Clinical trial NCT04610827
Conditions: Sleep Disorder Restless Legs Syndrome Periodic Limb Movement Sleep Disorder Iron-deficiency
Sponsor: Mayo Clinic
Start date: 2020-11-16; Completion date: 2021-06-29
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to see if the level of serum ferritin differs based on how often oral iron (in the form of ferrous sulfate) is given to children with restless leg syndrome/periodic limb movement disorder.

Detailed description:

Arms: arm 1: Subject will take 3 mg/kg oral iron in the morning arm 2: Subjects will take 1.5 mg/kg oral iron twice daily arm 3: 6 mg/kg oral iron every other day in the morning
Interventions: intervention 1: Ferrous sulfate
Intervention descriptions: intervention 1: Guideline-recommended 3 mg/kg/day dosing

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Optimum Frequency and Timing of Oral Iron 
Administration for Childhood Restless Leg 
Syndrome/Periodic Limb Movement Disorder   
 
NCT04610827 
 
February 2, 2021 


Date of protocol: February 2, 2021 
Optimum Frequency and Timing of Oral Iron Administration for Childhood Restless Leg 
Syndrome/Periodic Limb Movement Disorder 
Principal Investigator:  Julie Baughn, MD 
Co-investigators: Wendy Edlund, MD; Robin Lloyd, MD; Julie Baughn, MD; Mai Uyen Alissa Le, Pharm.D, 
R.Ph. 
Sleep Fellow Research Project for Wendy Edlund, MD; Approved by Sleep Research Committee 
7/28/2020; IRB # 20-007655 
 
RESEARCH QUESTION:  
Does every other morning dosing of liquid ferrous sulfate increase ferritin more than daily or twice daily 
dosing in children with iron deficiency (ferritin less than 24) and sleep disturbance?    
 
BACKGROUND:  
Oral iron is frequently used to treat low ferritin in childhood sleep disorders, including restless legs 
syndrome (RLS), periodic limb movement disorder (PLMD), and restless sleep.  Children under 6 years of 
age lack the language skills to describe their RLS symptoms, so polysomnography is often done to assess 
for the objective finding of periodic limb movements, as 80% of children with RLS have PLMs.  In RLS, 
increased serum ferritin correlates with increased CSF ferritin and RLS symptom improvement (1). Two 
prospective and four retrospective studies have shown that oral iron supplementation in children with 
RLS leads to an increase in serum ferritin and a corresponding decrease in RLS symptoms (2-7). The 
International Restless Legs Syndrome Study Group guidelines recommend 3 mg/kg/day of oral iron as 
first line treatment of RLS, with a goal of increasing ferritin to greater than 50 µg/L (1). The optimal 
timing of dosing is unclear and thus there is practice variation. Pediatricians and pediatric sleep 
specialists are seeking guidance on how to best dose oral iron.       
Emerging evidence about the diurnal variation of hepcidin and its sustained increase for 36-48 hours 
after iron intake suggest taking iron every other morning may be more effective than daily or twice 
daily. Hepcidin is a regulatory hormone that prevents iron deficit or overload by tightly controlling iron 
absorption via the GI tract as well as its bioavailability within the circulation (8). Hepcidin is lowest in the 
morning (9), and is regulated by an innate diurnal rhythm (10).  Hepcidin levels are decreased by both 
circulating and stored body iron; levels remains increased for 36 (9) to 48 (15) hours following oral iron 
intake, limiting absorption of subsequent doses. Studies in adult women with iron deficiency have 
shown significantly greater fractional iron absorption in patients taking iron every other day compared 
to daily (21.8% vs 16.3%) (16). Hepcidin levels are higher in children under 12 years of age (11), possibly 


further decreasing absorption in this population. Hepcidin levels are also increased by infection or 
inflammatory disorders (14).    
Several additional factors impact oral iron uptake. When not taken on an empty stomach, phosphates, 
phytates and tannates in food bind iron and impair its absorption (18). Oral iron should also be taken 
separately from dairy intake (12), and with juice (13) for optimal absorption. Antacids, H2 blockers, and 
proton pump inhibitors may also reduce pharmacologic iron absorption (14). Anemic patients with 
malabsorption, Helicobacter pylori infection, atrophic gastritis, or previous gastric or duodenal surgery 
do not respond or only partially respond to oral iron treatment (14).  
Children often have poor compliance with oral iron due to the bad taste or GI upset, thus less frequent 
dosage schedules may be better tolerated. In an adult anemia population, nausea, vomiting, 
constipation, or diarrhea led to noncompliance with therapy in 30% to 70% of cases (17). In a 
retrospective chart review of 77 children with RLS treated with oral iron, adherence to therapy occurred 
in 55% and was the only predictor of an increase in ferritin of ≥10 µg/L (19).  
 
SPECIFIC AIMS: 
1) To determine the relative increase in ferritin between children taking 3 mg/kg/day of oral liquid 
ferrous sulfate daily in the morning, twice daily, or every other morning.  
2) To determine the relative side effects for these dosage schedules.  
3) To determine adherence to these dosage schedules.  
 
STUDY DESIGN: 
Study design: Prospective, randomized clinical trial  
Subjects: Consecutive patients age 2 years to 10 years seen in in the sleep medicine clinic with ferritin < 
24 µg/L until the minimum number obtained. It is estimated that 2-5 such patients are seen per day in 
the Mayo sleep clinic.   
 
Inclusion criteria: 
• 
Ferritin equal to or lower than 24 µg/L drawn within the past 30 days. 
o Note: If ferritin ~10 µg/L, ~20% of oral iron absorbed; If ferritin between 50-75 
µg/L, ~2% is absorbed, oral iron not recommended over 75 µg/L (1).  
• 
Age 2 years through 10 years  
• 
RLS, PLMD, or sleep disturbance 
Exclusion criteria: 
• 
Currently taking oral iron other than a multivitamin. 


• 
Untreated Obstructive Sleep Apnea. 
• 
Presence of GI disorder, including GERD, Celiac disease. 
• 
Prior GI surgery, such as gastrectomy, duodenal bypass, presence of G tube. 
• 
Use of H2 blocker, antacid, or proton pump inhibitor.  
• 
Presence of inflammatory disorders, such as JIA or IBD. 
• 
Elevated CRP at time of initial ferritin or report of illness in past 4 weeks.  
Intervention: ferrous sulfate suspension. (Note: Generic and name brand are interchangeable per Peds 
Pharmacist) 
Methodology:  
• 
Patient selection 
o All patients 2 to 10 years of age presenting to the sleep medicine clinic with a ferritin 
<24 drawn in the past month who meet the inclusion/exclusion criteria are eligible for 
enrollment.  
o Mai Uyen Le, Pharm.D. or Wendy Edlund, MD will review the pediatric sleep schedules a 
few days prior to the Sleep Medicine appointment and identify possible subjects for 
inclusion.  They will contact the families by phone to alert them that they may be 
eligible for the study.   
o The pediatric sleep medicine providers will be informed which of their patients may 
qualify.   
• 
Patient enrollment 
o Telephone consent – if the subject is below age 8 years and qualifies for study 
enrollment, one of the investigators will reach out to the parent via telephone, explain 
the study further, and inquire whether the parent / guardian would like to have their 
child enrolled in the study. If the parent is agreeable to having the child enroll in the 
study, the phone consent script will be shared with the parent, any additional questions 
of the parent answered, and consent obtained over the phone.  Subject assent will not 
be considered due to the possibility that the subject may not fully comprehend details 
of participation.  
o Provider will ask if patient would like to hear more about the study and page Wendy 
Edlund, MD or Mai Uyen Le, Pharm.D., who will meet with the family.    
o Wendy Edlund, MD or Mai Uyen Le, Pharm.D. will ensure the patient meets the 
inclusion and exclusion criteria.  
o Informed consent will be obtained from parent, and assent from the child, when 
applicable. This will be done remotely via video or telephone, as needed. 
o Enrolled patients will be randomized (via computer randomization) to three arms, each 
with the guideline-recommended 3 mg/kg/day dosing:  
 
3 mg/kg oral iron in the morning 
 
1.5 mg/kg oral iron BID 
 
6 mg/kg oral iron every other day in the morning  


o In order to facilitate adherence, and control for other variables that impact oral iron 
absorption, patients will be given study materials which provide: 
 
Instructions specific to their arm of the study (e.g., how often to take the 
ferrous sulfate, dosage).  
 
A chart to track medication adherence and side effects.  
 
Instructions to maximize the uptake of oral iron (e.g., to take the iron on an 
empty stomach, with citric juice, and avoid dairy 1 hour prior and 2 hours after 
the dose).  
 
A list of side effects (e.g., stool color change, nausea, constipation, teeth 
staining) and instructions for how to mitigate (e.g., half capful of MiraLAX, wipe 
off teeth after taking iron).   
• 
Tracking adherence and side effects 
o Patients will track adherence and side effects with a daily chart.  
o Patients’ parents will be called to be reminded of study protocol and check on progress 
by Wendy Edlund, MD or Mai Uyen Le, Pharm.D. at week 2 and 5.   
• 
Obtaining outcomes at 2 months 
o Patients will have a ferritin drawn (standard of care). 
o Patients’ parents will turn in the tracking sheet. 
• 
Data collected 
o Patient data (age, gender, weight, dose, sleep diagnosis, comorbidities, other 
medications) 
o Pre and post ferritin (to calculate change in ferritin) 
o Side effects 
o Adherence 
Analysis: 
• 
Primary outcome measures: change in ferritin, side effects 
• 
Secondary outcome measure: adherence.  
• 
Null hypothesis: Ferritin will increase equally between the three arms.   
• 
Statistical analyses: 1 way ANOVA F-test. 
  


• 
The sample size required to identify a difference of >2 in the mean increase in ferritin between 
the three treatment arms is 48 total patients, 60 to allow for 20% drop out rate.  
• 
Intention to treat analysis.  
• 
To minimize the impact of adherence on our data, we will analyze patients with >70% 
adherence separately from those with <70% adherence within each of the three treatment 
arms.  
 
 
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