Clinical trial NCT02499354
Conditions: Restless Legs Syndrome Iron Deficiency Anemia
Sponsor: Auerbach Hematology Oncology Associates P C
Start date: 2014-08-01; Completion date: 2022-05-31
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to determine the relative effect size of standard IV and oral iron treatment of RLS with Iron deficiency anemia (IDA) and to determine the time course of treatment response.

Detailed description:
The restless legs syndrome (RLS) (also known as Willis Ekbom Disease) occurs in about 1/3rd of patients with iron deficiency anemia (IDA). Treatment correcting the IDA is expected to also be effective for reducing or eliminating the RLS with IDA. Two accepted treatments for IDA (oral ferrous sulfate, intravenous ferumoxytol) will be compared for efficacy and speed to response for treatment of RLS occurring with IDA (RLS-IDA). In this study 70 RLS-IDA patients will be randomly assigned 35 each to oral or IV iron treatment using double-blind procedures. Primary outcome with be determined at 6 weeks of treatment with a follow-up at 12 months after treatment. Non-responders at 6 weeks after treatment may, if they qualify, have an open-label IV iron treatment and they will be followed with the same evaluations used after the first set of IV iron treatments.

Both oral and IV iron are considered standard treatments for IDA. These same treatments also reduce RLS symptoms. The treatment doses are those accepted for treatment of RLS and also appropriate for treatment for RLS-IDA. Choosing doses equivalent to those for the treatment of RLS without IDA will allow a comparison with that literature. The investigators will therefore use for oral iron ferrous sulfate 325mg taken twice a day matching the dose used in the study of oral iron treatment for RLS without anemia. For IV iron investigators will use ferumoxytol, provided by the sponsor, two doses of 510 mg spaced 2 to 7 days apart. This is the FDA approved dose for treatment of IDA with end stage renal disease.

The study is a randomized, comparative open label study to evaluate effect size and time course of treatment response for RLS-IDA over 6 weeks with a 46-week follow-up extension. Two medications and placebos will be used, as described above, with equal random assignment to both groups.

Arms: arm 1: Ferrous Sulfate 325mg (oral) tabs morning and evening arm 2: Ferumoxytol intravenous (IV) 1020 mg - 2 vials of 510 mg (IV push, 2-3 mins) each given 2-7 days apart
Interventions: intervention 1: Ferumoxytol intravenous intervention 2: Ferrous sulfate
Intervention descriptions: intervention 1: IV iron, 2 vials of 510 mg given 2-7 days apart intervention 2: Oral iron, 325 mg tabs taken morning and evening

Protocol documents:
Prot_000.pdf: 
18 July 2014 
 
1
 
 
 
 
Title: Pilot study: randomized, placebo-controlled comparator trial of IV vs oral iron 
treatment of RLS with Iron deficiency anemia. (IVOR-IDA) 
 
Principal Investigator:  Michael Auerbach, M.D. 
 
 
 
 


18 July 2014 
 
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Protocol: IVOR-IDA   
 
Title: Pilot study: randomized, placebo-controlled comparator trial of IV vs oral iron 
treatment of RLS with Iron deficiency anemia. (IVOR-IDA) 
 
Principal Investigator:  Michael Auerbach, M.D. 
 
Type of Study:  Double-blind comparator of efficacy of oral (ferrous sulfate) vs.  
Intravenous iron (ferumoxytol) for treatment of the restless legs syndrome (RLS) 
occurring with iron deficient anemia (IDA) 
 
Supported by:  AMAG pharmaceuticals 
 
  
 
Summary: 
 
 The restless legs syndrome (RLS) (also known as Willis Ekbom Disease) occurs in about 1/3rd 
of patients with iron deficiency anemia (IDA).  Treatment correcting the IDA is expected to also 
be effective for reducing or eliminating the RLS with IDA. Two accepted treatments for IDA (oral 
ferrous sulfate, intravenous ferumoxytol) will be compared for efficacy and speed of response 
for treatment of RLS occurring with IDA (RLS-IDA).  In this study 70 RLS-IDA patients will be 
randomly assigned 35 each to oral or IV iron treatment using double-blind procedures. Primary 
outcome will be determined at 6 weeks of treatment with a follow-up at 12 months after 
treatment. Non-responders at 6 weeks after treatment may, if they qualify, have an open-label 
IV iron treatment and they will be followed with the same evaluations used after the first set of IV 
iron treatments.   
 
 
Primary objectives 
1. Determine relative effect sizes of standard IV and oral iron treatment of RLS with iron 
deficiency anemia 
2. Determine time course of treatment response  
 
Exploratory hypotheses:   
 
1) Primary exploratory hypothesis: Reduction in RLS-IDA severity measured by the 
CGI-2 ( much or very much improved) will be greater for IV  than oral iron treatment at 6 weeks 
after starting treatment.  
 
2) Secondary exploratory hypothesis:  there will be a greater change from baseline 
in the IRLS score assessing severity of RLS for IV than oral iron treated patients.  
 
 
Introduction 
Background:   
 
Low IRON status is associated with RLS:  RLS has been documented to have 
significant decreased iron concentrations in the substantia nigra [1] and other areas  [2]. This 
has been documented in multiple studies using both MRI [2] [3] [1]and ultrasound [4]. Peripheral 


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iron status also relates to RLS severity [5] and both oral and IV iron treatments significantly 
reduce RLS symptoms compared to placebo  [6, 7].  
 
RLS occurs commonly with iron deficiency anemia:  The prevalence of RLS among 
the IDA patients seen in the Auerbach clinic is 32% for any RLS and 24% for clinically significant 
RLS [8].  This is about 5  times the 7% prevalence of any  RLS in the general population and 
about 10 times the 2.7%  prevalence of clinically significant RLS  [9].  Thus RLS with IDA (RLS-
IDA) is not only more common and but also more severe than that in the general population. 
 
Standard treatments for IDA also treat RLS without IDA.  Both oral and IV iron are 
considered standard treatments for IDA [10].  These same treatments also reduce RLS 
symptoms.  Oral iron as ferrous sulfate 325mg taken twice a day produced significant reduction 
in RLS symptoms in a blinded placebo-controlled study [7].  IV iron given as ferric 
carboxymaltose in 2 doses of 510 mg spaced 5 days apart also reduces RLS symptoms 
significantly more than placebo [6].   
 
  Rationale for study: It is assumed the treatments that reverse the IDA will also 
reduce the RLS symptoms occurring with IDA.  This is supported by these treatments benefitting 
RLS patients without IDA.  But this has never been demonstrated in a prospective controlled 
trial.  The iron stores, however, are less in the IDA than general population. The IDA-RLS may 
therefore require more aggressive iron treatment than is used for RLS without IDA and possibly 
even more aggressive iron treatment than is usually given for IDA.  In particular despite the 
recovery of anemia after 6 weeks of oral iron treatment, the actual iron stores remain low.  In 
contrast the IV iron treatment  at about 1000 mg of iron corrects the anemia and provides a 
better increase in iron stores over a 6-week period [10].   Thus, if the IDA-RLS results more from 
the low iron than the anemia it may benefit significantly more from IV than oral iron treatment.   
 
Our major problem in testing the treatment benefits for IDA-RLS for either oral or IV 
iron is that we do not know the actual effect size of either treatment. We have as an initial 
estimates the effect sizes from clinical experience with oral and IV iron treatment of IDA-RLS.  
These have to be considered as provisional estimates of effect sizes. Thus, although we have 
set the sample size to give adequate power to differentiate iv from oral iron treatment assuming 
these effect sizes, we do not consider the power estimates to be accurate.  We feel they give us 
an adequate sample to establish effect sizes for future studies and to explore possible 
differential efficacy for the two treatments. The primary goal of the study is, therefore, to assess 
effect size. Evaluating differences between the treatments is a tertiary goal of this study.  
 
The decision not to do a placebo control is based on the assumption that the 
treatment effect size can be adequately determined without a placebo.  The decision to do a 
blinded comparator trial is based on the assumption that we will see differences between the 
treatments that will establish both the effect sizes and the procedures for a larger study to show 
these differences.  We feel it is very important to determine if efficacy of these treatments differ 
for RLS-IDA in order to develop guidelines for future treatment of this clinically significant 
condition affecting many with IDA. We have assumed IV iron will be the preferred treatment for 
RLS-IDA, but we need to first evaluate this in this pilot study and then in a larger adequately 
powered clinical study.   
 
Drugs used: The treatment doses are those accepted for treatment of RLS and also 
appropriate for treatment of RLS-IDA.  Choosing doses equivalent to those for the treatment of 
RLS without IDA will allow a comparison with that literature.  We will therefore use for oral iron 
ferrous sulfate 325 mg taken twice a day matching the dose used in the study of oral iron 
treatment for RLS without anemia [7].  For IV iron we will use ferumoxytol two doses of 510 mg 
spaced 2 to 7 days apart.  This is the FDA approved dose for treatment of IDA with end stage 
renal disease.  This dose matches the iron dosing used in the study of IV iron treatment for RLS 
without anemia [6], except we will use ferumoxytol provided by the sponsor rather than ferric 
carboxymaltose used in the prior trial.   


18 July 2014 
 
4
 
Study Design 
 
  The study is a randomized, comparative open label study to evaluate effect size and time 
course of treatment response for RLS-IAD over 6 weeks with a 46-week follow-up extension. 
Two medications and placebos will be used with equal random assignment to both groups 
 Ferumoxytol intravenous (IV) 1020 mg – 2 vials of 510 mg  (IV push, 2-3 mins) each 
given 2-7 days apart  
 Ferrous sulfate 325 mg (oral) tabs morning and evening.  
 Placebo:  oral vitamin C  500 mg tabs, Saline infusion  
Primary outcome is the CGI-2 score at  6 weeks after treatment starts.  IV ferumoxytol 1020 mg  
treatment  (2 separate doses 510 mg 2-7 days apart) will be offered to those  not significantly 
responding (CGI-2 scores less than much or very much improved) at 6 weeks after oral-iron 
treatment and still meeting all requirements for entry to study.  All responders will be followed for 
12 months after treatment.  
 
Study Objectives 
 
 
Primary objectives 
1. Determine relative effect sizes of standard IV and oral iron treatment of RLS with iron 
deficiency anemia for the PGI-2/CGI-2 (much and very much improved) and for IRLS scores 
2. Determine time course of treatment response for IRLS, PGI-1 and PGI-2 scores 
Secondary objectives 
1. Estimate survival times for effective treatment (no return to other RLS medications) for 1 year 
after treatment 
2. Evaluate possible predictors of treatment response  
a. Iron status or iron response 
b. IRLS severity 
c. Subject characteristics (age, gender) 
d. Medical factors affecting iron status 
Tertiary/exploratory objectives 
1. Evaluate significance of efficacy differences if any between oral and IV iron treatments at 6 
weeks after treatment: Hierarchical testing first for the percentage with CGI-2 of much or 
very much improved and second for change from baseline in the IRLS score. 
2. Evaluate efficacy benefits of each treatment for usual outcomes related to RLS morbidity: 
sleep, fatigue, quality of life, and mood.  
3. Compare lymphocytes of  RLS-IAD and non RLS-IAD  for differences in iron related 
proteins. 
 
Study Procedures 
RLS patient ascertainment:  A standard patient completed RLS diagnostic questionnaire is given 
to all of the patients at the Auerbach clinic as part of their routine clinical evaluation not limited to 
its use in this study. This questionnaire has a sensitivity and specificity of 87% and 94% 
respectively [11].  The patients identified by the questionnaire as probable RLS will be checked 
for meeting the inclusion criteria (see below). They will, If they meet criteria, be approached by 
the research coordinator to consent to this treatment protocol. If they consent then the 


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coordinator will assign them a protocol number and will obtain any needed blood samples. The 
coordinator will review the clinical history with the patient to ensure they meet inclusion criteria.  
If they qualify as determined by inclusion/exclusion criteria (see below) the coordinator will 
schedule the patient for both a validated telephone diagnostic interview [12] by an RLS 
specialist at Johns Hopkins and two treatment times to occur 2 – 7 days apart starting after the 
interview.  If the Hopkins interview confirms the RLS diagnosis the treatments will be given as 
scheduled. If the Hopkins interview does not confirm the diagnosis of RLS the patients 
participation in this study will end and routine care will be given.  
 
Randomization.  A table randomizing assignment of participants in order entered will be used to 
determine group placement.  Once a patient has been confirmed with RLS by the telephone 
clinical interview they will be given an appointment for IV treatment. At the time of IV treatment 
the subject will be assigned to either IV or oral iron treatment based on the order in the 
randomized table. The randomization will be in 7 blocks of 10 with equal treatments in each 
block. The nursing staff will follow the randomization table based on the order of the subjects 
tested. Each subject will be assigned a study number at the time of the IV treatment.  The 
subject data will be evaluated using this study number and not the protocol number assigned by 
the coordinator at the time the patient consented to the study.   
 
Dosing: The patient will receive 2 IV treatments spaced 2 to 6 days apart.  These will either be 
ferumoxytol or placebo.  At the time of the first infusion the patient will also be given an opaque 
bottle, containing either vitamin C tablets or ferrous sulfate 325 mg.  The patient is instructed to 
take each of these pills twice a day for the next 6 weeks.  They will be given enough pills to last 
for 7 weeks with the follow up appointment set for 6 weeks after the first IV treatment.  
 
Blinding: The treatment nurse will determine the assignment the day of the treatment and will 
complete the appropriate treatment.  The research coordinator will not know the patients 
treatment, will not be present when the patient is being treated and will not have access to files 
indicating the treatment dose given.  During IV treatments the patient will wear eye masks to 
ensure they do not notice any color differences between the iron and placebo treatments. 
 
Patient visits: There will be 2 to 3 visits at the clinic and telephone contact with the patient at 1,2 
and 4 weeks after the start of the IV treatment. During the 12 month follow up there will be 4 
more telephone contacts with the patient. (See appendix for schedule of visits.) 
  
Agent and administration for IV iron and placebo 
IV iron: The study will use a commercially available preparation of ferumoxytol. Ferumoxytol is 
currently marketed as an iron replacement product indicated for the treatment of iron defi ciency 
anemia in adult patients with chronic kidney disease (CKD), and it is FDA-approved for this 
indication. Ferumoxytol (30 mg/mL) is available for intravenous injection in single use vials. 
Each vial contains 510 mg of elemental iron in 17 mL. Ferumoxytol can be administered as an 
undiluted intravenous injection delivered at a rate of up to 1 mL/sec (30 mg/sec).  It is stored at 
controlled room temperature (20° to 25°C [68° to 77°F]). Excursions are permitted to 15° – 30°C 
(59° – 86°F). Pre-treatment medications are not required.  
 
In this study 501 mg of ferumoxytol (one vial) will be diluted in 100 ml normal saline and 
administered with an infusion pump over a 15- minute period.   
 
Patients will have vital signs measured and recorded immediately prior to drug 
administration and will be observed in the clinic for 60 minutes following completion of the 
infusion with frequent determination of vital signs and ascertainment of signs or symptoms of 
adverse effects 


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Placebo: Normal Saline will be administered following exactly the same procedure as that for IV 
iron.  
 
Agent and administration for oral iron and placebo  
Oral iron: This study will use Ferrous sulfate 325 mg tablets. The medication is to be taken 
together twice a day. If signifiant stomach distress occurs the patient may elect to take the 
medication with food and must then notify the research coordinator.  The pills will be provided in 
opaque bottles with exactly enough for 7 weeks and a pill count will be made at the 6-week 
follow up to determine compliance. The oral pills will be stopped at the 6-week evaluation time.  
 
Placebo: Standard vitamin C 250mg,  given in the same bottle as the oral iron.  
 
Subject schedule: (See appendix for chart of visits) 
There will be 2 – 3 visits at the Auerbach clinic and telephone evaluations conducted by the 
Hopkins doctors prior to the start of treatment. After the first IV treatment there will be a 
telephone evaluation at 1, 2 and 4 weeks later and a clinic visit for blood tests at 4 weeks after 
the first of the pairs of IV treatment and again at about 6 weeks after the first of the pair of IV 
iron treatments.  At 6 weeks after treatment responders will continue in the study with telephone 
evaluations of their RLS symptoms and medications at about 3, 6, 9 and 12 months after the 
first IV treatment.  At 6 weeks after treatment non-responders will be given the option of 
receiving the IV ferumoxytol following the same procedure as at the initial treatment with a 6-
week period of observation except this will be open label. Both the patient and the coordinator 
will know that ferumoxytol was given at this repeat dosing.  This option will be given only if the 
patient continues to meet all the inclusion/exclusion criteria for the study noted below, except 
they will not be excluded for their prior IV treatment in this study. Those receiving the repeat IV 
dosing at 6 weeks will follow all the same procedures used after the first IV dosing, e.g. 
telephone safety checks and RLS symptom evaluations at 24-48 hours, 1 week and 4 weeks 
after initial treatment and a repeat clinic visit at about 6 weeks after the first of the two repeated 
IV treatment.  This 6-week clinic visit will repeat blood tests, adverse event reporting and clinical 
evaluation of the RLS. The responders to this repeated IV treatment will be followed for up to 
one year following the same procedures as responders.  The non-responders will end the study 
at this point.   
 
Patients continuing in the one year follow up will be followed for RLS symptoms over the entire 
year. The telephone evaluation at 12 months after treatment will end the study for these patients 
Appendix A provides a flow sheet of the subject’s schedule. 
 
 
Subject population 
Subjects with diagnosis of RLS and iron deficiency anemia  
Inclusion criteria: 
1. Aged ≥ 18 years  
2. Diagnosis of RLS based on questionnaire and confirmed by Hopkins Telephone Diagnostic 
Interview conducted by Dr. Allen or Earley 
3. Iron deficiency anemia defined as  ID either ferritin < 20 mcg/l, Tsat<19%, anemia Hgb< 13  for 
both males and females. 
4. Willingness to use contraceptive to avoid pregnancy: Women have to be surgically sterile , post 
menopausal or use one of the following contraceptives during the whole study period and after the 


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study has ended for at least 5 times plasma biological half-life of the investigational medicinal 
product: intrauterine devices or hormonal contraceptives (contraceptive pills, implants, 
transdermal patches, hormonal vaginal devices, or injections with prolonged release).   
5. Willingness to participate and signing the informed consent form 
 
Exclusion criteria: 
A subject will not be eligible for inclusion in this study if they fulfill any of the following criteria: 
1. Iron overload or disturbances in utilization of iron (e.g. haemochromatosis and haemosiderosis) 
2. Decompensated liver cirrhosis or active hepatitis (ALAT > 3 times upper limit of normal) 
3. Serum ferritin > 500 ng/mL or transferrin saturation >40 %  
4. Active acute or chronic infections (assessed by clinical judgment that may be indicated by White 
Blood Cells (WBC) and C-Reactive Protein (CRP) when these are available) 
5. Rheumatoid arthritis with symptoms or signs of active inflammation 
6. Pregnant and nursing women 
7. History of multiple allergies    
8. Known hypersensitivity to parenteral or oral iron or any excipients in the drug products 
9. Previous IV iron treatment for RLS 
10. Other iron treatment or blood transfusion within 4 weeks prior to the screening or treatment visit 
11. Planned elective surgery during the study 
12. Current (past 4 weeks) use of drugs that treat RLS, e.g. opioids, alpha-2-delta anti-depressants, 
dopaminergics (dopamine promoters, dopamine antagonists/blockers) 
Any other medical condition that, in the opinion of Investigator, may cause the subject to be 
unsuitable for the completion of the study or place the subject at potential risk from being in the 
study, e.g. a malignancy, uncontrolled hypertension, unstable ischemic heart disease, or 
uncontrolled diabetes mellitus 
 
 
 
Study Endpoints for each subject 
The following are endpoints for each patient in the study : 
 
 
1. At evaluation in the clinic at about 6 weeks after the first IV iron treatment. 
 
 
 
 
2. Termination of participation because of significant adverse effect from the IV infusion in 
the hour observed after the infusion. 
 
 
 
3. Significant adverse event after starting the iron treatment  and before the 6 week 
follow-up evaluation that was judged to require ending the study. 
 
 
4. Subject decision not to continue in the study after the treatment and before the final 
evaluation.  
 
 
5. Dr. Auerbach decision that it would be harmful to the patient to continue in the study. 
 
 
6. Patient is non-compliant with study requirements and Dr. Auerbach judges this non-
compliance is enough to significantly alter evaluation of the treatment. (Note that stopping the 


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oral medication because of intolerance to the treatment is not considered non-compliance, but 
rather an outcome for the study.  Patients discontinuing oral medication for adverse effects may 
qualify for repeat IV treatment .) 
 
 
Duration of subject participation: 
Participation will continue for 6 weeks after treatment for the primary study and for 12 months 
after treatment for the extension study for those responding to the initial treatments or the open 
label repeated IV treatment.  
 
Early termination of study: 
Subjects may terminate the study at any time or maybe terminated from the study for non-
compliance or if continuation in the study is judged by Dr. Auerbach to be harmful to the patient. 
A telephone evaluation will be scheduled when possible at the time of early termination.  The 
reason for the early termination will be noted. 
 
Blood tests obtained: 
Iron panel, hemoglobin and hematocrit will be obtained from morning fasting venous samples at 
screening prior to treatment and at 4 and 6 weeks after the first treatment. About 15 ml of blood 
will be obtained for these tests  
An additional 24 ml of blood will be collected for lymphocytes the day of the first IV treatment 
before the treatment and again at 6 weeks after the treatment.  
The iron panel will include serum iron, ferritin, transferrin saturation and total iron binding 
capacity.  
Blood samples will routinely be obtained at Dr. Auerbach’s office, but in special cases may be 
arranged through a remote office, e.g. Quest.    
 
RLS clinical evaluations obtained: 
The primary clinical evaluations will be the clinician global rating of improvement (CGI-2), patient 
global rating of RLS severity (PGI-1) and the international RLS severity scale (IRLS). These will 
be obtained at each clinic visit and at each telephone evaluation, except CGI-2 will only be 
obtained after the treatment.  
The secondary clinical evaluations will be the MOS sleep scale [13], Fatigue severity scale [14], 
SF36 short form [15] and the Hospital anxiety and depression scale (HADS) [16]. These will be 
obtained at baseline and then again at the 6 week post IV clinic evaluation.    
 
Concomitant treatment/medication 
ESA, anti-histamines, drugs that treat RLS, dopaminergic treatment and iron drugs beside study 
drugs are not allowed during the study period 
 
Safety and adverse events  
 
Expected possible adverse events (AE) 
Across three randomized clinical a total of 605 patients were exposed to two injections of 510 
mg of ferumoxytol [17-19]. Most patients received their second ferumoxytol injection 3 to 8 days 
after the first injection. Adverse reactions related to ferumoxytol and reported by ≥ 1% of 
ferumoxytol-treated patients in the randomized clinical trials are listed in the table below. 
Diarrhea (4.0%), constipation (2.1%) and hypertension (1.0%) have also been reported in 
ferumoxytol-treated patients. In clinical trials, adverse reactions leading to treatment 
discontinuation and occurring in ≥ 2 ferumoxytol-treated patients included hypotension, infusion 


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site swelling, increased serum ferritin level, chest pain, diarrhea, dizziness, ecchymosis, 
pruritus, chronic renal failure, and urticaria.  
 
 
Adverse 
Reactions 
Ferumoxytol 2 × 510 mg 
elemental iron (n=605) 
Nausea 
3.1% 
Dizziness 
2.6% 
Hypotension 
2.5% 
Peripheral Edema 
2.0% 
Headache 
1.8% 
Edema 
1.5% 
Vomiting 
1.5% 
Abdominal Pain 
1.3% 
Chest Pain 
1.3% 
Cough 
1.3% 
Pruritus 
1.2% 
Pyrexia 
1.0% 
Back pain 
1.0% 
Muscle spasm 
1.0% 
Dyspnea 
1.0% 
Rash 
1.0% 
 
In addition oral iron can cause constipation, diarrhea, stomach cramps and upset stomach.  
The occurrence of these adverse events noted above for oral iron or ferumoxytol will be 
specifically recorded at each clinic visit following IV treatment and at the 1 , 2, and 4 week 
telephone evaluation after the start of the IV treatment.  
 
In the event a patient develops a hypersensitivity reaction during treatment, the patient will 
receive standard recommended treatment and may not continue in the study.    
 
Definition of Serious Adverse Events 
A serious adverse event (SAE) is defined as an AE that: 
 Is fatal 
 Is life threatening (places the patient at immediate risk of death) 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Met other significant medical hazard 
An AE necessitating hospitalization meets the regulatory definition for “serious” if the in-patient 
hospital admission includes a minimum of an overnight stay in a health care facility. Any AE that 
does not meet 1 of the definitions of serious (e.g. an AE requiring an emergency room visit, 
outpatient surgery, or requires urgent investigation) may be considered by the Investigator to 
meet the “other significant medical hazard” criterion for classification as an SAE. Examples 
include allergic bronchospasm, convulsions, and blood dyscrasia. 
If the above interventions are performed as standard of care and not associated with an AE, the 
health issue for which the intervention is being performed will not be considered an SAE. If there 


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is a complication as a result of the procedure and the complication meets at least 1 serious 
criterion, that complication would be reported as an SAE 
 
Definition of an Adverse Drug Reaction 
An ADR is an AE that is judged by the Investigator to be “related” or “possible related” to the 
study drug (see classification of relatedness below).  
In the event a patient develops a hypersensitivity reaction during treatment, the patient will 
receive standard recommended treatment and may not continue in the study.    
 
Adverse Event Reporting: 
Patients will be queried for occurrence of adverse effects following discharge from the clinic by 
means of follow up by telephone by the study coordinator at 24 hours and 1 and 4 weeks after 
administration of ferumoxytol. They will also be queried about adverse effects of the treatment at 
the 6 week follow up meeting.  If they continue in the study for the 1-year follow-up they will be 
asked about adverse effects with each efficacy evaluation conducted by telephone.  Adverse 
events will be recorded and evaluated for relatedness, severity, seriousness, and expectedness. 
They will be followed-up and reported according to current standards.  
 
The Investigator is responsible for ensuring that all AEs  observed by the Investigator or 
reported by the subject are properly collected and recorded in the subject’s medical record as 
well as in the AE pages of the data forms for this project.  
 
An AE should be described in the following manner: The nature of the event will be described in 
precise, standard medical terminology (i.e. not necessarily the exact words used by the subject). 
If known, a specific diagnosis should be stated. Furthermore the Investigator should describe an 
AE regarding severity, relatedness, action taken, and outcome.  
Severity 
 Mild: The AE does not interfere in a significant manner with the subject’s normal functioning 
level, but may be an annoyance 
 Moderate: The AE produces some impairment of functioning but is not hazardous to health, 
but is uncomfortable and/or an embarrassment 
 Severe: The AE produces significant impairment of functioning or incapacitation and is a 
hazard to the subject 
Relatedness 
 Related: The AE is related to the medicinal product 
 Possible related: A causal relationship is conceivable and cannot be dismissed 
 Unlikely related: The event is most likely related to an etiology other than the medicinal 
product 
 Not related: No relatedness to the medicinal product 
The categories "related" and "possible related" will be classified as related AEs and the 
categories "unlikely related" and "not related" will be classified as unrelated AEs for the final 
data review.  
 
Outcome 
 Recovered/resolved: Complete clinical recovery without any sequel attributable to the 
event as per Investigator’s discretion 


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 Recovered/resolved with sequelae: Complete clinical recovery but with one or more 
sequels attributable to the event as per Investigator’s discretion 
 Recovering/resolving: The condition is improving and the subject is expected to recover 
from the event. This term should only be used when the subject has completed the study 
 Not recovered/not resolved: The subject's condition has not improved and the symptoms 
are unchanged 
 Fatal 
 Unknown: The subject's condition is unknown. This term should only be used when no 
other definition is possible e.g. the subject is lost to follow-up 
 
For the purpose of medical management, all AEs and laboratory abnormalities that occur during 
the study will be evaluated by the Investigator. Each of these will be followed to satisfactory 
clinical resolution. Insofar as possible, all AEs will be followed-up to determine the final outcome 
of the event. The Investigator will follow-up all subjects with SAEs until the event has subsided 
(or disappeared), the condition has stabilized, the event is otherwise explained, or the subject is 
lost to follow-up. 
Risk Benefit Analyses 
The treatments given in this study will be the customary ones used for treatment of the iron 
deficiency anemia these patients with RLS-IAD.  The study procedures involve minimal risks: 
rare complications from standard venous blood samples, psychological distress from the 
number of questionnaires and telephone calls and a risk of loss of confidentiality regarding 
participating in the study and the diagnosis of RLS.  The blood samples will be obtained 
following standard procedures with standard treatment options provided for any adverse events 
occurring. These blood tests will be obtained as part of the routine care.  Psychological distress 
will be minimized by advanced notice of the length, topics and timing of the questionnaires and 
interviews.  The data when processed for review outside of the Auerbach clinic will be de-
identified to protect patient confidentiality. 
The study will benefit the patient by treating the iron deficiency and possibly treating the RLS. It 
will also benefit others with IAD-RLS by possibly indicating which is the preferred treatment- oral 
of IV iron.  
 
 
Statistical Analyses 
The percentage responding will be evaluated for each drug condition to determine overall effect 
size at 6 weeks after treatment. This will be calculated for the IRLS scale and the PGI as 
change from baseline and for the CGI with response determined as much or very much 
improved (scores of 1 or 2).  All scores greater than 2 on the CGI are considered to indicate no 
significant response. The onset of treatment will be described as the percentage showing much 
or very much improvement at each of the evaluations and by the change in IRLS score from 
baseline at each evaluation. The duration of treatment over the 12 month follow up will be 
described as the percentage of responders and the IRLS change from baseline at each time 
point for both oral and IV iron. The oral iron treatment will be stopped for all subjects at the 6-
week time point.   
 
The outcomes for the oral versus IV treatments at 6 weeks will be compared using a standard 
unpaired unequal variance t-test for the change in IRLS scores from baseline. The number of 
responders compared to no-responders  will be compared using the Fisher Exact test.   
 


18 July 2014 
 
12
Sample Size 
Uncontrolled experience observing IDA patients with RLS indicated that about 80% responded 
to IV iron (about 1000mg dose) and 50% responded to standard oral iron treatment over 6 to 12 
weeks.  These percentage outcomes require a sample size of 70 ( 35 with each treatment) to 
provide a power of >80% with alpha = 0.05 to test for differences between these treatments. 
This was considered a reasonable sample to ascertain the effect size of the two treatments and 
to provide enough positive outcomes to evaluate time course for improvement with treatment 
and persistence of the treatment effect.  
Breaking the blind 
The randomization is in cohort blocks of 10, 5 with each treatment.  The blind for the form of 
initial treatment will be broken for every cohort of 10 treated patients after all members of a 
cohort have completed the study. The blind may also be broken for specific subjects if the 
treatment information is needed for medical care of the patient.  
 
 
Concomitant Medication 
Permitted Medications 
Throughout the study, the subject may take any concomitant medications or treatments deemed 
necessary to provide adequate supportive care. When the subject is found eligible for the study, 
he/she is not allowed to take the medicine listed below as prohibited medications. Any 
concomitant medications administered while the subject is participating in the study must be 
recorded on the source document and transcribed into the concomitant medication form.  
 
Prohibited Medications  
The following medication is not allowed from baseline and until week 6 as it could potentially affect the 
primary endpoint: 
 Any iron supplementation other than investigational drug 
 Dopaminergic treatment 
 Opioids 
 Anti-depressives 
 Pain killers 
 Cannabis 
 Anti-convulsants including alpha-2-delta drugs 
 Centrally active anti-histamines   
 
 
 
 
 
 
 
 
 
 
 
1. 
Allen, R.P., et al., MRI measurement of brain iron in patients with restless legs syndrome. 
Neurology, 2001. 56(2): p. 263-5. 
2. 
Rizzo, G., et al., Low brain iron content in idiopathic restless legs syndrome patients 
detected by phase imaging. Mov Disord, 2013. 


18 July 2014 
 
13
3. 
Earley, C.J., et al., MRI-determined regional brain iron concentrations in early- and late-
onset restless legs syndrome. Sleep Med, 2006. 7(5): p. 458-61. 
4. 
Schmidauer, C., et al., Transcranial ultrasound shows nigral hypoechogenicity in restless 
legs syndrome. Ann Neurol, 2005. 58(4): p. 630-4. 
5. 
Sun, E.R., et al., Iron and the restless legs syndrome. Sleep, 1998. 21(4): p. 371-7. 
6. 
Allen, R.P., et al., Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment 
of RLS: A multi-centred, placebo-controlled preliminary clinical trial. Sleep Medicine, 
2011. 12(9): p. 906-913. 
7. 
Wang, J., et al., Efficacy of oral iron in patients with restless legs syndrome and a low-
normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep Med, 2009. 
10(9): p. 973-5. 
8. 
Allen, R.P., et al., The prevalence and impact of restless legs syndrome on patients with 
iron deficiency anemia. Am J Hematol, 2013. 88(4): p. 261-4. 
9. 
Allen, R.P., et al., Restless legs syndrome prevalence and impact: REST general 
population study. Arch Intern Med, 2005. 165(11): p. 1286-92. 
10. 
Schrier, S.L. and M. Auerbach Treatment of anemia due to iron deficiency. UpToDate, 
2013. 
11. 
Allen, R.P., et al., Validation of the self-completed Cambridge-Hopkins questionnaire 
(CH-RLSq) for ascertainment of restless legs syndrome (RLS) in a population survey. 
Sleep Med, 2009. 10(10): p. 1097-1100. 
12. 
Hening, W.A., et al., Validation of the Hopkins telephone diagnostic interview for restless 
legs syndrome. Sleep Med, 2008. 9(3): p. 283-289. 
13. 
Hays, R.D., et al., Psychometric properties of the Medical Outcomes Study Sleep 
measure. Sleep Medicine, 2005. 6(1): p. 41-4. 
14. 
Cuellar, N.G. and S.J. Ratcliffe, A comparison of glycemic control, sleep, fatigue, and 
depression in type 2 diabetes with and without restless legs syndrome. J Clin Sleep Med, 
2008. 4(1): p. 50-6. 
15. 
Stewart, A.L., R.D. Hays, and J.E. Ware, Jr., The MOS short-form general health survey. 
Reliability and validity in a patient population. Med Care, 1988. 26(7): p. 724-35. 
16. 
Bjelland, I., et al., The validity of the Hospital Anxiety and Depression Scale. An updated 
literature review. J Psychosom Res, 2002. 52(2): p. 69-77. 
17. 
Feraheme package insert 2009, AMAG Pharmaceuticals, Inc.: Lexington, MA. 
18. 
Spinowitz, B.S., et al., Ferumoxytol for treating iron deficiency anemia in CKD. J Am Soc 
Nephrol, 2008. 19(8): p. 1599-605. 
19. 
Provenzano, R., et al., Ferumoxytol as an intravenous iron replacement therapy in 
hemodialysis patients. Clin J Am Soc Nephrol, 2009. 4(2): p. 386-93. 
 

SAP_001.pdf: 
July 18, 2014 
Title: Pilot study: randomized, placebo-controlled comparator trial of IV vs oral iron treatment of RLS 
with Iron deficiency anemia. (IVOR-IDA)  
  
Principal Investigator:  Michael Auerbach, M.D.  
  
   
  
 


 
 


INTRODUCTION 
 
Summary: The restless legs syndrome (RLS), also known as Willis-Ekbom Disease, occurs in 40-
50% of patients with iron deficiency (ID) or its end stage, iron deficiency anemia (IDA) (Achebe, AJH, 
2023).  Treatment correcting the ID is expected to also be effective for reducing or eliminating the RLS 
with IDA.  Two accepted treatments for IDA, oral ferrous sulfate and ferumoxytol were compared for 
efficacy and speed of response for treatment of RLS occurring with IDA (RLS-IDA).  The original plan for 
this study was the accrual of 70 RLS-IDA patients to be randomly assigned 35 each to oral or IV iron 
using double-blind, double-dummy procedures.  The primary outcome was determined at 6 weeks of 
treatment.  Following initial evaluation, due to complications of performing a clinical trial during the 
pandemic and the death of the principal investigator, it was determined that the patient and clinical 
global impression scores, primary outcomes for the trial, were missing in 30 patients.  As a result, in 
order to maintain the prespecified statistical analysis, an additional 30 patients were accrued. 
 
Background: Low iron status is associated with RLS.  RLS has been documented to have 
significant deceased iron concentrations in the substantia nigra (Allen, Neurology, 2001) and other areas 
(Rizzo, Movement Disorders, 2013).  These associations have been documented into studies using both 
magenetic resonance imaging (Allen, Rizzo, Earley Sleep Med 2006) and ultrasound (Schmidauer, Ann 
Neuro 2005).  Peripheral iron status also relates to RLS severity (Sun, Sleep 1998) and both oral and IV 
iron treatments significantly reduce RLS symptoms compared with placebo (Allen, Sleep Med 2011 and 
Wang, Sleep Med 2009). 
 
RLS occurs commonly with IDA.  In the single institution in which the study was performed the 
prevalence of clinically significant RLS was approximately 45% (Achebe, AJH).  This is approximately 
seventeen times the prevalence of any RLS in the general population.  Standard treatments for IDA also 
treat RLS without IDA.  Both oral and IV iron are considered standard treatments for IDA (Schrier, UTD 
2013).  These same treatments also reduce RLS symptoms.  Oral iron as ferrous sulfate containing 60 mg 
of elemental iron per table, taken twice daily produced significant reduction of RLS symptoms in a 
blinded placebo-controlled study (Wang, Sleep Med).  IV iron administered as ferric carboxymaltose in 
two doses of 750 mg spaced five days apart, also reduced RLS symptoms significantly more than placebo 
(Allen, Sleep Med). 
 
Rationale for study: It is assumed the treatments which reverse IDA will also reduce the RLS 
symptoms occurring with IDA.  This is supported by the benefit observed in RLS patients without IDA.  
However, this benefit has never been demonstrated in a prospective controlled trial, especially in a 
blinded study.  The iron stores, however, are less in those with IDA than in the general population and 


therefore IDA-RLS may require more aggressive treatment than is used for RLS without IDA and possibly 
even more aggressive therapy than is usually administered for IDA.  In particular, despite the recovery of 
anemia after six weeks of oral iron therapy, the actual iron stores remain low.  In contrast the IV iron 
treatment with 1000 mg of IV iron corrects the anemia and provides a better increase in iron 
parameters over a 6-week period (Schrier UTD, 2013).  Accordingly, if the IDA-RLS results more from the 
low iron than the anemia, it may benefit significantly more from IV than oral iron [BUT IT DIDN’T—
DAMNIT!].   
 
Our major problem in testing the treatment benefits for IDA-RLS for either oral or IV iron was 
not knowing the actual effect size of either treatment.  We had as an initial estimates the effect sizes 
from clinical experience with oral and IV iron therapy for IDA-RLS.  Thus, we set the sample size to give 
adequate power to differentiate IV from oral iron assuming these estimates, without knowing if the 
estimates were accurate.  The decision not to do a placebo control is based on the assumption that the 
treatment effect size can be adequately determined without a placebo.  The decision to use a blinded 
comparator trial was based on the assumption that we would see differences between the treatments.   
 
METHODS 
 
The study was a randomized, comparative, double-blind study to evaluate effect size and time 
course of treatment response for RLS-IAD over six weeks.  Two medications and two placebos were used 
with equal random assignment to both groups: 
1. FCM group: Oral vitamin C, 500 mg tablets taken twice a day (placebo pill) and Ferumoxytol 
intravenous (IV) 1020 mg in two divided doses over 15 minutes 2-7 days apart 
2. FeSO4 group: Ferrous sulfate 325 mg (oral) tabs morning and evening and IV saline given 
over 15 minutes 2-7 days apart (placebo infusion) 
IV ferumoxytol, 1020 mg was be offered to those not significantly responding (CGI-I scores less than 
much or very much improved) at 6 weeks after oral iron and still meeting all the requirements for entry 
to study.   
 
All patients who presented to a single outpatient Hematology clinic for treatment for their iron 
deficiency anemia (IDA), completed the Cambridge-Hopkins diagnostic questionnaire (CDQ) as part of 
their routine clinical evaluation, which was not limited to its use in this study.  Those identified by the 
questionnaire as having RLS were checked for meeting the other inclusion criteria. The research 
coordinator reviewed the responses to the questionnaire, their clinical history and recent blood values 
to ensure inclusion criteria were met.  If all criteria were met, the research coordinator consented the 


patient for enrollment in the study.  After consenting, a protocol number was assigned and appropriate 
blood samples obtained. Diagnosis of RLS was then confirmed by Hopkins-Hening Telephone Diagnostic 
Interview (HTDI) conducted by Dr. Allen or Dr. Earley. 
 
A xcel-generated randomization table was used to randomly assign subjects to one of two 
treatment conditions. Blinding was done by a separate and independent “treatment nurse” who used 
the randomize table, made the assignments on the day of treat and then completed the appropriate 
treatment.  The randomization was in 7 blocks of 10 with equal treatments in each block.   The research 
coordinator did not know the treatment administered and was not present during treatment and did 
not have access to files indicating, which treatment was administered.  During IV infusions, the patients 
wore sleep masks that fully covered their eyes to ensure they did not notice any color differences 
between the iron and placebo administration. All investigators and the Analysts were blind to the 
assignment until completion of the analysis. 
 
Two IV treatments spaced 2-7 days apart were administered.  These were either ferumoxytol or 
placebo.  At the time of the first infusion, an opaque bottle containing either vitamin C or ferrous sulfate 
was given to the subject.  The patient was instructed to take each of the pills twice a day for the next six 
weeks.  Enough pills to last 7 seven weeks were given to allow for ongoing treatment for the follow-up 
appointment at six weeks after the first IV infusion. 
 
For IV iron treatment, the commercially available ferumoxytol was used.  Ferumoxytol is 
marketed as an iron replacement formulation indicated for the treatment of iron deficiency anemia and 
is FDA approved for this indication.  Ferumoxytol (30 mg/mL) is available for IV injection in single use 
vials containing 510 mg of elemental iron in 17 mL.  Ferumoxytol is stored at controlled room 
temperature (20-25o C).  Pre-treatment medications were not administered.  510 mg of ferumoxytol was 
diluted in 100 ml normal saline and administered with an infusion pump over a 15-minute period.  Vital 
signs were measured and recorded immediately prior to drug administration and were observed for 60 
minutes following completion of the infusion with observation for signs or symptoms of adverse events.  
For the placebo (normal saline) administration was exactly the same procedure as the IV iron 
formulation. 
 
For oral iron, ferrous sulfate 325 mg tablets containing 65 mg of elemental iron were used.  The 
pills were taken twice daily on an empty stomach.  If significant gastrointestinal perturbation occurred 
the medication could be taken with food.  The oral placebo was standard vitamin C 250 mg tablets given 
in the same bottle as oral iron. 


 
Following the first IV infusion, telephone evaluations were performed at 7, 14 and 28 days.  At 
four weeks after the first of the pair of IV treatment were completed, blood tests were performed to 
include hemoglobin concentration and iron parameters (serum iron, total iron binding capacity, serum 
ferritin, percent transferrin saturation).  A six weeks after the first of the pair of IV treatment were 
completed, another clinic visit was scheduled so a CGI form could be completed by involved medical 
personnel.   At 6 weeks, non-responders were given the option of receiving ferumoxytol as an open-
label infusion. At the 6-week clinic visit, repeat blood tests (see above), adverse event reporting and 
clinical evaluation of the RLS was performed.   
 
Inclusion criteria were as follows: 
1. Aged ≥ 18 years  
2. Diagnosis of RLS based on CHDQ and confirmed by HTDI 
3. International RLS Study Group Severity Scale (IRLS) score > 15. 
4. Iron deficiency anemia defined as ID either ferritin < 20 mcg/l, TSAT <19%, anemia Hb <13 g/dL 
for both males and females. 
5. Willingness to use contraceptive to avoid pregnancy: Women have to be surgically sterile, post 
menopausal or use one of the following contraceptives during the whole study period and after 
the study has ended for at least 5 times plasma biological half-life of the investigational 
medicinal product: intrauterine devices or hormonal contraceptives (contraceptive pills, 
implants, transdermal patches, hormonal vaginal devices, or injections with prolonged release).   
6. Willingness to participate and signing the informed consent form 
 
Exclusion criteria were as follows: 
1. Iron overload or disturbances in utilization of iron (e.g. haemochromatosis and hemosiderosis) 
2. Decompensated liver cirrhosis or active hepatitis (ALAT > 3 times upper limit of normal) 
3. Serum ferritin > 500 ng/mL or transferrin saturation >40 %  
4. Active acute or chronic infections (assessed by clinical judgment that may be indicated by white 
blood cells (WBC) and C-reactive protein (CRP) when these are available) 
5. Rheumatoid arthritis with symptoms or signs of active inflammation 
6. Pregnant and nursing women 
7. History of multiple allergies    
8. Known hypersensitivity to parenteral or oral iron or any excipients in the drug products 
9. Previous IV iron treatment for RLS 
10. Other iron treatment or blood transfusion within 4 weeks prior to the screening or treatment 
visit 
11. Planned elective surgery during the study 
12. Current (past 4 weeks) use of drugs that treat RLS, e.g. opioids, alpha-2-delta anti-depressants, 
dopaminergic agents (dopamine promoters, dopamine antagonists/blockers) 


Any other medical condition that, in the opinion of Investigator, may cause the subject to be unsuitable 
for the completion of the study or place the subject at potential risk from being in the study, e.g. a 
malignancy, uncontrolled hypertension, unstable ischemic heart disease, or uncontrolled diabetes 
mellitus. 
     The following endpoint were used for the study: 
 
1. At evaluation in the clinic at about 6 weeks after the first IV iron treatment. 
 
 
 
2. Termination of participation because of significant adverse effect from the IV infusion in the 
hour observed after the infusion. 
 
 
3. Significant adverse event after starting the iron treatment and before the 6 week follow-up 
evaluation that was judged to require ending the study. 
 
4. Subject decision not to continue in the study after the treatment and before the final 
evaluation.  
 
5. Physician’s decision that it would be harmful to the patient to continue in the study. 
              6. Patient is non-compliant with study requirements and was judged the non-compliance was 
enough to significantly alter evaluation of the treatment. (Note that stopping the oral medication 
because of intolerance to the treatment is not considered non-compliance, but rather an outcome for 
the study).  Patients discontinuing oral medication for adverse effects may qualify for repeat IV 
treatment. 
     Subjects could terminate the study at any time for could be terminated from the study for non-
compliance or if continuation in the study was judged by the PI (Dr. Auerbach) to be harmful.  Reasons 
for termination were recorded.  21 patients were terminated or lost to follow-up.  Some of these 
terminations may have been due to hiatuses in the study caused by the untimely death of the principal 
investigator (Dr. Allen) and the untimely occurrence of the COVID pandemic, interfering with patient 
visits.  A list of those terminated or lost to follow-up are reported in Table ___.  As a result, an additional 
30 patients were accrued above the planned prespecified number, to achieve appropriate statistical 
power. 
     There were two co-primary outcome measures: Clinician Global Inventory-Improvement (CGI-I) 
assessment at week 6 and the change-in-baseline at 6 weeks in International RLS Study Group Severity 
Scale (IRLS) score. The Patient Global Inventory-Severity (PGI-S) was a secondary outcome measure (PGI-
S). The IRLS and PGI-S were obtained at the clinic visits and at each telephone evaluation, while the CGI-i 
was only obtained at the Week-6 study endpoint. 
Statistical analysis 
Baseline and follow up laboratory values were described overall and within each study group. Means 
and standard deviations and medians and ranges were produced for continuous variables, and 
frequency counts and percentages were generated for describing variables that were dichotomous or 


polytomous in nature. Changes in laboratory values from baseline to follow up were calculated and the 
mean change in values was compared using t-tests. 
 
Results 
Baseline lab values of all subjects and by Group are found in Table 1. There was a significant difference 
between baseline ferritin and TSAT values. Group A had a higher baseline ferritin and TSAT values than 
Group B.  
 
Change in hemoglobin and iron parameters for all subjects and by group are shown in Table 3. The mean 
change in hemoglobin from baseline to follow up was 1.2 (SD 1.3) for Group A and 6.0 (17.2) for Group 
B. The mean change in Ferritin from baseline to follow up was 200.3 and 23.3 for Group A and Group B, 
respectively. The mean change in TSAT from baseline to follow up was 16.5 and 12.2 for Group A and 
Group B, respectively. The mean change in MCV from baseline to follow up was 24.2 and -17.6 for Group 
A and Group B, respectively. There was a significant difference between follow up ferritin and TSAT 
values. Group A had a higher follow up ferritin values (p=0. <0.0001) and higher TSAT (p=0.007) values 
compared to Group B. 
 
Table 4 shows the changes in patient severity scores from baseline to follow up, and the follow up 
patient and clinical global impression scores for all subjects and by group. No significant differences 
between the 2 groups in terms of change in (1) patient severity score from baseline to follow up, (2) 
follow up patient global impression score, or (3) clinical global impression score were observed. 
 
Table 5 shows the change in FSS from baseline to follow up. There were no significant differences 
between the 2 groups in terms of change in FSS.  
 
Table 6 shows the change in IRLS score from baseline to follow up for all subjects and by group. Group B 
had a greater reduction in IRLS score from baseline to follow up compared to Group A 
 
NOT SURE IF/HOW YOU WANT TO PRESENT THE ADVERSE REACTION DATA 
 
Commented [VS1]: These are results from my original 
analysis. I still need to double check the results. However, 
before doing so, I want to confirm that there are no new 
data to analyze.  
Commented [VS2]: Will define "Group A" and "Group B" 
once I know which group is which 


TABLES 
Table 1. Baseline hemoglobin and iron parameters for all subjects and by group. 
 
 
Total 
Group A 
Group B 
P-value1 
Hemoglobin 
Mean (SD) 
Median (IQR) 
Min, Max 
N=93 
11.1 (1.5) 
11.6 (10.2, 12.2) 
7.0, 13.1 
N=47 
11.3 (1.3) 
11.7 (10.8, 12.3) 
7.2, 13.1 
N=46 
10.8 (1.6) 
11.6 (9.7, 12.1) 
7.0, 13.0 
0.14 
Ferritin 
Mean (SD) 
Median (IQR) 
Min-Max 
N=91 
17.9 (16.7) 
11.0 (7, 24) 
3, 102 
N=45 
22.6 (19.6) 
19 (7, 29) 
4, 102 
N=46 
13.5 (12.1) 
10.0 (7-15) 
3.0, 59.0 
0.017 
TSAT 
Mean (SD) 
Median (IQR) 
Min-Max 
N=92 
10.4 (6.2) 
9.0 (6, 13) 
2, 36 
N=46 
11.4 (5.9) 
10.0 (8, 15) 
2, 36 
N=46 
9.5 (6.5) 
8.5 (6.0-11.0) 
2, 32 
0.025 
MCV 
Mean (SD) 
Median (IQR) 
Min-Max 
N=93 
88.7 (77.3) 
83 (75.5, 87.0) 
56.5, 825.0 
N=47 
82.2 (7.8) 
83.9 (77.9, 86.3) 
58.7, 100.0 
N=46 
95.4 (110.4) 
81.5 (71.6-87.0) 
56.5, 825.0 
0.233 
1 P value comparing Group A vs. Group B using Kruskal-Wallis Test. 
 
 
 
 


Table 2. Follow-up hemoglobin and iron parameters for all subjects and by group. 
 
 
Total 
Group A 
Group B 
P-value1 
Hemoglobin 
Mean (SD) 
Median (IQR) 
Min-Max 
n=70 
14.4 (11.8) 
12.4 (11.7, 13.3) 
9.7, 105.0 
N=36 
12.5 (1.0) 
12.6 (11.9, 13.2) 
10.4, 14.3 
N=33 
16.6 (17.0) 
12.3 (11.7, 13.4) 
9.7, 105.0 
.833 
Ferritin 
Mean (SD) 
Median (IQR) 
Min-Max 
n=70 
132.8 (136.7) 
66.5 (27.0, 214.0) 
7.0, 620.0 
N=36 
223.4 (136.6) 
209.5 (127.5, 308.5) 
11.0, 620.0 
N=33 
37.1 (29.5) 
33.0 (21.0-40.0) 
7.0, 159.0 
<0.0001 
TSAT 
Mean (SD) 
Median (IQR) 
Min-Max 
n=70 
24.4 (13.3) 
24.0 (14.0, 31.0) 
7.0, 89.0 
N=36 
27.7 (10.0) 
28.0 (20.5, 32.0) 
13.0, 59.0 
N=33 
21.4 (15.5) 
16.0 (12.0-28.0) 
7.0, 89.0 
0.026 
MCV 
Mean (SD) 
Median (IQR) 
Min-Max 
n=70 
95.1 (93.7) 
86.0 (82.0-88.6) 
36.8, 864.0 
N=36 
106.4 (130.2) 
86.8 (82.7, 88.8) 
36.8, 864.0 
N=33 
83.3 (10.6) 
85.1 (80.0-88.1) 
38.7, 101.0 
0.21 
1 P value comparing Group A vs. Group B using Kruskal-Wallis Test. 
 
 
 
 


Table 3. Change in hemoglobin and iron parameters from baseline to follow up for all subjects and 
by group. 
 
 
Total 
Group A 
Group B 
P-
value1 
Hemoglobin 
Mean (SD) 
Median (IQR) 
Min-Max 
N=70 
3.5 (12.0) 
1.4 (0.2-2.3) 
-0.9, 95.6 
N=36 
1.2 (1.3) 
1.4 (0.2, 1.8) 
-0.9, 5.0 
N=33 
6.0 (17.2) 
1.7 (0.3, 3.3) 
-0.9, 95.6 
0.17 
Ferritin 
Mean (SD) 
Median (IQR) 
Min-Max 
N=67 
113.1 (130.4) 
35.0 (18, 579) 
-7, 579 
N=34 
200.3 (133.0) 
190.0 (103.0, 290.0) 
-1.0, 579.0 
N=33 
23.3 (21.2) 
20.0 (9.0, 27.0) 
-7.0, 102.0 
<0.0001 
TSAT 
Mean (SD) 
Median (IQR) 
Min-Max 
N=68 
14.4 (12.6) 
13.5 (6.5, 19.4) 
-17.0, 82.0 
N=35 
16.5 (7.5) 
16.0 (11.0, 20.0) 
-5.0, 37.7 
N=33 
12.2 (16.3) 
7.0 (3.0, 18.0) 
-17.0, 82.0 
0.007 
MCV 
Mean (SD) 
Median (IQR) 
Min-Max 
N=70 
4.2 (129.9) 
3.2 (-0.2, 8.2) 
-736.9, 784.4 
N=36 
24.2 (130.9) 
3.3 (-0.4, 7.6) 
-58.4, 784.4 
N=33 
-17.6 (129.5) 
3.1 (1.2, 9.5) 
-736.9, 21.1 
0.49 
1 P value comparing Group A vs. Group B using Kruskal-Wallis Test. 
 
 
 
 


Table 4. Change in patient severity scores from baseline to follow up, and follow up patient and 
clinical global impression scores for all subjects and by group. 
 
 
Total 
Group A 
Group B 
P-value1 
Change in patient severity score2 
Mean (SD) 
Median (IQR) 
Min-Max 
N=57 
-1.9 (1.8) 
-2.0 (-3.0, -1.0) 
-5.0, 2.0 
N=30 
-1.7 (1.8) 
-2.0 (-3.0, -1.0) 
-5.0, 2.0 
N=27 
-2.1 (1.9) 
-3.0 (-4.0, -1.0) 
-5.0, 2.0 
0.24 
Follow up patient global impression score3 
Mean (SD) 
Median (IQR) 
Min-Max 
N=77 
2.1 (1.2) 
2.0 (1, 3) 
1-6 
N=40 
2.1 (1.1) 
2.0 (1, 3) 
1-5 
N=37 
2.1 (1.2) 
2 (1, 3) 
1-6 
.72 
Follow up clinical global impression score3 
Mean (SD) 
Median (IQR) 
Min-Max 
N=72 
2.1 (1.3) 
2.0 (1, 3) 
1-6 
N=38 
2.1 (1.2) 
2 (1, 3) 
1-5 
N=34 
2.1 (1.4) 
1.5 (1, 3) 
1-6 
.80 
1 P value comparing Group A vs. Group B using Kruskal-Wallis Test. 
2 Assessed at baseline and 6 weeks post-baseline. 
3 Assessed at 1-6 weeks post-baseline. 
 
NOTE: If missing 6 wk fup use most recent data point. Do not report change in impression patient and 
clinical scores - report 6 wk fup score 
 
 
 
 
 


Table 5. Change in FSS. 
 
 
Total 
Group A 
Group B 
P-value1 
Change in FSS 
Mean (SD) 
Median (IQR) 
Min-Max 
N=61 
-10.9 (14.6) 
-10 (-17, -2) 
-50, 17 
N=32 
-7.8 (14.2) 
-6 (-17, 3) 
-34, 17 
N=29 
-14.3 (14.5) 
-12 (-17, -6) 
-50, 9 
0.11 
1 P value comparing Group A vs. Group B using Kruskal-Wallis Test. 
2 Assessed at baseline and 6 weeks. 
 
 
Table 6. Change in IRLS score from baseline to follow up for all subjects and by group. 
 
 
Total 
Group A 
Group B 
P-value1 
Change in IRLS score2 
Mean (SD) 
Median (IQR) 
Min-Max 
N=74 
-10.1 (8.8) 
-11 (-15, -3) 
-34-10 
N=37 
-8 (7.7) 
-10 (-13, -3) 
-24-10 
N=36 
-12.2 (9.5) 
-12 (-18, -5) 
-34-7 
0.047 
1 P value comparing Group A vs. Group B using Kruskal-Wallis Test. 
2 Follow up periods:  1 week n=2 ; 2 weeks n=4 ; 4 weeks n=5 ; 6 weeks n=61 . 
 
 


 
Adverse Events 
 
Baseline 
 
Group A 
6 subjects 
 Constipation 
 Diarrhea 
 Mouth burns 
 Chest pain 
 Flushing 
 Sneezing 
 Scratchy throat 
Group B 
7 subjects 
 Fatigue 
 Constipation 
 stomach issues, constipation 
 unable to tolerate pills, stomach cramps, nausea 
 constipated, stopped pills 
 nausea, vomiting 
 
 
Day 7 
 
Group B 
3  
 stomach, headache 
 stomach, diarrhea, nausea 
 stomach, constipation 
 
 
Day 28 
 
Group A 
1 
 stomach issues, constipation 
Group B 
1 
 stomach issues and dyspnea 
 
 
Week 6 
 
Group A 
6  
 mild stomach issues 
 Stomach upset, stomach pain, constipation, diarrhea, nausea, vomiting, dizziness, 
hyptotension, headache, chest pain, back pain, cough, prexia, rash, Back pain, 
muscle spasms, Stomach upset, stomach pain, constipation, diarrhea, nausea, 
vomiting, dizziness, hypotension, peripheral edema, edema, headache, chest pain, 
back pain, cough, pruritus, Prexia, muscle spasms, Dyspnea, Rash, Diarrhea, 
Peripheral Edema, Back Pain, Cough, Muscle Spasms 
Group B 
10 
 Mild edema 
 Constipation 
 Mild constipation 
 Constipation 
 Diarrhea, Nausea, Dizziness, Headache, Chest Pain, Back Pain, Cough, Muscle 
Spasms 
 Constipation, Diarrhea 
Commented [VS3]: I don't know how you want to report 
the adverse events since there are numerous time points 
from baseline to 12 months follow up. 


 Stomach, Constipation 
 Headache, hives, stuffy noses 
 Diarrhea, Nausea, Muscle Spasms 
 Stomach issues 
 
 
Month 3 
 
Group B 
1 
 Constipation 
 
 
Month 12 
 
Group A 
1 
 Constipation