A pilot feasibility trial of daily versus every other day oral iron supplementation in patients with iron deficiency anaemia.

Iron deficiency anaemia (IDA) is the most common anaemia worldwide.1 IDA impacts physical2, 3 and cognitive function,4-6 and health-related quality of life.7 Oral iron is associated with gastrointestinal effects in 30%–70% of patients8 leading to non-adherence. A pilot open-label randomized trial of daily versus every other day (EOD) oral iron for adults with IDA explored the feasibility of a definitive trial. Full protocol details were published9 (Appendix S1) and approved by Health Canada (file no. 240558) and registered on ClinicalTrials.gov (NCT03725384). Written consent was obtained from participants. Participants were outpatients ≥16 years with haemoglobin <120 g/L (females) and <130 g/L (males), and ferritin <30 μg/L. Participants were randomized 1:1 using a computer-generated sequence in random blocks of 4–6 to daily or EOD oral ferrous sulfate 300 mg (60 mg elemental iron; JAMP) and 500 mg Vitamin C tablets (WAMPOLE), stratified by site and baseline haemoglobin (≥100 or <100 g/L) for 12 weeks. Bloodwork was performed at baseline, 4 and 12 weeks; adverse effects and quality of life were assessed at weeks 1, 4, 8, 12 and 13. Participants unable to adhere to daily iron dropped to EOD; then if needed, to twice weekly. The primary outcome was time to enrol 52 participants. Patient demographics, medical history, iron use and bleeding were collected at baseline. Quality of life was assessed using the FACIT-Fatigue scale.10, 11 A modified adverse effects of oral iron questionnaire was used.12 The sample size estimate of 52 participants was based on enrolling 26 participants/site at two sites to allow completion rate estimates for laboratory tests and questionnaires, and adherence of 90% defined as participants taking 90% of prescribed doses. Fifty-two participants were enrolled over 26 months (January 2019–October 2021), excluding a pandemic-induced pause in enrolment (Figure S1). One patient was ineligible post-randomization due to ineligible laboratory results, and one ineligible patient did not receive treatment (Figure S2). The groups were similar; although, daily had six blood donors and 11 participants with menorrhagia versus three and 17, respectively, in EOD (Table 1). Completion of study procedures was 86% (Table S1). Haemoglobin increments significantly increased from baseline to week 4 (daily 13 ± 11 g/L vs. EOD 9 ± 7 g/L) and to week 12 (daily 22 ± 17 g/L vs. EOD 16 ± 10 g/L) (Figure 1). The mean haemoglobin difference (daily minus EOD) was 4 g/L (95% CI −0.1 to 1.0) at week 4 and 6 g/L (95% CI −0.3 to 1.4) at week 12. Those receiving daily iron had higher serum iron (p = 0.003) and TSAT (p = 0.009; Figure 1). A complete response, Hb ≥120 g/L (females) or Hb ≥130 g/L (males) by week 12, occurred in 75% daily versus 59% EOD participants (p = 0.37). No participants required escalation in therapy. FACIT-Fatigue scores improved at weeks 4, 8 and 12 compared to baseline in all participants (p < 0.0001) with no differences between groups (daily 20.1 ± 8.5 vs EOD 21.9 ± 9.9; p = 0.45; Figure 1, Tables S2 and S3). Thirty-eight, 33 and 33% of the daily group reported adverse effects at weeks 4, 8 and 12 compared with 56%, 48% and 44% in the EOD group (Table S2). The most common adverse effects at week 4 were constipation (24%), and nausea, headache and breathlessness (22%). The only significant change over time was decreased breathlessness at week 12 (Tables S2 and S4). Week 4 adverse effects were mostly mild/moderate with one severe headache and one severe abdominal pain. Three participants dropped from daily to EOD by week 4 due to adverse effects, with no further changes in dosing thereafter. One daily patient withdrew due to travel and three were lost to follow-up (one daily, two EOD; Figure S2). Post-hoc subgroup analyses to evaluate haemoglobin and ferritin response to daily vs. EOD oral iron for different subgroups were consistent with the overall results (Table S5). This trial of daily versus EOD ferrous sulfate enrolled 52 participants over 26 months. Rates of completion of study procedures were over 86%, with 80% of participants taking at least 90% of prescribed doses. Key changes for the definitive trial include: (1) all virtual visits; (2) extend the study to 16 weeks; (3) perform morning laboratory tests before taking medication; (4) add reticulocyte-haemoglobin content; (5) remove vitamin C; and (6) increase sites to accelerate recruitment. Given median ferritin at week 12 was only 27 μg/L, patients may require longer oral iron supplementation, particularly those with ongoing menorrhagia or GI bleeding (Table S3). Adding the reticulocyte-haemoglobin content may help predict response to oral iron.13 Strengths of DEODO include generalizability, with participants of both sexes (albeit 80% females), various ages and several reasons for anaemia. Participants with anaemia were treated for longer duration compared to previous trials.14 The DEODO trial improved quality of life. With mean difference of 5 g/L at 12 weeks between the daily and EOD arms, 90% power, one-sided significance level of 5%, and non-inferiority margin (upper limit of the 95% CI 6 g/L), 49 patients are required per group for a non-inferiority study (total 98 patients) plus correction of an 8% drop out rate. Limitations include exclusion of patients previously intolerant of oral iron. Imbalances may have favoured the daily group (more blood donors) whereas the EOD group had more patients with menorrhagia with lower baseline haemoglobins. The inclusion of blood donors may need to be reconsidered in a definitive trial to ensure balance between groups due to difference in potential response to oral iron compared with patients. The sample size was small and there were multiple comparisons, so no definitive conclusions can be made regarding clinical outcomes. Questions remain as to what ferritin level signifies iron repletion,15 and whether the “best” dose regimens depend on the severity of anaemia or other concomitant factors. The DEODO study was a pilot randomized feasibility trial of daily versus EOD oral ferrous sulfate. It demonstrated feasibility in enrolment and study procedure completion despite interruption by COVID-19. A trend towards increased haemoglobin and ferritin levels in the daily group suggests the need for a definitive trial. Y.L. is the principal investigator and conceived the trial. Y.L., M.E.D.G., M.S., W.A. and J.C. substantially contributed to the study conception and design. A.K., H.M., V.S., M.H., L.D. and C.A., recruited participants and implemented the trial. Y.L., J.B. and A.K. drafted the manuscript and revised it critically. All authors reviewed the protocol and approved the final version. We would like to acknowledge Dr. Christine Cserti-Gazdewich, Dr. Robert Skeate and Alexandra Roche for assistance in protocol development, Attiya Waqqas for coordinating site activation and initial participant recruitment at Sunnybrook Health Sciences Centre, Karen Lam and Nathan Ma for drug dispensing and accountability, and Qi-Long Yi and Liying Zhang for statistical support. Financial support for this research is provided by the University of Toronto, Alexandra Yeo Chair Grant in Benign Hematology, and Canadian Blood Services (Transfusion Medicine Research Program Support Award), funded by the federal government (Health Canada) and the provincial and territorial ministries of health. The views herein do not necessarily reflect the views of Canadian Blood Services or the federal, provincial or territorial governments of Canada. The funding sources had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data or decision to submit results. Financial support for this research is provided by the University of Toronto, Alexandra Yeo Chair Grant in Benign Haematology, and Canadian Blood Services (Transfusion Medicine Research Program Support Award), funded by the federal government (Health Canada) and the provincial and territorial ministries of health. The views herein do not necessary reflect the views of Canadian Blood Services or the federal, provincial or territorial governments of Canada. The funding sources had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data or decision to submit results. Yulia Lin has research support from Canadian Blood Services and is a consultant with Choosing Wisely Canada. Michelle Sholzberg has research support from the Research Society for Thrombosis and Haemostasis, unrestricted research funding from Octapharma Canada and Pfizer Canada. James B Bussel is a consultant for Apple, Novartis, Sobi, Rigel, Astra Zeneca, RallyBio and UCB. Jeannie Callum has research support from Canadian Blood Services, Canadian Institutes for Health Research, and Octapharma Canada. Written consent was obtained from all participants. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.