A Multicenter Single-Arm Study of Switching to Ferric Citrate Hydrate for Iron Deficiency Anemia in Patients Intolerant to Oral Iron: RIO-SWITCH.

Why carry out this study? Iron deficiency anemia (IDA) is a common blood disorder treatable with iron preparations; however, symptoms such as nausea and vomiting may occur, making it difficult for patients to continue treatment. Ferric citric hydrate (FCH) is an oral iron preparation that has been shown to have fewer side effects than sodium ferrous citrate. This study investigated the effectiveness of FCH treatment in Japanese female patients with IDA who experienced nausea and/or vomiting with previous iron preparations. What was learned from the study? Switching to FCH reduced the incidence and severity of nausea and vomiting, improved medication compliance, and enhanced quality of life compared with previous oral iron preparations. FCH could be a promising new treatment option for patients with IDA, offering improved tolerability, adherence, and quality of life improvements.

Female patients with IDA were included if they were aged ≥ 18 years, had previously taken oral iron preparations (excluding over-the-counter medications) and were intolerant to treatment because of ADRs of N/V (as assessed by the study investigator), had a hemoglobin level < 11.0 g/dl, and were able to enter information into electronic patient-reported outcomes (ePRO). The inclusion criteria pertaining to hemoglobin level and time since the last administration of previous oral iron preparations were revised during the study period. Patients who met any of the following criteria were excluded: a history of hypersensitivity to the components of FCH, a gastrointestinal disorder, paroxysmal nocturnal hemoglobinuria, hepatitis, pregnant or breastfeeding at the time of the study, previous exposure to FCH, N/V caused by drugs other than oral iron preparations, participation in another clinical trial, or judged unsuitable for study inclusion by the collaborative study investigators. This open-label, uncontrolled, single-arm comparative study included patients from 12 sites throughout Japan. Enrollment was between March 1, 2022, and January 20, 2023. The FCH dosage was determined by investigators according to the typical use of FCH, and the decision was not arbitrarily changed. FCH was administered starting at week 0 (baseline), with patients taking 500 mg (2 × 250 mg tablets) once daily immediately after a meal, not to exceed 500 mg twice daily [ 22 ]. The study treatment period was set as follows to assess medication adherence and hemoglobin levels. Nausea and vomiting occurred in early stage of oral iron treatment [ 23 ]. It was determined that the treatment period was 4 weeks for patients with hemoglobin levels ≥ 11.0 g/dl at week 4 or 8 weeks for patients with hemoglobin levels < 11.0 g/dl at week 4 considering hemoglobin improvement with FCH in a previous report [ 21 ]. If a patient discontinued the study prior to week 4 or week 8, the study treatment period was still defined as 4 weeks or 8 weeks. During the study treatment period, patients entered information regarding medication status, gastrointestinal symptoms (N/V), and menstrual status into a patient diary using ePRO (Figure S1 ). Laboratory tests (red blood cell- and iron-related tests) and patient questionnaires using ePRO were completed at baseline and week 4 (± 2 weeks); patients with hemoglobin levels < 11.0 g/dl at week 4 were also evaluated at week 8 (± 2 weeks). The questionnaires assessed previous oral iron preparations by the degree of interference with daily life at baseline, the degree and interference with daily life of N/V at baseline and end of the study, and treatment satisfaction with FCH at the end of the study (Tables S1 and S2). Additionally, the questionnaire queried the patient’s current health condition/QoL based on a health-related QoL instrument, EuroQol 5 dimensions 5-level (EQ-5D-5L), after obtaining permission for use from the EuroQol Research Foundation. The Japanese version of the EQ-5D-5L was used in this study and was previously developed using country-specific value sets, as health state preferences differ among countries [ 24 ]. The Short-Form 36-Item Health Survey v2 (SF-36v2) was used to measure QoL, functional health, and well-being based on patient-reported outcome assessments. The Japanese version, which has been translated, adapted, and validated for use in Japan [ 25 – 27 ], was used. Three-component summary scores were used to assess the summary score for SF-36v2, which includes the addition of social aspects and is considered more suitable than two-component summary scores in the Japanese population [ 28 ]. National normative scores (norm-based scoring) were used for the following eight domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. Work productivity and activity impairment were also assessed, based on a Japanese version of the Modified Work Productivity and Activity Impairment questionnaire—General Health V2.2 (Japanese-Japan) (mWPAI-GH). The mWPAI-GH is a modified version of the Work Productivity and Activity Impairment questionnaire (WPAI) patient-reported health outcome measure developed and validated for use in clinical trials [ 29 ]. Safety analyses were conducted with AEs coded using Medical Dictionary for Regulatory Activities ver.25.1 and ADRs defined as AEs judged by the investigators to be related to the study treatment. The study protocol was approved by the University of Tokyo, Clinical Research Review Board (no. 2021506SP), and all patients provided written informed consent at enrollment. The study was conducted in accordance with the latest versions of the Declaration of Helsinki, the Clinical Trials Act, the Enforcement Regulation of Clinical Trials Act (Ministry of Health Labour, and Welfare ordinance), and all applicable laws and regulations. The study was registered with the Japan Registry of Clinical Trials (trial ID, jRCTs031210634). The primary endpoint was the medication completion rate, defined as the percentage of patients with a medication compliance rate ≥ 70%. If patients discontinued study treatment owing to an AE of N/V, they were excluded from this analysis even if their medication compliance rate was ≥ 70%. Secondary endpoints included the medication compliance rate (the percentage of days a patient received the treatment during the treatment period), the medication completion rate according to previous oral iron preparations, the medication completion rate from baseline to week 4 (all patients regardless of hemoglobin level), values and changes in red blood cell-related laboratory tests and iron-related laboratory tests, study treatment satisfaction questionnaire scores (degree of N/V, degree of interference with daily life, and overall degree of interference), and scores and changes in QoL (EQ-5D-5L, SF-36v2) and work productivity (mWPAI-GH) indices. For safety analyses, AEs and ADRs were recorded from the time of study drug administration to the end of treatment. Based on the incidence of adverse reactions of nausea and vomiting [ 21 ], we assumed a 50% medication completion rate in this study. The target sample size was calculated to be 30 patients in total, which is the required sample size to estimate the medication completion rate with confidence interval at ± 20%. The full analysis set comprised all enrolled patients except those who did not take any FCH doses during the study, those with significant study protocol violations, those who withdrew consent and refused the use of their data, and those who were misregistered. The safety analysis set comprised all enrolled patients who received at least one dose of the study treatment and was used to analyze AEs and ADRs. Frequencies and proportions of categories were used to summarize categorical variables, and descriptive statistics were calculated for continuous variables. The two-sided significance level was set at 5%; multiplicity was not considered. Confidence intervals (CIs) were calculated using the Clopper-Pearson method for two-sided 95% CIs. Changes from baseline in the secondary endpoints of red blood cell- and iron-related laboratory tests and QoL and work productivity indices were compared before and after the study treatment using paired t -tests. All statistical analyses were performed using SAS software, version 9.4 for Windows (SAS Institute Inc., Cary, NC, USA).

Of the 41 enrolled patients, 30 met the inclusion criteria, of whom 24 (80.0%) achieved the hemoglobin target (≥ 11.0 g/dl) at week 4, and six (20.0%) continued treatment until week 8 (Fig.  1 ). There were no study discontinuations. Both the full analysis set and safety analysis set included 30 patients. Fig. 1 Patient disposition. a Patients who did not meet the hemoglobin level criteria of < 10.0 g/dl (protocol ver.1.3) and < 11.0 g/dl (protocol ver.2.0) Patient disposition. a Patients who did not meet the hemoglobin level criteria of < 10.0 g/dl (protocol ver.1.3) and < 11.0 g/dl (protocol ver.2.0) The mean ± standard deviation (SD) age of the patients was 43.5 ± 6.4 years; all 30 patients were menstruating (Table  1 ). Twenty-nine patients (96.7%) had abnormal uterine bleeding, most commonly caused by leiomyoma (22/30 patients; 73.3%) as determined using the PALM-COEIN classification system [ 30 ]. Twenty-two patients (73.3%) had previous sodium ferrous citrate oral iron preparation use, with time since the last administration prior to study participation ranging from ≤ 3 days to > 52 weeks. The frequency of oral iron preparation administration prior to study participation was ≥ 8 times in 19/30 patients (63.3%), 2–7 times in 9/30 patients (30.0%), once in 1/30 patient (3.3%), and unknown in 1/30 patient (3.3%) (data not shown). Table 1 Baseline characteristics Characteristic N  = 30 Age, mean ± SD 43.5 ± 6.4 Menopausal status  Menopausal 0 (0.0)  Premenopausal 30 (100.0) Comorbidities causing iron deficiency anemia  Abnormal uterine bleeding 29 (96.7)  PALM-COEIN system a   Leiomyoma 22 (73.3)   Adenomyosis 3 (10.0)   Ovulatory disorders 1 (3.3)   Endometrial abnormalities 1 (3.3)   Endometrial polyps 1 (3.3)   Others 2 (6.7)  Unknown 1 (3.3) Previous oral iron preparation prior to study participation a  Sodium ferrous citrate 22 (73.3)  Dried ferrous sulfate 5 (16.7)  Soluble ferric pyrophosphate 2 (6.7)  Ferrous fumarate 1 (3.3)  Others 0 (0.0) Time since last administration of previous oral iron preparation prior to study participation  ≤ 3 days 5 (16.7)  > 3 days, ≤ 1 week 1 (3.3)  > 1 week, ≤ 2 weeks 0 (0.0)  > 2 weeks, ≤ 4 weeks 0 (0.0)  > 4 weeks, ≤ 8 weeks 1 (3.3)  > 8 weeks, ≤ 12 weeks 2 (6.7)  > 12 weeks, ≤ 24 weeks 4 (13.3)  > 24 weeks, ≤ 52 weeks 1 (3.3)  > 52 weeks 16 (53.3) Data are n (%) unless otherwise noted PALM-COEIN, polyp, adenomyosis, leiomyoma, malignancy, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not-yet-classified; SD, standard deviation a Multiple choices were allowed Baseline characteristics Data are n (%) unless otherwise noted PALM-COEIN, polyp, adenomyosis, leiomyoma, malignancy, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not-yet-classified; SD, standard deviation a Multiple choices were allowed Of the 30 patients, 29 started with FCH 500 mg and 1 with FCH 1000 mg once daily. In one patient started with FCH 500 mg, the dosage was decreased from 500 to 250 mg because of adverse events (nausea and diarrhea) at an investigator’s decision during the study period. The dose was not increased for any of the patients during the study period. All 30 patients met the criteria for medication completion, resulting in a medication completion rate of 100.0% (95% CI 88.4–100.0%). The medication completion rate from baseline to week 4 was the same as the primary endpoint (100.0%; 95% CI 88.4–100.0%). The overall medication compliance rate was 93.92% ± 8.11% (mean ± SD, Table  2 ). All 30 patients had a medication compliance rate of ≥ 70%, 16/30 patients (53.3%) had a rate of 100.0%, and the lowest rate was 75.0% (Table  3 ). The mean medication compliance rate was > 80.0%, regardless of the type of previous oral iron preparation used (sodium ferrous citrate, dried ferrous sulfate, soluble ferric pyrophosphate, and ferrous fumarate) (Table S3). Among the six patients who continued the study treatment to week 8, the mean ± SD medication compliance rate from baseline to week 4 was 93.38% ± 7.93%, and from week 4 to week 8 was 92.86% ± 8.49% (Table  2 ). Five patients had N/V on the day of, or the day before, missing a dose of FCH; the mean ± SD medication compliance rate for these patients was 87.75% ± 3.91%. The reasons for failure to take medication included forgetting it (37 events in 11 patients), diarrhea (two events in one patient), nausea (one event in one patient), and other reasons (six events in five patients, including lack of medicine). Table 2 Medication compliance rate Medication compliance, % Overall N  = 30 Hemoglobin level at 4 weeks  ≥ 11.0 g/dl n  = 24  < 11.0 g/dl n  = 6 Until week 4 93.97 ± 8.17 94.12 ± 8.39 93.38 ± 7.93 Week 4 to week 8 92.86 ± 8.49 NA 92.86 ± 8.49 Until the end of treatment 93.92 ± 8.11 94.12 ± 8.39 93.14 ± 7.53 Data are mean ± standard deviation. The medication compliance rate was defined as the percentage of days a patient received the study treatment during the study treatment period NA, not applicable Table 3 Distribution of medication compliance rate N  = 30 Medication compliance rate, %  < 70.0% 0 (0.0)  ≥ 70.0%, < 80.0% 2 (6.7)  ≥ 80.0%, < 90.0% 7 (23.3)  ≥ 90.0, < 100.0% 5 (16.7) 100.0% 16 (53.3) Range 75.0–100.0 Data are n (%). The medication compliance rate was defined as the percentage of days a patient received the study treatment during the study treatment period Medication compliance rate Data are mean ± standard deviation. The medication compliance rate was defined as the percentage of days a patient received the study treatment during the study treatment period NA, not applicable Distribution of medication compliance rate Data are n (%). The medication compliance rate was defined as the percentage of days a patient received the study treatment during the study treatment period At the end of treatment, mean hemoglobin, red blood cell, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, serum iron, serum ferritin, and transferrin saturation increased relative to baseline, while the total iron binding capacity decreased (all p  < 0.0001; Table  4 ). Hemoglobin levels were increased in all patients regardless of the dose. At baseline, patients with hemoglobin levels < 11.0 g/dl and ≥ 11.0 g/dl at week 4 had mean ± SD hemoglobin levels of 9.27 ± 0.89 g/dl and 8.72 ± 0.49 g/dl, respectively, which significantly increased by the end of treatment (change from baseline at week 4, 1.57 ± 0.20 g/dl, p  < 0.0001; and week 8, 3.07 ± 0.90, p  = 0.0004; respectively). All but one patient reached the hemoglobin target of ≥ 11.0 g/dl at week 4 or week 8 (data not shown). Table 4 Laboratory test values Variable Overall ( N  = 30) Patients who completed the study treatment at week 4 ( n  = 24) Patients who completed the study treatment at week 8 ( n  = 6) BL EOT Change from BL to EOT p value a BL EOT Change from BL to EOT p value a BL EOT Change from BL to EOT p value a Hemoglobin (g/dl) 9.16 ± 0.85 12.03 ± 0.71 2.87 ± 0.85  < 0.0001 9.27 ± 0.89 12.09 ± 0.64 2.82 ± 0.85  < 0.0001 8.72 ± 0.49 11.78 ± 0.99 3.07 ± 0.90 0.0004 RBC (× 10 4 /μL) 424.1 ± 51.5 484.9 ± 59.9 60.8 ± 29.1  < 0.0001 417.7 ± 42.7 482.0 ± 52.5 64.3 ± 27.8  < 0.0001 449.5 ± 77.7 496.3 ± 89.2 46.8 ± 32.3 0.0163 Hematocrit (%) 30.46 ± 2.52 38.43 ± 3.13 7.97 ± 2.69  < 0.0001 30.69 ± 2.45 38.58 ± 2.85 7.89 ± 2.69  < 0.0001 29.53 ± 2.83 37.85 ± 4.35 8.32 ± 2.92 0.0009 MCV (fL) 72.68 ± 9.01 79.90 ± 6.65 7.22 ± 4.44  < 0.0001 74.03 ± 7.85 80.49 ± 5.59 6.45 ± 4.46  < 0.0001 67.27 ± 11.95 77.57 ± 10.24 10.30 ± 2.90 0.0003 MCH (pg) 21.94 ± 3.55 25.10 ± 2.73 3.16 ± 1.30  < 0.0001 22.45 ± 3.38 25.31 ± 2.54 2.87 ± 1.26  < 0.0001 19.90 ± 3.79 24.25 ± 3.54 4.35 ± 0.66  < 0.0001 MCHC (%) 30.12 ± 2.33 31.38 ± 1.53 1.26 ± 1.12  < 0.0001 30.25 ± 2.51 31.42 ± 1.61 1.17 ± 1.22 0.0001 29.62 ± 1.43 31.23 ± 1.28 1.62 ± 0.45 0.0003 Iron (µg/dl) 29.8 ± 50.9 111.0 ± 94.5 81.2 ± 93.5  < 0.0001 33.9 ± 56.3 108.0 ± 93.0 74.1 ± 90.8 0.0006 13.5 ± 3.5 123.0 ± 108.8 109.5 ± 107.4 0.0546 Ferritin (ng/ml) 7.69 ± 7.92 22.59 ± 10.00 14.90 ± 9.51  < 0.0001 8.33 ± 8.77 24.79 ± 9.88 16.45 ± 9.93  < 0.0001 5.13 ± 0.43 13.82 ± 3.92 8.68 ± 3.69 0.0022 TIBC (µg/dl) 456.8 ± 52.7 381.6 ± 45.9 − 75.2 ± 36.6  < 0.0001 455.2 ± 51.5 385.1 ± 42.9 − 70.0 ± 31.2  < 0.0001 463.5 ± 61.7 367.7 ± 58.9 − 95.8 ± 51.7 0.0062 TSAT (%) 6.42 ± 10.49 28.55 ± 22.31 22.12 ± 22.16  < 0.0001 7.27 ± 11.61 27.48 ± 21.54 20.20 ± 21.14 0.0001 3.03 ± 1.02 32.83 ± 26.92 29.80 ± 26.55 0.0403 Data are mean ± standard deviation BL, baseline; EOT, end of treatment; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cell; TIBC, total iron binding capacity; TSAT, transferrin saturation a p values were calculated using a paired t -test (baseline vs the end of treatment) Laboratory test values Data are mean ± standard deviation BL, baseline; EOT, end of treatment; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cell; TIBC, total iron binding capacity; TSAT, transferrin saturation a p values were calculated using a paired t -test (baseline vs the end of treatment) The mean ± SD score for the most severe nausea experienced with treatment decreased from 5.7 ± 2.4 on previous treatment to 1.7 ± 2.1 on FCH treatment. The score distribution is shown in Fig.  2 a. In total, 27/30 (90.0%) patients had decreases in most severe nausea scores after switching to FCH. All 30 patients had experienced N/V during the previous treatment, while 11/30 (36.7%) experienced no N/V during the FCH treatment. The maximum number of times/day a patient experienced vomiting decreased from five during the previous treatment to one during FCH treatment, and complaints of vomiting were reduced from 16.7 to 13.3%, respectively. More patients reported that N/V did not interfere with daily life during FCH treatment compared with the previous treatment (Fig.  2 b). Of the patients who experienced N/V, fewer reported mental stress from expected N/V, feeling sluggish and unable to do anything for a more extended period of time, difficulty concentrating on work, or poor appetite (Fig.  2 c). The same trend was observed for patients who reported reduced appetite and those who reported a lack of appetite and needing to make an effort to eat (Fig.  2 d). Fewer patients experienced interference with daily life caused by oral iron and a reduction in the degree of interference (Fig.  3 a) after switching to FCH; difficulty in continuing oral iron treatment, along with the degree of difficulty, was also reduced (Fig.  3 b). Fig. 2 Impact of nausea and vomiting on patient daily life. A Score of most severe nausea during treatment, B significance of interference with daily life caused by nausea and vomiting, C disadvantages in daily life caused by nausea and vomiting, and D appetite due to nausea and vomiting with previous treatment and FCH treatment. The denominator for B , C , D is the number of patients with nausea or vomiting. During oral iron preparations prior to study participation (the previous treatment), all 30 patients completed the questionnaire assessing patient satisfaction with their previous oral iron preparations. During the FCH treatment, 19 patients who reported nausea or vomiting completed the questionnaire assessing patient satisfaction with FCH (nausea, n  = 19 [63.3%]; vomiting, n  = 4 [13.3%]). In A , the score was defined as that of the most severe nausea during treatment. Higher scores indicated more severe nausea; a score of 0 indicated none, while a score of 10 indicated the worst ever experienced. In B , the significance of interference with daily life caused by nausea and vomiting was defined as follows: occasional and intermittent, symptoms rarely interfere with daily life; moderate, symptoms sometimes interfere with daily life; severe and often, symptoms often interfere with daily life and concentration; severe and persistent, persistent symptoms significantly interfere with daily life and concentration. In D , slightly less appetite than usual was defined as eating less often or in smaller amounts. FCH, ferric citrate hydrate Fig. 3 Interference of oral iron treatment on patient daily life. A Significance of interference with daily life caused by oral iron preparations and B significance of difficulty in continuing oral iron preparation treatment during previous treatment ( N  = 30) and during FCH treatment ( N  = 30). FCH, ferric citrate hydrate Impact of nausea and vomiting on patient daily life. A Score of most severe nausea during treatment, B significance of interference with daily life caused by nausea and vomiting, C disadvantages in daily life caused by nausea and vomiting, and D appetite due to nausea and vomiting with previous treatment and FCH treatment. The denominator for B , C , D is the number of patients with nausea or vomiting. During oral iron preparations prior to study participation (the previous treatment), all 30 patients completed the questionnaire assessing patient satisfaction with their previous oral iron preparations. During the FCH treatment, 19 patients who reported nausea or vomiting completed the questionnaire assessing patient satisfaction with FCH (nausea, n  = 19 [63.3%]; vomiting, n  = 4 [13.3%]). In A , the score was defined as that of the most severe nausea during treatment. Higher scores indicated more severe nausea; a score of 0 indicated none, while a score of 10 indicated the worst ever experienced. In B , the significance of interference with daily life caused by nausea and vomiting was defined as follows: occasional and intermittent, symptoms rarely interfere with daily life; moderate, symptoms sometimes interfere with daily life; severe and often, symptoms often interfere with daily life and concentration; severe and persistent, persistent symptoms significantly interfere with daily life and concentration. In D , slightly less appetite than usual was defined as eating less often or in smaller amounts. FCH, ferric citrate hydrate Interference of oral iron treatment on patient daily life. A Significance of interference with daily life caused by oral iron preparations and B significance of difficulty in continuing oral iron preparation treatment during previous treatment ( N  = 30) and during FCH treatment ( N  = 30). FCH, ferric citrate hydrate Most patients reported an overall satisfactory experience with FCH compared with their previous oral iron preparations, and none reported not very satisfactory or unsatisfactory experiences (Table  5 ). Table 5 Overall satisfaction with ferric citrate hydrate compared with previous oral iron preparation End of treatment a N  = 30 Satisfactory 24 (80.0) Somewhat satisfactory 5 (16.7) No change 1 (3.3) Not very satisfactory 0 (0.0) Unsatisfactory 0 (0.0) Data are n (%) a For the 24 patients with a hemoglobin level ≥ 11.0 g/dl at week 4, the study period was from baseline to the day before week 4. For the six patients with a hemoglobin level < 11.0 g/dl at week 4, the study period was from baseline to the day before week 8 Overall satisfaction with ferric citrate hydrate compared with previous oral iron preparation Data are n (%) a For the 24 patients with a hemoglobin level ≥ 11.0 g/dl at week 4, the study period was from baseline to the day before week 4. For the six patients with a hemoglobin level < 11.0 g/dl at week 4, the study period was from baseline to the day before week 8 SF-36v2 scores increased from baseline to the end of treatment in all eight domain scores, with significant differences in physical functioning ( p  = 0.0002), body pain ( p  = 0.0013), vitality ( p  < 0.0001), social functioning ( p  = 0.0016), role emotional ( p  = 0.0088), and mental health ( p  = 0.0079) (Fig.  4 a). All SF-36v2 three-component summary scores increased from baseline to the end of treatment, but significant differences were reported only for the mental and role/social component summary scores ( p  = 0.0005 and p  = 0.0064, respectively) (Fig.  4 b). Fig. 4 Impact of nausea and vomiting on quality of life. A SF-36v2 eight domain scores and B SF-36v2 three-component summary scores at baseline and end of study. Mean scores for baseline versus end of treatment were compared using a paired t -test. * p  < 0.05. BP, bodily pain; FCH, ferric citrate hydrate; GH, general health; MCS, mental component summary; MH, mental health; PCS, physical component summary; PF, physical functioning; RCS, role/social component summary, RE, role emotional; RP, role physical; SD, standard deviation; SF, social functioning; SF-36v2, Short-Form 36-Item Health Survey version 2; VT, vitality Impact of nausea and vomiting on quality of life. A SF-36v2 eight domain scores and B SF-36v2 three-component summary scores at baseline and end of study. Mean scores for baseline versus end of treatment were compared using a paired t -test. * p  < 0.05. BP, bodily pain; FCH, ferric citrate hydrate; GH, general health; MCS, mental component summary; MH, mental health; PCS, physical component summary; PF, physical functioning; RCS, role/social component summary, RE, role emotional; RP, role physical; SD, standard deviation; SF, social functioning; SF-36v2, Short-Form 36-Item Health Survey version 2; VT, vitality The mean ± SD change in the EQ-5D-5L QoL index was 0.094 ± 0.106 ( p  < 0.0001) over the course of the study. At baseline and the end of treatment, 8/30 patients (26.7%) and 20/30 patients (66.7%), respectively, had scores greater than the EQ-5D-5L norms for the Japanese population. In addition, there were no statistically significant differences in the change from baseline to the end of the treatment in presenteeism, absenteeism, overall work impairment, or activity impairment scores as assessed using the mWPAI-GH in either the total population (Figure S2a) or the 11 patients with a presenteeism score > 0 at baseline (i.e., impaired presenteeism) (Figure S2b). In the 30 patients included in the safety analysis set, 17 AEs were reported in 12 (40.0%), all of which were non-serious. AEs with > 2 incidences included three events of nausea in three patients (10.0%) and two events each of abdominal discomfort, constipation, and nasopharyngitis in two patients each (all 6.7%) (Table S4). There were nine events of ADRs reported in six patients (20.0%), which included three events of nausea in three patients (10.0%), two events each of abdominal discomfort and constipation in two patients each (6.7%), and one event each of diarrhea and abdominal distension in one patient each (3.3%) (Table S5). All ADRs were non-serious and mild in severity and did not result in treatment discontinuation.

In this study, patients with IDA who had difficulty continuing treatment with previous oral iron preparations were switched to FCH. All patients completed the study treatment and had improvements in anemia. For patients who experienced N/V with previous oral iron preparations, switching to FCH improved multiple aspects of treatment, including medication compliance, the degree to which N/V interferes with daily life, and medication adherence through improvements in QoL. Improved medication compliance allows for continuous treatment of anemia in patients who are intolerant to oral iron preparations. FCH is expected to be an attractive first-line treatment option that is less burdensome for patients and allows them to continue treatment, given the associated QoL improvements.

This study indicates that FCH offers a viable treatment alternative for patients with IDA who experience intolerance to conventional oral iron preparations. The high treatment completion rate and improved symptom profile suggest several potential advantages in clinical practice. Before entering this study, all 30 patients experienced N/V when taking previous oral iron preparations. After switching to FCH, 36.7% patients had no N/V. For patients who did experience N/V, the severity was reduced with FCH compared with previous oral iron preparations (mean score decrease: 4.0). The high medication compliance rate (93.92%) may have been influenced by the reduced incidence and severity of N/V, which suggests improved gastrointestinal tolerability. In addition, all 30 patients had improved hemoglobin levels at the end of treatment. The observed improvements in both tolerability and adherence indicate FCH as an alternative treatment option for patients requiring continuous iron supplementation. Reports on medication compliance rates are limited. However, in an earlier study, a rate < 70% was considered under-adherence [ 31 ]. Based on the assumption that a certain percentage of patients occasionally forget to take their medication (1–2 days per week), it was reasonable to set the target medication compliance rate at ≥ 70% in the present study. The medication compliance rate was similar among six patients who continued the study treatment through week 8 and the group who ended the study treatment at week 4. Hemoglobin levels increased with the study treatment in all six patients. These patients had lower mean hemoglobin at baseline, which may have contributed to the prolonged duration of the study treatment. Previous studies have reported QoL improvements (i.e., SF-36) for patients with IDA following oral iron administration [ 32 , 33 ], but none have evaluated QoL changes in these patients when switching oral iron preparations. The present study found a reduction in the extent to which N/V interfered with daily life, particularly related to a reduced level of difficulty concentrating on daily activities such as work and housework, feeling sluggish, poor appetite, and mental stress from expected N/V. Therefore, it is possible that improvements in SF-36v2 scores could have been affected, at least in part, by improvements in anemia. It is also feasible that improvements in the extent to which N/V interfered with daily life contributed to QoL improvements following the switch. While there was a numeric increase in the physical functioning score from baseline to the end of the study, this change was not significant. This may have affected the physical component summary outcome, given the sizable contribution of physical functioning to the physical component summary in the conceptual model of three-component summary scores. The reduction in N/V following the switch may have also contributed to improvements in EQ-5D-5L QoL score, as suggested by a previous study that found N/V when taking oral iron preparations contributed to decreased EQ-5D-5L QoL scores [ 18 ]. A previous study reported the mean ± SD EQ-5D-5L scores by age group among the general population of Japanese female patients as 0.944 ± 0.104 in those aged 30–39 years and 0.945 ± 0.090 in those aged 40–49 years [ 34 ]. In the present study, more patients at the end of treatment had EQ-5D-5L scores higher than the reported norms for the female Japanese population than at baseline. This suggests that switching to FCH may have contributed to an improvement in QoL. No statistically significant differences were observed in work productivity scores from baseline to the end of treatment. Many patients had undisordered presenteeism at the start of the study treatment, with baseline values lower than in reports investigating dysmenorrhea [ 35 ], which makes it difficult to assess changes in work productivity scores. For approximately 80% of the patients in the present study, it had been > 1 week since their last administration of oral iron preparation, which may have affected baseline work productivity scores. The most common disease associated with IDA in this study was uterine leiomyoma, which, unlike dysmenorrhea, does not have pain as a predominant symptom, resulting in less impact on work productivity [ 36 ]. This may also explain the higher work productivity at baseline versus dysmenorrhea [ 35 ]. While IDA treatment recommendations state that patients undergo continuous iron supplementation for a minimum of 3–6 months until serum ferritin level normalization is achieved [ 15 ], this might be difficult to achieve if patients are experiencing intolerable side effects. FCH demonstrated improved tolerability compared with conventional oral iron preparations. Additionally, laboratory data demonstrated an improvement in anemia, which is in line with the findings of a phase 3 trial [ 21 ]. This study had a few limitations that should be noted. Over half of the patients received previous oral iron preparations > 52 weeks prior to initiating study treatment; for those patients, the EQ-5D-5L, SF-36v2, and mWPAI-GH scores obtained at baseline were not reflective of their condition at the time they were receiving previous oral iron preparations. This study was also limited by the single-arm design after switching, the small sample size, and short treatment period to replenish iron stores.

Iron deficiency anemia (IDA) is the most prevalent type of anemia worldwide [ 1 – 5 ]. The frequency of anemia among reproductive-aged women is higher in Japan than in the US [ 6 , 7 ], and it is reported that Japanese women frequently experience IDA because of low iron intake [ 8 ]. Several organizations have developed criteria for defining IDA based on sex, age, and other factors [ 5 , 9 ]. According to World Health Organization criteria, patients are considered to have IDA when hemoglobin levels fall below 12 g/dl for women or 13 g/dl for men [ 5 ]. IDA often occurs in several chronic conditions, including chronic kidney disease, congestive cardiac failure, and inflammatory bowel disease [ 4 ]. It also occurs more frequently in women than men, and it is particularly prevalent in reproductive-aged women [ 10 ]. IDA is usually caused by menstrual blood loss and/or abnormal uterine bleeding derived from uterine fibroids, endometrial polyps [ 11 , 12 ], gastrointestinal or other bleeding, or reduced iron absorption. In pregnant women, IDA is a common micronutrient deficiency and can have severe consequences, including mental health issues, impairment of the immuno-inflammatory system, premature birth, and fetal death [ 13 ]. Therefore, prevention of IDA is important for preconception and prenatal care. Oral iron preparations are considered first-line treatment for IDA [ 14 ], and although hemoglobin levels begin to improve within 2 weeks of initiating treatment, it is recommended that a patient undergo continuous iron supplementation for a minimum of 3–6 months until serum ferritin level normalization is achieved [ 15 ]. The most common adverse drug reactions (ADRs) with current oral iron preparations are gastrointestinal symptoms, including constipation, nausea, vomiting, and diarrhea [ 16 ]. It has been reported that medication adherence for oral iron therapy is inadequate among those with IDA, predominantly because of gastrointestinal side effects, worries about weight gain, and insufficient information about the duration of therapy [ 17 ]. Nausea and vomiting associated with oral iron therapy are reported to affect patient quality of life (QoL) negatively [ 18 ], which may make patients reluctant to continue their medication. Therefore, it is important to take measures against ADRs, such as nausea and vomiting, to support optimal treatment for anemia. Ferric citrate hydrate (FCH: Riona ® , 250 mg tablet, Torii Pharmaceutical Co., Ltd., Tokyo Japan) is approved in Japan as a phosphate binder for patients with chronic kidney disease [ 19 , 20 ] and as an oral iron supplement for patients with IDA [ 21 ]. The efficacy of FCH was demonstrated as non-inferior to an existing treatment, sodium ferrous citrate, in a Japanese phase 3 study in patients with IDA [ 21 ]. Nausea was the most frequent gastrointestinal symptom with sodium ferrous citrate treatment, and approximately 30% of patients with IDA who took oral iron preparations had experienced nausea and/or vomiting (N/V). Gastrointestinal symptoms were also the most frequent adverse events (AEs) experienced with FCH treatment; diarrhea was the most common, with a similar incidence to sodium ferrous citrate treatment. However, the incidence of N/V was significantly lower with FCH treatment versus sodium ferrous citrate treatment [ 21 ], which may make it an attractive option for patients with IDA. In clinical practice, medication is often switched to minimize treatment interruptions due to side effects. However, data on switching oral iron preparations for IDA are limited. In addition, the impact of switching to improve patient’s QoL may be important regarding treatment adherence. No previous studies have evaluated the clinical evidence and QoL changes when switching to FCH from another oral iron preparation among patients with IDA who have experienced N/V. This study evaluated the use, efficacy, and QoL changes when patients with IDA who were intolerant to their previous oral iron preparations due to N/V switched to FCH.

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