10.4%] SD, standard deviation; CDAI, Crohn’s Disease Activity Index; CAI, Clinical Colitis Activity Index; CRP, C-reactive protein; TSAT, transferrin saturation. aIncluding one patient with indeterminate IBD disease type. View Large 3.2 Exposure to [dosing of] iron A total of 495 intravenous FCM treatment courses were given to 193 IBD patients. Due to the non-interventional nature of the study, dose calculations and infusion regimens were determined by the treating physicians purely according to the patients’ medical needs and in the context of regular clinical practice. Median total FCM dosage of the 150 patients in the efficacy group was 975 mg, with total doses ranging from 100 mg to 4800 mg. FCM was most commonly administered at cumulative doses of between 500 mg and 2000 mg [76.7%] [7.3% received <500 mg, 9.3% received 2000–3000 mg, and 6.7% received >3000 mg]. The mean minimum single dose per patient was 431 ± 301.65 mg, and the mean maximum single dose was 508 ± 321.01 mg. In the efficacy group, 13 subjects received additional concomitant anti-anaemic treatment with oral iron compounds. The response in patients receiving oral iron was, however, not significantly different from patients treated with Ferinject® only [results not shown]. Concerning number of infusions, 1-10 infusions were applied to the patients in the efficacy group, with a median value of two infusions. The median time period from first to last infusion was 22 days [range 0–96]. Median infusion duration for all evaluable patients was 15 min [range 5 to 75 min]. Infusion times were longest for the lowest [<500 mg], as well as for higher [2000 mg to <3000 mg] dosages. Median dilution of infusion was 250 mL [range 10 mL to 500 mL]. 3.3 Treatment efficacy 3.3.1 Haemoglobin Within the efficacy group, haemoglobin [Hb] values were evaluable in 148 patients. Absolute Hb values were ≥10 g/dL in 86 patients [58.1%], 8 to 10 g/dL [33.1%] in 49 patients, and <8 g/dL in 13 patients [8.8%]. Visit-by-visit changes in Hb levels from BOS to EOS for subgroups according to baseline Hb are shown in Figure 2a. In all subgroups, the mean increase in Hb was statistically significant. In 114 patients [77%], Hb increased by more than 1 g/dL and to a value ≥11 g/dL. In 79 [53.4%] patients, Hb increased by more than 2 g/dL and up to LLN, i.e. ≥12 g/dL in women or ≥13 g/dL in men. The primary efficacy endpoint of Hb normalisation or increase of ≥2 g/dL was reached by 63.3% of patients. Figure 2. View largeDownload slide Visit-by-visit changes in clinical parameters for the two baseline haemoglobin groups. Figure 2. View largeDownload slide Visit-by-visit changes in clinical parameters for the two baseline haemoglobin groups. In subgroups of patients with lower [<10 g/dL] or higher [≥10 g/dL] Hb at baseline, a comparison of the visit-by-visit increments of Hb increase indicates rapid improvement between BOS and the second visit between Weeks 4 and 8 for both groups. Even though only 40 subjects had a visit between these two time points, a greater increase [Δ = 2.5 g/dL] was found in patients with low baseline Hb compared with patients with higher baseline Hb values [Δ = 1.5 g/dL] [data not shown]. These improvements were sustained for the whole observation period and resulted in a greater mean difference of 3.1 g/dL in subjects with low baseline Hb values compared with 1.7 g/dL in subjects with higher baseline Hb [data not shown]. 3.3.2 Serum ferritin and transferrin saturation Mean ferritin level in the efficacy group was 53 [±126] μg/L at BOS, increasing to 110 [±148] μg/L after treatment with FCM. Mean increase in ferritin from BOS to EOS was 58.5 [±160.0] μg/L [p <0.0001]. Figure 2b compares changes of ferritin values in patients with low [<10 g/dL] or higher [≥10 g/dL] Hb at baseline, indicating a rapid improvement between the first and second visits in the low Hb subgroup. Only minor changes in ferritin levels from BOS to EOS were observed in the subgroup with higher baseline Hb. Despite no significant difference in baseline ferritin values, the most substantial increase in ferritin occurred in patients with Hb levels <8 g/dL. Mean TSAT level in patients in the efficacy group increased under FCM treatment from 15.6 [±13.4]% at BOS to 24.2 [±20.2]% at EOS [p <0.001]. Stratification according to baseline Hb showed that mean TSAT was below LLN in all Hb subgroups. Mean TSAT values for Hb <10 g/dL and Hb ≥10 g/dL were 15% and both medians were 10%, and TSAT ranged from approximately 1% to far above the upper threshold of normal [85% vs 50% for the respective subgroups]. In all Hb subgroups, both mean [≈29% vs 23%] and median [25% vs 21%] TSAT values increased considerably, reaching normal range. Differences from EOS to BOS were +11.2% vs +6.7% [p <0.0001]. Changes in TSAT levels during the study are shown in Figure 2c. 3.3.3 Disease activity Although patients [n = 97] with elevated CD or UC activity indices [CDAI ≥150; CAI ≥5] presented with lower mean Hb values at BOS compared with those with normal activity indices, mean Hb levels at EOS were comparable, and changes in Hb from BOS to EOS were statistically significant for both patient groups [data not shown]. Subjects with higher indices also presented with higher mean CRP values at BOS [6.1 mg/L] compared with those with normal activity indices [3.6 mg/L]. Whereas at BOS, mean CRP levels were outside normal range, they were found to decrease during FCM therapy independently of baseline Hb levels [data not shown]. The change in CRP levels from BOS to EOS was statistically significant overall, as well as in patients with high disease activity, in CD and UC patients treated with a total dose of 500 to 1000 mg iron, and in patients who completed therapy. The decrease in disease activity indicated by lower CRP levels was confirmed by a reduction in mean values of the clinical disease activity indices CDAI and CAI [data not shown]. Patients in both CRP subgroups showed increases in Hb, serum ferritin, and TSAT. CRP and the number of symptoms decreased from baseline to end of study [Table 2]. Table 2. Parameters in CRP subgroups (only complete data pairs [BOS/EOS] were taken into account). Mean haemoglobin [g/dL] Mean ferritin [µg/L] Mean TSAT [%] Mean number of symptoms CRP [ mg/L] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] All patients 10.0 ± 1.4 12.3 ± 1.6 *** 53 ± 126 110 ± 148 *** 15.6 ± 13.4 24.2 ± 20.2 *** 4.8 ± 2.0 3.0 ± 2.0 *** 6.6 ± 14.5 4.1 ± 8.3 ** CRP <5 mg/L 9.9 ± 1.4 12.4 ± 1.6 *** 54 ± 122 105 ± 115 *** 17.0 ± 14.2 26.1 ± 14.4 *** 4.9 ± 2.0 3.0 ± 2.1 *** 1.5 ± 1.2 1.3 ± 1.7 CRP ≥5 mg/L 10.4 ± 1.3 12.0 ± 1.7 *** 49 ± 145 126 ± 230 9.8 ± 7.7 16.6 ± 34.5 ** 4.4 ± 1.8 3.1 ± 1.9 *** 22.3 ± 23.8 12.6 ± 13.4 * CRP 5–10 mg/L 10.3 ± 1.7 11.6 ± 2.1 * 25 ± 30 192 ± 339 11.5 ± 9.6 18.6 ± 53.6 4.4 ± 2.1 3.3 ± 2.0 * 7.3 ± 1.9 5.8 ± 3.2 * CRP >10 mg/L 10.5 ± 1.1 12.2 ± 1.3 *** 62 ± 178 89 ± 121 8.7 ± 6.0 15.3 ± 10.5 * 4.4 ± 1.5 3.0 ± 1.9 ** 30.3 ± 26.3 16.4 ± 14.4 * Mean haemoglobin [g/dL] Mean ferritin [µg/L] Mean TSAT [%] Mean number of symptoms CRP [ mg/L] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] All patients 10.0 ± 1.4 12.3 ± 1.6 *** 53 ± 126 110 ± 148 *** 15.6 ± 13.4 24.2 ± 20.2 *** 4.8 ± 2.0 3.0 ± 2.0 *** 6.6 ± 14.5 4.1 ± 8.3 ** CRP <5 mg/L 9.9 ± 1.4 12.4 ± 1.6 *** 54 ± 122 105 ± 115 *** 17.0 ± 14.2 26.1 ± 14.4 *** 4.9 ± 2.0 3.0 ± 2.1 *** 1.5 ± 1.2 1.3 ± 1.7 CRP ≥5 mg/L 10.4 ± 1.3 12.0 ± 1.7 *** 49 ± 145 126 ± 230 9.8 ± 7.7 16.6 ± 34.5 ** 4.4 ± 1.8 3.1 ± 1.9 *** 22.3 ± 23.8 12.6 ± 13.4 * CRP 5–10 mg/L 10.3 ± 1.7 11.6 ± 2.1 * 25 ± 30 192 ± 339 11.5 ± 9.6 18.6 ± 53.6 4.4 ± 2.1 3.3 ± 2.0 * 7.3 ± 1.9 5.8 ± 3.2 * CRP >10 mg/L 10.5 ± 1.1 12.2 ± 1.3 *** 62 ± 178 89 ± 121 8.7 ± 6.0 15.3 ± 10.5 * 4.4 ± 1.5 3.0 ± 1.9 ** 30.3 ± 26.3 16.4 ± 14.4 * CRP, C-reactive protein; BOS, beginning of study; EOS, end of study; p[Δ], p-value of change from BOS to EOS. *p < 0.05; **p < 0.01; ***p < 0.001. View Large Table 2. Parameters in CRP subgroups (only complete data pairs [BOS/EOS] were taken into account). Mean haemoglobin [g/dL] Mean ferritin [µg/L] Mean TSAT [%] Mean number of symptoms CRP [ mg/L] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] All patients 10.0 ± 1.4 12.3 ± 1.6 *** 53 ± 126 110 ± 148 *** 15.6 ± 13.4 24.2 ± 20.2 *** 4.8 ± 2.0 3.0 ± 2.0 *** 6.6 ± 14.5 4.1 ± 8.3 ** CRP <5 mg/L 9.9 ± 1.4 12.4 ± 1.6 *** 54 ± 122 105 ± 115 *** 17.0 ± 14.2 26.1 ± 14.4 *** 4.9 ± 2.0 3.0 ± 2.1 *** 1.5 ± 1.2 1.3 ± 1.7 CRP ≥5 mg/L 10.4 ± 1.3 12.0 ± 1.7 *** 49 ± 145 126 ± 230 9.8 ± 7.7 16.6 ± 34.5 ** 4.4 ± 1.8 3.1 ± 1.9 *** 22.3 ± 23.8 12.6 ± 13.4 * CRP 5–10 mg/L 10.3 ± 1.7 11.6 ± 2.1 * 25 ± 30 192 ± 339 11.5 ± 9.6 18.6 ± 53.6 4.4 ± 2.1 3.3 ± 2.0 * 7.3 ± 1.9 5.8 ± 3.2 * CRP >10 mg/L 10.5 ± 1.1 12.2 ± 1.3 *** 62 ± 178 89 ± 121 8.7 ± 6.0 15.3 ± 10.5 * 4.4 ± 1.5 3.0 ± 1.9 ** 30.3 ± 26.3 16.4 ± 14.4 * Mean haemoglobin [g/dL] Mean ferritin [µg/L] Mean TSAT [%] Mean number of symptoms CRP [ mg/L] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] BOS EOS p[∆] All patients 10.0 ± 1.4 12.3 ± 1.6 *** 53 ± 126 110 ± 148 *** 15.6 ± 13.4 24.2 ± 20.2 *** 4.8 ± 2.0 3.0 ± 2.0 *** 6.6 ± 14.5 4.1 ± 8.3 ** CRP <5 mg/L 9.9 ± 1.4 12.4 ± 1.6 *** 54 ± 122 105 ± 115 *** 17.0 ± 14.2 26.1 ± 14.4 *** 4.9 ± 2.0 3.0 ± 2.1 *** 1.5 ± 1.2 1.3 ± 1.7 CRP ≥5 mg/L 10.4 ± 1.3 12.0 ± 1.7 *** 49 ± 145 126 ± 230 9.8 ± 7.7 16.6 ± 34.5 ** 4.4 ± 1.8 3.1 ± 1.9 *** 22.3 ± 23.8 12.6 ± 13.4 * CRP 5–10 mg/L 10.3 ± 1.7 11.6 ± 2.1 * 25 ± 30 192 ± 339 11.5 ± 9.6 18.6 ± 53.6 4.4 ± 2.1 3.3 ± 2.0 * 7.3 ± 1.9 5.8 ± 3.2 * CRP >10 mg/L 10.5 ± 1.1 12.2 ± 1.3 *** 62 ± 178 89 ± 121 8.7 ± 6.0 15.3 ± 10.5 * 4.4 ± 1.5 3.0 ± 1.9 ** 30.3 ± 26.3 16.4 ± 14.4 * CRP, C-reactive protein; BOS, beginning of study; EOS, end of study; p[Δ], p-value of change from BOS to EOS. *p < 0.05; **p < 0.01; ***p < 0.001. View Large 3.3.4 Clinical [non-haematological] parameters In order to assess the influence of IV iron treatment on their general well-being, patients were asked at BOS and EOS to evaluate the following anaemia-associated, clinical, non-haematological parameters for intensity, by rating them on a ‘symptom’ scale of 0 for ‘not present’ to 4 for ‘very severe’: fatigue, lack of concentration, headache, paleness of mucous membranes, hair loss, [exertional] dyspnoea, sleeping disorders, and restless legs syndrome. Whereas 146 patients [97%] reported at least one non-haematological symptom at baseline, 14 patients [9.3%] reported all eight symptoms. The average number of symptoms per patient at baseline was 4.7 ± 0.3. At EOS, this figure had significantly declined, with patients reporting an average of 3.0 ± 0.3 symptoms [p <0.001]. Furthermore, 14.7% of patients [22] were symptom-free, with only one patient reporting the presence of all symptoms. The most frequent symptom at baseline was ‘fatigue’, with 93% of patients reporting at least mild symptoms, and the rarest was ‘restless legs syndrome’ with 22%. For each of the symptoms, the number of affected patients decreased from BOS to the EOS, the most evident decreases being associated with paleness of mucous membranes, followed by [exertional] dyspnoea and lack of concentration [Figure 3]. Figure 3. View largeDownload slide Intensity of symptoms. Figure 3. View largeDownload slide Intensity of symptoms. The mean intensity of reported non-haematological symptoms at baseline varied between 1.7 [headache] and 2.3 [fatigue]. At EOS, mean intensity decreased to 0.3-1.2 points on the rating scale, with the biggest decreases observed in fatigue [1.2], headache [1.1], and paleness of mucous membranes [1.0]. 3.3.5 Predictive factors for response to intravenous iron Logistic regression analyses of the current data were performed. However, after removal of excess values and missing data, the sample size was too small to allow the identification of any predictors of response. 3.3.6 Safety Among the 193 patients representing the safety population, only one adverse event was reported, an aggravation of UC. This exacerbation was estimated by both physician and sponsor to be a serious adverse event [SAE], but the treating physician judged it to be unrelated to the drug. Treatment was stopped and the patient recovered without sequelae. To sum up the tolerability of FCM therapy, no treatment-related adverse drug reaction was documented. One SAE occurred in 193 patients during the 12-month observation period, but this was not drug-related. Premature treatment discontinuation was documented in only one patient, but the termination was not due to an AE. No deaths occurred. No clinical changes were documented in vital signs or physical examinations which could be considered an AE. Elevated serum ferritin was observed in one patient at EOS. 4. Discussion Iron deficiency [ID] is the main cause of anaemia in IBD patients. ID arises due to dietary restrictions, malabsorption, intestinal bleeding, and/or undertreatment of anaemia.3 Oral iron replacement is often unsuitable for anaemia therapy in IBD patients because of intolerance to oral iron compounds, abnormal absorption due to inflammation, non-compliance, and large iron deficits, all factors which limit the success of oral iron treatment for anaemia.7,8 The literature indicates that high doses of iron are often required in anaemic patients, with IBD patients requiring up to 3600 mg daily,4 and several international guidelines recommend the administration of intravenous iron formulations in preference to oral iron in the correction of IBD-associated anaemia.10,25,26 Nevertheless, a retrospective analysis of clinical practice in nine European countries in 2011 found that oral iron was administered to 68% of IBD patients with anaemia [with national rates varying from 24% to 83%], but only 32% [16% to 79%] received intravenous iron therapy.27 Our results underline that awareness of international guidelines on anaemia and iron therapy in IBD is still lacking, as evidenced by the very wide total dose range of 100 mg to 4800 mg. Furthermore, the fact that dose duration was longest not only for the largest, but also for the smallest doses [<500 mg] indicates that there is still some trepidation among physicians concerning the application of intravenous iron in general. FCM therapy has been demonstrated to be very effective and convincingly safe in IBD-associated anaemia in a large cohort of patients under daily routine conditions, and has also been shown to sufficiently replenish iron stores. In this NIS, all goals of anaemia treatment were met in the majority of patients: to increase Hb to normal levels or by at least 2 g/dL, and to raise serum ferritin and transferrin saturation above the lower limit of normal. Our results from daily routine practice confirm the results obtained in two pivotal clinical trials with FCM,18,19 covering an equally sized but selective and strictly-defined IBD patient collective. In these controlled trials, median Hb increased from 8.7 to 12.3 g/dL. Increments of Hb increase were found to be greatest at the second [and third] visit. Mean ferritin level in this NIS increased from 52 μg/L to 103 μg/L. Again, the ferritin increase [+51 μg/L] was most pronounced after Visit 2. This evidence of early response [Visit 2] is in agreement with previous FCM trials showing full response after 4–8 weeks.18,19 CRP levels showed a significant decrease during the observation period, falling from 6.4 mg/L to 3.5 mg/L in mean values [median 1.9 to 1.0 mg/L], indicating a general reduction in inflammatory activity. A corresponding decrease of CRP was not described in the two randomized controlled trials [RCTs].18,19 However, a similar reduction in disease activity has previously been shown by Kaltwasser et al. during IV iron sucrose therapy of patients with rheumatoid arthritis and anaemia of chronic disease. The authors observed not only a slight overall reduction in CRP levels during IV iron treatment, but also significant decreases in several clinical disease activity variables.28 In the present study, multivariate analysis was performed in an attempt to assess any relation between intravenous iron therapy and inflammation parameters. However, after removal of excess values and missing data, the sample size was too small to allow a meaningful analysis. Nevertheless, FCM does not appear to prevent drug-induced amelioration of inflammation. Larger, well-designed, prospective studies are needed in order to identify clinical, demographic, or other predictors of response to intravenous iron therapy, and to investigate further the question of whether intravenous iron therapy may influence inflammation parameters. Shifts of clinical parameters during the observation period, particularly regarding fatigue, lack of concentration, and anaemic mucosa, indicated a tendency for clinical improvement during FCM treatment and reflect improvement in quality of life. Accordingly, acceptance of FCM therapy was high: 95% of patients assessed it to be superior to their previous substitution therapy and 79% preferred it to their previous parenteral therapy. Only one participant graded the current therapy to be inferior to the previous one, and the remaining subjects were reported as undetermined. Single doses of 1000 mg FCM were tolerated under routine daily practice conditions by a high proportion [21.3%] of patients without any signs of adverse reactions. This represents a clear advantage of FCM compared with intravenous iron sucrose [Venofer®, Vifor GmbH], which should not exceed 200 mg per infusion and thus often necessitates repeat infusions. FCM is also superior in terms of the short infusion time of 15 min in median [mean 22, maximum 75 min], compared with the longer infusion time of 30 to 210 min for iron sucrose. These considerable advantages of high dosage, high infusion speed, and reduced need for repeat infusions, clearly favour FCM in the daily routine therapy of anaemic IBD patients and minimise time expenditure and effort of physicians and patients. Until now, tolerability data from FCM therapy have been available from selected patient collectives in controlled clinical trials.18–21 About 57% of those patients experienced an AE and 29% an adverse drug reaction. Adverse events assessed to be clearly drug-related were mild erythematous rash, urticaria, and pruritus. However, no immunological reactions were encountered on re-challenge. It may be perceived as a limitation of the present study that no data were collected regarding changes in serum phosphate levels in patients treated with intravenous iron. Although isolated cases of symptomatic hypophosphataemia have been reported in patients receiving long-term FCM, iron polymaltose, and iron sucrose therapy, no serious AEs associated with hypophosphataemia were recorded in any of the large clinical trials of intravenous iron preparations. However, FCM seems to be associated with a higher risk of hypophosphataemia compared to other IV iron products. Although the mechanisms involved are not yet fully understood,29 limited data indicate that FCM-associated hypophosphataemia may be dose-dependent.30 Thus, serum phosphate values should be routinely monitored, especially in patients with low baseline phosphate values or other concomitant risk factors [e.g. vitamin D deficiency, renal tubular defects], and in those receiving long-term or repeated intravenous iron therapy.31 Reporting data from a prospective open non-interventional trial including 394 Swedish IBD patients from 14 centres, Befrits et al. describe 27 [7%] infusion reactions [most commonly pruritus, chest tightness, nausea, and slightly increased temperature] of which, however, only one was considered serious.32 In their recent network meta-analysis comparing efficacy and safety of IV iron compounds based on five trials in IBD patients, Aksan et al. found that 12% of patients reported adverse events in connection with FCM doses of 500-1000 mg, but all but one [pulmonary embolism] were minor and transient in nature.33 In contrast, during the 495 routine FCM applications discussed in this NIS, only one adverse event [0.5%] was monitored. As classified by MedDRA terminology, it was a gastrointestinal disorder [SOC], more precisely the deterioration of ulcerative colitis [PT]. This AE was not related to the therapy in question. Reasons for the obvious difference in tolerability between controlled enquiry and routine application remain unknown, and it is conceivable that some AEs were lost from the analysis due to missing patient data. However, our data have only recently been substantiated by the results of a contemporaneous Spanish trial34 which reports only one severe AE during 88 FCM infusions in 72 patients. Whereas it may be argued that the disparity is a result of more intensive monitoring in clinical trials compared with non-interventional studies, this remains hypothetical. Generally, however, the tolerability of FCM therapy can be described as excellent under regular day-to-day treatment conditions. In addition, data from routine practice provides important information for the advancement of therapeutic treatment strategies and for the updating of guidelines. 5. Summary and Conclusion Ferinject® therapy was proven to be effective and safe in a large cohort of patients with IBD-associated anaemia in routine practice. Rapid, high-dose application is convenient for physicians and reduces patients’ time lost from work. In this retrospective study analysing real-life data from IBD patients treated with FCM, clinical scores and quality of life improved due to the amelioration of anaemia symptoms. Nevertheless, there are still a number of important issues which need to be addressed in future studies, in particular concerning the long-term safety of high doses of intravenous iron and the utility of remission therapy to ensure and sustain normal haemoglobin and ferritin levels and to maintain patient quality of life. Funding This work was funded by Vifor Germany GmbH, Munich, Germany, who also supported the development of the study design. Conflict of Interest No conflicts of interest were disclosed to study participants in the informed consent form. SW-M: employee of Vifor Pharma, Germany. KN: employee of Vifor Pharma, Germany. AD: speaker’s honoraria from Vifor International and Vifor Germany. JS: consultancy and speaker’s honoraria from Vifor International and Vifor Germany. Author Contributions JS: contributed to acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and statistical analysis. AA: contributed to analysis and interpretation of data; critical revision of the manuscript for important intellectual content; statistical analysis; and preparation of the revised version of the manuscript. WK: acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. KN: contributed to analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; and study supervision. SW-M: contributed to analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; and study supervision. AD: contributed to acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript. Acknowledgments An independent clinical research organisation [MedPharm Tec-Services, Germany] conducted the trial and performed the statistical analyses. The authors interpreted the results and made the decision for submission independently. 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For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Crohn's and ColitisOxford University Press

Published: May 4, 2018

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