Clinical trial NCT03725384
Conditions: Anemia Iron Deficiency Anemia
Keywords: Anemia Iron deficiency hemoglobin oral iron Ferrous sulfate
Sponsor: Sunnybrook Health Sciences Centre
Start date: 2019-01-04; Completion date: 2022-01-26
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Iron deficiency anemia is a global health problem and the most common cause of anemia worldwide. Patients with iron deficiency (ID) and IDA can present with a multitude of symptoms including fatigue, restless legs syndrome and pica.Oral iron supplementation is associated with increasing hemoglobin in multiple studies in women, pregnant women and elderly patients.However, the optimal dose and frequency of oral iron supplementation for treatment remains unclear. The current proposed study attempts to address this gap in the literature.

Detailed description:
This is a pilot, pragmatic, non-inferiority, open label randomized controlled trial (RCT) in outpatients with iron deficiency anemia to evaluate the effectiveness of oral ferrous sulfate 300mg (60mg elemental iron) once daily versus every other day to improve hemoglobin at 12 weeks post-initiation. The rationale for this study includes: (1) IDA is a common and prevalent condition with potential adverse consequences if left untreated; (2) optimizing effectiveness of oral iron supplementation while minimizing side effects will improve treatment for patients.

Because IDA is a global health problem, common in clinical practice and treatable, this study will have a significant practical impact on how clinicians treat outpatients with iron deficiency anemia and how patients tolerate therapy.

For the patient, the expected benefit from taking part in this study is the potential to improve and treat iron deficiency anemia. These potential changes may lead to improved symptoms associated with iron deficiency anemia, such as cognitive and physical functioning, and fatigue.

Arms: arm 1: Ferrous sulfate 300mg tablet and vitamin C 500mg tablet taken by mouth every other day for 12 weeks arm 2: Ferrous sulfate 300mg tablet and vitamin C 500mg tablet taken by mouth every day for 12 weeks
Interventions: intervention 1: Ferrous Sulfate 300Mg Tablet intervention 2: Vitamin C 500Mg tablet
Intervention descriptions: intervention 1: oral dose of Ferrous Sulfate (300 mg) every day versus every other day along with vitamin C intervention 2: Vitamin C 500 Mg tablet every day versus every other day along with ferrous sulfate

Protocol documents:
Prot_SAP_000.pdf: 
Oral Iron Study (Version 5, July9, 2020)  
Page 1 
 
 
 
 
CONFIDENTIAL DOCUMENT 
 
Clinical Trial Protocol 
 
Title:  
Daily vs. every other day oral iron supplementation in patients with absolute iron 
deficiency anemia (DEODO): a multi-centered, pilot randomized controlled trial 
 
 
Protocol Number: 1534 
 
 
Principal Investigator/Institution: 
Yulia Lin, MD, Hematology, Sunnybrook Health Sciences Centre 
Co-Applicant(s)/Institution(s): 
Jeannie Callum, MD, Hematology, Sunnybrook Health Sciences Centre 
Christine Cserti-Gazdewich, MD, Hematology, University Health Network 
Lisa Del Giudice, MD, MSc, Family Medicine, Sunnybrook Health Sciences 
Centre 
Michelle Sholzberg, MD, MSc, Hematology, St. Michael’s Hospital 
Funding Agency 
Alexandra Yeo Grant, University of Toronto 
Investigational Product 
Oral Ferrous Sulfate (60mg of elemental iron) 
 
 
 
 
 
 
 
 
 
 
 
 
 


Oral Iron Study (Version 5, July9, 2020)  
Page 2 
SPONSOR STATEMENT OF COMPLIANCE 
This study will comply with the International Conference on Harmonization Good Clinical Practice E6 
(ICH-GCP), World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research 
Involving Human Participants, as well as applicable regulatory and institutional requirements.  
 
Personnel listed below are authorized to sign the protocol and any subsequent protocol amendments on 
behalf of the sponsor:  
 
 
Name: 
(Print) 
Yulia Lin 
Title:  
(Print) 
Principal Investigator 
 
Signature: 
 
Date of Approval: 
(yyyy-mmm-dd) 
 


Oral Iron Study (Version 5, July9, 2020)  
Page 3 
PROTOCOL SIGNATURE PAGE 
I have read this protocol in its entirety and its appendices.  I agree to comply with the requirements of 
the study protocol and procedures for data recording/reporting and acknowledge my responsibility for 
the well-being of each research participant, and to ensure that all persons involved in study activities are 
adequately informed about the protocol, the investigational product, and their trial-related duties.  The 
signature below constitutes the agreement to conduct this study in accordance with the REB approved 
protocol, GCP and  applicable regulatory requirements, including confidentiality, ethical guidelines and 
regulations regarding the conduct of research in humans. 
 
Qualified Investigator: 
Name: 
(Print) 
Yulia Lin 
Title & Institution:  
(Print) 
Principal Investigator, Sunnybrook Health Sciences 
Centre 
 
Signature: 
 
Date of signature: 
(yyyy-mmm-dd) 
 
 
 
 
 
 
 
 
 
 
 
 
 


Oral Iron Study (Version 5, July9, 2020)  
Page 4 
TABLE OF CONTENTS 
 
SPONSOR STATEMENT OF COMPLIANCE .............................................................................................2 
PROTOCOL SIGNATURE PAGE .............................................................................................................3 
TABLE OF CONTENTS ..........................................................................................................................4 
LIST OF ABBREVIATIONS .....................................................................................................................7 
PROTOCOL SUMMARY .......................................................................................................................8 
1.0 
KEY ROLES AND CONTACT INFORMATION ............................................................................. 10 
2.0 
INTRODUCTION ................................................................................................................... 12 
2.1  
Background ....................................................................................................................... 12 
2.1.1  Prevalence of iron deficiency anemia (IDA) ...................................................................... 12 
2.1.2 
Consequences of IDA ........................................................................................................ 12 
2.1.3 
Definition of IDA ............................................................................................................... 12 
2.1.4  Oral iron preclinical studies to date .................................................................................. 13 
2.1.5 
Oral iron clinical studies to date ....................................................................................... 13 
2.1.6 
Potential Risks ................................................................................................................... 14 
2.1.7 
Quality of Life Measures in IDA ........................................................................................ 14 
2.2 
Current Proposal and Rationale ........................................................................................ 14 
2.3 
Study Impact and Benefit ................................................................................................. 15 
3.0 
OBJECTIVES AND SCIENTIFIC AIMS ........................................................................................ 15 
3.1  
Primary Objective ............................................................................................................. 15 
3.2  
Trial Secondary Objective ................................................................................................. 15 
3.3  
Primary Outcome Measure ............................................................................................... 15 
3.4  
Secondary Outcome Measures ......................................................................................... 15 
4.0 
HYPOTHESES ........................................................................................................................ 16 
5.0 
STUDY METHODS ................................................................................................................. 16 
5.1 
Study Design ..................................................................................................................... 16 
5.2 
Study Population ............................................................................................................... 16 
5.2.1  Inclusion Criteria ............................................................................................................... 16 
5.2.2  Exclusion Criteria .............................................................................................................. 16 
5.3 
Study Activities.................................................................................................................. 17 
5.3.1  Patient recruitment, consent, screening and enrolment ................................................. 17 
5.3.2  Randomization and stratification ..................................................................................... 18 
5.3.3  Interventions ..................................................................................................................... 18 
5.3.3.1  Investigational Product ..................................................................................................... 18 
5.3.3.2  Acquisition and Formulation ............................................................................................. 18 
5.3.3.3  Packaging .......................................................................................................................... 19 
5.3.3.4 Treatment Assignment Procedures .................................................................................. 19 
5.3.3.5 Daily Dosing ...................................................................................................................... 19 
5.3.3.6 Every other day dosing ..................................................................................................... 19 
5.3.4  Adherence and Dose Modification ................................................................................... 19 
5.3.5 
Receiving, Storage, Dispensing and Return ...................................................................... 20 
5.3.5.1  Receipt of Investigational Product .................................................................................... 20 
5.3.5.2  Storage and Stability ......................................................................................................... 20 
5.3.5.3  Dispensing of Investigational Product .............................................................................. 20 
5.3.5.4  Return and Destruction of Investigational Product .......................................................... 20 
5.4 
Study Visits and Assessments ........................................................................................... 20 
5.4.1  Baseline Visit and Assessment .......................................................................................... 20 


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5.4.1.1  Screening and enrollment will occur within 1 week of randomization ............................ 20 
5.4.1.2 Baseline Laboratory Assessment ...................................................................................... 21 
5.4.2  Follow-up Visits and Assessments .................................................................................... 21 
5.4.2.1  Week 1 .............................................................................................................................. 21 
5.4.2.2 Week 4 .............................................................................................................................. 21 
5.4.2.3  Week 8 .............................................................................................................................. 22 
5.4.2.4  Week 12 Final Study Visit .................................................................................................. 22 
5.4.2.5 Week 13 ............................................................................................................................ 22 
5.4.2.6  Table of Assessments and Procedures to be Performed Throughout the Study ............. 22 
5.4.3 
Prior and Concomitant Medications ................................................................................. 22 
5.4.4  Participant Compliance Monitoring and Assessment ....................................................... 23 
5.4.5  Protocol Deviations ........................................................................................................... 23 
6.0 
STORAGE AND DISPENSATION OF FERROUS SULFATE ............................................................ 23 
7.0 
CRITERIA FOR OUTCOME ASSESSMENT ................................................................................. 23 
7.1 
Primary outcome assessment ........................................................................................... 23 
7.2 
Secondary outcome assessments ..................................................................................... 23 
8.0  
STATISTICAL CONSIDERATION .............................................................................................. 25 
8.1 
Sample Size and Sample Size Justification ........................................................................ 25 
8.2 
Final Analysis Plan ............................................................................................................. 26 
8.3 
Interim analysis ................................................................................................................. 27 
8.4 
Stopping Rules .................................................................................................................. 27 
9.0  
ASSESSMENT OF SAFETY ...................................................................................................... 27 
9.1 
Definitions ......................................................................................................................... 27 
9.1.1 
Adverse Event ................................................................................................................... 27 
9.1.2 
Expected adverse events with ferrous sulfate .................................................................. 27 
9.1.3  Unexpected Adverse Event ............................................................................................... 27 
9.1.4  Unexpected Adverse Drug Reaction (ADR) ....................................................................... 28 
9.1.5 
Serious Adverse Event (SAE) ............................................................................................. 28 
9.2 
Assessment of an Adverse Event ...................................................................................... 28 
9.2.1 
Relationship (Causality/Relatedness) ............................................................................... 28 
9.2.2 
Expectedness .................................................................................................................... 28 
9.2.3 
Seriousness ....................................................................................................................... 28 
9.2.4 
Severity ............................................................................................................................. 28 
9.2.5 
Adverse Event Recording .................................................................................................. 29 
9.3 
Procedures for Reporting a Serious Adverse Event and Unanticipated Events ............... 29 
9.3.1 
Investigator reporting: Notifying the REB ......................................................................... 29 
9.3.2 
Investigator reporting: Notifying the Sponsor .................................................................. 29 
9.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada ................................................. 30 
9.3.4 
Sponsor Reporting of SUADRs: Notifying Sites ................................................................. 30 
9.3.5 
Reporting and Entry Timelines.......................................................................................... 30 
9.4 
Data and Safety Monitoring Board (DSMB) ...................................................................... 30 
10.0 
CRITERIA FOR WITHDRAWAL AND DISCONTINUATION FROM STUDY .................................... 30 
10.1 
Early Termination and Reasons for Withdrawal ............................................................... 30 
10.2 
Data Collection and Follow-up for Withdrawn Participants ............................................. 31 
11.0 
ETHICAL ISSUES .................................................................................................................... 31 
11.1 
Ethical conduct and ethical issues .................................................................................... 31 
11.2 
Informed Consent ............................................................................................................. 31 
12.0 
STUDY ADMINISTRATION ..................................................................................................... 32 
12.1  
Arrangements for day-to-day management of the trial ................................................... 32 


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12.2 
Quality Assurance ............................................................................................................. 32 
13.0 
SITE MONITORING, auditing and inspecting .......................................................................... 32 
13.1 
Site Monitoring Plan ......................................................................................................... 32 
13.2 
Monitoring Plan ................................................................................................................ 33 
13.3 
Auditing and Inspecting .................................................................................................... 33 
14.0 
DATA HANDLING AND RECORD KEEPING .............................................................................. 34 
14.1 
Confidentiality ................................................................................................................... 34 
14.2 
Source Documents ............................................................................................................ 34 
14.3 
Data Management Responsibilities .................................................................................. 35 
14.4 
Data Capture ..................................................................................................................... 35 
14.4.1 Case Report Forms ............................................................................................................ 35 
14.5 
Records Retention ............................................................................................................ 35 
14.6 
Clinical Trial Registration .................................................................................................. 36 
References…….. ............................................................................................................................... 37 
APPENDIX A:….. ............................................................................................................................... 40 
APPENDIX B:….. ............................................................................................................................... 43 
APPENDIX C:…… ............................................................................................................................... 44 
APPENDIX D:….. ............................................................................................................................... 45 
 
 
 
 
 
 
 
 
 
 


Oral Iron Study (Version 5, July9, 2020)  
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LIST OF ABBREVIATIONS 
The following abbreviations describe terms, documents and study personnel used in the conduct of this 
study protocol. 
AE 
 
 
Adverse Event 
CBC 
 
 
Complete Blood Count 
CNS 
 
 
Central Nervous System 
CRP 
 
 
C Reactive Protein 
CSF 
 
 
Cerebrospinal Fluid 
CTCAE  
 
Common Terminology Criteria for Adverse Events 
DEODO  
 
Daily vs. every other day oral iron supplementation in patients with absolute    
 
 
 
iron deficiency anemia 
eCRF 
 
 
Electronic case report form 
FACIT  
 
Functional Assessment of Chronic Illness Therapy 
FACT 
 
 
Functional Assessment of Cancer Therapy 
GI 
 
 
Gastrointestinal  
Hb 
 
 
Hemoglobin 
Hg 
 
 
Mercury 
ID 
 
 
Iron Deficiency 
IDA 
 
 
Iron Deficiency Anemia 
LR 
 
 
Likelihood Ratio 
MCV 
 
 
Mean Cell Volume 
MRP 
 
 
Most Responsible Physician 
 
 
 
NCI 
 
 
National Cancer Institute 
PBAC 
 
 
Pictorial Blood Assessment Chart 
PM 
 
 
Product Monograph 
PO 
 
 
Oral Administration 
PI 
 
 
Principal Investigator 
QI 
 
 
Qualified Investigator 
RBC 
 
 
Red Blood Cell 
RCT 
 
 
Randomized Controlled Trial 
REB 
 
 
Research Ethics Board 
REDCap 
 
Research Electronic Data Capture 
SAE 
 
 
Serious Adverse Event 
SD 
 
 
Standard Deviation 
SHSC 
 
 
Sunnybrook Health Sciences Centre  
SUADR  
 
Serious Unexpected Adverse Drug Reaction  
TSAT 
 
 
Transferrin Saturation 
WHO 
 
 
World Health Organization 
 
 


Oral Iron Study (Version 5, July9, 2020)  
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PROTOCOL SUMMARY 
PRINCIPAL INVESTIGATOR 
Yulia Lin, MD 
PROTOCOL TITLE 
Daily vs. every other day oral iron supplementation in patients with 
absolute iron deficiency anemia (DEODO): a multi-centered, pilot 
randomized controlled trial 
PROTOCOL NUMBER 
1534 
PHASE 
lll 
INVESTIGATIONAL 
PRODUCT AND 
PLANNED USE 
To evaluate the effectiveness of oral ferrous sulfate (oral iron), 300mg oral 
tablets and vitamin C 500mg, once daily versus every other day to improve 
hemoglobin 12 weeks post-initiation 
STUDY DESIGN 
A phase lll, multi-centered, randomized, pragmatic, open-label, controlled 
pilot trial 
DURATION OF FOLLOW-UP 
From first dose of study drug to final study visit = 12 weeks 
TREATMENT 
ALLOCATIONS 
Experimental arm: Ferrous sulfate 300mg oral and vitamin C 500mg every 
other day x 12 weeks  
Control arm: Ferrous sulfate 300mg oral and vitamin C 500mg every day x 
12 weeks 
PATIENT POPULATION 
Patients with iron deficiency anemia defined as hemoglobin less than 120 
g/L in women or less than 130 g/L in men; AND ferritin less than 30 mcg/L 
SETTING 
A multi-centre study, outpatient clinical setting 
PLANNED SAMPLE SIZE 
52 patients  
The anticipated duration for this study’s recruitment period is 2 years. 
PATIENT 
INCLUSION/EXCLUSION 
Inclusion criteria: 
 
Age ≥ 16 years; 
 
Outpatients with iron deficiency anemia defined as Hb less than 
120 g/L in women or 130g/L in men; AND ferritin less than 30 
mcg/L  
Exclusion criteria:  
 
Pregnancy 
 
Currently breastfeeding 
 
Known history of inflammatory bowel disease 
 
Known history of celiac disease 
 
Known history of thalassemia or thalassemia trait 
 
Known inherited bleeding disorder  
 
Known intolerance or lack of response to oral ferrous gluconate, 
sulfate or fumarate in the last 12 weeks 
 
Multivitamin and mineral supplements (35 mg or more of 
elemental iron per day) in the 2 weeks prior to randomization  
 
Allergy to oral iron  
 
Allergy to any of the following medicinal and non-medicinal 
ingredients in ferrous sulfate: ferrous sulphate, 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, talc titanium 
dioxide  
 
Allergy to any of the following medicinal and non-medicinal 
ingredients in vitamin C: Ascorbic acid, Colloidal silicon dioxide, 


Oral Iron Study (Version 5, July9, 2020)  
Page 9 
croscarmellose sodium, magnesium stearate, microcrystalline 
cellulose and stearic acid  
 
Intravenous iron therapy in the past 12 weeks 
 
On new anticoagulant therapy initiated in the past 6-months (e.g. 
warfarin, apixaban, dabigatran, edoxaban, rivaroxaban)  
 
Surgery planned in upcoming 12 weeks 
 
Chemotherapy planned in upcoming 12 weeks 
 
Blood donation planned in upcoming 12 weeks 
 
Previously enrolled in the study 
 
Creatinine clearance less than 30 mL/min 
 
Hemoglobin less than 80 g/L with active bleeding (defined as WHO 
grade 2 bleeding or higher in the past week) 
RANDOMIZATION  
Computer generated allocation sequence; stratified in two groups: 
hemoglobin ≥ 100 g/L and hemoglobin < 100 g/L 
STUDY OUTCOMES 
Primary Feasibility Outcome: Time to enroll 52 patients 
Secondary Feasibility Outcomes  
 
Feasibility: proportion consenting to participate; proportion receiving 
allocated treatment; proportion completing laboratory tests, FACIT-
fatigue scale, side effects questionnaire; adherence 
Secondary Clinical Outcomes 
 
Mean hemoglobin increment at 4 and 12 weeks 
 
Proportion with complete hemoglobin response at 4 and 12 weeks 
 
Change in ferritin, serum iron and TSAT at 12 weeks 
 
Quality of life (FACIT-fatigue scale) at 4, 8 and 12 weeks 
 
Gastrointestinal adverse effects at 4, 8 and 12 weeks 
 
Need for escalation in therapy 
 
Proportion with a drop in hemoglobin of 10 g/L or more at 4 and 12 
weeks 
 STATISTICAL ANALYSIS 
The results of this pilot trial will be used to assess the feasibility and inform 
the design of the definitive trial.  We will present point estimates of feasibility 
outcomes with 95% confidence intervals.   
An intention-to-treat analysis will be performed on all patients randomized for 
the secondary clinical outcomes. A per protocol analysis will be conducted for 
patients who have taken at least 90% of the prescribed doses.  
 
 
 
 


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1.0 
KEY ROLES AND CONTACT INFORMATION 
Regulatory Sponsor: 
Sunnybrook Research Institute 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
Principal Investigator:   
Dr. Yulia Lin  
Academic Research Organization: 
Sunnybrook Health Sciences Centre 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
  
 
 
 
 
 
 
 


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Page 11 
Figure 1: Pilot Trial Schema 
 
 
 
Adult with iron deficiency anemia
(Hb < 120 g/L in women or Hb < 130 g/L in men; 
and ferritin < 30 mcg/L)
Physician to contact research coordinator
Obtain Voluntary  Informed Consent
Perform randomization
(n=52)
Experimental Group 
(Oral iron every other day)
(n=26)
Outcome Collection
Feasibility
Secondary Clinical Outcomes
Control group  
(Daily oral iron )
(n=26)


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2.0 
INTRODUCTION 
This study document is the protocol for research involving human participants.  This study is to be 
conducted according to Canadian and international standards, and in compliance with the protocol, 
International Conference on Harmonisation Good Clinical Practice E6 (ICH-GCP), World Medical 
Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Participants, 
as well as applicable regulatory and institutional requirements and research policies.  
2.1  
Background 
 
2.1.1  Prevalence of iron deficiency anemia (IDA) 
Iron deficiency anemia is a global health problem and the most common cause of anemia worldwide.1 
There is significant variation based on geographical location and population studies. In North America 
and Europe, its prevalence ranges from 1-2% in men2 to 2-5% in women2-5 to 9-11% in adolescent 
females6 and 17-31%3,7 in pregnant women.  
2.1.2 
Consequences of IDA  
Iron is an important nutrient for the production of red blood cells but also many biologic functions 
including energy production, DNA synthesis and cell proliferation.8 Patients with iron deficiency (ID) and 
IDA can present with a multitude of symptoms including fatigue, restless legs syndrome9 and pica.10 In 
addition, ID can also lead to impacts on physical function. Adverse effects include aerobic capacity 
(reduced VO2 max), work intolerance and fatigue11; diminished exercise capacity12,13; cognitive 
impairment specifically in attention, memory, speed and executive planning function14-16; and higher risk 
of depression17. There may be additional negative manifestations of IDA that have not yet been fully 
recognized. In one study, even after excluding patients with restless legs and accounting for the 
presence of depression and anxiety, IDA was still associated with worse sleep quality.18 In another 
retrospective cohort study of over 300,000 patients, iron deficiency was associated with combined and 
sensorineural hearing loss in US adults.19 Thus ID and IDA have significant consequences which may 
potentially benefit from treatment.  
 
2.1.3 
Definition of IDA  
The World Health Organization (WHO) defines anemia as a hemoglobin of less than 120 g/L for females 
and less than 130 g/L for males.20 Although the definition of anemia is well accepted, the definition of ID 
is less standardized. Based on a systematic review conducted by Guyatt et al to determine the diagnostic 
value of laboratory tests in the diagnosis of IDA, serum ferritin was found to be the most predictive and 
a better diagnostic test than mean cell volume (MCV) and transferrin saturation (TSAT).21 Serum ferritin 
values between 15-25 mcg/L were associated with a likelihood ratio (LR) of 8.83 for ID. Goodnough et al 
found that a serum ferritin of less than 30 mcg/L was associated with a sensitivity of 92% for IDA and a 
positive predictive value of 83%.22  
 
The issue becomes more complicated when considering ID in the setting of coexisting conditions where 
serum ferritin may be elevated as an acute phase reactant. The most recent preoperative anemia 
guidelines from the British Committee on Standards in Hematology state that a serum ferritin of less 
than 30 mcg/L is a sensitive marker of iron deficiency; however, iron therapy may be indicated for non-
anemic patients with low iron stores defined as ferritin less than 100 mcg/L and TSAT less than 20%, 
scheduled to undergo surgery.23 Studies in the setting of congestive heart failure have defined ID as a 
ferritin less than 100 mcg/L or a ferritin less than 300 mcg/L AND a TSAT less than 20%.24 In the setting 
of chemotherapy-induced anemia, the National Comprehensive Cancer Network Clinical Practice 
Guidelines in Oncology have defined absolute ID as ferritin less than 30 mcg/L AND TSAT less than 20%, 


Oral Iron Study (Version 5, July9, 2020)  
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but functional iron deficiency in patients receiving erythropoiesis stimulating agents as a ferritin of 30-
500 mcg/L AND TSAT less than 50%.25 
 
For the purposes of this study to ensure a population with a high likelihood of iron deficiency anemia, 
we have defined ID as a serum ferritin of less than 30 mcg/L.8,26,27 
2.1.4  Oral iron preclinical studies to date 
This section is not applicable.  
2.1.5 
Oral iron clinical studies to date  
The most common oral iron supplements currently used are ferrous gluconate, sulfate and fumarate 
each containing increasing doses of elemental iron (35, 60 and 100 mg elemental iron per 300mg tablet, 
respectively).8 Ferrous formulations have greater bioavailability than ferric preparations as it is in the 
ferrous form that iron is absorbed by the enterocyte. These supplements are inexpensive and often 
covered by provincial health plans. Although intravenous iron is also available, intravenous iron has 
been associated with rare serious infusion side effects including anaphylaxis, is hampered by a lack of 
resources for infusion facilities and nursing and thus, oral iron supplementation should be the first line 
of therapy when time permits.26,28,29  
 
Oral iron supplementation is associated with increasing hemoglobin in multiple studies in women, 
pregnant women and elderly patients.30-32 However, the optimal dose and frequency of oral iron 
supplementation for treatment remains unclear. A recent systematic review of 21 studies in 10,258 
women between menarche and menopause compared intermittent oral iron dosing (three times or less 
per week) compared with no intervention (or placebo) or daily oral iron dosing. When compared with 
intervention (or placebo), intermittent dosing reduced the risk of anemia (RR 0.73, 95% CI 0.56 to 0.95) 
and improved the concentration of hemoglobin (MD 4.58 g/L; 95% CI 2.56 to 6.59). When compared 
with daily supplementation, women on intermittent oral iron dosing presented more often with anemia 
(RR 1.26; 95% CI 1.04 to 1.51, six trials) although hemoglobin concentrations were similar (MD -0.15 g/L; 
95% CI -2.20 to 1.91, eight trials). The review also found no difference in diarrhea, any side effects or 
adherence between intermittent and daily dosing, although very few trials reported on these outcomes.  
 
Two more recent studies showed that dosing iron on alternate days may optimize iron absorption and 
may be preferable.33,34 The first study by Moretti et al sought to determine how the iron-induced 
increase in hepcidin influenced iron absorption for increasing doses of daily iron or twice-daily iron.33 
They found that doses of ferrous sulfate 60mg or higher resulted in an increase in hepcidin at 24 hours 
and resulted in a decrease of fractional iron absorption of 35-45%. Absolute iron absorption increased; 
however, with a six fold increase in dose, there was only a 3 fold increase in absorption. They also found 
that 3 doses given morning, afternoon then the following morning had the same total iron absorption as 
2 morning doses. These findings suggested that alternate day dosing of oral iron at lower dosages (40-
80mg) may maximize fractional iron absorption, increase dosage efficacy and improve tolerance of iron 
supplements. 
 
Stoffel et al investigated two different dosing regimens in women aged 18 to 45 years with a serum 
ferritin less than 25 mcg/L who did not have anemia. 34 In the first study, they compared consecutive 
daily oral ferrous sulfate 60mg for 14 days (N=21) with alternate day dosing for 28 days (N=19). At the 
end of treatment, the fractional absorption was 16.3% vs. 21.8% (p=0.0013) and the total iron 
absorption was 131.0 mg vs. 175.3 mg (p=0.0010), favouring the alternate day dosing schedule. In the 
second study, they compared 120mg of elemental iron in the morning (N=10) with two split doses of 
60mg given in the morning and evening for 3 consecutive days (N=10); then 14 days later, the groups 


Oral Iron Study (Version 5, July9, 2020)  
Page 14 
crossed-over. There was no difference in fractional absorption or total iron absorption between the two 
groups. The twice-daily divided dose had higher serum hepcidin concentrations. As a result, they 
concluded that oral iron supplements on alternate days, and as single doses might be a preferred dosing 
regimen and suggested confirming these findings in iron deficient anemic patients. The current 
proposed study attempts to address this gap in the literature.  
2.1.6 
Potential Risks  
Side effects of oral iron supplementation include constipation, nausea, diarrhea, abdominal pain, 
vomiting, heartburn, flatulence and dark stools.8,35 When compared to placebo in randomized controlled 
trials, ferrous sulfate had an increased incidence of gastrointestinal (GI) side effects with an OR 2.32 
(95% CI 1.74-3.08). The proportion of patients with GI side effects was 35% (range 10-90%) in the 
ferrous sulfate arms compared with 22 % (range 0-69%) in the placebo arms. The most common side 
effects were constipation, nausea and diarrhea with pooled estimates of incidence of 12%, 11% and 8% 
respectively.35 Additional side effects included abdominal pain, vomiting, heartburn, flatulence and dark 
stools. There did not appear to be a significant association between dose and GI side effects.  These side 
effects can have a significant impact on adherence with studies reporting up to 40% non-adherence and 
need to be carefully documented. 36 A recent study specifically developed a one page side effect 
questionnaire in patients on oral iron supplementation and was able to distinguish GI symptoms 
between participants on oral ferrous sulfate and placebo.37 A modification of this questionnaire will be 
used in the current study. 
2.1.7 
Quality of Life Measures in IDA 
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 
Functional Asessment of Chronic Illness Therapy (FACIT)-fatigue scale, previously the Functional 
Assessment of Cancer Therapy (FACT)-Fatigue scale, was developed and validated to assess cancer-
related fatigue. More recently it has also been validated in other chronic conditions such as systemic 
lupus erythematosus, rheumatoid arthritis and chronic immune thrombocytopenia. To date, there has 
been one study that has examined the effects of IDA on fatigue severity and life measures, the results of 
which validated the use of the FACIT-fatigue scale.38 The scale consists of 13 patient reported items as a 
measure of fatigue with a 7 day recall period. Items are scored from 0 (Not at all) to 4 (Very much so). 
Items are summed to a single fatigue score with a range of 0 to 52. Items can be reversed score to 
provide a scale in which higher scores represent better functioning or less fatigue. In this study, the 
internal consistency reliability was good (Cronbach’s α = 0.93). Known group analysis using the FACIT-
fatigue scale, using reverse scores,  showed that there was a mean difference of 5.51 between the high 
hemoglobin group (hemoglobin > 120 g/L = mean 35.96 (SD 10.82)) and the low hemoglobin group 
(hemoglobin ≤ 90 g/L = mean 30.45 (SD 11.64)). The wide-spread use of the FACIT-fatigue scale and 
demonstrated appropriateness in IDA validates the choice of the FACIT-fatigue scale for use in the 
current study.  
 
2.2 
Current Proposal and Rationale 
We propose a pilot, pragmatic, non-inferiority, open label randomized controlled trial (RCT) in 
outpatients  with iron deficiency anemia to evaluate the effectiveness of oral ferrous sulfate 300mg 
(60mg elemental iron) once daily versus every other day to improve hemoglobin at 12 weeks post-
initiation. The rationale for this study includes: (1) IDA is a common and prevalent condition with 
potential adverse consequences if left untreated; (2) optimizing effectiveness of oral iron 
supplementation while minimizing side effects will improve treatment for patients. We will enroll 52 


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patients in this pilot study at 2 centres. If this pilot trial is deemed to be feasible, we will plan a definitive 
multicentre trial.  
2.3 
Study Impact and Benefit 
Because IDA is a global health problem, common in clinical practice and treatable, this study, although 
simple in its question and design, will have a significant practical impact on how clinicians treat 
outpatients with iron deficiency anemia and how patients tolerate therapy.  
 
For the patient, the expected benefit from taking part in this study for the participant is the potential to 
improve and treat iron deficiency anemia. These potential changes may lead to improved symptoms 
associated with iron deficiency anemia, such as cognitive and physical functioning, and fatigue.  
 
3.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
3.1  
Primary Objective 
The primary purpose of this trial is to determine the feasibility of performing a pilot pragmatic, open-
label, randomized controlled trial to evaluate effectiveness of oral ferrous sulfate 300mg (60 mg 
elemental iron) once daily versus every other day to improve hemoglobin at 12 weeks post-initiation.  
 
3.2  
Trial Secondary Objective 
The secondary purpose of this trial is to determine the effectiveness of alternative oral iron 
supplementation dosing regimens on iron deficiency anemia, including hemoglobin, while minimizing 
side effects to improve patient treatment. 
 
3.3  
Primary Outcome Measure 
Feasibility: Time to enroll 52 patients  
 
3.4  
Secondary Outcome Measures 
 
Feasibility 
1. Proportion of eligible patients consenting to participate  
2. Proportion of consenting patients receiving the allocated treatment 
3. Proportion of treated patients completing 4 week and 12 week laboratory tests 
4. Proportion of treated patients completing 4 week, 8 week and 12 week FACIT-fatigue scale 
5. Proportion of treated patients completing 4 week, 8 week and 12 week side effect questionnaire 
6. Proportion of treatment doses taken as per protocol (adherence) 
7. Proportion of treated patients taking at least 90% of their prescribed doses 
8. Proportion of treated patients requiring a step down in therapy due to adverse side effects 
 
Clinical/Safety 
9. Mean hemoglobin increment at 4 and 12 weeks 
10. Proportion with complete hemoglobin response defined as hemoglobin greater than or equal to 
120 g/L at 4 weeks and 12 weeks for women and greater than or equal to 130 g/L at 4 weeks 
and 12 weeks for men. 


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11. Change in reticulocyte count at 4 and 12 weeks 
12. Change in ferritin, serum iron, TSAT at 12 weeks 
13. Quality of life (FACIT-fatigue scale) at 4, 8 and 12 weeks 
14. Proportion with side effects and type of side effects at 4, 8 and 12 weeks 
15. Proportion of patients who stop taking oral iron due to side effects at 4 and 12 weeks  
16. Need for escalation in therapy (need for 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, visit to emergency department related to anemia) at 12 weeks 
17. Proportion of patients with a drop in hemoglobin of 10 g/L or more from baseline at weeks 4 
and 12  
4.0 
HYPOTHESES 
We hypothesize that 52 patients will complete the trial within a 2-year period. This includes an expected 
drop out rate of 30% leaving 36 patients for analysis.  
 
5.0 
STUDY METHODS  
5.1 
Study Design 
This is a pilot pragmatic, non-inferiority, open label randomized controlled trial (RCT) in outpatients  
with iron deficiency anemia to evaluate the effectiveness of oral ferrous sulfate 300mg (60mg elemental 
iron) once daily versus every other day to improve hemoglobin at 12 weeks post-initiation. Patients will 
be randomized according to a computer-generated allocation sequence to receive either once daily 
dosing or every other day dosing. Randomization will be stratified by centre and baseline hemoglobin 
(hemoglobin ≥ 100 g/L OR < 100 g/L). Following randomization, patients will receive oral iron tablets for 
a period of 12 weeks, with clinical and subjective data collection occurring 1, 4, 8 and 12 weeks following 
the commencement of oral iron. The study will aim to recruit 52 patients in total, randomizing 26 
patients to each study arm. This sample size includes an anticipated 30% drop out rate (see section 8.1). 
5.2 
Study Population 
We propose broad eligibility criteria 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.  
 
5.2.1  Inclusion Criteria 
 
Age ≥ 16 years; 
 
Outpatients with iron deficiency anemia defined as hemoglobin less than 120 g/L in women or less 
than 130 g/L in men; AND ferritin less than 30 mcg/L. 
 
5.2.2  Exclusion Criteria 
 
Pregnancy 
 
Currently breastfeeding 
 
Known history of inflammatory bowel disease 
 
Known history of celiac disease 
 
Known history of thalassemia or thalassemia trait 
 
Known inherited bleeding disorder  


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 
Known intolerance or lack of response to oral ferrous gluconate, sulfate or fumarate in the last 
12 weeks 
 
Multivitamin and mineral  supplements (35 mg or more of elemental iron per day) in the 2 
weeks prior to randomization  
 
Allergy to oral iron  
 
Allergy to any of the following medicinal and non-medicinal ingredients in ferrous sulfate: 
ferrous sulphate, 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, talc titanium dioxide  
 
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  
 
Intravenous iron therapy in the past 12 weeks 
 
On new anticoagulant therapy initiated in the past 6 months (e.g. warfarin, apixaban, 
dabigatran, edoxaban, rivaroxaban)  
 
Surgery planned in upcoming 12 weeks 
 
Chemotherapy planned in upcoming 12 weeks 
 
Blood donation planned in upcoming 12 weeks 
 
Previously enrolled in the study 
 
Creatinine clearance less than 30 mL/min 
 
Hemoglobin less than 80 g/L with active bleeding (defined as WHO grade 2 bleeding or higher in 
the past week ) 
5.3 
Study Activities 
 
5.3.1  Patient recruitment, consent, screening and enrolment 
Patients meeting inclusion criteria will be identified through referring clinician offices (hematology and 
primary care physicians). Initial contact about the study will be made by a health care provider from the 
patient’s clinical team. Study personnel will approach the MRP for permission to approach the patient or 
ask that they introduce the study to the patient. With permission to enter the patient’s circle of care, 
the research coordinator will then approach potentially eligible patients. The research coordinator will 
introduce the trial, confirm eligibility and conduct the informed consent discussion. The study personnel 
will screen patients 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. Patients interested in 
participating and meeting both inclusion and no exclusion criteria will be given an Informed Consent 
Form. This discussion will include 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 will be offered an opportunity to ask questions and consult with their family and/or their 
physician before enrollment.  If the patient is deemed incapable of providing informed consent for the 
study, study personnel will 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 will be enough time to assess the patient for inclusion in the study before initiating 
treatment.  The subject will be invited to participate and must provide informed consent prior to any 
study related procedures. One signed copy of the informed consent will be placed in the participant’s 
medical record, another copy given to the participant and the original kept in the study file with the 
research coordinator. Once the subject is enrolled, his/her family physician will be informed about 


Oral Iron Study (Version 5, July9, 2020)  
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his/her participation in the study. If the participant does not wish to participate, the reason for declining 
will be documented. Patients will be identified by initials only on the screening log.  
  
Another potential recruitment site will be through Canadian Blood Services. Blood donors that have 
been deferred due to low hemoglobin levels (within the local Toronto area close to hospital study sites) 
will be provided with a letter (see Supporting Documents) which explains that the donor was deferred 
and for the donor to see visit their family physician for further investigation. In addition, a letter to the 
family physician will explain key points about the study purpose, rationale, procedures and detailed 
information about the DEODO trial. If the patient is interested in participating in the study, after visiting 
their family physician, the family physician can refer the patient to one of the study sites. The letter 
contains contact information for the Principal Investigator and Research Coordinator if the patient or 
their family physician has any questions. It is also acceptable for the patient to contact the study site 
directly in which case permission from the MRP is not required. Once the patient is referred to or has 
contacted a study site, then consent will occur as outlined in the previous paragraph.  
 
Once the patient has consented, bloodwork will be performed at the participating institution’s 
laboratory or at a local lab, if it has not been performed in the past 2 weeks.   Eligibility of the patient 
will be determined. If the eligibility is confirmed, then the patient will be enrolled (assigned a study ID) 
and randomized. Any additional bloodwork required within the pre-specified time frame (see 5.4.1.2) 
can be drawn or added on to the bloodwork already completed.  
 
All sites will obtain Research Ethics Board (REB) approval of the protocol and the informed consent form. 
A recruitment log of eligible and ineligible patients as well as reasons for non-consent will be kept at 
each participating centre.  We anticipate that this study will take 2 years to complete.  
 
5.3.2  Randomization and stratification 
Randomization allocation will be performed by Clinical Trial Services at Sunnybrook Health Sciences 
Centre using a computer generated allocation sequence. The randomization code will be generated in 
random blocks of 4 to 6, stratified by centre, and hemoglobin at time of randomization (hemoglobin 
greater or equal to 100 g/L or less than 100 g/L). Randomization will be provided to the sites in opaque 
numbered envelopes. The study is an open-label study. The research coordinator/assistant will enroll 
participants for this study. 
 
5.3.3  Interventions 
A schematic representation of the protocol summary is shown in Figure 1.  
 
5.3.3.1  Investigational Products 
Oral ferrous sulfate is the natural health product used throughout this study, and will be provided to 
patients in 300mg (60mg of elemental iron) tablets. 
 
Vitamin C is a natural health product used throughout this study, and will be provided to patients in 
500mg tablets.  
 
5.3.3.2  Acquisition and Formulation 
Once randomization has occurred, a prescription for the dosing regimen will be given to the patient to 
bring to pharmacy at the local site. Patients opting for virtual clinic visits will have their prescription 
filled by the study coordinator, and the pills couriered to their address on file. Patients will also have the 


Oral Iron Study (Version 5, July9, 2020)  
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option to pick-up their prescription from the study site (curbside pick-up). There will be two 
randomization groups, one for hemoglobin ≥ 100  g/L (Mild IDA) and one for hemoglobin < 100 g/L 
(Moderate IDA).  
 
5.3.3.3  Packaging 
The study drug will be shipped as bulk orders of tablets that will then be distributed into individual 
bottles by the pharmacy at the local site. The oral ferrous sulfate tablets will be packaged in bottles 
containing the corresponding amount of pills depending on which treatment arm the patient has been 
assigned to. One patient kit will contain a bottle of oral ferrous sulfate tablets and another standard 
package of Vitamin C pills that are to be taken along with the study drug. 
 
5.3.3.4 Treatment Assignment Procedures 
Once enrolled, patients will be randomized to either the daily, or every other day treatment arm 
through the randomization procedure described in section 5.3.2.   
5.3.3.5 Daily Dosing 
Starting on Day 1, patients will take ferrous sulfate 300mg (60 mg elemental iron) on an empty stomach 
with vitamin C 500mg daily for a period of 12 weeks. Patients will be instructed to take oral iron at 
bedtime but can take it at another time during the day if more convenient. If patients cannot tolerate 
the oral iron on an empty stomach, they will be instructed to take it with a small amount of food, as long 
as dairy and tannins are not ingested at the same time.  
 
5.3.3.6 Every other day dosing 
Starting on Day 1, patients will take ferrous sulfate 300mg (60 mg elemental iron) on an empty stomach 
with vitamin C 500mg every other day for a period of 12 weeks. Patients will be instructed to take oral 
iron at bedtime but can take it at another time during the day if more convenient. If patients cannot 
tolerate the oral iron on an empty stomach, they will be instructed to take it with a small amount of 
food, as long as dairy and tannins are not ingested at the same time.  
 
5.3.4  Adherence and Dose Modification 
This is a pragmatic trial. Adherence will be documented by patients by providing a patient diary (see 
Supporting Documents) which shows the days on which they are supposed to take oral iron. This will be 
provided in a paper format. The research team will remind the patient to fill in their patient diary at 4 
and 8 weeks. At the 12 week visit, the patient will be instructed to bring in their patient diary and pill 
bottle. A pill count will also be done to confirm adherence.  
 
It is anticipated that ~ 30% of patients may not tolerate oral iron. The patient adherence diary 
instructions (see Supporting Documents) can be referred to for simple instructions (under point # 5) if 
the patient is having mild symptoms with the oral iron. Side effects may improve over the initial 1-2 
weeks of oral iron. However, in some cases, patients may not be able to tolerate oral iron. Patients will 
be instructed to follow their planned schedule as prescribed. If they continue to have symptoms, 
patients will be 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 patients are unable to take the oral iron at all, they will be continued to be followed as long as they 
are willing to continue and do not meet any criteria for withdrawal. Please refer to Section 10. Criteria 
for withdrawal from study.  


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5.3.5 
Receiving, Storage, Dispensing and Return 
 
5.3.5.1  Receipt of Investigational Product 
McKesson Canada Corporation will act as the distributor for the oral ferrous sulfate supplements, and 
ship the tablets to Pharmacy at the local sites. The tablets will be transported under temperature 
controlled conditions. Once received, an inventory will be performed on the study product by study staff 
to ensure the correct product and amount were delivered, and the integrity of the product was not 
compromised during transportation. As such, any damaged or unusable product will be documented on 
the receipt log and the principal investigator will be notified.  
5.3.5.2  Storage and Stability 
Upon receipt of the product, the ferrous sulfate tablets require special handling and will be transferred 
to a temperature controlled area of the pharmacy, which is regularly monitored for quality assurance.  
5.3.5.3  Dispensing of Investigational Product 
The iron tablets will be provided in a bottle, with a child safety cap, to patients by the Pharmacy. The 
participants will be told how often they are to ingest the tablets, based on which treatment arm they 
have been randomized to, and will also be given a patient diary specific to their regimen that will be 
used for patient adherence. The patients will be directed to keep the study supplements at room-
temperature conditions.  
5.3.5.4  Return and Destruction of Investigational Product 
Participants will be made aware of their responsibility to return any unused ferrous sulfate tablets at the 
end of the 12 week treatment duration, they will bring in the unused tablets and original study bottle 
back to the research team during their 12 week in-person visit to the local study site. A 
remote/telephone visit for the week 12 follow-up is also acceptable given the current situation with 
COVID-19. Virtual visits will also be an option post-COVID-19. Patients opting for a virtual 12-week 
clinical visit will be requested to courier their pill bottles and adherence diary back to the local site. In 
this case, a pre-paid return envelope will be provided. Patients will also have the option to return their 
pill bottles and adherence diary via curbside drop off.  
5.4 
Study Visits and Assessments   
 
5.4.1  Baseline Visit and Assessment 
Baseline assessment will occur according to the schedule below and may be performed in 
person/remotely (telephone/zoom/OTN). The following assessments will be completed at baseline: 
 
5.4.1.1  Screening and enrollment will occur within 1 week of randomization 
 
Case logs will be initiated for each referral meeting inclusion criteria, indicating: 
 
Any applicable exclusion criteria as listed in 5.2.2 
 
Reason for lack of consent amongst eligible patients 
 
Protocol violations for enrolled patients 
Medical history: 
 
Demographics: age, sex, height, weight 
 
Diagnosis (reason for iron deficiency anemia, if known) 
o Example: gynecological, gastrointestinal, urologic, blood donation 


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 
History of observed bleeding in the past 2 months: Y/N 
o Location of bleeding 
o Severity by WHO grade 1-3 (see Appendix A) 
o If menstrual bleeding, use validated tool (see Appendix B) 
 
Diet 
o Vegetarian 
o Vegan 
 
Blood Donation: Y/N 
o Number of times in past year? 
o Number of times in past 4 months? 
 
Comorbidities 
o Rheumatologic disorders: e.g. SLE, rheumatoid arthritis 
o Smoking 
 
Medication history at time of enrollment 
o Ranitidine 
o Proton pump inhibitor use 
o Medications 
o Other vitamin supplements (not including iron) 
 
History of oral iron use: Y/N 
o Any iron use in the past year: Y/N 
o If yes, last oral iron intake: (date) 
o Type of oral iron and tolerability 
 
History of IV iron use in the past year: Y/N 
o Type of IV iron  
Questionnaire: 
 
FACIT-Fatigue scale (see Supporting Documents) 
5.4.1.2 Baseline Laboratory Assessment 
 
Hemoglobin, reticulocyte count, ferritin, serum iron, TSAT, C reactive protein within 2 weeks 
of randomization (and at least 2 weeks off any oral iron supplementation) 
 
Creatinine within 3 months of randomization 
 
Screening bloodwork can be used for the baseline laboratory assessment 
5.4.2  Follow-up Visits and Assessments 
5.4.2.1  Week 1 
Participants will be contacted by telephone or email for the following assessment at Day 7 ± 3 days 
 
Adherence as determined by patient diary (supporting documents) 
 
Side effect questionnaire (supporting documents) 
 
5.4.2.2 Week 4 
Participants will be contacted by telephone or email at Day 28 ± 7 days for the following assessment 
 
Adherence as determined by patient diary 
 
Side effect questionnaire 
 
FACIT-fatigue scale questionnaire 
 
Medication history (to confirm if any new or discontinued medications) 
 
Reminder to do laboratory tests (at the local site or local lab) for CBC, reticulocyte count 


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At the week 4 assessment, if the participant has a drop in hemoglobin of more than 10 g/L from 
baseline, then the patient will be referred back to the most responsible physician for management and 
escalation of therapy. If the patient receives escalation of therapy (need for 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, visit to emergency department related to anemia), the participant will no longer 
complete any further study assessments and the most responsible physician will be notified. The reason 
for the drop in hemoglobin will be classified as: ongoing bleeding; non-compliance (defined as less than 
50% of pills); other reason; or no clear reason. 
 
 
5.4.2.3  Week 8 
Participants will be contacted by telephone or email at Day 56 ± 7 days for the following assessment 
 
Adherence as determined by patient diary 
 
Side effect questionnaire 
 
FACIT-fatigue scale questionnaire 
 
Medication history (to confirm if any new or discontinued medications) 
 
5.4.2.4  Week 12 Final Study Visit 
Participants will be assessed in person/remotely (telephone/zoom/OTN) at Day 84 ± 7 days for the 
following assessment 
 
Adherence as determined by patient diary and pill count  
 
Side effect questionnaire 
 
FACIT-fatigue scale questionnaire 
 
Medication history (to confirm if any new or discontinued medications) 
 
Laboratory tests: CBC, reticulocyte count, ferritin, serum iron and TSAT  
 
Need for escalation in therapy: Y/N 
o Increase in oral iron regimen from every other day to daily 
o Intravenous iron  
o Transfusion  
o Visit to emergency department related to anemia 
 
5.4.2.5 Week 13 
Participants will be contacted by telephone or email at 7 days ± 3 days after the Week 12 final study visit 
for assessment of adverse and serious adverse events.  
5.4.2.6  Table of Assessments and Procedures to be Performed Throughout the Study 
See Appendix C. 
 
5.4.3 
Prior and Concomitant Medications 
Throughout the study duration, and two weeks leading up to randomization, patients are not permitted 
to receive other sources of iron supplementation, including but not limited to, other oral ferrous tablets 
and intravenous iron therapy.  
 
Patients should be advised not to take oral iron within 2 hours of antibiotics, bisphosphonates39, 
levodopa, methyldopa40, mycophenolate mofetil41, or thyroid medication42.  


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5.4.4  Participant Compliance Monitoring and Assessment 
Throughout the study duration, patients’ compliance with ingesting their oral iron tablets will be 
monitored through a personal patient diary, through direct contact between the patient and research 
coordinator/assistant at designated assessment times and a pill count following the 12 week 
supplementation period. Patients will have the opportunity to check-off when they have taken their 
tablet on the calendar pages of their patient diary, which indicate which days they should be ingesting 
the oral ferrous sulfate. At the first, fourth, and eighth weeks after beginning the study treatment, 
patients will either be called or emailed to assess patient adherence.  
 
If a patient misses a pill, they will continue with the next dose as directed on the calendar and will be 
advised not to double up dosing.  
 
Lastly, at the end of the 12 week supplementation period, patient will return the patient diary, the pill 
bottle provided to them and any unused tablets for a final pill count; this number is compared to the 
number of tablets the patient should have ingested during the 12 weeks. 
 
5.4.5  Protocol Deviations 
Planned or unplanned deviations may occur on the part of the participant, the investigator, or study 
research team. In resolution to a deviation, corrective/preventative actions are to be developed and 
implemented in a timely manner. Protocol deviations will be documented and reported as required and 
assessed where necessary during analysis. 
 
 6.0 
STORAGE AND DISPENSATION OF FERROUS SULFATE  
 
Pharmacy will dispense a 3 month prescription for each group (see Supporting Documents). The patient 
must keep the drug at room temperature. 
    
7.0 
CRITERIA FOR OUTCOME ASSESSMENT 
7.1 
Primary outcome assessment 
 
Feasibility: Enrollment in the trial will be defined as documentation of informed consent for patients 
approached 
 
If the study is unable to enroll 52 patients in a 2 year enrolment period, the study as it is currently 
designed will not be deemed feasible.  
7.2 
Secondary outcome assessments 
 
Feasibility 
1. Proportion of eligible patients consenting to participate  
 
# meeting eligibility criteria - # in whom consent not obtained 
# meeting eligibility criteria 
 
2. Proportion of consenting patients receiving the allocated treatment 


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# consenting to treatment - # not administered allocated treatment 
# consenting to treatment 
 
3. Proportion of treated patients completing 4 week and 12 week laboratory tests 
 
# completing 100% of 4 week and 12 week lab tests  
# consenting to treatment 
 
4. Proportion of treated patients completing 4 week, 8 week and 12 week side effect questionnaire 
 
# completing 100% of 4 week, 8 week and 12 week side effect questionnaire  
# consenting to treatment 
 
5. Proportion of treated patients completing 4 week, 8 week and 12 week FACIT-fatigue scale 
 
# completing 100% of 4 week, 8 week and 12 FACIT-fatigue scale  
# consenting to treatment 
 
6. Proportion of treatment doses taken as per protocol based on pill count 
 
total # of doses - # of missed doses  
total # of doses  
 
7. Proportion of treated patients taking at least 90% of their prescribed doses 
 
# of patients taking at least 90% of prescribed doses 
total # of treated patients  
 
8. Proportion of treated patients requiring a step down in therapy 
 
 # of patients requiring step down in therapy 
total # of treated patients  
 
Clinical/Safety 
9. Hemoglobin increment at 4 and 12 weeks is defined as the 4 or 12 week hemoglobin value 
minus the baseline hemoglobin value 
 
10. Proportion with complete hemoglobin response defined as hemoglobin greater than or equal to 
120 g/L in women; and 130 g/L in men at 4 weeks and 12 weeks 
 
11. Change in reticulocyte count at 4 and 12 weeks defined as the 4 or 12 week reticulocyte count 
minus the baseline reticulocyte count 
 
12. Change in ferritin, serum iron and TSAT at 12 weeks defined as the value at 12 weeks minus the 
baseline value 
 
13. Quality of life (FACIT-fatigue scale) at 4, 8 and 12 weeks 
 


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14. Proportion with side effects and type of side effects at 4, 8 and 12 weeks as determined by the 
oral iron side effect questionnaire 
 
15. Proportion of patients who stop taking oral iron due to side effects at 4 and 12 weeks 
 
16. Need for escalation in therapy (increase in oral iron regimen from every other day to daily, need 
for intravenous iron, need for transfusion, visit to emergency department related to anemia) 
assessed at 12 weeks 
 
17. Proportion of patients with a drop in hemoglobin of 10 g/L or more at weeks 4 and 12 
 
 
8.0  
STATISTICAL CONSIDERATION 
8.1 
Sample Size and Sample Size Justification 
The required sample size for this pilot RCT is calculated based on the primary outcome of the definitive 
study which is the mean hemoglobin increment in each group. For the every other day oral iron group to 
be considered non-inferior, the mean hemoglobin increment in the every other day oral iron group 
should not be more than 5 g/L less than the mean hemoglobin increment in the daily oral iron group. 
This is based on the Cochrane review31 of intermittent compared with daily dosing showing that the 
mean hemoglobin difference between intermittent and daily oral iron was -0.15 g/L (95% CI -2.2 g to 1.9 
g). Looking at individual studies within the Cochrane review, the standard deviations for the baseline 
and end of intervention hemoglobin measurements were approximately 10 g/L. Stoffel et al34 specifically 
studied the use of ferrous sulfate 300mg po daily over 14 days vs alternate day oral iron over 28 days. 
The baseline mean hemoglobin in each group was 128 g/L (-SD 117; + SD 140) and 132 g/L (-SD 125; +SD 
140) respectively. At the end of the intervention, the hemoglobin was 132 g/L (-SD 125; +SD 140) and 
136 g/L (-SD 129; +SD 144), respectively. Thus, the standard deviation for these 2 studies is closer to 10 
g/L.  
Table 2 below shows the sample size required to confirm non-inferiority of every other day oral iron 
compared with daily iron based on the true mean difference of the mean increment between the two 
groups, the standard deviation, the non-inferiority margin and the power of the study. The table also 
takes into account the adjusted sample size with a 30 % drop out considered.  
 
Table 2: Sample size calculation 
 
True difference 
of mean 
increment  
between two 
study groups, 
(g/L) A, D 
  
Standard  
Deviation (SD) 
of  
the increment 
(g/L) B 
Non-inferiority 
margin for the 
difference 
(g/L) C 
Power 
Total Sample 
size required 
to confirm 
non-inferiority 
Adjusted 
sample size 
with 30% 
drop out 
considered E 
0 
5 
>-5 
80% 
28 
40 
 
7.5 
>-5 
80% 
58 
84 
 
10 
>-5 
80% 
102 
146 


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0 
5 
>-5 
90% 
36 
52 
 
7.5 
>-5 
90% 
80 
116 
 
10 
>-5 
90% 
140 
200 
 
 
 
 
 
 
-0.15 
5 
>-5 
80% 
28 
40 
 
7.5 
>-5 
80% 
62 
90 
 
10 
>-5 
80% 
108 
156 
 
 
 
 
 
 
-0.15 
5 
>-5 
90% 
38 
56 
 
7.5 
>-5 
90% 
84 
120 
 
10 
>-5 
90% 
148 
212 
A.  Increment will be calculated from each subject first, and then mean increment for each study 
group.  A difference in the mean increment will be calculated as mean increment in the every 
other day oral iron group minus mean increment in the daily oral iron group. 
B. Standard deviation (SD) was not available for the increment.  It could be estimated from SDs or 
the pre- and post- treatment hemoglobin level and assumed correlation between pre- and post- 
hemoglobin.  If SDs for the pre- and post- hemoglobin are equal to 10, and correlation between 
them is 0.5, the estimated SD for the increment is 10. If the correlation between pre- and post- 
is 0.75, then the estimated SD for the increment is 7.1.   
C. One sided 95% confidence interval of the difference between two groups in the hemoglobin 
increment will be calculated (every other day minus daily). If the bound of the confidence 
interval is greater than -5, then non-inferiority can be confirmed. 
D. If we assume the true difference between two groups is -0.15 as reported from the meta- 
analysis, the sample size required could be slightly larger.   
E. Total sample size was divided by 70% to account for a 30% drop out. 
Given that this pilot trial is a proof-of concept study, a sample size of 52 patients was deemed 
appropriate. Therefore, we will aim to enroll 52 patients to determine the feasibility of the trial and to 
provide more accurate estimates of the numbers required for a definitive trial. The trial will be deemed 
feasible if we are able to enroll 52 patients over 2 years at two sites.  
 
The trial will proceed until there are 52 enrolled patients and at least 36 patients who complete the trial 
to 13 weeks.  
 
 
8.2 
Final Analysis Plan 
 
The results of this pilot trial will be used to assess the feasibility and inform the design of the definitive 
trial.  We will present point estimates of feasibility events, including enrolment, adherence to protocol 
and accrual, as proportions with 95% confidence intervals.  We will present continuous data as means 
and standard deviations, or medians and inter-quartile ranges, as appropriate.   
 
An intention-to-treat analysis will be performed on all patients randomized for the secondary efficacy 
outcome. A per protocol analysis will be conducted for patients who have taken at least 90% of the 


Oral Iron Study (Version 5, July9, 2020)  
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prescribed doses. Subgroup analysis will be performed on the stratified groups with hemoglobin 100g/L 
or greater and hemoglobin less than 100g/L. Additional subgroup analyses will include: patients with 
ongoing bleeding (WHO grade 2 or higher) vs no bleeding; and normal vs. increased CRP (based on the 
normal range).  
8.3 
Interim analysis 
Safety and interim analyses will be performed after enrolling 20 patients to the study.  
8.4 
Stopping Rules 
This study will be stopped prior to its completion if: (1) difficulty in study recruitment or retention will 
significantly impact the ability to evaluate the study endpoints; or (2) any new information becomes 
available during the trial that necessitates stopping the trial.  
9.0  
ASSESSMENT OF SAFETY  
9.1 
Definitions 
9.1.1 
Adverse Event 
 
An Adverse Event (AE) is defined as any new event that may jeopardize the patient which the study 
investigator physician perceives may be directly related to the enrolment in the pilot study or to the 
assigned arm. Adverse events are not study related if they are related primarily to the underlying 
disease. All AEs are to be documented and assessed for relatedness. If related to the study drug and 
occurring from baseline up to one week after the final study visit, the AE will be recorded on the eCRF 
and coded as per the most recent edition of the Common Terminology Criteria for Adverse Events 
(CTCAE).  
 
9.1.2 
Expected adverse events with ferrous sulfate 
 
Side effects of oral iron supplementation include constipation, nausea, diarrhea, abdominal pain, 
vomiting, heartburn, flatulence and dark stools.8,35 When compared to placebo in randomized controlled 
trials, ferrous sulfate had an increased incidence of gastrointestinal (GI) side effects with an OR 2.32 
(95% CI 1.74-3.08). The proportion of patients with GI side effects was 35% (range 10-90%) in the 
ferrous sulfate arms compared with 22 % (range 0-69%) in the placebo arms. The most common side 
effects were constipation, nausea and diarrhea with pooled estimates of incidence of 12%, 11% and 8% 
respectively.35 Additional side effects included abdominal pain, vomiting, heartburn, flatulence and dark 
stools. 
 
Overall, the risk to patients enrolled in this study is anticipated to be low, as 1) patients with IDA would 
normally be treated with oral iron; 2) patients with a prior history of intolerance to oral iron will be 
excluded; 3) exclusions include patients with baseline gastrointestinal disease such as inflammatory 
bowel disease; 4) patients will be monitored for side effects throughout the study; and 5) side effects 
stop immediately with stopping oral iron with no long term sequelae.     
 
9.1.3  Unexpected Adverse Event 
An unexpected adverse event is defined as any adverse event that is not identified in section 9.1.2 or in  
nature, severity or frequency in the current Health Canada Product Monograph. 


Oral Iron Study (Version 5, July9, 2020)  
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9.1.4  Unexpected Adverse Drug Reaction (ADR) 
An unexpected ADR is an adverse reaction, the severity of which is not consistent with the Health 
Canada Product Monograph.   All noxious and unintended responses to a medicinal product related to 
any dose should be considered an ADR.  
The phrase "responses to a medicinal product" means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled 
out.  
9.1.5 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) in the study is defined as: 
a) any event that is fatal or immediately life threatening, permanently disabling, severely 
incapacitating, or requires prolonged inpatient hospitalization, or  
b) any event that may jeopardize the patient and requires medical or surgical intervention to 
prevent one of the outcomes listed above, AND 
c) which the attending physician perceives may be directly related to enrolment in the study, or to 
the assigned arm.   
 
SAEs will be considered to be study-related if the event follows a reasonable temporal sequence from 
the study intervention and could readily have been produced by the intervention.  Adverse events are 
not study related if they are related primarily to the underlying disease. 
9.2 
Assessment of an Adverse Event 
9.2.1 Relationship (Causality/Relatedness) 
The causality assessment is the determination, according to the investigator’s clinical judgment, of the 
existence of a reasonable possibility that the study drug (IP) caused or contributed to an adverse event.  
If the investigator or delegated sub-investigator is unsure about whether or not the study drug caused 
or is related to the event, then the event will be handled as “related” to the study drug for reporting 
purposes of the trial.  If the causality assessment is "unknown but not related” to the study drug, this 
should be clearly documented in the source documents.  
9.2.2 
Expectedness 
Events are classified as unforeseen or unexpected if the nature, severity or frequency is not consistent 
with the risk information set out in Section 9.1.2 or the Product Monograph (PM) or label.     
9.2.3 
Seriousness 
Events are classified as serious if associated with effects threatening the life or physiological functions of 
a participant.  Refer to the definition for “Serious Adverse Events” in section 9.1.5. 
9.2.4 
Severity 
The term "severe" is often used to describe the intensity (severity) of a specific event (e.g. mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious," which is based on 
participant/event outcome or action criteria usually associated with events that pose a threat to a 


Oral Iron Study (Version 5, July9, 2020)  
Page 29 
participant's life or functioning. The terms “serious” and “severe” are not synonymous.  Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. 
To assess the severity of an adverse event the investigators will use the following: 
 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)  
9.2.5 
Adverse Event Recording 
Investigations into potential adverse events should be done during each contact with a participant.  
Investigations may be done through specific questioning and, as appropriate, by examination.  
Information on all adverse events should be recorded promptly in the source document, and assessed 
by an investigator in a timely manner allowing sufficient time to meet required reporting timelines for 
SAEs and serious unexpected adverse drug reactions (SUADRs) if needed.  Adverse event CRFs should be 
completed using source documents by a delegated research team member in a timely manner/within 15 
days of site awareness.  All clearly related signs, symptoms, and abnormal diagnostic procedures should 
be recorded in the source document, though should be grouped under one diagnosis. Each diagnosed 
adverse event should then be categorized in accordance with the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE).  
The following are not considered AEs and therefore do not require recording:  
 
Pre-existing diseases or conditions identified and recorded at screening/baseline unless, at the 
discretion of the investigator, the disease or condition worsens in severity or frequency  
 
At the discretion of the investigator, events considered likely manifestations of the underlying 
disease or that commonly occur in the study population independent of study drug exposure 
 
Elective medical or surgical procedures. 
9.3 
Procedures for Reporting a Serious Adverse Event and Unanticipated Events 
9.3.1 
Investigator reporting: Notifying the REB 
Serious adverse events and unanticipated events should be recorded and reported to the REB in 
accordance with local reporting requirements and timelines.    
9.3.2 
Investigator reporting: Notifying the Sponsor 
The investigator is responsible for reporting SAEs and SUADRs to the sponsor (Sunnybrook Research 
Institute) in accordance with applicable regulations and reporting requirements and timelines.    
Events that are assessed to be serious and unexpected and related or cannot be ruled out as related to 
the investigational product are considered SUADRs.  Reporting for SUADRs should include a description 
of the event in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality.  The minimum information required includes at least one 
identifiable participant, one identifiable reporter, one serious reaction, and one suspect product.  
Additionally, for SAEs and SUADRS, a Suspect Adverse Reaction Report – CIOMS I Form (see appendix D) 
must be completed by the investigator and forwarded to the Sponsor within 24 hours of site awareness.  


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Information on other possible causes of the event, such as concomitant medications and illnesses should 
also be provided as soon as is made available. 
9.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada 
The regulatory sponsor is responsible for reporting SUADRs to regulatory authorities in accordance with 
local expedited reporting requirements and timelines.  In addition, the Sponsor will complete the ADR 
Expedited Reporting Summary Form and submit this form in conjunction with the completed CIOMS 
Form to the appropriate Health Canada directorate.    
9.3.4 
Sponsor Reporting of SUADRs: Notifying Sites 
The regulatory sponsor is responsible for distributing expedited reports of SUADRs to each investigator 
for submission to local Ethics Committees within 15 days of sponsor awareness. 
9.3.5 
Reporting and Entry Timelines 
 Study investigators will report SAEs to the sponsor within the following timelines:   
 
All deaths and immediately life-threatening events, whether related or unrelated, will be 
recorded and reported to the sponsor within 24 hours of site awareness.  
 
Serious adverse events other than death and immediately life-threatening events, 
regardless of relationship, will be reported to the sponsor within 72 hours of site awareness.  
Adverse event information will be entered into the CRF in a timely manner and no later than 15 days 
from the time the investigator becomes aware of the event. 
Serious adverse event information will be entered into the CRF in a timely manner/within 72 hours from 
the time the investigator becomes aware of the event. 
9.4 
Data and Safety Monitoring Board (DSMB) 
A data and safety monitoring board is not deemed to be required because: 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; and 5) there are no ethical concerns regarding possible extreme efficacy of one arm so as to 
consider stopping the trial early.  
10.0 
CRITERIA FOR WITHDRAWAL AND DISCONTINUATION FROM STUDY 
Patients will be followed until 12 weeks or until there is an escalation of therapy as defined by need for: 
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 emergency department related to 
anemia.   
10.1 
Early Termination and Reasons for Withdrawal 
Patients may find that they are not able to continue in the study due to intolerable side effects from the 
oral iron despite simple measures to address the side effects. Patients are permitted to withdraw 
consent at any time if they desire and will not undergo further trial investigations if they do so. 
Additionally, patients who become pregnant during the course of the study will be stopped from using 
the study medications and withdrawn from the study. Other reasons for withdrawal include use of 


Oral Iron Study (Version 5, July9, 2020)  
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intravenous iron, use of blood transfusion, any deviation from inclusion/exclusion criteria and serious 
adverse events (as described in section 9.3). 
Participants withdrawing from the study should be contacted by the study research team requesting a 
final visit and to follow up with any unresolved adverse events. Once withdrawn from the study, no 
further study procedures or evaluations should be performed, or additional study data collected.  
However, every effort should be made to obtain permission to document the reason for withdrawal and 
to collect participant outcomes, such as survival data up to the protocol-described end of participant 
follow up period, where possible. Any data collected prior to the withdrawal of consent may be retained 
and used by the sponsor. If the patient withdraws from the study, the research team will notify the 
patient’s referring physician.  
10.2 
Data Collection and Follow-up for Withdrawn Participants 
Patients will be asked to continue with follow-up quality of life assessment and laboratory tests. It is 
important to continue to follow these patients and capture outcomes that occur once they have 
discontinued study intervention to determine feasibility. Through telephone calls and emails, every 
effort will be made to obtain permission to document the reason participants withdrew consent and to 
continue collecting the quality of life assessments and laboratory values previously mentioned. Patients 
who have completed at least 90% of the prescribed doses will be included in the per-protocol analysis.   
11.0 
ETHICAL ISSUES 
11.1 
Ethical conduct and ethical issues 
Approval for patient accrual must be obtained from research ethics board (REB) at the study center 
before patient recruitment can begin.  Any additional correspondence with REB must be maintained by 
the research coordinator/assistant at each participating site.  
11.2 
Informed Consent 
Study personnel will approach the MRP for permission to approach the patient or ask that they 
introduce the study to the patient. With permission, the research coordinator will then approach 
potentially eligible patients to introduce the trial and conduct the informed consent discussion.  By 
being invited into the patient’s circle of care with the permission of the MRP, study personnel will screen 
patients 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. Patients interested in 
participating and meeting both inclusion and no exclusion criteria will be given an Informed Consent 
Form. This discussion will include 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 will be offered an opportunity to ask questions and consult with their family and/or their 
physician before enrollment.  If the patient is deemed medically incapable, study personnel will 
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 will be enough time 
to assess the patient for inclusion in the study before initiating treatment.  The subject will be invited to 
participate and must provide informed consent prior to any study related procedures. One signed copy 
of the informed consent will be placed in the participant’s medical record, another copy given to the 
participant and the original kept in the study file with the research coordinator. Once the subject is 
enrolled, his/her family physician will be informed about his/her participation in the study. If the 
participant does not wish to participate, the reason for declining will be documented and the patient 
will be considered a screening failure (failure to provide informed consent).  


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12.0 
STUDY ADMINISTRATION 
The coordinating site will be Sunnybrook Health Sciences Centre. The site research coordinators will be 
responsible for trial coordination, site training, site start-up/activation, document management, supply 
management, database development, data management and statistical analysis. Study data and patient 
surveys will be entered and maintained on a secure password protected database developed using 
REDCap (www.projectredcap.org) and will be accessible via the Internet for data entry purposes.  
 
12.1  
Arrangements for day-to-day management of the trial 
The research coordinator will be responsible for this aspect of the study, including system checks, 
maintenance, and data back-up.  Patient data will be collected monthly and entered into the electronic 
case report forms. Data queries will be generated monthly for participating sites. A bi weekly status 
report will include an update on the recruitment and status of all randomized patients.  Monthly to bi-
monthly audit and feedback meetings will be held for participating sites. Protocol violations will be 
audited at each site and recorded on designated Protocol Violation Forms. 
Clinical research coordinators at each site will work with site investigators on start-up activities (REB 
applications; study contract; organizing study materials; local in-services). Thereafter, research 
coordinators will screen, consent and enrol patients, complete case report forms, and respond to data 
queries.    
 
12.2 
Quality Assurance 
Study data will be maintained on a secure password protected database accessible to study centres 
from the world-wide-web. Each centre will enter data for the study participants enrolled at their site.  
Quality control will be ensured by oversight by the research coordinator at Sunnybrook Research 
Institute, who will review the electronic data for all participants on a regular basis for completeness and 
consistency.  
 
Quality and completeness of data entry will be reviewed as soon as possible after data entry, within five 
business days of data entry for the first five participants randomized at each site, and within 15 days of 
data entry thereafter.  Data queries generated by identification of incomplete or inconsistent data will 
be raised and should be resolved by the study coordinator or PI in a timely manner. Corrections or 
changes in the data management system are tracked with the retention of the original data and the 
corrected data with the date of data entry and submitting personnel.  
13.0 
SITE MONITORING, auditing and inspecting 
13.1 
Site Monitoring Plan 
Site monitoring is conducted to ensure the safety of human study participants and the protection of 
their rights and well-being.  Monitoring also verifies that collected study data is accurate, complete and 
verifiable by source documentation and that the study is conducted in accordance with the protocol and 
operating procedures. 
Monitoring for this study is the responsibility of the sponsor, Sunnybrook Research Institute.  The 
delegated monitor will evaluate study processes and documentation based on the approved 
protocol/amendment(s), of the Natural Health Product Regulations, the International Conference on 
Harmonisation (ICH), E6: Good Clinical Practice guidelines (GCP) and institutional policies. 
The extent and nature of monitoring is outlined in the Monitoring Plan. The monitoring plan specifies 
the frequency of monitoring, monitoring procedures, the level of site monitoring activities, and the 
distribution of monitoring reports.  Monitoring activities will be performed both in person and remotely.  


Oral Iron Study (Version 5, July9, 2020)  
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Reports of findings identified during monitoring activities will be provided to sites detailing any required 
actions.  Documentation of monitoring activities and findings will be provided to the site study team and 
the study QI. The institution and/or local REB reserves the right to conduct independent audits as 
necessary. 
The Investigator is responsible for ensuring monitors and/or quality assurance reviewers are given 
access to all study-related documents noted above and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and have adequate space to conduct the monitoring visit or audit. 
13.2 
Monitoring Plan 
The monitoring plan will consist of the following: 1) A site initiation visit for non-Sunnybrook sites will be 
conducted prior to the commencement of the study to ensure both sites are appropriately aware and 
prepared to conduct study procedures to institutional, provincial and Health Canada standards. During 
this initiation teleconference, any issues that may be raised will be adequately dealt with and recorded 
in a report for future reference. 2) A site monitoring visit will be conducted by Clinical Trial Services or its 
delegate. This visit will involve reviewing study procedures, participant data and Health Canada 
regulation compliance. A report will be generated based on the visit which addresses any changes that 
need to be made or considered for appropriate regulatory compliance and patient safety.   
 13.3 
Auditing and Inspecting 
The investigator will provide direct access to source data/documents for the purposes of study-related 
monitoring, audits, and inspections by the REB, the sponsor, and applicable regulatory bodies.  The 
investigator will permit the review of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.) and will ensure access to applicable study-
related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 


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14.0 
DATA HANDLING AND RECORD KEEPING 
14.1 Confidentiality 
Information about study participants will be kept confidential and managed according to the 
requirements of the Personal Health Information Protection Act of 2004 (PHIPA) and the Research Ethics 
Board.  PHIPA outlines the rules for the collection, use and disclosure of personal health information.  
The Act requires each participant to consent to the collection, use and access of personal health 
information (PHI), unless consent is waived by the REB.  As consent is required, each participant will be 
informed of the following:  
 What PHI will be collected during this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research participant to revoke their authorization for use of their PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the investigator may use all 
information collected prior to the revocation of participant authorization.  For participants that have 
revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the participant is alive) at the end of their scheduled study period. 
14.2 Source Documents 
Source data/documents are original documents, data and records in a clinical study that are 
necessary for the reconstruction and evaluation of the study.  Original documents and data records in 
this study include, but are not limited to: 
 
Worksheets 
 
hospital records  
 
medical records 
 
memorandum  
 
participants’ diaries or evaluation checklists  
 
pharmacy dispensing records  
 
copies or transcriptions certified after verification as being accurate and complete  
 
participant files and records kept at the pharmacy  
 
entries entered directly into the source documents 
 
Source documents have been developed for the  baseline assessment (including, medical history), 
week 1 contact information, week 4 contact information, , week 8 contact information, week 12 
contact information, week 12 assessment, week 12 pill count, side effect questionnaire and quality of 
life questionnaire, and protocol deviations.  
 
Each participating site will maintain appropriate medical and research records for this study, in 
addition to regulatory and institutional requirements for the protection of confidentiality of 
participants.  If electronic source data documents are printed it should be signed and dated by the 
investigator to confirm content and filed with other source documents.  
The investigator(s) and research team members listed on the Task Delegation Log (TDL) will have 
access to participant medical records and will collect only the information needed for the study.  


Oral Iron Study (Version 5, July9, 2020)  
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Sponsor delegated monitors, representatives of institutional committees and regulatory authority 
representatives of the country in which the study is being conducted will also have access to examine 
records for the purposes of quality assurance reviews, audits and evaluation of study safety and 
progress. 
14.3 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study personnel under the 
supervision of the investigator.  All source documents and applicable laboratory reports will be reviewed 
as needed and used to ensure that data collected for the purposes of the study are accurate and 
complete.  Contemporaneous review of laboratory results and the assessment of clinical significance for 
those results considered out of range will be documented by means of dated signature by the reviewing 
investigator. Study personnel, including data entry team members, should use source documents to 
complete case report forms (CRFs).  
As part of the safety plan for this study, the investigator will review individual study participant records 
to ensure that appropriate mechanisms to protect the safety of study participants are being followed, 
that protocol requirements are being adhered to, and that data is accurate, complete, and secure. 
Participant records include, but are not limited to: consent forms, case report forms, data forms, 
laboratory specimen records, inclusion/exclusion forms, and medical charts. All study data will be 
collected by a member of the study research team and recorded in accordance with applicable 
procedures. 
14.4 Data Capture 
14.4.1 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for this study.  
Electronic/Paper case report forms (eCRFs/pCRFs) will be used to collect data for this study. CRFs will be 
completed by data capture personnel and signed off by the investigator in a timely manner.  Good 
documentation practices will be implemented according to standard operating procedures.  All data 
requested on the CRF must be recorded and verifiable by source document.   
14.5 Records Retention 
It is the responsibility of the REB, investigator and regulatory sponsor to retain study essential 
documents as per local regulatory requirements and GCP Guidelines.   
Study essential documents must be maintained in a secure and confidential manner for participating 
Canadian sites for a period of 25 years.  For the purposes of this study, the start date of the retention 
period is the date of the final report of the trial.  Exceptions may be made for sites which close 
prematurely, wherein the start date for the retention period will be the date of notification to Health 
Canada of the sites closure. All study records are then to be destroyed according to local and national 
policy and requirements. It is the investigator’s responsibility to request authorization for destruction at 
the completion of the retention period and/or for the sponsor to inform the investigator/institution 
when these documents may be destroyed.  


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14.6 Clinical Trial Registration 
In accordance with Health Canada’s Notice “Registration and Disclosure of Clinical Trial Information, 
November 30, 2007”, the investigator will register this study on Clinicaltrials.gov (www.clinicaltrials.gov), 
a publically available registry that conforms to international standards for registries. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Murat S, Ali U, Serdal K, Suleyman D, Ilknur P, Mehmet S, Bahattin A, Tunahan U. Assessment of 
subjective sleep quality in iron deficiency anaemia. Afr Health Sci 2015;15: 621-7. 
19. 
Schieffer KM, Chuang CH, Connor J, Pawelczyk JA, Sekhar DL. Association of Iron Deficiency 
Anemia With Hearing Loss in US Adults. JAMA Otolaryngol Head Neck Surg 2017;143: 350-4. 
20. 
World Health Organization. Nutritional anaemias: report of a WHO scientific group (meeting 
held in Geneva from 13 to 17 March 1967). Geneva: World Health Organization; 1968. 


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21. 
Guyatt GH, Oxman AD, Ali M, Willan A, McIlroy W, Patterson C. Laboratory diagnosis of iron-
deficiency anemia: an overview. J Gen Intern Med 1992;7: 145-53. 
22. 
Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted 
erythropoiesis. Blood 2010;116: 4754-61. 
23. 
Kotze A, Harris A, Baker C, Iqbal T, Lavies N, Richards T, Ryan K, Taylor C, Thomas D. British 
Committee for Standards in Haematology Guidelines on the Identification and Management of 
Pre-Operative Anaemia. Br J Haematol 2015;171: 322-31. 
24. 
Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, 
Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, 
Ponikowski P, Investigators F-HT. Ferric carboxymaltose in patients with heart failure and iron 
deficiency. N Engl J Med 2009;361: 2436-48. 
25. 
NCCN Clinical Practice Guidelines in Oncology. Cancer- and Chemotherapy-Induced Anemia 
Version 2.2017 [monograph on the internet]. 2017. Available from: 
https://www.colegiodeginecologosoncologos.com/wp-content/uploads/2017/02/Cancer-and-
Chemotherapy-Induced-Anemia.pdf 
26. 
Nielsen OH, Coskun M, Weiss G. Iron replacement therapy: do we need new guidelines? Curr 
Opin Gastroenterol 2016;32: 128-35. 
27. 
Munoz M, Acheson AG, Auerbach M, Besser M, Habler O, Kehlet H, Liumbruno GM, Lasocki S, 
Meybohm P, Rao Baikady R, Richards T, Shander A, So-Osman C, Spahn DR, Klein AA. 
International consensus statement on the peri-operative management of anaemia and iron 
deficiency. Anaesthesia 2017;72: 233-47. 
28. 
Gurusamy KS, Nagendran M, Broadhurst JF, Anker SD, Richards T. Iron therapy in anaemic adults 
without chronic kidney disease. Cochrane Database Syst Rev 2014: CD010640. 
29. 
Munoz M, Gomez-Ramirez S, Bhandari S. The safety of available treatment options for iron-
deficiency anemia. Expert Opin Drug Saf 2018;17: 149-59. 
30. 
Tay HS, Soiza RL. Systematic review and meta-analysis: what is the evidence for oral iron 
supplementation in treating anaemia in elderly people? Drugs Aging 2015;32: 149-58. 
31. 
Fernandez-Gaxiola AC, De-Regil LM. Intermittent iron supplementation for reducing anaemia 
and its associated impairments in menstruating women. Cochrane Database Syst Rev 2011: 
CD009218. 
32. 
Berber I, Diri H, Erkurt MA, Aydogdu I, Kaya E, Kuku I. Evaluation of ferric and ferrous iron 
therapies in women with iron deficiency anaemia. Adv Hematol 2014;2014: 297057. 
33. 
Moretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, Melse-Boonstra A, Brittenham 
G, Swinkels DW, Zimmermann MB. Oral iron supplements increase hepcidin and decrease iron 
absorption from daily or twice-daily doses in iron-depleted young women. Blood 2015;126: 
1981-9. 
34. 
Stoffel NU, Cercamondi CI, Brittenham G, Zeder C, Geurts-Moespot AJ, Swinkels DW, Moretti D, 
Zimmermann MB. Iron absorption from oral iron supplements given on consecutive versus 
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women: two open-label, randomised controlled trials. Lancet Haematol 2017;4: e524-e33. 
35. 
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. 
36. 
Gereklioglu C, Asma S, Korur A, Erdogan F, Kut A. Medication adherence to oral iron therapy in 
patients with iron deficiency anemia. Pak J Med Sci 2016;32: 604-7. 
37. 
Pereira DI, Couto Irving SS, Lomer MC, Powell JJ. A rapid, simple questionnaire to assess 
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Acaster S, Dickerhoof R, DeBusk K, Bernard K, Strauss W, Allen LF. Qualitative and quantitative 
validation of the FACIT-fatigue scale in iron deficiency anemia. Health Qual Life Outcomes 
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39. 
Canadian Pharmacists Association. Compendium of Pharmaceuticals and Specialties. Toronto, 
Canada: Canadian Pharmacists Association, 2013. 
40. 
Campbell NR, Hasinoff BB. Iron supplements: a common cause of drug interactions. Br J Clin 
Pharmacol 1991;31: 251-5. 
41. 
Morii M, Ueno K, Ogawa A, Kato R, Yoshimura H, Wada K, Hashimoto H, Takada M, Tanaka K, 
Nakatani T, Shibakawa M. Impairment of mycophenolate mofetil absorption by iron ion. Clin 
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42. 
Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate reduces thyroxine efficacy 
in patients with hypothyroidism. Ann Intern Med 1992;117: 1010-3. 
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Josephson CD, Granger S, Assmann SF, Castillejo MI, Strauss RG, Slichter SJ, Steiner ME, 
Journeycake JM, Thornburg CD, Bussel J, Grabowski EF, Neufeld EJ, Savage W, Sloan SR. Bleeding 
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44. 
Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. 
Br J Obstet Gynaecol 1990;97: 734-9. 
45. 
El-Nashar SA, Shazly, S.A.M., Famuyide, A.O. Pictorial blood loss assessment chart for 
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63. 
 
 
 


Oral Iron Study (Version 5, July9, 2020)  
Page 40 
APPENDIX A: 
 
WHO Bleeding Severity Scale43 
 
Grade 1 
 
Grade 2 
Grade 3 
Oral and nasal 
 Oropharyngeal 
bleeding – total 
duration of all 
episodes in previous 
24 hours ≤30 
minutes* 
 Petechiae of oral 
mucosa 
 Epistaxis – total 
duration of all 
episodes in previous 
24 hours ≤30 
minutes* 
 Oropharyngeal 
bleeding – total 
duration of all 
episodes in previous 
24 hours >30 
minutes* 
 Epistaxis – total 
duration of all 
episodes in previous 
24 hours >30 
minutes* 
 Any bleeding 
requiring RBC 
transfusion over 
routine transfusion 
needs† 
Skin, soft tissue, 
musculoskeletal  
 Petechiae of skin 
 Purpura ≤1 inch 
diameter 
 One or more 
spontaneous 
hematomas in the 
soft tissue or muscle 
>1 inch 
 Purpura >1 inch 
diameter 
 Spontaneous 
hematoma in deeper 
tissues 
 Joint bleeding 
(confirmed by 
aspiration, imaging 
study or other 
accepted technique) 
 Any bleeding 
requiring RBC 
transfusion over 
routine transfusion 
needs† 
Gastrointestinal 
 Positive stool occult 
blood test‡ 
 Melanotic stool 
 Hematochezia – 
visible red blood 
mixed in stool, not 
requiring a transfusion 
 Hematemesis – 
grossly visible blood in 
emesis or in 
nasogastric drainage 
tube (not related or 
secondary to 
swallowed blood) 
 Any bleeding 
requiring RBC 
transfusion over 
routine transfusion 
needs† 
Genitourinary 
 Any biochemical or 
microscopic Hb/RBCs 
without red urine‡ 
 Abnormal vaginal 
bleeding (unexpected 
bleeding out of 
normal cycle or 
bleeding heavier 
than normal or 
breakthrough 
bleeding (patient on 
hormonal therapy to 
 Gross/visible 
hematuria without 
need for transfusion 
 Abnormal vaginal 
bleeding (unexpected 
bleeding out of 
normal cycle or 
bleeding heavier than 
normal or 
breakthrough 
bleeding (patient on 
hormonal therapy to 
 Any bleeding 
requiring RBC 
transfusion over 
routine transfusion 
needs† 


Oral Iron Study (Version 5, July9, 2020)  
Page 41 
prevent bleeding)) 
with spotting 
prevent bleeding)) 
more than spotting 
Pulmonary 
 
 Hemoptysis – visible 
blood 
 Blood in broncho-
pulmonary lavage, or 
blood tinged sputum 
(excluding those with 
nose or oropharyngeal 
bleeding) 
 Any bleeding 
requiring RBC 
transfusion over 
routine transfusion 
needs† 
Body cavity 
 
 Visible blood in body 
cavity fluid (e.g. red 
cells apparent in fluid 
aspirate) shore of 
criteria for Grade 3 or 
4 
 Grossly bloody 
body cavity fluids 
and organ 
dysfunction with 
symptoms, and/or 
need to intervene 
(e.g. to aspirate), 
and/or need for 
transfusion 
Central nervous 
system 
 
 Retinal bleeding 
without visual 
impairment 
 Lumbar puncture with 
blood (>5 RBC/µL in 
CSF on microscopic 
analysis and non-
traumatic tap), no 
symptoms and no 
visible red color 
 Lumbar puncture 
with visible red 
color in absence of 
symptoms, and 
non-traumatic tap 
Invasive sites 
 
 Bleeding at invasive 
sites (venipuncture 
sites, intravenous lines 
or catheter exit sites): 
active oozing at site 
for a cumulative total 
of >1 hour in the 
previous 24 hours 
 Any bleeding 
requiring RBC 
transfusion over 
routine transfusion 
needs† 
Hemodynamic 
instability 
 
 
 Any bleeding 
associated with 
moderate 
hemodynamic 
instability 
(hypotension; 
>30mmHg fall or 
>30% decrease in 
either systolic or 
diastolic blood 
pressure) and 
requiring RBC 
transfusion over 
routine transfusion 
needs† 
Grade 4: 


Oral Iron Study (Version 5, July9, 2020)  
Page 42 
 Any bleeding associated with severe hemodynamic instability (hypotension; >50mm/Hg fall or >50% 
decrease in either systolic or diastolic blood pressure, with associated tachycardia (heart rate increase of 
≥20% for 20 minutes) and requiring RBC transfusion over routine transfusion needs  
 Fatal bleeding from any source 
 Retinal bleeding with visual impairment (Visual impairment is defined as a field deficit, and patients with 
suspected visual impairment require an ophthalmologic consult for documentation) 
 CNS symptoms with non-traumatic bloody lumbar puncture 
 CNS bleeding on imaging study with or without dysfunction 
RBC indicates red blood cell; Hb, hemoglobin; CSF, cerebrospinal fluid; Hg, mercury; and CNS, central 
nervous system 
*Count actual bleeding (i.e. “running out” or need for basin, Kleenex, towel, etc.) not minor bleeding 
†Red cell transfusion must be specifically related to treatment of bleeding within 24 hours of onset of 
bleeding  
‡Not assessed in PLADO 
  
 
 


Oral Iron Study (Version 5, July9, 2020)  
Page 43 
APPENDIX B: 
 
Pictorial Blood Assessment Chart (PBAC) for menstrual bleeding44,45 
A score of > 100 on the PBAC is defined as menorrhagia. 
 
 
Completed by: ____________________  
Date: _______________________ 
Reviewed by: _____________________  
Date: _______________________ 
 


Oral Iron Study (Version 5, July9, 2020)  
Page 44 
APPENDIX C: 
 
Table 1: Flow Chart of Assessments/Procedures to be Performed Throughout the Study 
 
 
Procedures 
 
 
Prior to 
Enrolment 
 
After 
Enrolment  
 
Week 
1  
(±3 
days) 
 
Week 
4 
(±7 
days) 
 
Week 
8 
(±7 
days) 
 
Week 
12 
(±7 
days) 
 
Week 
13 
(7 
days ± 
3 days 
after 
final 
study 
visit)  
Referring clinician offices identify potential 
patients as participants 
        X 
 
 
 
 
 
 
Patient (surrogate) informed consent 
X 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Baseline Data 
 
 
 
 
 
 
 
Case Logs (reason for lack of consent, protocol 
violations) 
X 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
Hemoglobin 
X 
 
 
X 
 
X 
 
Reticulocyte Count  
X 
 
 
X 
 
X 
 
C reactive protein (CRP) – acute phase reactant 
X 
 
 
 
 
 
 
Ferritin 
X 
 
 
 
 
X 
 
Serum Iron 
X 
 
 
 
 
X 
 
Transferrin Saturation (TSAT) 
X 
 
 
 
 
X 
 
Creatinine clearance 
X 
 
 
 
 
 
 
Subjective Patient Assessments 
 
 
 
 
 
 
 
FACIT-Fatigue Scale Questionnaire 
 
X 
 
X 
X 
X 
 
Patient Diary Adherence  
 
 
X 
remin
der 
X 
X 
X 
 
Side Effect Questionnaire 
 
 
 
X 
X 
X 
 
Pill Count 
 
 
 
 
 
X 
 
Adverse and Serious Adverse Events  
 
 
X 
X 
X 
X 
X 
Need for Therapy Escalation 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 


Oral Iron Study (Version 5, July9, 2020)  
Page 45 
APPENDIX D:  
 
Suspect Adverse Reaction Report 
 
 
 


Oral Iron Study (Version 5, July9, 2020)  
Page 46 
Daily vs. every other day oral iron supplementation in patients with absolute iron deficiency anemia (DEODO): 
a multi-centered, pilot randomized controlled trial 
Summary of Changes Table  
Protocol Summary of Changes   
Protocol V5 dated July 9, 2020 (updated from Protocol V4 dated December 6, 2020)  
Section 
Change 
Rationale 
Page 1 
Added protocol number 1534 
Was left blank in previous 
protocol version 
5.3.1 Patient recruitment, 
consent, screening and 
enrolment 
 
Add: Once the patient has 
consented, bloodwork will be 
performed at the participating 
institution’s laboratory or at a 
local lab 
Allow for patients the option to 
complete bloodwork at a local 
lab if they feel unsafe entering 
the hospital due to COVID-19.   
5.3.3.2 Acquisition and 
Formulation 
Add:  Once randomization has 
occurred, a prescription for the 
dosing regimen will be given to 
the patient to bring to pharmacy 
at the local site. Patients opting 
for virtual clinic visits will have 
their prescription filled by the 
study coordinator, and the pills 
couriered to their address on 
file. Patients will also have the 
option to pick-up their 
prescription from the study site 
(curbside pick-up). 
Allow for patients to pick 
up/drop-off their prescription 
without in-person contact at the 
hospital.  
5.3.5.4 Return and Destruction 
of Investigational Product  
Add: the local study site. A 
remote/telephone visit for the 
week 12 follow-up is also 
acceptable given the current 
situation with COVID-19. Virtual 
visits will also be an option post-
COVID 19. Patients opting for a 
virtual 12-week clinical visit will 
be requested to courier their pill 
bottles and adherence diary back 
Allow for patients the option to 
complete their week 12 visit 
virtually if they feel unsafe 
entering the hospital due to 
COVID-19.  
Allow for patients to pick 
up/drop-off their prescription 
and adherence diary without in-
person contact at the hospital. 


Oral Iron Study (Version 5, July9, 2020)  
Page 47 
to the local site. In this case, a 
pre-paid return envelope will be 
provided. Patients will also have 
the option to return their pill 
bottles and adherence diary via 
curbside drop off. 
5.4.1 Baseline Visit and 
Assessment 
Add: Baseline assessment will 
occur according to the schedule 
below and may be performed in 
person/remotely 
(telephone/zoom/OTN). 
Allow for patients the option to 
complete their week baseline 
visit virtually if they feel unsafe 
entering the hospital due to 
COVID-19.  
5.4.2.2 Week 4 
Add: Reminder to do laboratory 
tests (at the local site or local 
lab) 
Allow for patients the option to 
complete bloodwork at a local 
lab if they feel unsafe entering 
the hospital due to COVID-19.   
5.4.2.4 Week 12 Final Study Visit 
Add: Participants will be 
assessed in person/remotely 
(telephone/zoom/OTN) at Day 
84 ± 7 days for the following 
assessment 
Allow for patients the option to 
complete their week 12 visit 
virtually if they feel unsafe 
entering the hospital due to 
COVID-19.  
List of changes 
Updated list of changes 
Include all changes made to 
study documents 
 
Protocol V4 dated Dec 6, 2019 (updated from Protocol V3 dated June 27, 2019) 
Section 
Change 
Rationale 
Protocol  Summary 
 
Revised exclusion criteria from 
‘on anti-coagulant therapy’ to 
‘on new anticoagulant therapy 
initiated in the past 6 months’ 
Patients who have been on 
anticoagulants for longer than 6 
months have had stability on 
their anticoagulation; thus 
should be eligible 
5.2.2 Exclusion criteria 
 
Revised exclusion criteria from 
‘on anti-coagulant therapy’ to 
‘on new anticoagulant therapy 
initiated in the past 6 months’ 
Patients who have been on 
anticoagulants for longer than 6 
months have had stability on 
their anticoagulation; thus 
should be eligible 


Oral Iron Study (Version 5, July9, 2020)  
Page 48 
5.3.1 Patient recruitment, 
consent, screening and 
enrolment  
Adding the following to clarify 
the general process of 
recruitment ‘with permission to 
enter the patient’s circle of care 
the research coordinator will 
then approach potentially 
eligible patients 
For recruitment through 
Canadian Blood Services it has 
been clarified that ‘It is also 
acceptable for the patient to 
contact the study site directly in 
which case permission from the 
MRP is not required’  
As the Canadian Blood Services 
donor letter contains the 
Research Coordinator’s contact 
information for both sites, it is 
acceptable for patients to 
contact study personnel directly 
regarding their interest.   
 
Protocol V3 dated Jun 27, 2019 (updated from Protocol V1.2 dated Aug 31, 2018)  
Section 
Change 
Rationale 
Title page 
Removed: Research Coordinator 
name and credentials 
Since CRC keeps changing for the 
research study, it is best to not 
have this mentioned on the front 
page of the protocol. 
Key role and contact information 
Removed clinical 
laboratory/department contacts 
and address for the research 
coordinators 
Same reason as above 
5.3.1 Patient, recruitment, consent, 
screening and enrolment 
Added “once the patient has 
consented, screening bloodwork 
will be performed at the 
participating institution’s 
laboratory, if it has not been 
performed in the past 2 weeks. 
Eligibility of the patient will be 
determined. If the eligibility is 
confirmed, then the patient will be 
enrolled (assigned a study ID) and 
randomized. Once the patient has 
been enrolled, additional 
bloodwork not already performed 
within the pre-specified time frame 
(5.4.1.2) will be conducted (either 
drawn from the patient or added 
To clarify the process of eligibility, 
enrolment and randomization of 
the study. Also clarifying the the 
time period of the blood-test that 
can be used to assess the eligibility. 


Oral Iron Study (Version 5, July9, 2020)  
Page 49 
on to the bloodwork already done). 
 
Removed “once patient has been 
enrolled, additional bloodwork not 
already performed within the pre 
specified time frame (5.4.1.2) will 
be conducted (either drawn from 
the patient or added on to 
bloodwork already done). If the 
patient is deemed eligible, the 
patient will be randomized.  
5.3.3.3 packaging 
Removed 120 from the sentence 
“standard package of 120 vitamin C 
pills that are to be taken along with 
the study drug”. 
Participants receive either ‘45’ or 
‘90’ tablets in their packaging 
depending on their randomization 
schedule.  Standard package does 
not include 120 vitamin C pills.  
5.4.1.1 screening and enrollment 
will occur within 1 week of 
randomization 
Removed ‘response’ for both IV 
and oral iron. 
Lack of response to oral iron is 
already captured in the eligibility 
checklist. Response to IV iron does 
not impact this study.  
5.4.1.2 Baseline laboratory 
assessment 
Added “screening bloodwork can 
be used for the baseline laboratory 
assessment” 
To clarify that the screening 
bloodwork can be used for baseline 
laboratory assessment.  
5.4.2.2 week 4 
Added “medication history (to 
confirm if any new medications or 
discontinued any previous 
medications)”.  
To clarify that the study team will 
be asking the participants if they 
have started any new medication 
at each visit during the trial. 
5.4.2.3 week 8 
Added “medication history (to 
confirm if any new medications or 
discontinued any previous 
medications)”. 
Same as 5.4.2.2 
5.4.2.4 Week 12 Final study visit 
Added “medication history (to 
confirm if any new medications or 
discontinued any previous 
medications)”. 
Same as 5.4.2.2 
5.4.4 participant compliance 
monitoring and assessment 
Added “if a patient misses a pill, 
they will continue with the next 
dose as directed on the calendar 
and not to double up dosing”.  
To specify the procedure if a 
participant misses a pill.  Also to 
clarify that missing a pill is not 
considered a protocol violation. 
8.1 sample size and sample size 
justification 
Added “the trial will proceed until 
there are 52 enrolled patients and 
at least 36 patients who complete 
the trial to 13 weeks without 
dropping out”.  
To specify the number of patients 
needed in order for the trial to be 
considered complete.  
Appendix B 
Added “completed by, date and 
reviewed by and date” 
To record the personnel 
completing and reviewing the 
PBAC score calculation. 


Oral Iron Study (Version 5, July9, 2020)  
Page 50 
Appendix C 
Revised inclusion/exclusion criteria 
to “prior to enrolment” from “after 
enrolment “ 
Revised Medical History to “after 
enrolment” to “prior to enrolment” 
Added checkmarks for AE and SAE 
under week 1, week 4, week 8, 
week 12 
Added checkmarks for need for 
therapy escalation under week 1, 
week 4, week 8  
To correct the order of procedures 
followed for enrollment. Inclusion 
and exclusion criteria are always 
reviewed prior to enrolment versus 
after.  Medical history are 
reviewed after enrolment.   
Additionally, the team will be 
assessing the patient for AE and 
SAE at each follow-up call and visit 
with the participant during the 
duration of the trial.  
 

ICF_001.pdf: 
 
  
 
Version 3.0 09 July 2020 
 
Page 1 of 12 
 
Informed Consent Form for Participation in a Research Study 
 
Study Title:  Daily vs. every other day oral iron supplementation in patients with absolute iron 
deficiency anemia (DEODO): a multi-centered, pilot randomized controlled trial  
 
Study Doctor:  Dr. Yulia Lin, Transfusion Medicine & Hematology 
 
 
Phone: 416-480-4042 
  
Sponsor/Funder(s): This study is an investigator initiated study funded by the University of 
Toronto – Alexandra Yeo Grant.  
 
 
INTRODUCTION 
 
You are being invited to participate in a clinical trial (a type of study that involves research). You 
are invited to participate in this trial because you have iron deficiency anemia (low iron with low 
red blood cell count) and are 16 years or older. This consent form provides you with information 
to help you make an informed choice. Please read this document carefully and ask any 
questions you may have. All your questions should be answered to your satisfaction before you 
decide whether to participate in this research study. 
 
Please take your time in making your decision.  You may find it helpful to discuss it with your 
friends, family and/or your family doctor.  
 
Taking part in this study is voluntary.  Deciding not to take part or deciding to leave the study 
later will not result in any penalty or affect current or future health care. 
 
As a Substitute Decision Maker, you are being asked to provide informed consent on behalf of a 
person who is unable to provide consent for him/herself.  If the participant gains the capacity to 
consent for him/herself, your consent for them will end.  Throughout this form, “you” means the 
person you are representing.  
 
IS THERE A CONFLICT OF INTEREST?  
 
There are no conflicts of interest to declare related to this study.  
 
 
WHAT IS THE BACKGROUND INFORMATION FOR THIS STUDY? 
The standard initial treatment for iron deficiency anemia is an oral iron supplement.  
 
Oral ferrous sulfate is an oral iron supplement commonly used to treat iron deficiency anemia. 
Laboratory tests show that it may improve anemia, such as the hemoglobin level (measure of 
red blood cells in the blood) and ferritin (measure of iron stores). It is less clear if taking oral iron 
daily (standard treatment) compared with every other day may result in the same improvement 
in hemoglobin level with fewer side effects.  
 
Health Canada, the regulatory body that oversees the use of natural health products in Canada, 
has not approved the use of oral ferrous sulfate tablets for the treatment of iron deficiency 
anemia, based on the Health Canada Product Monograph, which indicates its use as prevention 


 
  
 
Version 3.0 09 July 2020 
 
Page 2 of 12 
 
for iron deficiency anemia.  Health Canada has allowed the use of oral ferrous sulfate to be 
used in this study to treat iron deficiency anemia.  
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to optimize the effectiveness of oral iron supplementation while 
minimizing side effects to improve patient treatment. As this study is a pilot study, another 
primary purpose is to test the study plan and to determine whether enough participants will join 
a larger study and accept the study procedures. This type of study involves a small number of 
participants and so it is not expected to definitively prove safety or effectiveness. The results 
may be used as a guide for larger studies, although there is no guarantee that they will be 
conducted. Participation in a pilot study does not mean that you will be eligible to participate in a 
future larger study.  
 
The purpose of this study is to compare the effects of taking oral ferrous sulfate tablets with 
vitamin C every other day, on you and your iron deficiency anemia, compared to taking oral 
ferrous sulfate with vitamin C daily, which is commonly-used to treat iron deficiency anemia. 
Vitamin C is taken with oral iron to improve iron absorption.  
 
WHAT OTHER CHOICES ARE THERE?  
You do not have to take part in this study in order to receive treatment or care.  Other options (in 
addition to the standard or usual treatment described above) may include, but are not limited to: 
 
 
other oral iron supplements, including, but not limited to; oral ferrous gluconate or 
fumarate;  
 
intravenous iron therapy, if oral iron is not tolerated or effective;  
 
other research studies may be available if you do not take part in this study; 
 
no therapy at this time. 
 
Please talk to your usual doctor or the study doctor about the known benefits and risks of these 
other options before you decide to take part in this study. Your usual doctor or the study doctor 
can also discuss with you what will happen if you decide not to undertake any treatment at this 
time. 
 
You do not have to take part in this study. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
It is anticipated that about 52 people will take part in this study, from research sites located in 
Toronto, Ontario, Canada.  
 
This study should take approximately two years to complete and the results should be known in 
about 1 year after completion.  
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 
ASSIGNMENT TO A GROUP  
If you decide to participate then you will be "randomized" into one of the groups described 


 
  
 
Version 3.0 09 July 2020 
 
Page 3 of 12 
 
below. Randomization means that you are put into a group by chance (like flipping a coin). 
There is no way to predict which group you will be assigned to. You will have a 50% chance of 
being placed in either group. Neither you, the study staff, nor the study doctors can choose what 
group you will be in. However, you will be told which group you are in. 
 
 
WHAT IS THE STUDY INTERVENTION? 
Group 1 (Experimental intervention): Every other day oral ferrous sulfate supplementation 
 
If you are randomized to this group you will take a 300mg (60mg elemental iron) tablet of 
ferrous sulfate on an empty stomach at bedtime, with a 500mg vitamin C tablet every other day, 
for a period of 12 weeks.  
 
Group 2 (Non-Experimental Intervention): Daily oral ferrous sulfate supplementation 
 
If you are randomized to this group you will take a 300mg (60mg elemental iron) tablet of 
ferrous sulfate on an empty stomach at bedtime, with a 500mg vitamin C tablet daily, for a 
period of 12 weeks.  
 
 
Medicinal and non medicinal ingredients of ferrous sulfate: ferrous sulphate, 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, talc titanium dioxide. 
 
Medicinal and non medicinal ingredients of vitamin C: Ascorbic acid, Colloidal silicon 
dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose and 
stearic acid. 
 
WHAT ELSE DO I NEED TO KNOW ABOUT THE STUDY INTERVENTION? 
If you have side effects while you are on this study, the study doctor may make changes to the 
intervention.   
 
Normally, as part of usual care, you would receive daily oral iron tablets with vitamin C for initial 
treatment of iron deficiency anemia.  If you decide to take part in this study, you may not receive 
daily oral tablets as usual treatment.   
 
If you opt for virtual clinic visits you will have your prescription filled by the study coordinator, 
and the pills couriered to your address on file. You will also have the option to pick-up your 
prescription from the study site (curbside pick-up). At the end of the study, we will ask you to 
courier back your pill bottles and adherence diary to the local study site. We will provide a pre-
paid return envelope to you. You also have the option to return your pill bottles and adherence 
diary via curbside drop off.  
 
WHAT ARE THE STUDY PROCEDURES? 
 
Non-Experimental Procedures 
The following tests will be done as part of this study.  Some of these tests may be done as part 
of your standard care, in which case the results may be used.  Some of these tests may be 


 
  
 
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done more frequently than if you were not taking part in this study and some may be done only 
for the purpose of the study. If the results show that you are not able to continue participating, 
the study doctor(s) will let you know.  
 
 
A complete blood count at the baseline assessment, 4 and 12 weeks after study 
intervention has begun, this involves drawing a blood sample and is standard of care for 
those who have, or are suspected to have, iron deficiency anemia.   
 
Ferritin measure at the baseline assessment and 12 weeks after study intervention has 
begun, this involves drawing a blood sample and is standard of care for those who have, 
or are suspected to have, iron deficiency anemia. 
 
Reticulocyte count at the baseline assessment, 4 and 12 weeks after study intervention 
has begun, this involves drawing a blood sample and is standard of care for those who 
have, or are suspected to have, iron deficiency anemia.  
 
C reactive protein measure at the baseline assessment, this involves drawing a blood 
sample and is not standard of care for those who have, or are suspected to have, iron 
deficiency anemia.  
 
Serum iron measure at the baseline assessment and 12 weeks after study intervention 
has begun, this involves drawing a blood sample and is not standard of care for those 
who have, or are suspected to have, iron deficiency anemia.  
 
Transferrin saturation measure at the baseline assessment and 12 weeks after study 
intervention has begun, this involves drawing a blood sample and is not standard of care 
for those who have, or are suspected to have, iron deficiency anemia.  
 
Creatinine measure at the baseline assessment, this involves drawing a blood sample 
and is not standard of care for those who have, or are suspected to have, iron deficiency 
anemia.  
 
Questionnaires 
You will be provided with questionnaires during your visits when you are enrolled, as well as 1, 
4, 8 and 12 weeks following your enrollment. The purpose of the side-effect questionnaire is to 
account for any gastrointestinal effects resulting from the oral iron tablets. The purpose of the 
FACIT-fatigue scale questionnaire is to understand how the iron tablets may affect fatigue 
severity and life measures associated with iron deficiency anemia. Each questionnaire will take 
about 5 minutes to complete, and will be conducted through phone calls or emails; at the end of 
this consent form you will be asked for your consent to receiving phone calls and/or emails from 
our research team. 
 
The information you provide is for research purposes only. Some of the questions are personal.  
You can choose not to answer questions if you wish. 
 
Participant Diaries 
You will be asked to keep a diary of when you take your iron tablets. A patient calendar with 
specific reminders will be provided to patients; please record whether you have taken your 
tablet, using a checkmark, on the days indicated with a blank box on the calendar. During the 
follow up phone-calls or emails at weeks 1, 4, 8, 13, and the in-person or virtual visit at week 12, 
you will be prompted by our research team to answer questions about your adherence to the 
study schedule.   
 
MANDATORY SAMPLE COLLECTION  


 
  
 
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The researchers doing this study need to do tests on samples (described below) to determine 
the results of oral iron supplementation on biological markers.  
 
The collection of the blood samples is a necessary part of this study and will be collected 
without fasting. Samples will be used only for these purposes. The samples will not be sold.  
 
Once these tests have been completed, any leftover samples will be destroyed according to the 
site’s policy. 
 
Reports about research tests done with your samples will be given to the study doctor(s).  If you 
would like to learn the results of this research, please let them know. 
 
 
Blood Collection (Required) 
Blood samples will be taken by inserting a needle into a vein in your arm. These will be taken at 
the same time as your study related visits whenever possible, at entry into the study, and at four 
and twelve weeks after beginning the study treatment. Throughout the entire study duration, the 
total amount of blood that will be drawn is 22ml (11ml at the baseline assessment, 3ml at the 
week 4 assessment and 8ml at the 12 week assessment), and will be used to determine the 
following measures; complete blood count, reticulocyte count, C reactive protein, ferritin, serum 
iron, transferrin saturation and creatinine clearance. These blood samples will be examined by 
the local laboratory where your blood is drawn.  
 
How will samples be identified? 
As these samples would already be drawn as part of your usual care, the samples will be 
identified with your name and medical record number. To protect your identity, the information 
that will be on your samples for research purposes will be limited to your assigned participant 
identification code. .   
 
Despite protections being in place, there is a risk of unintentional release of information.  
 
Can I withdraw these samples? 
If you no longer want your samples to be used in this research, you should contact the 
Research Coordinator or Study Doctor, who will ensure the samples are retrieved and 
destroyed according to local hospital policy.  
 
If tests have already been done on your sample(s) it will not be possible to withdraw those 
results. However, no further testing will be done.  
 
If samples are withdrawn, participants may continue to participate in the main part of the study.  
 
WHAT ARE THE RESPONSIBILITIES OF STUDY PARTICIPANTS? 
If you choose to participate in this study, you will be expected to: 
 
Tell the study doctor about your medical history and current medical conditions; 
 
Tell the study doctor about all prescription and non-prescription medications and 
supplements, including vitamins and herbals, and check with the study doctor before 
starting, stopping or changing any of these. This is for your safety as these may interact with 
the intervention you receive on this study.  


 
  
 
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 
It is especially important to tell the study doctor if you are taking any other medications 
containing iron or vitamin C. 
 
Tell the doctor if you are allergic to any of the following medicinal and non-medicinal 
ingredients in Ferrous Sulfate: : ferrous sulphate, 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, talc 
titanium dioxide  
 
Tell the doctor if you are allergic 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. 
 
Tell the study doctor If you are taking any multivitamin or mineral supplements containing 
35mg or more of elemental iron per day. 
 
Tell the study doctor if you are thinking about participating in another research study 
 
Tell the study doctor if you become pregnant or are breastfeeding or father a child while 
participating in this study  
 
Study participants should not become pregnant while on the study 
 
Avoid drinking/eating dairy products, antacids, calcium, tea and coffee for 1 hour prior to and 
1 hour after ingesting the iron tablet, throughout the study duration. 
 
Stop taking other iron supplementations for two weeks prior to randomization, and during 
the study duration 
 
The oral iron tablets are for you alone, and must not be shared with others. If someone 
accidentally takes an excessive amount of the iron tablets, they should promptly seek 
medical attention. 
 
Follow a visit schedule for timely assessments as follows: 
Visit 
Baseline 
Week 
Week 1 
Week 4 
Week 8 
Week 12 
Week 
13 
Clinic 
assessments 
(in-
person/virtual) 
  
 
 
 
  
 
Laboratory (lab 
assessments) 
  
 
  
 
  
 
Email/phone 
(questionnaires) 
 
  
  
  
 
  
 
 
Return the study diary that you take home to complete 
 
Return any unused study medication 
 
HOW LONG WILL PARTICIPANTS BE IN THE STUDY? 
The study intervention will last for about 12 weeks; however the total study duration for a patient 
may exceed this amount due to the randomization and consenting period.     


 
  
 
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There will be a follow-up visit at 12 weeks after the first dose of the study treatment. 
 
You may be seen more often if the study doctor determines that this is necessary. 
 
No matter which group you are randomized to, and even if you stop the study intervention early, 
we would like to keep track of your health for the duration of the 12 week treatment period, to 
capture outcomes that occur once they have discontinued study intervention to determine 
feasibility. We would do this by having you complete the scheduled laboratory tests and quality 
of life assessments.  
 
There will be one final phone call or email at 13 weeks to check if you have had any side effects 
or adverse events. 
 
CAN PARTICIPANTS CHOOSE TO LEAVE THE STUDY? 
 
You can choose to end your participation in this research (called withdrawal) at any time without 
having to provide a reason.  If you choose to withdraw from the study, you are encouraged to 
contact the study doctor or study staff.   
 
You may withdraw your permission to use information that was collected about you for this 
study at any time by letting the study doctor know. However, this would also mean that you 
withdraw from the study.  
 
Information that was recorded before you withdrew will be used by the researchers for the 
purposes of the study, but no information will be collected or sent to the sponsor after you 
withdraw your permission. 
   
CAN PARTICIPATION IN THIS STUDY END EARLY? 
 
The study doctor may stop your participation in the study early, and without your consent, for 
reasons such as: 
 
The study intervention does not work for you 
 
You are unable to tolerate the study intervention 
 
You are unable to complete all required study procedures 
 
The study doctor no longer feels this is the best option for you 
 
The Regulatory Authorities (for example, Health Canada) or research ethics board 
withdraw permission for this study to continue 
 
If you plan to become pregnant or breastfeeding 
 
If this happens, it may mean that you would not receive the study intervention for the full period 
described in this consent form. If you are removed from this study, the study doctor will discuss 
the reasons with you and plans will be made for your continued care outside of the study.   
 


 
  
 
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WHAT ARE THE RISKS OR HARMS OF PARTICIPATING IN THIS STUDY?  
 
You may experience side effects from participating in this study.  Some side effects of oral iron 
are known and are listed below, but there may be other side effects that are not expected. 
There are no side effects from vitamin C. You should discuss these with the study doctor.  
 
The study doctor will watch you closely to see if you have side effects. When possible, other 
medicine will be given to you to make side effects less serious and more tolerable. Many side 
effects go away shortly after the study intervention is stopped, but in some cases side effects 
can be serious, long-lasting, permanent, or may even cause death. 
 
Risks and side effects related to the experimental intervention of oral ferrous sulfate, we are 
studying include: 
 
 
Very likely (21% -100%): 
 
Gastrointestinal Distress 
 
Abdominal Pain 
 
Dark stools 
 
Less likely (5 – 20%): 
 
Constipation  
 
Nausea  
 
Heartburn 
 
Vomiting  
 
Diarrhea  
 
Flatulence  
 
All of the aforementioned risks may vary in severity and reversibility, but are highly likely to stop 
once study supplementation stops if you are experiencing these symptoms.  
 
The risks and side effects of the standard or usual treatment will be explained to you as part of 
your standard care.  These risks are not included in this consent form.   
 
It is possible that other drugs (prescription and non-prescription drugs), vitamins, or herbals can 
interact with the study intervention. This can result in either the intervention not working as 
expected or result in severe side effects. 
 
Long term effects of unmonitored oral iron intake can lead to iron overload. Although, this is very 
unlikely to happen in the 12 week period of the study intervention.  
 
If you should have a side effect or any other unexpected effects from the medication, please 
contact the study investigator listed at the end of this form. 
 
WHAT ARE THE REPRODUCTIVE RISKS? 
 
There are no reproductive risks associated with this study.  
 


 
  
 
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WHAT ARE THE BENEFITS OF PARTICIPATING IN THIS STUDY? 
The expected benefit from taking part in this study is the potential to improve iron deficiency 
anemia, such as your hemoglobin levels. These potential changes may lead to improved 
symptoms associated with iron deficiency anemia, such as; cognitive and physical functioning, 
and fatigue.    
 
If you agree to take part in this study, the experimental intervention may or may not be of direct 
benefit to you.  
 
Additionally, we hope the information learned from this study will advise the optimal tablet 
dosing schedule for other people with iron deficiency anemia in the future.  
  
HOW WILL PARTICIPANT INFORMATION BE KEPT CONFIDENTIAL? 
 
If you decide to participate in this study, the study doctors and study staff will only collect the 
information they need for this study. 
 
Records identifying you at this centre will be kept confidential for 25 years and, to the extent 
permitted by the applicable laws, will not be disclosed or made publicly available, except as 
described in this consent document. 
 
Authorized representatives of the following organizations may look at your original (identifiable) 
medical/clinical study records at the site where these records are held, to check that the 
information collected for the study is correct and follows proper laws and guidelines. 
 
 
The research ethics board who oversees the ethical conduct of this study in Ontario 
 
Representatives of Sunnybrook Research Institute, who oversee the ethical conduct of 
research at this location 
 
Health Canada (because they oversee the use of natural health products/drugs/devices in 
Canada)  
 
Information that is collected about you for the study (called study data) may also be sent to the 
organizations listed above.  Representatives of Clinical Trials Ontario, a not-for-profit 
organization, may see study data that is sent to the research ethics board for this study.  Your 
name, address, or other information that may directly identify you will not be used. The records 
received by these organizations may contain your participant code, sex and date of birth 
(month, year only). 
 
If the results of this study are published, your identity will remain confidential. It is expected that 
the information collected during this study will be used in analyses and will be published/ 
presented to the scientific community at meetings and in journals. This information may also be 
used as part of a submission to regulatory authorities around the world to support the approval 
of the study intervention. 
 
Even though the likelihood that someone may identify you from the study data is very small, it 
can never be completely eliminated.  
 


 
  
 
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A copy of the consent form that you sign to enter the study may be included in your health 
record/hospital chart. 
 
Data collected using your email server resides on that respective server (i.e. Google, Apple) and 
no assurance can be made about its confidentiality or that it will only be used for research 
purposes. 
 
Upon enrolment, participants will be asked by the research team if they prefer to be contacted 
via email and/or telephone. Based on the participant’s response, they will provide information 
regarding their email address or personal telephone number. Please note that the Sunnybrook 
email network is secure, however personal email accounts or those used by participants may 
not be secure and no assurance can be made about its confidentiality. 
 
WILL FAMILY DOCTORS/HEALTH CARE PROVIDERS KNOW WHO IS PARTICIPATING IN 
THIS STUDY? 
 
Your family doctor/health care provider will be informed that you are taking part in a study so 
that you can be provided with appropriate medical care. If you do not want your family 
doctor/health care provider to be informed, please discuss this with the study team. 
 
WILL INFORMATION ABOUT THIS STUDY BE AVAILABLE ONLINE? 
A description of this clinical trial will be available on https://clinicaltrials.gov/ and 
http://www.transfusionquest.ca/.  These websites will not include information that can identify 
you.  You can search this website at any time. 
 
WHAT IS THE COST TO PARTICIPANTS? 
The oral ferrous sulfate supplements will be supplied at no charge while you take part in this 
study.   
 
You may not be able to receive the study intervention after your participation in the study is 
completed. There are several possible reasons for this, some of which are:  
 
The intervention may not turn out to be effective or safe. 
 
Your caregivers may not feel it is the best option for you. 
 
You may decide it is too expensive and insurance coverage may not be available. 
 
The intervention, even if approved in Canada, may not be available free of charge.  
 
The study doctor will talk to you about your options. 
 
Taking part in this study may result in added costs to you.  For example: 
 
You may miss work as a result of participation in this study. However this is not unique 
to the study protocol as patients with iron deficiency anemia would potentially miss work 
as a result of standard care and attending standard appointments anyways.  
 
ARE STUDY PARTICIPANTS PAID TO BE IN THIS STUDY?  
You will not be paid for taking part in this study. 
 
If you decide to participate in this study, you will be reimbursed up to $10 for parking, during 
your week 4 visit to a clinic that will obtain necessary blood samples and up to $25, for your 


 
  
 
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week 12 visit to your corresponding site. For study related expenses, specifically hospital 
parking, you will need to provide your receipts for parking to the research staff in order to be 
reimbursed. Participants attending their week 4 and 12 visits in-person are eligible for the 
parking reimbursement.  
 
In the case of research-related side effects or injury, medical care will be provided by the study 
Doctor.  
 
WHAT ARE THE RIGHTS OF PARTICIPANTS IN A RESEARCH STUDY? 
You will be told, in a timely manner, about new information that may be relevant to your 
willingness to stay in this study. 
 
You have the right to be informed of the results of this study once the entire study is complete.  
If you would like to be informed of the results of this study, please let the study doctor know. The 
results of this study will also be available on the clinical trial registry (see the “Will information 
about this study be available online” section for more details). 
 
Your rights to privacy are legally protected by federal and provincial laws that require 
safeguards to ensure that your privacy is respected. 
 
By signing this form you do not give up any of your legal rights against the study doctor or 
involved institutions for compensation, nor does this form relieve the study doctor or their agents 
of their legal and professional responsibilities. 
 
You will be given a copy of this signed and dated consent form prior to participating in this 
study. 
 
WHAT IF RESEARCHERS DISCOVER SOMETHING ABOUT A RESEARCH PARTICIPANT? 
During the study, the researchers may learn something about you that they didn’t expect.  For 
example, the researchers may find out that you have another medical condition.  
 
If any new clinically important information about your health is obtained as a result of your 
participation in this study, you will be given the opportunity to decide whether you wish to be 
made aware of that information. 
 
WHOM DO PARTICIPANTS CONTACT FOR QUESTIONS? 
 
If you have questions about taking part in this study, or if you suffer a research-related injury, 
you can talk to your study doctor, or the doctor who is in charge of the study at this institution. 
That person is: 
 
 
Dr. Yulia Lin   416-480-4042 
 
Name 
Telephone  
 
If you have questions about your rights as a participant or about ethical issues related to this 
study, you can talk to someone who is not involved in the study at all. That person is: 
 


 
  
 
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Chair of the Sunnybrook Research Ethics Board 
 
416-480-6100 ext. 88144 
Name 
 
Telephone  
 
SIGNATURES 
 
All of my questions have been answered, 
 
I understand the information within this informed consent form, 
 
I allow access to my medical records and specimens as explained in this consent form, 
 
I allow research personnel involved with this study to contact me by telephone and/or email,  
 
I do not give up any of my legal rights by signing this consent form, 
 
I understand that my family doctor/health care provider will be informed of my participation in 
this study  
 
I agree, or agree to allow the person I am responsible for, to take part in this study. 
 
 
____________________________ ______________________ 
_________________ 
Signature of Participant/ 
PRINTED NAME 
Date 
Substitute Decision-Maker 
 
____________________________ ______________________ 
_________________ 
Signature of Person Conducting  
PRINTED NAME & ROLE 
Date 
the Consent Discussion 
 
____________________________ ______________________ 
_________________ 
Signature of Principal Investigator  
PRINTED NAME 
Date 
 
 
Complete the following section only if the participant is unable to read or requires an oral 
translation: 
 
 
The informed consent form was accurately explained to, and apparently understood by, the 
participant/substitute decision maker, and 
 
Informed consent was freely given by the participant/substitute decision maker 
 
 
____________________________ ______________________ 
_________________ 
Signature of Impartial  
PRINTED NAME 
Date 
Witness/Translator 
(If participant were unable to  
read/required an oral translation)