Participants, interventions, and outcomes

Study setting

This study is taking place at two large academic hospitals in Toronto, Canada, affiliated with the University of Toronto: Sunnybrook Health Sciences Centre and St. Michael’s Hospital, Unity Health Toronto.

Eligibility criteria

The eligibility criteria of this study are broad to increase the generalizability and feasibility of the proposed trial. The exclusion criteria are predominantly conditions where oral iron has already been shown to be ineffective. There are no exclusions based on sex, race, or ethnicity in this trial.

Inclusion criteria

  1. 1.

    Age ≥ 16 years

  2. 2.

    Outpatients with iron deficiency anemia defined as hemoglobin less than 12.0 g/dL in females or less than 13.0 g/dL in males AND ferritin less than 30 mcg/L.

Exclusion criteria

  1. 1.

    Pregnancy and/or currently breastfeeding

  2. 2.

    Known history of inflammatory bowel disease, celiac disease, thalassemia or thalassemia trait, and/or inherited bleeding disorder

  3. 3.

    Known intolerance or lack of response to oral ferrous gluconate, sulfate, or fumarate in the last 12 weeks

  4. 4.

    Multivitamin and mineral supplements (35 mg or more of elemental iron per day) in 2 weeks prior to randomization

  5. 5.

    Allergy to oral iron

  6. 6.

    Allergy to any of the following medicinal and non-medicinal ingredients in ferrous sulfate: ferrous sulfate, calcium citrate, crospovidone, FD&C Red #40-Aluminum Lake, FD&C Yellow #6-Aluminum Lake, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, purified water, and talc titanium dioxide

  7. 7.

    Allergy to any of the following medicinal and non-medicinal ingredients in vitamin C: ascorbic acid, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and stearic acid

  8. 8.

    Intravenous iron therapy in the past 12 weeks

  9. 9.

    On new anticoagulant therapy initiated in the past 6 months (e.g., warfarin, apixaban, dabigatran, edoxaban, rivaroxaban)

  10. 10.

    Surgery, chemotherapy, and/or blood donation planned in upcoming 12 weeks

  11. 11.

    Previously enrolled in the study

  12. 12.

    Creatinine clearance less than 30 mL/min

  13. 13.

    Hemoglobin less than 8.0 g/dL with active bleeding (defined as WHO grade-2 bleeding or higher in the past week)

Consent

Patients interested in participating and meeting inclusion and exclusion criteria are given an informed consent form (Additional file 2). The study coordinator conducts an informed consent discussion which includes the rationale for the study, the anticipated risks and benefits of participation, and their rights as a study participant (including withdrawal at any time). Capable participants are offered an opportunity to ask questions and consult with their family and/or their primary care physician before enrollment. If the patient is deemed incapable of providing informed consent for the study, study personnel approach the patient’s physician to determine if it is safe to delay treatment while a substitute decision-maker is identified and approached. As the initiation of oral iron is not urgent, there is enough time to assess the patient for inclusion in the study before initiating treatment. The subject is invited to participate and must provide written informed consent prior to any study-related procedures. Remote consent using a certified signature software (e.g., Adobe Sign) is permitted; this change was made as a result of the COVID-19 pandemic. Once the subject is enrolled, his/her family physician is informed about his/her participation in the study. If the participant does not wish to participate, the reason for declining is documented. All sites obtained Research Ethics Board (REB) approval of the protocol and informed consent form before commencing any study activities.

Interventions

Open-label oral ferrous sulfate-300 mg (60 mg of elemental iron; JAMP, Boucherville, Québec, Canada) and vitamin C 500-mg tablets (WAMPOLE, Boucherville, Québec, Canada) are the natural health products used throughout this study. Once enrolled, participants are randomized to either the daily or every other day treatment arm. Randomization occurs within 1 week of enrollment. Once randomization occurs, a prescription for the dosing regimen is given to the participant to bring to the pharmacy at the local study site. Participants opting for virtual clinical visits may receive their study drug by courier. As participants receive the total treatment for 12 weeks at once, they were notified by the research coordinator that it was their responsibility to not share the tablets with others. The consent form warned participants that the pills should be kept away from children as a child taking an excessive amount of tablets would need to seek prompt medical attention.

Daily dosing

Starting on day 1, participants take ferrous sulfate on an empty stomach with vitamin C daily for a period of 12 weeks. Participants are instructed to take oral iron at bedtime but can take it at another time during the day if more convenient. If participants cannot tolerate the oral iron on an empty stomach, they are instructed to take it with a small amount of food and avoid eating dairy, antacids, calcium, and tannins (e.g., coffee/tea) at the same time.

Every other day dosing

Starting on day 1, participants take ferrous sulfate on an empty stomach with vitamin C every other day for a period of 12 weeks. Participants following this dosing schedule are instructed to take the tablets in the same manner as those on the daily dosing schedule.

Packaging

The oral ferrous sulfate tablets are packaged in bottles containing the corresponding amount of pills depending on which treatment arm the patient has been assigned to. One patient kit contains a bottle of oral ferrous sulfate and another bottle of vitamin C to be taken together.

Modifications

Participants are followed until 12 weeks or until there is an escalation in therapy as defined by the need for the following: alternative oral iron therapy (including if a participant in the every other day group escalates to daily iron), need for intravenous iron, need for transfusion, or a visit to the emergency department related to anemia. At the week 4 assessment, participants with a drop in hemoglobin of more than 1.0 g/dL from baseline are referred back to the most responsible physician (MRP) for management and therapy escalation. It is anticipated that approximately 30% of participants may not tolerate oral iron. Side effects may improve over the initial 1–2 weeks of intervention. In some cases, participants may not be able to tolerate the intervention and, in such cases, are instructed to follow their planned schedule as prescribed. If they continue to have symptoms, participants are instructed to step down in frequency (e.g., from daily to every other day, from every other day to two times per week, from two times per week to once per week) and to record how frequently they are able to take oral iron. If participants are unable to take the oral iron at all, they continue to be followed as long as they do not meet any of the following criteria for withdrawal: become pregnant during the course of the study, any deviation from inclusion/exclusion criteria, and serious adverse events.

Adherence

Throughout the study duration, participant compliance with ingesting oral iron is monitored through an adherence diary, direct contact between the patient and study coordinator at designated assessment times (i.e., 1, 4, 8, and 12 weeks post-initiation), and a pill count following the 12-week supplementation period. Participants check off when they have taken their tablet on the diary calendar (provided in paper format), which indicates which days they should be ingesting oral ferrous sulfate. At the 1st, 4th, and 8th weeks after beginning the study treatment, participants are contacted (telephone or email) to assess adherence. If a participant misses a pill, they are advised to continue with the next dose as directed on the calendar and not to double up on dosing. At the end of the 12-week supplementation period, the participant returns the adherence diary, the pill bottle provided to them, and any unused tablets for a final pill count; this number will be compared to the number of tablets the participant should have ingested during the 12 weeks. Participants opting for remote assessments are requested to courier their pill bottles and adherence diary back to the local site, in which case a prepaid return envelope is provided to participants by the study site.

Prior and concomitant medications

Throughout the study duration, and 2 weeks leading up to randomization, participants are not permitted to receive other sources of iron supplementation, including, but not limited to, other oral ferrous tablets and intravenous iron therapy. Participants are advised not to take oral iron within 2 h of antibiotics, bisphosphonates [28], levodopa, methyldopa [29], mycophenolate mofetil [30], or thyroid medication [31]. To allow tracking of confounders, participants are asked to notify the study coordinator if they choose to take part in another intervention during the study.

Outcome measures

Feasibility outcome measures

The primary feasibility outcome of the trial is enrollment defined as documentation of informed consent and confirmation of eligibility. If the study is unable to enroll 52 participants in a 2-year period, the study as it is currently designed will not be deemed feasible. To determine feasibility of this study, the following proportions will be evaluated at the end of the trial: (1) eligible participants consenting to participate and receiving the allocated treatment; (2) treated participants completing laboratory tests, side-effect questionnaire, and the Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue scale; (3) treatment doses taken as per protocol based on pill count; (4) participants taking at least 90% of their prescribed doses; and (5) participants requiring a step down in therapy. Methods of aggregation and specific measurement time points of interest for analysis are outlined in Table 1.

Table 1 Methods of aggregation for feasibility outcome measures

Secondary clinical and safety outcome measures

Laboratory assessments

Hemoglobin increments will be calculated from the hemoglobin levels at 4 and 12 weeks minus the baseline hemoglobin value. A complete hemoglobin response will be defined as the proportion of participants with a hemoglobin greater than or equal to 12.0 g/dL in females and 13.0 g/dL in males at 4 and 12 weeks. Change in reticulocyte count at 4 and 12 weeks will be defined as the 4- or 12-week reticulocyte count minus the baseline count. Change in ferritin, serum iron, and TSAT at 12 weeks will be defined as the value at 12 weeks minus the baseline value.

Quality-of-Life (FACIT-fatigue scale)

Given the impacts of IDA extend beyond anemia and can affect an individual’s physical, emotional, and social well-being, quality-of-life measures are important to incorporate in the current study. The FACIT-fatigue scale is administered to participants at the 4-, 8-, and 12-week assessment to evaluate anemia-related fatigue [32]. The scale is administered by the study coordinator and consists of 13 patient-reported items with a 7-day recall period. Items are scored from 0 (not at all) to 4 (very much so).

Side-effect questionnaire

The side effects of oral iron can have a significant impact on adherence with studies reporting up to 40% nonadherence [33]. A recent study specifically developed a one-page side-effect questionnaire in patients on oral iron supplementation [34]. A modified version of this questionnaire is used in the current study to assess the proportion of participants with side effects at 4, 8, and 12 weeks. The proportion of participants who stop taking oral iron due to side effects at 4 and 12 weeks is also documented.

Need for escalation of therapy

At the 12-week assessment, participants are assessed for the need for escalation in therapy defined as an increase in oral iron regimen from every other day to daily, need for intravenous iron, or a visit to an emergency department related to anemia. The proportion of participants with a drop in hemoglobin of 1.0 g/dL of more at weeks 4 and 12 from baseline is also recorded. Patients with unexplained iron deficiency or ongoing bleeding are referred by the study doctor for further assessment (e.g., gastroenterologist, gynecologist).

Participant timeline

The participant timeline is described in Table 2.

Table 2 Schedule of enrollment, interventions, and assessments/procedures

Sample size

The sample size of the study is based on an anticipated enrollment of 26 patients per year at the two sites combined. With a sample size of 52, we will be able to estimate a completion rate for laboratory tests and questionnaires and an adherence rate (participants taking at least 90% of their prescribed doses) of 90% to within a 95% confidence interval of +/−8%. For participants requiring a step down in therapy, we will be able to estimate a rate of 5% to within a 95% confidence interval of +/−6%.

Recruitment

Recruitment will occur for the duration of 2 years. Participants meeting inclusion criteria are identified through referring clinician offices (hematology and primary care physicians). With permission from the MRP to enter the patient’s circle of care, the study coordinator approaches potentially eligible participants. The study coordinator introduces the trial, confirms eligibility, and conducts the informed consent discussion. Study personnel screen participants for exclusion criteria by asking about the patient’s medical history and reviewing their bloodwork that will be taken as a standard of care when visiting the MRP.

Another recruitment site is the Canadian Blood Services (CBS). Toronto area blood donors that have been deferred due to low hemoglobin levels are provided with a letter explaining that the donor was deferred and for the donor to visit their family physician for further investigation. In addition, a letter to the family physician explains key points about the study purpose, rationale, procedures, and detailed information about the trial. If the patient is interested in participating, their physician can refer the patient to one of the study sites. It is also acceptable for the patient to contact the study site directly in which case permission from the MRP is not required.

Assignment of interventions

Allocation, concealment, and implementation

Participants are randomized in a 1:1 ratio according to a computer-generated allocation sequence to receive either once daily dosing or every other day dosing. The randomization code is generated in random blocks of 4 to 6, stratified by center and baseline hemoglobin (hemoglobin ≥ 10 g/dL OR < 10 g/dL). Randomization is provided by the Centre for Clinical Trial Services at Sunnybrook Health Sciences Centre to the sites in opaque numbered envelopes to ensure concealment and no members of the study team have access to the allocation scheme. The envelope is only opened by the study coordinator once baseline measurements have been completed and the participant has been enrolled in the trial. Following randomization, participants receive oral iron tablets for a period of 12 weeks, with clinical and subjective data collection occurring 1, 4, 8, and 12 weeks following commencement of oral iron (see Fig. 1). The study aims to recruit 52 participants in total, randomizing 26 participants to each study arm.

Blinding

This study is an open-label trial. The statistician will remain blinded when performing the final analysis.

Data collection, management, and analysis

Data collection methods

Source documents have been developed for each assessment throughout the study and are used by study personnel to complete case report forms (CRFs). Demographic and medical history data are collected at the baseline visit using a baseline assessment questionnaire (Additional file 3) and participant medical records. Dietary assessments (e.g., vegetarian, vegan) were done at the baseline visit to allow for an estimate of dietary iron intake. For female participants where menorrhagia is the cause of iron deficiency anemia, a pictorial blood assessment chart [35, 36] is used to assess the level of menstrual bleeding. Laboratory results are reviewed by the principal investigator and assessed for clinical significance for results considered out of range. Participants may obtain bloodwork at the local study site or at a local blood lab; the same laboratory must be used for the duration of the study. Paper patient adherence diaries are used to assess adherence and photos of the calendar e-mailed at the follow-up visits to the study coordinator. Adverse events and quality of life are assessed using the side-effect questionnaire and FACIT-fatigue scale, respectively. A medication log is used throughout the study to confirm if a participant has started any new or discontinued medications. Participants will also be compensated for parking expenses incurred if they choose to have their follow-up assessments and/or bloodwork completed at the local study site. Intervention discontinuation, withdrawal of consent, and participants lost to follow-up are documented.

Data management

Site research coordinators are responsible for document management and database development and management. Study data from original study forms and patient surveys are entered and maintained on a secure password-protected database developed using REDCap [37, 38] located at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. REDCap is accessible to study team members only for data entry purposes. Each center enters data for the study participants enrolled at their site, and quality control oversight is done by the research coordinator located at the coordinating center (Sunnybrook Health Sciences Centre). The study coordinator reviews the electronic data for all participants on a regular basis for completeness and consistency. Quality and completeness of data entry are reviewed as soon as possible after data entry. Data integrity is enhanced through controls that require entry of valid data types and, where applicable, values within expected reference ranges. Data queries generated by identification of incomplete or inconsistent data is raised and resolved by the study coordinator or principal investigator in an ongoing manner. Corrections or changes to the data set are tracked by the data management system. Data does not continue to be collected for participants discontinuing the intervention. For participants deviating from intervention protocols, data is not collected for those agreeable to proceed with study participation.

Statistical methods

All analyses will be conducted by MacroStat Inc. using Statistical Analysis Software (v9.4 for Windows, Cary, NC) and R package (v3.6.1). For the final analysis plan, point estimates of feasibility events, including enrollment, adherence to protocol and accrual, will be presented as proportions with 95% confidence intervals. Continuous data will be presented as means and standard deviations, or medians and interquartile ranges, as appropriate. An intention-to-treat analysis will be performed on all participants randomized for the secondary efficacy outcome. A per-protocol analysis will be conducted for participants who have taken at least 90% of the prescribed doses. Subgroup analysis will be performed on the stratified groups with hemoglobin 10.0 g/dL or greater and hemoglobin less than 10.0 g/dL. Additional subgroup analysis will include the following: participants with ongoing bleeding (WHO grade 2 or higher) versus no bleeding and normal vs. increased C-reactive protein (based on the normal range). Given that the current study is a feasibility trial, sex and gender differences are not being accounted for.

Monitoring

Data monitoring

A data monitoring committee is not deemed to be required for this study because of the following: (1) this is a pilot randomized trial to assess feasibility, (2) there are no concerns regarding unacceptable toxicity, (3) the experimental arm is the same drug but at a lower dose, (4) the primary outcome is not a “major endpoint” such as mortality, (5) there are no ethical concerns regarding possible extreme efficacy of one arm so as to consider stopping the trial early, and (6) the study investigators are able to perform a safety assessment. Safety and interim analyses will be performed by an independent statistician blinded to treatment allocation after enrolling 20 participants into the study. The principal investigator will stop the study prior to its completion if difficulty in study recruitment or retention significantly impacts the ability to evaluate study endpoints, or any new information becomes available during the trial that necessitates stopping the study.

Harms

All adverse events (AE) are documented and assessed for relatedness from 1 week from baseline up to 1 week after the final study visit. Investigations into potential AEs are done during each contact with the participant using the side-effect questionnaire. All AEs are recorded on the eCRF and coded as per the Common Terminology Criteria for Adverse Events (v4.0). Study investigators will report serious adverse events (SAEs) to the sponsor within the following timelines: all deaths and immediately life-threatening events, whether related or unrelated, within 24 h of site awareness, and SAEs other than death and immediately life-threatening events, regardless of relationship, within 72 h of site awareness.

Auditing

Independent monitoring for this study is the responsibility of the sponsor, Sunnybrook Research Institute, and occurs both in person and remotely. A monitoring plan has been developed to outline the frequency of monitoring, monitoring procedures, the level of site monitoring activities, and the distribution of monitoring report. The monitor performed a site initiation visit for all sites prior to study commencement to ensure sites were prepared to conduct study procedures to institutional, provincial, and Health Canada standards. Monitoring visits involve reviewing study procedures, participant data, and Health Canada regulation compliance. After each visit, reports are generated to address any changes that need to be made or considered for appropriate regulatory compliance and patient safety.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Disclaimer:

This article is autogenerated using RSS feeds and has not been created or edited by OA JF.

Click here for Source link (https://www.biomedcentral.com/)