Clinical trial NCT05007899
Conditions: Iron Deficiency Anemia Heavy Menstrual Bleeding Abnormal Uterine Bleeding
Sponsor: Baylor College of Medicine
Start date: 2020-12-21; Completion date: 2022-12-22
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Iron deficiency anemia affects over half of girls and young women with heavy periods and is the most common cause of anemia worldwide. Most girls with heavy periods who also have iron deficiency anemia are prescribed iron to take by mouth every day by their doctor. There are some studies showing that taking iron every other day may actually help the iron be absorbed into the bloodstream better. This study is trying to compare how taking iron every other day compares to taking iron daily for treatment of anemia.

The goal of this clinical research study is to learn which of the two methods of care will be the best way for girls and young women with iron deficiency anemia to take iron supplementation.

Detailed description:
The research will be conducted at the following location(s):

Baylor College of Medicine, TCH: Texas Children's Hospital, and TCH: Texas Children's Hospital Clinic.

If patient appears to qualify for the study they will sign and date this consent form, and the doctor will confirm that they are eligible for the study. The patient will complete the following procedures:

* Medical history including prior hospitalizations, lab results, medications, diet, social and family history
* Physical Examination
* Blood samples: The patient will not have any extra blood draws (pokes) for this study. However, we will ask to take about 1/2 (0.5) teaspoons (3 mL) of extra blood for an extra research test when you have follow up blood test(s) in one month.

Patient will be on the study for 24 weeks (6 months),and will receive an information sheet about how to take iron to help it absorb in the stomach and on iron-rich foods.

There are 2 different treatments in this study. If a patient enrolls, they cannot choose which treatment to receive. Instead, they will be randomly assigned to one of the two treatments. That means there is a fifty percent chance they will receive iron medicine to take every day and a fifty percent chance they will receive iron medicine to take every other day.

Arms: arm 1: Patients receive standard regimen of ferrous sulfate 325 mg (65 mg elemental iron) once every morning. arm 2: Patients receive ferrous sulfate 325 mg (65 mg elemental iron) once every other morning.
Interventions: intervention 1: Ferrous sulfate
Intervention descriptions: intervention 1: Alternate day dosing of ferrous sulfate

Protocol documents:
Prot_SAP_001.pdf: 
Protocol H-46363  
 
Administrative information 
Title 
ALTERNATE DAY VERSUS DAILY ORAL IRON THERAPY IN ADOLESCENTS WITH IRON DEFICIENCY ANEMIA 
AND HEAVY MENSTRUAL BLEEDING: A RANDOMIZED CLINICAL TRIAL  
 
Trial registration 
Pending registration at clinicaltrials.gov 
 
Protocol version 
Issue date: 4/10/2020  
Protocol version number: 1.3 
 
Funding 
Foundation for Women and Girls with Blood Disorders (FWGBD) Special Research Grant Award 
 
Protocol contributors 
Chelsea A. Kebodeaux (CAK), Principal investigator 
Oluyemisi A. Adeyemi-Fowode (OA), Co-investigator 
Jacquelyn M. Powers (JP), Co-investigator 
Lakshmi V. Srivaths (LS), Co-investigator 
Huirong Zhu (HZ), Biostatistician 
 
OA and CAK conceived of the study. CAK, OA, JP and LS initiated the study design. HZ provided statistical 
expertise in the clinical trial design and will be conducting the primary statistical analysis. All authors 
contributed to refinement of the study protocol and approved the final protocol.  
 
I.  Introduction 
IA.  
Background and rationale 
Anemia is a significant public health problem with high prevalence in both non-pregnant females (29%) 
and children (43%) [Stevens 2013]. Iron deficiency is the most significant contributing risk factor to 
anemia globally, affecting at least half of all cases [Stoltzfus 2004]. In the pediatric population, 
adolescent females are one of the populations at greatest risk for developing iron deficiency due to 
inadequate dietary iron intake and menstrual blood loss during a time of rapid growth [Wang 2013]. 
Until recently, there was little data in the literature characterizing iron deficiency and its course in 
adolescent females [Cooke 2017]. In adolescents with heavy menstrual bleeding (HMB), iron deficiency 
anemia (IDA) is a common co-morbid condition, as high as 60% in severe (defined as requiring inpatient 
stay or blood transfusion) HMB [Cooke 2017, Wang 2013, ACOG 2019]. Iron deficiency without anemia is 
also common in young women with non-severe anemia (not requiring blood transfusion), noted in 50% 
of this population in one study [Johnson 2016].  
 
Iron deficiency and HMB have been separately associated with decreased quality of life and fatigue in 
adolescents. HMB in adolescents has been independently associated with fatigue compared to healthy 
controls [Wang 2013]. Treatment of iron deficiency in non-anemic women has been shown to improve 
fatigue, especially in women with very low ferritin (<15 ng/mL) [Krayenbuehl 2011]. Iron 
supplementation has also been shown to increase quality of life and cognitive function [Murray-Kolb 
2011]. A large observational study of school children showed a correlation between iron deficiency and 


decreased math scores [Halterman 2001]. A randomized trial of oral iron therapy versus placebo in iron 
deficient adolescent girls demonstrated that those receiving iron supplementation had improved scores 
on specific cognitive function tests [Bruner 1996]. 
 
First line therapy for IDA is considered oral iron supplementation [CDC 1998, ACOG 2019]. This 
recommendation may seem straightforward; however, iron absorption from supplements is generally 
poor, and significant gastrointestinal side effects can decrease compliance, resulting in worse clinical 
outcomes [Smith 2014, Tolkien 2015]. Recently, pharmacologic studies have shown promise that 
alternate day dosing increases the fractional iron absorption per dose. After an individual dose of an iron 
supplement, an increase in hepcidin (an iron regulatory hormone) is observed and results in decreased 
subsequent iron absorption for up to 24 hours. Thus recent studies have shown promise that iron 
absorption is increased when given at 48 hour intervals compared to 24 hour intervals [Stoffel 2017, 
Stoffel 2019, Moretti 2015]. This data also suggests that less frequent iron supplementation dosing (i.e. 
with an alternate day regimen) may decrease unwanted side effects while increasing the absorption per 
dose, resulting in improved treatment compliance. A longer-term, pragmatic trial of iron 
supplementation comparing daily versus alternate day dosing has not yet been performed. 
IB.  
Objective 
i. 
Objective: To assess the feasibility of performing a randomized trial comparing standard care 
daily dosing of oral iron to alternate day dosing of oral iron in adolescent girls with iron 
deficiency anemia (IDA) and heavy menstrual bleeding (HMB). 
ii. 
Research Hypotheses:  
a. Enrollment will be feasible (>50% of patients who meet eligibility criteria will agree to 
enroll in the trial).  
b. The interventions will be acceptable (>75% study retention rate in both arms at 12 week 
follow up and >80% adherence rate in both arms). 
IC.  
Trial design 
This study is a randomized, open-label, two arm feasibility trial. The subjects will be randomized 1:1 to 
(a) daily dosing of oral iron or (b) alternate day dosing of oral iron. The pilot trial of 40 subjects will test 
the (1) feasibility of randomization of daily versus alternate day oral ion, (2) acceptability of alternate 
day oral iron versus standard daily oral iron dosing, (3) oral iron adherence rates in both arms, and (4) 
clinical efficacy of both arms as measured by change in hemoglobin concentration at 1-, 3- and 6-month 
clinic visits.  
 
 
 
Enrollment 
N = 40
Randomization
1:1
Daily Oral 
Iron 
Alternate 
Day Oral Iron
Post-
intervention 
Assessment
Visits (all arms): 
Initial, 1, 3, & 6 mo 
Outcomes:  
 Feasibility 
 Acceptability 
 Adherence 
 Efficacy 
Feasibility trial of daily vs alternate day oral iron in adolescents with IDA and HMB 


II.  Methods 
IIA.  
Study setting  
The study will be conducted at Texas Children’s Hospital in Houston, Texas, United States of America. 
The study will be conducted in pediatric gynecology inpatient service and outpatient clinic settings.  
 
IIB.  
Eligibility criteria 
Patients (or their parent/legal guardian) must provide written, informed consent before any study 
procedures occur. Patients under age 18 must also provide verbal assent which will be recorded by the 
parent in the presence of study personnel.  
 
IIC.  
Inclusion Criteria 
Patients eligible for the trial must meet all of the following criteria at enrollment: 
 
Criteria 
Rationale 
Age 9 years or greater and less than age 22 years 
 
Age group most affected by HMB and severe 
anemia 
Heavy menstrual bleeding, defined as a Pictorial 
Blood Assessment Chart (PBAC) Score >100 (see 
“PBAC” attachment) 
Used in many studies as a standard definition of 
HMB, and has been studied for use in 
adolescents. 
Iron deficiency anemia, defined as: 
 
Hemoglobin <12 g/dL AND 
 
Ferritin <15 ng/mL 
Hemoglobin <12 is the definition of anemia in 
teenage girls and women. Severely low ferritin is 
defined as <15 in many studies and patients in 
this category are most in need of iron therapy. 
 
IID.  
Exclusion Criteria 
Patients will be excluded from enrollment in the study if they have any of the following:  
 
Criteria 
Rationale 
Non-uterine cause of vaginal bleeding 
Outside the scope 
Pregnancy 
Protected population, different physiology 
Chronic kidney disease 
Multifactorial etiology for IDA, difficult to treat 
with oral iron alone 
Gastrointestinal (GI) disease, defined as: 
 
Serology confirmed celiac disease 
 
Active GI blood loss (gross blood, 
hemoccult positive stool) 
Increased risk of additional causes of anemia 
Active malignancy 
May cause increased risk of bleeding 
Inability to follow-up at TCH 
 
Receipt of intravenous iron  within 30 days prior 
to enrollment 
Expect IDA resolution to occur 
Known inability to tolerate oral iron or allergy to 
oral iron 
 
 
IIE.  
Interventions 
i. 
Oral iron therapy 


a. At enrollment, patients will be randomized 1:1 between daily versus alternate day 
dosing of ferrous sulfate 325 mg tablet (65 mg elemental iron). Randomization will occur 
as described in section IIIFi. 
i. Arm A: ferrous sulfate 65 mg elemental iron once every morning 
ii. Arm B: ferrous sulfate 65 mg elemental iron once every other morning 
b. Subjects in both arms will receive an informational handout on how to properly take 
iron for maximal absorption every 24 or every 48 hours depending on the arm. (Please 
see attachments “Patient Iron Info Alternate Day” and “Patient Iron Info Daily”). 
c. All subjects will receive a 28 day pill box at enrollment. Subjects in Arm A will receive 
100 iron tablets and subjects in Arm B will receive 50 tablets for first 12 weeks of 
therapy.  
d. At the end of 12 weeks of oral iron therapy, those subjects with resolution of IDA will be 
instructed to discontinue iron therapy. Those subjects who have partial or incomplete 
resolution of IDA will receive next 100 tabs (Arm A) or 50 tabs (Arm B) for continuation 
of study treatment for an additional 12 weeks.  
ii. 
Laboratory follow up 
a. All subjects will have the following labs obtained as part of the study: 
i. CBC without differential obtained at 4, 12 and 24 weeks (standard of care) 
ii. Iron panel at 12 and 24 weeks (standard of care) 
iii. Iron panel at 4 weeks (study purposes, will be obtained with standard of care 
blood draw and require 0.5-1mL of additional blood drawn)  
iii. 
Clinical assessment  
a. All subjects will complete the following procedures at enrollment, 4, 12 and 24 weeks: 
i. Menstrual bleeding: Pictorial blood assessment chart (PBAC) will be filled out 
and score calculated at enrollment and each subsequent visit (see attachment 
“PBAC”) [Sanchez 2012, El-Nashar 2015] 
ii. Gastrointestinal side effects: Participants will be asked a standardized set of 
questions regarding common side effects of iron therapy (see attachment “GI 
side effects”) [Pereira 2014]  
iii. Fatigue assessment: NIH PROMIS Pediatric Fatigue – Short Form 10a will be 
used to assess fatigue at enrollment and each subsequent visit (see attachment 
“PROMIS Pediatric Fatigue 10a”)  
b. All subjects will complete the following procedures at 4, 12 and 24 weeks: 
i. Adherence: patients will be asked to bring any remaining pills to the visit and 
these will be counted as a direct measure of adherence.  
iv. 
Concomitant care 
a. Subjects will be instructed that they should not take a multivitamin containing iron 
during the study. Otherwise, there will be no limitation on concomitant hormonal 
therapy, antifibrinolytic therapy, or other treatment of HMB.  
b. There will be a prohibition of IV iron administration. Any receipt of IV iron prior to 12 
week follow up would lead to withdrawal from the study.  
c. Patients who develop severe anemia requiring pRBC transfusion >7 days after 
enrollment and prior to 12 week follow up will be removed from the study. 
d. Other hematologic treatments (i.e. Amicar, Lysteda) will not be directed by or have an 
effect on the study protocol but will be recorded as part of the study. 
e. Hormonal therapies (i.e. IV estrogen, combined contraceptive pills, levonorgestrel 
intrauterine device, etc.) will not be limited but will be recorded as part of the study. 


f. Additional imaging and laboratory studies (pelvic ultrasound, bleeding disorder work up) 
will not be directed by the study protocol but will be recorded as part of the study. 
 
TIMELINE 
Study procedures 
Baseline 
Week 4 
(+/- 3 days) 
Week 12 
(+/- 1 week) 
Week 24 
(+/- 1 week) 
Screening 
X 
 
 
 
Consent/Enrollment 
X 
 
 
 
Randomization 
X 
 
 
 
Clinical visit 
X 
X 
X 
X 
*Laboratory studies 
X 
X 
X 
X 
Medication dispense 
X 
 
X 
 
Adverse effects review 
 
X 
X 
X 
Questionnaires (PBAC, fatigue) 
X 
X 
X 
X 
Adherence assessment  
 
X 
X 
X 
*Laboratory studies at each visit include: CBC without differential and iron panel 
 
III. Outcomes 
IIIA.  
Primary outcome measures 
The primary outcome will be the percentage of eligible patients enrolled. 
 
IIIB.  
Secondary outcome measures 
i. 
The following outcomes will be assessed for the pilot study: 
a. Agreement with randomization (willingness to receive treatment arm assigned) 
b. Retention (visit follow-up adherence) 
c. Adherence (rate of adherence to medication at 12 weeks in both arms based on 
returned medication volume) 
ii. 
The following laboratory and clinical data will be collected to inform future clinical trial design 
(i.e. estimates of variability). 
a. CBC, iron studies at 4, 12 and 24 week follow up 
b. Additional laboratory data collected on the patient at enrollment 
c. PBAC score 
d. Fatigue score 
e. Gastrointestinal side effects 
f. Demographic information at enrollment 
g. Gynecologic medical and/or surgical treatment 
h. Hematologic treatment 
i. 
Adverse events 
 
IIIC.  
Sample size 
We plan to enroll 40 patients in this feasibility study. This sample size was calculated based on 
hypothesized feasibility of enrollment and data on patient population of the pediatric gynecology 
service.  On average from July to December 2019, 2-4 patients were admitted to the gynecology 
inpatient service and 5-10 patients who present to the gynecology outpatient service per month who 
would meet criteria for enrollment in the study. At minimum, this would mean 84 patients would 
present over 12 months (7 per month) who would meet eligibility criteria. With an anticipated study 


enrollment rate of 50% of eligible patients, it will be reasonable to enroll 40 patients over a 12 month 
period.  
 
IIIE.  
Recruitment 
i. 
The PI will inform all gynecology providers of the study and eligibility criteria prior to study 
implementation. Two of the PIs are included in a total of ten gynecology providers who practice 
at the Texas Children’s Hospital Main campus (including 4 attendings, 2 nurse practitioners and 
4 fellow physicians). Information about the clinical trial will be provided via direct 
communication by the PI and co-investigators with these practitioners at Texas Children’s 
Hospital. 
ii. 
Potential subjects will be identified through review of new patient referrals to Texas Children’s 
Pediatric and Adolescent Gynecology Division, inpatient admissions and/or consultations for 
HMB. The PI has access to these patient’s clinical data as part of routine clinical care and shared 
patient lists. The outpatient gynecology 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 
gynecology provider about those subjects who are potentially eligible. The PI or a Co-I will 
describe the study to eligible patients and their parent/guardian (if less than 18). The voluntary 
nature of the study will be emphasized. 
a. If interested in enrollment and meets eligibility criteria, then informed consent will be 
obtained and the subject enrolled. Patients or parents must provide written, informed 
consent before any study procedures occur.  
b. If interested but laboratory evaluation not yet obtained and eligibility unable to be 
determined at the time of the visit, the PI or a Co-I will obtain a phone number and 
permission to contact the patient/patient’s parent for follow up if eligible. If the patient 
then meets eligibility criteria and has given permission to be contacted, the data 
manager will call the patient or her parent to schedule a research only visit within 1 
week. At this visit, informed consent will be obtained. Patients or parents must provide 
written, informed consent before any study procedures occur.  
iii. 
Screening and enrollment log 
a. A secure screening and enrollment log will be kept. 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. 
 
IIIF.  
Allocation 
i. 
Sequence generation and concealment: Participants will be randomly assigned to either the 
control (daily) or intervention (alternate day) group with a 1:1 allocation per a computer-
generated randomization schedule stratified by initial (or post-transfusion if transfusion is given) 
hemoglobin (less than or equal to 8 g/dL vs greater than 8 g/dL). 
ii. 
Implementation: The study personnel enrolling the participant will enter the participant’s study 
ID number and enrollment hemoglobin (initial or post-transfusion) into REDCap software 
programmed for allocation and the software will then assign the subject to an intervention 
group. The study personnel will then provide information regarding the intervention to the 
participant, who will not be blinded to the intervention.  
iii. 
Blinding: Due to the nature of the intervention, blinding of participants or staff is not feasible. 
Every attempt will be made, in the study literature and in training of personnel, to avoid bias of 
participants related to expected outcomes especially as related to adverse effects. An employee 
outside the research team will have information regarding the allocated group assignment in a 


separate data sheet so the researchers and statistician can analyze data without having access 
to information regarding the allocation.  
 
IIIG.  
Data 
i. 
Collection: Data on the primary outcome will be collected by study personnel as the number of 
patients enrolled out of the number of patients approached for enrollment. Secondary 
outcomes will either be obtained through data entry from the medical record for demographic 
information, lab results and gynecologic or hematologic treatment received by the patient 
during the study period. Participants will be assessed for adherence, PBAC score, fatigue score 
and GI side effects at each subsequent visit.  
ii. 
Retention: All reasonable efforts will be made by study investigators and staff to promote 
participant retention in the study. Data collection will continue on participants who are known 
to have discontinued the study intervention regardless of reason for discontinuation, which will 
not be a reason for withdrawal from the study. Participants may withdraw from the study at any 
time and no additional data collection would be performed on patients who choose to 
withdraw.  
iii. 
Management: All data will be entered electronically and 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. Documents such as signed informed consent and other 
paper files will be kept in a locked cabinet that only the PI and her staff have access to in a 
secure Baylor College of Medicine office building. These files will be maintained in storage for 3 
years after completion of the study.  
 
IIIH.  
Statistical methods 
i. 
All planned analyses will be descriptive in nature. Summary statistics such as mean, standard 
deviation, and 95% confidence intervals will be reported. No formal hypothesis testing will be 
performed. 
 
IIII.  
Harms 
Significant harms related to the study intervention are not anticipated considering the planned 
intervention is a commonly prescribed medication that can also be obtained over the counter. The 
participants may experience discomfort related to common side effects of iron administration including 
unpleasant taste, nausea, abdominal pain, dark stools, constipation, and/or diarrhea. Participants and 
their families will be made aware that accidental or intentional iron overdose is a serious potential 
effect and will be advised to keep iron pills away from small children for the duration of the study.  It is 
possible that subjects randomized to the alternate day intervention may have a slower resolution of iron 
deficiency anemia. Serious adverse events following initiation of iron supplementation during the study 
period will be reported to the IRB. Gastrointestinal side effects and adherence will be tracked and will be 
compared between study groups. 
 
IIIJ.  
Auditing 


After the first subject is enrolled, compliance personnel will audit pharmacy, laboratory and consenting 
procedures for proper conduct and documentation. Additional audits may occur without warning as 
warranted by the initial review or spontaneously. 
 
IV.  Ethics and dissemination 
IVA.  
Research ethics approval 
The protocol, informed consent form, participant education materials, and participant questionnaires 
and any subsequent modifications will be approved by the Institutional Review Board (IRB). Subsequent 
to initial review and approval, the IRB will review the protocol at least annually. 
 
IVB.  
Protocol amendments 
Any modifications of the study protocol which substantially impact the patient safety, study objectives, 
study design, patient population, sample sizes, or significant administrative changes will be approved by 
the IRB prior to implementation. 
 
IVC. 
Consent/assent 
Patients who meet the inclusion criteria in the outpatient or inpatient service will be invited to 
participate in the study. Study personnel will explain the purpose of the study and provide an 
information sheet regarding the study. The voluntary nature of the study will be emphasized. An 
informed consent form will be obtained from a parent/legal guardian of participants <18 years. 
Participants who are 18 years old or older will sign their own consent form. Information regarding the 
study in age-appropriate language will be provided to the participant if less than 18 years old and assent 
will be obtained from the participant.  
 
IVD. 
Confidentiality  
There is a minimal risk of loss of confidentiality, but all efforts will be made to protect subject privacy 
and confidentiality. Upon enrollment in the study, participants will be assigned a study ID number. 
Identifying data will be linked to the study ID number in a separate data set. All data will be entered 
electronically and 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. Documents such as signed informed consent and other paper 
files will be kept in a locked cabinet that only the PI and her staff have access to in a secure Baylor 
College of Medicine office building. These files will be maintained in storage for 3 years after completion 
of the study.  
 
IVE. 
Costs/payments 
i. 
Clinical Costs: Patients will be undergoing laboratory evaluation and treatment for abnormal 
uterine bleeding and iron deficiency anemia. These are not research costs but clinical costs 
which would be incurred whether or not the patient participated in the study. Subjects/subjects' 
insurance will be responsible for the costs of the tests/analyses and clinical visits during 
participation in the study. The only additional laboratory test that will be obtained through the 
study that is not standard of care is a serum iron study panel to be obtained at 4 weeks. This will 
be covered by research costs and not charged to the patient or patient's insurance. The cost of 
the prescribed iron medication will be covered as part of the study.  


ii. 
Patient payments: A pill box worth $15 will be provided at study enrollment. A $13 parking 
voucher will be provided at enrollment and at 3 subsequent follow up clinic visits for a total of 
$52. Total compensation for participation will therefore be $67 over a 6 month period.  
 
IVF.  
Declaration of interests 
The authors of this study have no conflicts of interest to report. 
 
IVG. 
Access to data 
The principal investigator will have access to all trial data. The PI will provide access to additional 
approved co-investigators as needed during study analysis.   
 
IVH. 
Ancillary/post-trial care 
Ancillary and post-trial care will be provided by the patient’s primary gynecologist as needed.  
 
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