Clinical trial NCT02397057
Conditions: Restless Legs Syndrome (RLS)
Sponsor: American Regent, Inc.
Start date: 2015-01-01; Completion date: 2018-01-01
Enrollment: 209 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This will be a Phase III, double blinded, multi-center, randomized, placebo-controlled study. Eligible subjects will be randomized in a 1:1 ratio to receive Injectafer or Placebo on days 0 and 5. All treated subjects will be followed for efficacy and safety for 12 months. The subject's participation in the study will be for approximately 1 year from Day 0.

Detailed description:
This will be a Phase III, double blinded, multi-center, randomized, placebo-controlled study. Eligible subjects will be randomized in a 1:1 ratio to receive Injectafer or Placebo on days 0 and 5. All treated subjects will be followed for efficacy and safety for 12 months. Subjects will visit the clinic on Days 0 and 5 for treatment, and then on Days 14, 42, 168, and 365. In between the clinic visits subjects will be contacted remotely on Days 84, 126, 210, 252, 294, and 336. The subject's participation in the study will be for approximately 1 year from Day 0.

Arms: arm 1: Two doses of Injectafer 750 mg undiluted dose at 100 mg/minute given 5 days apart for a total of 1500 mgs. arm 2: IV Placebo (15ml of Normal Saline) IV push at 2ml/minute
Interventions: intervention 1: Injectafer intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
NCT02453334 1VIT14039 
Can Iron Lessen Anemia Due to Cancer and Chemotherapy: A Study to 
Investigate the Efficacy and Safety of Injectafer® (IRON CLAD) 
 
 
Protocol No. 1VIT14037 
 
PROTOCOL DATE: 02 April 2014  
AMENDMENT I DATE: 05 August 2014  
AMENDMENT II DATE: 05 January 2015  
AMENDMENT III DATE: 13 July 2015  
CZECH REPUBLIC AMENDMENT IV DATE: 02 June 2016 


16. 
APPENDICES 
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
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Table of Contents
16. APPENDICES .........................................................................................................................
16.1 Study Information ............................................................................................................
16.1.1 Protocol and Protocol Amendments .......................................................................
Table of Contents .........................................................................................................
LUITPOLD PHARMACEUTICALS, INC. PROTOCOL No. 1VIT14037, CZECH
REPUBLIC AMENDMENT IV - 02 June 2016..........................................................
LUITPOLD PHARMACEUTICALS, INC. PROTOCOL No. 1VIT14037,
AMENDMENT IV - 02 June 2016.............................................................................
LUITPOLD PHARMACEUTICALS, INC. PROTOCOL No. 1VIT14037,
CZECH REPUBLIC AMENDMENT III - 13 July 2015.........................................
LUITPOLD PHARMACEUTICALS, INC. PROTOCOL No. 1VIT14037,
AMENDMENT III - 13 July 2015............................................................................
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LUITPOLD PHARMACEUTICALS, INC. 
 
 
 
PROTOCOL 
 
 
No. 1VIT14037 
 
 
IND #: 73,076 
 
 
 
A Double-Blind, Multi-Center, Randomized, Placebo-Controlled Study to Investigate the Efficacy and 
Safety of Injectafer® (Ferric Carboxymaltose) in the Treatment of Restless Legs Syndrome (RLS)  
 
 
 
SPONSOR 
 
Luitpold Pharmaceuticals, Inc. 
Clinical Research and Development 
800 Adams Avenue 
Norristown, PA 19403 
(610) 650-4200 
 
 
 
 
PROTOCOL DATE: 02 April 2014 
AMENDMENT I DATE: 05 August 2014  
AMENDMENT II DATE: 05 January 2015 
AMENDMENT III DATE: 13 July 2015 
CZECH REPUBLIC AMENDMENT IV DATE: 02 June 2016 
 
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Luitpold Pharmaceuticals Inc.
CONT]DENTIAL
SIGNATURES OF AGREEMENT TOR PROTOCOL
Sumita
, MD, MPH
Head of Clinical Research and Development
Luitpold Pharmaceutical s,pr
Marsha Si
Sr, Manager-Regulatory Affairs
Luitpold Pharmaceutical s, Inc.
Protocol: IVITl4037
Amendment IV Date: 02 June 2016
Date
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David Moris, PhD
Senior Director, Statistics
WebbWrites, LLC
Date
Page 2
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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Page 3 
STUDY SYNOPSIS 
Protocol 1VIT14037 
 
Title:  A Double-Blind, Multi-Center, Randomized, Placebo-Controlled Study to Investigate the Efficacy and 
Safety of Injectafer® (Ferric Carboxymaltose) in the Treatment of Restless Legs Syndrome (RLS). 
 
Investigational Drug: Injectafer® (Ferric Carboxymaltose)  
                                     
Objectives:  The primary objective of this study is to evaluate the efficacy and safety of intravenous 
Injectafer®  in subjects with Restless Leg Syndrome (RLS). 
 
Study Design:  This will be a Phase III, double blind, multi-center, randomized, placebo-controlled study. All 
subjects who meet the inclusion requirements and no exclusion criteria will qualify to enter up to a 7 day 
Screening Phase to enroll 200 eligible subjects for study drug treatment.  All eligible subjects will be stratified 
at baseline by RLS medication-related augmentation (no augmentation, uncertain augmentation, definitive 
augmentation).  Randomization will occur in a 1:1 ratio within each stratum to receive Injectafer® or Placebo 
on Days 0 and 5.  All treated subjects will be followed for efficacy and safety for 12 months.  Subjects will visit 
the clinic on Days 0 and 5 for treatment, and then on Days 14, 42, 168, and 365. In between the clinic visits 
subjects will be contacted remotely (phone) on Days 28, 84,126, 210, 252, 294, and 336. The subject’s 
participation in the study will be for 1 year from Day 0.  
 
Study Drug Treatment:  The duration of treatment will be 5 days.  On Day 0 (start of Treatment Phase) 
subjects will be randomized to receive either a 750 mg undiluted blinded dose of IV Injectafer® at 
100mg/minute or a blinded Placebo (15 ml of Normal Sterile Saline [NSS]) IV push at 2 ml/minute.  On Day 5 
subjects will receive the same blinded treatment as given on Day 0. 
 
Tapering Algorithms of RLS Treatment Regimens:  Each subject will be tapered from the prescribed RLS 
medication post treatment beginning on the evening of Day 5 or starting on Day 6.   The tapering regimen will 
depend on the subject’s current medication and dosing (see Appendix III).  It is expected that all subject’s will 
be tapered off their current treatment for RLS, but in the rarity a subject, at the end of the allotted tapering 
period, is unable to achieve a dose of zero (0) the subject should maintain on the lowest dose level attained at 
the end of the tapering period and that dose should remain stable for the duration of the subjects participation in 
the study. During the tapering period and through Day 42 subjects will continue to keep an RLS diary to record 
their symptoms related to their RLS.    
 
Additional Treatment Post Day 42: Subjects who have not had an intervention may receive additional blinded 
study drug treatment at the discretion of the Investigator after Day 42.  An intervention is defined as either 1) an 
increase in dosage from the RLS medication at study entry, 2) the initiation of a new RLS medication, or 3) 
resumption of the previous medication prescribed for RLS, or 4) increase in dosage from the RLS medication 
achieved at the end of the tapering period.  The subject will receive the same blinded study medication that was 
previously assigned.  Subjects will receive either a single blinded dose of Injectafer® at 750 mg undiluted at 
100mg/minute or a Placebo (15 ml of Normal Sterile Saline [NSS]) IV push at 2 ml/minute on two independent 
days separated by 5 days. Dosing should mirror the original treatment / follow-up period (dosing 5 days apart 
with safety follow-up visits, to include laboratory assessments only, on 14 and 42 Days post the first dose).  No 
subject assessments are completed unless the dosing or follow-up days fall on an assessment day in the follow-
up period.  Eligible subject will have met the following requirements prior to receiving additional treatment: 
 IRLS score ≥15  
 TSAT <45% (confirmation can be through a local laboratory) 
 Ferritin <300 ng/mL  (confirmation can be through a local laboratory) 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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No additional iron may be administered between Day 320 and the Day 365 visit. 
 
Efficacy and Safety Follow-up:  The duration of the study will be 12 months.  After treatment on Days 0 and 5 
subjects will visit the clinic on Days 14, 42, 168, and 365. In between the clinic visits subjects will be contacted 
remotely (phone) on Days 28, 84, 126, 210, 252, 294, and 336.  Subjects will be considered to have reached the 
end of the study for efficacy when intervention is required for RLS symptoms and the subjects will continue the 
follow-up phase for safety.   
 
Efficacy and Safety Evaluations (see Table 1, Schedule of Events, for details) 
 
Efficacy evaluations will include: 
 
1. Clinical Global Impression (CGI) performed by Investigator (CGI-I)  
2. International Restless Legs Syndrome (IRLS) Score 
3. Clinical Global Impression (CGI) performed by Subject (CGI-S) 
4. Restless Legs Syndrome Quality of Life (RLS-QLI)  
5. Medical Outcome Study (MOS) Sleep Scale 
6. Fatigue Linear Analog Scale 
Safety Evaluations will include: 
 
1. Adverse events 
2. 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) and  other (transferrin receptor and Lymphocyte 
samples) 
3. Vital signs  
4. Physical examinations 
 
Intervention:   
 
Intervention is defined as either 1) an increase in dosage from the RLS medication at study entry, 2) the 
initiation of a new RLS medication, 3) resumption of the previous medication prescribed for RLS or, 4) increase 
in dosage from the RLS medication achieved at the end of the tapering period. Any subject who has an 
intervention will no longer be evaluated for efficacy starting at the time of the intervention, however these 
subjects will remain in the study and be evaluated for safety.  
Inclusion Criteria: 
                   
1. Male or female subject’s ≥18 years of age, willing and able to give informed consent to the study. 
2. RLS symptoms affirming diagnosis.  The IRLS Diagnostic Criteria must be met: 
a. An urge (distressing need) to move the legs usually associated with painful or uncomfortable 
sensations in the legs.  The urge to move may be present without the uncomfortable sensations.  
The arms or other body parts may be involved in addition to the legs. 
b. The urge to move or unpleasant sensations are worse or exclusively present at rest or inactivity, 
such as lying down or sitting.  
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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c. The urge to move or unpleasant sensations are partially/temporarily relieved with walking or 
moving the legs.  
d. The urge to move or unpleasant sensations are worse in the evening or night than during the day 
or only occur in the evening or night.  When symptoms are severe, the worsening at night may 
not be noticeable but must have been previously present. 
3. Subjects should be on monotherapy for RLS.  Treatment should be stable for at least 8 weeks prior to 
screening (See approved RLS Therapies/Regimen in Appendix III). 
4. A score ≥15 on the IRLS Rating Scale at screening and on Day 0 prior to dosing. 
5. Subjects on anti-depressants and sleep medications must be on a stable dose for at least 6 months.  
6. Subject has regular sleep hours between 9 pm and 9 am. 
7. All patients must use one highly reliable contraception with reliability index < 1 for example IUD, 
sterilization of one of the partners, assuming one sexual partner relationship during the clinical trial will 
occur, hormonal implants, injections, patches, pills, accompanied with one barrier form of contraception 
with spermicide. Men should always use condom. Use of two barrier methods simultaneously with 
spermicide is considered a reliable contraceptive method. A sexual abstinence throughout the clinical 
trial is allowed only if this is a lifestyle choice of the patient 
Exclusion Criteria: 
 
1. RLS 2° to other disease or injury.   
2. Disorders that require treatment with the same medications used for RLS include: peripheral neuropathy 
and neurodegenerative disorders (i.e. Parkinson’s Disease or Dementia).    
3. Stage 4 – 5 CKD, subjects on dialysis or anticipated to start dialysis while participating in this study. 
4. Any pain related (e.g., frequent muscle cramps, myalgia, fibromyalgia) or sleep related disorders (e.g. 
sleep apnea, unless on stable Continuous Positive Airway Pressure [CPAP]) which may confound the 
outcome measures.   
5. Subjects with multiple sclerosis.   
6. History of neuroleptic akathisia. 
7. Parenteral iron use within 6 weeks prior to screening. 
8. History of >10 blood transfusions in the past 2 years. 
9. Anticipated need for blood transfusion during the study. 
10. Known hypersensitivity reaction to any component of Injectafer® (Ferric Carboxymaltose).        
11. Previously randomized to Injectafer® (FCM or VIT-45) in a clinical trial.  
12. Current, active or acute or chronic infection other than viral upper respiratory tract infection  
13. Malignancy (other than basal or squamous cell skin cancer or the subject has been cancer free for ≥ 5 
years). 
14. Pregnant or lactating women. 
15. Seizure disorder currently being treated with medication. 
16. Baseline ferritin ≥300 ng/mL.  
17. Baseline TSAT ≥45%. 
18. History of hemochromatosis, hemosiderosis, or other iron storage disorders. 
19. AST or ALT greater than 2 times the upper limit of normal (ULN). 
20. Hemoglobin greater than the ULN. 
21. 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 upper limit of normal). 
22. Known positive HIV-1/HIV-2 antibodies (anti-HIV). 
23. Received an investigational drug within 30 days before randomization. 
24. Chronic alcohol or drug abuse within the past 6 months. 
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25. Any other pre-existing laboratory abnormality, medical condition or disease, which per the investigator
may put the subject at risk if they participate in the study.
26. Subject unable or unwilling to comply with the study requirements.
RLS
Therapy:  
All subjects should be on a stable RLS monotherapy regimen (see Appendix III) for at least 8 weeks prior 
to screening. These therapies should remain unchanged until the tapering process begins post Day 5 
treatment with study drug.  An algorithm of RLS medication taper regimens is provided (Appendix III).  
If and when the subject is tapered off the RLS medication, the goal will be for the subject to remain off 
their medication or remain on the lowest dose level achieved for the duration of the study.  If during the 
course of the study it becomes necessary to restart therapy via subject and physician decision, these data 
points will be collected and the subject will no longer be evaluated for efficacy, but the subject will 
continue in the study for safety analysis.   
Study Endpoints:    
The co-primary efficacy variables will be IRLS total score change from baseline to Day 42 and the proportion 
of patients rated as “much” or “very much” improved with the Clinical Global Impression (CGI) performed by 
Investigator (CGI-I) on Day 42.   
The major secondary endpoints will be tested in a hierarchical order, that is, statistical significance for major 
secondary efficacy endpoint will be declared only if the primary efficacy test (IRLS and CGI-I on Day 42) is 
statistically significant.  Because a hierarchical testing scheme is used, no adjustments of the alpha level will be 
needed at each stage of testing.  All tests will be done at an alpha ≤ 0.05. 
The major secondary efficacy endpoints in ranked order of testing include: 
1. Clinical Global Impression (CGI) performed by Subject (CGI-S) on Day 42.
2. Restless Legs Syndrome Quality of Life (RLS-QLI) change from baseline to Day 42.
3. Medical Outcome Study (MOS) Sleep Scale change from baseline to Day 42.
4. Fatigue Linear Analog Scale change from baseline to Day 42.
Other efficacy endpoints: 
1. Proportion of responders (any improvement) based on CGI-I at each time point.
2. IRLS total score change from baseline at each time point.
3. Proportion of responders based on CGI-S at each time point.
4. RLS-QLI scores change from baseline at each time point.
5. MOS Sleep scale total score change from baseline at each time point.
6. Fatigue Linear Analog Scale total score change from baseline at each time point.
7. Augmentation Scale change between baseline, Day 42, Day 168 and end of study (Day 365).
8. Proportion of subjects require intervention for RLS.
9. Number of days from Day 5 to next dose of study drug.
The safety endpoints include: 
1. Incidence of treatment emergent adverse events (TEAE) and incidence of serious adverse events (SAE)
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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2. Change in clinical laboratory tests 
3. Change in vital signs    
4. Change in Columbia-Suicide Severity Rating Scale (C-SSRS) 
                                                      
Blinding:     
                
All subjects, investigators and study personnel will be blinded to the content of study drug with the exception of 
the unblinded study personnel who will be responsible for the following: 
o Randomizing the subject on Day 0 through IRT system.  
o Preparing, concealing and administering the study drug on Day 0 and 5 (as Injectafer®  is reddish-brown 
and slightly viscous).1 
o Completing the Study Drug Accountability Form, study drug dosing record and applicable electronic case 
report form 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. post-
randomization IRLS questionnaires/scores, subjects’ CGI scores, dosing information). 
 
Study Duration:  
 
 Screening Phase:  up to 7 days 
 Treatment Phase:  5 days  
 Follow-up Phase: 12 months 
 
Number of Subjects: 
 
Enrollment is planned for 200 subjects (100 per group) at study sites in the United States (US), Poland, 
Hungary, Czech Republic, Ukraine and Spain. 
 
Sample Size: 
 
Sample size estimates were based on the modified intent to treat (MITT) population for Study 1VIT05009.  The 
last observation carried forward (LOCF) and observed cases (OC) results on Day 28 were used for the co-
primary efficacy endpoint (CGI) and first-ranked secondary endpoint (IRLS).  It is unclear how treatment 
differences on Day 42 results might differ from Day 28, apart from a higher dropout rate, but it is reasonable to 
assume that treatment differences will decrease.  Therefore, power calculations were based on smaller treatment 
differences and larger standard deviations. 
 
Co-primary efficacy endpoint (IRLS): The smallest treatment difference for change from baseline to Day 28 
was 4.4 with a standard deviation of 8.5.  A sample size of per 100/group provides 95% power under this 
scenario. 
 
Co-primary efficacy endpoint (CGI-I): The smallest treatment difference on Day 28 was 45% versus 15% of 
patients in the FCM and placebo groups, respectively, who reported much or very much improvement on the 
patient CGI.  A sample size of 100/group provides >99% power.  A sample size of per 100/group has at least 
90% power when the treatment difference is as small as 45% versus 22%. 
 
Statistical Methods: 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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Treatment group differences for CGI scores will be assessed with the Cochran-Mantel-Haenszel test using 
region (US, Europe) as the stratification factor.  Treatment group differences for changes in total and domain 
scores of rating scales (eg, IRLS) will be assessed with the analysis of covariance with fixed factors for region 
(US, Europe) and treatment and with baseline score as a covariate.  Treatment differences for proportions will 
be assessed with the continuity-corrected chi-square test.   
 
The primary imputation method for the CGI and change in total/domain scores will be LOCF.  Sensitivity 
analyses will assess the impact of missing values on inferences. 
 
Time from Day 5 to the next dose of study drug will be analyzed with the log-rank test. Subjects who 
discontinue or complete the study before an intervention will be censored at last study visit. 
 
Analyses of safety data will be descriptive and no formal statistical comparisons will be made. 
 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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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 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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TABLE OF CONTENTS 
STUDY SYNOPSIS ............................................................................................................................................... 3 
1.0 
INTRODUCTION ..................................................................................................................................... 15 
1.2 
Role of Iron in the Pathogenesis and Pathophysiology of RLS ............................................................. 15 
1.3 
The Role of Iron Treatment in RLS ....................................................................................................... 16 
1.4  
Injectafer®  (Ferric Carboxymaltose) .................................................................................................... 17 
1.4.1 
Key features of Injectafer® ................................................................................................................ 17 
1.4.2 
Injectafer®  versus Other Parenteral Iron Agents .............................................................................. 17 
1.4.3 
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 ............................................................................................................................................ 18 
4.0  
SUBJECT SELECTION ............................................................................................................................ 21 
4.1  
Number and Type of Subjects ................................................................................................................ 21 
4.2 
Screening Phase ...................................................................................................................................... 21 
4.2.1  
Inclusion Criteria ................................................................................................................................ 21 
4.2.2 Exclusion Criteria .................................................................................................................................... 22 
4.3 
Subject Assignment and Randomization Process .................................................................................. 22 
4.4 
RLS Standard of Care Therapy:  Tapering Procedures .......................................................................... 23 
4.5 
Duration of Study / Withdrawal from Study .......................................................................................... 23 
4.6 
Intervention ............................................................................................................................................ 23 
5.0 
STUDY DRUG .......................................................................................................................................... 23 
5.1 
Formulation Packaging and Storage ...................................................................................................... 23 
5.2  
Study Drug Blinding/Administration ..................................................................................................... 24 
5.2.1  
Study Drug Blinding ........................................................................................................................... 24 
5.2.1.1    Unblinded Personnel .......................................................................................................................... 24 
5.2.1.2 
  Blinded Personnel ......................................................................................................................... 24 
5.2.1.3 
  Investigator Blinding .................................................................................................................... 24 
5.3  
Study Drug Administration .................................................................................................................... 24 
5.4 
IV Iron Precautions ................................................................................................................................ 24 
5.5 
Drug Accountability ............................................................................................................................... 25 
5.6 
Concomitant Medication ........................................................................................................................ 25 
6.0 
STUDY PROCEDURES ........................................................................................................................... 26 
6.1 
Informed Consent ................................................................................................................................... 26 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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6.2 
Screening ................................................................................................................................................ 26 
6.3 
Study Days 0 - 365 ................................................................................................................................. 27 
6.3.1 
Day 0................................................................................................................................................... 27 
6.3.2. 
Day 5................................................................................................................................................... 28 
6.3.3. 
Days 14, 42, and 168 (in-clinic visits) ................................................................................................ 29 
6.3.3.1 
Day 14 ............................................................................................................................................. 29 
6.3.3.2 
Day 42 and 168 ............................................................................................................................... 29 
6.3.4. 
Days 28, 84, 126, 210, 252, 294, and 336 (remote contact by phone) ............................................... 29 
6.3.5 
Additional Treatment Post Day 42 ..................................................................................................... 30 
6.3.6. 
Day 365 (End of Study) ...................................................................................................................... 31 
6.4 
Central Laboratory Assessments ............................................................................................................ 31 
7.0  
ASSESSMENT OF SAFETY .................................................................................................................... 32 
7.1 
Adverse Events ....................................................................................................................................... 32 
7.2 
Reporting of Adverse Events ................................................................................................................. 33 
7.3 
Serious Adverse Events (SAE) .............................................................................................................. 33 
7.4      Other Reportable Information ............................................................................................................... 34 
7.5     Events associated with tapering of RLS medications ............................................................................. 35 
8.0 
STATISTICS ............................................................................................................................................. 36 
8.1 
Sample Size Rationale ............................................................................................................................ 36 
8.2 
Analysis Populations .............................................................................................................................. 37 
8.3 
Disposition and Baseline Characteristics ............................................................................................... 37 
8.4 
Endpoints and Definitions ...................................................................................................................... 37 
8.4.1 
Primary Endpoints .............................................................................................................................. 37 
8.4.2 
Secondary Endpoints .......................................................................................................................... 38 
8.4.3 
Safety Evaluations .............................................................................................................................. 38 
8.5 
Statistical Analyses of Efficacy .............................................................................................................. 38 
8.6 
Statistical Analyses of Safety ................................................................................................................. 39 
8.7 
Interim Analyses .................................................................................................................................... 39 
9.0 
ADMINISTRATIVE CONSIDERATIONS .............................................................................................. 39 
9.1 
Retention and Availability of Records ................................................................................................... 39 
9.2 
Investigator Responsibilities .................................................................................................................. 40 
9.3 
Financial Disclosure ............................................................................................................................... 40 
9.4 
Advertisement for Subject Recruitment ................................................................................................. 40 
9.5 
Documents Required for Study Initiation .............................................................................................. 41 
9.6 
Quality Control and Quality Assurance ................................................................................................. 41 
9.6.1 
Investigator Selection Criteria ............................................................................................................ 41 
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9.6.2 
Clinical Monitoring ............................................................................................................................ 41 
9.6.3 
Quality Assurance Audit .................................................................................................................... 41 
9.7 
Ethics ...................................................................................................................................................... 42 
9.7.1 
Ethical and Legal Issues ..................................................................................................................... 42 
9.7.2 
Institutional Review Board (IRB)....................................................................................................... 42 
9.7.3 
Informed Consent ............................................................................................................................... 42 
9.7.4 
Good Clinical Practice ........................................................................................................................ 42 
9.8 
Data Handling and Record Keeping ....................................................................................................... 43 
9.8.1 
Electronic Case Report Form (eCRF) ................................................................................................ 43 
9.8.2 
Confidentiality .................................................................................................................................... 43 
9.8.3 
Termination of the Study .................................................................................................................... 43 
9.8.4 
Protocol Revisions .............................................................................................................................. 43 
9.8.5 
Protocol Administrative Changes ....................................................................................................... 44 
9.9 
Publication Policy .................................................................................................................................. 44 
10.0  
GOVERNANCE COMMITTEE............................................................................................................ 44 
10.1 
Data and Safety Monitoring Board (DSMB) ...................................................................................... 44 
INVESTIGATOR’S ACKNOWLEDGEMENT .................................................................................................. 46 
APPENDIX I: Injectafer® Package Insert ........................................................................................................... 47 
APPENDIX II: RLS Assessment Tools:............................................................................................................... 48 
APPENDIX III: RLS Medications at study entry and Taper Regimen ................................................................ 49 
APPENDIX IV: Amendment I Changes............................................................................................................... 50 
APPENDIX V: Amendment II Changes............................................................................................................... 59 
APPENDIX VI: Amendment III Changes ............................................................................................................ 62 
Appendix VI: Amendment IV Changes ................................................................................................................ 75 
 
Tables 
 
Table 3.2.1  
Schedule of Events ...................................................................................................................... 20 
Table 7.1.1  
Grading of Adverse Event Severity as per CTCAE v 4.0 ........................................................... 32 
Table 7.5.1     Class-specific adverse events and withdrawal signs and symptoms during taper  
of RLS medications…………………...………………………………………………………………………….35 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
2o  
 
 
 
 
Secondary 
bpm                                                     Beats per minute 
C 
 
 
 
 
Degree celsius 
CFR 
 
 
 
 
Code of Federal Regulations 
CGI-I                                                  Clinical Global Impression-Global Improvement 
CGI-S  
 
 
 
Clinical Global Impression- Subject 
C-SSRS 
 
 
 
Columbia-Suicide Severity Rating Scale 
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 
eCRF  
 
 
 
Electronic Case Report Form 
F 
 
 
 
 
Degree Fahrenheit 
FAS 
 
 
 
 
Full Analysis Set 
FDA  
 
 
 
Food and Drug Administration 
GCP 
 
 
 
 
Good Clinical Practice 
g/dL 
 
 
 
 
Grams per deciliter 
Hgb 
 
 
 
 
Hemoglobin 
IBD 
 
 
 
 
Inflammatory Bowel Disease 
ICH 
 
 
 
 
International Clinical Harmonization Guideline 
IRB 
 
 
 
 
Investigational Review Board 
IRLS  
 
 
            International Restless Legs Syndrome  
IRLSSG                                              International Restless Legs Syndrome Study Group 
ITT 
 
 
 
 
Intent-to-treat 
IV 
 
 
 
 
Intravenous 
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 Study 
MRI 
 
 
 
 
Magnetic Resonance Imaging 
NCI 
 
 
 
 
National Cancer Institute 
Ng 
 
 
 
 
Nanogram 
NSS 
 
 
 
 
Normal Sterile Saline 
PD  
 
 
 
 
Peritoneal Dialysis 
PET 
 
 
 
 
Positron Emission Tomography 
PLMS  
 
 
 
Periodic Limb Movements of Sleep 
PLMA  
 
 
            Periodic Limb Movements while awake 
PSG 
 
 
 
 
Polysomnogram measurement of sleep  
Qod 
 
 
 
 
every other day 
Q3d 
 
 
 
 
every 3 days 
Q5d 
 
 
 
 
every 5 days 
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QOL  
 
 
 
Quality of Life 
RLS 
 
 
 
 
Restless Legs Syndrome 
RLS-QLI 
 
 
 
Restless Legs Syndrome – Quality of Life 
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             
1.1  
The Natural History, Disease Understanding, and Treatment Guidance for Restless Legs 
Syndrome (RLS) 
Restless legs syndrome (RLS), is a circadian disorder of sensory-motor integration that may be related to 
dysregulation of iron transport across the blood-brain barrier.1   Epidemiologic data suggest geographic 
variation in the prevalence of RLS, with estimates ranging from 2-10% in general populations, and as high as 20 
% in certain target populations with secondary RLS/.2-5    Pharmacologic therapy for primary RLS are broadly 
based on short-term randomized, controlled trials that enrolled highly-selected patient populations with long-
term, high-moderate to very severe symptoms.6-8 Current treatment regimens for RLS include dopamine 
agonists, calcium channel alpha-2-delta (α2δ) ligands, opioids, and benzodiazepines.9-11 While these 
medications reduce RLS symptoms and improve outcomes related to sleep-specific quality of life, adverse 
effects and treatment withdrawal due to adverse effects have been common.6  Medication tolerance, 
augmentation, and symptom, if not worsening of symptoms, are concerns with sustained RLS treatment 
effect.9,11-13 Evidence-based guidelines and practice support investigations that target trials of intravenous (IV) 
iron in RLS.9     
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.14  
Nordlander first associated anemia from various causes (gastric ulcer, leukemia, and chronic nephritis) with the 
development of restless legs and as well as symptom resolution following blood transfusions.15  Subsequent 
associations of RLS have been reported with conditions such as in pregnancy, hemodialysis, and frequent blood 
donations.2,3,16   Several findings have contributed to the disease understanding of low central nervous system 
iron stores in RLS as follows:   

In 2000, C. J. Earley et al. reported a comparison of 16 patients with idiopathic RLS compared to 8 age-
matched healthy control subjects.17 Cerebrospinal fluid (CSF) ferritin levels were lower (1.11+ 0.25 mg/L 
versus 3.50 + 0.55 mg/L; p =0.0002) and CSF transferrin levels were higher (26.4 + 5.1 mg/L versus 6.71 
+ 1.6 mg/L; p = 0.018) in idiopathic RLS subjects compared with control subjects.17  There were no 
differences in serum ferritin and serum transferrin levels between the 2 groups.   

In 2001, R.P. Allen et al. reported  a  study of 5 RLS patients and 5 control subjects that assessed brain
iron concentrations.18  A magnetic resonance imaging (MRI) measurement utilizing relaxation rates of 
both hemispheres (R21 and R2) identified that R21 was significantly decreased in the substantia nigra, and 
somewhat less significantly in the putamen, of subjects with RLS, both in proportion to the RLS severity.18  

In 2003, J.R. Connor et al.  demonstrated reduced iron concentrations in the substantia nigra using MRI
techniques and concluded that RLS may be a functional disorder resulting from impaired iron acquisition 
in the central nervous system (CNS).19 

Subsequent studies over the past decade support that reduction in CNS iron among patients with RLS may
be a functional consequence to impaired iron acquisition by the neuromelanin cells, with a putative defect 
in regulation of the transferrin receptors.20-24  
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 [ICDs], mood disturbances) and the 
emergence of new problems during long-term treatment (e.g., augmentation, loss of efficacy).”9  Overall, 
extensive RLS research has led to the conclusion that the pathophysiology of idiopathic RLS involves iron 
homeostatic dysregulation and that there is a role for iron treatment in RLS.    
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1.3 
The Role of Iron Treatment in RLS 
In studied populations, iron therapy appears to treat the specific mechanism of RLS pathology in some patients 
with low iron levels in the brain.25  Very early after the identification of the condition, IV treatment with 
saccharated oxide of iron was shown to be quite successful.26  Nordlander reported that IV iron therapy 
(generally given as 100 – 200 mg every 1 to 4 days) was completely effective at eliminating symptoms in 21 of 
22 patients (95.5%) for periods of up to 3-9 months, as well as effective in eliminating symptoms even in 
patients without anemia and with normal serum iron.26  Earley et al. reported similar efficacy in an open label 
study of 10 RLS patients, of whom 60% reported complete remission of RLS symptoms for 3 to 36 months after 
intravenous iron dextran.27  
In 2005, Earley et al.evaluated the efficacy and safety of repeated infusions of IV iron to maintain symptomatic 
RLS improvements achieved with a prior single 1,000 mg infusion of iron dextran.28  If symptoms returned at 
any time in the 2-year period after initial iron treatment, supplemental infusions of 450 mg of iron gluconate 
infusions could be given, provided the ferritin was <300 mcg/l.  Five out of 10 subjects received supplemental 
iron,  three of whom received between 2-4 courses of supplemental iron over the 2 year study period.28 The 
authors concluded that achieving high ferritin levels was not a guarantee of sustained improvements.28  In a 
randomized, placebo controlled study of IV iron in RLS in 25 subjects with end stage renal disease (ERSD), 
1,000 mg (given at <6 mg/min) of IV iron dextran produced a significant reduction in the symptoms of RLS as 
measured by the RLS severity score.29  In a multicentered, placebo-controlled clinical trial of IV ferric 
carboxymaltose (FCM) treatment for RLS, FCM significantly improved primary and secondary outcomes 
compared to placebo.30 In the comparison of FCM to placebo treatment, the IRLS severity scale mean  (SD) 
decrease was 8.9 (8.52) versus 4.0 (6.11), p=0.040, and the Clinical Global Inventory of Change (CGI-1) score 
of very much or much improved was 48.3% versus 14.3%, p=0.004; there were no significant adverse events.30  
The conclusions from this study were that IV FCM provided a safe and effective treatment for RLS that lasted 
for at least 24 weeks for patients.30  
Oral iron has been demonstrated to be effective in RLS patients with iron deficiency but not in patients without 
iron deficiency. 31-33 The explanation in part may be due to the poor absorption of oral iron in non iron deficient 
patients and that large iron doses are required to cross the blood brain barrier.  Silber and Richardson described 
a RLS patient population  who were identified as having iron deficiency and a history of frequent blood 
donations.16  The hemoglobin range was 10.6 to 15.5 gm/dl in this cohort and all 8 patients were iron deficient 
(defined as low serum ferritins ranges 3 to 15 g/l).  After correction of iron stores with oral iron, symptoms of 
RLS resolved in 2 patients and 2 others were able to discontinue other RLS medications.16 
The 2012 Cochrane Database Systematic Review of iron for RLS provided a summary of 192 subjects from six 
studies.29,33-38   In the four trials that used the IRLS severity scale, there were trials of IV iron sucrose (N=2), 
oral iron (N=1), and IV FCM (N=1).33,35,36,38   The combined IRLS data from these RLS trials was not 
associated with clear benefit (mean difference in scores of -3.79, 95% CI: -7.68 to 0.10, p = 0.06), yet the 
placebo-controlled trial of FCM and of oral iron (in low-normal ferritin subjects) reported significant treatment 
benefit compared to placebo.33,35  The subsequent data in the publication of the FCM trial was aligned with the 
preliminary findings reported in the Cochrane Database Systematic Review.30,34,35   
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1.4  
Injectafer®  (Ferric Carboxymaltose) 
1.4.1 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 reticaloendothelial system (RLS) 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 an investigational product on the study of RLS. 
1.4.2 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.  
Iron dextran, the first parenteral iron product available in the US, has been associated with an incidence of 
anaphylaxis/anaphylactoid reactions (i.e., dyspnea, wheezing, hypotension, urticaria, angioedema) as high as 
1.7%.  Over the last 20 years, 30 deaths have been attributed to the use of IV iron dextran. The 
anaphylaxis/anaphylactoid reactions are believed to be caused by the formation of antibodies to the dextran 
moiety.   Iron dextran is limited to second-line therapy for treatment of iron deficiency.  High molecular weight 
(HMW) iron dextran is reportedly associated with a higher rate of life-threatening adverse events and 
anaphylactic reactions in comparison to low molecular weight (LMW) iron dextran, the US Food and Drug 
Administration was unable to find a clear difference after an examination of post-marketing data, clinical trial 
data, death certificates, and emergency room diagnoses.   
Non-dextran IV irons like iron sucrose and iron gluconate do not contain the dextran moiety, but they have 
significant dosage and administration rate limitations.   If the body’s ability to handle (i.e., sequester, store, and 
transport) iron is overwhelmed, a reaction to excess free iron referred to as a bioactive iron reaction may occur.    
These reactions are characterized by hypotension (without allergic signs) accompanied by pain in the chest, 
abdomen, flank and/or nausea, vomiting, diarrhea.  
 
Due to its structure, Injectafer® is more stable than iron gluconate and iron sucrose.  Injectafer® a slow 
delivery of the complexed iron to endogenous iron binding sites and has an acute toxicity in animals 
approximately 1/5 that of iron sucrose.  These characteristics of Injectafer® make it possible to administer much 
higher single doses over shorter periods of time 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.  
 
1.4.3 Injectafer® Human Experience:  Marketed Use and the RLS indicator 
 
The Injectafer®  clinical development program demonstrated the safety and effectiveness of IV Injectafer®  in 
the treatment of IDA.  The drug is indicated for the treatment of IDA in adult populations who have intolerance 
to oral iron or have had unsatisfactory responses to oral iron or 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 (PET) demonstrated a 
fast initial elimination of radioactively labeled iron (Fe) 52Fe/59Fe Injectafer®  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 was still 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) approval on June 15, 2007 for the use of Injectafer®  (EU Trade name: Ferinject) 
in 18 European Union (EU) countries and later in Switzerland.  Ferric carboxymaltose was first approved as a 
prescription only medicine on July 6, 2007 in The Netherlands.  Up until now, Injectafer®  has received 
regulatory approval for marketing authorization in 58 countries worldwide: Argentina, Australia, Austria, 
Bangladesh, Belgium, Bolivia, Brazil, Bulgaria, Chile, Costa Rica, Croatia, Cyprus, Czech Republic, Denmark, 
Ecuador, El Salvador, Estonia, Finland, France, Germany, Greece, Guatemala, Honduras, Hungary, Iceland, 
India, Iran, Ireland, Israel, Italy, Kazakhstan, Kuwait, Latvia, Lebanon, Liechtenstein, Lithuania, Luxembourg, 
Malta, Mexico, New Zealand, Norway, Pakistan, Peru, Poland, Portugal, Romania, Russia, Singapore, Slovenia, 
Slovak Republic, South Korea, Spain, Sweden, Switzerland, The Netherlands, Turkey, Ukraine, and United 
Kingdom.  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 
 
The primary objective of this study is to evaluate the efficacy and safety of an IV Injectafer® in subjects with 
Restless Leg Syndrome (RLS). 
 
3.0  
RATIONALE AND OVERALL STUDY DESIGN 
 
3.1  
Rationale 
 
Injectafer® is a non-dextran IV iron approved by the US Food and Drug Administration (FDA).  In an earlier 
phase II study (1VIT05009) Injectafer® was found to be safe and well tolerated for the treatment of RLS.30  Based 
on these findings a larger phase III trial will be conducted to further investigate and confirm the use of Injectafer®  
in the treatment of RLS.   
 
Further justification is also based on the pathophysiology of iron in RLS as summarized in the Introduction 
(Section 1.0)  
 
3.2  
Trial Design 
 
This is a Phase III, double blinded, multi-center, randomized, placebo-controlled study. All subjects who meet 
the inclusion requirements and no exclusion criteria will qualify to enter up to a 7 day Screening Phase to enroll 
200 eligible subjects for study drug treatment.  All eligible subjects will be stratified at baseline by RLS 
medication-related augmentation (no augmentation, uncertain augmentation, definitive augmentation) on 
standard of care RLS therapy.  Subjects will be randomized in a 1:1 ratio within each stratum to receive either 
Injectafer® or IV Placebo on Days 0 and 5. All treated subjects will be followed for efficacy and safety for 12 
months.  Subjects will visit the clinic on Days 0 and 5 for treatment, and then on Days 14, 42, 168, and 365. In 
between the clinic visits subjects will be contacted remotely (phone) on Days 28, 84, 126, 210, 252, 294, and 
336. The subject’s participation in the study will be for 1 year from Day 0.  
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 Subjects will receive either a 750 mg undiluted blinded dose of IV Injectafer® at 100mg/minute 
or a blinded  IV Placebo (15 ml of Normal Sterile Saline [NSS]) IV push at 2ml/minute on Days 
0 and 5.   
After treatment on Days 0 and 5 subjects will visit the clinic on Days 14, 42, 168, and 365. In between the clinic 
visits subjects will be contacted remotely (phone) on Days 28, 84, 126, 210, 252, 294, and 336.  Subjects will be 
considered to have reached the end of the study for efficacy when intervention is required for their RLS 
symptoms; those subjects will continue the follow-up phase for safety.  Table 3.2.1 below summarizes the 
Schedule of Events. 
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Table 3.2.1  
Schedule of Events 
 
Scr. 
Treatment 
Efficacy and Safety Follow-up 
** Contact completed remotely via phone 
Study Day 
-7 
(+ 2 
days) 
0 
5 
14 
28** 
42 
84** 
126** 
168 
210** 
252** 
294** 
336** 
365 
Informed Consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility  
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History8 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
D/C oral iron products  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site contact IRT 
x1 
x2 
 
 
 
 
 
 
 
 
 
 
 
x 
Physical exam 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
Vital Signs 
x3 
x4 
x4 
 
 
x3 
 
 
x3 
 
 
 
 
x3 
Height and Weight without 
shoes 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Augmentation Subject 
Questionnaire 
x12 
 
 
 
 
 
 
 
 
 
 
 
 
 
Augmentation Investigator 
Assessment 
x13 
 
 
 
x 
 
 
x 
 
 
 
 
x 
RLS Diary15 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
Phone contact treatment 
phase 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
IRLS Scale  
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CGI-I and CGI-S 
 
 
xI,S 
 
xs 
xI,S 
xs
xs
xI,S
xs 
xs 
xs
xs
xI,S 
RLS QLI 
x5 
x5 
 
 
 
x 
 
 
x 
 
 
 
 
x 
MOS Sleep Scale  
x5 
x5 
x 
 
 
x 
 
 
x 
 
 
 
 
x 
Fatigue Linear Analog Scale  
x5 
x5 
x 
 
 
x 
 
 
x 
 
 
 
 
x 
C-SSRS14 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
Hematology 
x 
 
x 
x 
 
x 
 
 
x 
 
 
 
 
x 
Iron Indices 
x 
 
x 
x 
 
x 
 
 
x 
 
 
 
 
x 
Chemistry 
x 
 
x 
x 
 
x 
 
 
x 
 
 
 
 
x7 
Pregnancy test9 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transferrin receptor 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
Study Drug Dosing  
 
x 
x 
 
 
 
See section 6.3.5 for additional study drug dosing 
requirements 
 
RLS Treatment Stability11 / 
Tapering review / assessment 
x 
x 
x10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant Meds  
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Events6 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1 Contact IRT for screening number assignment during screening, and on Day 365 to complete subject from the study. 
2 Contact IRT for randomization assignment, unblinded site personnel 
3 Vital Signs includes sitting BP and heart rate. 
4 On study drug dosing days sitting vital signs including blood pressure and heart rate should be collected immediately pre dosing, immediately and 
30 minutes post dosing. Body temperature will also be collected pre dosing on Days 0 and 5. 
5 RLS QLI, MOS Sleep Scale, and Fatigue Linear Analog Scale may be completed at screening or prior to dosing on Day 0. 
6 Adverse event assessments will start at the time of the first dose of study drug.  All events noted prior to the 1st dose of study drug should be 
considered history and captured on the medical history page of the eCRF. 
7If the phosphorous is below the LLN at the time of early termination or end of the study (Day 365) the subject should return (as directed by the 
Investigator) for repeat phosphorous until the value is back WNL’s or the subject’s baseline. 
8 To include past and present treatment for RLS. 
9 Female subjects only. 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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10 After dosing on Day 5 the site will review the tapering requires with the subject. 
11 Assess compliance of tapering.  Once the taper period is complete assess stability (off meds, decrease dose, baseline dose). 
12 Augmentation questionnaire should be completed at screening prior to the Investigator’s Augmentation Assessment. 
13 Augmentation assessment can be done either at screening or prior to dosing on Day 0 but after the subject has completed the augmentation 
questionnaire. 
14  The Columbia-Suicide Severity Rating Scale will be used throughout the study to assess the subjects suicide ideation or behavior.  This scale is an 
assessment tool, it is ultimately the Investigators responsibility to evaluate each subject’s risk and treat as appropriate. 
15 Subject Diary reviewed for compliance at Day 0,5,14 and 28. The completed diary will be returned by the subject to the site on Day 42. 
I,S Investigator and Subject Assessment.  
S Subject only Assessment.  
4.0  
SUBJECT SELECTION 
4.1  
Number and Type of Subjects 
Two hundred (200) subjects (100 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 to receive Injectafer® or 
IV Placebo.    
 
4.2 
Screening Phase 
 
Once a subject enters the screening phase, they will be assigned a unique screening number, via the Interactive 
Response Technologies (IRT) system. 
 
4.2.1  Inclusion Criteria   
 
1. Male or female subject’s ≥18 years of age or older, able and willing to give informed consent to the 
study. 
2. RLS symptoms affirming diagnosis.  The IRLS Diagnostic Criteria for RLS must be met: 
a. An urge (distressing need) to move the legs usually associated with painful or uncomfortable 
sensations in the legs.  The urge to move may be present without the uncomfortable sensations.  
The arms or other body parts may be involved in addition to the legs. 
b. The urge to move or unpleasant sensations are worse or exclusively present at rest or inactivity, 
such as lying down or sitting.  
c. The urge to move or unpleasant sensations are partially/temporarily relieved with walking or 
moving the legs.  
d. The urge to move or unpleasant sensations are worse in the evening or night than during the day 
or only occur in the evening or night.  When symptoms are severe, the worsening at night may 
not be noticeable but must have been previously present. 
3. Subjects should be on monotherapy for RLS.  Treatment should be stable for at least 8 weeks prior to 
screening. (See approved RLS Therapies/Regimen in Appendix III). 
4. A score ≥15 on the IRLS Rating Scale at screening and on Day 0 prior to dosing. 
5. Subjects on anti-depressants and sleep medications must be on a stable dose for at least 6 months.  
6. Subject has regular sleep hours between 9 pm and 9 am.  
7. All patients must use one highly reliable contraception with reliability index < 1 for example IUD, 
sterilization of one of the partners, assuming one sexual partner relationship during the clinical trial will 
occur, hormonal implants, injections, patches, pills, accompanied with one barrier form of contraception 
with spermicide. Men should always use condom. Use of two barrier methods simultaneously with 
spermicide is considered a reliable contraceptive method. A sexual abstinence throughout the clinical 
trial is allowed only if this is a lifestyle choice of the patient. 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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4.2.2 Exclusion Criteria   
1. RLS 2° to other disease or injury.   
2. Disorders that require treatment with the same medications used for RLS include: peripheral neuropathy 
and neurodegenerative disorders (i.e. Parkinson’s Disease or Dementia).    
3. Stage 4 – 5 CKD, subjects on dialysis or anticipated to start dialysis while participating in this study. 
4. Any pain related (e.g., frequent muscle cramps, myalgia, fibromyalgia) or sleep related disorders (e.g. 
sleep apnea, unless on stable Continuous Positive Airway Pressure [CPAP]) which may confound the 
outcome measures.  
5. Subjects with Multiple Sclerosis.   
6. History of neuroleptic akathisia. 
7. Parenteral iron use within 6 weeks prior to screening. 
8. History of >10 blood transfusions in the past 2 years. 
9. Anticipated need for blood transfusion during the study. 
10. Known hypersensitivity reaction to any component of Injectafer® (Ferric Carboxymaltose).        
11. Previously randomized to Injectafer® (FCM or VIT-45) in a clinical trial.  
12. Current, active, or acute or chronic infection other than viral upper respiratory tract infection.  
13. Malignancy (other than basal or squamous cell skin cancer or the subject has been cancer free for ≥ 5 
years). 
14. Pregnant or lactating women. 
15. Seizure disorder currently being treated with medication. 
16. Baseline ferritin ≥300 ng/mL.  
17. Baseline TSAT ≥45%. 
18. History of hemochromatosis or hemosiderosis or other iron storage disorders. 
19. AST or ALT greater than 2 times the upper limit of normal. 
20. Hemoglobin greater than the upper limit of normal. 
21. 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 upper limit of normal). 
22. Known positive HIV-1/HIV-2 antibodies (anti-HIV) 
23. Received an investigational drug within 30 days before randomization. 
24. Chronic alcohol or drug abuse within the past 6 months. 
25. Any other pre-existing laboratory abnormality, medical condition or disease which per the investigator 
may put the subject at risk if they participate in the study. 
26. Subject unable or unwilling to comply with the study requirements. 
4.3 
Subject Assignment and Randomization Process 
Subjects that meet all inclusion requirements and no exclusionary criteria will be offered participation in this 12 
month study. Subjects will be stratified by augmentation (no augmentation, uncertain augmentation, definitive 
augmentation) and randomized in a 1:1 ratio via an IRT system to receive either a blinded dose of IV 
Injectafer® or a blinded dose of Placebo. 
 
 Each subjects will receive either a 750 mg undiluted blinded dose of IV Injectafer® at 100mg/minute  or 
a blinded IV Placebo (15ml of Normal Sterile Saline [NSS]) IV push at 2ml/minute on Days 0 and 5.   
 
 
 
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4.4 
RLS Standard of Care Therapy:  Tapering Procedures 
Each subject will be tapered from the current RLS medication, post treatment on Day 5.   The tapering regimen 
will depend on the subject’s current medication and dosing (see tapering schedule in Appendix III).  Starting at 
screening, during the tapering period and through Day 42 subjects will be asked to keep an RLS diary to record 
their progress.    
 
4.5 
Duration of Study / Withdrawal from Study 
 
All subjects will be followed for efficacy.  The subset of subjects requiring intervention for treatment of RLS will 
continue to be followed for safety of efficacy or until Day 365.  
 
Any subject who wishes to withdraw from the study may do so at any time without the need to justify their 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.  
 
If withdrawal is prior to Day 42, the Day 42 procedures should be performed at the time of withdrawal.  If the 
withdrawal occurs after Day 42, then the procedures for the Day 365 visit must be performed.  
 
In the event the subject has received any study drug and discontinues early at a minimum the subject should be 
contacted 28 days following the last dose of study drug to assess adverse events, if possible. 
 
4.6 
Intervention  
 
Intervention is defined as either 1) an increase in dosage from the RLS medication at study entry, 2) the 
initiation of a new RLS medication,  3) resumption of the previous medication prescribed for RLS, or, 4) 
increase in dosage from the RLS medication achieved at the end of the tapering period.  Any subject who has an 
intervention will no longer be evaluated for efficacy starting at the time of the intervention, however these 
subjects will remain in the study and will be continued to be evaluated for safety.  
 
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). 
 
Injectafer®  (Ferric carboxymaltose injection) 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 
monitor. 
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5.2  
Study Drug Blinding/Administration 
5.2.1  Study Drug Blinding    
All subjects, investigators, and study personnel will be blinded to the content of study drug with the exception 
of the unblinded study personnel.  All study personnel will be blinded to the iron indices (after randomization) 
throughout the study.   
 
5.2.1.1    Unblinded Personnel             
 
The unblinded study personnel will be responsible for the following: 
 
o Randomizing the subject on Day 0 through IRT system  
o Preparing, concealing and administering the study drug on Day 0 and 5 (as Injectafer® is reddish-brown 
and slightly viscous).1 
o Completing the Study Drug Accountability Form, study drug dosing record and applicable electronic case 
report form 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 (ie. post-
randomization IRLS questionnaires/scores, subjects’ CGI scores, 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 as the values may reveal the blind.  
 
The blinding will be maintained until the study is complete and the database has been locked. 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 IRLS score and subject CGI score for each 
subject after randomization.  
 
5.3  
Study Drug Administration      
 
On Days 0 and 5, subjects will either receive a 750 mg undiluted blinded dose of IV Injectafer® at 
100mg/minute or a blinded Placebo (15 ml of Normal Sterile Saline [NSS]) IV push at 2ml/minute.  
 
5.4 
IV Iron Precautions 
 
When administering IV iron, the following precautions will be taken: 
 
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
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, and 30 minutes post
administration.  If the subject is an outpatient, they will be discharged from the site by the Investigator
only if there are no significant signs or symptoms 30 minutes after the administration 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 treatment of serious hypersensitivity
reactions. Most reactions associated with intravenous 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®.  They will not allow 
Injectafer® to be used for purposes other than as directed by this protocol.  The investigator agrees that he/she will not 
supply study medication to any persons other than those screened and randomized in the study, or to investigators not 
listed on the FDA 1572.  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 their route of administration and duration must be recorded in the 
electronic case report form (eCRF).  No additional iron preparations, IV iron from 6 weeks prior to 
screening or oral iron including multivitamins with iron from time of consent will be allowed.  No blood 
transfusions or erythropoiesis stimulating agents will be allowed. Once a subject is randomized, 
additional anti-depressants, anti-seizure, sleep medications, dopamine agonists, benzodiazepines, 
narcotics, or other RLS treatments are not permitted for the duration of the study. Non-narcotic 
analgesics are permitted.     
All subjects should be on a stable RLS monotherapy regimen (see Appendix III) for at least 8 weeks prior to 
screening. These therapies should remain unchanged until the tapering process begins post Day 5 treatment with 
study drug.  Once the subject is tapered off RLS medication (Appendix III) the subject should stay removed 
from medication for the duration of the study, but if a subject, at the end of the allotted tapering period, is 
unable to achieve a dose of zero (0) the subject should be maintained on the lowest dose level attained at the end 
of the tapering period and that dose should remain stable for the duration of the study.  If during the course of 
the study it becomes necessary to restart or increase therapy via physician decision, these data points will be 
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collected and the subject will no longer be evaluated for efficacy, but the subject will continue in the study for 
safety analysis.   
 
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 
 
Prior to any study specific procedures, the investigator 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  
 
Each subject who qualifies to participate will undergo the following clinical evaluations to confirm eligibility 
for the study: 
 Obtain screening number from IRT system 
 Medical history, including prior iron therapy use  
 All prior medications, to include current treatments for RLS and side effects associated with those medications 
 IRLS scale will be completed 
 Medical Outcome Study (MOS) Sleep Scale (range 0-100)  
 Restless Legs Syndrome Quality of Life (RLS-QLI)  
 Fatigue Linear Analog Scale 
 Columbia Suicide Severity Rating Scale (C-SSRS): The Columbia-Suicide Severity Rating Scale will be used 
throughout the study to assess the subject’s suicide ideation or behavior.  This scale is an assessment tool, it is 
ultimately the Investigators responsibility to evaluate each subject’s risk and treat as appropriate. 
 Physical exam 
 Vital signs (sitting heart rate and blood pressure) 
 Height and Weight without shoes 
 Blood samples for hematology, chemistries, iron indices and transferrin receptor, fasting if indicated. A 
serum pregnancy test will be performed on female subjects.  
 All oral iron products will be discontinued on the day of the first screening visit   
 RLS Diary:  
 Three-item RLS diary.  Subjects will complete the RLS diary daily, screening through Day 42. The diary should 
be completed around the same time each day.  The following 3 questions will be assessed: 
 
1. How many hours did you nap/sleep in the prior 24 hours? _________________ 
2. For the nap/sleep hours, how many times were you interrupted by your symptoms of 
restless legs syndrome? ________________ 
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3.   For the awake time, how many times were you interrupted by your symptoms of 
restless legs syndrome? __________________ 
 Augmentation subject questionnaire to be completed 
 Augmentation Investigator assessment (can be completed in screening, once the subject questionnaire is complete 
or on Day 0 prior to randomization). The physician will assess the subject and provide the following: 
 
o Step 1.  Please provide a percent (%) score using the scale outline below for the following question:    
 
 How likely is it that the subject has developed augmentation to the RLS medication? _______% 
  
o Step 2.  Convert this percentage estimate to the strata category for randomization 
 
Step 1 percentage (%) 
Randomization Strata 
0% to < 25% 
No Augmentation 
25% to ≤ 75% 
Uncertain Augmentation 
>75% 
Definitive Augmentation 
 
o Step 3.  Randomize the subject via the augmentation strata 
 
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 
Study Days 0 - 365 
 
6.3.1 Day 0  
 
The following must be obtained PRIOR to dosing the subject: 
 Confirm the subject continues to meet the Inclusion/Exclusion criteria 
 IRLS scale will be completed 
 Vital signs to include temperature 
 Concomitant medications, to include RLS treatment stability 
 The investigator will assess the subject’s augmentation status (if not completed during screening): no 
augmentation, uncertain augmentation, definitive augmentation. See section 6.2 
 Review RLS Diary for compliance 
 Subject will complete the following, if not already completed during screening: 
 
 Medical Outcome Study (MOS) Sleep Scale (range 0-100)  
 Restless Legs Syndrome Quality of Life (RLS-QLI)  
 Fatigue Linear Analog Scale 
 
 Unblinded personnel will perform dosing assignment through the IRT. 
 
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A separate Dosing Record will be maintained by the unblinded study personnel responsible for preparation 
and administration of the study drug. See Section 5.0 for details of study drug administration, blinding and 
precautions. 
 
The Dosing Record will include: 
 
 Starting and stopping time of study drug administration 
 Total dose in mg and ml of Injectafer® administered (i.e. 750 mg / 15 ml) 
 Total volume of Normal Sterile Saline administered (15 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.    
6.3.2. Day 5  
 
Prior to administering study drug, the following must be confirmed or obtained in the following order: 
 
 Adverse events 
 Concomitant medications, to include RLS treatment stability 
 IRLS scale will be completed 
 Physician will complete the Investigator CGI-I Score. The physician is to remain blinded to the IRLS Scale and the 
subject CGI-S Score after randomization.  
 Subject will independently complete the following:  
 Subject CGI-S Score  
 MOS Sleep Scale  
 Fatigue Linear Analog Scale 
 Review RLS Diary for compliance 
 Blood sample for hematology, chemistries and iron indices 
 Vital signs to include temperature 
 Study drug dosing 
 
A separate Dosing Record will be maintained by the unblinded study personnel responsible for preparation 
and administration of the study drug. See Section 5.0 for details of study drug administration, blinding and 
precautions. 
 
The Dosing Record will include: 
 
 Start and stop time of study drug administration 
 Total dose in mg and ml of Injectafer® administered (i.e. 750 mg / 15 ml) 
 Total volume of Normal Sterile Saline administered (15 ml) 
 
The following will be obtained / conducted by blinded study personnel following administration of the study 
drug (review Sections 5.0): 
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 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.    
 
Once dosing is complete, an overview of the tapering algorithm (see Appendix III) will be discussed with the subject.  
The subject will be instructed on the appropriate tapering regimen depending on the RLS medication and dose of that 
medication that the subject is currently taking.  At the end of the tapering period those subjects off medication, 
decreased the dose, or remained on baseline dose should remain stable throughout the trial Day 365.  Any new, 
resumption, or increase in medication will be considered an intervention (See Section 4.6). 
 
 
6.3.3. Days 14, 42, and 168 (in-clinic visits) 
 
6.3.3.1 Day 14 
 
The subject will return to the clinic on Day 14 for blood samples (hematology, chemistries and iron indices), subject 
RLS diary review, RLS treatment tapering progress, and assessment of concomitant medications and adverse events 
only. 
6.3.3.2 Day 42 and 168 
The following should be assessed or obtained: 
 Adverse events 
 Concomitant medications 
 Subjects’ tapering period is complete and compliance should be assessed.   
 Physical exam 
 IRLS scale will be completed 
 Physician will complete the Investigator CGI-I Score. The physician is to remain blinded to the IRLS Scale and the 
subject CGI-S Score after randomization.  
 Augmentation Assessment by Investigator 
 C-SSRS: The Columbia-Suicide Severity Rating Scale will be used throughout the study to assess the subject’s 
suicide ideation or behavior.  This scale is an assessment tool, it is ultimately the Investigators responsibility to 
evaluate each subject’s risk and treat as appropriate. 
 Subject will independently complete the following:  
 Subject CGI-S Score 
 Restless Legs Syndrome Quality of Life (RLS-QLI)  
 MOS Sleep Scale  
 Fatigue Linear Analog Scale  
 Subject completed diary should be returned to the site (Day 42 only) 
 Blood sample for hematology, chemistries, iron indices and transferrin receptor, fasting if indicated 
 Vital signs (sitting heart rate and blood pressure) 
 
6.3.4. Days 28, 84, 126, 210, 252, 294, and 336 (remote contact by phone) 
 
The following should be assessed or obtained via a phone contact: 
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 IRLS scale (principle investigator completing the CGI-I is to remain blinded to score) 
 Subject CGI-S Score (principle investigator completing the CGI-I is to remain blinded to score) 
 Concomitant medication 
 Adverse events 
 Subjects’ tapering period is complete and compliance should be assessed.   
 Compliance with Subject diary (Day 28 only) 
 
6.3.5 Additional Treatment Post Day 42 
 
Subjects who have not had an intervention may receive additional blinded study drug treatment after Day 42 at 
the discretion of the Investigator.  An intervention is defined as either 1) an increase in dosage from the RLS 
medication at study entry, 2) the initiation of a new RLS medication, or 3) resumption of the previous 
medication prescribed for RLS, or 4) increase in dosage from the RLS medication achieved at the end of the 
tapering period. The subject will receive the same blinded study medication as previously randomized to receive 
during the treatment phase.  Subjects will receive either a single blinded dose of either Injectafer® at 750 mg 
undiluted at 100mg/minute or a Placebo (15 ml of Normal Sterile Saline [NSS]) IV push at 2 ml/minute on two 
independent days separated by 5 days. Dosing should mirror the original treatment / follow-up period (dosing 5 
days apart with follow-up visits, to include laboratory assessments only, on 14 and 42 Days post the first dose). 
No subject assessments are completed unless the dosing or follow-up days fall on an assessment day in the 
follow-up period.   
 
Eligible subject will have met the following requirements prior to receiving additional treatment:   
 
 IRLS score ≥15  
 *TSAT <45% (confirmation can be through a local laboratory) 
 *Ferritin <300 ng/mL (confirmation can be through a local laboratory) 
 
*Central laboratory results obtained during the Day 42 or Day 168 visit can be used to qualify a subject for 
additional dosing if those labs have occurred with 14 days of the first dose of study medication. 
 
No additional iron may be administered between Day 320 and the Day 365 visit. 
 
If the subject qualifies to receive additional dosing the following will be required /collected: 
 
 Unblinded personnel will perform dosing assignment 
 
A separate Dosing Record will be maintained by the unblinded study personnel responsible for preparation 
and administration of the study drug. See Section 5.0 for details of study drug administration, blinding and 
precautions. 
 
The Dosing Record will include: 
 Start and stop time of study drug administration 
 Total dose in mg and ml of Injectafer® administered (i.e. 750 mg / 15 ml) 
 Total volume of Normal Saline administered (15 ml) 
 
The following will be obtained /conducted by blinded study personnel following administration of the study 
drug (review Sections 5.0): 
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 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. 
 
6.3.6. Day 365 (End of Study) 
 
The following should be assessed or obtained: 
 
 Adverse events 
 Concomitant medications 
 Subjects’ tapering compliance 
 Physical exam 
 IRLS scale will be completed 
 Physician will complete the Investigator CGI-I Score. The physician is to remain blinded to the IRLS Scale and the 
subject CGI-S Score after randomization.  
 Augmentation assessment by Investigator 
 C-SSRS: The Columbia-Suicide Severity Rating Scale will be used throughout the study to assess the subjects 
suicide ideation or behavior.  This scale is just an assessment tool, it is ultimately the Investigators responsibility to 
evaluate each subject’s risk and treat as appropriate. 
 Subject will independently complete the following:  
 Subject CGI-S Score 
 Restless Legs Syndrome Quality of Life (RLS-QLI)  
 MOS Sleep Scale  
 Fatigue Linear Analog Scale  
 Vital signs (sitting heart rate and blood pressure) 
  Blood sample for hematology, chemistries and iron indices 
 Contact IRT to complete the subject from the study 
 
**NOTE: If the subject early terminates or the Day 365 phosphorus value is below the LLN the subject 
should return (as directed by the Investigator)  for a repeat blood sample until the value is back Within 
Normal Limit’s (WNL).** 
 
6.4 
Central Laboratory Assessments 
 
Serum samples for laboratory analyses must be obtained at all appropriate visits and will be analyzed by the 
central 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 Day 42 laboratory test, this test may be obtained 
after notification to the Sponsor.  If a subject’s phosphorous is below the LLN at Day 365 the subject should 
return (as directed by the Investigator) for repeat phosphorous until the value is back WNL’s.  The following 
laboratory assessments will be determined as listed in Section 3.2.1  
 
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)   
 
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Chemistry: 
sodium, potassium, chloride, BUN, creatinine, albumin, alkaline phosphatase, total 
bilirubin, gamma-GGT, AST, ALT, LDH, calcium, phosphorus, glucose, bicarbonate, 
and magnesium  
Other: 
 transferrin receptor and serum pregnancy  
7.0  
ASSESSMENT OF SAFETY 
7.1 
Adverse Events 
Any untoward medical event (clinical), 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 case 
report form.  
A distinction of symptomology, when feasible, should be made for study drug versus RLS medication taper. 
For any laboratory abnormality, the physician will make a judgment as to its clinical significance.  If the laboratory 
value is outside the safety limits and is felt to represent 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, 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 trials 
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.)  
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4 
Life-threatening 
Life-threatening consequences; urgent intervention 
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 Day 365.  AE’s will be captured during a follow-up phone call 28 days following their last 
dose of study drug for subjects who are randomized and early terminate from the trial.  All ongoing adverse events 
related to study drug (i.e., Injectafer® or Normal Sterile Saline) 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 
nois 
 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 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 eCRF.  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 
eCRF.  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."  
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.
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 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 Day 365.  The SAEs will be captured during 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 eCRF and 
reported immediately to your IRB / ethics committee per their reporting guidelines. 
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: tapering of RLS 
medications (Section 7.5) as well as 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 
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Luitpold Pharmaceuticals, Inc. 
pv@luitpold.com 
Tel: (610) 650-4200          Fax: (610) 650-0170 
 
7.5     Events associated with tapering of RLS medications 
 
The dose-specific, time-varying taper of the subject’s study entry RLS medications will begin on day 6 after 
receipt of the second dose of study medication (day 5).  The withdrawal from the standard of care RLS 
medications must not be abrupt.  The discontinuation of the standard of care RLS medications must be tapered 
(see Appendix III).   Abrupt discontinuations of the standard of care RLS medications have been reportedly 
associated with severe and life-threatening events inclusive dopamine agonist withdrawal syndrome (DAWS) 
and the neuroleptic malignant syndrome (dopamine agonists), seizures (calcium channel α2δ ligands), and the 
acute abstinence syndrome (opioids).8,39  The response to the recommended tapering regimen of the dopamine 
agonists, calcium channel α2δ ligands, and opioids will be variable yet there are expectant class-specific signs 
and symptoms of withdrawal (Table 7.5.1) along with potential for mild, moderate, or severe worsening of RLS 
symptoms during the taper regimen and especially for the initial 10-day interval after the taper regimen is 
complete.  The first 96 hours (4 days) of the RLS standard of care drug-free interval from the entry RLS 
monotherapy regimen may be associated with severe insomnia and ongoing withdrawal (Table 7.5.1).   
 
Table 7.5.1 Class-specific adverse events and withdrawal signs and symptoms during taper of RLS 
medications 
Class 
(medications) 
Adverse events** 
Withdrawal signs and symptoms 
Dopamine 
agonist 
(pramipexole, 
ropinirole, 
rotigotine 
patch, 
levodopa) 
Nausea, vomiting, somnolence, 
asthenia, constipation, dyspepsia, 
dizziness, orthostatic hypotension, 
hallucinations, impulse control 
disorders 
Dopamine agonist withdrawal 
syndrome (DAWS) inclusive of 
anxiety, panic attacks, dysphoria, 
depression, agitation, irritability, 
suicidal ideation, fatigue, orthostatic 
hypotension, nausea, vomiting, 
diaphoresis, generalized pain, and 
drug cravings.8,39 
Neuroleptic malignant syndrome 
(hyperpyrexia, confusion). 
Calcium 
channel α2δ 
ligand 
(gabapentin 
enacarbil, 
gabapentin, 
pregabalin) 
Angioedema, suicidal behavior and 
ideation, CNS effects (emotional 
lability, hostility, thought disorder, 
hyperkinesia), peripheral edema, 
weight gain, ophthalmological 
effects (eg, blurred vision, 
decreased visual acuity, visual field 
changes), creatinine kinase 
elevations, decreased platelet count, 
PR interval prolongation, 
hypersensitivity reactions, DRESS/ 
multi-organ hypersensitivity, 
dizziness, unsteadiness, 
somnolence, sedation 
Insomnia, nausea, headache, anxiety, 
hyperhidrosis, diarrhea 
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Opioid 
(methadone, 
oxycodone, 
hydrocodone, 
tramadol) 
Respiratory depression, miosis, QT 
prolongation, seizures, myoclonus, 
hypotension, apnea, circulatory 
collapse, cardiac arrest, 
anaphylactoid reactions, biliary 
colic, urinary retention, renal 
toxicity, decreased gastrointestinal 
motility, ileus, bradycardia, 
serotonin syndrome, skeletal 
muscle rigidity, spasm of the 
sphincter of Oddi, increased serum 
amylase, hypersensitivity reactions, 
drowsiness, dizziness, constipation 
Restlessness, lacrimination, 
rhinorrhea, yawning, perspiration, 
gooseflesh, mydriasis, anxiety, 
weakness, muscle twitching, kicking 
movements, severe backache, severe 
abdominal and leg pains, abdominal 
and muscle cramps, hot and cold 
flashes, insomnia, nausea, vomiting, 
anorexia, coryza, repetitive sneezing, 
and increase in body temperature, 
blood pressure, heart rate, and 
respiratory rate. 
CNS = central nervous system  
DRESS = drug-reaction with eosinophilia and systemic symptoms 
**Additional resources can be found within the FDA approved package insert for each medication. 
8Nirenberg MJ.  Drugs & Aging 2013. 
39Pondal M.  J Neurol Neurosurg Psychiatry 2015. 
In addition to the reporting of adverse events (Section 7.2) and serious adverse events (Section 7.3), the 
potential risks associated with the taper and withdrawal from RLS medication will be elicited and determined 
by the study investigator to be related or not related to the taper and the withdrawal of the RLS medication and 
captured in the eCRF.   The signs and symptoms associated with taper and withdrawal from RLS medications 
may include worsening of RLS symptoms, inclusive of an increase in limb movements, periodic leg movement 
symptoms defined as Periodic Limb Movement of Sleep (PLMS) or Periodic Limb Movement while Awake 
(PLMA), insomnia, decreased daytime alertness, low mood, depression, anxiousness, and hallucinations.  
Reported class-specific events associated with the tapering and withdrawal of RLS medications, as potentially 
distinct from adverse events (Section 7.2) and serious adverse events (Section 7.3) are listed in Table 7.5.1.   
The dopamine agonist withdrawal syndrome (DAWS) has been defined as a severe, stereotyped cluster of 
physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent 
manner.8,39 The severity and prognosis of DAWS (Table 7.5.1) is variable in duration.   While there are several 
potential adverse events associated with the calcium channel α2δ ligands, the withdrawal symptoms likely 
include insomnia, nausea, headache, anxiety, hyperhidrosis, diarrhea (Table 7.5.1).  The high-potency opioids 
and opioid agonist have several known adverse events and withdrawal symptoms (Table 7.5.1).   It is 
anticipated that in the monitoring for adverse events and severe adverse events, as distinct from mediation 
withdrawal events, some subjects may experience benefits associated with withdrawal of the RLS medications 
such as decrease, if not resolution, of the symptoms of augmentation (symptoms earlier in the day after an 
evening dose of medication, including earlier onset of symptoms, increased intensity of symptoms, or spread of 
symptoms to the arms).6 
8.0 
STATISTICS 
8.1 
Sample Size Rationale 
Sample size estimates were based on the mITT population for Study 1VIT05009.  The last observation carried 
forward (LOCF) and observed cases (OC) results on Day 28 were used for the co-primary efficacy endpoints 
(CGI) and first ranked secondary endpoint (IRLS).  It is unclear how treatment differences on Day 42 results 
might differ from Day 28, apart from a higher dropout rate, but it is reasonable to assume that treatment 
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differences will decrease.  Therefore, power calculations were based on smaller treatment differences and larger 
standard deviations. 
Co-primary endpoint (IRLS): The smallest treatment difference for change from baseline to Day 28 was 4.4 
with a standard deviation of 8.5.  A sample size of 100/group provides 95% power under this scenario. 
 
Co-primary efficacy endpoint (CGI-I): The smallest treatment difference on Day 28 was 45% versus 15% of 
patients in the FCM and placebo groups, respectively, who reported much or very much improvement on the 
patient CGI (Tables 3.7.1.1 and 3.7.2.1).  A sample size of 100/group provides >99% power.  A sample size of 
100/group has at least 90% power when the treatment difference is as small as 45% versus 22%. 
 
8.2 
Analysis Populations 
 
There will be 2 analysis populations: 
 
 Safety population: All subjects who receive at least one dose of randomized treatment.  
 Full analysis set (FAS) population: All subjects who received at least one dose of randomized treatment 
and had at least one post-randomization measurement of the IRLS and Clinical Global Impression 
performed by Investigator (CGI-I). 
 
8.3 
Disposition and Baseline Characteristics 
 
Disposition and baseline characteristics will be summarized by treatment group for the Safety and FAS 
populations.  The number and percentage of subjects, who are randomized, treated, prematurely discontinued, 
and completed the study will be summarized after the study’s conclusion.  
 
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 treatment group will be summarized for each investigative site. 
Baseline characteristics (e.g., sex and race) 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 
 
The co-primary efficacy variables will be IRLS total score change from baseline to  Day 42 and the proportion 
of patients rated as much or very much improved per the CGI-I performed by Investigator (CGI-I) on Day 42.  
Baseline values used for evaluation will be defined as the latest value obtained prior to the first dose of study 
drug.  For those subjects with only one value prior to dosing, the single value will be used as baseline.  
 
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8.4.2 Secondary Endpoints 
The major secondary endpoints will be tested in a hierarchical order, that is, statistical significance for major 
secondary efficacy endpoint will be declared only if the primary efficacy test (IRLS and CGI-I on Day 42) is 
statistically significant.  Because a hierarchical testing scheme is used, no adjustments of the alpha level will be 
needed at each stage of testing.  All tests will be done at an alpha ≤0.05. 
The major secondary efficacy endpoints in ranked order of testing include: 
1. Clinical Global Impression (CGI) performed by Subject (CGI-S) on Day 42 
2. Restless Legs Syndrome Quality of Life (RLS-QLI) change from baseline to Day 42 
3. Medical Outcome Study (MOS) Sleep Scale change from baseline to Day 42 
4. Fatigue Linear Analog Scale change from baseline to Day 42 
5. Time off pre-enrollment prescribed RLS medications 
Other efficacy endpoints: 
1. Proportion of responders (any improvement) based on CGI-I at each time point 
2. IRLS total score change from baseline at each time point. 
3. Proportion of responders based on CGI-S at each time point 
4. CGI-I and CGI-S scores at each time point and by baseline RLS treatment group. 
5. RLS-QLI scores change from baseline at each time point 
6. MOS Sleep scale total score change from baseline at each time point 
7. Fatigue Linear Analog Scale total score change from baseline at each time point 
8. Augmentation assessment by Investigator change between baseline, Day 42, Day 168 and end of study 
(Day 365) 
9. Proportion of subjects required intervention for RLS  
10. Time from Day 5 to the next dose of study drug. 
8.4.3 Safety Evaluations  
The safety endpoints include: 
1. Incidence of treatment emergent adverse events and incidence of serious adverse events 
2. Change in clinical laboratory tests 
3. Change in vital signs    
4. Change in C-SSRS 
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.  
Treatment group differences for CGI scores will be assessed with the Cochran-Mantel-Haenszel test using 
region (US, Europe) as the stratification factor.  Treatment group differences for changes in total and domain 
scores of rating scales (eg, IRLS) will be assessed with the analysis of covariance with fixed factors for region 
(US, Europe) and treatment and with baseline score as a covariate.  Treatment differences for proportions will 
be assessed with the continuity-corrected chi-square test.   
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The primary imputation method for the CGI and change in total/domain scores will be LOCF.  Sensitivity 
analyses will assess the impact of missing values on inferences. 
 
Time from Day 5 to the next dose of study drug will be analyzed with the log-rank test. Subjects who 
discontinue or complete the study before an intervention will be censored at their last study visit. 
 
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-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 
 
An interim analysis of efficacy will be conducted after 100 subjects have completed Day 42. The blinded code 
of the treatment groups will be broken by a third party statistician chosen by the sponsor. The un-blinded data 
will only be available to the sponsors experts or consultants to assist in the planning of future studies. The 
sponsor, blinded PI, study staff and study participant will remained blinded to the data. Therefore, no 
adjustment to Type I error will be made. 
  
9.0 
ADMINISTRATIVE CONSIDERATIONS 
 
9.1 
Retention and Availability of Records 
 
Investigators are required to maintain all study documentation, including electronic copies of eCRFs 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 the completion of the study. Permission should 
be obtained from Luitpold Pharmaceutical Inc. prior to destroying any study records. 
 
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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.  
 
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 their obligations in 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 
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, 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. 
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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 eCRFs will be checked for completeness and accuracy. Source documents from 
which the data are obtained will be made available at the time of review.  Interim checks on progress will be made 
when deemed appropriate (i.e. telephone or email). 
9.6.3 Quality Assurance Audit 
For the purpose of data validation, the principal investigators 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 eCRFs.  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 all investigators 
in advance. 
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9.7 
Ethics 
9.7.1 Ethical and Legal Issues  
This study will be performed in accordance with the United States (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 informed 
consent and ICH guidelines.  Translations of the informed consent must be certified by a qualified translator and their 
use must be documented. 
The Informed Consent documents the information the Investigator 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 Edinburgh, Scotland Revision of the “Declaration of Helsinki”, the local legal 
requirements and the guidelines on “Good Clinical Practice”, [21 CFR Part 312 and ICH guidelines]. 
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9.8 
Data Handling and Record Keeping 
9.8.1 Electronic Case Report Form (eCRF) 
 eCRFs 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. 
 eCRF used will be 21 CFR 11 compliant.   The system used for eCRF will meet all applicable regulatory 
requirements for recordkeeping and record retention as would be provided with a paper system.  
Security measures will be utilized to prevent unauthorized access to the data and to the computerized 
system. Changes made to data that are stored on electronic media will always require an audit trail, in 
accordance with 21 CFR 11.10(e). 
 eCRFs must be reviewed and verified for accuracy by the Principal Investigator. A copy of the eCRF 
will remain at the site at the completion of the study. 
 All eCRFs are to be reviewed by the Clinical Monitor at Luitpold Pharmaceuticals, Inc. 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. 
9.8.3 Termination of the Study 
The study may be terminated if the sponsor, investigator, or 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 
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Pharmaceuticals, Inc.  personnel and the investigator and be approved by the site's IRB, before the revision may be 
implemented. The protocol revision will 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 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 
Data and Safety Monitoring Board (DSMB) 
 
The DSMB will be composed of approximately 3-5 senior academic individuals, including the DSMB Chair. 
They will have high-level expertise in neurology, hematology, cardiology and/or statistics. A senior statistician 
assigned to the trial from the group performing data management services for this trial will oversee the 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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provision of interim data reports for use by the DSMB. The data management group for this trial will transfer 
pre-agreed datasets to the DSMB. During the Open Session of the DSMB meetings, the Study Chair or Luitpold 
representatives may present updates on the trial status or the safety profile of Ferric Carboxymaltose, but will 
not be privy to discussions of the data conducted during the Closed Sessions and will not vote. Proceedings and 
minutes of the Closed Session will be held in strict confidence and will not be shared outside the DSMB while 
the trial is ongoing. 
The DSMB will be responsible for the interests of the patients and, to this end, will undertake reviews of the 
safety data. The DSMB will have access to an agreed subset of the study data as listed in the DSMB charter 
(updated as necessary during the trial) throughout the study duration. In addition, the DSMB will evaluate the 
data approximately (as outlined in the Charter) either by face to face meeting or teleconference.   The DSMB 
will determine if it believes the trial should be terminated early because clear evidence of a significant safety 
concern exists. 
If the DSMB finds it necessary to recommend actions regarding interruption of the study or changes to the 
protocol based on medical rationale that would make it unethical to continue the study in its present form, those 
recommendations will be forwarded to the Study Chair and Sponsor. The details of the DSMB's functions and 
the early stopping rules will be delineated in a separate DSMB charter. 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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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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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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APPENDIX I: Injectafer® Package Insert 
 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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APPENDIX II: RLS Assessment Tools: 
1. Clinical Global Impression-performed by Investigator (CGI-I) 
2. IRLS Rating Scale for RLS severity 
3. Clinical Global Impression-performed by Subject (CGI-S) 
4. RLS Quality of Life – RLS-QLI 
5. MOS Sleep Scale  
6. Fatigue Linear Analog Scale 
7. Augmentation Questionnaire (modified) 
8. Columbia-Suicide Severity Rating Scale (C-SSRS) 
9. Subject Diary 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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APPENDIX III: RLS Medications at study entry and Taper Regimen 
 
Entry medication 
(after 4P)1 
Maximum 
entry 
dose/day 
Taper 
Regimen2 
Maximum days 
Dopamine agonist 
 
 
 
Pramipexole (not ER)3 
0.75 mg 
0.25 q3d 
6 
Ropinirole (not ER)3 
4 mg 
0.5 mg q3d 
21 
Rotigotine (patch)3 
3 mg
1 mg q3d 
6 
Levodopa 
200 mg 
50 mg q3d 
9 
Calcium channel α2δ ligand  
 
 
 
            Gabapentin enacarbil 
1200 mg 
600 q5d 
5 
     Gabapentin 
2400 mg 
300 qod 
14 
            Pregabalin 
300 mg 
75 mg q3d 
9 
Opioid 
 
 
 
Methadone 
15 mg 
5 mg q5d 
10 
Oxycodone IR/ER 
30 mg 
5 mg q3d 
15 
Hydrocodone IR/ER 
20 mg 
5 mg q3d 
9 
Tramadol 
200 mg 
50 mg q3d 
9 
ER = extended release 
IR = immediate release 
1Standard of care yet no combination regimen permitted 
2Dose-specific, time-varying taper after 2 doses Injectafer® (Ferric Carboxymaltose) vs. placebo to be initiated 
after the second dose of study drug 
3US Food and Drug Administration approval for RLS treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX IV: Amendment I Changes 
 
Amendment I Changes 
 
Title Page 
 
Original Wording 
Protocol Date 02 April 2014 
New Wording 
Protocol Date 02 April 2014 
Amendment  
SIGNATURES OF 
AGREEMENT  
FOR PROTOCOL 
Remove: Ariel Abreu, MD Medical Director, Pharmacovigilance 
Add: Syed Quadri, MD Medical Director, Pharmacovigilance 
 
Synopsis Study 
Design Original 
Wording 
This will be a double blinded, multi-center, randomized, placebo-controlled study. 
All subjects who meet the inclusion requirements and no exclusion criteria will 
qualify to enter up to a 14 day Screening Phase to get 600 eligible subjects for study 
drug treatment.  Eligible subjects will be randomized in a 1:1 ratio to receive 
Injectafer® or Placebo on Days 0 and 5. All treated subjects will be followed for 
efficacy and safety for 12 months.  Subjects will visit the clinic on Days 0 and 5 for 
treatment, and then on Days 14, 42 and 365. In between the clinic visits subjects will 
be contacted remotely (phone or email) on Days 28, 84, 126,168, 210, 252, 294 and 
336. The subject’s participation in the study will be for approximately 1 year from 
Day 0. 
Synopsis Study 
Design New 
Wording 
This will be a Phase III, double blinded, multi-center, randomized, placebo-
controlled study. All subjects who meet the inclusion requirements and no exclusion 
criteria will qualify to enter up to a 7 day Screening Phase to get 200 eligible subjects 
for study drug treatment.  Eligible subjects will be randomized in a 1:1 ratio to 
receive Injectafer® or Placebo on Days 0 and 5. All treated subjects will be followed 
for efficacy and safety for 12 months.  Subjects will visit the clinic on Days 0 and 5 
for treatment, and then on Days 14, 42, 168 and 365. In between the clinic visits 
subjects will be contacted remotely (phone or email) on Days 84,126, 210, 252, 294 
and 336. The subject’s participation in the study will be for approximately 1 year 
from Day 0.  
Synopsis Study 
Drug Treatment 
Original Wording 
The duration of treatment phase will be 5 days.  On Day 0 (start of Treatment Phase) 
Group A will receive a 750 mg undiluted blinded dose of IV Injectafer® at 
100mg/minute.  Group B will receive a blinded placebo (15 ml of Normal Saline 
[NS]) IV push at 2 ml/minute.  On Day 5 Group A will receive a 750 mg undiluted 
blinded dose of IV Injectafer® at 100mg/minute.  Group B will receive a blinded 
placebo (15ml of Normal Saline [NS]) IV push at 2 ml/minute. 
Synopsis Study 
Drug Treatment 
New Wording 
The duration of treatment phase will be 5 days.  On Day 0 (start of Treatment Phase) 
subjects will be randomized to receive either a 750 mg undiluted blinded dose of IV 
Injectafer® at 100mg/minute or a blinded Placebo (15 ml of Normal Saline [NS]) IV 
push at 2 ml/minute.  On Day 5 subjects will receive the same blinded treatment as 
given on Day 0. 
Synopsis New 
Wording 
Additional Treatment 
Post Day 42: Subjects may receive additional blinded study drug treatment after 
Day 42 at the discretion of the Investigator.  The subject will receive the same 
blinded study medication that they were previously randomized to receive.  Subjects 
will receive either a single blinded dose of either Injectafer® at 750 mg undiluted at 
100mg/minute or a Placebo (15 ml of Normal Saline [NS]) IV push at 2 ml/minute 
on two independent days separated by 5 days. Dosing days should mirror the original 
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treatment / follow-up period (dosing 5 days apart with follow-up visits 14 and 42 
Days post the first dose).   Eligible subject will have met the following requirements 
prior to receiving additional treatment: 
 IRLS score ≥ 15  
 TSAT < 45% (confirmation can be through a local laboratory) 
 Ferritin < 300 ng/mL  (confirmation can be through a local laboratory) 
No additional iron may be administered between Day 320 and the Day 365 visit. 
Rescue Medication 
Removed 
Intervention 
Original Wording 
Intervention and Relapse:   
Intervention is defined as the initiation or resumption of equivalent or increased 
treatment previously prescribed by a physician used to specifically relieve the 
symptoms of RLS following the subject’s assessment that the RLS symptoms are 
intolerable. Any subject who has an intervention will no longer be evaluated for 
efficacy starting at the time of the intervention, however these subjects will remain in 
the study and will be continued to be evaluated for safety.  
Relapse is defined as the prescribed treatment for the subject’s RLS symptom is at a 
lower dose than previously taken. Efficacy and safety evaluation will continue to be 
performed on all subjects who have relapsed. 
Intervention New 
Wording 
Intervention is defined as an increase or change in the treatment currently 
prescribed by a physician used to specifically relieve the symptoms of RLS 
following the subject’s assessment that the RLS symptoms are intolerable or the 
subject meets the criteria and qualifies for additional treatment with study drug.  Any 
subject who has an intervention will no longer be evaluated for efficacy starting at 
the time of the intervention, however these subjects will remain in the study and will 
be continued to be evaluated for safety. 
Inclusion Criteria 
Original Wording 
3. Subjects not currently receiving treatment, have RLS symptoms ≥ 5 nights 
per week for at least the past 3 months.  
4. A baseline score ≥ 15 on the IRLS Rating Scale. 
Inclusion Criteria 
New Wording 
3. Subjects should be on a stable (FDA approved) RLS treatment for at least 8 
weeks prior to screening. 
4. A score ≥ 15 on the IRLS Rating Scale at screening and on Day 0 prior to 
dosing. 
New Wording 
RLS 
  
Therapy:  
 
All subjects should be on a FDA approved RLS therapy.  The subject’s 
therapy should be stable for at least 8 weeks prior to screening.  These 
therapies should remain unchanged throughout the duration of the study.  If 
during the course of the study it becomes necessary to change or start new or 
additional therapy via physician decision these data points will be collected 
and the subject will no longer be evaluated for efficacy, but the subject will 
continue in the study for safety analysis.   
Study Endpoints in 
Synopsis and 
Section 8.4.2 
Original Wording 
The primary efficacy variable will be the proportion of patients rated as much or very 
much improved with the Clinical Global Impression (CGI) performed by Investigator 
(CGI-I) on Day 42.  The major secondary endpoints will be tested in a hierarchical 
order, that is, statistical significance for major secondary efficacy endpoint will be 
declared only if the primary efficacy test (CGI-I on Day 42) is statistically 
significant.  Because a hierarchical testing scheme is used, no adjustments of the 
alpha level will be needed at each stage of testing.  All tests will be done at an alpha 
≤ 0.05. 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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The major secondary efficacy endpoints in ranked order of testing include: 
1. International Restless Legs Syndrome (IRLS) Score change from baseline to 
Day 42 
2. Clinical Global Impression (CGI) performed by Subject (CGI-S) on Day 42 
3. RLS QOL measured by Restless Legs Syndrome – Quality of Life Instrument 
(RLS-QLI) change from baseline to Day 42 
4. Medical Outcome Study (MOS) Sleep Scale change from baseline to Day 42 
5. Fatigue Linear Analog Scale change from baseline to Day 42 
6. HADS  change from baseline to Day 42 
Other efficacy endpoints: 
1. Proportion of responders (any improvement) based on CGI-I at each time 
point 
2. IRLS total score change from baseline at each time point. 
3. Proportion of responders based on CGI-S at each time point 
4. RLS QOL scores change from baseline at each time point 
5. MOS Sleep scale total score change from baseline at each time point 
6. Fatigue Linear Analog Scale total score change from baseline at each time 
point 
7. HADS total score change from baseline at each time point 
8. Proportion of subjects required intervention for RLS and time to RLS 
intervention 
9. Proportion of subjects with relapse. 
The safety endpoints include: 
1. Incidence of treatment emergent adverse events, incidence of serious adverse 
events, and incidence of severe adverse events 
2. Change in clinical laboratory tests 
3. Change in vital signs    
Study Endpoints in 
Synopsis and 
Section 8.4.2 New 
Wording 
The co-primary efficacy variables will be IRLS total score change from baseline to 
Day 42 and the proportion of patients rated as much or very much improved with the 
Clinical Global Impression (CGI) performed by Investigator (CGI-I) on Day 42.   
The major secondary endpoints will be tested in a hierarchical order, that is, 
statistical significance for major secondary efficacy endpoint will be declared only if 
the primary efficacy test (IRLS and CGI-I on Day 42) is statistically significant.  
Because a hierarchical testing scheme is used, no adjustments of the alpha level will 
be needed at each stage of testing.  All tests will be done at an alpha ≤ 0.05. 
The major secondary efficacy endpoints in ranked order of testing include: 
1. Clinical Global Impression (CGI) performed by Subject (CGI-S) on Day 42 
2. Restless Legs Syndrome Quality of Life (RLS-QoL) change from baseline to 
Day 42 
3. Medical Outcome Study (MOS) Sleep Scale change from baseline to Day 42 
4. Fatigue Linear Analog Scale change from baseline to Day 42 
5. HADS  change from baseline to Day 42 
Other efficacy endpoints: 
1. Proportion of responders (any improvement) based on CGI-I at each time 
point 
2. IRLS total score change from baseline at each time point. 
3. Proportion of responders based on CGI-S at each time point 
4. RLS QOL scores change from baseline at each time point 
5. MOS Sleep scale total score change from baseline at each time point 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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6. Fatigue Linear Analog Scale total score change from baseline at each time 
point 
7. HADS total score change from baseline at each time point 
8. Augmentation Scale change between baseline and end of study (Day 365) 
9. Proportion of subjects require intervention for RLS  
10. Number of days from Day 5 to next dose of study drug. 
The safety endpoints include: 
1. Incidence of treatment emergent adverse events, incidence of serious adverse 
events, and incidence of severe adverse events 
2. Change in clinical laboratory tests 
3. Change in vital signs    
Screening Period 
and Sample Size 
Original Wording 
Screening Phase:  up to 14 days 
It is planned to enroll 600 subjects (300 per group) study sites in the US and other 
countries. 
Screening Period 
and Sample Size 
New Wording 
Screening Phase:  up to 7 days 
It is planned to enroll 200 subjects (100 per group) study sites in the US and other 
countries. 
Sample Size 
Estimates Original 
Wording 
Sample size estimates were based on the MITT population for Study VIT 5009.  The 
last observation carried forward (LOCF) and observed cases (OC) results on Day 28 
were used for the primary efficacy endpoint (CGI) and first ranked secondary 
endpoint (IRLS).  It is unclear how treatment differences on Day 42 results might 
differ from Day 28, apart from a higher dropout rate, but it is reasonable to assume 
that treatment differences will decrease.  Therefore, power calculations were based 
on smaller treatment differences and larger standard deviations. 
Primary efficacy endpoint (CGI): The smallest treatment difference on Day 28 was 
45% versus 15% of patients in the FCM and placebo groups, respectively, who 
reported much or very much improvement on the patient CGI (Tables 3.7.1.1 and 
3.7.2.1).  A sample size of 300/group provides >99% power.  A sample size of 
300/group has at least 95% power when the treatment difference is as small as 28% 
versus 15%. 
First ranked secondary endpoint (IRLS): The smallest treatment difference for 
change from baseline to Day 28 was 4.4 with a standard deviation of 8.5.  Given 
concerns that the treatment difference could decrease and variability increase at Day 
42, one standard error was subtracted from the treatment difference (4.4 – 1.8 = 2.6) 
and the standard deviation was rounded up to 9.  A sample size of 300/group 
provides 95% power under this scenario. 
Sample Size 
Estimates New 
Wording 
Sample size estimates were based on the MITT population for Study VIT 5009.  The 
last observation carried forward (LOCF) and observed cases (OC) results on Day 28 
were used for the primary efficacy endpoint (CGI) and first ranked secondary 
endpoint (IRLS).  It is unclear how treatment differences on Day 42 results might 
differ from Day 28, apart from a higher dropout rate, but it is reasonable to assume 
that treatment differences will decrease.  Therefore, power calculations were based 
on smaller treatment differences and larger standard deviations. 
Co-primary endpoint (IRLS): The smallest treatment difference for change from 
baseline to Day 28 was 4.4 with a standard deviation of 8.5.  A sample size of 
100/group provides 95% power under this scenario. 
Co-primary efficacy endpoint (CGI-I): The smallest treatment difference on Day 28 
was 45% versus 15% of patients in the FCM and placebo groups, respectively, who 
reported much or very much improvement on the patient CGI (Tables 3.7.1.1 and 
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3.7.2.1).  A sample size of 100/group provides >99% power.  A sample size of 
100/group has at least 90% power when the treatment difference is as small as 45% 
versus 22%. 
Section 3.2 Original 
Wording 
This will be a double blinded, multi-center, randomized, placebo-controlled study. 
All subjects who meet the inclusion requirements and no exclusion criteria will 
qualify to enter up to a 14 day Screening Phase to get 600 eligible subjects for study 
drug treatment.  Eligible subjects will be randomized in a 1:1 ratio to receive 
Injectafer® (Group A) or Placebo (Group B) on Days 0 and 5. All treated subjects 
will be followed for efficacy and safety for 12 months.  Subjects will visit the clinic 
on Days 0 and 5 for treatment, and then on Days 14, 42 and 365. In between the 
clinic visits subjects will be contacted remotely (phone or email) on Days 28, 84, 
126,168, 210, 252, 294 and 336. The subject’s participation in the study will be for 
approximately 1 year from Day 0.  
 Subjects in Group A will receive a 750 mg undiluted blinded dose of IV 
Injectafer® at 100mg/minute on Days 0 and 5.   
 Subjects in Group B will receive a blinded placebo (15 ml of Normal Saline 
[NS]) IV push at 2ml/minute on Days 0 and 5. 
After treatment on Days 0 and 5 subjects will visit the clinic on Days 14, 42and 365. 
In between the clinic visits subjects will be contacted remotely (phone or email) on 
Days 28, 84, 126, 168, 210, 252, 294 and 336.  Subjects will be considered to have 
reached the end of the study for efficacy when intervention is required for their RLS 
symptoms; those subjects will continue the follow-up phase for safety.  Subjects who 
relapse will continue to stay in the follow-up phase for efficacy and safety. 
Section 3.2 New 
Wording 
This will be a Phase III, double blinded, multi-center, randomized, placebo-
controlled study. All subjects who meet the inclusion requirements and no exclusion 
criteria will qualify to enter up to a 7 day Screening Phase to get 200 eligible subjects 
for study drug treatment.  Eligible subjects will be randomized in a 1:1 ratio to 
receive either Injectafer® or IV Placebo on Days 0 and 5. All treated subjects will be 
followed for efficacy and safety for 12 months.  Subjects will visit the clinic on Days 
0 and 5 for treatment, and then on Days 14, 42, 168 and 365. In between the clinic 
visits subjects will be contacted remotely (phone or email) on Days 84, 126, 210, 
252, 294 and 336. The subject’s participation in the study will be for approximately 1 
year from Day 0.  
 Subjects will receive either a 750 mg undiluted blinded dose of IV 
Injectafer® at 100mg/minute or a blinded  IV Placebo (15 ml of 
Normal Saline [NS]) IV push at 2ml/minute on Days 0 and 5.   
After treatment on Days 0 and 5 subjects will visit the clinic on Days 14, 42, 168 and 
365. In between the clinic visits subjects will be contacted remotely (phone or email) 
on Days 84, 126, 210, 252, 294 and 336.  Subjects will be considered to have reached 
the end of the study for efficacy when intervention is required for their RLS 
symptoms; those subjects will continue the follow-up phase for safety.   
Schedule of Event 
Updated to reflect changes noted 
Section 4.1 Original 
Wording 
Approximately six  hundred  (600) subjects (300 per group) who have given written 
informed consent with a diagnosis of Restless Leg Syndrome (RLS) who fulfill the 
inclusion criteria, do not meet any of the exclusion criteria will be randomized into 
Group A (Injectafer®) or Group B (Placebo).    
Section 4.1 New 
Wording 
Approximately two  hundred  (200) subjects (100 per group) who have given written 
informed consent with a diagnosis of Restless Leg Syndrome (RLS) who fulfill the 
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inclusion criteria, do not meet any of the exclusion criteria will be randomized to receive 
Injectafer® or IV Placebo.    
Section 4.3 Original 
Wording 
Subjects that meet all inclusion requirements and no exclusionary criteria will be 
offered participation in this approximately 12 ½ month study. Subjects will be 
randomized in a 1:1 ratio via an Electronic Data Capture (EDC) system to receive 
either a blinded dose of IV Injectafer®  (Group A) or a blinded dose of Placebo 
(Group B).  
 Subjects in Group A will receive a 750 mg undiluted blinded dose of IV 
Injectafer® at 100mg/minute on Days 0 and 5.   
 Subjects in Group B will receive a blinded placebo (15ml of Normal Saline 
[NS]) IV push at 2ml/minute on Days 0 and 5. 
Section 4.3 New 
Wording 
Subjects that meet all inclusion requirements and no exclusionary criteria will be 
offered participation in this approximately 12 ½ month study. Subjects will be 
randomized in a 1:1 ratio via an Interactive Web Response/Electronic Data Capture 
(IWR/EDC) system to receive either a blinded dose of IV Injectafer® or a blinded 
dose of Placebo. 
 Subjects will receive either a 750 mg undiluted blinded dose of IV 
Injectafer® at 100mg/minute  or a blinded IV Placebo (15ml of Normal 
Saline [NS]) IV push at 2ml/minute on Days 0 and 5.   
Section 4.5 Original 
Wording 
Intervention and Relapse 
Intervention is defined as the initiation or resumption of equivalent or increased 
treatment previously prescribed by a physician used to specifically relieve the 
symptoms of RLS following the subject’s assessment that the RLS symptoms are 
intolerable. Non-narcotic analgesics will not be considered an intervention.   Any 
subject who has an intervention will no longer be evaluated for efficacy starting at 
the time of the intervention, however these subjects will remain in the study and will 
be continued to be evaluated for safety.  
Relapse is defined as the prescribed treatment for the subject’s RLS symptom is at a 
lower dose than previously taken. Efficacy and safety evaluation will continue to be 
performed on all subjects who have relapsed. 
Section 4.5 New 
Wording 
Intervention  
Intervention is defined as an increase or change in the treatment currently 
prescribed by a physician used to specifically relieve the symptoms of RLS following 
the subject’s assessment that the RLS symptoms are intolerable or the subject meets 
the criteria and qualifies for additional treatment with study drug . Non-narcotic 
analgesics will not be considered an intervention.   Any subject who has an 
intervention will no longer be evaluated for efficacy starting at the time of the 
intervention, however these subjects will remain in the study and will be continued to 
be evaluated for safety.  
Section 5.3 Original 
Wording 
On Days 0 and 5: 
o Group A will receive a 750 mg undiluted blinded dose of IV Injectafer® at 
100mg/minute.  
o Group B will receive a blinded placebo (15 ml of Normal [NS]) IV push at 
2ml/minute.   
Section 5.3 New 
Wording 
On Days 0 and 5: 
o Subjects will either receive a 750 mg undiluted blinded dose of IV 
Injectafer® at 100mg/minute or a blinded Placebo (15 ml of Normal [NS]) IV 
push at 2ml/minute.  
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Section 5.6 Original 
Wording 
Concomitant medications along with their route of administration and duration must 
be recorded in the electronic case report form (eCRF).  No additional iron 
preparations (IV iron from 6 weeks prior to screening or oral iron including 
multivitamins with iron, from time of consent), will be allowed.  No blood 
transfusions, erythropoiesis stimulating agents will be allowed. Anti-depressants, 
anti-seizure, sleep medications, dopamine agonists, benzodiazepines, narcotics or 
other RLS treatments are not permitted for the duration of the study. Non-
narcotic analgesics are permitted.     
No prophylactic medications may be administered prior to Injectafer®  
administration without prior approval from Luitpold Pharmaceuticals, Inc. 
Section 5.6 New 
Wording 
Concomitant medications along with their route of administration and duration must 
be recorded in the electronic case report form (eCRF).  No additional iron 
preparations (IV iron from 6 weeks prior to screening or oral iron including 
multivitamins with iron, from time of consent), will be allowed.  No blood 
transfusions, erythropoiesis stimulating agents will be allowed. Once a subject is 
randomized no additional anti-depressants, anti-seizure, sleep medications, 
dopamine agonists, benzodiazepines, narcotics or other RLS treatments are not 
permitted for the duration of the study. Non-narcotic analgesics are permitted.     
All subjects should be on a FDA approved RLS therapy.  The subject’s therapy 
should be stable for at least 8 weeks prior to screening.  These therapies should 
remain unchanged throughout the duration of the study.  If during the course of the 
study it becomes necessary to change or start new or additional therapy via physician 
decision these data points will be collected and the subject will no longer be 
evaluated for efficacy, but the subject will continue in the study for safety analysis.  
Section 6.2 
Additional Wording 
 All prior medications, to include current treatments for RLS  
 RLS treatment stability 
 Medical Outcome Study (MOS) Sleep Scale (range 0-100)  
 Restless Legs Syndrome Quality of Life (RLS-QoL)  
 Fatigue Linear Analog Scale 
 HADS  
 Augmentation Scale 
Section 6.3.1 
Additional Wording 
 RLS treatment stability 
 Subject will complete the following: 
 Restless Legs Syndrome Quality of Life (RLS-QoL)  
Sections 6.3.2 and 
6.3.4 Additional 
Wording 
 Concomitant medications, to include RLS treatment stability 
Sections 6.3.3, 
6.3.3.1 and 6.3.3.2 
Additional wording 
Add Day 168 as a face to face visit 
Concomitant medications, to include RLS treatment stability 
Restless Legs Syndrome Quality of Life (RLS-QoL) 
Section 6.3.5 New 
Wording 
Additional Treatment 
Post Day 42: Subjects may receive additional blinded study drug treatment after 
Day 42 at the discretion of the Investigator.  The subject will receive the same 
blinded study medication that they were previously randomized to receive.  Subjects 
will receive either a single blinded dose of either Injectafer® at 750 mg undiluted at 
100mg/minute or a Placebo (15 ml of Normal Saline [NS]) IV push at 2 ml/minute 
on two independent days separated by 5 days. Dosing days should mirror the original 
treatment / follow-up period (dosing 5 days apart with follow-up visits 14 and 42 
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Days post the first dose).   Eligible subject will have met the following requirements 
prior to receiving additional treatment: 
 IRLS score ≥ 15  
 TSAT < 45% (confirmation can be through a local laboratory) 
 Ferritin < 300 ng/mL  (confirmation can be through a local laboratory) 
No additional iron may be administered between Day 320 and the Day 365 visit. 
If the subject qualifies to receive additional dosing the following will be required 
/collected: 
 Un-blinded personnel will perform dosing assignment 
A separate Dosing Record will be maintained by the un-blinded study personnel 
responsible for preparation and administration of the study drug. See Section 5.0 for 
details of study drug administration, blinding and precautions. 
The Dosing Record will include: 
 Starting and stopping time of study drug administration 
 Total dose in mg and ml of Injectafer®  administered (i.e. 750 mg / 15 
ml) 
 Total volume of Normal Saline administered (15 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. 
Section 6.3.6 
Additional Wording 
 Concomitant medications, to include RLS treatment stability 
 Subject will independently complete the following:  
 Restless Legs Syndrome Quality of Life (RLS-QoL)  
 Augmentation Scale 
Section 8.1 
Additional Wording 
Co-primary endpoint (IRLS): The smallest treatment difference for change from 
baseline to Day 28 was 4.4 with a standard deviation of 8.5.  A sample size of 
100/group provides 95% power under this scenario. 
Co-primary efficacy endpoint (CGI-I): The smallest treatment difference on Day 28 
was 45% versus 15% of patients in the FCM and placebo groups, respectively, who 
reported much or very much improvement on the patient CGI (Tables 3.7.1.1 and 
3.7.2.1).  A sample size of 100/group provides >99% power.  A sample size of 
100/group has at least 90% power when the treatment difference is as small as 45% 
versus 22%. 
Section 8.4.1 
Original Wording 
The primary efficacy variable will be the proportion of patients rated as much or very 
much improved with the Clinical Global Impression (CGI) performed by Investigator 
(CGI-I) on Day 42.  
Section 8.4.1 New 
Wording 
The co-primary efficacy variables will be IRLS total score change from baseline to  
Day 42 and the proportion of patients rated as much or very much improved with the 
Clinical Global Impression (CGI) performed by Investigator (CGI-I) on Day 42.  
Baseline values used for evaluation will be defined as the latest value obtained prior 
to the first dose of study drug.  For those subjects with only one value prior to dosing, 
the single value will be used as baseline.  
Section 8.5 Original 
Wording 
Categorical variables will be summarized with the number and percent of subjects in 
each treatment group with the characteristic.  Quantitative variables will be 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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summarized with the mean, median, standard deviation, minimum value, and 
maximum value.  Baseline will be defined as the last value obtained before 
randomization.  
Treatment group differences for CGI scores will be assessed with the Cochran-
Mantel-Haenszel test using study site as the stratification factor.  Treatment group 
differences for changes in total and domain scores of rating scales (eg, IRLS) will be 
assessed with the analysis of covariance with fixed factors for study site and 
treatment and with baseline score as a covariate.  Treatment differences for 
proportions will be assessed with the continuity-corrected chi-square test.   
The primary imputation method for the CGI and change in total/domain scores will 
be LOCF.  For the proportion of subjects with relapse, subjects who discontinue or 
complete the study before an intervention will be considered as not having 
experienced relapse. Sensitivity analyses will assess the impact of missing values on 
inferences. 
Time from first dose of randomized study drug to intervention will be analyzed with 
the log-rank test. Subjects who discontinue or complete the study before an 
intervention will be censored at their last study visit. 
Section 8.5 New 
Wording 
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.  
Treatment group differences for CGI scores will be assessed with the Cochran-
Mantel-Haenszel test using study site as the stratification factor.  Treatment group 
differences for changes in total and domain scores of rating scales (eg, IRLS) will be 
assessed with the analysis of covariance with fixed factors for study site and 
treatment and with baseline score as a covariate.  Treatment differences for 
proportions will be assessed with the continuity-corrected chi-square test.   
The primary imputation method for the CGI and change in total/domain scores will 
be LOCF.  Sensitivity analyses will assess the impact of missing values on 
inferences. 
Time from Day 5 to the next dose of study drug will be analyzed with the log-rank 
test. Subjects who discontinue or complete the study before an intervention will be 
censored at their last study visit. 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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APPENDIX V: Amendment II Changes 
 
Amendment II Changes 
 
Title Page: 
 
Original Wording 
Protocol Date 05 August 2014 
Amendment I 
New Wording 
Protocol Date 05 January 2015 
Amendment II 
Exclusion Criteria 
 
Original Wording 
1 RLS 2° to other CNS disease or injury.  Such disorders include: peripheral 
neuropathy, neurodegenerative disorders and multiple sclerosis.    
New Wording 
1. RLS 2° to other CNS disease or injury.  Such disorders include: peripheral 
neuropathy and neurodegenerative disorders.    
Original Wording 
2. RLS 2  ͦ Chronic Kidney Disease  
New Wording 
2. Stage 4 – 5 CKD, subjects on dialysis or anticipated to start dialysis while 
participating in this study. 
Original Wording 
3.  Any pain related (e.g., frequent muscle cramps, myalgia, fibromyalgia) or 
sleep related disorders (e.g. sleep apnea, which may confound the outcome 
measures.   
 
New Wording 
3. Any pain related (e.g., frequent muscle cramps, myalgia, fibromyalgia) or 
sleep related disorders (e.g. sleep apnea, unless on stable CPAP) which may 
confound the outcome measures.   
 
Exclusion Criteria 
 
Original Wording 
17. AST or ALT greater than the upper limit of normal. 
New Wording: 
17. AST or ALT greater than 2 times the upper limit of normal. 
Removed 
11. Active inflammatory arthritis (e.g. rheumatoid arthritis, SLE). 
Removed 
14. Severe  peripheral vascular disease with significant skin changes 
Removed 
       21. Calcium or phosphorous outside the normal range. 
Original Wording 
All subjects should be on a FDA approved RLS therapy.  The subject’s therapy 
should be stable for at least 8 weeks prior to screening.  These therapies should 
remain unchanged throughout the duration of the study.  If during the course of the 
study it becomes necessary to change or start new or additional therapy via physician 
decision these data points will be collected and the subject will no longer be 
evaluated for efficacy, but the subject will continue in the study for safety analysis.   
New Wording 
All subjects should be on a FDA approved RLS therapy.  FDA approved therapies 
used outside of the United States are permitted at doses approved in the applicable 
country of use.   The subject’s therapy should be stable for at least 8 weeks prior to 
screening, unless the dose has been decreased.  If the dose has been decreased during 
the 8 weeks prior to screening that reduced dose should be stable for at least 4 weeks 
prior to screening. These therapies should remain unchanged throughout the duration 
of the study.  If during the course of the study it becomes necessary to change or start 
new or additional therapy via physician decision these data points will be collected 
and the subject will no longer be evaluated for efficacy, but the subject will continue 
in the study for safety analysis.   
 
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Procedures: 
Screening, Day 0, 5, 
42, 168, and 365 
 
Added: 
 C-SSRS 
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 
 
List of 
Abbreviations 
 
Added 
CPAP Continuous Positive Airway Pressure 
Schedule of Events 
 
Added 
C-SSRS:   Screening, Days 5, 42, 168 and 365 
₅ IRLS, RLS QoL, MOS Sleep Scale, Fatigue Severity Scale, HADS and C-SSRS may 
be completed on Day 0 prior to randomization. 
Other Efficacy 
Endpoints 
 
Original Wording: 
2. IRLS total score change from baseline at each time point. 
 
New Wording 
2. IRLS total score change from baseline at each time point and by baseline 
RLS treatment group. 
 
Added Wording: 
4. CGI-I and CGI-S scores at each time point and by baseline RLS treatment 
group 
Safety Endpoints 
 
Added Wording 
4. Change in C-SSRS 
 
Governance 
Committee: Data 
Safety Monitoring 
Board 
 
Added Wording 
The DSMB will be composed of approximately 3-5 senior academic individuals, 
including the DSMB Chair. They will have high-level expertise in neurology, 
hematology, cardiology and/or statistics. A senior statistician assigned to the trial 
from the group performing data management services for this trial will oversee the 
provision of interim data reports for use by the DSMB. The data management group 
for this trial will transfer pre-agreed datasets to the DSMB. During the Open Session 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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of the DSMB meetings, the Study Chair or Luitpold representatives may present 
updates on the trial status or the safety profile of Ferric Carboxymaltose, but will not 
be privy to discussions of the data conducted during the Closed Sessions and will not 
vote. Proceedings and minutes of the Closed Session will be held in strict confidence 
and will not be shared outside the DSMB while the trial is ongoing. 
 
The DSMB will be responsible for the interests of the patients and, to this end, will 
undertake reviews of the safety data. The DSMB will have access to an agreed subset 
of the study data as listed in the DSMB charter (updated as necessary during the trial) 
throughout the study duration. In addition, the DSMB will evaluate the data 
approximately (as outlined in the Charter) either by face to face meeting or 
teleconference.   The DSMB will determine if it believes the trial should be 
terminated early because clear evidence of a significant safety concern exists. 
 
If the DSMB finds it necessary to recommend actions regarding interruption of the 
study or changes to the protocol based on medical rationale that would make it 
unethical to continue the study in its present form, those recommendations will be 
forwarded to the Study Chair and Sponsor. The details of the DSMB's functions and 
the early stopping rules will be delineated in a separate DSMB charter. 
 
APPENDIX II: RLS 
Assessment Tools 
 
 
Added 
9. Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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APPENDIX VI: Amendment III Changes 
 
 
Title Page: 
 
Original Wording: 
AMENDMENT II DATE: 05 January 2015 
 
New Wording: 
AMENDMENT III DATE: 13 JULY 2015 
SIGNATURES OF 
AGREEMENT  
FOR PROTOCOL 
NEW LANGUAGE ADDED:  
Linda Mundy, MD, PhD 
Sr. Medical Director, Clinical Development  
 
 
Updates throughout 
the Protocol 
Day 28 added to the remote contact by phone 
Email deleted from remote contact visits 
RLS-QoL changed to RLS-QLI 
Normal Saline [NS] changed to Normal Sterile Saline [NSS] 
Hospital Anxiety and Depression Scale (HADS) removed 
IWR/EDC changed to IRT (Interactive Response Technologies)  
C-SSRS: The Columbia-Suicide Severity Rating Scale will be used throughout the study 
to assess the subject’s suicide ideation or behavior.  This scale is an assessment tool, it is 
ultimately the Investigators responsibility to evaluate each subject’s risk and treat as 
appropriate. 
Minor spelling and grammatical updates were made throughout the protocol 
Study Synopsis Study 
Design: 
 
Original Wording 
Eligible subjects will be randomized in a 1:1 ratio to receive Injectafer® or 
Placebo on Days 0 and 5. 
In between the clinic visits subjects will be contacted remotely (phone or email) on 
Days 84,126, 210, 252, 294 and 336. 
New Wording 
 All eligible subjects will be stratified at baseline by RLS medication-related 
augmentation (no augmentation, uncertain augmentation, definitive augmentation).  
Randomization will occur in a 1:1 ratio within each stratum to receive Injectafer® 
or Placebo on Days 0 and 5.   
In between the clinic visits subjects will be contacted remotely (phone) on Days 
28, 84,126, 210, 252, 294 and 336. 
New  Procedures  
Added 
Tapering Algorithms of RLS Treatment Regimens:  Each subject will be 
tapered from the prescribed RLS medication post treatment beginning on Day 5.   
The tapering regimen will depend on the subject’s current medication and dosing 
(see Appendix III).  During the tapering period and through Day 42 subjects will 
continue to keep a RLS diary to record their symptoms related to their RLS.    
Additional Treatment 
New Wording 
throughout protocol 
Subjects who have not had an intervention may receive additional blinded study 
drug treatment at the discretion of the Investigator after Day 42. An intervention is 
defined as either 1) an increase in dosage from the RLS medication at study entry, 
2) the initiation of a new RLS medication, or 3) resumption of the previous 
medication prescribed for RLS.  Dosing days should mirror the original treatment / 
follow-up period (dosing 5 days apart with safety follow-up visits, to include 
laboratory assessments only, on 14 and 42 Days post the first dose).   
Intervention New 
Wording: 
 
Original Wording 
Intervention is defined as an increase or change in the treatment currently 
prescribed by a physician used to specifically relieve the symptoms of RLS 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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following the subject’s assessment that the RLS symptoms are intolerable or the 
subject meets the criteria and qualifies for additional treatment with study drug.  
Any subject who has an intervention will no longer be evaluated for efficacy 
starting at the time of the intervention, however these subjects will remain in the 
study and will be continued to be evaluated for safety. 
New Wording 
Intervention is defined as 1) an increase in dosage from the RLS medication at 
study entry, 2) the initiation of a new RLS medication, or 3) resumption of the 
previous medication prescribed for RLS. Any subject who has an intervention will 
no longer be evaluated for efficacy starting at the time of the intervention, however 
these subjects will remain in the study and be evaluated for safety.  
 
Inclusion Criteria 
Updated 
 
Original Wording 
1. Male or female subjects ≥18, able to give 
informed consent to the study 
New Wording 
1. Male or female subjects ≥18 years of age or 
older, able and willing to give informed consent 
to the study 
Original Wording 
3. Subjects should be on a stable (FDA approved) RLS treatment for at least 8 
weeks prior to screening. (See RLS Therapy) 
 
New Wording 
3. Subjects should be on monotherapy for RLS.  Treatment should be stable 
for at least 8 weeks prior to screening. (See approved RLS 
Therapies/Regimen in Appendix III). 
 
Exclusion Criteria 
Updated 
 
Original Wording 
1. RLS 2° to other CNS disease or injury.  Such disorders include: peripheral 
neuropathy and neurodegenerative disorders.    
19. Known positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody 
(HCV) with evidence of active hepatitis (i.e., AST/ALT greater than the 
upper limit of normal). 
 
New Wording 
1. RLS 2° to other disease or injury.   
Added new #5 
5. Subjects with multiple sclerosis.   
21. 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 upper limit of normal). 
Original Wording 
12. Current or acute or chronic infection other than viral upper respiratory tract 
infection 
New Wording 
12. Current, active, acute or chronic infection other than viral upper respiratory 
tract infection 
Original Wording 
25. Any other pre-existing laboratory abnormality, medical condition or 
disease which in view of the investigator participation in this study may put the 
subject at risk. 
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New Wording 
25. Any other pre-existing laboratory abnormality, medical condition or 
disease which per the investigator may put the subject at risk if they participate 
in the study. 
Original Wording 
26. Subject unable to comply with the study requirements 
New Wording 
26.  Subject unable or unwilling to comply with the study requirements 
RLS Therapy 
 
Original Wording 
All subjects should be on a FDA approved RLS therapy.  FDA approved therapies 
used outside of the United States are permitted at doses approved in the applicable 
country of use.   The subject’s therapy should be stable for at least 8 weeks prior to 
screening, unless the dose has been decreased.  If the dose has been decreased 
during the 8 weeks prior to screening that reduced dose should be stable for at 
least 4 weeks prior to screening. These therapies should remain unchanged 
throughout the duration of the study.  If during the course of the study it becomes 
necessary to change or start new or additional therapy via physician decision these 
data points will be collected and the subject will no longer be evaluated for 
efficacy, but the subject will continue in the study for safety analysis.   
New Wording 
All subjects should be on a stable monotherapy regimen (see Appendix III) for at 
least 8 weeks prior to screening. These therapies should remain unchanged until 
the tapering process begins post Day 5 treatment with study drug.  An algorithm of 
RLS medication taper regimens is provided (Appendix III).  If and when the 
subject is tapered off the RLS medication, the goal will be for the subject to 
remain off medication for the duration of the study. If during the course of the 
study it becomes necessary to change or start new or additional therapy via subject 
and physician decision, these data points will be collected and the subject will no 
longer be evaluated for efficacy, but the subject will continue in the study for 
safety analysis.   
 
Study End Points 
New language added: Change in C-SSRS 
 
Original Wording 
Restless Legs Syndrome Quality of Life (RLS-QoL) change from baseline to Day 
42 
RLS-QoL scores change from baseline at each time point 
Augmentation Scale change between baseline, Day 42 and end of study (Day 365) 
 
New Wording 
Augmentation Scale change between baseline, Day 42,  Day 168 and end of study 
(Day 365) 
 
 
Blinding 
New language added: Assessment of blinded laboratory parameters (iron indices 
and phosphorus). 
Number of Subjects 
 
Original Wording 
Enrollment is planned for 200 subjects (100 per group) at study sites in the Unites 
States (US) and in Eastern Europe 
New Wording 
Enrollment is planned for 200 subjects (100 per group) at study sites in the Unites 
States (US) and in Eastern Europe (EU) 
Statistical Methods 
 
Original Wording 
Treatment group differences for CGI scores will be assessed with the Cochran-
Mantel-Haenszel test using study site as the stratification factor.  Treatment group 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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differences for changes in total and domain scores of rating scales (eg, IRLS) will 
be assessed with the analysis of covariance with fixed factors for study site and 
treatment and with baseline score as a covariate.  Treatment differences for 
proportions will be assessed with the continuity-corrected chi-square test. 
New Wording 
Treatment group differences for CGI scores will be assessed with the Cochran-
Mantel-Haenszel test using region (US, Europe) as the stratification factor.  
Treatment group differences for changes in total and domain scores of rating 
scales (eg, IRLS) will be assessed with the analysis of covariance with fixed 
factors for region (US, Europe) and treatment and with baseline score as a 
covariate.  Treatment differences for proportions will be assessed with the 
continuity-corrected chi-square test.   
 
1.3: The Role of Iron 
Treatment in RLS 
Updated 1.3: The Natural History, Disease Understanding, and Treatment 
Guidance for Restless Legs Syndrome (RLS) 
 
Original Wording 
Restless Legs Syndrome (RLS) is a common under-diagnosed disorder occurring 
in 2% to 15% of the general population depending on the source of information.  It 
is reported principally in the elderly but may occur at any time.  As early as the 
1950’s, iron was thought to play a role in the onset and treatment of Restless Legs 
Syndrome (RLS), first described by Ekbom.1 Nordlander first associated anemia 
from various causes (gastric ulcer, leukemia and chronic nephritis) with the 
development of restless legs that disappeared following treatment with blood 
transfusion.2  More recent studies have found RLS to be associated with other 
conditions where iron is limiting such as in pregnancy3, hemodialysis4, and 
frequent blood donations.5 It was also noted that the incidence of the condition 
increased from the general population to more than 20% in these patient 
populations.  
 
New Wording 
Restless legs syndrome (RLS), is a circadian disorder of sensory-motor integration 
that may be related to dysregulation of iron transport across the blood-brain 
barrier.1      Epidemiologic data suggest geographic variation in the prevalence of 
RLS, with estimates ranging from 2-10% in general populations, and as high as 20 
% in certain target populations with secondary RLS/.2-5    Pharmacologic therapy 
for primary RLS are broadly based on short-term randomized, controlled trials that 
enrolled highly-selected patient populations with long-term, high-moderate to very 
severe symptoms.6-8 Current treatment regimens for RLS include dopamine 
agonists, calcium channel alpha-2-delta (α2δ) ligands, opioids, and 
benzodiazepines.9-11 While these medications reduce RLS symptoms and improve 
outcomes related to sleep -specific quality of life, adverse effects and treatment 
withdrawal due to adverse effects have been common.6  Medication tolerance, 
augmentation, and symptom, if not worsening of symptoms, are concerns with 
sustained RLS treatment effect.9,11-13 Evidence-based guidelines and practice 
support investigations that target trials of intravenous (IV) iron in RLS.9     
 
Original Wording 
Eligible subjects will be randomized in a 1:1 ratio to receive either Injectafer® or 
IV Placebo on Days 0 and 5. 
New Wording 
All eligible subjects will be stratified at baseline by RLS medication-related 
augmentation (no augmentation, uncertain augmentation, definitive augmentation) 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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on standard of care RLS therapy. Subjects will be randomized in a 1:1 ratio within 
each stratum to receive either Injectafer® or IV Placebo on Days 0 and 5. 
Original Wording 
The combined IRLS data from these RLS trials was not associated with clear 
benefit (mean difference in scores of -3.79, 95% CI: -7.68 to 0.10, p = 0.06), yet 
the placebo-controlled trial of FCM and of oral iron (in low-normal ferritin 
subjects) reported significant treatment benefit compared placebo.33,35   
New Wording 
The combined IRLS data from these RLS trials was not associated with clear 
benefit (mean difference in scores of -3.79, 95% CI: -7.68 to 0.10, p = 0.06), yet 
the placebo-controlled trial of FCM and of oral iron (in low-normal ferritin 
subjects) reported significant treatment benefit compared to placebo.33,35   
1.4.3 Injectafer® 
Human Experience: 
Marketed Use and the 
RLS indicator 
 
Original Wording 
The drug is indicated for the treatment of IDA in adult populations who have 
intolerance to oral iron or have had unsatisfactory responses to oral iron or non-
dialysis depended 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®. 
New Wording 
The drug is indicated for the treatment of IDA in adult populations who have 
intolerance to oral iron or have had unsatisfactory responses to oral iron or 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®. 
Table 3.2.1: Schedule 
of Events 
Table and footnotes have been updated 
4.3: Subject 
Assignment and 
Randomization 
Process 
 
Original Wording 
Subjects that meet all inclusion requirements and no exclusionary criteria will be 
offered participation in this approximately 12 ½ month study. Subjects will be 
randomized in a 1:1 ratio via an Interactive Web Response/Electronic Data 
Capture (IWR/EDC) system to receive either a blinded dose of IV Injectafer® or a 
blinded dose of Placebo. 
 
New Wording 
Subjects that meet all inclusion requirements and no exclusionary criteria will be 
offered participation in this approximately 12 month study. Subjects will be 
stratified by augmentation (no augmentation, uncertain augmentation, definitive 
augmentation) and randomized in a 1:1 ratio via an IRT system to receive either a 
blinded dose of IV Injectafer® or a blinded dose of Placebo. 
New section added 4.4: 
Tapering Procedures 
Each subject will be tapered from the current RLS medication, post treatment on 
Day 5.   The tapering regimen will depend on the subject’s current medication and 
dosing (see tapering schedule in Appendix III).  During the tapering period and 
through Day 42 subjects will be asked to keep an RLS diary to record their 
progress.   
4.6: Intervention 
 
Original Wording 
Intervention is defined as an increase or change in the treatment currently 
prescribed by a physician used to specifically relieve the symptoms of RLS 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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following the subject’s assessment that the RLS symptoms are intolerable or the 
subject meets the criteria and qualifies for additional treatment with study drug. 
Non-narcotic analgesics will not be considered an intervention.   Any subject who 
has an intervention will no longer be evaluated for efficacy starting at the time of 
the intervention, however these subjects will remain in the study and will be 
continued to be evaluated for safety. 
New Wording 
Intervention is defined as either 1) an increase in dosage from the RLS 
medication at study entry, 2) the initiation of a new RLS medication, or 3) 
resumption of the previous medication prescribed for RLS. Any subject who has 
an intervention will no longer be evaluated for efficacy starting at the time of the 
intervention, however these subjects will remain in the study and will be continued 
to be evaluated for safety. 
 
5.2.1.1: Unblinded 
Personnel 
New language added: Assessment of blinded laboratory parameters (iron indices 
and phosphorus). 
 
5.2.1.2: Blinded 
Personnel 
 
Original Wording 
The blinding will be maintained until the study is complete and the database has 
been locked. In the event the subject’s well being requires knowledge of the 
treatment assignment, the blind may be broken. The investigator should make 
every effort to contact the sponsor’s Medical Director or designee prior to un-
blinding. If a subject’s treatment assignment is un-blinded, the sponsor must be 
contacted immediately via telephone. 
 
New Wording: 
The blinding will be maintained until the study is complete and the database has 
been locked. 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’s recommended to contact 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. 
5.3: Study Drug 
Administration 
 
Original Wording 
Subjects will either receive a 750 mg undiluted blinded dose of IV Injectafer® at 
100mg/minute or a blinded Placebo (15 ml of Normal [NS]) IV push at 
2ml/minute. 
New Wording 
On Days 0 and 5, subjects will either receive a 750 mg undiluted blinded dose of 
IV Injectafer®  at 100mg/minute or a blinded Placebo (15 ml of Normal Saline 
[NS]) IV push at 2ml/minute.  
5.4 IV Iron 
Precautions 
 
Original Wording 
 Sitting heart rate and blood pressure will be assessed pre-, immediately 
post, and 30 minutes post administration.  If the subject is an outpatient, 
they will be discharged from the site by the Investigator only if there are no 
significant signs or symptoms 30 minutes after the administration is 
completed. 
 
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New Wording 
 Sitting heart rate and blood pressure will be assessed pre-dosing, 
immediately post, and 30 minutes post administration.  If the subject is an 
outpatient, they will be discharged from the site by the Investigator only if 
there are no significant signs or symptoms 30 minutes after the 
administration is completed. 
 
Original Wording 
In the event a serious acute reaction is seen, the site must have the capability to 
provide appropriate resuscitation measures.  These may include IV NS, IV 
epinephrine, steroids, and/or antihistamines 
New Wording 
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 
5.6: Concomitant 
Medication 
 
Original Wording 
All subjects should be on a FDA approved RLS therapy.  FDA approved therapies 
used outside of the United States are permitted at doses approved in the applicable 
country of use.   The subject’s therapy should be stable for at least 8 weeks prior to 
screening, unless the dose has been decreased.  If the dose has been decreased 
during the 8 weeks prior to screening that reduced dose should be stable for at least 
4 weeks prior to screening. These therapies should remain unchanged throughout 
the duration of the study.  If during the course of the study it becomes necessary to 
change or start new or additional therapy via physician decision these data points 
will be collected and the subject will no longer be evaluated for efficacy, but the 
subject will continue in the study for safety analysis. 
New Wording 
All subjects should be on a stable RLS monotherapy regimen (see Appendix III) 
for for at least 8 weeks prior to screening. These therapies should remain 
unchanged until the tapering process begins post Day 5 treatment with study drug.  
Once the subject is tapered off  RLS medication (Appendix III) the subject should 
stay removed from medication for the duration of the study.  If during the course 
of the study it becomes necessary to restart therapy via physician decision, these 
data points will be collected and the subject will no longer be evaluated for 
efficacy, but the subject will continue in the study for safety analysis.   
6.2: Screening 
 
Original Wording 
Each subject who qualifies for inclusion will undergo the following clinical 
evaluations to confirm eligibility for the study  
 Obtain screening number from IWR/EDC system 
 Medical history, including prior iron therapy use  
 All prior medications, to include current treatments for RLS  
 RLS treatment stability 
 Subject will complete the Subjects IRLS scale 
 Medical Outcome Study (MOS) Sleep Scale (range 0-100)  
 Restless Legs Syndrome Quality of Life (RLS-QoL)  
 Fatigue Linear Analog Scale 
 HADS  
 Augmentation Scale 
C-SSRS:  
Physical exam 
 Vital signs (sitting heart rate and blood pressure) 
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 Weight without shoes 
 Blood samples for hematology, chemistries, iron indices and transferrin 
receptor, fasting if indicated. A serum pregnancy test will be performed on 
female subjects.  
 All oral iron products will be discontinued on the day of the first screening visit   
 
Subjects who do not meet the entry criteria should be entered into the IWR/EDC 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. 
 
New Wording 
Each subject who qualifies for inclusion will undergo the following clinical 
evaluations to confirm eligibility for the study  
 Obtain screening number from IRT system 
 Medical history, including prior iron therapy use  
 All prior medications, to include current treatments for RLS and side effects 
associated with those medications 
 IRLS scale will be completed 
 Medical Outcome Study (MOS) Sleep Scale (range 0-100)  
 Restless Legs Syndrome Quality of Life (RLS-QLI)  
 Fatigue Linear Analog Scale 
 Columbia Suicide Severity Rating Scale (C-SSRS): The Columbia-Suicide 
Severity Rating Scale will be used throughout the study to assess the subject’s 
suicide ideation or behavior.  This scale is an assessment tool, it is ultimately the 
Investigators responsibility to evaluate each subject’s risk and treat as appropriate. 
 Physical exam 
 Vital signs (sitting heart rate and blood pressure) 
 Height and Weight without shoes 
 Blood samples for hematology, chemistries, iron indices and transferrin 
receptor, fasting if indicated. A serum pregnancy test will be performed on 
female subjects.  
 All oral iron products will be discontinued on the day of the first screening visit   
 RLS Diary:  
 Three-item RLS diary.  Subjects will complete the RLS diary daily, screening 
through Day 42. The diary should be completed around the same time each day.  
The following 3 questions will be assessed: 
 
1. How many hours did you nap/sleep in the prior 24 
hours? _________________ 
2. For the nap/sleep hours, how many times were you 
interrupted by your symptoms of restless legs 
syndrome? ________________ 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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3.   For the awake time, how many times were you 
interrupted by your symptoms of restless legs 
syndrome? __________________ 
 Augmentation subject questionnaire to be completed 
 Augmentation Investigator assessment (can be completed in screening, once the 
subject questionnaire is complete or on Day 0 prior to randomization). The 
physician will assess the subject and provide the following: 
 
o Step 1.  Please provide a percent (%) score using the scale outline 
below for the following question:    
 
 How likely is it that the subject has developed augmentation to the 
RLS medication? _______% 
  
o Step 2.  Convert this percentage estimate to the strata category for 
randomization 
 
 
Step 1 percentage (%) 
Randomization Strata 
0% to < 25% 
No Augmentation 
25% to ≤ 75% 
Uncertain Augmentation 
>75% 
Definitive Augmentation 
 
o Step 3.  Randomize the subject via the augmentation strata 
 
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. 
6.3.1: Day 0 
 
Original Wording 
The following must be obtained PRIOR to dosing the subject: 
 
 Subject will complete the Subjects IRLS scale 
 Vital signs to include temperature 
 RLS treatment stability 
 Subject will complete the following: 
 
 Medical Outcome Study (MOS) Sleep Scale (range 0-100)  
 Restless Legs Syndrome Quality of Life (RLS-QoL)  
 Fatigue Linear Analog Scale 
 HADS  
 
 Un-blinded personnel will perform dosing assignment 
New Wording 
The following must be obtained PRIOR to dosing the subject: 
 
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 Confirm the subject continues to meet the Inclusion/Exclusion criteria 
 IRLS scale will be completed 
 Vital signs to include temperature 
 Concomitant medications, to include RLS treatment stability 
 The investigator will assess the subject’s augmentation status (if not completed 
during screening): no augmentation, uncertain augmentation, definitive 
augmentation. See section 6.2 
 Review RLS Diary for compliance 
 Subject will complete the following: 
 
 Medical Outcome Study (MOS) Sleep Scale (range 0-100)  
 Restless Legs Syndrome Quality of Life (RLS-QLI)  
 Fatigue Linear Analog Scale 
 
 Unblinded personnel will perform dosing assignment through the IRT. 
6.3.2: Day 5 
New language added: Review RLS Diary for compliance 
Removed: HADS 
New language added: Once dosing is complete, an overview of the tapering algorithm 
(see Appendix III) will be discussed with the subject.  The subject will be instructed on 
the appropriate tapering regimen depending on the RLS medication and dose of that 
medication that the subject is currently taking. At the end of the tapering period, those 
subjects off medication, decreased the dose, or remained on baseline dose should 
remain stable throughout the trial Day 365. Any new, resumption, or increase in 
medication will be considered an intervention (See Section 4.6) 
 
6.3.3.1: Day 14 
 
Original Wording 
The subject will return to the clinic on Day 14 for blood samples (hematology, 
chemistries and iron indices), RLS treatment stability and assessment of adverse events 
only. 
New Wording 
The subject will return to the clinic on Day 14 for blood samples (hematology, 
chemistries and iron indices), subject RLS diary review, RLS treatment tapering 
progress, and assessment of adverse events only. 
6.3.3.2: Day 42 and 
168 
New language added: Subject completed diary should be returned to the site (Day 42) 
 
Removed: **NOTE: If the subjects Day 42 or Day 168 phosphorus value is 
below the LLN the subject should return (as directed by the Investigator)  for 
a repeat blood sample until the value is back WNL’s.** 
 
Original Wording 
Concomitant medications, to include RLS treatment stability 
 
New Wording 
Concomitant medications 
 
Subjects’ tapering period is complete and compliance should be assessed.   
6.3.4: Days 28,  84, 
126, 210, 252, and 336 
(remote contact by 
phone) 
New language added: Compliance with subject diary (Days 28 only) 
Original Wording 
The following should be assessed or obtained via a phone or email contact: 
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 Subject IRLS scale 
 Subject CGI-S Score 
 Concomitant medication, to include RLS treatment stability 
 Adverse events 
 
New Wording 
The following should be assessed or obtained via a phone contact: 
 
 IRLS scale (principle investigator completing the CGI-I is to remain 
blinded to score) 
 Subject CGI-S Score (principle investigator completing the CGI-I is 
to remain blinded to score) 
 Concomitant medication 
 Adverse events 
 Subjects’ tapering period is complete and compliance should be 
assessed.   
Compliance with Subject diary (Day 28 only) 
6.3.6: Day 365 (End of 
Study) 
New language added: Contact IRT to complete the subject from the study 
New language added: **NOTE: If the subject early terminates or the Day 365 
phosphorus value is below the LLN the subject should return (as directed by the 
Investigator)  for a repeat blood sample until the value is back 
WNL’s.**Injectafer® 
Original Wording 
Concomitant medications, to include RLS treatment stability 
Physician will complete the Investigator CGI-I Score. The physician is to remain blinded 
to the IRLS Scale and the subject CGI-I Score after randomization.  
Physician will complete the Investigator CGI-I Score. The physician is to remain blinded 
to the IRLS Scale and the subject CGI-I Score after randomization.  who have not had 
an intervention An intervention is defined as either 1) an increase in dosage from the 
RLS medication at study entry, 2) the initiation of a new RLS medication, or 3) 
resumption of the previous medication prescribed for RLS. as Injectafer®  
New Wording 
Concomitant medications 
Physician will complete the Investigator CGI-I Score. The physician is to remain blinded 
to the IRLS Scale and the subject CGI-S Score after randomization. 
6.4: Central 
Laboratory 
Assessments 
 
Original Wording 
If a subjects phosphorous is below the LLN at Day 42 or Day 168 the subject should 
return (as directed by the Investigator) for repeat phosphorous until the value is back 
WNL’s.   
New Wording 
If a subject’s phosphorous is below the LLN at Day 365 the subject should return (as 
directed by the Investigator) for repeat phosphorous until the value is back WNL’s. 
Original Wording 
Serum samples for laboratory analyses must be obtained at all appropriate visits 
and will be analyzed by the central laboratory.  All serum laboratory testing will 
be provided to the physician for review and assessment. If the Investigator wishes 
to obtain a follow-up of an abnormal Day 42 laboratory test, this test may be 
obtained after notification of the Sponsor.  If a subject’s phosphorous is below the 
LLN at Day 365 the subject should return (as directed by the Investigator) for 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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repeat phosphorous until the value is back WNL’s.  The following laboratory 
assessments will be determined as listed in Section 3.2.1  
New Wording 
Serum samples for laboratory analyses must be obtained at all appropriate visits 
and will be analyzed by the central 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 Day 42 laboratory test, this test may be 
obtained after notification to the Sponsor.  If a subject’s phosphorous is below the 
LLN at Day 365 the subject should return (as directed by the Investigator) for 
repeat phosphorous until the value is back WNL’s.  The following laboratory 
assessments will be determined as listed in Section 3.2.1  
 
7.3: Serious Adverse 
Event 
 
Original Wording 
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 (by 
the end of the next business day) to Luitpold Pharmaceuticals, Inc. by telephone, 
email and/or fax of the written SAE report form to the contacts listed below:
New Wording 
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:
New section added 
7.5: Events Associated with Tapering of RLS Medications 
 
Table 7.5.1: Class-specific adverse events and withdrawal signs and symptoms 
during taper of RLS medications
8.4.2: Secondary 
Endpoints 
New language added: Time off RLS SoC medications 
Original Wording New 
section added 
Restless Legs Syndrome Quality of Life (RLS-QoL) change from baseline to Day 
42 
IRLS total score change from baseline at each time point and by baseline RLS 
treatment group. 
RLS-QoL scores change from baseline at each time point 
Augmentation Scale change between baseline and end of study (Day 365) 
Time from Day 5 to the next dose of study drug will be analyzed with the log-rank 
test. 
New Wording:8.4.2 
Secondary Endpoints 
Restless Legs Syndrome Quality of Life (RLS-QLI) change from baseline to Day 
42 
IRLS total score change from baseline at each time point. 
RLS-QLI scores change from baseline at each time point 
Augmentation Scale change between baseline, Day 42, Day 168 and end of study 
(Day 365) 
Time from Day 5 to the next dose of study drug. New language added: Time off 
RLS SoC medications 
8.5: Statistical 
Analyses of Efficacy 
Original Wording 
Restless Legs Syndrome Quality of Life (RLS-QoL) change from baseline to Day 
42 
IRLS total score change from baseline at each time point and by baseline RLS 
treatment group. 
RLS-QoL scores change from baseline at each time point 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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Augmentation Scale change between baseline and end of study (Day 365) 
Time from Day 5 to the next dose of study drug will be analyzed with the log-rank 
test. 
Original Wording 
Treatment group differences for CGI scores will be assessed with the Cochran-
Mantel-Haenszel test using study site as the stratification factor.  Treatment group 
differences for changes in total and domain scores of rating scales (eg, IRLS) will 
be assessed with the analysis of covariance with fixed factors for study site and 
treatment and with baseline score as a covariate.  Treatment differences for 
proportions will be assessed with the continuity-corrected chi-square test 
New Wording 
Treatment group differences for CGI scores will be assessed with the Cochran-
Mantel-Haenszel test using region (US, Europe) as the stratification 
factor.  Treatment group differences for changes in total and domain scores of rating 
scales (eg, IRLS) will be assessed with the analysis of covariance with fixed factors 
for region (US, Europe) and treatment and with baseline score as a 
covariate.  Treatment differences for proportions will be assessed with the 
continuity-corrected chi-square test.   
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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APPENDIX VII: Amendment IV Changes 
Title Page 
 
Original Wording 
Amendment III Date: 13 July 2015 
New Wording 
Amendment IV Date:  
 
 
SIGNATURES OF 
AGREEMENT  
FOR PROTOCOL 
Removal: Sylvan Hurewitz, MD 
                 Medical Director, Clinical Development 
                 Syed Quadri, MD 
                 Medical Director, Pharmacovigilance 
 
 
Synopsis - 
Tapering 
algorithms of RLS 
Treatment 
Regimens 
 
Original Wording 
Each subject will be tapered from the prescribed RLS medication post 
treatment beginning on Day 5.   The tapering regimen will depend on 
the subject’s current medication and dosing (see Appendix III).  During 
the tapering period and through Day 42 subjects will continue to keep 
an RLS diary to record their symptoms related to their RLS. 
New Wording 
Each subject will be tapered from the prescribed RLS medication post 
treatment beginning on the evening of Day 5 or starting on Day 6.   
The tapering regimen will depend on the subject’s current medication 
and dosing (see Appendix III).  It is expected that all subject will be 
tapered off their current treatment for RLS, but in the rarity a subject, 
at the end of the allotted tapering period, is unable to achieve a dose of 
zero (0) the subject should maintain on the lowest dose level attained 
at the end of the tapering period and that dose should remain stable for 
the duration of the subjects participation in the study. During the 
tapering period and through Day 42 subjects will continue to keep an 
RLS diary to record their symptoms related to their RLS.   
 
 
Synopsis - 
Additional 
Treatment Post 
Day 42 and 
Intervention is 
defined and 4.6 
Intervention and 
6.3.5 Additional 
Treatment Post 
Day 42 
 
Additional wording 
4) increase in dosage from the RLS medication achieved at the end of 
the tapering period 
 
No subject assessments are completed unless the dosing or follow-up 
days fall on an assessment day in the follow-up period. 
 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
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Synopsis - RLS 
Therapy 
 
Additional wording 
If and when the subject is tapered off the RLS medication, the goal will 
be for the subject to remain off their medication or remain on the 
lowest dose level achieved for the duration of the study. 
 
 
Synopsis - Number 
of Subjects 
 
Additional wording 
Spain added 
 
 
LIST OF 
ABBREVIATIONS 
AND 
DEFINITIONS 
 
Additional wording 
Qod 
every other day 
Q3d 
every 3 days 
Q5d 
every 5 days 
 
 
3.2.1 Schedule of 
Events 
 
Additional wording 
Added + 2 day window to 7 day screening period, deletion of fasting 
and renumbering of footnotes. 
 
 
4.4 RLS Standard 
of Care therapy: 
Tapering 
Procedures 
 
Additional wording 
Starting at screening, during the tapering period and through Day 42 
subjects will be asked to keep an RLS diary to record their progress.    
 
 
5.6 Concomitant 
Medication 
 
Additional wording 
if a subject, at the end of the allotted tapering period, is unable to 
achieve a dose of zero (0) the subject should be maintained on the 
lowest dose level attained at the end of the tapering period and that 
dose should remain stable for the duration of the study.  If during the 
course of the study it becomes necessary to restart or increase therapy 
via physician decision, these data points will be collected and the 
subject will no longer be evaluated for efficacy, but the subject will 
continue in the study for safety analysis. 
 
 
6.3.1 Day 0 
 
Additional wording 
Subject will complete the following, if not already completed during 
screening: 
 
 
6.3.5 Additional 
Treatment Post Day 
42 
 
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Page 77 
New wording 
*Central laboratory results obtained during the Day 42 or Day 168 visit can 
be used to qualify a subject for additional dosing if those labs have occurred 
with 14 days of the first dose of study medication. 
 
 
8.7 Interim 
Analyses 
 
New wording 
An interim analysis of efficacy will be conducted after 100 subjects have 
completed Day 42. The blinded code of the treatment groups will be 
broken by a third party statistician chosen by the sponsor. The un-
blinded data will only be available to the sponsors experts or consultants 
to assist in the planning of future studies. The sponsor, blinded PI, study 
staff and study participant will remained blinded to the data. Therefore, 
no adjustment to Type I error will be made. 
 
 
Appendix III 
 
New wording  
Ropinirole (not ER) maximum entry dose 4mg;  maximum taper days 21 
 
 
Additional wording 
2Dose-specific, time-varying taper after 2 doses Injectafer® (Ferric 
Carboxymaltose) vs. placebo to be initiated after the second dose of study 
drug 
 
 
 
 
 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
CONFIDENTIAL                                                                                                                                 Amendment IV Date: 02 June 2016 
Page 78 
References  
1. Wijemanne S. Jankovic J.  Restless legs syndrome:  clinical presentation, diagnosis, and treatment. Sleep 
Med 2015; 16(6):678-90. 
 
2. Lee KA, Zaffke ME, Baratte-Beebe K. Restless Legs Syndrome and sleep disturbance during pregnancy: 
the role of folate and iron. J. Women’s Health Gender Based Med 2001;10: 335-45. 
 
3. Collado-Seidel V. et al. Clinical and biochemical findings in uremic patients with and without Restless Leg 
Syndrome. (1998). Am J. Kidney Dis 1998;31(2):324-328. 
 
4. Garcia-Borreguero D, Williams A. An update on restless legs syndrome.  (Willis-Ekbom disease): clinical 
features, pathogenesis and treatment.  Current Opinion in Neurology 2014;27(4):493-501. 
 
5. Güler S, et al. The prevalence of restless legs syndrome in Edirne and its districts concomitant comorbid 
conditions and secondary complications.  Neurol Sci 2015 May 20. 
 
6. Wilt TJ, MacDonald R, Ouellette J, Khawaja IS, Rutks I, Butler M, Fink HA.  Pharmacologic therapy for 
primary restless legs syndrome:  A systematic review and meta-analysis.  JAMA Intern Med 
2013:173(7):496-505. 
 
7. Garcia-Borreguero D, Stillman P, Benes H, Buschmann H, Ray Chaudhuri K, Gonzalez Rodriguez V, Hogl 
B, et al Algorithms for the diagnosis and treatment of restless legs syndrome in primary care. BMC 
Neurology 2011, 11:28.  
 
8.  Nierenberg, MJ. Dopamine agonist withdrawal syndrome:  implications for patient care. Drugs & Aging 
2013 Aug; 30(8):587-92. 
 
9. Garcia-Borreguero D, et al.  The long-term treatment of restless legs syndrome/Willis-Ekbom disease:  
evidence-based guidelines and clinical consensus best practice guidance:  a report from the International 
Restless Legs Syndrome Study Group.  Sleep Med 2013;14:675-84. 
 
10. Trenkwalder C, Paulus W, Walters AS. The restless legs syndrome. Lancet Neurol. 2005 Aug; 4 (8): 465-75 
review. 
 
11. Frohlich AC, Eckeli AL, Bacelar A, Poyares D, Pachito DV, Stelzer FG, Coelho FMS, et al.  Brazilian 
consensus on guidelines for diagnosis and treatment for restless legs syndrome.  Arq Neuropsiquiatr 
2015;73(3):260-280. 
 
12. Allen RP, Earley CJ.  Augmentation of the restless legs syndrome with carbidopa/levodopa.  Sleep 
1996;19:205-213. 
 
13. Trenkwalder C, Paulus W.  Restless legs syndrome:  pathophysiology, clinical presentation and 
management.  Nature Reviews 2010;6:337-346. 
 
14. Ekbkom, K.A. Restless legs syndrome. Neurology 1960;10:868-873. 
 
15. Norlander, N.B. Restless Legs. Brit J Phys Med 1954;17:160-162. 
 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
CONFIDENTIAL                                                                                                                                 Amendment IV Date: 02 June 2016 
Page 79 
 
16. 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. 
 
17. Earley, CJ, Allen, RP, Beard, JL, Conner, JR. Insight into the pathophysiology of restless legs syndrome. J. 
Neurosci. Res. 62:623-628, 2000. 
 
18. Allen RP, Earley. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 2001. 
Jan 23, 56 (2):263-5. 
 
19. Connor JR, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs 
syndrome.  Neurology 2003;61:304-9. 
 
20. 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. 
 
21. Ondo WG. Restless legs syndrome. Curr Neurol Neurosci Rep 2005 Jul; 5(4):266-74.  
 
22. Hogl B, PoweW. Restless Legs Syndrome. Curr Opin Neurol 2005 Aug 18 (4):405-10. 
 
23. 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. 
 
24. 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. 
 
25.  Earley CJ, et al.   Altered brain iron homeostasis and dopaminergic function in restless legs syndrome 
(Willis-Ekbom Disease).  Sleep Med 2014;15:1288-1301.  
 
26. Norlander, N.B. Therapy in restless legs. Acta Med Scand 1953;145;453-57. 
 
27. Earley CJ, Heckler D, Allen RP The treatment of restless legs syndrome with intravenous iron dextran. 
Sleep Med. 2004 May;5(3):231-35. 
 
28. 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. 
 
29. 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. 
 
30. 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.  
 
31. O’Keefe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing. 1994 
May:23 (3):200-3. 
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Luitpold Pharmaceuticals Inc.                                                                                                                                     Protocol: 1VIT14037 
CONFIDENTIAL                                                                                                                                 Amendment IV Date: 02 June 2016 
Page 80 
 
32. 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. 
 
33. 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.  
 
34. Trotti LM, Bhadriraju S, Becker LA.  Iron for restless leg syndrome.  Cochrane Database Syst Rev 2012 
May;5. 
 
35. 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. 
 
36. 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. 
 
37. 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.  
 
38. 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. 
 
39. Pondal M. Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic J 
Neurol Neurosurg Psychiatry 2013 Feb;84(2):130-5. 
 
 
 
 
 
                                              
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Luitpold Pharmaceuticals Inc. 
CONFlDENTIAL 
Protocol: IVITJ4037 
Amendment IV Date: 02 June 2016 
32. Davis BJ, Rajput A, Rajput ML, Aul EA, Eichorn GR. A randomized, double-blind placebo-controlled trial 
of iron in restless legs syndrome. Eur Neural 2000, 43(2):70-5. 
33. 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. 
34. Trotti LM, Bhadriraju S, Becker LA. Iron for restless leg syndrome. Cochrane Database Syst Rev 2012 
May;5. 
35. 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. 
36. 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. 
37. 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. 
38. 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. 
39. Pondal M. Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic J 
Neural Neurosurg Psychiatry 2013 Feb;84(2):130-5. 
Page 80 
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SAP_001.pdf: 
 
NCT02453334 1VIT14039 
Can Iron Lessen Anemia Due to Cancer and 
Chemotherapy: A Study to Investigate the Efficacy and 
Safety of Injectafer® (IRON CLAD) 
 
 
Statistical Analysis Plan Protocol No. 1VIT14037, Version 
1.0 - 22 November 2016  


16.1.9 
Documentation of Statistical Methods 
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Table of Contents
16.1.9 Documentation of Statistical Methods ................................................................................
Table of Contents .....................................................................................................................
Statistical Analysis Plan Protocol No. 1VIT14037, Version 1.0 - 22 November 2016 ...........
1
2
3
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
Page 1 of 27
 
 
 
Statistical Analysis Plan 
 
Protocol No.: 1VIT14037  
 
A Double-Blind, Multi-Center, Randomized, Placebo-Controlled 
Study to Investigate the Efficacy and Safety of Injectafer® (Ferric 
Carboxymaltose) in the Treatment of Restless Legs Syndrome (RLS) 
 
 
 
 
 
 
Sponsor: 
 
Luitpold Pharmaceuticals, Inc. 
 
Version: 
 
Version 1.0 
 
Issue Date: 
22 November, 2016 
 
 
 
 
 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
No:.J...YIT14037 Am¢ndtnentIV 
STATISTICAL ANALYSIS PLAN APPROVAL 
Author: 
/tin: Yin, PhD 
Biostatistician, Biostatistics, FMD K&Linc. 
Reviewed and approved by: 
J&_in C/uA 
Kevin Chen, PhD 
Sr. Director, Biostatistics, FMD K&L Inc. 
Sponsor Review: 
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Lmda 
, Mundy, MD, PhDu 
V (...)1 (' vY\ () 
St'Medical -Director, Clinical Devefopment 
Luitpold Pharmaceuticals, Inc. 
Davld Morris, PhD 
Sr. Director, Statistics 
WebbWrites, LLC 
Version: 1.0 
Confidential 
. Statistical Analysis Plan 
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Page 2 of27 
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Final, 26 November 2018
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Sponsor: Luitpold Pharmaceuticals, Inc. 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
Version: 1.0 (22-November-2016)  
Confidential 
Page 3 of 27
TABLE OF CONTENTS 
ABBREVIATIONS 
5 
1.
INTRODUCTION
7 
1.1 
STUDY OBJECTIVES
 7
1.1.1  Primary Objective(s) 
7 
1.2 
STUDY ENDPOINTS
1.2.1  Primary Efficacy Endpoint(s) 
7 
1.2.2  Secondary Efficacy Endpoint(s) 
7 
1.2.3  Other Efficacy Endpoint(s) 
7 
1.2.4  Safety Endpoints 
8 
1.3 
SUMMARY OF THE STUDY DESIGN
1.3.1  General Study Design and Plan 
8 
1.3.2  Randomization and Blinding 
10 
1.3.3  Sample Size and Statistical Power Considerations 
10 
2.
STATISTICAL METHODS
11 
2.1 
GENERAL CONSIDERATIONS
2.1.1  Reporting Precision 
11 
2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS)
12 
2.2.1    Safety Population 
12 
2.2.1    Full Analysis Set Population 
12 
2.3 
TIME WINDOWS FOR ANALYSIS
2.4 
POOLING OF CENTERS
2.5 
HANDLING OF MISSING DATA
2.6 
ANALYSIS SOFTWARE
3.
STUDY SUBJECTS
15 
3.1 
DISPOSITION OF SUBJECTS
3.2 
PROTOCOL DEVIATIONS
4.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
15 
4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
4.2 
MEDICAL HISTORY
5.
STUDY DRUG AND EXPOSURE
16 
5.1 
TREATMENT COMPLIANCE AND EXTENT OF EXPOSURE
5.2 
PRIOR AND CONCOMITANT THERAPY
6.
EFFICACY ANALYSES
17 
6.1 
PRIMARY EFFICACY ANALYSIS
6.1.1  IRLS total score change from baseline to Day 42 
17 
7 
12 
14 
14 
15 
15 
15 
16
16
16
15
17 
8 
11 
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6.1.2  Proportion of patients rated as much or very much improved 
with the Clinical Global Impression (CGI) performed by 
Investigator (CGI-I) on Day 42. 
17 
6.1.3  Sensitivity Analyses 
17 
6.1.4  Examination of Subgroups 
19 
6.2 
SECONDARY EFFICACY ANALYSES
6.2.1  CGI-S on Day 42 
19 
6.2.2  RLS-QLI, MOS Sleep Scale, and Fatigue Linear Analog 
Scale Change From Baseline to Day 42 
19 
6.2.3  Time off pre-enrollment prescribed RLS medications 
19 
6.3 
OTHER EFFICACY ENDPOINT(S) 
20 
6.3.1  Proportion of responders based on CGI-I / CGI-S at each 
time point 
20 
6.3.2  IRLS, RLS-QLI, MOS Sleep Scale, and Fatigue Linear 
Analog Scale Change from baseline at each time point 
20 
6.3.3  CGI-I and CGI-S scores at each time point 
20 
6.3.4  Augmentation assessment by Investigator change between 
baseline, Day 42, Day 168 and end of study (Day 365) 
20 
6.3.5  Proportion of subjects required intervention for RLS 
21 
6.3.6  Time from Day 5 to the next dose of study drug 
21 
7.
SAFETY ANALYSIS
21 
7.1 
ADVERSE EVENTS
7.1.1  Deaths, Serious and Other Significant Adverse Events 
22 
7.2 
CLINICAL LABORATORY PARAMETERS
7.3 
VITAL SIGNS, PHYSICAL EXAMINATION FINDINGS, AND C-SSRS 
23 
7.3.1  Vital Signs 
23 
7.3.2  Physical Examination 
24 
7.3.3  Columbia-Suicide Severity Rating Scale (C-SSRS) 
24 
7.4 
OTHER ANALYSES
8.
INTERIM ANALYSES AND DATA AND SAFETY MONITORING
BOARD (DSMB) 
25 
8.1 
INTERIM ANALYSES
8.2 
DATA AND SAFETY MONITORING BOARD (DSMB) 
25 
9.
SUMMARY OF MAJOR CHANGES IN THE PLANNED
ANALYSES 
26 
REFERENCES 
27 
19 
21 
23 
24 
25 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
Version: 1.0 (22-November-2016)  
Confidential 
Page 5 of 27
ABBREVIATIONS 
Abbreviation 
Term 
ALT 
Alanine Aminotransferase  
ANCOVA 
Analysis Of Covariance  
AST 
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical  
BUN 
Blood Urea Nitrogen 
CGI-I 
Clinical Global Impression-Global Improvement 
CGI-S 
Clinical Global Impression- Subject 
CI 
Confidence Intervals 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSMB 
Data And Safety Monitoring Board  
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
GGT 
Gamma-Glutamyl Transferase 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
IRLS 
International Restless Legs Syndrome 
ITT 
Intent-To-Treat 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase  
LOCF 
Last Observation Carried Forward 
MAR 
Missing At Random 
MCH 
Mean Corpuscular Hemoglobin  
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
MOS 
Medical Outcomes Study 
NSS 
Normal Sterile Saline 
OC 
Observed Cases  
PCS 
Potentially Clinically Significant 
PT 
Preferred Term 
RBC 
Red Blood Cells 
RDW 
Red Cell Distribution Width  
RLS 
Restless Leg Syndrome  
RLS-QLI 
Restless Legs Syndrome – Quality Of Life 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
Page 6 of 27
 
Abbreviation 
Term 
ROS 
Rest of World 
SAEs 
Serious AEs  
SAP 
Statistical Analysis Plan  
SD 
Standard Deviation 
SI 
Système International  
SOC 
System Organ Class  
TEAE 
Treatment-Emergent Adverse Event  
TIBC 
Total Iron Binding Capacity  
TSAT 
Percentage Serum Transferrin Saturation  
US 
United States 
WBC 
White Blood Cells 
WHO 
World Health Organization  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
Page 7 of 27
 
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 1VIT14037 (Amendment IV, 
Date: 02 June 2016). 
1.1 
STUDY OBJECTIVES 
1.1.1 
Primary Objective(s) 
The primary objective of the study was to evaluate the efficacy and safety of an IV Injectafer® in 
subjects with Restless Leg Syndrome (RLS).  
 
1.2 
STUDY ENDPOINTS 
1.2.1 
Primary Efficacy Endpoint(s) 
The co-primary efficacy variables include: 
 IRLS total score change from baseline to Day 42.  
 Proportion of subjects rated as much or very much improved with the Clinical Global 
Impression (CGI) performed by Investigator (CGI-I) on Day 42.  
 
1.2.2 
Secondary Efficacy Endpoint(s) 
The major secondary endpoints will be tested in a hierarchical order, that is, statistical 
significance for major secondary efficacy endpoint will be declared only if the primary efficacy 
test (IRLS and CGI-I on Day 42) is statistically significant. Because a hierarchical testing 
scheme is used, no adjustments of the alpha level will be needed at each stage of testing. All tests 
will be done at an alpha ≤ 0.05. 
 
The major secondary efficacy endpoints in ranked order of testing include: 
1. Clinical Global Impression (CGI) performed by Subject (CGI-S) on Day 42. 
2. Restless Legs Syndrome Quality of Life (RLS-QLI) change from baseline to Day 42. 
3. Medical Outcome Study (MOS) Sleep Scale change from baseline to Day 42. 
4. Fatigue Linear Analog Scale change from baseline to Day 42. 
5. Time off pre-enrollment prescribed RLS medications. 
    
1.2.3 
Other Efficacy Endpoint(s) 
The Other efficacy endpoints include: 
1. Proportion of responders (any improvement) based on CGI-I at each time point. 
2. IRLS total score change from baseline at each time point. 
3. Proportion of responders based on CGI-S at each time point. 
4. CGI-I and CGI-S scores at each time point and by baseline RLS treatment group. 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
Page 8 of 27
 
5. RLS-QLI scores change from baseline at each time point. 
6. MOS Sleep scale total score change from baseline at each time point. 
7. Fatigue Linear Analog Scale total score change from baseline at each time point. 
8. Augmentation assessment by Investigator change between baseline, Day 42, Day 168 
and end of study (Day 365). 
9. Proportion of subjects required intervention for RLS. 
10. Time from Day 5 to the next dose of study drug. 
1.2.4 
Safety Endpoints 
Safety endpoints include: 
1. Incidence of treatment emergent adverse events and incidence of serious adverse 
events 
2. Change in clinical laboratory tests 
3. Change in vital signs 
4. Change in C-SSRS 
1.3 
SUMMARY OF THE STUDY DESIGN  
1.3.1 
General Study Design and Plan 
This is a Phase III, double blinded, multi-center, randomized, placebo-controlled study 
evaluating the efficacy and safety of an IV Injectafer® in subjects with Restless Leg Syndrome 
(RLS).  
 
Injectafer® is a stable type I polynuclear iron (III)-hydroxide carbohydrate complex developed 
as an IV iron replacement therapy for the treatment of iron deficiency anemia. RLS has been 
reported to be associated with the reduction of iron in central nervous system [1]. In a previous 
phase II trial Injectafer® was found to be safe and well tolerated in the treatment of RLS [2].  
In this study, 200 eligible subjects will be randomized in a 1:1 ratio to receive either a 750 mg 
undiluted blinded dose of IV Injectafer® at 100mg/minute or a blinded IV Placebo (15 ml of 
Normal Sterile Saline [NSS]) at 2ml/minute during clinic site visits. The randomization will be 
stratified by Augmentation at baseline (no augmentation, uncertain augmentation, definitive 
augmentation). The study duration is 12 months, including a 5 day treatment phase (Dosing on 
Day 0 and Day 5), and a 12 months efficacy and safety follow-up phase. Subjects will visit the 
clinic on Days 14, 42, 168, and 365. In between the clinic visits subjects will be contacted 
remotely by phone on Days 28, 84, 126, 210, 252, 294, and 336. Subjects will be considered to 
have reached the end of the study for efficacy when intervention is required for their RLS 
symptoms; those subjects will continue the follow-up phase for safety. Subjects who have not 
had an intervention may receive additional blinded study drug treatment after Day 42 at the 
discretion of the Investigator. The additional dosing will be the same blinded study medication as 
previously randomized to receive during the treatment phase, and the dosing days should mirror 
the original treatment/follow-up period (dosing 5 days apart with follow-up visits, to include 
laboratory assessments only, on 14 and 42 Days post the first dose). No additional iron maybe 
administered between Day 320 and the Day 365 visit. 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
Page 9 of 27
 
 
The Schedule of Events is presented by Table 1.  
Table 1 Schedule of Event 
  
1 Contact IRT for screening number assignment during screening, and on Day 365 to complete subject from the study. 
2 Contact IRT for randomization assignment, unblinded site personnel 
3 Vital Signs includes sitting BP and heart rate. 
4 On study drug dosing days sitting vital signs including blood pressure and heart rate should be collected immediately pre 
dosing, immediately and 30 minutes post dosing. Body temperature will also be collected pre dosing on Days 0 and 5. 
5 IRLS, RLS QLI, MOS Sleep Scale, and Fatigue Linear Analog Scale may be completed on Day 0 prior to randomization. 
6 Fasting, if indicated. 
7 Adverse event assessments will start at the time of the first dose of study drug. All events noted prior to the 1st dose of study 
drug should be considered history and captured on the medical history page of the eCRF. 
8 If the phosphorous is below the LLN at the time of early termination or end of the study (Day 365) the subject should return (as 
directed by the Investigator) for repeat phosphorous until the value is back WNL’s or the subject’s baseline. 
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9 To include past and present treatment for RLS. 
10 Female subjects only. 
11 After dosing on Day 5 the site will review the tapering requires with the subject. 
12 Assess compliance of tapering. Once the taper period is complete assess stability (off meds, decrease dose, baseline dose). 
13 Augmentation questionnaire should be completed at screening prior to the Investigator’s Augmentation Assessment. 
14 Augmentation assessment can be done either at screening or prior to dosing on Day 0 but after the subject has completed the 
augmentation questionnaire. 
15 The Columbia-Suicide Severity Rating Scale will be used throughout the study to assess the subjects suicide ideation or 
behavior. This scale is an assessment tool, it is ultimately the Investigators responsibility to evaluate each subject’s risk and treat 
as appropriate. 
16 Subject Diary reviewed for compliance at Day 0,5,14 and 28. The completed diary will be returned by the subject to the site on 
Day 42. 
I,S Investigator and Subject Assessment. 
S Subject only Assessment. 
 
1.3.2 
Randomization and Blinding 
Eligible subjects will be randomly assigned in a 1:1 ratio to IV Injectafer® or IV Placebo via an 
IRT system. Randomization will be stratified by baseline RLS medication-related augmentation 
(no augmentation, uncertain augmentation, definitive augmentation). The randomization 
schedule was generated by FMD K&L Inc. The schedule was approved by Sponsor before being 
loaded into the IRT system. 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 IRLS score and subject CGI score for each subject after 
randomization. 
 
1.3.3 
Sample Size and Statistical Power Considerations 
Sample size estimates were based on the mITT population for Study 1VIT05009. The last 
observation carried forward (LOCF) and observed cases (OC) results on Day 28 were used for 
the co-primary efficacy endpoints (CGI) and first ranked secondary endpoint (IRLS). It is 
unclear how treatment differences on Day 42 results might differ from Day 28, apart from a 
higher dropout rate, but it is reasonable to assume that treatment differences will decrease. 
Therefore, power calculations were based on smaller treatment differences and larger standard 
deviations.  
 
Co-primary endpoint (IRLS): The smallest treatment difference for change from baseline to Day 
28 was 4.4 with a standard deviation of 8.5. A sample size of 100/group provides 95% power 
under this scenario. 
 
Co-primary efficacy endpoint (CGI-I): The smallest treatment difference on Day 28 was 45% 
versus 15% of subjects in the FCM and placebo groups, respectively, who reported much or very 
much improvement on the patient CGI-S. A sample size of 100/group provides >99% power. A 
sample size of 100/group has at least 90% power when the treatment difference is as small as 
45% versus 22%. 
 
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2. 
STATISTICAL METHODS 
2.1 
GENERAL CONSIDERATIONS 
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. If applicable, hypothesis 
testing will be carried out at the two-sided α=0.05 level unless otherwise specified; 2-sided 95% 
confidence intervals (CIs) will be presented, where specified.  
In general, summary tables will present data by treatment group. Source data for the summary 
tables and statistical analyses will be presented as subject data listings, which include data 
collected on the electronic case report forms (eCRFs as well as any derived variables for all 
enrolled subjects.  
Baseline will be defined as the last non-missing value obtained prior to the first dose of study 
drug.  
2.1.1 Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
Statistics 
Degree of Precision 
Mean, Geometric mean, Median, 
Quartiles, Confidence limit boundaries 
One decimal place more than the raw data. 
Standard deviation, Standard error 
Two decimal places more than the raw data. 
Minimum, Maximum 
The same as the raw data. 
p-value 
Rounded to 4 decimal places and therefore 
presented as 0.xxxx; p-values smaller than 0.0001 
as ‘<0.0001’; p-values greater than 0.9999 as 
‘>0.9999’. 
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). 
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2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) 
2.2.1   Safety Population 
All subjects who received at least one dose of randomized treatment.  
2.2.1   Full Analysis Set Population 
All subjects who received at least one dose of randomized treatment and had at least one post-
randomization measurement of the IRLS and Clinical Global Impression performed by 
Investigator (CGI-I). 
2.3 
TIME WINDOWS FOR ANALYSIS 
For the following analyses no windows will be applied, including safety shift, efficacy shift, and 
safety potential clinical significant (PCS) summaries.  
For safety and efficacy by visit descriptive statistical summaries (mean, standard deviation, 
median, minimum and maximum), all CRF collected observations (including scheduled and 
unscheduled visits) will be summarized with adjusted analysis-defined visit windows based on 
the scheduled days of protocol. Variables will be windowed to the closest scheduled visit for that 
variable. Visit windows have been constructed to ensure every post-dose observation collected 
by CRF can be allocated to a particular visit. No windows will be applied for the screening visit. 
The adjusted analysis-defined windows are summarized in Table 2.   
 
Table 2 Visit windows for assessments  
Assessment 
Defined Windows 
Visit 
Scheduled 
Study Day  
Maximum Windows  
Vital Signs* 
 
 
 
 
Day 0 
1 
Study Day=1 
 
Day 5 
6 
2 ≤Study Days≤ 24  
 
Day 42 
43 
25 ≤Study Days≤ 105  
 
Day 168 
169 
106 ≤Study Days≤ 267  
 
Day 365 
366 
268 ≤Study Days  
 
 
 
 
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Assessment 
Defined Windows 
Visit 
Scheduled 
Study Day  
Maximum Windows  
C-SSRS, Physical Exam, 
Augmentation Investigator 
Assessment, RLS QLI 
 
 
 
 
Day 42 
43 
1 ≤Study Days≤ 105  
 
Day 168 
169 
106 ≤Study Days≤ 267  
 
Day 365 
366 
268 ≤Study Days  
 
 
 
 
CGI-I, MOS Sleep Scale, 
Fatigue Linear Analog 
Scale,  
 
 
 
 
Day 5 
6 
1 ≤Study Days≤ 24  
 
Day 42 
43 
25 ≤Study Days≤ 105  
 
Day 168 
169 
106 ≤Study Days≤ 267  
 
Day 365 
366 
268 ≤Study Days  
 
 
 
 
IRLS Scale, CGI-S 
 
 
 
 
Day 5 
6 
1 ≤Study Days≤ 17  
 
Day 28 
29 
18 ≤Study Days≤ 35  
 
Day 42 
43 
36 ≤Study Days≤ 63  
 
Day 84 
85 
64 ≤Study Days≤ 105  
 
Day 126 
127 
106 ≤Study Days≤ 147  
 
Day 168 
169 
148 ≤Study Days≤ 189  
 
Day 210 
211 
190 ≤Study Days≤ 231  
 
Day 252 
253 
232 ≤Study Days≤ 273  
 
Day 294 
295 
274 ≤Study Days≤ 315  
 
Day 336 
337 
316 ≤Study Days≤ 351  
 
Day 365 
366 
352 ≤Study Days  
 
* Vital signs will be summarized by time-point of each visit, i.e. immediately post dose and 30 minutes post dose. 
For assignment of post-dose data to adjusted analysis-defined visit windows, study day will be 
defined as follows:  
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 Date of assessment – date of first treatment + 1 
 
By this definition, the first dose day will be study day 1 for example.  
 
If multiple readings are recorded within a single adjusted visit window, please refer to the rules 
below.  
 If there are 2 or more valid, non-missing observations within the same visit 
window, then the non-missing one closest to the scheduled visit will be used in 
the analysis.  
 If 2 valid observations are equidistant from the scheduled visit, then the scheduled 
visit (if one of the two observations is) will be used in the analysis, or else the 
non-missing observation with the earlier collection date will be used. 
 If 2 valid observations are collected on the same day, then the scheduled visit (if 
one of the two observations is) will be used in the analysis, or else the non-
missing observation with the earlier collection time will be used. 
If a visit window does not contain any observations, then the data will remain missing, excepting 
for the efficacy inferential analyses where LOCF will be used for missing data imputation. 
 
Any repeated or additional assessments performed will be included in the individual patient data 
listings. 
 
2.4 
POOLING OF CENTERS  
This study was a multi-center study.  For statistical inferences (models), sites will be pooled into 
2 geographic regions (United States [US] and Europe).  For summaries using descriptive 
statistics, data of all sites will be combined.  Subgroup analyses by pooled regions (US and 
Europe) will be performed for the co-primary efficacy endpoints using descriptive statistics.  
2.5 
HANDLING OF MISSING DATA 
Missing data will not be imputed for descriptive statistical summaries in safety or efficacy 
analyses. 
 
For statistical inferences (models) analyses, missing data will be imputed using last observation 
carried forward (LOCF) method for CGI and other efficacy endpoints. e.g. for primary endpoint, 
IRLS total score, when Day 42 data is missing (subject has discontinued before Day 42, or 
measurement not taken at Day 42 though subject was not discontinued), Day 28 result will be 
carried forward. If the post-baseline value of the first scheduled visit is missing, the worst value 
obtained from the same time point of all subjects in FAS population will be used for both 
treatment groups. The worst value is defined as “Non-responder” for CGI responder rate 
analysis, the highest score for IRLS, RLS-QLI, MOS sleeping scale, Fatigue Linear Analog 
Scale and CGI, and “Definitive Augmentation” for augmentation scale.  
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Sensitivity analyses will assess the impact of missing values on inferences based on primary 
efficacy endpoints (Section 6.1.1). 
2.6 
ANALYSIS SOFTWARE 
All summaries and statistical analyses will be generated using SAS® version 9.2 or later. 
3.
STUDY SUBJECTS
3.1 
DISPOSITION OF SUBJECTS 
Disposition will be summarized by treatment group and overall for all enrolled subjects. 
The disposition will include the following: 

Subjects who are randomized

Subjects who are in the Safety Population

Subjects who are in the FAS

Subjects who complete the study

Subjects who complete the Day 42 visit

Subjects who discontinue the study
The number and percent of subjects will be summarized for each reason for premature 
discontinuation. For subjects who are prematurely discontinued from the study, the reasons for 
discontinuation as recorded on the disposition page in the CRF will also be presented.  
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 summarized for each type of 
deviation. A subject data listing of clinically important protocol deviations will be listed. 
4.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and baseline characteristics (e.g., gender, age, race, ethnicity, body height, weight, 
and the status of iron intolerance) will be summarized with descriptive statistics by treatment 
group and overall for the Safety Population and FAS Population.  
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A subject data listing of demographics and baseline characteristics will be provided. 
4.2 
MEDICAL HISTORY 
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 (PT) by treatment 
group and overall for Safety Population.  
 
5. 
STUDY DRUG AND EXPOSURE 
5.1 
TREATMENT COMPLIANCE AND EXTENT OF EXPOSURE 
Treatment compliance will not be summarized, as each subject will receive a single dose of study 
drug on Day 0 and Day 5 in an inpatient setting.  
The total number of study drug injections received will be summarized via descriptive statistics 
by treatment group. The number (percentage) of subjects who received IV injections of study 
drug will be summarized by the number of doses received by treatment group in safety 
population. 
A subject data listing of treatment exposure will be provided by treatment. 
5.2 
PRIOR AND CONCOMITANT THERAPY 
Prior medications are defined as medications that started prior to the first dose of study drug. 
Concomitant medications are defined as medications (other than the study drug) taken on or after 
the first does of the study drug during the study. Medications started before the first dose of study 
drug and continuing at the time of the first dose of study drug are considered both prior 
medication 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 2014).  The number (percentage) of subjects who 
took prior and concomitant medications will be summarized on the Safety Population by 
treatment group, ATC Classification, and WHO Drug preferred term.  
A subject data listing of priori and concomitant therapy will be provided by treatment. 
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6.
EFFICACY ANALYSES
All efficacy analyses will be based on the FAS Population. Missing data will be imputed per 
Section 2.5 for statistical inference analyses (no imputation for descriptive statistical summaries). 
Subject who has an intervention will no longer be evaluated for efficacy starting at the time of 
the intervention (these subjects will remain eligible for the safety evaluation).  
An intervention is defined as either 
(1) An increase in dosage from the RLS medication at study entry 
(2) The initiation of a new RLS medication 
(3) Resumption of the previous medication prescribed for RLS (the previous prescribed RLS 
medication should remain unchanged until the tapering process begins post Day 5 
treatment with study drug). 
6.1 
PRIMARY EFFICACY ANALYSIS 
6.1.1 
IRLS total score change from baseline to Day 42  
The actual values of IRLS total score on baseline and Day 42, and the change from baseline to 
Day 42 will be summarized via descriptive statistics by treatment group. Treatment group 
difference for change in IRLS total score will be assessed with the analysis of covariance 
(ANCOVA), with region (United States [US], Europe), and baseline RLS medication-related 
augmentation and treatment as fixed factors and baseline IRLS total score as a covariate. Missing 
value will be imputed using LOCF as specified in Section 2.5. P-values to test treatment effect 
will be determined. Point estimates, associated 95% confidence interval and p-values will be 
reported.  
6.1.2 
Proportion of patients rated as much or very much improved with the Clinical 
Global Impression (CGI) performed by Investigator (CGI-I) on Day 42.  
Responder is defined as subjects rated as much or very much improved with the CGI-I on Day 
42. The number (percentage) of CGI-I responder will be summarized by treatment group.
Treatment differences for proportions will be assessed with the Logistic regression with 
treatment, region (US, Europe), and baseline RLS medication related augmentation as fixed 
factors, and baseline IRLS total score as a covariate. Missing value will be imputed using LOCF 
as specified in Section 2.5 .  Odds ratio for treatment comparison and associated 95% confidence 
interval and p-values will be presented.  
A subject data listing will be provided by treatment for each endpoint. 
6.1.3 
Sensitivity Analyses 
To assess the robustness of the primary efficacy analysis, sensitivity analyses will be performed 
using the following approaches: 
MMRM Analysis of Change in IRLS Total Score: 
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A mixed model repeated measures (MMRM) model will be conducted to provide an analysis 
under the assumption that data are missing at random (MAR). The MMRM model will include 
changes in IRLS total score from baseline to Day 5, 28 and 42 as the dependent variables; and 
baseline RLS medication-related augmentation, treatment group, visit, treatment group by visit 
interaction, and regions (US, Europe) as fixed effects; and subjects within treatment group as 
random effects; and baseline IRLS total score as covariate. An unstructured covariance matrix will 
be used to allow for unequal variances between visits.  If the model does not converge with 
unstructured variance – covariance matrix, then the Toeplitz, first-order autoregressive, 
compound symmetric, variance components structures will be tried and the covariance structure 
will be decided based on model convergence status and the AKaike information criterion.   The 
Kenward-Roger approximation will be used to calculate the denominator of degrees of freedom for 
the fixed effect. If the interaction term is not significant, it will be dropped from the model. No 
imputation of missing data other than that inherent in the MMRM model will be performed.  P-
values to test treatment effect on Day 42 will be determined. Point estimates, associated 95% 
confidence interval and p-values will be reported.  
Logistic Regression Based on Observed Cases for Proportion of Responders based on CGI-
I: 
A Logistic regression model will be used to assess the treatment group difference in proportion 
of subjects rated as much or very much improved with the CGI-I on Day 42. The model will 
have treatment, region (US, Europe), and baseline RLS medication related augmentation as fixed 
factors, and baseline IRLS total score as a covariate. If the Day 42 data are missing, no 
imputation will be performed. Subjects with missing data will be excluded from the statistical 
testing. Odds ratio for treatment comparison and associated 95% confidence interval and p-
values will be presented. 
 
Logistic Regression with Missing Data Imputed as Non-Responder for Proportion of 
Responders based on CGI-I: 
The same Logistic regression model as the primary analysis will be used to assess the treatment 
group difference in proportion of subjects rated as much or very much improved with the CGI-I 
on Day 42. Missing data of Day 42 will be imputed as “Non-Responder”. Odds ratio for 
treatment comparison and associated 95% confidence interval and p-values will be presented. 
 
CMH with Missing Data Imputed as Non-Responder for Proportion of Responders based 
on CGI-I: 
Cochran-Mantel-Haenszel test will be used to assess the treatment group difference in proportion 
of responder (i.e. subjects rated as much or very much improved) with the CGI-I on Day 42, 
using baseline RLS medication-related augmentation and region (US, Europe) as the 
stratification factors. Subjects with missing data will be imputed as non-responder. Point 
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estimate of the treatment difference and associated 95% confidence interval and p-values will be 
presented. 
 
6.1.4 
Examination of Subgroups 
The co-primary endpoints will be summarized descriptively by region, baseline augmentation, 
sex, race, and age (<65 years, ≥65 years). 
6.2 
SECONDARY EFFICACY ANALYSES 
6.2.1 
CGI-S on Day 42 
The number (percentage) of subjects of each CGI-S category on Day 42 will be summarized by 
treatment group. Treatment group differences for CGI-S scores will be assessed with the 
Cochran-Mantel-Haenszel test, with LOCF (Section 2.5), using baseline RLS medication-related 
augmentation and region (US, Europe) as the stratification factors at each time point. P-values to 
test treatment effect will be determined.  
 
6.2.2 
RLS-QLI, MOS Sleep Scale, and Fatigue Linear Analog Scale Change From 
Baseline to Day 42 
The actual values on baseline and Day 42, and the change from baseline to Day 42 will be 
summarized via descriptive statistics by treatment group for RLS-QLI, MOS sleep scale and 
fatigue linear analog scale, separately. Treatment group difference for change from baseline will 
be assessed with the analysis of covariance (ANCOVA) using LOCF (Section 2.5), with 
treatment, and region (US, Europe) and baseline RLS medication-related augmentation as fixed 
factors, and baseline score as a covariate, for each endpoint. P-values to test treatment effect will 
be determined. Point estimates, associated 95% confidence interval and p-values will be 
reported.  
A subject data listing will be provided by treatment for each endpoint. 
6.2.3 
Time off pre-enrollment prescribed RLS medications 
Subjects will start tapering of pre-enrollment prescribed RLS medications after Day 5 study drug 
administration until an intervention will be given. An intervention is defined as Section 6. 
Therefore, time off pre-enrollment prescribed RLS medications will be estimated with time from 
Day 5 to the next RLS intervention. The endpoint will be analyzed with log-rank test stratified 
by baseline RLS medication augmentation and region (US, Europe). P-value of the treatment 
effect will be reported.   Time from Day 5 to the next RLS intervention will be calculated as the 
date of the next RLS intervention minus date of Day 5 plus 1. Subjects who discontinue or 
complete the study before an intervention will be censored at last study visit. If the subject does 
not return to the clinic after Day 5, the subject will be censored at Day 5. Kaplan-Meier curves 
will be presented for each of the treatment groups.   
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6.3 
OTHER EFFICACY ENDPOINT(S) 
6.3.1 
Proportion of responders based on CGI-I / CGI-S at each time point 
A responder for CGI-I / CGI-S is defined as any improvement seen at each time point. The 
number (percentage) of responders will be summarized for each time point (clinical visits and 
telephone follow-ups) by treatment group, for CGI-I and CGI-S, separately. Treatment 
differences for proportions will be assessed using the Cochran-Mantel-Haenszel (CMH) test, 
with baseline RLS medication-related augmentation and region (US, Europe) as the stratification 
factors. Missing data at each time point will be imputed using LOCF as specified in Section 2.5. 
Point estimate of the treatment difference and associated 95% confidence interval and p-values 
will be presented. 
 
6.3.2 
IRLS, RLS-QLI, MOS Sleep Scale, and Fatigue Linear Analog Scale Change 
from baseline at each time point 
The actual values and the changes from baseline will be summarized for each time point (clinical 
visits and telephone follow-ups) via descriptive statistics by treatment group, for IRLS, RLS-
QLI, MOS sleep scale, and Fatigue Linear Analog Scale, separately. Treatment group difference 
for change from baseline will be assessed with the analysis of covariance (ANCOVA) using 
LOCF (Section 2.5), with treatment, and region (US, Europe) and baseline RLS medication-
related augmentation as fixed factors, and baseline score as a covariate, for each endpoint. P-
values to test treatment effect will be determined. Point estimates, associated 95% confidence 
interval and p-values will be reported.  
 
6.3.3 
CGI-I and CGI-S scores at each time point  
The number (percentage) of subjects of each CGI category will be summarized for each time 
point (clinical visits and telephone follow-ups) by treatment group, for CGI-S and CGI-I, 
separately. Treatment group differences for CGI scores will be assessed at each time point via 
Cochran-Mantel-Haenszel with LOCF (Section 2.5), using baseline RLS medication-related 
augmentation and region (US, Europe) as the stratification factors. P-value of treatment group 
difference will be determined and reported.  
 
6.3.4 
Augmentation assessment by Investigator change between baseline, Day 42, Day 
168 and end of study (Day 365) 
 
The number (percentage) of subjects of each category (no augmentation, uncertain augmentation, 
and definitive augmentation) will be summarized for baseline, Days 42, 168 and 365 by 
treatment group. 
 
The change from baseline will be summarized by a shift table for each post baseline visit above. 
Treatment group differences will be assessed at each post baseline time point with the Cochran-
Mantel-Haenszel test (row mean score), with LOCF (Section 2.5), using baseline RLS 
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medication-related augmentation and region (US, Europe) as the stratification factors. P-value of 
treatment group difference will be determined and reported. 
 
6.3.5 
Proportion of subjects required intervention for RLS 
The number (percentage) of subjects required intervention after the first dose of study drug will 
be summarized by treatment group. Treatment differences for proportions will be assessed using 
continuity-corrected chi-square test. p-values of treatment effect will be determined.  
 
6.3.6 
Time from Day 5 to the next dose of study drug 
Time from Day 5 to the next dose of study drug will be analyzed with log-rank test stratified by 
region (US, Europe) and baseline RLS medication augmentation. P-value of the treatment effect 
will be reported. Time from Day 5 to the next dose of study drug will be calculated as the date of 
the next dose of study drug minus Day 5 date plus 1. Subjects who discontinue or complete the 
study before receiving a second dose of study drug will be censored at last study visit. If the 
subject does not return to the clinic after Day 5, the subject should be censored at Day 5. The 
Kaplan-Meier curve will be presented for each of the treatment groups.    
A subject data listing will be provided by treatment for each efficacy endpoint. 
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: 
 Incidence of treatment emergent adverse events and incidence of serious adverse events 
 Clinical laboratory tests 
 Vital signs 
 Columbia-Suicide Severity Rating Scale (C-SSRS) 
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 18.0/AECODE). 
The verbatim term will be included in the AE listings. 
A treatment-emergent adverse event (TEAE) is defined as an AE that that occur or worsen on or 
after the first dose of study drug. Only TEAEs will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings. 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
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The incidence of TEAEs will be summarized as the number (percentage) of subjects with TEAEs 
within SOC and PT by treatment group.  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/RLS treatment tapering when summarized by relationship. 
If a subject reports multiple PT for a SOC, the subject will be counted only once for that SOC. 
Treatment related AEs are defined as those events recorded on the CRF as ‘Probably Related’ or 
‘Possibly Related’, others will not be related AEs. 
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 RLS treatment tapering related TEAEs 
o TEAEs by severity  
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 
 RLS treatment tapering related TEAEs by SOC and PT 
 SAEs by SOC and PT 
 TEAEs leading to study discontinuation by SOC and PT 
All AE tables will be sorted by SOC and PT in decreasing frequency of the number and 
percentage of subjects in the treatment group.   
7.1.1 
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.  
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
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7.2 
CLINICAL LABORATORY PARAMETERS 
Laboratory assessments include hematology, clinical chemistry, and iron indices/phosphorus: 
 Hematology: Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, differential 
count. 
 Clinical chemistry: sodium, potassium, chloride, BUN, creatinine, albumin, alkaline 
phosphatase, total bilirubin, gamma-GGT, AST, ALT, LDH, calcium,  glucose, 
bicarbonate. 
 Iron indices and Phosphorus: serum iron, serum ferritin, and total iron binding capacity 
(TIBC), percentage serum transferrin saturation (TSAT), transferrin receptor, 
Phosphorus. 
All laboratory parameters will be presented in conventional units. Quantitative results (including 
actual value, and change from baseline to each smallest value after baseline, largest value after 
baseline, and end of study) will be summarized using descriptive statistics by treatment, for each 
laboratory test group above. All laboratory data will be included in the listings. 
Laboratory test results will be assigned an LNH classification according to whether the value 
was below (L), within (N), or above (H) the laboratory parameter’s reference range.  Shifts from 
baseline to the smallest value after baseline, largest value after baseline, and end of study in 
low/normal/high classification for each parameter in hematology and clinical chemistry will be 
summarized by treatment group. 
The number and percent of subjects with treatment-emergent potentially clinically significant 
(PCS) laboratory values at any time after baseline will be summarized by treatment. The 
denominator is all subjects with normal baseline and at least one post baseline assessment in the 
safety population 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, PHYSICAL EXAMINATION FINDINGS, AND C-SSRS 
7.3.1 
Vital Signs 
Vital signs 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 only be collected immediately pre dosing. 
All vital signs will be presented in standard units. Frequency and percentage of subjects with 
values considered PCS occurring at any time post-baseline in dosing days will be summarized by 
visit (and time point) and by treatment. The denominator is all subjects with a baseline 
assessment in the safety population and the numerator is the number of subjects with PCS at 
post-baseline.  Criteria for PCS are presented below Table 3. 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
Page 24 of 27
 
 Table 3 
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.  
 
  
  
All vital sign data will be included in the listings 
 
7.3.2 
Physical Examination 
Physical examination (PE) results were collected at screening, Days 42, 168 and 365, including 
five body systems, i.e. skin, cardiovascular, pulmonary, abdominal, and central nervous system. 
Each component of the baseline physical examination will be recorded as normal or abnormal.  
Each component of the post baseline physical examinations will be recorded as No Significant 
Change from Previous PE or Significant Change from Previous PE.  
Physical examination results will be listed.  
 
7.3.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) questionnaire will be completed at 
screening (baseline), Days 42, 168 and 365. The number (percentage) of subjects with a “yes” 
response will be summarized and listed for each question each visit by treatment group. 
7.4 
OTHER ANALYSES 
Pregnancy test result (assessed at screening) will be listed. 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
Page 25 of 27
 
8. 
INTERIM ANALYSES AND DATA AND SAFETY MONITORING BOARD 
(DSMB)  
8.1 
INTERIM ANALYSES 
An interim analysis (IA) of efficacy will take place after all 200 subjects have completed Day 84.  
The efficacy endpoints analyzed will include: 
 The treatment group difference in the IRLS total score change from baseline to Day 28, 
Day 42 and Day 84 estimated using the same analysis method as in Section 6.1.1, i.e. 
ANCOVA. 
 The proportion of patients rated as much or very much improved with CGI-I on Day 42, 
and the treatment differences for proportions will be assessed with Logistic regression as 
in Section 6.1.2.  
 The number (percentage) of subjects who receive a second dose of study product between 
Day 42 and Day 84, and the number (percentage) of subjects who discontinue the study 
between Day 42 and Day 84.  Treatment difference for proportion will be assessed using 
Logistic regression with treatment, region (US, Europe), and baseline RLS medication 
related augmentation as fixed factors, and baseline IRLS total score as a covariate. 
All endpoints will be analyzed by treatment group in overall FAS population. For IRLS total 
score and CGI-I, additional subgroup analyses will be conducted:  
 by region (US vs. Rest of World) 
 by baseline RLS medication related augmentation (no augmentation, uncertain 
augmentation, definitive augmentation)  
Data from Day 0 to Day 84 will be frozen to generate IA results.  Therefore, no adjustment to 
Type I error will be made. 
 
8.2 
DATA AND SAFETY MONITORING BOARD (DSMB)  
 
The DSMB will be established and composed of approximately 3-5 senior academic individuals, 
including the DSMB Chair. They will have high-level expertise in neurology, hematology, 
cardiology and/or statistics. A senior statistician assigned to the trial from the group performing 
data management services for this trial will oversee the provision of interim data reports for use 
by the DSMB. The data management group for this trial will transfer pre-agreed datasets to the 
DSMB. During the Open Session of the DSMB meetings, the Study Chair or Luitpold 
representatives may present updates on the trial status or the safety profile of Ferric 
Carboxymaltose, but will not be privy to discussions of the data conducted during the Closed 
Sessions and will not vote. Proceedings and minutes of the Closed Session will be held in strict 
confidence and will not be shared outside the DSMB while the trial is ongoing. The DSMB will 
be responsible for the interests of the subjects and, to this end, will undertake reviews of the 
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
Page 26 of 27
 
safety data. The DSMB will have access to an agreed subset of the study data as listed in the 
DSMB charter (updated as necessary during the trial) throughout the study duration. In addition, 
the DSMB will evaluate the data approximately (as outlined in the Charter) either by face to face 
meeting or teleconference. The DSMB will determine if it believes the trial should be terminated 
early because clear evidence of a significant safety concern exists. 
 
If the DSMB finds it necessary to recommend actions regarding interruption of the study or 
changes to the protocol based on medical rationale that would make it unethical to continue the 
study in its present form, those recommendations will be forwarded to the Study Chair and 
Sponsor. The details of the DSMB's functions and the early stopping rules will be delineated in a 
separate DSMB charter. 
 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
Compared with the study protocol (June 02, 2016 Amendment IV), below items are the major 
changes made in this SAP:  
 
1. 
Efficacy analyses:  
 IRLS domain scores will not be analyzed, because only IRLS total score will be 
collected in EDC. 
 Baseline RLS medication-related augmentation will be included in statistical 
models where appropriate. In the protocol, it is not included. 
 CMH is the primary analysis method for CGI-I responder rate on Day 42 in study 
protocol. To get baseline covariate adjustment, Logistic regression model is 
proposed in this SAP. CMH will be performed as sensitivity analysis.   
 
2. 
Interim analysis: The IA timelines have been updated from what is currently specified in 
the protocol.  Originally, the IA was planned to take place once 100 subjects had 
completed Day 42, but due to a greater than anticipated rate of enrollment the IA will be 
performed after all 200 subjects have completed Day 84 to allow for a more accurate 
interpretation of the data. The change will be documented and submitted to FDA but not 
in a form of protocol amendment.  
 
3. 
Disposition will be summarized for all enrolled subjects vs. for safety and FAS 
populations proposed in protocol. Number (percentage) of subjects who complete the 
Day 42 visit will be included in disposition summary that is not specified in protocol.   
 
4. 
Medical history will be summarized for safety population vs. for all enrolled subjects 
proposed in protocol.  
 
 
 
 
 
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Final, 26 November 2018
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Sponsor: Luitpold Pharmaceuticals, Inc. 
 
Protocol No:  1VIT14037 Amendment IV  
Statistical Analysis Plan
 
 
Version: 1.0 (22-November-2016)  
Confidential 
Page 27 of 27
 
REFERENCES 
1. 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. 
 
 
 
 
 
 
 
 
 
 
2. 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-centered, placebo-controlled 
preliminary clinical trial.  Sleep Medicine 2011Oct;12(9):906-13.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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