Explanation for the choice of comparators

Feroba-you tablet is a dried ferrous sulfate that is widely used in actual clinical practice for oral iron supplementation, and its safety is tolerable, so it was designated as a comparator.

Intervention description

Iron supplementation will be initiated on the day of randomization. Patients assigned to the intravenous iron supplementation group will receive ferric carboxymaltose in doses based on body weight and serum hemoglobin levels (Table 1). Patients with serum hemoglobin ≤ 10 g/dL (6.2 mmol/L) will receive a dose of 1500 mg if their weight is 35 to 70 kg or 2000 mg if over 70 kg. Patients with serum hemoglobin > 10 g/dL (6.2 mmol/L) will receive a dose of 1000 mg if their weight is 35 to 70 kg or 1500 mg if over 70 kg. The dose per administration should not exceed 1000 mg, and administrations should not occur more than once per week. Therefore, if an additional infusion for the remainder of the dose is required, it will be administered 1 week after the initial infusion. Patients assigned to the oral iron supplementation group will take 256 mg of ferrous sulfate, two tablets a day (one in the morning and one in the evening), for a total daily dose of 512 mg, until the day before surgery. If anemia persists after surgery, they will continue taking the oral medication until the anemia is corrected. Ferric carboxymaltose will be administered intravenously by clinical staff in a designated injection room, following protocol guidelines, while ferrous sulfate will be self-administered orally by patients based on the dosage instructions provided by the study team.

Table 1 Cumulative dose of ferric carboxymaltose based on body weight and serum hemoglobinCriteria for discontinuing or modifying allocated interventions

Participants are free to discontinue their participation at any time, for any reason, without any consequences. If a participant meets previously unrecognized exclusion criteria or develops an urgent medical condition that disqualifies participating, the investigator may choose to discontinue their participation in this study. If a patient discontinues from the trial, all data collected up to the point of discontinuation will be retained and included in the final analysis unless the patient explicitly requests the deletion of their data. No modifications to the intervention are planned for this trial. Any unforeseen changes will be documented and considered in the data analysis.

Strategies to improve adherence to interventions

Patients taking oral iron supplementation will receive a medication diary to improve adherence and maintain their medications as planned. The daily intake of oral iron recorded by participants will be reviewed to measure adherence.

Relevant concomitant care permitted or prohibited during the trial

Blood transfusions will be permitted based on international guidelines [18]. Transfusions will be administered when serum hemoglobin is below 7 g/dL for hematologically stable adult patients and below 8 g/dL for patients with cardiovascular disease.

Provisions for post-trial care

In case of any adverse events related to the research procedures, appropriate medical treatment will be provided, and compensation will be given based on the established regulations of our institution.

Outcomes

Our primary endpoint is the percentage of patients achieving normalization of serum hemoglobin levels on the day of admission for surgery (serum hemoglobin ≥ 12 g/dL for women and ≥ 13 g/dL for men). Our secondary endpoints include serum hemoglobin levels, iron assay parameters (serum iron, ferritin, TIBC), length of hospital stay, time interval to achieve normalized serum hemoglobin levels, the necessity and volume of blood transfusions, and perioperative complications (Clavien-Dindo classification, Comprehensive Complication Index) [19, 20]. Blood samples to assess hemoglobin will be taken at baseline, after CRT, at admission, and on postoperative day 1, as well as at 1 week, 4 weeks, 8 weeks, 3 months, 6 months, and 1 year, to compare the effects of intravenous and oral iron supplementation at each time point. Iron values will be measured after CRT, on postoperative day 1, at 1 week, and at 4 weeks. All iron assay parameters in this study can be assessed through serum laboratory tests. Iron deficiency will be determined by serum ferritin levels of less than 30 ng/mL and serum transferrin saturation (serum iron × 100/TIBC) of less than 20%. The length of hospital stay will be measured from the day of admission for rectal cancer surgery until the day of discharge following the surgery. The time interval to achieve normalized serum hemoglobin levels will be compared, with a focus on the values identified after CRT. The necessity for blood transfusion will be determined by international guidelines [18], with the transfusion volume adjusted based on individual patient factors, including underlying disease and intraoperative bleeding.

Participant timeline

At the initial outpatient visit, an assessment will be conducted to diagnose IDA and confirm eligibility based on the inclusion criteria, followed by obtaining informed consent. Eligible patients will undergo randomization at the next outpatient visit, and iron supplementation will be initiated. Ferinject injection as intravenous iron supplementation will be administered either once or twice at weekly intervals, while ferrous sulfate as oral iron supplementation will be continued until just before surgery. Follow-up will maintain until 1-year post-operation, with scheduled hematologic tests (complete blood count, albumin, C-reactive protein) and iron assays (serum iron, ferritin, TIBC) performed. The detailed schedule of assessments is presented in Table 2.

Table 2 Schedule of assessmentsSample size

Based on a previous randomized controlled trial [16], we hypothesized that the rate of achieving normalization of serum hemoglobin levels 3 months after initiating iron supplementation would be 70% in the experimental arm and 40% in the control arm. With a two-sided α of 0.05 and a power of 0.8, the sample size was calculated as 94 patients (47 per group), considering an estimated drop-out rate of 10%.

Recruitment

All rectal cancer patients visiting the outpatient clinic will be closely monitored to determine if they meet the inclusion criteria. Once eligibility is confirmed, the surgeon will contact the patient to provide details about the study background and process and request participation in the study. Patients will be given ample time to consider participation and to ask any questions they may have.