Clinical trial NCT02826681
Conditions: Restless Legs Syndrome (RLS)
Sponsor: American Regent, Inc.
Start date: 2017-07-10; Completion date: 2022-07-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Treatment Phase I and II Primary Objective: To evaluate the efficacy and safety of FCM (750 mg dose x 2) for treatment of Restless Legs Syndrome (RLS) in patients with iron-deficiency anemia (IDA).

Long-Term Extension Phase III Primary Objective: To evaluate the duration of effect of prior FCM treatment and to determine the effectiveness of further iron repletion with FCM when RLS symptoms worsen or reoccur.

Detailed description:
This will be a Phase II, randomized, placebo-controlled study. All subjects who meet the inclusion criteria, with no exclusion criteria, will qualify to enter the Screening Phase. The study will enroll 70 eligible subjects to receive blinded study drug in Treatment Phase I. All eligible subjects will be randomized in a 1:1 ratio to receive a blinded dose of either FCM 750 mg undiluted slow intravenous (IV) push at 100 mg/minute or a Placebo (15 ml of Normal Saline \[NS\]) IV push at 2 ml/minute on Day 0 and 7.

A subject will be defined at Day 42 as a Responder if the International Restless Legs Syndrome Severity Scale (IRLSS) score is ≤10 or if the IRLSS score is \>10 with a Clinical Global Impression-Improvement (CGI-I) score of much or very much improvement and the subject does not request further treatment for RLS. A subject will be defined as a treatment Non-Responder if neither of these criteria are met.

Non-Responders who do not meet the laboratory criteria for additional dosing will be discontinued from the study and treated for RLS as deemed appropriate by the referring physician. Subjects who are Non-Responders at the end of Treatment Phase I and met the necessary laboratory criteria (ferritin \<300 ng/mL and a TSAT \<45%) will consented for enrollment in Treatment Phase II of the study. These subjects will receive the first of two unblinded doses of FCM (undiluted slow IV push 750 mg 100 mg/minute) on Day 0 of Phase II, which will occur within 7 days of the completing Treatment Phase I visit. The subjects will then receive the second dose of FCM (undiluted slow IV push 750 mg 100 mg/minute) on Day 7. All treated subjects will have blood samples taken for hematology, chemistries and iron indices on Day 14. Treatment efficacy (IRLSS score), medication review and adverse events assessment by phone will be done on Day 28. All subjects will return to the clinic on Day 42 for end of study assessments. Subjects completing Treatment Phase II will be re-evaluated on Day 42 and defined as either a Responder or Non-Responder, using the same criteria described above. Subjects deemed as treatment Non-Responders will be discontinued from the study after final assessments are complete.

Subjects who are evaluated on Day 42 (Week 6) as Responders from either Treatment Phase I or Treatment Phase II will continue through into the 46-Week, Long-Term Extension Phase III of the study, and be monitored and assessed by phone for RLS symptoms (IRLSS and Hopkins RLS-Sleep Quality Questionnaire \[HRSQ\]) and adverse events on (approximately every 9 weeks) Weeks 15, 25, 34, 43 and 52 (final follow-up visit). During Phase III subjects may receive additional unblinded treatments with FCM if at any time the subject reports worsening of RLS symptoms (an increase \>4 points on the IRLSS compared to the last evaluation captured for that subject) and laboratory criteria are met (ferritin \<300 ng/mL and a TSAT \<45%). Subjects will receive a single FCM 750 mg undiluted slow IV push at 100 mg/minute. See section 6.6 for dosing and assessment outline. No additional treatment will be allowed after the Week 46. A final face-to-face study visit will occur on Week 52 (approximately 365 days since initial Day 0 Treatment). If a clinic visit is not possible, final evaluation will be completed by phone.

Arms: arm 1: 750 mg undiluted slow IVpush (100 mg/minute) of Injectafer® (Ferric Carboxymaltose - FCM) arm 2: Placebo (15 ml of Normal Saline \[NS\]) IV push at 2 ml/minute on Day 0 and 7.
Interventions: intervention 1: Injectafer® (Ferric Carboxymaltose - FCM) intervention 2: Placebo (Normal Saline)
Intervention descriptions: intervention 1: Intravenous Iron intervention 2: Normal Saline Solution

Protocol documents:
Prot_000.pdf: 
Table of Contents
Table of Contents
Protocol No. 1VIT15042: NCT Number: 02826681: Date: 25APR2016
5
New Protocol Submission 1VIT15042
6
Signatures of Agreement for Protocol
7
Study Synopsis
8
Table of Contents
16
List of Abbreviations and Definitions
19
1.0 Introduction
21
1.2 Role of Iron in the Pathogenesis and Pathophysiology of RLS
21
1.3 Injectafer (Ferric Carboxymaltose)
22
1.3.1 Key features of Injectafer
22
1.3.2 Injectafer versus Other Parenteral Iron Agents
22
1.3.3 Injectafer Human Experience: Marketed Use and the RLS Indicator
22
2.0 Trial Objective
23
2.1 Primary Objective
23
3.0 Rationale and Overall Study Design
23
3.1 Rationale
23
3.2 Trial Design
24
Table 3.2.1 Schedule of Events Treatment Phase I and Treatment Phase II
26
Table 3.2.2 Schedule of Events Long-Term Extension Phase III
26
4.0 Subject Selection
27
4.1 Number and Type of Subjects
27
4.2 Screening Phase
27
4.2.1 Inclusion Criteria
27
4.2.2 Exclusion Criteria
27
4.3 Subject Assignment and Randomization Process
28
4.4 Duration of Study/Withdrawal from Study
28
4.5 Endpoint sin participation/Early termination endpoints
29
4.6 Treatment Respodner and Non-Responder:
29
5.0 Study Drug
29
5.1 Formulation Packaging and Storage
29


5.2 Study Drug Blinding/Administration
30
5.2.1 Study Drug Blinding
30
5.3 Study Drug Administration
31
5.4  IV Iron Precautions
31
5.5 Drug Accountability
32
5.6 Concomitant Medication
32
6.0 Study Procedures
33
6.1 Informed Consent
33
6.2 Screening (up to 14 days)
33
6.3 Ranomization
33
6.4 Treatment Phase I/Treatment Phase II Assessments
34
6.4.1 Treatment Phase I
34
6.4.2 Treatment Phase II (Repeat Days 0-42)
36
6.5 Long-Term Extension Phase III (46-Week extension of Treatment Responders 
from Pahse I or II)
37
6.6 Long-Term Extension Phase III Treatment
38
6.7 Laboratory Assessments
38
7.0 Assessment of Safety
39
7.1 Adverse Events
39
Table 7.1.1 Grading of Adverse Event Severity as per CTCAE v4.0
39
7.2 Reporting of Adverse Events
40
7.3 Serious Adverse Events (SAE)
41
7.4 OTher Reportable Information
42
8.0 Statistics
42
8.1 Sample Size Rationale
42
8.2 Analysis Populations
42
8.3 Disposition and Baseline Characteristics
43
8.4 Endpoints and Definitions
43
8.4.1 Primary Endpoints
43
8.4.2 Secondary Endpoints
44
8.4.3 Safety Evaluations
44
8.5 Statistical Analyses of Efficacy
44
8.5.1 Exploratory Analyses
45
8.6 Statistical Analyses of Safety
45


8.7 Interim Analyses
46
9.0 Administrative Considerations
46
9.1 Retention and Availabilty of Records
46
9.2 Investigator Responsibilities
47
9.3 Financial Disclosure
47
9.4 Advertisement for Subject Recruitment
47
9.5 Documents Required for Study Initiation
48
9.6 Quality Control and Quality Assurance
48
9.6.1 Investigator Selection Criteria
48
9.6.2 Clinical Monitoring
48
9.6.3 Quality Assurance Audit
49
9.7 Ethics
49
9.7.1 Ethical and Legal Issues
49
9.7.2 Institutional Review Board (IRB)
49
9.7.3 Informed Consent
49
9.7.4 Good Clinical PRactice
50
9.8 Data Handling and Record Keeping
50
9.8.1 Case Report Form (CRF)
50
9.8.2 Confidentiality
50
9.8.3 Termination of the Study
51
9.8.4 Protocol Revisions
51
9.8.5 Protocol Administrative Changes
51
9.9 Publication Policy
51
10.0 Governance Committee
52
10.1 There will be no Data Safety Monitoring Board for this study
52
Investigator's Acknowledgement
53
Appendix I: RLS Assessment Tools
54
Clinical Global Impression-Improvement (CGI-I)
59
International RLS Severity Scale (IRLSS)
60
Personal Global Impression-Improvement (PGI-I)
63
Medical Outcome Survery of Sleep Scale (MOS-Sleep)
64
Cambridge-Hopkins Diagnostic Questionnaire (CHDQ)
66
The Hopkins-Hening Telephone Diagnostic Interview (HTDI)
68
Hopkins RLS-Sleep Quality Questionnaire (HRSQ)
67


References
55


PROTOCOL
Protocol No.: 1VIT15042
andomized, placebo-controlled trial of ferric carboxymaltose 
in Restless Legs Syndrome patients with iron-deficiency 
anemia  
NCT Number: 02826681 
Date: 25APR2016


Page 1 
LUITPOLD PHARMACEUTICALS, INC. 
PROTOCOL 
No. 1VIT15042 
IND #: 73,076 
Randomized, placebo-controlled trial of ferric carboxymaltose in Restless Legs Syndrome 
patients with iron-deficiency anemia  
SPONSOR 
Luitpold Pharmaceuticals, Inc. 
Clinical Research and Development 
800 Adams Avenue 
Norristown, PA 19403 
(610) 650-4200
PROTOCOL DATE: 25 April 2016 




Luitpold Pharmaceuticals Inc. 
 
 Protocol: 1VIT15042                                            
CONFIDENTIAL                                                                                                             Protocol Date: 25April2016 
Page 3 
STUDY SYNOPSIS 
Protocol 1VIT15042 
Title:  Randomized, placebo-controlled trial of ferric carboxymaltose in Restless Legs Syndrome 
patients with iron-deficiency anemia  
Investigational Drug: Injectafer® (Ferric Carboxymaltose - FCM)  
                                     
Treatment Phase I and II Primary Objective:  To evaluate the efficacy and safety of  
FCM (750 mg dose x 2) for treatment of Restless Legs Syndrome (RLS) in patients with iron-
deficiency anemia (IDA). 
Long-Term Extension Phase III Primary Objective:  To evaluate the duration of effect of 
prior FCM treatment and to determine the effectiveness of further iron repletion with FCM when 
RLS symptoms worsen or reoccur. 
Study Design:  This will be a Phase II, randomized, placebo-controlled study. All subjects who 
meet the inclusion criteria, with no exclusion criteria, will qualify to enter the Screening Phase. 
The study will enroll 70 eligible subjects to receive blinded study drug in Treatment Phase I.  
All eligible subjects will be randomized in a 1:1 ratio to receive a blinded dose of either  
FCM 750 mg undiluted slow intravenous (IV) push at 100 mg/minute or a Placebo  
(15 ml of Normal Saline [NS]) IV push at 2 ml/minute on Day 0 and 7.  
 
 
A subject will be defined at Day 42 as a Responder if the International Restless Legs 
Syndrome Severity Scale (IRLSS) score is ≤10 or if the IRLSS score is >10 with a 
Clinical Global Impression-Improvement (CGI-I) score of much or very much 
improvement and the subject does not request further treatment for RLS.  A subject will 
be defined as a treatment Non-Responder if neither of these criteria are met.  
Non-Responders who do not meet the laboratory criteria for additional dosing will be 
discontinued from the study and treated for RLS as deemed appropriate by the referring 
physician. Subjects who are Non-Responders at the end of Treatment Phase I and met the 
necessary laboratory criteria (ferritin <300 ng/mL and a TSAT <45%) will consented for 
enrollment in Treatment Phase II of the study. These subjects will receive the first of two 
unblinded doses of FCM (undiluted slow IV push 750 mg 100 mg/minute) on Day 0 of Phase II, 
which will occur within 7 days of the completing Treatment Phase I visit. The subjects will then 
receive the second dose of FCM (undiluted slow IV push 750 mg 100 mg/minute) on Day 7.  All 
treated subjects will have blood samples taken for hematology, chemistries and iron indices on 
Day 14. Treatment efficacy (IRLSS score), medication review and adverse events assessment by 
phone will be done on Day 28. All subjects will return to the clinic on Day 42 for end of study 
assessments.  Subjects completing Treatment Phase II will be re-evaluated on Day 42 and 
defined as either a Responder or Non-Responder, using the same criteria described above.  
Subjects deemed as treatment Non-Responders will be discontinued from the study after final 
assessments are complete. 


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Subjects who are evaluated on Day 42 (Week 6) as Responders from either Treatment Phase I or 
Treatment Phase II will continue through into the 46-Week, Long-Term Extension Phase III of 
the study, and be monitored and assessed by phone for RLS symptoms (IRLSS and  
Hopkins RLS-Sleep Quality Questionnaire [HRSQ]) and adverse events on (approximately every 
9 weeks) Weeks 15, 25, 34, 43 and 52 (final follow-up visit).  During Phase III subjects may 
receive additional unblinded treatments with FCM if at any time the subject reports worsening of 
RLS symptoms (an increase >4 points on the IRLSS compared to the last evaluation captured for 
that subject) and laboratory criteria are met (ferritin <300 ng/mL and a TSAT <45%).  Subjects 
will receive a single FCM 750 mg undiluted slow IV push at 100 mg/minute.  See section 6.6 for 
dosing and assessment outline.  No additional treatment will be allowed after the Week 46.  A 
final face-to-face study visit will occur on Week 52 (approximately 365 days since initial Day 0 
Treatment).  If a clinic visit is not possible, final evaluation will be completed by phone. 
All subject assessments (screening through end of study) are in the schedule of events  
(section 3.2.1).    
Study Drug Dosing Regimen:  
Treatment Phase I:  Subjects will be randomized to receive either a 750 mg undiluted slow IV 
push (100 mg/minute) of FCM or Placebo (15 ml of Normal Saline [NS]) IV push at  
2 ml/minute on Day 0 and 7.   
Treatment Phase II: Non-Responders from Phase I who qualify will receive an unblinded 750 
mg undiluted slow IV push (100 mg/minute) of FCM on Day 0 and 7 of Phase II.   
Long-Term Extension Phase III:  Qualified subjects can potentially receive an unblinded single 
750 mg undiluted slow IV push (100 mg/minute) of FCM when RLS symptoms worsen or 
reoccur. 
Efficacy and Safety Follow-up:  
 
Primary efficacy endpoint in Treatment Phase I is to determine the effectiveness of FCM in 
improving RLS severity associated with IDA.   Effectiveness will be evaluated by: 
 IRLSS score change from baseline to Day 42 with comparison between 
FCM vs. Placebo. 
 CGI-I at Day 42.  
Primary efficacy endpoint in Treatment Phase II is to determine the effectiveness of an 
additional unblinded single FCM treatment in improving RLS severity in non-responders from 
Treatment Phase I.  Effectiveness will be evaluated by: 
 IRLSS score change from baseline (For Phase II the “baseline” is established on 
Day 42 of Phase I) compared  to Day 42 of Treatment Phase II 
  
 CGI-I at Day 42 in Treatment Phase II. 
Secondary efficacy endpoints evaluated in both Treatment Phase’s I and II are: 


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Page 5 
 Number of treatment responders at Day 42 (Treatment Phase I).  
 Number of treatment responders at Day 42 (Treatment Phase II). 
 IRLSS score change from Baseline (For Phase II the “Baseline” is established on 
Day 42 of Phase I) compared to Day 42 of Treatment Phase II. 
 
 Number of Responders at Day 42 who receive FCM vs. Placebo in Treatment 
Phase I.  
 Number of Responders at Day 42 in Treatment Phase II who receive FCM  
vs. Placebo in Treatment Phase I. 
 CGI-I and PGI-I at each visit and percentage of subjects who are much or very 
much improved at Day 42. (Treatment Phase I and II). 
 Change in IRLSS score from Day 42 (Treatment Phase I and II). 
 Change from baseline brain MRI-determined iron concentration in the substantia 
nigra at or within 4 days after Day 42 (Treatment Phase I and II). 
 Change in sleep quality, Medical Outcome Survey for Sleep (MOS), from Day 42 
for Treatment Phase I and II subjects. 
Primary efficacy endpoint in Long-Term Extension Phase III is to evaluate the duration of 
effect of FCM as defined as the number of weeks from the initial treatment without need for 
further treatment. Initial treatment is defined as Day 0 of Phase I for Responders in Phase I and 
Day 0 of Phase II for Responders in Phase II.   
Secondary object is to determine the effectiveness (number of subjects who remain in the study) 
of additional FCM treatment, in the Long-Term Extension, in those who have worsening of RLS 
symptoms after the initial response. 
 
Primary safety endpoint is to determine the safety of FCM in RLS patients with IDA  
 Safety Evaluations will include: 
o Adverse events 
o Laboratory assessments, including hematology (Hgb, Hct, RBC, WBC, MCV, 
MCH, MCHC, RDW, platelets, differential count ), iron indices (serum iron, 
serum ferritin, and total iron binding capacity (TIBC), percentage serum 
transferrin saturation (TSAT)), clinical chemistry (sodium, potassium, 
chloride, BUN, creatinine, albumin, alkaline phosphatase, total bilirubin, 
gamma-GGT, AST, ALT, LDH, calcium, phosphorus, glucose, bicarbonate)  
o Vital signs  
o Physical examinations. 
Exploratory Aims:  
1. Evaluate potential predictors of Day 42 (Treatment Phases I and II) treatment response 
using clinical, hematologic, and brain MRI data.  
2. The change from baseline in MRI-determined iron concentration for other brain regions. 
3. Correlation between changes in brain iron distribution and measures of peripheral iron 
status, RLS severity, and sleep quality.  


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Page 6 
4. Correlation between CBC, iron indices, and change from Baseline to Day 42 (Treatment 
Phases I and II) RLS severity, sleep, and PGI-I. 
5. Correlation of baseline Vitamin D and post dose change in phosphate. 
6. Vitamin D at each visit. 
 
 
Inclusion Criteria: 
1. Male or female subject ≥18 years of age who is able to give informed consent. 
2. Confirmed diagnosis of RLS based on the Cambridge-Hopkins Diagnostic Questionnaire 
(CHDQ) and the Hopkins-Hening Telephone Diagnostic Interview (HDTI).  
3. IRLSS score ≥15 plus RLS symptoms for at least 3 months and currently occurring ≥2 
nights per week.   
4. Iron-deficiency anemia defined as an Hgb <12 g/dl with a ferritin <20 ng/mL,  
or ferritin <100 when TSAT is <18%. 
5. Subjects on sleep medication must be on a stable dose for at least 6 months prior 
screening. 
6. Subjects at risk for pregnancy must have a negative pregnancy test at screening and be 
practicing an acceptable form of birth control, have had a hysterectomy or tubal ligation, 
or otherwise be incapable of pregnancy, or have practiced any of the following methods 
of contraception for at least one month prior to study entry: hormonal contraceptives, 
spermicide with barrier, intrauterine device, or partner sterility. 
Exclusion Criteria 
 
1. Disorders that require treatment with the same medications used for RLS include: 
peripheral neuropathy and neurodegenerative disorders (i.e. Parkinson’s disease or 
dementia). 
2. Current (past 4 weeks) use of drugs that may cause or treat RLS, e.g. opioids, calcium 
channel alpha-2-delta ligands, anti-depressants, dopaminergic agonist or antagonists, or 
centrally-acting antihistamines. 
3. Any medical conditions contraindicated to MRI. 
4. Abnormal MRI at baseline that would confound the outcome measures. 
5. Secondary RLS due to neurological conditions or head trauma. 
6. History of hemochromatosis, hemosiderosis, other iron storage disorders or iron 
metabolism disorders. 
7. Women with clinically significant uterine bleeding (>200 cc blood loss) during the six 
months prior to screening. 
8. Liver transaminases (AST or ALT) greater than two times the upper limit of normal 
(ULN). 
9. Known positive Hepatitis B antigen (HBs Ag), unless positive test can be attributed to 
receipt of Hepatitis B vaccination in childhood or Hepatitis C viral antibody (HCV) with 
evidence of active hepatitis (i.e., AST/ALT greater than two times the ULN). 
10. Known positive HIV-1 or HIV-2 antibodies (anti-HIV). 
11. Active acute or known chronic infections.  
12. Rheumatoid arthritis with symptoms or signs of active inflammation. 


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Page 7 
13. Pregnant and lactating women.  
14. Known 
hypersensitivity 
reaction 
to 
any 
component 
of 
Injectafer® 
(ferric 
carboxymaltose).  
15. Previously randomized to Injectafer® (FCM or VIT-45) in a clinical trial. 
16. Previous IV iron treatment for RLS. 
17. Parenteral iron, erythropoiesis stimulating agent use or blood transfusion within six 
weeks prior to the screening visit. 
18. Planned elective surgery during the study year. 
19. Chronic alcohol or drug abuse within the past six months. 
20. Any other pre-existing laboratory abnormality, medical condition, or disease that, in the 
opinion of Investigator, may cause the subject to be unsuitable for 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. 
21. Subject is unwilling or has conditions that would prohibit them from complying with the 
study requirements. 
RLS Therapy:  
Subject should not be receiving treatment for RLS.  All 
treatment 
for 
RLS 
should 
be 
discontinued at least 4 weeks prior to screening. 
Study Duration – One year:  
 Screening Phase:  up to 14 days  
 Treatment Phase I:  42 days  
 Treatment Phase II:  42 days  
 Long-term Extension Phase III:  up to 46 weeks 
Number of Subjects / Sample Size: 
Enrollment is planned for completion (reaching Day 42 final assessment) of 70 randomized 
subjects (35 per treatment group).  Based on Study 1VIT05009 in RLS subjects without IDA, 
approximately 50% of subjects  in the FCM group and 15% of subjects in the placebo group are 
anticipated to have much or very much improvement on the CGI-I.35 The proposed sample size 
provides >85% power to detect this difference with the chi-square test.  The mean treatment 
difference and standard deviation of 5.0 (7.3) is estimated for change from Baseline to Day 42 
for IRLSS score.  The proposed sample size provides >80% power to detect this difference with 
the unpaired t-test. 
 
Statistical Analyses: 
 
The percentage responding to treatment will be evaluated for each drug condition in Treatment 
Phase I to determine the treatment difference at Day 42.  This will be calculated from the IRLSS 
as change from Baseline and for the CGI-I with response determined as much or very much 
improved (scores of 1 or 2).  All scores greater than 2 on the CGI-I are considered to indicate no 
significant response.  For Phase II, the proportion of treatment non-responders in Phase I who 


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 Protocol: 1VIT15042                                            
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Page 8 
respond to FCM in Phase II will be estimated and the IRLSS score, CGI-I, and PGI-I will be 
summarized at Day 42.  The duration of treatment over the follow-up to end of study will be 
described as the percentage of responders and the IRLSS score change from Baseline at each 
time point.  Time to first FCM dose after start of Phase III will be estimated with Kaplan-Meier 
methodology. 


Page 9 
Study Design 
 


Page 10 
 
 
CONTACT PERSON FOR THE STUDY 
 
For study related questions please contact: 
 
Angelia D. Butcher 
Senior Clinical Project Manager 
Luitpold Pharmaceuticals, Inc. 
800 Adams Avenue, Suite 100 
Norristown, PA 19403 
 
Telephone: 610-650-4200 
Fax: 610-650-7781 
 
 


Luitpold Pharmaceuticals Inc. 
 
 Protocol: 1VIT15042                                            
CONFIDENTIAL                                                                                                             Protocol Date: 25April2016 
Page 11 
TABLE OF CONTENTS 
LUITPOLD PHARMACEUTICALS, INC. ........................................................................................................... 1 
STUDY SYNOPSIS ............................................................................................................................................... 3 
1.0 
INTRODUCTION ..................................................................................................................................... 16 
1.2 
Role of Iron in the Pathogenesis and Pathophysiology of RLS ..................................... 16 
1.3  
Injectafer® (Ferric Carboxymaltose) ............................................................................. 17 
1.3.1 
Key features of Injectafer® ........................................................................................ 17 
1.3.2 
Injectafer® versus Other Parenteral Iron Agents ....................................................... 17 
1.3.3 
Injectafer® Human Experience:  Marketed Use and the RLS indicator .................... 17 
2.0  
TRIAL OBJECTIVE ................................................................................................................................. 18 
2.1  
Primary Objective .......................................................................................................... 18 
3.0  
RATIONALE AND OVERALL STUDY DESIGN ................................................................................. 18 
3.1  
Rationale......................................................................................................................... 18 
3.2  
Trial Design .................................................................................................................... 19 
4.0  
SUBJECT SELECTION ............................................................................................................................ 22 
4.1  
Number and Type of Subjects ........................................................................................ 22 
4.2 
Screening Phase.............................................................................................................. 22 
4.2.1  
Inclusion Criteria ........................................................................................................ 22 
4.2.2 Exclusion Criteria ............................................................................................................ 22 
4.3 
Subject Assignment and Randomization Process .......................................................... 23 
4.4 
Duration of Study / Withdrawal from Study .................................................................. 23 
4.5 
Endpoints in participation / Early termination endpoints .............................................. 24 
4.6 
Treatment Responder and Non-Responder: ................................................................... 24 
5.0 
STUDY DRUG .......................................................................................................................................... 24 
5.1 
Formulation Packaging and Storage .............................................................................. 24 
5.2  
Study Drug Blinding/Administration ............................................................................. 25 
6.2.1 
Study Drug Blinding ................................................................................................... 25 
5.2.1.1    Unblinded Personnel .................................................................................................. 25 
5.2.1.2 
  Blinded Personnel ................................................................................................. 25 
5.2.1.3 
  Investigator Blinding ............................................................................................ 26 
5.3 
Study Drug Administration ............................................................................................ 26 
5.4 
IV Iron Precautions ........................................................................................................ 26 
5.5 
Drug Accountability ....................................................................................................... 27 
5.6 
Concomitant Medication ................................................................................................ 27 
6.0 
STUDY PROCEDURES ........................................................................................................................... 28 


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6.1 
Informed Consent ........................................................................................................... 28 
6.2 
Screening (up to 14 days) ............................................................................................... 28 
6.3 
Randomization ............................................................................................................... 28 
6.4 
Treatment Phase I / Treatment Phase II Assessments .................................................... 29 
6.4.1 
Treatment Phase I ....................................................................................................... 29 
6.4.1.1 
 Day 0 ...................................................................................................................... 29 
6.4.1.2 
 Day 7 ...................................................................................................................... 30 
6.4.1.3 
 Day 14 .................................................................................................................... 30 
6.4.1.4   
Day 28 Phone contact .......................................................................................... 30 
6.4.1.5 
 Day 42 (End of Treatment Phase I) ....................................................................... 30 
6.4.2 
Treatment Phase II (Repeat Days 0 – 42) ................................................................... 31 
6.4.2.1 
Day 0 and Day 7 ..................................................................................................... 31 
6.4.2.2 
Day 14 ..................................................................................................................... 32 
6.4.2.3 
Day 28 (Phone Contact) .......................................................................................... 32 
6.4.2.4 
 Day 42 (End of Treatment Phase II) ...................................................................... 32 
6.5 
Long-Term Extension Phase III (46-Week extension of Treatment Responders from 
Phase I or II) ............................................................................................................................. 32 
6.6 
Long-Term Extension Phase III Treatment .................................................................... 33 
6.7 
Laboratory Assessments ................................................................................................. 33 
7.0  
ASSESSMENT OF SAFETY .................................................................................................................... 34 
7.1 
Adverse Events ............................................................................................................... 34 
7.2 
Reporting of Adverse Events ......................................................................................... 35 
7.3 
Serious Adverse Events (SAE) ...................................................................................... 36 
7.4      Other Reportable Information ....................................................................................... 37 
8.0 
STATISTICS ............................................................................................................................................. 37 
8.1 
Sample Size Rationale .................................................................................................... 37 
8.2 
Analysis Populations ...................................................................................................... 37 
8.3 
Disposition and Baseline Characteristics ....................................................................... 38 
8.4 
Endpoints and Definitions .............................................................................................. 38 
8.4.1 
Primary Endpoints ...................................................................................................... 38 
8.4.2 
Secondary Endpoints .................................................................................................. 39 
8.4.3 
Safety Evaluations ...................................................................................................... 39 
8.5 
Statistical Analyses of Efficacy...................................................................................... 39 
8.5.1 
Exploratory Analyses ................................................................................................. 40 
8.6 
Statistical Analyses of Safety ......................................................................................... 40 


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8.7 
Interim Analyses ............................................................................................................ 41 
9.0 
ADMINISTRATIVE CONSIDERATIONS .............................................................................................. 41 
9.1 
Retention and Availability of Records ........................................................................... 41 
9.2 
Investigator Responsibilities .......................................................................................... 42 
9.3 
Financial Disclosure ....................................................................................................... 42 
9.4 
Advertisement for Subject Recruitment ......................................................................... 42 
9.5 
Documents Required for Study Initiation ...................................................................... 43 
9.6 
Quality Control and Quality Assurance ......................................................................... 43 
9.6.1 
Investigator Selection Criteria .................................................................................... 43 
9.6.2 
Clinical Monitoring .................................................................................................... 43 
9.6.3 
Quality Assurance Audit ............................................................................................ 44 
9.7 
Ethics .............................................................................................................................. 44 
9.7.1 
Ethical and Legal Issues ............................................................................................. 44 
9.7.2 
Institutional Review Board (IRB)............................................................................... 44 
9.7.3 
Informed Consent ....................................................................................................... 44 
9.7.4 
Good Clinical Practice ................................................................................................ 45 
9.8 
Data Handling and Record Keeping............................................................................... 45 
9.8.1 
Case Report Form (CRF) ............................................................................................ 45 
9.8.2 
Confidentiality ............................................................................................................ 45 
9.8.3 
Termination of the Study ............................................................................................ 46 
9.8.4 
Protocol Revisions ...................................................................................................... 46 
9.8.5 
Protocol Administrative Changes ............................................................................... 46 
9.9 
Publication Policy .......................................................................................................... 46 
10.0  
GOVERNANCE COMMITTEE ........................................................................................................... 47 
10.1 
There will be no Data Safety Monitoring Board for this study .................................. 47 
INVESTIGATOR’S ACKNOWLEDGEMENT .................................................................................................. 48 
APPENDIX I: RLS Assessment Tools: ................................................................................................................ 49 
 
 
Tables 
Table 3.2.1  
Schedule of Events Treatment Phase I and Treatment Phase II .......................... 21 
Table 3.2.2  
Schedule of Events Long-Term Extension Phase III .......................................... 21 
Table 7.1.1  
Grading of Adverse Event Severity as per CTCAE v 4.0 ................................... 34 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
 
bpm 
 
 
 
 
Beats per minute 
C 
 
 
 
 
Degree Celsius 
CFR 
 
 
 
 
Code of Federal Regulations 
CGI-I  
 
 
 
Clinical Global Impression- Improvement 
CHDQ  
 
 
 
Cambridge-Hopkins Dianostic Questionnaire 
CKD  
 
 
 
Chronic Kidney Disease 
CNS  
 
 
 
Central Nervous System                           
CRF 
 
 
 
 
Case Report Form 
CSF 
 
 
 
 
Cerebral Spinal Fluid 
CPAP  
 
 
 
Continuous Positive Airway Pressure 
CTCAE 
 
 
 
Common Terminology Criteria for Adverse Events 
DAWS 
 
 
 
Dopamine agonist withdraw syndrome 
F 
 
 
 
 
Degree Fahrenheit 
FAS 
 
 
 
 
Full Analysis Set 
FDA  
 
 
 
Food and Drug Administration 
GCP  
 
 
 
Good Clinical Practice 
g/dL 
 
 
 
 
Grams per deciliter 
Hgb 
 
 
 
 
Hemoglobin 
HDTI  
 
 
 
Hopkins-Hening Telephone Diagnostic Interview 
HRSQ  
 
 
 
Hopkins RLS-Sleep Quality Questionnaire 
ICH 
 
 
 
 
International Clinical Harmonization Guideline 
IRB 
 
 
 
 
Investigational Review Board 
IRLSS  
 
 
 
International Restless Legs Syndrome Severity Scale  
IRLSSG 
 
 
 
International Restless Legs Syndrome Study Group 
ITT 
 
 
 
 
Intent-to-treat 
IV 
 
 
 
 
Intravenous 
LAM  
 
 
 
Leg Activity Meters 
LASA  
 
 
 
Linear Analog Scale Assessment 
LLN 
 
 
 
 
Lower Limit of Normal 
MedDRA 
 
 
 
Medical Dictionary for Regulatory Activities 
mg 
 
 
 
 
Milligrams 
mL 
 
 
 
 
Milliliter 
MITT  
 
 
 
Modified Intent-to-Treat 
MOS  
 
 
 
Medical Outcomes Survey for Sleep 
MRI 
 
 
 
 
Magnetic Resonance Imaging 
NCI 
 
 
 
 
National Cancer Institute 
ng 
 
 
 
 
Nanogram 
NSS 
 
 
 
 
Normal Sterile Saline 
PGI-I  
 
 
 
Patient Global Impression-Improvement 
PD  
 
 
 
 
Peritoneal Dialysis 
PET 
 
 
 
 
Positron Emission Tomography 
PSG 
 
 
 
 
Polysomnogram Measurement of Sleep  
QOL  
 
 
 
Quality of Life 
RLS 
 
 
 
 
Restless Legs Syndrome 


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SAE 
 
 
 
 
Serious Adverse Event 
SOC  
 
 
 
System Organ Class 
TEAE  
 
 
 
Treament Emergent Adverse Event 
TFR 
 
 
 
 
Transferrin Receptor 
TSAT  
 
 
 
% Transferrin Saturation 
ULN  
 
 
 
Upper Limit of Normal 
US 
 
 
 
 
United States 
WNL  
 
 
 
Within Normal Limit 
 
 
 


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1.0 
INTRODUCTION 
 
Restless Legs Syndrome (RLS) is a chronic, disabling, sensory (akathisia) disorder that 
significantly disrupts sleep and markedly affects an individual’s health and quality of life.  
Altered iron homeostatic mechanism appears to be a primary component underlying RLS 
pathology and is seen most prominently as decreased brain iron in the substantia nigra 
demonstrated in brain magnetic resonance imaging (MRI), brain ultrasonography, and post-
mortem brain tissue.3  These changes in brain iron are present despite normal blood levels of 
iron.  Peripheral iron status does, however, relates to RLS severity 2 and both oral and IV iron 
treatments significantly reduce RLS symptoms compared to placebo even in persons who are not 
anemic.3, 38  Thus, there appears to be a relation between peripheral and brain iron homeostasis. 
In keeping with the concept of peripheral-brain relation to iron homeostasis, conditions 
associated with severe iron deficiency (e.g., pregnancy and IDA) show a five to six-fold increase 
in the prevalence of RLS.3  
 
The National Heart Lung and Blood Institute estimates that “about 1 in 5 women of childbearing 
age has iron-deficiency anemia”.5  Based on a 2010 United States (US) Bureau of Statistics 
survey, there are 62 million women of childbearing age (14-44 years) in the US, of whom at least 
12.4 million have IDA.  These estimates suggest roughly 25% of women aged 14-44 years of age 
may have moderate to severe RLS.  In a hematology practice for the management of IDA, 32% 
of patients self-reported RLS, relatively higher than the estimated 5% RLS prevalence in the 
general population.3  The majority (75%) of this sample also reported moderate to severe RLS, 
which was substantially higher than the 30% estimate for the general population.  Additionally, 
patients with moderate to severe RLS have been reported to have greater disabilities and 
diminished quality of life.4  
 
Findings from a pilot study of treatment for RLS with IDA reported 65% of subjects had rapid 
improvements in RLS symptoms after receipt of 1000 mg of low molecular weight iron dextran.6 
This sentinel study in RLS with IDA also reported that a single iron dextran 1000 mg dose 
resulted in a mean hemoglobin response of 11.6 g/dL, suggesting that this dose was inadequate 
iron repletion for the majority of the subjects.  Additionally, one-third of treatment responders 
did not have sustained improvement beyond six months.  Finally, it would have been expected 
that after the IDA was corrected the RLS symptoms would have returned to the prevalence seen 
in the general population (5%) and this did not occur in this study.  The findings from this 
exploratory study suggest that a single iron infusion of 1000 mg was inadequate to achieve and 
maintain iron levels sufficient enough to resolve or prevent brain iron insufficiency. 
1.2 
Role of Iron in the Pathogenesis and Pathophysiology of RLS 
As early as the 1950s, the role of iron was hypothesized to have a role in the onset and treatment 
of RLS.19    Nordlander first associated anemia from gastric ulcer, leukemia, and chronic 
nephritis with the development of restless legs.20   Subsequent associations of RLS have been 
reported with conditions such as pregnancy, hemodialysis, and frequent blood donations.7,8,21   
Several findings have contributed to the disease understanding of low central nervous system 
iron 
stores  
in RLS.22-29 


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In 2013, the report from the International Restless Legs Syndrome Study Group included 
evidence-based guidelines and clinical consensus on best practice guidance for RLS.  The report 
summarized that “Long-term clinical experience with the treatment of patients with RLS has 
revealed both the significance of problems that arise during the short term (e.g., weight gain, 
impulse control disorders, mood disturbances) and the emergence of new problems during long-
term treatment (e.g., augmentation, loss of efficacy).”14  Overall, extensive RLS research has led 
to the hypothesis that the pathophysiology of idiopathic RLS involves iron homeostatic 
dysregulation and that there is a role for iron treatment in RLS.    
  
1.3  
Injectafer® (Ferric Carboxymaltose) 
 
1.3.1 Key features of Injectafer®  
 
Injectafer® (Ferric Carboxymaltose Injection) is a stable Type I polynuclear iron (III)-hydroxide 
carbohydrate complex developed as an IV iron replacement therapy for the treatment of IDA.  
After IV administration, Injectafer® is mainly found in the reticuloendothelial system which 
includes the liver, spleen, and bone marrow.  The iron slowly dissociates from the complex and 
can be efficiently used in the bone marrow for hemoglobin synthesis.  The carbohydrate moiety 
of Injectafer® is metabolized by the glycolytic pathway.  Injectafer® is approved for the 
treatment of IDA and as an investigational product on the study of RLS. 
 
1.3.2 Injectafer® versus Other Parenteral Iron Agents 
 
There is considerable efficacy and safety experience with the various available parenteral iron 
preparations. However, prior to the approval of non-dextran formulations, the risk of systemic 
adverse reactions restricted their use.  Injectafer® offers significant advantages compared to 
other available IV iron preparations.  
Due to its structure, Injectafer® is more stable than iron gluconate and iron sucrose.  Injectafer® 
is a slow delivery of the complexed iron to endogenous iron binding sites, and has an acute 
toxicity in animals approximately 1/5th that of iron sucrose.  These characteristics of Injectafer® 
make it possible to administer much higher single doses over shorter periods of time than iron 
gluconate or iron sucrose, resulting in fewer administrations to replenish iron stores, and 
convenient outpatient use (Table 1.3.2.1).  Ferumoxytol is a modified-dextran derivative 
currently indicated for IDA associated with chronic kidney disease (CKD).   It was recently 
withdrawn from use in the EU and given a black box warning in the US.  
1.3.3 Injectafer® Human Experience:  Marketed Use and the RLS indicator 
The Injectafer® clinical development program demonstrated the effectiveness and safety of 
Injectafer® in the treatment of IDA.  The drug is approved for the treatment of IDA in adult 
populations who have intolerance to oral iron or have had unsatisfactory responses to oral iron or 
who have non-dialysis dependent CKD (see Appendix I).  Clinical data are currently available 
from 20 Phase 2 and 3 studies including 5,799 patients, with IDA or IDA associated with CKD 
who received Injectafer®. 


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A clinical pharmacokinetic study (VIT-IV-CL-001) using positron emission tomography 
demonstrated a fast initial elimination of radioactively labeled iron (Fe) 52Fe/59Fe Injectafer  
(ferric carboxymaltose injection) from the blood, with rapid transfer to the bone marrow and 
rapid deposition in the liver and spleen.  Eight hours after administration, 5 to 20% of the 
injected amount of radioactively-labeled Fe was still detected in the blood. 
 
Important details of pre-clinical and clinical safety and efficacy can be found in the 
Investigator’s Brochure.  Ferric carboxymaltose received approval from the United Kingdom 
(UK) Medicines and Healthcare Products Regulatory Agency (MHRA) on June 15, 2007 (EU 
Trade name: Ferinject).  Injectafer® now has marketing authorization in 63 countries and is 
currently marketed in 55 of these countries.  Injectafer® received approval for the treatment of 
IDA from the Food and Drug Administration (FDA) on July 25, 2013. 
2.0  
TRIAL OBJECTIVE 
2.1  
Primary Objective 
To evaluate the efficacy and safety of FCM (750 mg dose x 2) for treatment of RLS with IDA. 
3.0  
RATIONALE AND OVERALL STUDY DESIGN 
3.1  
Rationale 
Since Norlander 31 proposed the relationship between the administration of iron and the 
resolution of symptoms associated with RLS in 1953, many studies have been conducted to 
identify the mechanism for this relationship and the ideal treatment regimen.  To date, studies 
suggest that the specific iron preparation, the amount of iron administered, and the timing of the 
administered iron may contribute to the magnitude and duration of the treatment effect.  
Nonetheless, few human clinical studies have investigated these treatment factors or the 
plausible mechanisms of action for RLS. 
Studies of IV iron dextran suggest robust results in the control of RLS symptoms lasting two to 
48 months.31,32  Given that iron dextran preparations are associated with significant risk of 
anaphylaxis, severe hypersensitivity reactions, and death, other IV iron formulations are now 
being investigated.  Allen et al. 35 reported the results of a 46-subject trial that compared FCM  
500mg X 2, FCM 1000 mg, and placebo.35   Subjects treated with either dose of FCM 
demonstrated a reduction of RLS symptoms lasting for up to 24 weeks without additional need 
for alternative RLS medications.  Currently, a 200-subject multicenter trial of FCM versus 
placebo is underway to expand upon these results in subjects with iron deficiency with or 
without IDA (NCT02397057).  These studies utilize the FDA approved dose of 750mg X 2 that 
has been shown to be safe and effective in the treatment of IDA.  This proposed trial will 
investigate 
the 
approved 
FCM  
750mg X 2 dose in RLS-associated IDA patients and provide data on the long-term need for 
subsequent IV iron dosing in RLS subjects who respond to FCM therapy. 


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An altered iron homeostatic mechanism appears to be a primary component underlying RLS 
pathology and is reported to date as most prominently noted decreased brain iron in the 
substantia nigra.30  This decreased brain iron is present in RLS patients even with normal 
peripheral iron stores.  Systemic iron deficiency as seen with IDA appears to further accentuate 
this iron homeostatic imbalance, leading to a six-fold increase in RLS expression.30  In this 
study, RLS subjects with IDA will undergo pre- and post-treatment brain MRI scans for 
comparative characterization of brain iron concentrations. 
3.2  
Trial Design 
This will be a Phase II, randomized, placebo-controlled study.  All subjects who meet the 
inclusion requirements and no exclusion criteria will qualify to enter the Screening Phase.  
Seventy enrolled subjects will receive blinded study drug in Treatment Phase I after 1:1 
randomization as either FCM 750 mg undiluted slow IV push at 100 mg/minute or Placebo (15 
ml of Normal Saline [NS]) IV push at 2 ml/minute) on Day 0 and 7 for a total dose 1500 mg.  All 
treated subjects will have blood samples taken for hematology, chemistries and iron indices on 
Day 14.  Treatment efficacy (IRLSS), medication review and adverse events assessment by 
phone will be done on Day 28. The primary endpoint for efficacy will be a face-to-face visit at 
the end of Treatment Phase I (Day 42) during which all subjects will be interviewed by the PI, 
complete questionnaires, have adverse events assessment, medication review, physical exam and 
complete set of blood studies will be done. At Day 42 visit, subjects will also be categorized as 
either treatment responders or treatment non-responders defined as: 
 
Responder:  IRLSS score ≤10 or >10 with a CGI-I score of much or very much 
improvement and the patient does not request further treatment for RLS.   
Non-Responder if these criteria are not met.  
Non-Responders who do not meet the laboratory criteria for additional dosing will be 
discontinued from the study and treated for RLS as deemed appropriate by the referring 
physician. Subjects who are Non-Responders at the end of Treatment Phase I and who have met 
the necessary laboratory criteria (ferritin <300 ng/mL and a TSAT <45%) will consent for 
enrollment in Treatment Phase II study. These subjects will receive the first of two unblinded 
doses of FCM (undiluted slow IV push 750 mg 100 mg /minute) on Day 0 of Phase II, which 
will occur within 7 days of completing the Treatment Phase I visit. The subjects will then receive 
the second dose of FCM (undiluted slow IV push 750 mg 100 mg / minute) on Day 7.  All 
treated subjects will have blood samples taken for hematology, chemistries and iron indices on 
Day 14.  Treatment efficacy (IRLSS), medication review and adverse events assessment by 
phone will be done on Day 28. All subjects will return to the clinic on Day 42 for end of study 
assessments.  Subjects completing Treatment Phase II will be re-evaluated on Day 42 and 
defined as either a Responder or Non-Responder, using the same criteria described above. 
Those subjects deemed as treatment Non-Responders will be discontinued from the study after 
final assessments are complete. 
 
Subjects who are evaluated on Day 42 (Week 6) as Responders from either Treatment Phase I or 
Treatment Phase II will continue through into the 46-Week, Long-Term Extension Phase III of 


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the study, and be monitored and assessed by phone for RLS symptoms (IRLSS and HRSQ) and 
adverse events on Weeks 15, 25, 34, 43 and 52 (final follow-up visit). During Phase III, subjects 
may receive additional unblinded treatments with FCM if at any time the subject reports 
worsening of RLS symptoms (an increase >4 points on the IRLSS compared to the last 
evaluation captured for that subject) and laboratory criteria are met  
(ferritin <300 ng/mL and a TSAT <45%).  Subjects will receive a single FCM 750 mg undiluted 
slow IV push at 100 mg/minute.  See section 6.6 for dosing and assessment outline.  No 
additional treatment will be allowed after the Week 46.  A final face-to-face study visit will 
occur on Week 52.  If a clinic visit is not possible, final evaluation will be completed by phone. 
 


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Table 3.2.1  
Schedule of Events Treatment Phase I and Treatment Phase II 
 
 
SCREENING 
Treatment Phase I and Treatment Phase II 
STUDY VISIT 
PROCEDURES 
-14 
DAY 0 
DAY 7 
DAY 14 
DAY 28 
(PHONE CONTACT) 
DAY 42 
Informed Consent  
X 
 
 
 
 
X** 
Eligibility  
X 
X 
 
 
 
X 
Medical History, including prior iron 
therapy 
X 
X 
 
 
 
 
RLS History 
X 
X 
 
 
 
 
D/C oral iron products  
X 
 
 
 
 
 
Site contact IRT 
X 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
X 
Vital Signs 
X 
X 
X 
 
 
X 
Height and Weight without shoes 
X 
 
 
 
 
 
CHDQ 
X 
 
 
 
 
 
HTDI 
X 
 
 
 
 
 
IRLSS   
X 
X 
 
 
X 
X 
HRSQ 
 
X 
 
 
 
X 
CGI-I  
 
 
 
 
 
X 
PGI-I 
 
 
 
 
 
X 
MOS Sleep Scale  
 
X 
 
 
 
X 
Hematology 
X 
X 
X 
X 
 
X 
Iron Indices 
X 
X 
X 
X 
 
X 
Chemistry 
X 
X 
X 
X 
 
X 
Vitamin D 
 
X 
X 
X 
 
X 
Erythropoietin 
 
X 
 
 
 
X 
Trace Element 
 
X 
 
 
 
 
Urine Pregnancy test 
X 
 
 
 
 
 
Study Drug 
 
X 
X 
 
 
 
Brain MRI 
X 
 
 
 
 
X 
Concomitant Meds  
X 
X 
X 
 
X 
X 
Adverse Events 
 
X 
X 
 
X 
X 
** All Subject will be consented to participate in Treatment Phase II prior to any study procedures being completed 
Table 3.2.2  
Schedule of Events Long-Term Extension Phase III 
STUDY VISIT 
PROCEDURES 
Week 15 Phone 
Contact 
Week 25  Phone 
Contact 
Week 34 Phone 
Contact 
Week 43 Phone 
Contact 
Week 52 EOS  
IRLSS 
X 
X 
X 
X 
X 
HRSQ 
X 
X 
X 
X 
X 
MOS / PGI-I 
 
 
 
 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Physical Exam / VS 
See Section 6.6 for procedures for additional FCM dosing 
 
Iron Indices / 
Chemistries / 
Hematology 
X 
FCM Dosing 
 


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4.0  
SUBJECT SELECTION 
 
4.1  
Number and Type of Subjects 
 
Seventy (70) subjects (35 per group) who have given written informed consent with a diagnosis of 
RLS who fulfill the inclusion criteria and do not meet any of the exclusion criteria will be randomized 
into Treatment Phase I to receive a blinded dose of Injectafer® or IV Placebo.   Subjects will be 
consented prior to entering Treatment Phase II.   
4.2 
Screening Phase 
Once a subject enters the screening phase, a unique screening number will be assigned via the 
Interactive Response Technologies (IRT) system. 
4.2.1  Inclusion Criteria   
                   
1. Male or female subject ≥18 years of age, willing and able to give informed consent. 
2. Confirmed diagnosis of RLS based on the Cambridge-Hopkins Diagnostic Questionnaire 
(CHDQ) and the Hopkins-Hening Telephone Diagnostic Interview (HDTI). 
3. IRLSS score ≥15 plus RLS symptoms for at least 3 months and currently occurring ≥2 
nights per week.   
4. Iron-deficiency anemia defined as an Hgb <12 g/dl with a ferritin <20 ng/mL or <100  
when TSAT is <18%. 
5. Subjects on sleep medication must be on a stable dose for at least 6 months prior 
screening. 
6. Subjects at risk for pregnancy must have a negative pregnancy test at screening and be 
practicing an acceptable form of birth control: have had a hysterectomy or tubal ligation, 
or otherwise be incapable of pregnancy, or have practiced any of the following methods 
of contraception for at least one month prior to study entry: hormonal contraceptives, 
spermicide with barrier, intrauterine device, or partner sterility. 
 
4.2.2 Exclusion Criteria   
 
1. Disorders that require treatment with the same medications used for RLS include: 
peripheral neuropathy and neurodegenerative disorders (i.e. Parkinson’s disease or 
dementia). 
2. Current (past 4 weeks) use of drugs that may cause or treat RLS, e.g. opioids, calcium 
channel alpha-2-delta ligands, anti-depressants, dopaminergic agonist or antagonists, or 
centrally-acting antihistamines. 
3. Any medical conditions contraindicated to MRI. 
4. Abnormal MRI at baseline that would confound the outcome measures. 
5. Secondary RLS due to neurological conditions or head trauma. 
6. History of hemochromatosis, hemosiderosis, other iron storage disorders or iron 
metabolism disorders. 


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7. Women with clinically significant uterine bleeding (>200 cc blood loss) during the six 
months prior to screening. 
8. Liver transaminases (AST or ALT) greater than 2 times the upper limit of normal (ULN). 
9. Known positive Hepatitis B antigen (HBsAg), unless positive test can be attributed to 
receipt of hepatitis B vaccination in childhood or hepatitis C viral antibody (HCV) with 
evidence of active hepatitis (i.e., AST/ALT greater than the ULN). 
10. Known positive HIV-1 or HIV-2 antibodies (anti-HIV). 
11. Active acute or known chronic infections.  
12. Rheumatoid arthritis with symptoms or signs of active inflammation. 
13. Pregnant and lactating women.  
14. Known hypersensitivity reaction to any component of Injectafer® (Ferric 
carboxymaltose).  
15. Previously randomized to Injectafer® (FCM or VIT-45) in a clinical trial. 
16. Previous IV iron treatment for RLS. 
17. Parenteral iron, erythropoiesis stimulating agent use or blood transfusion within six 
weeks prior to the screening visit. 
18. Planned elective surgery during the study year. 
19. Chronic alcohol or drug abuse within the past six months. 
20. Any other pre-existing laboratory abnormality, medical condition, or disease that, in the 
opinion of Investigator, may cause the subject to be unsuitable for 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 
21. Subject is unwilling or has conditions that would prohibit them from complying with the 
study requirements. 
4.3 
Subject Assignment and Randomization Process 
Subjects who meet all inclusion requirements and no exclusionary criteria will be offered 
participation in this study.  Subjects will initially be randomized in a 1:1 ratio via an IRT system 
to receive either a blinded dose of IV FCM or a blinded dose of IV Placebo. 
 Each subject will be randomized to receive either a FCM 750 mg undiluted slow IV push 
(100 mg/minute) or Placebo (15 ml of Normal Saline [NS]) IV push at 2 ml/minute on 
Day 0 and 7. 
 
4.4 
Duration of Study / Withdrawal from Study 
All subjects will be followed for efficacy and safety.  The subset of subjects requiring 
withdrawal from the study or an intervention for treatment of RLS symptoms will continue to be 
followed for safety for at least 28 days after the last dose of study medication (Injectafer® or 
Placebo).  
Any subject who wishes to withdraw from the study may do so at any time without the need to justify 
the decision.  The Investigator may withdraw a subject from the trial at any time if it is felt to be in the 
best interest of the subject.  
 


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For subjects requiring withdrawal from the study or an intervention, final study procedures should be 
performed at the time of withdrawal/intervention.  
 
 
4.5 
Endpoints in participation / Early termination endpoints  
 
Termination in participation is defined as: 
1. The subject is considered a treatment Non-Responder (see definition of non-responder 
below) as assessed at Day 42 of Treatment Phase I and is not eligible for Treatment 
Phase II. 
2. The subject is considered a treatment Non-Responder (see definition of non-responder 
below) as assessed at Day 42 of Treatment Phase II.  
3. The subject in Long-Term Extension Phase III who has “worsening of RLS” by 
definition but cannot receive further iron treatment because laboratory criteria are not 
met and wishes to have alternative treatment for RLS. 
4. The subject in Long-Term Extension Phase III who wishes to have alternative treatment 
for RLS other than FCM. 
 
5. Completes Long-Term Extension Phase III. 
Endpoints for early termination is defined as: 
1. Significant adverse effect during the treatment period. 
2. Significant adverse event or health issues after starting the iron treatment, and before the 
final evaluation that was judged to require ending the study. 
3. Subject decision not to continue in the study after the treatment and before the final 
evaluation. 
4. The Principal Investigator has determined it would be harmful to the subject to continue 
in the study. 
5. Subject is non-compliant with study requirements. 
6. Use of other medications to treat RLS, other than study medication. 
 
4.6 
Treatment Responder and Non-Responder:    
   
Subject will have been determined to have met the definition of Responder when the IRLSS 
score is ≤10 or a >10 with a CGI-I score of much or very much improvement and the subject 
does not request further treatment for RLS.  Subjects who do not meet the primary endpoint will 
be deemed treatment Non-Responders. 
5.0 
STUDY DRUG 
 
5.1 
Formulation Packaging and Storage 
 
All medication to be used in this study that has been supplied by Luitpold Pharmaceuticals, Inc. will 
have been prepared according to Good Manufacturing Practices (GMP). 


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Injectafer®  (FCM) will be supplied as 15 mL vials, containing 750 mg of iron as 5% w/v   
(weight/volume) iron containing a polynuclear iron(III)-hydroxide 4(R)–(poly-(1-->4)-O α -D-
glucopyranosyl)-oxy-2 (R), 3(S), 5(R), 6-tetrahydroxy-hexonate complex in a solution of water for 
injection (50 mg/mL) and will be labeled according to FDA investigational regulatory requirements.   
 
Injectafer® supplied by Luitpold Pharmaceuticals, Inc. must be kept in a secure place at the 
investigational site and stored at room temperature (see: USP).  Injectafer® should not be frozen.   
 
Vials may not be used for more than 1 dose or for more than 1 subject.  All vials (used and 
unused) should be kept and returned to Luitpold Pharmaceuticals, Inc., after drug 
accountability has been completed by the study monitor. 
 
5.2  
Study Drug Blinding/Administration 
 
6.2.1 Study Drug Blinding    
The treatment personnel who are not blinded will determine, through the IRT system, the 
treatment assignment on the day of treatment and will administer the appropriate treatment.  The 
research coordinator will not know the subject’s treatment, will not be present when the subject 
is treated, and will not have access to files indicating the treatment dose given.  During IV 
treatment, the subject will be blinded to treatment administration (i.e. wear eye masks) to ensure 
minimal risk for detection of color differences between FCM and placebo treatments. All study 
personnel will be blinded to the iron indices and phosphorous (after randomization) throughout 
the study. 
5.2.1.1    Unblinded Personnel             
The unblinded study personnel will be responsible for the following: 
o Randomization of the subject on Day 0 through IRT system. 
o Preparing, concealing, and administering the study drug on Day 0 (as Injectafer® is 
reddish-brown and slightly viscous).1 
o Completing the Study Drug Accountability Form, study drug dosing record and 
applicable CRF pages.  
o Assessment of blinded laboratory parameters (iron indices and phosphorus). 
o Retention of any source documents to which the Investigator and the site study team is 
blinded (i.e. dosing information). 
5.2.1.2   Blinded Personnel             
The blinded study personnel will be responsible for all other study-related activities.  During 
the period of study drug administration, the blinded personnel will not be present.  However, the 
Principal Investigator or designee will be available in the event of an emergency and/or the need 
for adverse event assessment.  All study personnel will be blinded to the post-treatment iron 
indices and phosphorous as the values may unmask the study assignment.  


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The blinding will be maintained in Phase I.  In the event of an emergency that would require the 
Investigator to be aware of the treatment allocation prior to database lock, the Investigator can 
obtain this information, on a per subject basis, from the Sponsor’s electronic database at the 
Investigative site.  It is recommended to contact the sponsor’s Medical Monitor or designee 
prior to unblinding.  If a subject’s treatment assignment is unblinded, the sponsor must be 
contacted immediately via telephone. 
5.2.1.3   Investigator Blinding             
In addition to the above, the blinded investigator will be blinded to the IRLSS score and PGI-I score 
for each subject after randomization.  
5.3 
Study Drug Administration    
   
Treatment Phase I:  On Day 0 subjects will be randomized to receive either FCM 750 mg 
undiluted slow IV push (100 mg/minute) or Placebo (15 ml of Normal Saline [NS]) IV push at 
2 ml/minute on Day 0 and 7.   
 
Treatment Phase II: Non-Responders from Phase I who qualify will receive an unblinded  
750 mg undiluted slow IV push (100 mg/minute) of FCM on Day 0 and 7 of Phase II.   
Long-Term Extension Phase III:  Qualified subjects will receive an unblinded single 750 mg 
undiluted slow IV push (100 mg/minute) of FCM when RLS worsen or reoccur. 
 
5.4 
IV Iron Precautions 
When administering IV iron, the following precautions will be taken: 
 The subject will be clinically evaluated prior to drug administration to assess the 
development of clinically significant conditions.   
 The vials will be visually inspected for particulate matter and discoloration before each 
use. If noted, the vial will not be used and the Investigator or his/her designee will notify 
the sponsor, or sponsor’s designee, for replacement of the study drug and for directions to 
return the unused vial. 
 Sitting heart rate and blood pressure will be assessed pre-dosing, immediately post-
treatment, and 30 minutes post-treatment administration.  All subjects will be discharged 
from the site by the Investigator only if there are no significant changes in vital signs or 
symptoms 30 minutes after the administration of study drug is completed. 
 Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which 
have been life-threatening and fatal, have been reported in patients receiving IV iron 
therapies.  Subjects may present with shock, clinically significant hypotension, loss of 
consciousness, and/or collapse.  If hypersensitivity reactions or signs of intolerance occur 
during administration, stop IV iron administration immediately.  Monitor subjects for 
signs and symptoms of hypersensitivity during and after IV iron administration for at least 
30 minutes, and until clinically stable following completion of the infusion.  Only 
administer IV iron when personnel and therapies are immediately available for the 


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treatment of serious hypersensitivity reactions.  Most reactions associated with IV iron 
preparations occur within 30 minutes of the completion of the iron infusion.  
o In the event a serious acute reaction is seen, the site must have the capability to 
provide appropriate resuscitation measures.  These may include IV NSS, IV 
epinephrine, steroids, and/or antihistamines. 
5.5 
Drug Accountability 
Investigators will keep adequate records of the receipt, administration, and return of Injectafer®.  The 
study drug must not be used for any purposes other than as directed by this protocol.  The Investigator 
agrees that study medication will not be supplied to any persons other than those screened and 
randomized in the study.  When the study is completed, or if it is prematurely terminated, a final 
inventory of all clinical supplies must be compiled and the remainder of used and unused Injectafer® 
will be returned to Luitpold Pharmaceuticals, Inc.  All data regarding Injectafer® must be recorded on 
the Drug Accountability Forms provided by the sponsor.  
 
5.6 
Concomitant Medication 
 
Concomitant medications along with the route of administration and duration must be recorded 
in the case report form (CRF).  No additional IV iron, blood transfusion and erythropoiesis 
stimulating agents (ESA) from six weeks prior to screening or oral iron from time of 
consent through the end of study.  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 medicines 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.  
The following medications are 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 (agonist or antagonist) 
 Opioids 
 Anti-depressives 
 Narcotics (Pain killers) 
 Cannabis 
 Anti-convulsants including alpha-2-delta drugs 
 Centrally-active anti-histamines.  
The dose of all medications (oral contraceptives, progestins, estrogens, androgens, 
antifibrinolytics, NSAID, etc.) that may affect the degree of uterine bleeding must have been 
stable from 6 weeks prior to screening and remain stable for the entire study period.  The dose 
and the number of days treated per month must remain stable.  Hormonal agents that are not 
dosed in this manner (i.e. for an acute bleeding episode) are not allowed to be used in the study.  
NSAID may be taken on an as needed basis, but the average monthly dose should remain stable 
from Baseline until the end of study.  


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No pre-treatment prophylactic medications may be administered prior to Injectafer® 
administration without prior approval from Luitpold Pharmaceuticals, Inc.  
 
 
6.0 
STUDY PROCEDURES 
 
6.1 
Informed Consent 
 
During Screening and Treatment Phase II,  prior to any study specific procedures, the Investigator or 
designee must explain to each subject the nature of the study, its purpose, procedures to be performed, 
expected duration, and the benefits and risks of study participation.  After this explanation the subject 
must voluntarily sign an informed consent statement (see: Required Elements of Informed Consent, 
21 CFR 50.25).  The subject will be given a copy of the signed consent form. 
6.2 
Screening (up to 14 days) 
Subjects will undergo the following to confirm eligibility for the study:  
 Informed Consent obtained  
 Obtain screening number from IRT system  
 Blood samples for hematology, iron indices, chemistries  
 Physical Exam to include height and weight (without shoes) 
 Vital signs (sitting heart rate and blood pressure) 
 Urine pregnancy test (if indicated) 
 A review of medical history, including prior iron therapy use and RLS history  
 All prior medications (subjects should not be receiving treatment for RLS).  All oral iron products 
will be discontinued on the day of the first screening visit 
 If the CHDQ and IRLSS confirm the subject qualifies, the following will occur during the 
screening period: 
o Phone call assessment of HTDI 
o Brain MRI will be scheduled. 
Subjects who do not meet the entry criteria should be entered into the IRT system as a screen failure.  
A subject may be re-screened, one time, once it is believed that they would qualify for study entry.  
The subject will need to re-sign a new consent form and all screening procedures above will need to 
be repeated. 
6.3 
Randomization 
Randomization can be completed during the screening period or on Day 0 once it is confirmed 
the subject qualifies for study participation. The un-blinded treatment nurse will determine the 
subject’s treatment assignment through the IRT system. 


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6.4 
Treatment Phase I / Treatment Phase II Assessments  
 
6.4.1 Treatment Phase I 
 
6.4.1.1  
Day 0  
 
The following must be obtained PRIOR to dosing the subject: 
 Confirm the subject continues to meet the Inclusion/Exclusion criteria 
o Review medical / RLS history 
o Re-confirm IDA diagnosis  
 Blood samples for hematology, iron indices, chemistries, Vitamin D, erythropoietin and trace 
elements 
 IRLSS will be complete 
 Subject will complete the following: 
 
 Medical Outcome Study (MOS) Sleep Scale (range 0-100) 
 Hopkins RLS-Sleep Quality Questionnaire (HRSQ) 
 Vital signs to include temperature 
 Concomitant medications. 
Once the subject is determined to continue to meet entry criteria the unblinded treatment 
personnel will contact the IRT system for treatment assignment. 
A separate Dosing Record will be maintained by the unblinded treatment personnel 
responsible for preparation and administration of the study drug. See Section 5.0 for details of 
study drug administration and precautions. 
The Dosing Record will include: 
 Starting and stopping time of study drug administration 
 Total dose in mg and ml of FCM administered (i.e. 750 mg / 15 ml) 
 Total volume of Normal Sterile Saline administered (250 ml). 
 
The following will be obtained/conducted by blinded study personnel following administration 
of the study drug (review Sections 5.0): 
 Blood pressure and heart rate, immediately post and 30 minutes post-study drug 
administration  
 Adverse events, starting with the first dose of study drug    
 If there are no significant signs or symptoms at the 30 minute post-study drug vital 
sign assessments, the subject will be released.    
 


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6.4.1.2  
Day 7 
 
The following must be obtained in the following order: 
 Adverse Events  
 Vital signs to include temperature 
 Concomitant medications 
 Blood samples for hematology, iron indices, chemistries, and Vitamin D 
  Study drug dosing. 
 
A separate Dosing Record will be maintained by the unblinded treatment personnel 
responsible for preparation and administration of the study drug. See Section 5.0 for details of 
study drug administration and precautions. 
The Dosing Record will include: 
 Starting and stopping time of study drug administration 
 Total dose in mg and ml of FCM administered (i.e. 750 mg / 15 ml) 
 Total volume of Normal Sterile Saline administered (250 ml). 
The following will be obtained/conducted by blinded study personnel following administration 
of the study drug (review Sections 5.0): 
 Blood pressure and heart rate, immediately post and 30 minutes post-study drug 
administration  
 Adverse events, starting with the first dose of study drug    
 If there are no significant signs or symptoms at the 30 minute post-study drug vital 
sign assessments, the subject will be released.    
6.4.1.3  
Day 14  
 Blood sample for hematology, chemistries, and iron indices.  
 
6.4.1.4   
Day 28 Phone contact 
 Adverse events 
 Concomitant medications 
 IRLSS will be completed. 
6.4.1.5  
Day 42 (End of Treatment Phase I) 
The following should be assessed or obtained: 
 Adverse events 
 Concomitant medications 
 IRLSS will be completed 
 Investigator CGI-I Score  


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 Subject will independently complete the following:  
 Subject PGI-1 Score  
 Medical Outcome Study (MOS) Sleep Scale (range 0-100)  
 Hopkins RLS-Sleep Quality Questionnaire (HRSQ) 
 Blood sample for hematology, iron indices, chemistries, and Vitamin D  
 Physical exam 
 Vital signs (sitting heart rate and blood pressure) 
 Brain MRI will be scheduled 
 Consent Non-Responders to participate in Treatment Phase II  
 Re-educate Responders about the 46-week Long-term Extension (Phase III). 
Subjects will be assessed by the Investigator and identified as either a treatment Responder or a 
Non-Responder.  If the subject is a treatment Non-Responder in Phase I, the subject will be eligible 
to re-consent and enroll in Treatment Phase II (section 6.4.2).  If the subject is determined to be 
treatment Responder, the subject will continue through into the Long-Term Extension Phase III 
(section 6.5) of the study. 
For Non-Responder subjects that do not qualify for treatment Phase II due to laboratory parameters 
this will be the end of the subject’s participation in the study.  Subjects should be removed from the 
study and treated as deemed appropriate by the physician. 
6.4.2 Treatment Phase II (Repeat Days 0 – 42) 
The following must be obtained PRIOR to scheduling the subject for dosing: 
 Confirm consent that the laboratory samples obtained at Day 42 in Treatment Phase I 
qualifies the Non-Responder for additional treatment with unblinded FCM. 
 
o Ferritin <300 ng/mL and a TSAT <45% 
 
6.4.2.1  
Day 0 and Day 7 
Prior to dosing the subject review the following: 
 Adverse events 
 Concomitant medications  
 Vital signs to include temperature. 
Once the above procedures have been completed the subject will receive unblinded single FCM at 750 
mg (100 mg/minute) undiluted IV push.  The following should be verified: 
 Starting and stopping time of FCM administration 
 Total dose in mg and ml of FCM administered (i.e. 750 mg / 15 ml) 
 Blood pressure and heart rate, immediately post and 30 minutes post-study drug 
administration  


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 Adverse events  
 If there are no significant signs or symptoms at the 30 minute post-study drug vital 
sign assessments, the subject will be released.    
 
6.4.2.2             Day 14 
 
 Blood sample for hematology, chemistries, iron indices, chemistries, and Vitamin D 
 
6.4.2.3             Day 28 (Phone Contact) 
 
 Adverse events 
 Concomitant medications 
 IRLSS will be completed.  
 
6.4.2.4  
Day 42 (End of Treatment Phase II) 
The following should be assessed: 
 Adverse events 
 Concomitant medications 
 IRLSS will be completed 
 Investigator CGI-I Score.  
 Subject will independently complete the following:  
 Subject PGI-1 Score  
 Medical Outcome Study (MOS) Sleep Scale (range 0-100) 
 Hopkins RLS-Sleep Quality Questionnaire (HRSQ)  
 Blood sample for hematology, iron indices, chemistries, erythropoietin and Vitamin D 
 MRI  
 Physical exam 
 Vital signs (sitting heart rate and blood pressure) 
 Re- educate Responders about the 46-week Long-term Extension (Phase III). 
Subjects completing Treatment Phase II will be re-evaluated on Day 42 as either a Responder or 
Non-Responders.  Subjects evaluated as treatment Non-Responder will be discontinued from 
the study after final assessments are complete.  Subjects who are evaluated as Responder will 
continue through into the Long-Term Extension Phase III. 
6.5 
Long-Term Extension Phase III (46-Week extension of Treatment Responders from 
Phase I or II) 
Responders from either Treatment Phase I or Treatment Phase II will continue through into the 
Long-Term Extension Phase III. Subjects in this Phase will be monitored and assessed by phone 
for RLS symptoms (IRLSS and HRSQ) and adverse events on (approximately every 9 weeks) 
Weeks 15, 25, 34, 43 and 52 (final face-to-face study follow-up visit).  Study evaluations during 
the phone contacts will include:  


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 IRLSS will be completed  
 Concomitant medications  
 Adverse event assessment.  
There will be a final face-to-face study visit on Week 52 (approximately 365 days since initial  
Day 0 Treatment).  If a clinic visit is not possible, final evaluation will be completed by phone 
and recommend that blood studies be completed. The subject will complete the following during 
the face-to-face study visit: 
 IRLSS  
 PGI-I 
 MOS-sleep  
 Hopkins RLS-Sleep Quality Questionnaire (HRSQ) 
 Blood samples for hematology, iron indices, and chemistries  
 Adverse event and concomitant meds assessment. 
   
6.6 
Long-Term Extension Phase III Treatment  
During Phase III, subjects could potentially receive additional, unblinded single FCM treatment 
if, at any time during this Phase, subjects report worsening of RLS symptoms (an increase >4 
points on the IRLSS compared to the last evaluation captured for that subject).  Blood samples 
will be taken prior to dosing to make certain the laboratory criteria are met (ferritin <300 ng/mL 
and a TSAT <45%).  Subjects will receive a single FCM 750 mg undiluted slow IV push at  
100 mg/minute.  On Day 14 and 42, subjects will have a serum phosphate assessed. The subject 
will have a RLS symptoms (IRLSS and HRSQ) and adverse event assessment on Day 28 and 42 
Days post dose by phone.  No additional treatment will be allowed after the Week 46.   
 
6.7 
Laboratory Assessments 
 
Serum samples for laboratory analyses must be obtained at all appropriate visits and will be 
analyzed by the laboratory.  All serum laboratory results will be provided to the physician for 
review and assessment. If the Investigator wishes to obtain a follow-up of an abnormal 
laboratory test, this test may be obtained after notification to the Sponsor.  If a subject’s 
phosphorous is below the LLN at the end of study participation the subject should return, as 
directed by the Investigator, for repeat phosphorous laboratory tests until the value is back WNL.    
Hematology: Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, differential 
count, and reticulocyte count. 
 
Iron indices: serum iron, serum ferritin, and total iron binding capacity (TIBC), and 
percentage serum transferrin saturation (TSAT).   
 
Chemistry: 
sodium, potassium, chloride, BUN, creatinine, albumin, alkaline 
phosphatase, total bilirubin, gamma-GGT, AST, ALT, LDH, calcium, 
phosphorus, glucose, bicarbonate, and magnesium.  
 


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Other: 
urine pregnancy (if indicated), other metals (serum copper and zinc),  
1,25 dihydroxy Vitamin D (1,25 [OH]2D); 25 hydroxy Vitamin D  
(25OH-D) and erythropoietin.  
 
7.0  
ASSESSMENT OF SAFETY 
7.1 
Adverse Events 
Any untoward medical (clinical) event at any dose experienced by a subject during the course of this 
clinical trial, whether or not it is related to the investigational product, must be recorded on the 
Adverse Event page of the CRF.  
For any laboratory abnormality, the physician will make a judgment as to its potential clinical 
significance.  If the laboratory value is outside the safety limits and deemed a clinically-significant 
worsening from the baseline value, it should be considered an adverse event and should be recorded 
on the Adverse Events page of the case report form.  If the laboratory value is outside the normal 
range, but not an adverse event, the Investigator should comment on the findings (i.e. “not clinically 
significant” or “unchanged from baseline”) in the source documentation [laboratory report]. 
For the purposes of this study, worsening of RLS symptoms and low or high iron indices will not be 
considered adverse events.  These values are reported in efficacy summaries.          
 
To quantify the severity of adverse events the National Cancer Institute, NCI-Common Terminology 
Criteria for Adverse Events [CTCAE], Version 4.0 should be used to grade all events.  These criteria 
are provided in the trial’s study guide. 
If a CTCAE criterion does not exist, the investigator should use Table 7.1.1 to assign the adverse 
event grade. 
Table 7.1.1  
Grading of Adverse Event Severity as per CTCAE v 4.0 
Grade Adjective 
Description 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental activities 
of daily living (i.e., preparing meals, shopping for 
groceries or clothes, using the telephone, managing 
money, etc.)  
3 
Severe 
Severe or medically significant but not immediately life-
threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization indicated; disabling; limiting self care 
activities of daily living (i.e., bathing, dressing and 
undressing, feeding self, using the toilet, taking 
medications, and not bedridden.)  
4 
Life-threatening 
Life-threatening 
consequences; 
urgent 
intervention 


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indicated. 
5 
Death 
Results in Death due to the AE 
Timing: Non-serious adverse events will be reported from the initial treatment with study drug 
through the completion of the study or a follow-up phone call 28 days following the last dose of study 
drug for subjects who are randomized and terminate early from the trial.  All ongoing adverse events 
related to study drug (i.e., FCM or Placebo) should be followed until they are no longer related, have 
taken a confounding medication or return to baseline grade. 
Relationship (Causality): The Investigator will be asked to document his/her opinion of the 
relationship of the event to the study drug as follows: 
 NONE 
There is no evidence of any causal relationship. 
 
 UNLIKELY There is little evidence to suggest there is a causal relationship.  There is 
another reasonable explanation for the event (e.g., the subject’s clinical 
condition, other concomitant treatments). 
 POSSIBLE 
There is some evidence to suggest a causal relationship (i.e. there is a 
reasonable possibility that the adverse experience may have been caused 
by the agent).  However, the influence of other factors may have 
contributed to the event (e.g., the subject’s clinical condition, other 
concomitant events). 
 PROBABLE There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. 
For the purposes of this trial, “study drug” is defined as: Injectafer® or Placebo 
(Normal Sterile Saline).  
7.2 
Reporting of Adverse Events 
Adverse experiences will be elicited by nonspecific questions such as “Have you noticed any 
problems?”  Subjects will be encouraged to report adverse events at the onset.  Any adverse 
experience spontaneously reported by, elicited from the subject or observed by the physician or 
study staff shall be recorded on the appropriate Adverse Event page of the CRF.  The 
Investigator will record the date and time of onset, severity, the relationship to study medication, 
the date and time of resolution (or the fact that the event is still continuing), the action taken, and 
the outcome of the adverse experience on the Adverse Event page of the CRF.  Whenever 
possible, the Investigator should group together, into a single term, signs and symptoms which 
constitute a single diagnosis.  For example, cough, rhinitis and sneezing might be grouped 
together as "upper respiratory infection."  
 
 
 


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7.3 
Serious Adverse Events (SAE) 
 
Definition: An adverse event is classified as SERIOUS if it meets any one of the following 
criteria:  
 Death. 
 Life-Threatening: The subject was at substantial risk of dying at the time of the adverse 
event or it is suspected that the use / continued use of the product would result in the 
subject's death. 
 Hospitalization (initial or prolonged): Required admission to the hospital or 
prolongation of a hospital stay. 
 Disability: Resulted in a significant, persistent, or permanent change, impairment, 
damage or disruption in the subject's body function/structure, physical activities or 
quality of life. 
 Congenital Anomaly/Birth Defect. 
 Important medical events: Other medically important events that, in the opinion of the 
investigator, may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed above. 
 
A distinction should be drawn between SAE and severe AE.  A severe AE is a major experience 
of its type.  A severe AE is not necessarily serious: e.g. nausea, which persists for several hours, 
may be considered severe nausea, but it is not an SAE.  In contrast, a stroke, which results in 
only a limited degree of disability may be considered a mild stroke, but would be a SAE. 
 
Timing:   
All SAEs will be reported from the day of initial treatment with study drug through the 
completion of the study or a follow-up phone call 28 days following the last dose of study drug 
for subjects who are randomized and early terminate from the trial.  Hospitalizations resulting 
from historical conditions (present prior to initial treatment with study drug or 
prescheduled prior to treatment with study drug) that have not increased in severity or 
lead to prolongation of hospital stay should not be considered SAE’s.  All reported serious 
adverse events should be followed until they are no longer serious or return to baseline grade.   
 
Reporting:   
Any SAE, starting with the first dose of study drug, that is to be reported (as outlined in 
Timing section above) must be reported immediately (within 24 hours of the Investigator 
becoming aware of the event) to Luitpold Pharmaceuticals, Inc. by telephone, email and/or 
fax of the written SAE report form to the contacts listed below: 
Safety Monitor 
Luitpold Pharmaceuticals, Inc. 
pv@luitpold.com 
Tel: (610) 650-4200          Fax: (610) 650-0170 
 
In addition to the above reporting, all SAEs must be recorded on the Adverse Event page of the 
CRF and reported immediately to your IRB / ethics committee per their reporting guidelines. 


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The responsible investigator must determine whether the degree of any untoward event warrants 
removal of any subject from the study.  He/she should, in any case, institute appropriate 
diagnostic and/or therapeutic measures, and keep the subject under observation for as long as is 
medically indicated. 
7.4      Other Reportable Information 
As part of the continuous assessment of the risk-benefit profile for the life cycle of 
pharmaceutical products, regulatory agencies require monitoring of occurrences that while not 
considered adverse events, are considered “other reportable information”.  For this protocol, 
other reportable information refers to: drug exposure during pregnancy and / or lactation 
exposure (irrespective of any reported fetal abnormalities or any adverse effect in mother and/or 
child).  Pregnancy exposure and lactation exposure should be reported to the Luitpold’s 
Pharmacovigilance Department by email and/or fax using the pregnancy tracking form to the 
contact listed below: 
Safety Monitor 
Luitpold Pharmaceuticals, Inc. 
pv@luitpold.com 
Tel: (610) 650-4200          Fax: (610) 650-0170 
 
8.0 
STATISTICS 
 
8.1 
Sample Size Rationale 
 
Enrollment is planned for 70 randomized subjects (35 per treatment group).  Based on Study 
1VIT05009 in patients without IDA, approximately 50% of patients in the FCM group and 15% 
of patients in the placebo group are anticipated to have much or very much improvement on the 
CGI-I.  The proposed sample size provides >85% power to detect this difference with the chi-
square test.  The mean treatment difference and standard deviation for change from baseline to 
Day 42 for IRLSS is anticipated to be 5.0 (7.3).  The proposed sample size provides >80% power 
to detect this difference with the unpaired t-test. 
 
8.2 
Analysis Populations 
The following analysis populations will be defined: 
 Safety population: All subjects who receive randomized treatment.  
 Treatment Phase I Safety population:  All subjects who receive randomized treatment.  
 Treatment Phase II Safety Population:  All treatment non-responders in Treatment 
Phase I who receive FCM in Treatment Phase II. 
 Long-Term Extension Phase III Safety Population:  All treatment responders in 
Treatment Phase I or Phase II who enter the Phase III assessment period. 


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 Treatment Phase I Full analysis set (FAS) population:  All subjects who received 
randomized treatment and had a post-randomization measurement of the IRLSS and 
Clinical Global Impression performed by Investigator (CGI-I) in Phase I. 
 Treatment Phase II FAS population:  All subjects with a measurement of the IRLSS and 
CGI-I in Phase II. 
 Long-Term Extension Phase III FAS population:  All subjects in the Phase III Safety 
population with at least one telephone contact or treatment intervention during the Phase 
III assessment period. 
8.3 
Disposition and Baseline Characteristics 
Disposition and baseline characteristics will be summarized by treatment group for each analysis 
population.  For Phase I, the number and percentage of subjects, who are randomized, treated, 
prematurely discontinued, and completed the study phase will be summarized.  For Phases II and 
III, the number and percentage of subjects, who are treated with FCM, prematurely discontinued, 
and completed the study phase will be summarized. 
Subjects with clinically important protocol deviations will be identified for each analysis 
population, treatment group, and type of deviation.  The clinical team will identify deviations 
and the deviations will be identified in the database.   
The number of subjects in each analysis population will be summarized for investigative site. 
 
Baseline characteristics (e.g., sex, race, and ethnicity) will be summarized with the number and 
categorical percent of subjects with the characteristic in each analysis population and treatment 
group.  
 
Quantitative characteristics (e.g., age and weight) will be summarized with the mean, median, 
standard deviation, minimum value, and maximum value in each analysis population and 
treatment group.   
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) 
Terminology. The number and percent of subjects with clinically significant medical history at 
screening will be summarized by System Organ Class (SOC) and preferred term for all subjects. 
8.4 
Endpoints and Definitions 
8.4.1 Primary Endpoints 
Treatment Phase I co-primary endpoints are: 
 Change in IRLSS score from Baseline to Day 42 with comparison between FCM vs. 
Placebo, and 
 Percentage of subjects who are much or very much improved at Day 42 as measured by 
the CGI-I. 
 
Treatment Phase II primary efficacy endpoints are: 


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 IRLSS score change from Baseline (For Phase II the “baseline” is established on Day 42 
of Phase I) compared to Day 42 in phase II. 
 CGI-I at Day 42 in Treatment Phase II. 
Long-Term Extension Phase III primary efficacy endpoints are: 
 Estimate the time from first dose of FCM (Day 0 in either Phase I or Phase II) to time of 
FCM treatment intervention. 
8.4.2 Secondary Endpoints 
Phase I and Phase II: 
 Change in IRLSS score from Baseline to Day 42. (Treatment Phase I and II) 
 IRLSS score change from Baseline (For Phase II the “Baseline” is established on Day 42 
of Phase I) compared to Day 42 of Treatment Phase II. 
 CGI-I and PGI-I at each visit and percentage of subjects who are much or very much 
improved at Day 42. (Treatment Phase I and II) 
 Change in sleep quality (MOS Sleep) from Baseline to Day 42. (Treatment Phase I and 
II) 
 Estimate the proportion of treatment non-responders in Phase I who respond to FCM in 
Phase II for each randomized treatment group. (Phase II only) 
 Change in substantia nigra iron index from Baseline to Day 42. The index will be 
determined using measures of MRI relaxation rate (R2*) or Quantitative Susceptibility 
Mapping (QSM).  (Treatment Phase I and II)  
 Change in iron index (R2* or QSM) for thalamus and motor cortex from Baseline to Day 
42. (Treatment Phase I and II). 
Phase III: 
 Change in IRLSS from Baseline to each scheduled assessment. 
 Number of subjects who remained in the study to Week 52. 
8.4.3 Safety Evaluations  
Safety Evaluations will include: 
 Adverse events 
 Laboratory assessments 
 Vital signs  
 Physical examinations. 
 
8.5 
Statistical Analyses of Efficacy  
Categorical variables will be summarized with the number and percent of subjects in each 
treatment group with the characteristic.  Quantitative variables will be summarized with the 
mean, median, standard deviation, minimum value, and maximum value.  Baseline will be 
defined as the last value obtained before randomization.  
Phase I 


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The treatment differences for the changing IRLSS score from Baseline to Day 42 will be 
assessed with the analysis of covariance with treatment as a fixed effect and baseline value as a 
covariate. 
The treatment difference for the percentage of subjects who are much or very much improved at 
Day 42 as measured by the CGI-I will be assessed with the chi-square test.  
 
Change from Baseline for IRLSS at Day 28, MOS at Day 42, and brain iron distribution at Day 
42 will be assessed with the same method as IRLSS at Day 42.  The percentage of subjects who 
are much or very much improved at Day 42 as measured by the PGI-I will be assessed with the 
chi-square test. 
Phase II and III 
All analyses will be descriptive. 
For Phase II, the proportion of treatment Non-Responders in Phase I who respond to FCM in 
Phase II will be estimated and the IRLSS, CGI-I, PGI-I and brain iron distribution will be 
summarized at Day 42. 
The Kaplan-Meier method will be used to estimate time from first dose of FCM to treatment 
intervention.  Subjects in Phase III who discontinue the study before requiring treatment 
intervention will be censored on the day of the last contact with the Investigator. 
8.5.1 Exploratory Analyses 
 Evaluate for possible predictors of Day 42 (Treatment Phases I and II) treatment response 
using clinical variables, hematologic, and brain MRI data.  
 Evaluate for possible predictors of Day 42 treatment responders (Phase I) in correlation 
of baseline trace element levels (i.e. copper, zinc) 
 Correlation of baseline Vitamin D and post dose change in phosphate 
 Vitamin D at each visit. 
 The change from baseline in brain MRI-determined iron concentration for other brain 
regions. 
 Correlation between changes in brain iron and measures of peripheral iron status, RLS 
severity and MOS.  
 Correlation between CBC/iron indices and changes from Baseline to Day 42 
(Treatment Phases I and II) RLS severity and MOS. 
8.6 
Statistical Analyses of Safety 
Analyses of safety data will be descriptive and no formal statistical comparisons will be made. 
The MedDRA Terminology will be used to classify all adverse events with respect to system 
organ class and preferred term.  The number and proportion of subjects who report treatment-


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emergent adverse events will be summarized for each treatment group.  A similar summary will 
be provided for all treatment emergent serious adverse events. 
 
The adverse event profile will be characterized with severity (as graded by Version 4.0 of the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]) 
and relationship to study drug.  Relationship to study drug will be categorized as related 
(possibly or probably related) and unrelated.  Events with unknown severity or relationship will 
be counted as unknown.   
 
Subjects who report the same preferred term on multiple occasions will be counted once for the 
preferred term: under the highest severity when summarized by severity and under the closest 
relationship to study drug when summarized by relationship.  If a subject reports multiple 
preferred terms for a SOC, the subject will be counted only once for that SOC.   
 
Change in clinical laboratory and vital signs from baseline to each scheduled study visit will be 
summarized descriptively with the mean, median, standard deviation, minimum value, and 
maximum value.  The number and percent of patients with potentially clinically significant 
clinical laboratory and vital signs will be summarized for each treatment group. 
 
8.7 
Interim Analyses 
 
No formal interim analyses are planned. 
9.0 
ADMINISTRATIVE CONSIDERATIONS 
9.1 
Retention and Availability of Records 
Investigators are required to maintain all study documentation, including electronic copies of CRFs 
that will be provided to the Investigator after database lock, Informed Consent documents, and 
adequate records for the receipt and disposition of study medications, for a period of two years 
following a supplemental application for the drug for the indication being investigated or until two 
years after the drug investigational program is discontinued.  Permission should be obtained from 
Luitpold Pharmaceuticals, Inc. prior to destroying any study records. 
 
The Investigator must make study data accessible to the monitor, Sponsors, or other authorized 
representatives of the Sponsor and Regulatory Agency (i.e., FDA inspectors.)  A case history for each 
subject must be maintained, that includes the signed Informed Consent form and copies of all study 
documentation related to that subject. The Investigator must ensure the availability of source 
documents from which the information on the eCRF was derived.  


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9.2 
Investigator Responsibilities 
 
By signing the Form FDA 1572 the Investigator agrees to: 
1. 
Conduct the study in accordance with the protocol and only make changes 
after notifying the Sponsor, except when necessary to protect the safety, 
rights or welfare of subjects. 
2. 
Personally conduct or supervise the study (or investigation). 
3. 
Inform any subjects that the drug is being used for investigational purposes.  
4. 
Ensure that the requirements relating to obtaining informed consent and IRB 
review and approval meet Federal guidelines, as stated in 21 CFR, parts 50  
and 56. 
5. 
Report to the Sponsor any adverse events that occur in the course of the 
study, in accordance with 21 CFR 312.64. 
6. 
Have read and understood the Injectafer® Investigator Brochure, including 
potential risks and side effects of the drug. 
7. 
Ensure that all associates, colleagues and employees assisting in the conduct 
of the study are informed about study obligations and meeting the above 
commitments. 
8. 
Maintain adequate and accurate records, in accordance with 21 CFR 312.62 
and to make those records available for inspection with the Sponsor, their 
designated representative, the US Food and Drug Administration (FDA) or 
any agency authorized by law. 
9. 
Ensure that an Institutional Review Board (IRB) that complies with the 
requirements of 21 CFR Part 56 will be responsible for initial and continuing 
review and approval of the clinical study. 
10. Promptly report to the IRB and the Sponsor all changes in the research 
activity and all unanticipated problems involving risks to subjects or others 
(including amendments and IND safety reports). 
11. Not make any changes in the research study without approval, except when 
necessary to eliminate hazards to the subjects. 
12. To comply with all other requirements regarding the obligations of the 
clinical investigators and all other pertinent requirements listed in 21 CFR 
Part 312. 
9.3 
Financial Disclosure 
All Principal Investigators and co-investigators will be required to complete FDA-required financial 
forms provided by Luitpold Pharmaceuticals, Inc.  All signed financial disclosure forms must be 
submitted to the Sponsor prior to the site enrolling subjects into the study. 
9.4 
Advertisement for Subject Recruitment 
All advertisements for subject recruitment must be reviewed and approved by the Sponsor and the 
site's IRB prior to implementation.  Advertisements may include but is not limited to newspaper, 


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fliers, radio, television, etc.  Any compensation to the subject included in the advertisement must be 
identical to the compensation stated in the IRB-approved informed consent. 
 
9.5 
Documents Required for Study Initiation 
 
Prior to study initiation, the Investigator must provide Luitpold Pharmaceuticals, Inc. with the 
following documentation: 
 Curriculum Vitae and medical license for Principal Investigators and co-
investigators. 
 Form FDA 1572. 
 Financial disclosure form. 
 IRB approval of protocol and informed consent. 
 Copy of IRB approved informed consent. 
 IRB membership list or assurance number. 
 Protocol signature page. 
 IRB approval of any advertising for subject recruitment [if applicable]. 
 Copy of advertising [if applicable]. 
 IRB approval of translation of informed consent [if applicable]. 
 
9.6 
Quality Control and Quality Assurance 
9.6.1 Investigator Selection Criteria 
Each Investigator participating in this study will meet the following criteria: 
 Accessible, interested, and well-organized support staff. 
 Availability of diagnostic facilities to support study data requirements. 
 Availability of physician emergency response at all times. 
 Adequate time to conduct study. 
 Adequate training and experience of personnel to conduct study. 
 Ability to recruit enough subjects to conduct study. 
 
Luitpold Pharmaceuticals, Inc. will insure that no investigator is on FDA’s Debarment List or 
Disqualified Investigator List. 
9.6.2 Clinical Monitoring 
This study will be monitored by the Sponsor or its designee in accordance with FDA and International 
Conference on Harmonisation (ICH) Good Clinical Practices (GCPs), 21CFR Part 312.  Each study 
site will be visited by the Clinical Monitor as outlined in the study-specific Monitoring Plan.  At this 
time, the progress of the study will be discussed with the Principal Investigator and the CRFs will be 
checked for completeness and accuracy.  Source documents from which the data are obtained will be 
made available to the Clinical Monitor at the time of review.  Interim checks on progress will be made 
when deemed appropriate (i.e. telephone or email). 


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9.6.3 Quality Assurance Audit 
 
For the purpose of data validation, the Principal Investigator will permit a member of the Quality 
Assurance Unit of Luitpold Pharmaceuticals, Inc. or its designee to inspect the source data and 
compare them with the CRFs.  Pre-study audits, interim audits and post-study audits may be 
performed and may also include review of facilities, equipment, pertinent site documentation, and 
personnel qualifications.  Notification of these audits will be sent to the investigator in advance. 
9.7 
Ethics 
9.7.1 Ethical and Legal Issues  
This study will be performed in accordance with the (US Code of Federal Regulations on Protection 
of Human Subjects (21 CFR 50), IRB regulations (21 CFR 56), the  most current version of the  
Fortaleza, Brazil 2013 Revision of the Declaration of Helsinki, all applicable local and state 
regulations, 21 CFR Part 312 and applicable ICH guidelines. 
9.7.2 Institutional Review Board (IRB) 
The protocol and the Informed Consent must be approved by an appropriate IRB before the study is 
initiated. Documentation of this approval on institutional letterhead must be provided to the Sponsor 
or designee.  The IRB must comply with current US Regulations (21 CFR 56).  Investigators are 
responsible for the following: 
 Obtain IRB approval of the protocol, Informed Consent, and any 
advertisements to recruit subjects; obtain IRB approval for any protocol 
amendments and Informed Consent revisions before implementing the 
changes. 
 Provide the IRB with any information it requests before or during the study. 
 Submit progress reports and a final report to the IRB, as required, during the 
conduct of the study; request re-review and approval of the study as needed; 
provide copies of all IRB re-approvals and relevant communication with the 
Sponsor. 
 Notify the IRB within 10 days, or per their reporting guidelines of all Serious 
Adverse Events that occur or are reported to you by the Sponsor. 
9.7.3 Informed Consent  
Informed Consent must be obtained from each subject prior to study participation.  The Informed 
Consent will be provided in the native language of the subject.  The consent form must be signed by 
the subject or the subject's legally authorized representative.  Each investigational site must provide 
the Sponsor (or designee) with a copy of the Informed Consent approved by that site's IRB. The 
original signed consent form will be retained in the subject's study records, and a copy will be 
provided to the subject. The Clinical Monitor will assure that each Informed Consent meets the 
requirements of Parts 50.20 and 50.25 of Title 21 of the CFR, which outlines the basic elements of 


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Informed Consent and ICH guidelines.  Translations of the informed consent must be certified by a 
qualified translator and their use must be documented by that site’s IRB. 
 
The Informed Consent documents the information the Investigator or designee provides to the subject 
and the subject's agreement to participate.  The Investigator will fully explain the nature of the study, 
along with the aims, methods, anticipated benefits, potential hazards and discomfort that participation 
might entail.  The Informed Consent must be signed and dated by each subject or legal representative 
before entering the study and prior to the performance of any study specific procedures. 
 
9.7.4 Good Clinical Practice 
 
The conduct of the study will conform to the recommendations for clinical studies in human subjects 
as set out in the most current version of the of the “Declaration of Helsinki”, the local legal 
requirements and the guidelines on “Good Clinical Practice”, [21 CFR Part 312 and ICH guidelines]. 
9.8 
Data Handling and Record Keeping 
9.8.1 Case Report Form (CRF) 
 CRFs will be provided for each subject on this study.  The participants in this study will be 
identified only by initials and subject number on these forms. 
 CRFs must be reviewed and verified for accuracy by the Principal Investigator. A copy of 
the CRF will remain at the site at the completion of the study. 
 All CRFs are to be reviewed by the Clinical Monitor at Luitpold Pharmaceuticals, Inc. (or 
designee) to insure accuracy, completeness and compliance with the protocol.  
 
9.8.2 Confidentiality 
 All unpublished information given to the Investigator or institution dealing with this study, 
study drug or the conduct, financial agreements, or methodologies used in this protocol, as 
well as information obtained during the course of the study remains confidential and 
proprietary to the Sponsor [“Proprietary Information”].  The Investigator shall not disclose 
any such Proprietary Information to any third party without prior written consent from the 
sponsor [See: Section 9.9 Publication Policy].  For purposes of this Section, “Investigator” 
includes, but is not limited to the Principal Investigator and/or his/her agents, designees, 
sub-investigators or other individuals involved in the running, administration, collection or 
evaluation of subjects or data for this study. 
 All pharmaceutical formulations supplied by Luitpold Pharmaceuticals, Inc. for the 
purpose of the trial shall remain the sole property of Luitpold Pharmaceuticals, Inc.  They 
will be used for the purposes specified in the protocol.  Any unused medication will be 
returned to the sponsor at the conclusion of the study. 
 No patent application based on the results of this study should be made by the Investigator 
and all such rights assigned to Luitpold Pharmaceuticals, Inc., and no assistance should be 
given to any third party to make such an application without the written authorization of 
Luitpold Pharmaceuticals, Inc. 


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9.8.3 Termination of the Study 
 
The study may be terminated if the Sponsor, Investigator, or Clinical Study Monitor discovers 
conditions arising during the course of the study, which indicate that the clinical investigation should 
be halted.  The study may be terminated after appropriate consultation and discussion. 
Conditions that may warrant study termination include, but are not limited to, the discovery of a 
significant, unexpected and unacceptable risk to the subjects, failure of the Investigator to enroll 
subjects at an acceptable rate, insufficient adherence to the protocol requirements, completion of study 
objectives or at the discretion of the sponsor. 
9.8.4 Protocol Revisions 
Changes in any portion of this protocol that affect subject safety, welfare, or which alter the scientific 
validity of the study must be documented in the form of an amendment.  This change must be signed 
by the appropriate Luitpold Pharmaceuticals, Inc. personnel and the Investigator, and be approved by 
the site's IRB before the revision can be implemented.  The protocol revision will also be submitted to 
the FDA. 
 
The IRB Chairperson may approve minor changes, or may designate one or more members of the 
IRB to approve a protocol amendment. 
 
9.8.5 Protocol Administrative Changes 
 
Clarification or interpretation of the study protocol or changes in the methods of statistical analysis 
may be documented in the form of an administrative change.  Administrative changes do not require 
the Investigator’s signature or IRB approval, but do require IRB notification.  Administrative changes 
will be transmitted to the Investigator and a copy provided to the IRB for completeness. 
9.9 
Publication Policy 
All information resulting from this study is the Proprietary Information of Luitpold Pharmaceuticals, 
Inc., as per the Confidentiality Section of this protocol. Luitpold Pharmaceuticals, Inc., alone will own 
the copyrights in any publication of the results of the study in its entirety. 
Luitpold Pharmaceuticals, Inc., alone shall have the right to publish the results of the study in its 
entirety, or on data involving multiple sites provided, however, that at least 10 days prior to any 
submission of a work for publication, Luitpold Pharmaceuticals, Inc. shall provide any potential 
authors with a copy of same for the authors’ and if indicated Institutions’ review and comments.  Any 
publication based upon the study in its entirety or on data involving multiple sites, will be submitted at 
the discretion of the Sponsor.  Authorship will include the Investigator assigned with the primary 
responsibility to write the manuscript, which will be listed first.  Additional authors will be listed 
according to site enrollment, with one author listed per site at Luitpold Pharmaceuticals, Inc.’s sole 


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discretion.  The Principal Investigator at each site may designate an alternate for authorship at his/her 
discretion.  If required for publication, the number of authors may be limited by the sponsor.  
 
Luitpold Pharmaceuticals, Inc. and the Publication Committee shall have final and sole control over 
the content of any publication. The Principal Investigator and any sub-investigators may make 
presentations on the study or may publish results of the study at their site, but only after the results of 
the study have been published or with the prior approval of Luitpold Pharmaceuticals, Inc. 
 
The Investigator will provide to the Sponsor any announcement, publication or presentation of data 
from this study for the Sponsor’s review and comments at least 10 days in advance of such disclosure.  
Sponsor may, at its sole discretion, require the removal of any proprietary information from the 
disclosure.  The Investigator agrees to provide the Sponsor, at the sponsor’s discretion, with any 
byline credit in any publication proposed by the Investigator.  This is in order to enable Luitpold 
Pharmaceuticals, Inc. to make constructive comments about the manuscript or text and to give the 
opportunity of assessing whether patent protection should be sought by Luitpold Pharmaceuticals, Inc. 
on any results or ideas connected with the study. 
 
10.0  
GOVERNANCE COMMITTEE 
 
10.1 
There will be no Data Safety Monitoring Board for this study 
 


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INVESTIGATOR’S ACKNOWLEDGEMENT 
 
I have read this protocol and agree to conduct the study as outlined herein, 
complying with the obligations and requirements of clinical investigators and all 
other requirements listed in 21 CFR part 50, 54, 56 and 312 and all applicable 
local, state, and federal regulations and ICH guidelines. 
 
 
_______________________________________________________________ 
Investigator’s signature 
 
__________________ 
Date 
 
___________________________________________ 
Investigator’s Name (Please print) 
 


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APPENDIX I: RLS Assessment Tools: 
1.
Clinical Global Impression-Improvement (CGI-I): This is performed by the 
Investigator.  This was developed and validate by the National Institute of Mental 
Health[19] and has been used in many RLS treatment trial including prior FCM trial in 
RLS studies [3, 16-18].  CGP-I is a 7-point scale that requires the clinician to assess how 
much the patient's illness has improved or worsened relative to a baseline state at the 
beginning of the intervention and rated as: 1, very much improved; 2, much 
improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 
or 7, very much worse.
2.
International RLS Severity Scale (IRLSS):  This is a validated, 10-item 
severity scale with each item on the scale having five severity categories form 0 to 
4[15].  The total score is used for a severity measure with values range from 0-40.  
The scale has been used in several RLS clinical trial including the FCM study in 
RLS[3, 16-18].
3.
Personal Global Impression-Improvement (PGI-I): This is performed by the 
subject.  Similar to the CGI-I except this is self-reported, 7-item scale for assessment 
of symptoms  after treatment with the rating as: 1, very much improved; 2, much 
improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 
or 7, very much worse.
4.
Medical Outcome Survey of Sleep Scale (MOS-Sleep):  The MOS-Sleep is a 
12-item standardized, validated questionnaire for sleep assessment [27-28], which has 
been used in prior RLS treatment trials and has been demonstrated to be sensitive to 
RLS treatment effects [29].  This questionnaire provides information about sleep 
quality. Individual questions can be used for analysis but summary or index scores of 
a group of questions, is more commonly used in analysis [30] .
5.
Cambridge-Hopkins Diagnostic Questionnaire (CHDQ): Used at the screening 
visit, this is a validated, self-report, 13-item questionnaire, developed by the Johns 
Hopkins RLS group and used in prior studies [10-11]. Responses on Questions 11 and 
12 are also used as part of the inclusion criteria. The sensitivity and specificity for 
diagnosing RLS is 87.2% and 94.4% and specificity for Not-RLS is 98%.  The 
diagnosis based on the CHDQ is the primary outcome measure of RLS prevalence 
with adjustments in the estimate based on the HTDI. The diagnostic categories are: 
definite RLS, probable RLS, possible RLS, not RLS, and unknown[10, 12].
6.
Hopkins-Hening Telephone Diagnostic Interview (HTDI):  The HDTI is an 18-
item scripted interview that was developed and validated by the Johns Hopkins RLS 
group [12-13] and used in several RLS epidemiology studies[9, 14].  The HTDQ is 
considered the “gold standard” for making the diagnosis of RLS and is used to 
support the accuracy of CHDQ-determined diagnosis.  The five diagnostic categories 
defined by the HDTI are: definite RLS, probable RLS, possible RLS, not RLS, and 
unknown [10, 12].
7.
Hopkins RLS-Sleep Quality Questionnaire (HRSQ): This is a 13-item 
questionnaire, which includes a question on “weakness” and on “energy” and a series 
of questions related to how RLS might affect sleep.  The questions are part of a larger 
set of questions used in the NIH/NIA Baltimore Longitudinal Study on Ageing, and 
were used in our pilot study of Dr Auerbach’s IDA population. The data from the
questionnaire will be to validate the HRSQ against other measured of severity that will 
be used in this study.


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13. Nierenberg, MJ. Dopamine agonist withdrawal syndrome:  implications for patient care. 
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15. Trenkwalder C, Paulus W, Walters AS. The restless legs syndrome. Lancet Neurol. 2005 
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Arq Neuropsiquiatr 2015; 73(3):260-280. 
17. Allen RP, Earley CJ.  Augmentation of the restless legs syndrome with carbidopa/levodopa.  
Sleep 1996; 19:205-213. 
18. Trenkwalder C, Paulus W.  Restless legs syndrome:  pathophysiology, clinical presentation 
and management.  Nature Reviews 2010; 6:337-346. 
19. Ekbkom, K.A. Restless legs syndrome. Neurology 1960; 10:868-873. 
 
20. Norlander, N.B. Restless Legs. Brit J Phys Med 1954;17: 160-162. 
21. Silber M H Richardson  J W Multiple blood donations associated with iron deficiency in 
patients with restless legs syndrome. Mayo Clin. Proc. 2003; 78:52-54. 
22. Earley, CJ, Allen, RP, Beard, JL, Conner, JR. Insight into the pathophysiology of restless 
legs syndrome. J. Neurosci. Res. 62:623-628, 2000. 
23. Allen RP, Earley. MRI measurement of brain iron in patients with restless legs syndrome. 
Neurology. 2001. Jan 23, 56 (2):263-5. 
24. Connor JR, et al. Neuropathological examination suggests impaired brain iron acquisition in 
restless legs syndrome.  Neurology 2003; 61:304-9. 
25. Connor JR, Wang XS, Patton SM, Menzies SL, Troncosco JC, Earley CJ, Allen RP. 
Decreased transferring receptor expression by neuromelantin cells in restless legs syndrome. 
Neurology 2004 May 11; 62(9):1563-7. 
26. Ondo WG. Restless legs syndrome. Curr Neurol Neurosci Rep 2005; Jul; 5(4):266-74.  
 
27. Hogl B, PoweW. Restless Legs Syndrome. Curr Opin Neurol 2005; Aug 18 (4):405-10. 
28. Connor JR, Ponnuru P, Wang X, Patton SM, Allen RP, Earley CJ.  Profile of altered brain 
iron acquisition in restless legs syndrome.  Brain 2011; 134:959-68. 


Luitpold Pharmaceuticals Inc. 
 
 Protocol: 1VIT15042                                            
CONFIDENTIAL                                                                                                             Protocol Date: 25April2016 
Page 52 
 
29. Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WG.  Willis-Ekbom Disease 
Foundation Revised consensus Statement on the Management of Restless Legs Syndrome.  
Mayo Clin Proc 2013; 88(9):977-86. 
30.  Earley CJ, et al.   Altered brain iron homeostasis and dopaminergic function in restless legs 
syndrome (Willis-Ekbom Disease).  Sleep Med 2014; 15:1288-1301.  
31. Norlander, N.B. Therapy in restless legs. Acta Med Scand 1953; 145; 453-57. 
32. Earley CJ, Heckler D, Allen RP The treatment of restless legs syndrome with intravenous 
iron dextran. Sleep Med. 2004 May; 5(3):231-35. 
33. Early CJ, Heckler D, Allen RP. Repeated IV doses of iron provides effective supplemental 
treatment of restless legs syndrome. Sleep Med. 2005 Jul; 6 (4):301-5. 
34. Sloand JA, Shelly MA, Feigin A, Berstein P, Monk RD. A double-blind, placebo-controlled 
trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. 
Am J Kidney Dis. 2004 Apr; 43(4):663-70. 
35. Allen RP, Adler CH, Du W, Butcher A, Bregman DB, Earley CJ.  Clinical efficacy and 
safety of IF ferric carboxymaltose (FCM) treatment of RLS:  A multi-centred, placebo-
controlled preliminary clinical trial.  Sleep Medicine 2011Oct; 12(9):906-13.  
36. O’Keefe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age 
Ageing. 1994 May: 23 (3):200-3. 
37. Davis BJ, Rajput A, Rajput ML, Aul EA, Eichorn GR. A randomized, double-blind placebo-
controlled trial of iron in restless legs syndrome.  Eur Neurol 2000, 43(2):70-5. 
 
38. Wang J, O’Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A.  Efficacy of oral iron in 
patients with restless legs syndrome and a low-normal ferritin:  A randomized, double-blind, 
placebo-controlled study.  Sleep Medicine 2009; 10(9); 973-975.  
39. Trotti LM, Bhadriraju S, Becker LA.  Iron for restless leg syndrome.  Cochrane Database 
Syst Rev 2012 May16; 5:CD007834. doi: 10.1002/14651858.CD007834.pub2. Review. 
 
40. Allen RP, Butcher A, Du W.  Double-blind, placebo controlled multi-center evaluation of 
restless legs syndrome (RLS) treatment with a 1,000 mg of IV iron (ferric carboxymaltose - - 
FCM).  Sleep 2009; 32(Abstract supplement):A294-A295. 
41. Grote L, Leissner L, Hedner J, Ulfberg J.  A randomized, double-blind, placebo-controlled, 
multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs 
syndrome.  Movement Disorders 2009; 24(10):1445-52. 


Luitpold Pharmaceuticals Inc. 
 
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CONFIDENTIAL                                                                                                             Protocol Date: 25April2016 
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42. Davis BJ, Rajput A, Rajput ML, Aul EA, Eichhorn GR.  A randomized, double-blind, 
placebo-controlled trial of iron in restless legs syndrome.  European Neurology 2000;  
43:70-5.  
43. Earley CJ. Horska A, Mohamed MA, Barker PB, Beard JL, Allen RP.  A randomized, 
double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome.  
Sleep Medicine 2009; 10:206-11. 
44. Pondal M. Clinical features of dopamine agonist withdrawal syndrome in a movement 
disorders clinic J Neurol Neurosurg Psychiatry 2013 Feb; 84(2):130-5. 


 
 
 
Investigator Rated Global Impression – Global Improvement  
 
  
1. 
   
 
Global Assessment of Effect (check one):  
 
   5   
        
   4  
 
   3  
 
   2 
 
   1   
 
 
 
 
 
 
 
 
 
 
No effect 
 
Mild effect 
 
Moderate effect 
 
Marked effect 
 
Dramatic effect 
 2. 
   
Global Assessment of Improvement (check one): 
                     7 
 
                     6 
 
                     5 
 
                     4 
 
                     3 
 
                     2 
 
                     1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very much worse 
 
Much worse 
 
Minimally worse 
 
No change 
 
Minimal change 
 
Much improved 
 
Very much improved 
 
 
 
Investigator Initials:_____________        
 


 
 
 
© IRLS Study Group  2001 
IRLS – United States/English 
IRLS_AU2.2_eng-USori.doc 
International Restless Legs Syndrome Study Group Rating Scale 
(IRLS) 
(Investigator Version 2.2) 
 
Have the patient rate his/her symptoms for the following ten questions. The patient and not 
the examiner should make the ratings, but the examiner should be available to clarify any 
misunderstandings the patient may have about the questions. The examiner should mark the 
patient's answers on the form.   
 
 
In the past week… 
 
(1)  Overall, how would you rate the RLS discomfort in your legs or arms? 
 
 
4□   Very severe 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None  
 
 
In the past week… 
 
(2)  Overall, how would you rate the need to move around because of your RLS symptoms?  
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
In the past week… 
 
(3)  Overall, how much relief of your RLS arm or leg discomfort did you get from moving 
around? 
 
 
4□   No relief  
 
3□   Mild relief  
 
2□   Moderate relief  
 
1□   Either complete or almost complete relief  
 
0□   No RLS symptoms to be relieved  


 
 
 
© IRLS Study Group  2001 
IRLS – United States/English 
IRLS_AU2.2_eng-USori.doc 
In the past week… 
 
(4) How severe was your sleep disturbance due to your RLS symptoms? 
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
In the past week… 
 
(5) How severe was your tiredness or sleepiness during the day due to your RLS symptoms? 
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None  
 
 
In the past week… 
 
(6) How severe was your RLS as a whole? 
 
 
4□   Very severe  
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
In the past week… 
 
(7) How often did you get RLS symptoms? 
 
 
4□   Very often (This means 6 to 7 days a week) 
 
3□   Often (This means 4 to 5 days a week)  
 
2□   Sometimes (This means 2 to 3 days a week) 
 
1□   Occasionally (This means 1 day a week)  


 
 
 
© IRLS Study Group  2001 
IRLS – United States/English 
IRLS_AU2.2_eng-USori.doc 
 
0□   Never 
 
In the past week… 
 
(8) When you had RLS symptoms, how severe were they on average?  
 
 
4□   Very severe (This means 8 hours or more per 24 hour day) 
 
3□   Severe (This means 3 to 8 hours per 24 hour day) 
 
2□   Moderate (This means 1 to 3 hours per 24 hour day) 
 
1□   Mild (This means less than 1 hour per 24 hour day) 
 
0□   None 
 
 
In the past week… 
 
(9) Overall, how severe was the impact of your RLS symptoms on your ability to carry out 
your daily affairs, for example carrying out a satisfactory family, home, social, school or 
work life? 
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
In the past week… 
 
(10) How severe was your mood disturbance due to your RLS symptoms - for example angry, 
depressed, sad, anxious or irritable? 
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
 
 


Pt NUM _________Date: ____________ 
 
 
 
VISIT:   
 
 
 
Patient Global Impression 
 
For the Past Week rate how much you feel your RLS symptoms have changed since you 
started the study 
 
 
 
 
 
 
 
 
 
 
1 = Very much improved 
 
 
 
 
 
 
 
 
 
2=  Much improved  
 
 
 
 
 
 
 
 
 
3 = Minimally improved 
 
 
 
 
 
 
 
 
4 = No Change 
 
 
 
 
 
 
5 = Minimally worse 
 
 
 
 
 
 
6 = Much worse 
 
 
 
 
 
 
7=  Very much worse 
 
 
 
 
 
 
 
 


Sleep Scale from the Medical Outcomes Study
1. How long did it usually take for you to fall asleep during the past 4 weeks?
(Circle One)
0-15   minutes…………..…1
16-30 minutes……………..2
31-45 minutes……………..3
46-60 minutes……………..4
More than 60 minutes …….5
_________________________________________________________
2. On the average, how many hours did you sleep each night during the past 4
weeks?
Write in number
of hours per night:
_________________________________________________________


Copyright, 1986, RAND
Hays, R. D., & Stewart, A. L. (1992). Sleep measures. In A. L. Stewart & J. E. Ware (eds.), Measuring functioning and well-being: The
Medical Outcomes Study approach (pp. 235-259), Durham, NC: Duke University Press.
How often during the past 4 weeks did you…
        (Circle One Number On Each Line)
All of
the
Time
W
Most
of the
Time
W
A Good
Bit of
the Time
W
Some
of the
Time
W
A Little
of the
Time
W
None
of the
Time
W
3.   feel that your sleep was not quiet
(moving restlessly, feeling tense,
speaking, etc., while sleeping)?
1
2
3
4
5
6
4.   get enough sleep to feel rested upon
waking in the morning?
1
2
3
4
5
6
5.   awaken short of breath or with a
headache?
1
2
3
4
5
6
6.   feel drowsy or sleepy during the
day?
1
2
3
4
5
6
7.   have trouble falling asleep?
1
2
3
4
5
6
8.   awaken during your sleep time and
have trouble falling asleep again?
1
2
3
4
5
6
9.   have trouble staying awake during
the day?
1
2
3
4
5
6
10. snore during your sleep?
1
2
3
4
5
6
11. take naps (5 minutes or longer)
during the day?
1
2
3
4
5
6
12. get the amount of sleep you needed?
1
2
3
4
5
6


Version 2  Jan 2008   copyright:  Richard P Allen, PhD, FAASM; Brendan Burchell, PhD (RichardJHU@me.com) 
Page 1 of 1 
Cambridge- Hopkins Restless Legs Syndrome  
Short Form 2 DIAGNOSITC QUESTIONNAIRE  (CH-RLSq13) 
Answer the questions as completely as you can. Please circle the one best answer to each question thus:   ●   
1. Do you have, or have you had, recurrent uncomfortable feelings or sensations in your legs  
while you are sitting or lying down? 
 Yes 
 No 
2. Do you, or have you had, a recurrent need or urge to move your legs while you were  
sitting or lying down?  
 Yes 
 No 
If you answered YES to either question 1 or 2 continue Question 3. If you answered NO to BOTH stop here  
 The following is about these feelings 
3. Are you more likely to have these feelings when you are resting (either sitting or 
lying down) or when you are physically active? 
● Resting  
● Active 
4. Do these feelings usually start when you are resting (either sitting or lying 
down)? 
● Yes   
● No 
5. If you get up or move around when you have these feelings do these feelings 
get any better while you actually keep moving? 
●   Yes      ●   No   
●   Don’t know 
6. Which times of day are these feelings in your legs most likely to occur? 
 (Please circle one or more than one) 
 
 
●  Morning     ●  Mid-day 
●  Afternoon   ● Evening 
●  Night  
●  About equal at all times 
7. Which times of day are these feelings in your legs least likely to occur? (Please 
circle one or more than one) 
●  Morning     ●  Mid-day 
●  Afternoon   ● Evening 
●  Night  
●  About equal at all times 
8.  Will simply changing leg position by itself once without continuing to move 
usually relieve these feelings?   
 
● Usually relieves   
● Does not usually relieve  
● Don’t know 
 
9. Are these feelings ever due to muscle cramps?  
 
 
 ●   Yes    ●   No      
 ●   Don’t know 
9b. If so, are they always due to muscle cramps?  
 
 ●   Yes    ●   No      
 ●   Don’t know 
10. Do these feelings occur only when sitting or only when lying down? 
● Neither         
● Only when sitting       
● Only when lying down 
● Both when sitting and   .    
when lying down.   
11. When you actually experience the feelings in your legs, how distressing are 
they? 
 
 
 
● Not at all distressing 
● A little bit   
● Moderately       
●  Extremely distressing 
12. In the past 12 months, how often did you experience these feelings in your 
legs?  (please circle only one answer) 
 ● Every day                
 ● 4-5 days per wk       
 ● 2-3 days per wk          
 ● 1 day per wk  
 
 ● 2 days per month            
 ● 1 day per month or less   
 ● Never 
13. Approximately how old were you when you first noticed these feelings in your 
legs?(please write age) 
       
          Yrs 
 


NAME:  ____________________________________________________     DATE:  _____________________ 
 
 
1. In the past week, on average, what time did your RLS symptoms usually start: _______  AM / PM 
 
 
 
2. During the past week, how satisfied did you feel with the treatment for RLS,  
 
Not Satisfied 
      at all 
 
 
 
 
 
 
 
 
Very 
Satisfied 
 
Don’t 
know 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
 
⃝ 
         1 
 2 
  3 
 4 
 5 
 6 
  7 
 8 
  9 
   10 
 
     
 
3. During the past week, how would you rate the  Intensity of the sensation or Discomfort you  
experienced when your RLS symptoms did occur,  
 
Minimal  
Discomfort 
 
 
 
 
 
 
 
 
Quite 
Severe 
 
Don’t 
know 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
 
⃝ 
      1 
 2 
  3 
 4 
  5 
6 
  7 
 8 
  9 
   10 
 
     
 
 
     12. Overall, in the past week, was your typical night’s sleep…? 
          Very sound or restful      Sound or restful        Average quality        Restless    Very restless        Don’t know  
 
 
 
 
 
 
 
  
     13. On average, in the past week, how many hours of sleep did you get each night? 
          More than 7         More than 6, up to 7        More than 5, up to 6           5 or fewer             Don’t know    
       
      14.  List your current RLS medications and total daily dose:   
In the past week, how often did you: 
Never 
<1/week 
1-2/week 
3-4/week 
5+/week 
Don’t 
know 
4. …have trouble falling asleep within 30 
minutes because of your RLS symptoms? 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
5. …wake up several times at night? 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
6. … have trouble getting back to sleep 
because of your RLS symptoms? 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
7. … have RLS symptoms when you awakened 
for the day? 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
8. …need to take more medication for the RLS 
symptoms? 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
9. …find that your RLS medications just did 
not seem to work as well? 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
10. … find that the RLS symptoms were 
starting earlier than usual? 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
11. …have RLS symptoms in other parts of 
the body other than your legs? 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 
⃝ 


 
 
 
The Hopkins-Hening  RLS  
Diagnostic Interview 
 
 
Subject Name:    ____________________________  ID #:  ____________  DOB:  _____________ 
                   
           
             
Interviewer:  _______________________________  Date:  ____________  Time:  _____________ 
 
 
 
Final Diagnosis: 
 
Definite RLS;         
 
 
Probable RLS;   
 
Possible RLS;        
 
Secondary Definite;     
 
Secondary  Possible;  
Cause: _____________________ 
Not-RLS;                                   
Diagnosis Unknown  
 
Circle if subject reports growing pains:     ____  Yes        ____   No 
 
 
 
 
General Note – The final standard for answering questions is the judgment of the interviewer.  As a 
result, answers may be revised if later questions make it clear that an earlier answer was inaccurate.  
When revising answers, document why this was done (e.g. questions on sleep indicate there are leg 
discomforts, etc.).  If an interviewee mentions multiple different feelings, be clear which is indicated by 
any given answer.  Remember, to be diagnosed with RLS, all relevant criteria must be satisfied by a 
single feeling.  Where it is not indicated to skip ahead, continue the interview with the next question. 
Revised 17mar2008 
 


Hopkins Diagnostic Phone Interview – Page 2 of 6 
Subject Identifier _______________________________ 
1.  Have you ever had unpleasant or uncomfortable feelings in your legs that occurred mainly while you 
were either sitting or lying down?  
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
Yes 
 
No 
 
If NO, go to 3    
 
 
2.  Are these feelings painful rather than just uncomfortable?  
 
Yes 
 
No 
 
3.  Have you ever felt the need or urge to move your legs that occurred mainly while you were sitting  
or lying down? 
 
 
 
 
 
 
 
 
 
 
 
 
 Yes 
 
  No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If NO to both questions #1 and #3, go to #15. 
 
3a.  Do both the urge to move and the unpleasant sensations occur at the same time? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Yes 
 
  No 
 
If NO, there may be two different symptoms and this should be explored and clarified.  Remember – all 
criteria must be satisfied by a single symptom. 
 
 
 
3b) How would you describe these feelings or sensations? 
       
 
________________________________________________________ 
       
 
________________________________________________________ 
 
      
3c.  Do these feelings in your legs ever become overwhelming to the point that you cannot resist  
       
 
moving your legs? 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
No 
 
 
 
 
 
3d.  How would you feel if you developed this feeling and were in a situation where you couldn’t  
                   move?   (Note: Can Give Examples)   
       
 
 
 
 
________________________________________________________ 
 
 
 
 
 
________________________________________________________ 
 
 
3e.  Do these feelings only occur when your legs are in specific positions, such as crossed  
 
 
or bent a particular way? 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
No 
 
 
 
 
 
 
If YES, explain ___________________________________________________ 
 
 
3f.  When you have these feelings, how long do they last before they have gone away so that you 
can sit or lie down for an  hour or more without having the feelings? 
  


Hopkins Diagnostic Phone Interview – Page 3 of 6 
Subject Identifier _______________________________ 
This means that the person does not have to continue moving to relieve the feelings. 
 
 
 
________________________________________________________ 
 
 
 
 
 
 
If answer is 5 minutes or less, explain how consistent with RLS  
 
 
4.  Have you ever experienced a muscle cramp in the legs? 
 
 
 
 
 
 
 
 
 
 
 
 Yes 
 
        No 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
If YES, go to 4a 
 
If NO, go to 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4a.  Were these feelings you described earlier muscle cramps in the legs? 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
                     No 
If YES, go to 4b 
 
If NO, go to 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4b. Were the feelings you described earlier always muscle cramps in the legs? 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
                     No 
 
If YES, Conclude the interview, subject is NOT RLS 
If NO, continue or revisit 1 and 3 
 
If NO, the subject has two different feelings – a cramp is one and something else is the other – since 
cramps are not RLS, you need to go back to 1 and be sure and indicate that all answers correspond to 
this other feeling. 
 
5.  If you had these feelings and you got up to walk -- while you are actually walking around, do you 
get any relief from these feelings? 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
The answer to this question does not require complete relief, but only some relief. 
NOTE:  If any suspicion of confusion, indicate that this is before sitting or lying down again. 
 
 
 
 
 
 
 
 
 
 
 Yes 
           No                       Don’t Know 
 
 
 
 
5a.  If you move your legs, do you get any relief from these feelings, even temporarily? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Yes 
       
   
  No 
 
 
 
 
 
 
 
 


Hopkins Diagnostic Phone Interview – Page 4 of 6 
Subject Identifier _______________________________ 
 
5b. What do you do to get relief from these feelings (this question is to be answered by behaviors 
 
and not by medications taken)? 
 
 
________________________________________________________ 
      
 
________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
5c.  If you move your leg once to a new position, but don’t continue to move or do anything else, 
             will that single change of position be enough to relieve the feelings? 
 
 
 
 
 
 
 
 
 
 
 
Yes 
      No 
If YES, explain__________________________________________________________ 
 
6.  Do these feelings ever start when you are walking?              
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
      No 
 
If YES, explain_____________________________________________________________ 
 
 
 
7.  Do these feelings occur more often when you are sitting or more often when you are lying down?  
 
 
More sitting ________   About the same _____________    More lying ________________ 
 
 
 If more sitting – GO TO 7a 
 If more lying or about the same – GO TO 8 
 
 
 
 
 
 
 
 
7a.  Would it be true to say that you have these feelings almost exclusively when you 
                        are sitting?  That is, do these feelings occur 90% or more of the time they occur when  
                        you are sitting? 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
Yes 
      No 
 
 
 
 
 
 
7b. Do these feelings ever occur while you are lying down?  
 
 
 
 
 
 
 
 
 
 
 
Yes 
      No 
 
 
 
8. Are these feelings in your legs worse at night or in the evening than other times of the day? 
 
 
 
 
 
 
 
 
 
 
       Yes 
      No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Note:  Ask 8a only if 8 is NO and symptoms are severe, daily, and consistent with RLS. 
 
 
 
8a. Was there ever a time in your life when these feelings were worse at night than other times of 
 
 
the day? 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
      No 


Hopkins Diagnostic Phone Interview – Page 5 of 6 
Subject Identifier _______________________________ 
 
 
9.  Approximately, how old were you when you first noticed these feelings in your legs? 
 
 
 
 
 
 
 
 
 
 
 
 
__________ years old 
 
 
10. Are you presently on medication for these feelings?  
 
Yes                               No 
  
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
If YES, go to 10a. 
 
If NO, go to 11 
 
 
 
 
 
 
 
 
 
 
 
10a.  Please respond to the following questions the way you think you would be if you  
                    were not on any treatment at this time.    
 
 
 
10b.  Please respond to the following questions for the period of time during which 
                     you  had these feelings.   
 
** Note to interviewer:  Select tense appropriate to patient’s symptoms: either present or past 
 
 
11.  How many days in the month do (did) you have these feelings?   ___________________ 
 
 
 
 
 
 
 
 
 
11a. For how many years has it been occurring (did it occur) at least this frequently?    
                   _________________ 
 
 
 
 
  
 
11b.  At what time of day do (did) these feelings usually start? 
 
 
 
 
    _____during sleep        
 
 
_____at bedtime 
 
    
                       _____after 6 p.m., but before bedtime 
_____before 6 p.m. 
  ______before noon 
 
 
 
 
Note to interviewer:  The answers to questions 13 and 14 should reflect the interviewer’s judgment that 
the medications or medical problems detailed are at least possibly the cause of the RLS symptoms.  
Enough information should be entered to allow a reviewer to determine if this judgment is correct, 
especially the time course of the medication use or medical problem. 
 
12.  Are you aware of any medications or medical problems which might be causing (have caused) these 
feelings?  (Answer YES indicates interviewer believes problem has caused RLS) 
 
 
 
 
 
 
 
 
 
 


Hopkins Diagnostic Phone Interview – Page 6 of 6 
Subject Identifier _______________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
      No 
 
 
 
12a.  (If yes)  What is the medication or medical problem?   
 
 
 
 
 
 
 
_______________________________________________ 
  
For all medical problems, identify when they started, before or after the feelings began, and whether 
they have continued while the feelings continued. 
 
 
 
 
 
13.  Do the sensations in your legs disrupt your sleep or cause you to loss sleep?  
 
       
      
Yes 
  
       No 
 
 


 
 
 
Investigator Rated Global Impression – Global Improvement  
 
  
1. 
   
 
Global Assessment of Effect (check one):  
 
   5   
        
   4  
 
   3  
 
   2 
 
   1   
 
 
 
 
 
 
 
 
 
 
No effect 
 
Mild effect 
 
Moderate effect 
 
Marked effect 
 
Dramatic effect 
 2. 
   
Global Assessment of Improvement (check one): 
                     7 
 
                     6 
 
                     5 
 
                     4 
 
                     3 
 
                     2 
 
                     1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very much worse 
 
Much worse 
 
Minimally worse 
 
No change 
 
Minimal change 
 
Much improved 
 
Very much improved 
 
 
 
Investigator Initials:_____________        
 


 
 
 
© IRLS Study Group  2001 
IRLS – United States/English 
IRLS_AU2.2_eng-USori.doc 
International Restless Legs Syndrome Study Group Rating Scale 
(IRLS) 
(Investigator Version 2.2) 
 
Have the patient rate his/her symptoms for the following ten questions. The patient and not 
the examiner should make the ratings, but the examiner should be available to clarify any 
misunderstandings the patient may have about the questions. The examiner should mark the 
patient's answers on the form.   
 
 
In the past week… 
 
(1)  Overall, how would you rate the RLS discomfort in your legs or arms? 
 
 
4□   Very severe 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None  
 
 
In the past week… 
 
(2)  Overall, how would you rate the need to move around because of your RLS symptoms?  
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
In the past week… 
 
(3)  Overall, how much relief of your RLS arm or leg discomfort did you get from moving 
around? 
 
 
4□   No relief  
 
3□   Mild relief  
 
2□   Moderate relief  
 
1□   Either complete or almost complete relief  
 
0□   No RLS symptoms to be relieved  


 
 
 
© IRLS Study Group  2001 
IRLS – United States/English 
IRLS_AU2.2_eng-USori.doc 
In the past week… 
 
(4) How severe was your sleep disturbance due to your RLS symptoms? 
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
In the past week… 
 
(5) How severe was your tiredness or sleepiness during the day due to your RLS symptoms? 
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None  
 
 
In the past week… 
 
(6) How severe was your RLS as a whole? 
 
 
4□   Very severe  
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
In the past week… 
 
(7) How often did you get RLS symptoms? 
 
 
4□   Very often (This means 6 to 7 days a week) 
 
3□   Often (This means 4 to 5 days a week)  
 
2□   Sometimes (This means 2 to 3 days a week) 
 
1□   Occasionally (This means 1 day a week)  


 
 
 
© IRLS Study Group  2001 
IRLS – United States/English 
IRLS_AU2.2_eng-USori.doc 
 
0□   Never 
 
In the past week… 
 
(8) When you had RLS symptoms, how severe were they on average?  
 
 
4□   Very severe (This means 8 hours or more per 24 hour day) 
 
3□   Severe (This means 3 to 8 hours per 24 hour day) 
 
2□   Moderate (This means 1 to 3 hours per 24 hour day) 
 
1□   Mild (This means less than 1 hour per 24 hour day) 
 
0□   None 
 
 
In the past week… 
 
(9) Overall, how severe was the impact of your RLS symptoms on your ability to carry out 
your daily affairs, for example carrying out a satisfactory family, home, social, school or 
work life? 
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
In the past week… 
 
(10) How severe was your mood disturbance due to your RLS symptoms - for example angry, 
depressed, sad, anxious or irritable? 
 
 
4□   Very severe 
 
3□   Severe 
 
2□   Moderate 
 
1□   Mild 
 
0□   None 
 
 
 
 


Sleep Scale from the Medical Outcomes Study
1. How long did it usually take for you to fall asleep during the past 4 weeks?
(Circle One)
0-15   minutes…………..…1
16-30 minutes……………..2
31-45 minutes……………..3
46-60 minutes……………..4
More than 60 minutes …….5
_________________________________________________________
2. On the average, how many hours did you sleep each night during the past 4
weeks?
Write in number
of hours per night:
_________________________________________________________


Copyright, 1986, RAND
Hays, R. D., & Stewart, A. L. (1992). Sleep measures. In A. L. Stewart & J. E. Ware (eds.), Measuring functioning and well-being: The
Medical Outcomes Study approach (pp. 235-259), Durham, NC: Duke University Press.
How often during the past 4 weeks did you…
        (Circle One Number On Each Line)
All of
the
Time
W
Most
of the
Time
W
A Good
Bit of
the Time
W
Some
of the
Time
W
A Little
of the
Time
W
None
of the
Time
W
3.   feel that your sleep was not quiet
(moving restlessly, feeling tense,
speaking, etc., while sleeping)?
1
2
3
4
5
6
4.   get enough sleep to feel rested upon
waking in the morning?
1
2
3
4
5
6
5.   awaken short of breath or with a
headache?
1
2
3
4
5
6
6.   feel drowsy or sleepy during the
day?
1
2
3
4
5
6
7.   have trouble falling asleep?
1
2
3
4
5
6
8.   awaken during your sleep time and
have trouble falling asleep again?
1
2
3
4
5
6
9.   have trouble staying awake during
the day?
1
2
3
4
5
6
10. snore during your sleep?
1
2
3
4
5
6
11. take naps (5 minutes or longer)
during the day?
1
2
3
4
5
6
12. get the amount of sleep you needed?
1
2
3
4
5
6


Pt NUM _________Date: ____________ 
 
 
 
VISIT:   
 
 
 
Patient Global Impression 
 
For the Past Week rate how much you feel your RLS symptoms have changed since you 
started the study 
 
 
 
 
 
 
 
 
 
 
1 = Very much improved 
 
 
 
 
 
 
 
 
 
2=  Much improved  
 
 
 
 
 
 
 
 
 
3 = Minimally improved 
 
 
 
 
 
 
 
 
4 = No Change 
 
 
 
 
 
 
5 = Minimally worse 
 
 
 
 
 
 
6 = Much worse 
 
 
 
 
 
 
7=  Very much worse 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Table of Contents
Table of Contents
5
Statistical Analysis Plan: Protocol No.: 1VIT15042 NCT Number: 02826681
4
16.1.9 Statistical Analysis Plan: Protocol No.: 1VIT15042 20AUG2021
5
STATISTICAL ANALYSIS PLAN APPROVAL
6
LIST OF ABBREVIATIONS AND DEFINITIONS
7
1. INTRODUCTION
9
1.1 STUDY OBJECTIVES
9
1.1.1 Primary Objective(s)
9
1.2 STUDY ENDPOINTS
9
1.2.1 Primary Efficacy Endpoint(s)
9
1.2.2 Secondary Efficacy Endpoint(s)
10
1.2.3 Safety Endpoints
10
1.3 SUMMARY OF THE STUDY DESIGN
10
1.3.1 General Study Design and Plan
10
Table 1.1 Schedule of Events Treatment Phase I and Treatment Phase II
12
Table 1.2 Schedule of Events Long-Term Extension Phase III
13
1.3.2 Randomization and Blinding
13
1.3.3 Sample Size and Statistical Power Considerations
13
2. STATISTICAL METHODS
13
2.1 GENERAL CONSIDERATIONS
13
2.1.1 Reporting Precision
14
2.2 DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS)
14
2.2.1 ITT Population
14
2.2.2 Safety Population
14
2.3 TIME WINDOWS FOR ANALYSIS
15
2.4 HANDLING OF MISSING DATA
15
2.5 ANALYSIS SOFTWARE
15
3. STUDY SUBJECTS
16
3.1 DISPOSITION OF SUBJECTS
16
3.2 PROTOCOL DEVIATIONS
16
4. DEMOGRAPHICS AND BASELINE CHARACTERISTICS
16


4.1 DEMOGRAPHICS AND BASELINE CHARACTERISTICS
16
4.2 MEDICAL HISTORY
16
5. STUDY DRUG AND EXPOSURE
17
5.1 TREATMENT COMPLIANCE AND EXTENT OF EXPOSURE
17
5.2 PRIOR AND CONCOMITANT THERAPY
17
6. EFFICACY ANALYSES
17
6.1 PRIMARY EFFICACY ANALYSIS
17
6.1.1 Phase I and Phase II: Change in IRLSS total score from baseline to Day 42
17
6.1.2 Phase I and Phase II: Percentage of subjects who are much or very much 
improved at Day 42 as measured by the CGI-I
18
6.1.3 Phase III: Time from initial FCM treatment to further FCM treatment
18
6.2 SECONDARY EFFICACY ANALYSES
18
6.2.1 Phase I and II: Change in IRLSS total score from baseline to Day 42 (Non-
responders in Phase I Placebo group)
18
6.2.2 Phase I and II: Change in IRLSS total score from baseline to Day 42 (Non-
responders in Phase I FCM group)
18
6.2.3 Phase I and Phase II: CGI-I and PGI-I score at Day 42
18
6.2.4 Phase I and Phase II: Percentage of subjects who are much or very much 
improved at Day 42 as measured by the PGI-I
18
6.2.5 Phase I and Phase II: Change in sleep quality measured by MOS from 
baseline to Day 42
19
6.2.6 Phase I and Phase II: Number (percentage) of treatment non-responders at 
Day 42 of Phase I who respond to FCM in Phase II
19
6.2.7 Phase I and Phase II: Number (percentage) of treatment responders at Day 42
19
6.2.8 Phase I and Phase II: Change in substantia nigra iron index from baseline to 
Day 42
19
6.2.9 Phase I and Phase II: Change in thalamus and motor cortex iron index from 
baseline to Day 42
19
6.2.10 Phase III: Change in IRLSS total score from baseline to each visit
20
6.3 EXPLORATORY ANALYSES
20
6.3.1 Phases I and II: Vitamin D at each visit
20
6.3.2 Phases I and II: Change in thalamus and motor cortex iron index from 
baseline to Day 42 for other brain regions
20
7. SAFETY ANALYSIS
20


7.1 ADVERSE EVENTS
20
7.1.1 Adverse Events of Special Interest
22
7.1.2 Deaths, Serious and Other Significant Adverse Events
22
7.2 CLINICAL LABORATORY PARAMETERS
22
7.3 VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS
23
7.3.1 Vital Signs
23
Table 2 Criteria for Potentially Clinically Significant Vital Signs
23
7.3.2 Physical Examination
24
7.4 OTHER ANALYSES
24
8. INTERIM ANALYSES AND DATA AND SAFETY MONITORING BOARD 
(DSMB)
24
8.1 INTERIM ANALYSES
24
8.2 DATA AND SAFETY MONITORING BOARD (DSMB)
24
9. SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES
24


Statistical Analysis Plan 
Protocol No.: 1VIT15042 
Randomized, placebo-controlled, multi-center trial of ferric 
carboxymaltose in Restless Legs Syndrome patients with iron 
deficiency anemia 
NCT Number: 02826681 
Date: 20AUG2021


Sponsor: American Regent, Inc. 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
Statistical Analysis Plan 
Confidential 
Page 1 of 20 
Statistical Analysis Plan 
Protocol No.: 1VIT15042 
Randomized, placebo-controlled, multi-center trial of ferric 
carboxymaltose in Restless Legs Syndrome patients with iron-
deficiency anemia 
Sponsor: 
American Regent, Inc. 
Version: 
Version 1.0 
Issue Date: 
20AUG2021 


for Nicole Blackman
08
20
2021


Sponsor: American Regent, Inc. 
 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
 
Statistical Analysis Plan 
 
 
Confidential 
Page 3 of 20 
 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
AST 
Aspartate Aminotransferase Test 
ALT   
Alanine Transaminase Test 
ATC                                      Anatomical Therapeutic Chemical 
ANCOVA 
Analysis of Covariance 
BP   
Blood Pressure 
BUN 
Blood Urea Nitrogen  
CBC 
Complete Blood Count 
CGI-I 
Clinical Global Impression- Improvement 
CHDQ  
Cambridge-Hopkins Dianostic Questionnaire 
CRF 
Case Report Form 
CI 
Confidence Interval 
DSMB    
Data and Safety Monitoring Board  
FCM   
Ferric Carboxymaltose 
Hct 
Hematocrit Test 
Hgb 
Hemoglobin 
HTDI  
Hopkins-Hening Telephone Diagnostic Interview 
HRSQ 
Hopkins RLS-Sleep Quality Questionnaire 
IDA    
Iron-deficiency aAnemia 
IRLSS  
International Restless Legs Syndrome Severity Scale 
IRT     
Interactive Response Technology 
IV 
 
Intravenous 
LDH 
Lactate Dehydrogenase 
MCH    
Mean Cell Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV         
Mean Corpuscular Volume 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
mL 
Milliliter 
MOS 
Medical Outcomes Survey for Sleep 
MRI 
Magnetic Resonance Imaging 
PCS 
Potentially Clinically Significant  
PE     
Physical Examination 
PGI-I  
Patient Global Impression-Improvement 
PT      
Preferred Term 
QSM    
Quantitative Susceptibility Mapping 
RBC    
Red Blood Cells 
RDW     
Red Cell Distribution Width Test 
RLS     
Restless Legs Syndrome 
SAE 
 
Serious Adverse Event 
SAP    
Statistical Anlaysis Plan 
SOC 
System Organ Class 
SD    
Standard Deviation 
TEAE  
Treament Emergent Adverse Event  


Sponsor: American Regent, Inc. 
 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
 
Statistical Analysis Plan 
 
 
Confidential 
Page 4 of 20 
 
TIBC   
Total Iron Binding Capcacity  
TSAT 
% Transferrin Saturation 
VS 
Vital Sign 
WBC 
White Blood Cells 
WHO       
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sponsor: American Regent, Inc. 
 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
 
Statistical Analysis Plan 
 
 
Confidential 
Page 5 of 20 
 
1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Protocol 1VIT15042 (Date: 4 September 
2019). This SAP should be read in conjunction with the study protocol and case report forms 
(CRFs).  
1.1 
STUDY OBJECTIVES 
1.1.1 
Primary Objective(s) 
Treatment Phases I and II primary objective is to evaluate the efficacy and safety of FCM (750 mg 
dose x 2) for treatment of Restless Legs Syndrome (RLS) in patients with iron-deficiency anemia 
(IDA). 
 
Long-term extension Phase III primary objective is to evaluate the duration of effect of 
prior FCM treatment and to determine the effectiveness of further iron repletion with FCM when 
RLS symptoms worsen or reoccur. 
 
1.2 
STUDY ENDPOINTS 
1.2.1 
Primary Efficacy Endpoint(s) 
 
Primary efficacy endpoint in Treatment Phase I is to determine the effectiveness of FCM in 
improving RLS severity associated with IDA.   Effectiveness will be evaluated by: 
• IRLSS score change from baseline to Day 42 with comparison between 
FCM vs. Placebo. 
• CGI-I at Day 42.  
 
Primary efficacy endpoint in Treatment Phase II is to determine the effectiveness of an additional 
unblinded single FCM treatment in improving RLS severity in non-responders from Treatment 
Phase I.  Effectiveness will be evaluated by: 
• IRLSS score change from baseline (For Phase II the “baseline” is established on 
Day 42 of Phase I) compared to Day 42 of Treatment Phase II 
• CGI-I at Day 42 in Treatment Phase II. 
 
Primary efficacy endpoint in Long-Term Extension Phase III is to evaluate the duration of effect 
of FCM as defined as the number of weeks from the initial treatment without need for further 
treatment. Initial treatment is defined as Day 0 of Phase I for Responders in Phase I and Day 0 of 
Phase II for Responders in Phase II.   
 
 
 
 
 


Sponsor: American Regent, Inc. 
 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
 
Statistical Analysis Plan 
 
 
Confidential 
Page 6 of 20 
 
1.2.2 
Secondary Efficacy Endpoint(s) 
Treatment Phase I and Phase II: 
• Change in IRLSS score from Baseline to Day 42. (Treatment Phase I and II) 
• IRLSS score change from Baseline (For Phase II the “Baseline” is established on Day 42 
of Phase I) compared to Day 42 of Treatment Phase II. 
• CGI-I and PGI-I at each visit and percentage of subjects who are much or very much 
improved at Day 42. (Treatment Phase I and II) 
• Change in sleep quality (MOS Sleep) from Baseline to Day 42. (Treatment Phase I and II) 
• Estimate the proportion of treatment non-responders in Phase I who respond to FCM in 
Phase II for each randomized treatment group. (Phase II only) 
• Change in substantia nigra iron index from Baseline to Day 42. The index will be 
determined using measures of MRI relaxation rate (R2*) or Quantitative Susceptibility 
Mapping (QSM). (Treatment Phase I and II) 
• Change in iron index (R2* or QSM) for thalamus and motor cortex from Baseline to Day 
42. (Treatment Phase I and II). 
 
Treatment Phase III: 
• Change in IRLSS total score from baseline to each scheduled visit.  
• Number (and percentage) of subjects who remain in the study to Week 52. 
 
1.2.3 
Safety Endpoints 
Safety endpoints include: 
• Adverse events 
• Laboratory assessments, including hematology (Hgb, Hct, RBC, WBC, MCV, MCH, 
MCHC, RDW, platelets, differential count), iron indices (serum iron, serum ferritin, and 
total iron binding capacity (TIBC), percentage serum transferrin saturation (TSAT)), 
clinical chemistry (sodium, potassium, chloride, BUN, creatinine, albumin, alkaline 
phosphatase, total bilirubin, gamma-GGT, AST, ALT, LDH, calcium, phosphorus, glucose, 
bicarbonate)  
• Vital signs  
 
1.3 
SUMMARY OF THE STUDY DESIGN  
1.3.1 
General Study Design and Plan 
This is a Phase II, randomized, placebo-controlled multi-center study to evaluate the efficacy and 
safety of Injectafer® (FCM Injection) for treatment of Restless Leg Syndrome (RLS) with iron-
deficiency anemia (IDA).   
 
 
 
 


Sponsor: American Regent, Inc. 
 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
 
Statistical Analysis Plan 
 
 
Confidential 
Page 7 of 20 
 
FCM is a stable Type I polynuclear iron (III)-hydroxide carbohydrate complex developed as an 
intravenous (IV) iron replacement therapy for the treatment of IDA1. All subjects who meet the 
inclusion requirements and no exclusion criteria will qualify to enter the screening phase. The 
study will include 3 treatment phases, i.e. Phase I (42 days), II (42 days) and III (46 weeks long-
term extension), and will enroll 70 subjects to be randomized into Treatment Phase I.  
 
In Treatment Phase I, all eligible subjects will be randomized in a 1:1 ratio to receive a blinded 
dose of either FCM 750 mg undiluted slow IV push at 100 mg/minute or a Placebo (15 ml of 
Normal Saline) IV push at 2 ml/minute on Days 0 and 7. At the end of treatment Phase I (i.e. Day 
42), all subjects will be defined as either treatment responders or non-responders defined as: 
 
Responder: IRLSS total score ≤10, or IRLSS total score >10 with a CGI-I score of much 
or very much improvement and the patient does not request further treatment for RLS.  
 
Non-Responder: if neither of these above criteria are met. 
 
In Treatment Phase II, Treatment Phase I Non-Responders who have met the necessary 
laboratory criteria (ferritin <300 ng/mL and a TSAT <45%) will be consented for enrollment in 
Treatment Phase II. Day 0 of treatment Phase II will occur within 7 days of the completing 
Treatment Phase I Day 42 visit. These subjects will receive an unblinded 750 mg dose of FCM, 
treatments will be given as an undiluted slow IV push at 100 mg/minute on Days 0 and 7 of Phase 
II consequently. Treatment Phase I Non-Responders who do not meet the laboratory criteria for 
additional dosing will be discontinued from the study and treated for RLS as deemed appropriate 
by the referring physician. Subjects completing Treatment Phase II will be re-evaluated on Day 42 
and defined as either a Responder or Non-Responder, using the same criteria described above. 
Treatment Phase II Non-Responders will be discontinued from the study after final assessments 
are complete. 
 
In Treatment Phase III, responders from either Treatment Phase I or Treatment Phase II will 
continue through into this 46-week long-term extension phase of the study, and be monitored and 
assessed by phone for RLS symptoms (IRLSS and HRSQ) and adverse events on Weeks 15, 25, 
34, 43 and 52 (final follow-up visit) from treatment Phase I Day 0. During Phase III, subjects may 
receive additional unblinded treatments (i.e. a single FCM 750 mg undiluted slow IV push at 100 
mg/minute) if at any time the subject reports worsening of RLS symptoms (an increase >4 points 
on the IRLSS compared to the last evaluation captured for that subject) and laboratory criteria are 
met (ferritin <300 ng/mL and a TSAT <45%). No additional treatment will be allowed after the 
Week 46. A final face-to-face study visit will occur on Week 52. If a clinic visit is not possible, 
final evaluation will be completed by phone. 
 
The Schedule of Events for Phases I, II and III are presented as Table 1.1 and Table 1.2  


Sponsor: American Regent, Inc. 
 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
 
Statistical Analysis Plan 
 
 
Confidential 
Page 8 of 20 
 
Table 1.1 Schedule of Events Treatment Phase I and Treatment Phase II 
 
SCREENING 
Treatment Phase I and Treatment Phase II 
STUDY VISIT 
PROCEDURES 
-14 
DAY 0 
DAY 7+1 
DAY 14+3 
DAY 28+3 
(PHONE CONTACT) 
DAY 42+3 
Informed Consent  
X 
 
 
 
 
X** 
Eligibility  
X 
X 
 
 
 
X 
Medical History, 
including prior iron 
therapy 
X 
X 
 
 
 
 
RLS History 
X 
X 
 
 
 
 
D/C oral iron 
products  
X 
 
 
 
 
 
Site contact IRT 
X 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
X 
Vital Signs 
X 
X 
X 
 
 
X 
Height and Weight 
without shoes 
X 
 
 
 
 
 
CHDQ 
X 
 
 
 
 
 
HTDI 
X 
 
 
 
 
 
IRLSS   
X 
X 
 
 
X 
X 
HRSQ 
 
X 
 
 
 
X 
CGI-I  
 
 
 
 
 
X 
PGI-I 
 
 
 
 
 
X 
MOS Sleep Scale  
 
X 
 
 
 
X 
Hematology 
X 
X 
X 
X 
 
X 
Iron Indices 
X 
X 
X 
X 
 
X 
Chemistry 
X 
X 
X 
X 
 
X 
Vitamin D 
 
X 
X 
X 
 
X 
Erythropoietin 
 
X 
 
 
 
X 
Trace Element 
 
X 
 
 
 
 
Urine Pregnancy 
test 
X 
 
 
 
 
 
Study Drug 
 
X 
X 
 
 
 
Brain MRI 
X 
 
 
 
 
X 
Concomitant Meds  
X 
X 
X 
 
X 
X 
Adverse Events 
 
X 
X 
 
X 
X 
** All Subject will be consented to participate in Treatment Phase II prior to any study procedures being completed 


Sponsor: American Regent, Inc. 
 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
 
Statistical Analysis Plan 
 
 
Confidential 
Page 9 of 20 
 
Table 1.2  
Schedule of Events Long-Term Extension Phase III 
STUDY VISIT 
PROCEDURES 
Week 15 Phone 
Contact 
Week 25 Phone 
Contact 
Week 34 Phone 
Contact 
Week 43 Phone 
Contact 
Week 52 EOS 
IRLSS 
X 
X 
X 
X 
X 
HRSQ 
X 
X 
X 
X 
X 
MOS / PGI-I 
 
 
 
 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Physical Exam / VS 
See protocol Section 6.6 for procedures for additional FCM dosing 
 
Iron Indices / 
Chemistries / 
Hematology 
X 
FCM Dosing 
 
 
1.3.2 
Randomization and Blinding 
On Day 0 of treatment Phase I, all eligible subjects will be randomized via IRT system in a 1:1 
ratio to receive a blinded dose of either FCM 750 mg undiluted slow IV push at 100 mg/minute or 
a Placebo (15 ml of Normal Saline) IV push at 2 ml/minute.  
 
Other than designated randomization personnel, all subjects, investigators, and study conduct 
personnel are blinded to study drug assignment. The blinded investigators are also blinded to the 
IRLSS total score and PGI-I score for each subject after randomization. All study personnel will 
be blinded to the post treatment iron indices and phosphorous (after randomization) throughout 
the study.  
 
1.3.3 
Sample Size and Statistical Power Considerations 
Enrollment was planned for 70 randomized subjects (35 per treatment group in Phase I). Based on 
Study 1VIT05009 in patients without IDA, approximately 50% of patients in the FCM group and 
15% of patients in the placebo group are anticipated to have much or very much improvement on 
the CGI-I. The proposed sample size provides >85% power to detect this difference with the chi-
square test. The mean treatment difference (and standard deviation) for change from baseline to 
Day 42 for IRLSS is anticipated to be 5.0 (7.3).  The proposed sample size provides >80% power 
to detect this difference with a two-sided t-test with alpha=0.05. 
 
2. 
STATISTICAL METHODS 
2.1 
GENERAL CONSIDERATIONS 
Analysis datasets will be produced according to CDISC standards. All study-collected data will be 
summarized in tables or graphs. Listing will be produced when appropriate and all ICH-required 
listings will be produced. In general, continuous variables will be summarized by number of 
subjects, mean, standard deviation (SD), median, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of subjects in each category  
In general, summary tables will present data by treatment group (for Phase I) and treatment phase.  
 


Sponsor: American Regent, Inc. 
 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
 
Statistical Analysis Plan 
 
 
Confidential 
Page 10 of 20 
 
Baseline definitions: 
• Phase I: baseline (other than iron index) is the last non-missing value prior to receiving 
randomized study medication.  
• Phase II: phase II baseline (other than iron index) is the last non-missing value prior to 
receiving unblinded FCM in Phase II. 
• Phase I and Phase II: baseline for iron index measured by MRI is measured in screening. 
• Phase III:  phase III baseline is defined as Day 0 of Phase I for responders in Phase I 
and Day 0 of Phase II for responders in Phase II. 
 
2.1.1 
Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
Statistics 
Degree of Precision 
Mean, Median, Quartiles,  
One decimal place more than the raw data. 
Standard deviation 
Two decimal places more than the raw data. 
Minimum, Maximum 
The same as the raw data. 
Percentage 
One decimal place. A percentage of 100% will be 
reported as 100%. Percentages of zero will be 
reported as 0. 
For weight and height, one decimal place will be used for summary statistics. Fractional numeric 
values will be presented with a zero to the left of the decimal point (for example, 0.12 – 0.30). 
2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) 
2.2.1  
ITT Population 
ITT population includes all the subjects who were randomized.  
Summaries for ITT population will be based on the treatment group to which they were 
randomized. 
2.2.2  
Safety Population 
Safety population includes all the subjects who were randomized and received at least one dose of 
study medication.  
 
Summaries for safety population will be based on the actual treatment they received. 
 


Sponsor: American Regent, Inc. 
 
Protocol No:  1VIT15042 Amendment I (04SEP2019) 
 
Statistical Analysis Plan 
 
 
Confidential 
Page 11 of 20 
 
2.3 
TIME WINDOWS FOR ANALYSIS 
No visit window will be constructed. For analyses, only scheduled visits will be summarized in 
tables.  
 
2.4 
HANDLING OF MISSING DATA 
Missing data will not be imputed for descriptive statistical summaries in safety or efficacy 
analyses. 
 
For the PGI-I score, missing data at Day 42 will be considered as failure in analysis.  
Dates missing the day or both day and month of the year will adhere to the following conventions 
to classify TEAE and to classify prior/concomitant medications. 
• A medication with a completely missing start date will be considered a prior medication. 
A medication with a completely missing stop date will be considered a concomitant 
medication. 
• If complete AE onset date is missing and AE end date is on or after the first dose date then 
it will be counted as a treatment emergent AE (TEAE) for the study. If complete AE onset 
date is missing and AE end date is before the first dose date then it will be counted as a not 
treatment emergent AE (TEAE) for the study. 
 
• If an AE or a medication has a partial missing start or stop date, the following rules will be 
used for imputation:  
 
o If year is present but month and day are missing, impute start date as January 1 of that 
year or first dose date if the year is the same as the year of first dose date and impute 
stop date as December 31 of that year.  
 
o If year and day are present but month is missing, impute start month as January or the 
month of the first dose date if the year and day is the same as the year and day of first 
dose date and impute stop month as December. 
  
o If year and month are present but day is missing, impute start date as first day of that 
month or first dose date if the year and month are the same as the year and month of 
first dose date and impute stop date as last day of that month. 
 
2.5 
ANALYSIS SOFTWARE 
All summaries and statistical analyses will be generated using SAS® version 9.4 or higher. 
 


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3. 
STUDY SUBJECTS 
3.1 
DISPOSITION OF SUBJECTS 
Disposition will be summarized for all randomized subjects. 
 
The disposition will include the following: 
• Subjects who are randomized (for Phase I only) 
• Subjects who are in Safety Population  
• Subjects who are in ITT population 
• Subjects who complete the study  
• Subjects who discontinue the study  
 
The number and percent of subjects will be summarized for each reason for premature 
discontinuation.    
A listing of dispositions will be provided for all subjects. 
3.2 
PROTOCOL DEVIATIONS 
The clinical team will identify deviations and the deviations will be identified and classified into 
types in the database. The number and percent of subjects will be presented.  Summaries will 
include type of deviation by treatment phase, treatment group (for Phase I only). 
 
A subject data listing of protocol deviations will be provided. 
 
4. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline characteristics (e.g., sex, age, race, ethnicity, height and weight) will be summarized with 
descriptive statistics or frequency counts by treatment phase, treatment group (for Phase I only) 
and overall for the Safety population.  
 
4.2 
MEDICAL HISTORY 
Medical history will be collected prior to the treatment Phase I. Data will be coded with the 
Medical Dictionary for Regulatory Activities (MedDRA) Terminology. Events will be coded to 
System Organ Class (SOC) and preferred term (PT) using MedDRA Version 24.0 or higher. The 
number and percent of subjects with clinically significant medical history at screening will be 
summarized by system organ class (SOC) and preferred term (PT) by treatment phase, treatment 
group (for phase I only) and overall for safety Population.  
 


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5. 
STUDY DRUG AND EXPOSURE 
5.1 
TREATMENT COMPLIANCE AND EXTENT OF EXPOSURE 
Treatment compliance will not be summarized, as each subject will be treated in an inpatient 
setting to receive a single dose of study drug on Day 0 and Day 7 of Phase I or II or a single dose 
during any time before week 46 of Phase III.  
The number (percentage) of subjects who received IV injections of study drug will be summarized 
by treatment phase, treatment group (for Phase I only) and overall for safety population. The 
number (percentage) of subjects who received additional IV injection of study drug in Phase III 
will be summarized for Phase III safety population.  
5.2 
PRIOR AND CONCOMITANT THERAPY 
Prior only medications are defined as medications that stopped prior to the first dose of study drug 
in Phase I. Concomitant only medications are defined as medications (other than the study drug) 
taken on or after the first dose of the study drug in Phase I during the study. Medications started 
before the first dose of study drug in Phase I and continuing at the time of the first dose of study 
drug are considered as both prior and concomitant medication.  
 
All investigator terms for medications recorded on the CRF will be coded using the World Health 
Organization (WHO) Anatomical Therapeutic Chemical (ATC) drug dictionary (Version WHO 
Drug Dictionary Enhanced, WHO DDE March 2021 or higher). The number (percentage) of 
subjects who took prior medications will be summarized by treatment group in Phase I and overall 
for Treatment Phase I safety population. Prior general medications and iron/RLS therapies will be 
summarized separately. The number (percentage) of subjects who took concomitant medications 
will be summarized by treatment phase, treatment group (for Phase I only) and overall for safety 
population.  
6. 
EFFICACY ANALYSES 
All efficacy analyses will be based on the Safety Population for each phase accordingly.   
 
Statistical testing for treatment effect: 
• Phase I, II and III: no formal statistical testing will be performed. Data will be 
reported via descriptive statistics only. 
6.1 
PRIMARY EFFICACY ANALYSIS 
6.1.1 
Phase I and Phase II: Change in IRLSS total score from baseline to Day 42 
The actual value of IRLSS total score on baseline and Day 42, and change from baseline to Day 
42 will be summarized via descriptive statistics by treatment group for each treatment phase.  
 
 A subject data listing of IRLSS total score for each visit will be provided. 
 


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6.1.2 
Phase I and Phase II: Percentage of subjects who are much or very much improved 
at Day 42 as measured by the CGI-I 
The number (percentage) of subjects who are rated as much or very much improved with the CGI-
I on Day 42 will be summarized by treatment group (for Phase I only) for each treatment phase. 
The denominator should be the Phase I Safety population for each treatment group in Phase I. For 
Phase II, the denominator is the Safety population in Phase II. 
 
6.1.3 
Phase III: Time from initial FCM treatment to further FCM treatment  
Time (weeks) from the initial FCM treatment to further FCM treatment received in Phase III will 
be calculated as the integer of (date of the further FCM treatment in Phase III - date of the initial 
FCM treatment)/7 + 1. The time duration will be summarized via descriptive statistics including 
number of subjects, median, minimum (min) and maximum (max). Initial treatment is defined as 
Day 0 of Phase I for responders in Phase I and Day 0 of Phase II for responders in Phase II. At any 
time before week 46 subject could receive a single dose of unblinded FCM treatment (i.e. the 
further FCM treatment) if RLS symptom is worsened.  
6.2 
SECONDARY EFFICACY ANALYSES 
6.2.1 
Phase I and II: Change in IRLSS total score from baseline to Day 42 (Non-
responders in Phase I Placebo group) 
 The change is defined as IRLSS total score at Day 42 minus IRLSS total score at baseline in each 
phase. The number of subjects, mean, median, standard deviation, minimum (min) and maximum 
(max) for the observed values, and change from baseline will be reported in summary table.  
 
6.2.2 
Phase I and II: Change in IRLSS total score from baseline to Day 42 (Non-
responders in Phase I FCM group) 
IRLSS total score from baseline to Day 42 between Phase I and Phase II will be summarized. The 
change is defined as IRLSS total score at Day 42 minus IRLSS total score at baseline in each 
phase. The number of subjects, mean, median, standard deviation, minimum (min) and maximum 
(max) for the observed values, and change from baseline will be reported in summary table.  
 
6.2.3 
Phase I and Phase II: CGI-I and PGI-I score at Day 42 
The number (percentage) of subjects of each category will be summarized for CGI-I and PGI-I, 
separately.  
 
6.2.4 
Phase I and Phase II: Percentage of subjects who are much or very much improved 
at Day 42 as measured by the PGI-I   
The number (percentage) of subjects who are rated as much or very much improved with the PGI-
I on Day 42 will be summarized by treatment group (for Phase I only) for each treatment phase.  


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6.2.5 
Phase I and Phase II: Change in sleep quality measured by MOS from baseline to 
Day 42 
The actual value of MOS score on baseline and Day 42, and change from baseline to Day 42 will 
be summarized via descriptive statistics by treatment group (for Phase I only) for each treatment 
phase.  
 
6.2.6 
Phase I and Phase II: Number (percentage) of treatment non-responders at Day 42 
of Phase I who respond to FCM in Phase II 
The number (percentage) of treatment non-responders at Day 42 in Phase I who are turned into 
responders in Phase II, and the treatment responders of each phase, will be summarized by 
treatment group, separately. For Phase I, treatment differences in percentage will be assessed with 
the chi-square test, p-values will be presented. The subjects who missing responder/non-responder 
classification will be considered as non-responder. 
 
6.2.7 
Phase I and Phase II: Number (percentage) of treatment responders at Day 42  
The number (percentage) of treatment responders at Day 42 of Phase I and Phase II will be 
summarized by treatment group in Phase I, separately. The subjects who missing responder/non-
responder classification will be considered as non-responder. 
 
6.2.8 
Phase I and Phase II: Change in substantia nigra iron index from baseline to Day 
42   
The actual value of substantia nigra iron index on baseline and Day 42, and change from baseline 
to Day 42 will be summarized via descriptive statistics by treatment group (for Phase I only) for 
each treatment phase. 
 
Substantia nigra iron index will be measured using MRI relaxation rate (R2*) or QSM. 
 
6.2.9 
Phase I and Phase II: Change in thalamus and motor cortex iron index from baseline 
to Day 42   
The actual value of thalamus and motor cortex iron index on baseline and Day 42, and change 
from baseline to Day 42 will be summarized via descriptive statistics by treatment group (for Phase 
I only) for each treatment phase, separately.  
 
Iron index will be measured using MRI relaxation rate (R2*) or QSM. 
 


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6.2.10 
Phase III: Change in IRLSS total score from baseline to each visit 
The actual value of IRLSS total score on baseline and each scheduled visit (i.e. Weeks 15, 25, 34, 
43 and 52 via phone contact), and change from baseline to each scheduled visit will be summarized 
via descriptive statistics.  
 
6.3 
EXPLORATORY ANALYSES 
  
6.3.1 
Phases I and II: Vitamin D at each visit 
The actual value of serum Vitamin D concentration on baseline, each post-baseline visit, and 
change from baseline to each post-baseline visit will be summarized via descriptive statistics by 
treatment group (for Phase I only) for each treatment phase.  
A subject data listing of Vitamin D and phosphate for each visit will be provided.  
 
6.3.2 
Phases I and II: Change in thalamus and motor cortex iron index from baseline to 
Day 42 for other brain regions  
The actual value of iron index in other brain regions (including caudate, putamen, nucleus 
accumbens, globus pallidus, subthalamic nuclei (STN), dentate and pulvinar) on baseline and Day 
42, and change from baseline to Day 42 will be summarized via descriptive statistics by treatment 
group (for Phase I only) for each treatment phase, separately.  
 
7. 
SAFETY ANALYSIS 
All safety analyses will be performed on the Safety Population. No formal statistical testing will 
be performed for safety. Safety assessments include: 
• Adverse events 
• Laboratory assessments (hematology, iron indices, chemistry, and other) 
• Vital signs  
 
7.1 
ADVERSE EVENTS 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA®, version 24.0 or higher). The 
verbatim term will be included in the AE listings. 
 
 
 
 
 


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A treatment-emergent adverse event (TEAE) is defined as an AE that occurs or worsen on or after 
the first dose of study drug in Phase I. Only TEAEs will be included in summary tables by 
treatment group (for Phase I only) for each phase. For AEs occurring on the first dosing day, if the 
start time cannot be ascertained, the event will be counted as treatment emergent. All AEs, 
treatment emergent or otherwise, will be presented in subject data listings. 
 
The incidence of TEAEs will be summarized as the number (percentage) of subjects with TEAEs 
within SOC and PT by treatment group (for Phase I only) for each phase.  Subjects who report the 
same PT on multiple occasions will be counted once for the PT: under the highest severity (severe 
> moderate > mild) when summarized by severity and under the closest relationship (probably 
related > possibly related > unlikely related > none) to study drug when summarized by 
relationship. If a subject reports multiple PT for a SOC, the subject will be counted only once for 
that SOC. Events with unknown severity or relationship will be counted as unknown.  
 
TEAEs will be summarized as below.  
• An overview table, including number of subjects with  
o TEAEs 
o serious AEs (SAEs) 
o study drug related TEAEs 
o study drug related SAEs 
o TEAEs by severity  
o TEAE of special interest (AESI) 
o TEAEs leading to study discontinuation 
o TEAEs leading to death 
• TEAE by SOC and PT 
• TEAE by SOC, PT, and Severity 
• Study drug related TEAEs by SOC, PT 
• SAEs by SOC and PT 
• TEAEs leading to study discontinuation by SOC and PT 
All TEAE tables will be sorted by SOC and PT in decreasing frequency of the number and 
percentage of subjects in the treatment group.   


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7.1.1 
Adverse Events of Special Interest  
Adverse events of special interest include hypophosphatemia, hypersensitivity/anaphylactoid 
reactions, and injection/infusdion site reactions. The search strategy will be identified as follows: 
 
• TEAEs of hypophosphatemia by SOC and PT <Use the following MedDRA PTs to identify 
these TEAEs > 
o MedDRA PT Blood phosphorus decrease 
o MedDRA PT Blood phosphorus abnormal 
o MedDRA PT Hypophosphataemia 
o MedDRA PT Hypophosphataemic rickets 
o MedDRA PT Rickets familial hypophosphataemic 
 
• TEAEs indicative of hypersensitivity/anaphylactoid reactions by SOC and PT 
o Hypersensitivity/anaphylactoid reaction search is based on the following search 
criteria:  2 SMQ (Anaphylactic reaction and Angioedema), and 1 PT of 
Hypersensitivity 
 
• TEAEs of injection/infusion site reactions by SOC and PT <Use the following MedDRA 
PTs  to identify these TEAEs > 
o MedDRA HLT Infusion site reactions 
o MedDRA HLT Injection site reactions 
o MedDRA HLT Administration site reactions NEC 
o MedDRA PT Infusion related reaction 
The AEs of special interest will be summarized by SOP and PT. 
7.1.2 
Deaths, Serious and Other Significant Adverse Events  
The listings of serious AEs, AE leading to study discontinuation, and subjects who died during the 
study will be listed.  
7.2 
CLINICAL LABORATORY PARAMETERS 
Laboratory assessments include hematology, clinical chemistry/ phosphorus, and iron indices: 
• Hematology: Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, differential 
count and reticulocyte count.  
• Clinical chemistry: sodium, potassium, chloride, BUN, creatinine, albumin, alkaline 
phosphatase, total bilirubin, gamma-GGT, AST, ALT, LDH, calcium, phosphorus, 
glucose, bicarbonate and magnesium.  
• Iron indices and Phosphorus: serum iron, serum ferritin, and total iron binding capacity 
(TIBC), percentage serum transferrin saturation (TSAT). 


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• Other: urine pregnancy (if indicated), other metals (serum copper and zinc), 1,25 dihydroxy 
vitamin D, 25 hydroxy Vitamin D (25OH-D) and erythropoietin. 
All laboratory parameters will be presented in standard units. The actual value and change from 
baseline will be summarized by visit and treatment group (for Phase I only) using descriptive 
statistics. 
The number and percent of subjects with treatment-emergent potentially clinically significant 
(PCS) laboratory values after baseline will be summarized by visit and treatment group (for Phase 
I only) for each phase. The denominator is all subjects with normal baseline and at least one post 
baseline assessment in the safety population of that phase and the numerator is the number of 
subjects with PCS (i.e., meets Grade III or Grade IV toxicity criteria from the National Cancer 
Institute Common Terminology Criteria) at post-baseline. 
 
7.3 
VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS 
7.3.1 
Vital Signs 
Vital signs will be collected for Phase I and Phase II, include sitting body temperature, blood 
pressure (BP) and heart rate. On study drug dosing days BP and heart rate will be collected 
immediately pre-dosing, immediately and 30 minutes post dosing, and body temperature will be 
collected on the dosing dates.  
All vital signs will be presented in conventional units as in Table 3. Frequency and percentage of 
subjects with values considered PCS occurring at post-baseline in dosing days will be summarized 
by visit and by treatment group (for Phase I only) for each Phase. The denominator is all subjects 
with a baseline assessment in the full analysis population and the numerator is the number of 
subjects with PCS at post-baseline.  Criteria for PCS are presented below Table 2. 
 Table 2 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign 
Criterion Definition of PCS at Any Post-baseline Time Point  
Systolic blood pressure 
Low 
Value 90 mmHg and decreased 20 mmHg [1]  
 
High 
Value 180 mmHg and increased 20 mmHg [1] 
 
 
 
Diastolic blood pressure Low 
Value 50 mmHg and decreased 15 mmHg [1] 
 
High 
Value 105 mmHg and increased 15 mmHg [1] 
 
 
 
Pulse 
Low 
Value 50 bpm and decreased 15 bpm [1] 
 
High 
Value  120 bpm and increased 15 bpm [1] 
[1] 
For immediately and 30 minutes post-dose assessments on Dosing Days, the change (decrease or increase) is 
based on the pre-dose value obtained on each corresponding dosing day.  
 


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7.3.2 
Physical Examination 
Any significant findings from physical examinations will be documented in medical history or 
adverse events.  
 
7.4 
OTHER ANALYSES 
Cambridge-Hopkins Diagnostic Questionnaire (CHDQ), Hopkins-Henning Telephone Diagnostic 
Interview (HTDI), Hopkins RLS-Sleep Quality Questionnaire (HRSQ), and urine  
 
8. 
INTERIM ANALYSES AND DATA AND SAFETY MONITORING BOARD 
(DSMB) 
8.1 
INTERIM ANALYSES 
No formal interim analysis is planned for this study.  
 
8.2 
DATA AND SAFETY MONITORING BOARD (DSMB)  
No Data Safety Monitoring Board for this study.  
 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
Compared with the study protocol 1VIT15042 (Date: 4 September 2019), below items are the 
major changes made in this SAP:  
 
 
1. Due to early termination of the study, no statistical analysis will be performed. Hence no 
primary, and secondary end points will not be tested with statistical model. 
 
2. Physical examinations was removed from safety analysis list and any significant findings 
will go to medical history or adverse event summaries.  
 
3. The secondary endpoint “Number of Subjects who remained in the study to Week 52” will 
be summarized in disposition table for n (%) of study completer. It will not be considered 
as an efficacy endpoint in this SAP.  
 
4. Adverse events of special interest were added in this SAP in Section 7.1.1.