Clinical trial NCT04371536
Conditions: Iron Deficiency Anemia Iron-deficiency
Keywords: Iron Deficiency Anemia Nutritional iron deficiency Ferrous sulfate oral liquid formulation
Sponsor: Baylor College of Medicine
Start date: 2021-07-09; Completion date: 2022-03-09
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Iron deficiency anemia (IDA) affects nearly half a million young children in the United States. Most children take liquid iron medicine by mouth for at least 3 months. However, some children take longer to get better with this medicine. This study is trying to compare different ways of giving iron medicine to young children.

For young children in the US, the main cause of IDA is nutritional, or not having enough iron in the foods they eat. This often happens when kids drink too much cow milk and/or not eating enough foods that have a lot of iron. Iron deficiency is most common in children ages 1 to 4 years of age, during a time that is important for brain development. More severe and long-lasting IDA is associated with worse brain development outcomes. That is why researchers want to understand the fastest way for kids with IDA to get better.

Standard treatment is oral iron medicine for 3 to 6 months. Many children do not take their iron medicine the full amount of time needed because of side effects like abdominal discomfort, nausea, constipation, and bad taste. Different factors can contribute to patients not completing their IDA therapy. Many families do not understand how important it is to treat IDA or do not have the motivation to continue the medication.

This study will offer different methods for treating IDA, including a different method to taking the oral iron therapy.

This new method gives oral iron by increasing a family's understanding and motivation. Another research study that interviewed families of young children with IDA found ways that helped the patients to continue their therapy. Using that information, a website called IRONCHILD was created to help motivate parents to get their children to continue the oral iron medicine.

Research studies that compare these different IDA treatment methods in young children are needed and could have benefits to short-term clinical and long-term brain development. However, we do not know whether families of young children with IDA will be willing to participate in this type of study that has different treatment methods (oral iron therapy and oral iron therapy with a web-based adherence intervention).

The goal of this clinical research study is to learn which of the two methods of care will be the best way for children with iron deficiency anemia to receive therapy.

Detailed description:
First, the doctor will confirm that patients are eligible for the study. Patients will complete the following procedures:

* Medical history including prior hospitalizations, lab results, medications, diet, social and family history
* Comprehensive Physical Examination which includes measurement of vital signs, examination of the head, eyes, ears, nose, mouth, heart, lungs, abdomen, and skin.
* Blood samples: Patients will not have any extra blood draws for this study, as the investigators will draw the blood during routine blood draws. Investigators will ask to take a little extra blood (less than half a teaspoon) for research tests. All other blood draws that patients have while on study will be for routine care and not for research purposes.

Patients will be on the study for 12 weeks. Patients will receive dietary counseling on the amount of cow milk they may have and information sheets on iron-rich foods.

There are 2 different treatments in this study and patients cannot choose which treatment they receive. Instead, they will be randomly assigned to one of the two treatments. That means there is a 50-50 chance that patients will receive liquid iron medicine by itself or that patients will receive liquid iron medicine with access to the website.

Depending on which method of care patients are assigned to, they will complete the following procedures below.

1. Oral Iron Therapy:

   Patients will receive liquid iron medicine by mouth once per day for 12 weeks. Patients will first receive this medicine during their first visit.

   During the Week 4 visit, patients will compete the following procedures:
   * Blood Samples: Patients will not have any extra blood draws (pokes) for this study as blood for research will be collected during routine blood draws. About less than half a teaspoon of extra blood will be drawn for research tests. All other blood draws that patients have while on study will be for routine care and not for research purposes
   * Focused Physical Exam which includes measurement of vital signs, examination of the eyes, mouth, heart, lungs, abdomen, and skin.
   * Patients will be asked of any side effects that they may be having.

   During the Week 8 visit, patients will return to the clinic only to pick up the oral iron medicine.

   During the Week 12 visit, patients will complete the following procedures:
   * Medical history including prior hospitalizations, lab results, medications, diet, social and family history
   * Blood Samples: Patients will not have any extra blood draws (pokes) for this study as blood for research will be collected during routine blood draws. About less than half a teaspoon of extra blood will be drawn for research tests.
   * Focused Physical Exam which includes measurement of vital signs, examination of the abdomen and skin.
   * Patients will be asked of any side effects that they may be having.
2. Oral Iron Therapy and IRONCHILD:

Patients will receive liquid iron medicine by mouth once per day for 12 weeks. Patients will receive this medication during their first visit. Patients will also be given access to a website called IRONCHILD. Patients will be shown the website, including videos, at each in-clinic visit (Baseline, Week 4, and Week 12). This website was created for patients and their parent/guardian to help patients learn more about the importance of taking their oral iron therapy.

The study team will show patients how to use the website. Patients will be given a unique log-in and password with instructions on how to access the site between visits. There are 3 sessions (one per clinic visit). One session will be completed per visit, and each session should be about 15 minutes or less. Patients will also be able to access this website from home.

During the Week 4 visit, patients will compete the following procedures:

* Blood Samples: Patients will not have any extra blood draws (pokes) for this study as blood for research will be collected during routine blood draws. About less than half a teaspoon of extra blood will be drawn for research tests. All other blood draws that patients have while on study will be for routine care and not for research purposes.
* Focused Physical Exam which includes measurement of vital signs, examination of the eyes, mouth, heart, lungs, abdomen, and skin.
* Patients will be asked of any side effects that they may be having.

During the Week 8 Visit, patients will return to the clinic only to pick up their oral iron medicine.

During the Week 12 visit, patients will complete the following procedures:

* Medical history including prior hospitalizations, lab results, medications, diet, social and family history
* Blood Samples: Patients will not have any extra blood draws (pokes) for this study as blood for research will be collected during routine blood draws. About less than half a teaspoon of extra blood will be drawn for research tests. All other blood draws that patients have while on study will be for routine care and not for research purposes
* Focused Physical Exam which includes measurement of vital signs, examination of the abdomen and skin.
* Patients will be asked of any side effects that they may be having.

Arms: arm 1: Arm A is standard oral iron therapy for 3 months. arm 2: Oral iron therapy as per Arm A plus the IRONCHILD web-based intervention aimed at promoting oral iron adherence. This web-based intervention was developed specifically for caregivers of young children with nutritional iron deficiency anemia to promote oral iron adherence.
Interventions: intervention 1: Ferrous Sulfate intervention 2: IRONCHILD
Intervention descriptions: intervention 1: Patients receive ferrous sulfate 3 mg/kg elemental iron once daily in liquid formulation. intervention 2: Delivery of the intervention at each visit should take 15 minutes or less.

* Baseline visit (Session 1) content will be viewed
* At 1-month follow-up visit, additional (Session 2) content will be viewed
* At 3-month final visit, patients will view final (Session 3) content

Protocol documents:
Prot_SAP_000.pdf: 
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Oral Iron Versus Oral Iron Plus a Web-based Behavioral Intervention  
in Young Children (IRONCHILD) 
BCM IRB# H-45869 
Clinicaltrials.gov NCT 04371536 
May 27, 2020 
Principal Investigator: 
Jacquelyn M. Powers, MD, MS 
Co-Investigators: 
Amanda Grimes, MD 
Susan Kirk, PA 
Donald Mahoney, MD 
Jean Raphael, MD 
Deborah Thompson, PhD 
Statistician: 
Charles Minard, PhD 
Texas Children’s Cancer and Hematology Centers 
6701 Fannin St., Suite D.1400 
Houston, TX  77030 


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TABLE OF CONTENTS 
1. STUDY OVERVIEW………………………………………………………….......................
1.1. Title 
1.2. Trial registration 
1.3. Protocol version 
1.4. Funding 
1.5. Roles and responsibilities 
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2. INTRODUCTION……………………………………………………………………………..
2.1. Background and rationale 
2.2. Objective………………………………………………………………………………... 
2.3. Hypotheses 
2.4. Trial design 
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3. METHODS (PARTICIPANTS, INTERVENTIONS, OUTCOMES)………………………
3.1. Study setting 
3.2. Eligibility criteria 
3.3. Interventions…………………………………………………………………………… 
3.3.1. Dietary (all Arms) 
3.3.2. Arm A 
3.3.3. Arm B 
3.4. Risks..………………………………...………………………………………………... 
3.4.1. Definitions 
3.4.2. Risks: Arms A and B 
3.5. Safety / Adverse event reporting……………………………………………………. 
3.6. Benefits 
3.7. Assessment of medication adherence……………………………………………… 
3.8. Treatment failure 
3.9. Withdrawal 
3.10. Stopping rules 
3.11. Concomitant care 
3.12. Outcomes 
3.13. Participant timeline……………………………………………………………………. 
3.14. Sample size 
3.15. Recruitment 
3.16. Screening and enrollment log 
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4. METHODS (RANDOMIZATION/ASSIGNMENT OF ROLES)….………………………
4.1. Randomization 
4.2. Sequence generation 
4.3. Allocation concealment mechanism / blinding 
4.4. Implementation 
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5. METHODS: DATA COLLECTION, MANAGEMENT, & ANALYSIS…………………
5.1.   Data collection methods 
5.2.   Data management 
5.3.   Statistical methods 
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6. METHODS: MONITORING………………………………………………………………...
6.1.   Data monitoring 
6.2.   Auditing 
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7.
ETHICS AND DISSEMINATION……………………………………….………………….
7.1.   Research ethics approval 
     7.2.   Protocol amendments 
     7.3.   Consent or assent 
     7.4.   Confidentiality 
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8.  DECLARATION OF INTERESTS………………………………………………………….
8.1.   Access to data 
     8.2.   Ancillary and post-trial care 
     8.3.   Dissemination policy 
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REFERENCES……………………………………………………………………………..........
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APPENDIX………………………………………………………………………………………..
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1. STUDY OVERVIEW 
1.1. TITLE: A single-center, open-label, randomized feasibility trial of standard oral iron therapy 
versus oral iron plus a web-based behavioral intervention in young children with nutritional iron 
deficiency anemia 
1.2. TRIAL REGISTRATION: Clinicaltrials.gov No. NCT04371536 
1.3. PROTOCOL VERSION 
Issue date: May, 27, 2020 
Protocol Version number: 2 
1.4. FUNDING: NHLBI K23 HL132001 
1.5. ROLES AND RESPONSIBILITIES:  
Principal Investigator: 
Jacquelyn Powers, MD, MS 
Biostatistician: 
Charles Minard, PhD 
Co-Investigators: 
Amanda Grimes, MD, Co-Investigator 
Susan Kirk, PA, Co-Investigator 
Donald Mahoney, MD, Co-Investigator 
Jean Raphael, MD, Co-Investigator 
Deborah Thompson, PhD, Co-Investigator 
All co-investigators contributed to refinement of the study protocol and will approve the final 
manuscript. 
2. INTRODUCTION 
2.1. BACKGROUND AND RATIONALE
Iron deficiency anemia (IDA) is a major health problem, affecting 2 billion persons worldwide including 
nearly half a million young children in the U.S. For young children in the US, the primary etiology is 
nutritional, often resulting from excessive cow milk intake and limited iron rich foods in the diet. Peak 
incidence is 1 to 4 years of age, a period of rapid and critical neurodevelopment. Children from low 
socioeconomic status homes are disproportionately affected by IDA. Low-income children who are at 
risk for food insecurity as well as underserved racial/ethnic minority groups, specifically Latinos, have 
higher rates of iron deficiency and IDA.  
IDA is associated with inferior neurodevelopmental outcomes, poorer executive functioning, and 
decreased visual and auditory processing time. The World Health Organization evaluated key studies 
examining the association of IDA with neurocognitive outcome and estimated that a decrement in 
hemoglobin of 1 g/dL due to iron deficiency results in approximately 1.73 IQ points lost. More severe 
and chronic IDA is associated with worse outcomes, and therefore incomplete therapy prolongs the 
extent and severity of such consequences. The cumulative effect, especially on children from socially 
disadvantaged groups disproportionately affected by IDA, is yet another setback that contributes to 
suboptimal outcomes in quality of life, educational achievement, and overall contribution to society. 
Successful treatment of nutritional IDA will directly address the US Department of Health and Human 
Services’ Healthy People 2020 objective of reducing iron deficiency among young children. Yet, 
research on therapeutic approaches that directly address a key health condition within this group is 
lacking. Standard therapy is oral iron therapy for a minimum of 3 months. Yet, non-adherence often 


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results in treatment failure, prolonging the negative consequences of IDA. Its unpleasant effects, 
including abdominal discomfort, nausea, constipation, and bad taste often result in medication refusal. 
Poor understanding by caregivers of its long-term impact, lack of motivating factors to promote 
adherence, and the need for a prolonged treatment course also contribute to non-adherence.  
We propose that an alternative approach to standard oral iron therapy exists. This alternative 
approach is an intervention that promotes oral iron adherence by increasing caregiver motivation. 
Previous successful pediatric adherence interventions include educational and behavioral 
components with or without a technology-based component. The majority target caregivers of older 
children with chronic medical conditions that require long-term therapy. We conducted formative 
research with caregivers of children with nutritional IDA to characterize barriers and facilitators to 
adherence. Utilizing that data, we developed a self-determination theory-based web intervention, 
IRONCHILD, to increase parental motivation to adhere to oral iron therapy. 
Well-designed randomized trials that compare different IDA treatment approaches in young children 
are sorely needed and would result in significant benefit to short-term clinical and long-term 
developmental outcomes. However, it is unknown whether families of young children with IDA are 
willing to be randomized to this different treatment approach (standard delivery of oral iron and oral 
iron with a web-based adherence intervention). The results of this feasibility study will assess the 
ability to successfully conduct such important comparative RCTs.  
2.2. OBJECTIVE
To determine the feasibility of conducting a randomized controlled trial comparing standard care oral 
iron to oral iron with a web-based intervention in young children with nutritional IDA. 
2.3. Hypotheses: 
 
Enrollment will be feasible (>50% enrollment of eligible patients). 
 
The interventions will be viewed as acceptable.  
o Subjects will be willing to receive the treatment intervention as assigned (>80% 
agreement with randomization per Arm). 
o The IRONCHILD (Arm B) intervention will be viewed as acceptable (>70% retention 
per Arm). 
2.4. TRIAL DESIGN 
This study is a randomized, open-label single center, two-arm feasibility trial to evaluate the feasibility 
of randomizing young children with nutritional iron deficiency anemia to (a) usual care with oral or (b) 
oral iron with a web-based behavioral intervention.  
Arm A: Usual Care Oral 
Iron Regimen 
Arm B: Optimized Oral Iron 
Regimen with Web-based 
Behavioral Intervention 
Post-Intervention 
Assessment 
Randomization 
Enrollment 
N = 20
Visits (All Arms): 
Initial, 1 mo & 3 mo
Feasibility study to assess acceptability of oral vs adherence intervention
Outcomes:

Feasibility

Acceptability

Adherence

Clinical
1:1


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This pilot trial of 20 subjects will test the (1) feasibility of randomization to oral versus oral iron with a 
behavioral intervention, (2) acceptability of the optimized adherence intervention versus standard 
delivery of oral iron, (3) oral iron adherence rates in arms A and B, and (4) clinical efficacy in all arms 
as measured by change in hemoglobin concentration at 1- and 3-month clinic visits. 
3. METHODS: PARTICIPANTS, INTERVENTIONS, AND OUTCOMES 
3.1. STUDY SETTING 
 
This study will be conducted at a single academic hospital. Subjects will be evaluated in the 
Texas Children’s Cancer and Hematology Center. 
3.2. ELIGIBILITY CRITERIA
INCLUSION CRITERIA 
RATIONALE 
1.  Age ≥ 12 months to < 48 months  
Nutritional iron deficiency rarely seen at other 
ages 
2.  IDA confirmed by hematologic indices and 
iron laboratory parameters1* 
 
Hgb between >6 g/dL AND <10 g/dL  
 
MCV <70 fl 
 
Ferritin <15 ng/mL OR TIBC >425 g/dL
Iron deficiency without anemia but depleted 
iron stores is extremely common, but only 
children with frank, moderate anemia will be 
enrolled. This will allow for conclusive 
assessment of treatment efficacy in patients 
in whom outpatient oral iron therapy is 
considered safe (i.e. pRBC transfusion is not 
indicated for severe anemia). 
3.  Clinical history consistent with nutritional IDA 
such as prolonged breastfeeding without 
adequate iron supplementation or excessive 
milk intake (cow milk, almond milk, soy milk, 
goat milk or other milk, excluding breastmilk), 
defined as >3 cups (24 ounces)/day 
Low iron diet is the most common etiology of 
IDA in this age group.  
4.  Primary language of English or Spanish 
Behavioral Intervention (IRONCHILD, Arm B) 
available in English or Spanish 
5. Access to a smartphone with data plan and/or 
other internet access (i.e. home computer) 
Randomization to Arm B would require 
internet access to view content from home 
*CBC indices must be performed with 7 days of study enrollment. Iron indices must be performed within 30 
days of study enrollment.
EXCLUSION CRITERIA
RATIONALE 
1.  Iron deficiency likely or definitely due to blood 
loss from the intestine or other sites.  
Ongoing gastrointestinal or other blood loss 
would confound the effects of oral iron 
treatment. 


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2.  Administration of a blood transfusion 
The goal of this study is to enroll with IDA 
who are clinically stable that may be 
managed in an outpatient setting.  
3.  History or evidence of intestinal malabsorption
Oral iron cannot be expected to be effective 
in malabsorption states 
4.  History of prior intravenous iron therapy
Effects of intravenous iron would confound 
treatment responses
5.  Major co-morbidity such as a serious chronic 
medical condition unrelated to iron deficiency 
apparent on history, physical examination, or 
laboratory tests 
Other medical conditions may result in 
malabsorption, bleeding, renal disease, 
inflammation or other confounders that would 
affect observed changes in the primary 
outcome independent of the intervention
6.  Other cause of anemia (sickle cell disease, 
thalassemia, bone marrow failure, etc.) 
apparent by history, physical examination, 
and/or laboratory tests. 
Children with anemia due to other causes 
would not be expected to respond to iron
7.  Inability to tolerate oral medications 
Some children with feeding or swallowing 
disorders, severe neurological problems 
and/or inability to easily take liquids are 
unsuitable candidates 
8.  Other medical or social factors at discretion of 
treating physician 
Unforeseen circumstances that will 
undermine the ability to determine the relative 
efficacy of the two study medications 
3.3. INTERVENTIONS 
3.3.1. Dietary recommendations 
 
Both arms will receive the same dietary counseling: limitation of cow milk to <16 ounces/day 
and information sheet on iron-rich foods.  
3.3.2. Arm A: Usual care oral iron regimen  

Oral iron therapy: All subjects receiving oral iron therapy will receive ferrous sulfate 3 mg/kg 
elemental iron once daily in liquid formulation.  
o This dose is chosen because it is within the standard recommended dosing range2,3, 
has demonstrated efficacy in previous IDA studies4,5, and is recommended by the 
Centers for Disease Control as a simplified treatment dosing regimen with the goal of 
improved adherence rates.6
o Further, it has demonstrated efficacy in a RCT of 80 children with nutritional IDA.7
o Families will be instructed not to give the iron with milk as it will limit iron absorption. 
3.3.3. Arm B: Optimized oral iron regimen with adherence intervention (IRONCHILD) 

Oral iron therapy as per Arm A 

IRONCHILD web-based intervention aimed at promoting oral iron adherence. This web-
based intervention was developed specifically for caregivers of young children with nutritional 
IDA to promote oral iron adherence (Appendix).  


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o Information will be delivered in the clinic setting via a tablet device concurrent with 
clinical visits. Incorporating the intervention at standard visits will test the ability of the 
intervention to effect change in a real-world setting. 
o Caregivers will be provided tablet computer in clinic and oriented to website 
o Caregivers will be given a unique log-in and password with instructions on how to 
access the site between visits  
o Delivery of the intervention at each visit should take 15 minutes or less.  
 
Baseline visit (Session 1) content will be viewed  
 
At 1-month follow-up visit, additional (Session 2) content will be viewed 
 
At 3-month final visit, subjects will view final (Session 3) content 
3.4. ADVERSE EVENT REPORTING AND RISKS 
3.4.1. Definitions: Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment. An AE is therefore any unfavorable and unintended sig 
(including an abnormal laboratory finding), symptom or disease temporally associated with the 
administration of an investigational product, whether or not related to that investigational 
product. 
 
An unexpected AE is one of a type not identified in nature, severity, or frequency in the current 
Drug Label or of greater severity or frequency than expected based on the information in the 
Drug Label. 
 
Information regarding occurrence of AEs will be captured throughout the study. The collection 
period for all AEs will begin after informed consent is obtained and end after procedures for 
the final study visit have been completed, or thirty days after the subject takes the last dose of 
study drug, whichever is later. 
 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during 
each subject visit and record the information in the site’s source documents. AEs will be 
recorded in the patient CRF and will be described by duration (start and stop dates and times), 
severity, outcome, treatment and relation to study drug, or if unrelated, the cause. Abnormal 
laboratory values or test results occurring after informed consent constitute AEs only if they 
induce clinical signs or symptoms, are considered clinically significant, require therapy (e.g., 
hematologic abnormality that requires transfusion or other support), or require changes in 
study medication(s). 
 
AEs that begin or worsen after first dose of study drug should be recorded in the AE CRF. AE 
monitoring should be continued until the date of the last dose of study treatment. 
 
Once an AE is detected, it must be followed until its resolution or until judged to be permanent, 
and an assessment must be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
 
If an AE occurs more than once in a course of therapy, only the most severe grade of the 
event is reported. If an AE progresses through several grades during the course of therapy, 
only the most severe grade is reported.  
 
For reporting purposes, the duration of the AE should be the duration of the highest (most 
severe) grade of the toxicity. The resolution date of the AE is defined as the date at which the 
AE returns to baseline (note that the resolution date may therefore be different from the date at 


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which the grade of the AE decreased from its highest grade). If the AE does not return to 
baseline the resolution date is recorded as “ongoing”. Dates used in AE reporting for 
laboratory test abnormalities should be the date the sample was collected (not the date the 
sample was processed or the date the results were reported).  
 
The completed CRF summarizing the non-serious AE should be reviewed and signed by the 
PI or their designee. 
AE Severity Grading 
Severity (Toxicity Grade)
Description
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of 
the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as 
it occurred. This does not refer to an experience that 
hypothetically might have caused death if it were more severe. 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines. 
Relationship
to Drug
Comment
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that is not explained by any 
other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the subject’s 
clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to that 
suspected drug; but that could readily have been produced by a number of 
other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study drug. 
Serious Adverse Events (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 

death 


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
a life-threatening adverse experience 

inpatient hospitalization or prolongation of existing hospitalization++

a persistent or significant disability/incapacity 

a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
Unanticipated Problem Involving Risk to Subjects or Others (UPIRSO)  
An UPIRSO is defined as incident, experience or outcome that is unexpected (in terms of the 
nature, severity or frequency) given  
(a) the description of the likely harms in the protocol, the consent form or the other materials 
submitted to the IRB and  
(b) the characteristics of the subject population; related to a subject's participation in the 
research; and suggests that the research places subjects or  others at greater risk of harm - 
physical, psychological, economic or social harms - than was previously known or recognized. 
In accordance with the standard operating procedures and policies of the local Institutional Review 
Board (IRB) the site investigator will report SAEs/UPIRSOs to the IRB and regulatory agencies as 
required.   
3.4.2. RISKS: ARMS A and B  
 
All enrolled subjects will be treated with an oral iron preparation in the standard dose. Oral iron 
medications, labelled as “supplements’ by the FDA, are approved for this purpose, and when 
used appropriately, are without significant risks. The AEs of special interest and SAEs that will 
be captured are listed below.
 
AEs of special interest (assessed at Weeks 4 and 12):
o Staining of teeth
o Constipation
o Nausea
o Vomiting
o Abdominal Pain
o Diarrhea
 
SAE:  
o Accidental ingestion of a large amount of an oral iron preparation by the patient may 
result in acute iron poisoning which can manifest as severe diarrhea, acidosis, shock, 
and death. Iron ingestion is one of the most common causes of accidental drug related 
death in children. Therefore, study medications will be administered in a child-proof 
container, and parents will be given strict instructions to keep the study medicine in a 
safe location out of the child’s reach. 
o Study subjects will be asked to report accidental ingestion immediately to the study 
team but will be specifically asked about this complication at the Weeks 4 and 12.
3.5. SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS
 
See definitions of AEs and SAEs in section 3.4. 


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 
This protocol has a category 1 risk, research involving minimal risk with the prospect of direct 
benefit to the individual subjects. Monitoring and reporting of adverse events will comply with 
the BCM Institutional Review Board requirements.  
 
AE capture (Study database) 
o All AEs of special interest described in section 3.4, will be captured. 
o All SAEs will be captured (expected and unexpected). 
o Other expected childhood ailments, unrelated to the study treatment, including but not 
limited to upper respiratory infections and other non-specific viral infections, asthma, 
ear infections and environmental allergies may occur, unrelated to study, and will not 
be captured. 
o All captured AEs will be scored utilizing criteria listed in the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5, and will be included in the visit data 
collection.  
 
The PI will provide a Continuing Review Report to the Baylor College of Medicine IRB at least 
annually.  
 
In addition, all SAEs and any unanticipated problems involving risk to subjects or others 
(UPIRSOs) that meet reporting criteria as defined by the BCM IRB will be submitted to the 
BCM IRB per their policy.  
 
All safety data collected on study participants will be reviewed by the Texas Children’s Cancer 
and Hematology Centers Data Review Committee.  
AEs of special interest and SAEs will be captured from start of treatment to Week 12 unless otherwise 
indicated above. 
3.6. BENEFITS 
Study subjects may discontinue their participation at any time. However, information regarding the 
benefits to continued iron therapy, with or without additional interventions, will be made explicitly clear 
prior to their discontinuation. 
 
Whichever Arm the subject is randomized to, he or she will be receiving therapeutic iron, 
regular structured follow-up, and careful monitoring of hematologic parameters consistent with 
standard of care.  
 
Successful treatment of the subjects’ iron deficiency is expected to improve their overall 
wellbeing, energy level and color, and possibly correct or mitigate any impaired cognitive and 
behavioral outcomes resulting from iron deficiency.  
 
Alternative care will be offered to the subjects, which might include less or longer follow-up 
and fewer laboratory studies.  
 
Every effort will be made to retain study subjects in the trial for the entire 12 weeks to enable 
complete follow-up data collection. 
3.7. ASSESSMENTS OF MEDICATION ADHERENCE 
 
Study visit attendance (All Arms)
 
Volume of unused medication returned at each visit (All Arms )


12
3.8. TREATMENT FAILURE 
 
At the 4 week visit, a lack of response in hemoglobin concentration (Hgb rise <1 gm/dL) will be 
addressed with increased emphasis on adherence and dietary recommendations.
3.9. WITHDRAWAL/TERMINATION 
 
Subjects that ‘No Show’ for 4 or 12-week visits and are unable to be contacted/rescheduled. 
Data already collected will be used in the analysis.
 
Alternative diagnosis discovered
 
In the investigator’s medical opinion, it is best to withdraw the subject from the protocol
3.10. STOPPING RULES 
 
If more than one subject has the serious AE of iron poisoning (Arms A or B), the study will be 
suspended while an assessment of the child-proof containers and safety is performed. 
 
The study will be discontinued if one of the products is recalled by the manufacturer or Food 
and Drug Administration (FDA).
3.11. CONCOMITANT CARE 
 
Follow-up visits occur at 1- and 3-months but may occur more frequently depending on the 
severity of the anemia.   
 
Patients are ineligible for study if they have received a pRBC transfusion prior to enrollment. 
Enrolled subjects whose clinical course worsen and in whom a hematologist elects to treat 
with pRBC transfusion will be taken off study.  
 
Subjects enrolled on Arms A and B may not receive IV iron therapy during the 12 week study.  
 
Subjects who continue to have iron deficiency or IDA upon study completion will receive 
treatment at discretion of their attending hematologist. 
3.12. OUTCOMES 
The primary endpoints for this study are the feasibility outcomes.  

Primary: Enrollment 

Secondary 
o Agreement with randomization (willingness to receive the treatment arm assigned) 
o Retention (visit follow-up attendance) 
Data on the following outcomes will also be collected to inform future clinical trial design.  

Oral iron adherence 
o Returned medication volume  

Clinical 
o Change in hemoglobin concentration at the 1 month visit  
o Resolution of IDA at the 3 month clinic visit, defined as:  
 
Hgb >11 g/dL, MCV >70 fl, ferritin >15 ng/mL, and TIBC <425 g/dL.   

Adverse events (All Arms, see section 3.4 and 3.5) 


13
3.13. PARTICIPANT TIMELINE 
#Week 4 and 12 visit windows are ±3 days of treatment initiation date.  
*Laboratory studies (SOC) include: CBC, Retic, Iron Panel 
&Research laboratory studies: serum hepcidin (0.5-1 mL) to be drawn at the same time of SOC laboratory studies (All Arms) 
Serum hepcidin will be collected to characterize changes in iron laboratory parameters in patients with IDA enrolled on this 
study that are not routinely performed as standard of care. Week 4 and 12 research labs will include: serum iron, ferritin, 
transferrin, total iron binding capacity. 
**Medical history: prior hospitalizations, laboratory results, medications, dietary and review of systems; social and family 
history. 
+Physical exam: Comprehensive PE consists of vital signs, general, HEENT, cardio-respiratory, abdominal, extremities and 
skin; Focused PE consists of vital signs, general, cardio-respiratory, abdominal and skin 
3.14. SAMPLE SIZE 
The sample size of 20 patients is determined primarily by consideration of feasibility.  We expect that 
this study will provide compelling preliminary data to demonstrate the ability to conduct a fully 
powered randomized clinical trial. Collecting data on clinical response will allow us to estimate 
standard deviation for the design of future studies.  Suppose the true standard deviation of 
hemoglobin change is 1.7, a sample size of 20 patients allows us to estimate the standard deviation 
with a margin of error <±0.47.
3.15. RECRUITMENT 
Information regarding the trial will be available at clinicaltrials.gov. The PI will inform all hematology 
providers of the study and eligibility criteria prior to study implementation. Information about the 
clinical trial will be provided via direct communication by the PI and co-investigators with physicians at 
Texas Children’s Hospital including Emergency Department (ED) physicians, hospitalists, house staff 
and community practice providers.  
Potential subjects will be identified through review of new patient referrals to Texas Children’s 
Hospital Cancer and Hematology Center, inpatient admissions and/or consultations for iron deficiency 
anemia. The outpatient hematology clinic schedule will be pre-screened daily by the data manager, 
who will notify the PI of potential patients. The PI will assess eligibility and notify the primary 
hematology provider about those subjects who are potentially eligible. After confirmation of eligibility, 
the PI or a Co-I will describe the study to eligible patients’ families. If interested, informed consent will 
be obtained and the subject enrolled. Parents must provide written, informed consent before any 
study procedures occur. 
STUDY VISITS
STUDY PROCEDURES
Wk 0 (Baseline) 
#Wk 4 
$Wk 8 
#Wk 12 
Eligibility screening 
x 
Consent/Enrollment 
x 
Randomization 
x 
*Laboratory Studies, 
standard of care (SOC) 
x 
x 
x 
&Laboratory Studies 
(Research) 
x 
x 
x 
**Comprehensive History 
x 
x 
+Comprehensive Exam 
x 
+Focused Physical Exam  
x 
x 
Iron Medication 
x  
x  
x  
AE Review 
x  
x  


14
All research related costs, including drug, will be covered by the study. In addition, each subject will 
receive financial compensation for participation. Payment will be made at completion of the study 
visits at week 4 ($50), and 12 ($50) based on attendance for a total of $100 in compensation.   
Expected recruitment rate will be 1-2 participants per week. Duration of recruitment period is expected 
to be approximately 6 to 9 months. Assessment of study recruitment and retention will be performed 
when 5 participants have been enrolled on the study, or at approximately 2 months. 
3.16. SCREENING AND ENROLLMENT LOG 
A secure study screening and enrollment log will be kept for IRONCHILD. Each screened patient will 
be categorized as either: ineligible, eligible but not approached, eligible and enrolled, eligible and 
declined. If the latter (eligible and declined), the reason for declining will also be obtained and noted in 
the study log. Information on all enrolled subjects will include: date of consent, date of randomization, 
agreement with randomization (yes/no), and follow-up visits within study windows (scheduled and 
actual). After the 12 week study period, subjects will be noted to have either completed all visits, 
removed from the study, or to have been lost-to-follow-up. For any subjects who do not complete the 
study, the time point at which they were removed or lost-to-follow-up will also be noted.   
4. METHODS: RANDOMIZATION / ASSIGNMENT OF INTERVENTIONS  
4.1. RANDOMIZATION 
 
Subjects will be randomly assigned to one of two groups with a 1:1 allocation by a utilizing a 
randomization generator program.  
4.2. SEQUENCE GENERATION 
 
Participants will be randomly assigned to an experimental arm with a 1:1 allocation by a 
computer generated randomization schedule using permuted blocks of 2 and 4. 
4.3. ALLOCATION CONCEALMENT MECHANISM / BLINDING  
 
Not applicable - this is an open-label study 
4.4. IMPLEMENTATION 
 
An investigational pharmacist will perform the sequence generation. Trial investigators will 
perform enrollment and implementation of study group assignments and will not be involved in 
the allocation process.  
5. METHODS: DATA COLLECTION, MANAGEMENT, & ANALYSIS 
5.1. DATA COLLECTION METHODS  
Clinical information for all patients will be collected from each patient’s electronic medical record at all 
visits while on study on electronic Case Report Forms (eCRF). This information will include the 
following: name, gender, race, ethnicity, primary language spoken in the home, socioeconomic status 
(annual income and number of persons living in the home), number of caregivers in home, date of 
birth, current medications, medical history, physical exam, and laboratory results.  
Data specific to subjects randomized to Arm B (web intervention) will also be automatically collected 
and stored as participants navigate the website. The database and website will be hosted on a 
secure, password protected website, and the database will be further protected by a password set by 
the study team. Parents will be assigned a unique password by the study team, and this password will 
be used to login to the secure website. Rather than their actual name, the data collected as a family 
navigates the website (e.g., logins, goals, etc.) will be stored in the database by a unique identifier 
accessible only to the study team.  


15
5.2. DATA MANAGEMENT  
The eCRF will be housed in Texas Children’s Hospital REDCap. REDCap is a self-managed, secure, 
web-based data support system. The data is backed up offsite nightly and hosted in a secure 
environment maintained by Information Resources. This password protected study database will 
include a subject’s personal identifiers and all Protected Health Information (PHI) such as medical 
history. All personnel who will be accessing the data will be trained in REDCap and have individual 
user ID and passwords. Subjects will have a study ID number that will be utilized in lieu of personally 
identifiable information for all research data provided to statisticians.  
5.3. STATISTICAL METHODS 
All planned analyses are descriptive in nature.  Summary statistics such as mean, standard deviation, 
and 95% confidence intervals will be reported.  No formal hypothesis testing will be performed.
6. METHODS: MONITORING 
6.1. DATA MONITORING 
All health information collected by which subjects can be identified will be coded for research 
purposes. Each participant will be assigned a unique study identification number. Directly identifying 
information will not be kept with the data. All research results will be presented/published in a manner 
which ensures that no individual can be identified. 
All paper records will be stored in a locked cabinet behind a locked door in a co-investigator’s office at 
Texas Children’s Hospital. All electronic records will be secured under a password protected file on 
the TCH server in which only members of the study protocol will have access. All data will be 
maintained on a server managed and maintained by institutional IT staff.  PHI will be destroyed at the 
earliest possible opportunity and kept for no longer than 5 years after the end of the study. 
The study will be monitored by the Texas Children's Cancer and Hematology Centers (TXCH) Data 
Review Committee according to the Data Safety Monitoring Plan set forth. 
6.2. AUDITING 
Quality assurance and audits will be conducted in accordance with the TXCH clinical research quality 
assurance plan.   
7. ETHICS AND DISSEMINATION 
7.1. RESEARCH ETHICS APPROVAL 
This protocol and template informed consent forms will be reviewed and approved by Baylor College 
of Medicine IRB with respect to scientific content and compliance with applicable research and human 
subjects regulations. Subsequent to initial review and approval, the investigators will make safety and 
progress reports to the IRB at least annually and within three months of study completion. 
7.2. PROTOCOL AMENDMENTS 
Any modifications to the protocol, which impact the conduct of the study, or potential risk/benefit of the 
participants, will require a formal amendment to the protocol with IRB approval. 
7.3. CONSENT OR ASSENT 
Informed consent will be obtained after information has been provided to patients’ families along with 
a discussion of the risks and benefits along with opportunity for questions. Consent forms will be 
provided for all parents involved in the trial. Due to the young age of the patient population and short 
study participation assent will not be required. 
7.4. CONFIDENTIALITY 
Records of each patient’s participation in this study, including the original informed consent document, 
will be kept in a locked file cabinet in the Texas Children’s Cancer and Hematology Center by Clinical 


16
Research staff. Access to local research files is limited to data management personnel, study team 
members, and the Institutional Review Board. These entities may need to view data for quality 
assurance and data management purposes. Confidentiality of all medical records would be 
maintained by correct identification of the appropriate person before viewing the medical record and 
ascertaining the reason for the viewing of the medical records.  
8. DECLARATION OF INTERESTS 
Jacquelyn Powers, MD, No financial or other competing interests. 
8.1. ACCESS TO DATA 
The PI and data manager will be given direct access to the data sets. Additional study team members 
will be given access to portions of the data as needed for study analysis and manuscript preparation. 
8.2. ANCILLARY AND POST TRIAL CARE 
Participants who continue to have iron deficiency upon study completion will receive treatment at 
discretion of their provider. 
8.3. DISSEMINATION POLICY 
Every attempt will be made to reduce the interval between completion of data collection and the 
release of the study results. After completion of the trial by all participants we expect to take about 3 
to 4 months to compile the final results and submit them for presentation at a prominent society 
meeting and publication in a high profile peer reviewed journal.  


17
REFERENCES
1.
Powers JM, Buchanan GR. Disorders of Iron Metabolism: New Diagnostic and Treatment 
Approaches to Iron Deficiency. Hematology/oncology clinics of North America. Jun 
2019;33(3):393-408. 
2.
Heeney MM. Anemia. In: Rudolph AM, Lister GE, First LR, A.A. G, eds. Rudolph's Pediatrics. 
New York: McGraw-Hill; 2011. 
3.
Lerner NB, Sills R. Iron deficiency anemia. In: Kliegman RM, Stanton BF, Gemelll JW, Schor 
NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19 ed. Philadelphia: Elsevier; 
2011:1658. 
4.
Yewale VN, Dewan B. Treatment of iron deficiency anemia in children: a comparative study of 
ferrous ascorbate and colloidal iron. Indian J Pediatr. May 2013;80(5):385-390. 
5.
Zlotkin S, Arthur P, Antwi KY, Yeung G. Randomized, controlled trial of single versus 3-times-
daily ferrous sulfate drops for treatment of anemia. Pediatrics. Sep 2001;108(3):613-616. 
6.
Recommendations to Prevent and Control Iron Deficiency in the United States. Centers for 
Disease Control and Prevention;1998. 
7.
Powers JM, Buchanan GR, Adix L, Zhang S, Gao A, McCavit TL. Effect of Low-Dose Ferrous 
Sulfate vs Iron Polysaccharide Complex on Hemoglobin Concentration in Young Children With 
Nutritional Iron-Deficiency Anemia: A Randomized Clinical Trial. JAMA. Jun 13 
2017;317(22):2297-2304. 
8.
Powers JM, Shamoun M, McCavit TL, Adix L, Buchanan GR. Intravenous Ferric 
Carboxymaltose in Children with Iron Deficiency Anemia Who Respond Poorly to Oral Iron. J 
Pediatr. Jan 2017;180:212-216. 
9.
Mantadakis E, Roganovic J. Safety and efficacy of ferric carboxymaltose in children and 
adolescents with iron deficiency anemia. J Pediatr. May 2017;184:241. 
10. 
Powers JM, Shamoun MP, McCavit TL, Buchanan GR. Efficacy and safety of intravenous 
ferric carboxymaltose for children with iron deficiency anemia unresponsive to oral iron 
therapy. Pediatr Blood Cancer. Jun 2015;62 Suppl 2:S38. 
11. 
Auerbach M, Macdougall IC. Safety of intravenous iron formulations: facts and folklore. Blood 
transfusion = Trasfusione del sangue. Jul 2014;12(3):296-300. 
12. 
Wolf M, Chertow GM, Macdougall IC, Kaper R, Krop J, Strauss W. Randomized trial of 
intravenous iron-induced hypophosphatemia. JCI insight. Dec 6 2018;3(23). 
13. 
Drotar D. Strategies of adherence promotion in the management of pediatric chronic 
conditions. Journal of developmental and behavioral pediatrics : JDBP. Nov-Dec 
2013;34(9):716-729. 
14. 
Ryan RM, Deci EL. Self-determination theory and the facilitation of intrinsic motivation, social 
development, and well-being. The American psychologist. Jan 2000;55(1):68-78. 
15. 
Katz I, Madjar N, Harari A. Parental support and adolescent motivation for dieting: the Self-
Determination Theory perspective. The Journal of psychology. 2015;149(5):461-479. 


18
APPENDIX. IRONCHILD Intervention  
Development of IRONCHILD 
IRONCHILD is a theoretically-based intervention designed to be delivered via an interactive website 
(www.iron-child.com) at standard clinical visits over a three month period with an overall objective of 
improving adherence to oral iron therapy in caregivers of young children with nutritional IDA. Its 
development involved both stakeholder input and incorporation of behavioral theory. Formative 
research was conducted via a mixed-methods study of children with nutritional IDA and their primary 
caretaker, which included demographic and clinical information and semi-structured interviews with 
caregivers to characterize barriers to and facilitators of iron therapy.  
Results from the formative research, along with constructs from the self-determination theory of 
motivation (autonomy, competence, relatedness), informed message content for IRONCHILD. This 
theory was selected because the degree to which its three principle constructs (basic psychology 
needs) are met drives levels of motivation to perform a specific behavior such as medication 
adherence. Three scripted online intervention sessions were developed, professionally translated into 
Spanish, and then animated by a professional animation and web design studio. Audio recording with 
a professional bilingual voice actor provided the narration.  
Session Content (Figure) 
At the initial visit, participants are introduced to a relational agent or virtual health educator, Maria, 
who is a pediatric nurse and mother of a child formerly treated for IDA. Maria provides an introduction 
to the overall program format and content and guides each session. Participants next view a Topic 
Introduction animation that provides an overview of the diagnosis of IDA, its clinical consequences, 
and a typical treatment course with oral iron therapy. This is followed by two unique content segments 
that provide information on (1) dietary counseling and (2) administration of oral iron therapy. Following 
each segment, participants view question/response options, make a selection, and receive feedback. 
At the end of the session, participants select goal(s) related to therapy adherence for the interval 
between clinical visits.  
The second session provides two additional content segments that focus on (1) problem-solving for 
difficulties related to medication administration and (2) identifying motivating factors to adhere to 
therapy (Figure 3). The third session allows users to access all previous content and provides closing 
information about adhering to any ongoing treatment recommendations from their child’s provider. 
Between visits, access to the website occurs via a unique username and password caregivers can 
use to logon to the website and view previous sessions. All aspects of IRONCHILD are available in 
both English and Spanish. Finally, an administrative dashboard for IRONCHILD captures program 
usage information as families log onto the program and navigate the sessions (e.g., number of log-ins; 
responses to question prompts; goals set; goal attainment).


19

ICF_001.pdf: