Clinical trial NCT02410213
Conditions: Iron Deficiency Anemia (IDA)
Sponsor: American Regent, Inc.
Start date: 2015-02-19; Completion date: 2017-06-01
Enrollment: 35 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase II, open-label, non-randomized, multi-center, single arm study to characterize the pharmacokinetic and pharmacodynamics (PK/PD) profile of Ferric Carboxymaltose dosing in pediatric subjects with IDA after receiving either a 7.5 mg/kg or 15 mg/kg dose of Ferric Carboxymaltose.

Detailed description:
This is a Phase II, open-label, non-randomized, multi-center, single arm study to characterize the pharmacokinetic and pharmacodynamics (PK/PD) profile of Ferric Carboxymaltose dosing in pediatric subjects with IDA after receiving either a 7.5 mg/kg or 15 mg/kg dose of Ferric Carboxymaltose.

Arms: arm 1: FCM at 7.5 mg/kg or 15 mg/kg to a maximum single dose of 750 mg iron, whichever is smaller
Interventions: intervention 1: Ferric Carboxymaltose (FCM)
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
1 
LUITPOLD PHARMACEUTICALS, INC. 
PROTOCOL 
No. 1VIT13036 
 
IND #: 63,243 
 
 
A Multi-center, Open-label, Single Arm Study to Characterize the Pharmacokinetics and 
Pharmacodynamics Profile of Intravenous Ferric Carboxymaltose in Pediatric Subjects 1 – 
17 years old with Iron Deficiency Anemia (IDA) 
 
 
SPONSOR 
Luitpold Pharmaceuticals, Inc. 
Clinical Research and Development 
800 Adams Avenue 
Norristown, PA 19403 
(610) 650-4200 
 
 
 
 
Protocol Date: 27 March 2014 
Amendment I Date: 29 July 2014 
Amendment II Date: 08 October 2014 
 
 




CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 3 of 50 
Study Synopsis 
Protocol No. 1VIT13036 
Title:   
A Multi-center, Open-label, Single Arm Study to Characterize the 
Pharmacokinetics and Pharmacodynamics Profile of Intravenous Ferric 
Carboxymaltose in Pediatric Subjects 1 – 17 years old with Iron Deficiency 
Anemia (IDA). 
Drug:  
Ferric Carboxymaltose 
Objectives:   The primary objectives of this study are to characterize the pharmacokinetics and 
determine appropriate dosing and safety of Ferric Carboxymaltose for the 
pediatric population suffering from iron deficiency (ID) with anemia.  
 
Study Design:This is a Phase II, open-label, non-randomized, multi-center, single arm study to 
characterize the pharmacokinetic and pharmacodynamics  (PK/PD) profile of 
Ferric Carboxymaltose dosing in pediatric subjects with IDA after receiving either 
a 7.5 mg/kg or 15 mg/kg dose of Ferric Carboxymaltose®.  
 
Treatment 
 
Cohort 1: 16 subjects will be treated with Ferric Carboxymaltose at 7.5 mg/kg to a 
maximum single dose of 750 mg iron, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have 
completed 4 weeks of therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Ferric Carboxymaltose at 15 mg/kg to a 
maximum single dose of 750 mg iron, whichever is smaller.   
 
Inclusion Criteria:  
1. Male or female subjects 1 to 17 years of age with assent to participation and 
his/her parent or guardian is willing and able to sign the informed consent 
approved by the Independent Review Board / Ethics Committee.  
2. Screening TSAT < 20% 
3. Screening Hemoglobin < 11 g/dL 
4. For subjects who are receiving an erythropoietin stimulating agent (ESA): stable 
ESA therapy (+/- 20% of current dose) for > 8 weeks prior to the qualifying 
screening visit and no ESA dosing or product changes anticipated for the length 
of the trial 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 4 of 50 
Exclusion Criteria:    
1. Known hypersensitivity reaction to any component of Ferric Carboxymaltose. 
2. Subject previously randomized and treated in this study or any other clinical study 
of Ferric Carboxymaltose (FCM or VIT-45). 
3. Body mass index (BMI) ≤ 5th percentile for age (see APPENDIX 2) 
4. Male or Female subject 1 year of age weighing < 12kg. 
5. History of acquired iron overload, hemochromatosis or other iron accumulation 
disorders. 
6. Chronic kidney disease subjects on hemodialysis. 
7. Screening Ferritin level > 300ng/mL 
8. Subjects with significant severe diseases of the liver, hemopoietic system, 
cardiovascular system, psychiatric disorder or other conditions which on the 
opinion of the investigator may place a subject at added risk. 
9. Any active infection.  
10. Known positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody (HCV) 
with evidence of active hepatitis. 
11. Known positive HIV-1/HIV-2 antibodies (anti-HIV). 
12. Anemia due to reasons other than iron deficiency (i.e. hemoglobinopathy). 
Subjects treated with vitamin B12 or folic acid deficiency are permitted. 
13. Intravenous iron and /or blood transfusion in the 4 weeks prior to screening.  
14. Immunosuppressive therapy that may lead to anemia (i.e. cyclophosphamide, 
azathioprine, mycophenolate mofetil).  Note steroid therapy is permitted. 
15. Administration and / or use of an investigational product (drug or device) within 
30 days of screening. 
16. Alcohol or drug abuse within the past six months. 
17. Female subjects who are pregnant or lactating, or sexually active female who are 
of childbearing potential not willing to use an acceptable form of contraceptive 
precautions during the study. 
18. Subject is unable to comply with study assessments. 
 
Subject 
Assessments:  
All subjects that provide informed consent / assent will enter a screening period 
up to 14 days prior to Day 0.  During this time subjects will be evaluated to insure 
they meet the study entry criteria.  Subjects will have vital signs, medical history 
review and laboratory samples to include hematology, chemistries and iron 
indices.  Once it has been determined the subject qualifies for participation the 
subject will be scheduled to return to the clinic 1 day prior to Day 0 (Day -1) at 
which time additional blood samples will be taken (8am, 12pm and 8pm) to 
characterize the subjects iron profile. 
 
Blood samples for PK/PD will also be assessed immediately prior to Ferric 
Carboxymaltose dosing on Day 0, at 1, 2, 6, 12, 24, 48 hours and at 72 hours.  
 
Safety assessments, including vital signs and adverse events, will be assessed 
starting on Day 0 at the time of Ferric Carboxymaltose dosing through Day 35.   


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 5 of 50 
Erythropoietin 
Dosage: 
 
If receiving an Erythropoiesis Stimulating Agent (ESA), a stable (± 20%) dose is 
required for > 8 weeks prior to screening.  The ESA type, route, frequency and 
dose will remain unchanged throughout the remainder of the study unless the dose 
should be decreased or held per the package label.  Once decreased or held, it may 
not be increased or restarted unless thought necessary by the subject’s physician. 
If the latter event occurs, the ESA dose changes will be collected and the subject 
will continue for safety analysis. 
Study Duration 
per subject:  up to 9 weeks  
Number of  
Subjects:   
32 subjects 
Sites:   
Approximately 10 
Sample Size: 
 
Determination of sample size for this single-arm, pediatric, pharmacokinetic study 
is a compromise between obtaining sufficiently precise estimates of 
pharmacokinetic parameters and the ethics of including a large number of 
pediatric patients in an experiment. The precision of estimation can be quantified 
as the width of the 95% confidence interval for AUC0-72 from this single-arm 
study (i.e., smaller width indicates better precision). Based on Study VIT-IV-CL-
002 in adults, the standard deviation for total serum iron AUC0-72 following a 500 
mg intravenous dose is approximately 300 µg◦hour/mL. The width of a 95% 
confidence interval, using a standard deviation of 300 µg◦hour/mL, is presented 
below for selected sample sizes. As seen in the figure, 16 patients appears to be a 
reasonable compromise between precision and number of exposed pediatric 
patients.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 6 of 50 
 
 
Approximately 32 subjects will be enrolled in this study, 16 subjects in cohort I 
and 16 subjects in cohort II.  Within each cohort of 16 subjects will be equally 
distributed by age, which will include 8 subject’s 1 – 6 years of age and 8 
subjects > 6 – 17 year of age.   Subject enrollment and ages will be tracked and 
monitored via interactive web response (IWR) system. 
 
0 
100 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1100 
1200 
1300 
1400 
1500 
0 
8 
16 
24 
32 
40 
48 
56 
64 
Width of 95% CI 
Number of Subjects 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 7 of 50 
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 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 8 of 50 
TABLE OF CONTENTS 
1.0 INTRODUCTION .................................................................................................................... 12 
1.1 
Treatment of Iron Deficiency Anemia ............................................................................ 12 
1.2 
Ferric Carboxymaltose .................................................................................................... 13 
1.2.1 
Key features of Ferric Carboxymaltose ...................................................................... 13 
1.2.2 
Ferric Carboxymaltose versus Other Parenteral Iron Agents ................................... 13 
1.2.3 
Ferric Carboxymaltose Human Experience ............................................................... 14 
2.0 MAIN TRIAL OBJECTIVE ..................................................................................................... 15 
3.0  
OVERALL STUDY DESIGN AND RATIONALE .......................................................... 16 
3.1 
 Trial Design ................................................................................................................... 16 
3.2 
Rationale ......................................................................................................................... 16 
3.2.1 
Rationale for Trial Design .......................................................................................... 16 
4.0  
SUBJECT SELECTION ..................................................................................................... 18 
4.1 
Number and Type of Subjects......................................................................................... 18 
4.2 
Screening Phase .............................................................................................................. 18 
4.2.1  
Entry Criteria .......................................................................................................... 18 
4.3 
Subject Assignment and Registration Process ................................................................ 19 
4.4 
Withdrawal from Study................................................................................................... 19 
4.5 
Intervention ..................................................................................................................... 19 
5.0 STUDY DRUG ......................................................................................................................... 20 
5.1 
Formulation Packaging and Storage ............................................................................... 20 
5.2 
Drug Administration / Regimen...................................................................................... 20 
5.3 
IV Iron Precautions ......................................................................................................... 21 
5.4 
Drug Accountability........................................................................................................ 21 
5.5 
Concomitant Medication ................................................................................................. 21 
6.0 STUDY PROCEDURES .......................................................................................................... 22 
6.1 
Informed Consent............................................................................................................ 22 
6.2 
Screening (up to 14 days) ............................................................................................... 22 
6.3 
Study Visits .................................................................................................................. 23 
6.3.1. 
Day (-1) ................................................................................................................... 23 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
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6.3.2 
Day 0 ........................................................................................................................... 23 
6.3.2. 
Days 1 and 2 (24 and 48 hour) ............................................................................... 23 
6.3.3. 
 72 hour, and Days 14 and 28 (weeks 2 and 4)....................................................... 24 
6.3.4. 
Day 35 (week 5) End of Study ................................................................................. 24 
6.3.5. 
Pharmacokinetics and Pharmacodynamics (PK/PD) ............................................. 24 
6.4 
Central Laboratory Assessments..................................................................................... 25 
7.0  
ASSESSMENT OF SAFETY ............................................................................................. 25 
7.1 
Adverse Events ............................................................................................................... 25 
7.2 
Reporting of Adverse Events .......................................................................................... 27 
7.3 
Serious Adverse Events .................................................................................................. 27 
8.0 STATISTICS ............................................................................................................................ 28 
8.1 
 Sample Size .................................................................................................................... 28 
8.2 
Analysis Populations ....................................................................................................... 29 
8.3 
Demographic Characteristics .......................................................................................... 29 
8.4 
Endpoints and Definitions............................................................................................... 30 
8.4.1 
Clinical Endpoints ...................................................................................................... 30 
8.5 
 Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints .................................... 30 
8.6 
Statistical Analyses of Safety .......................................................................................... 31 
8.7 
DSMB Analyses.............................................................................................................. 31 
9.0 ADMINISTRATIVE CONSIDERATIONS ............................................................................. 31 
9.1 
Retention and Availability of Records ............................................................................ 31 
9.2 
Investigator Responsibilities ........................................................................................... 32 
9.3 
Financial Disclosure........................................................................................................ 32 
9.4 
Advertisement for Subject Recruitment.......................................................................... 33 
9.5 
Documents Required for Study Initiation ....................................................................... 33 
9.6 
Quality Control and Quality Assurance .......................................................................... 33 
9.6.1 
Investigator Selection Criteria .................................................................................... 33 
9.6.2 
Clinical Monitoring .................................................................................................... 33 
9.6.3 
Quality Assurance Audit ............................................................................................. 34 
9.7 
Ethics............................................................................................................................... 34 
9.7.1 
Ethical and Legal Issues ............................................................................................. 34 


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9.7.2 
Institutional Review Board ......................................................................................... 34 
9.7.3 
Informed Consent ........................................................................................................ 34 
9.7.4 
Good Clinical Practice ............................................................................................... 35 
9.8 
Data Handling and Record Keeping ............................................................................... 35 
9.8.1 
Electronic Case Report Form (eCRF) ........................................................................ 35 
9.8.2 
Confidentiality............................................................................................................. 35 
9.8.3 
Termination of the Study ............................................................................................. 36 
9.8.4 
Protocol Revisions ...................................................................................................... 36 
9.8.5 
Protocol Administrative Changes ............................................................................... 36 
9.9 
Publication Policy ........................................................................................................... 37 
10.0  GOVERNANCE COMMITTEE ........................................................................................ 37 
10.1 
Data and Safety Monitoring Board............................................................................. 37 
INVESTIGATOR’S ACKNOWLEDGEMENT ............................................................................ 39 
REFERENCES .............................................................................................................................. 40 
APPENDIX 1:  FERRIC CARBOXYMALTOSE PACKAGE INSERT ................................ 42 
APPENDIX 2:  WEIGHT CHARTS FOR BOYS AND GIRLS ................................................... 43 
APPENDIX 3:  ADMENDMENT I CHANGES ........................................................................ 47 
APPENDIX 4:  ADMENDMENT II CHANGES ....................................................................... 49 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 11 of 50 
LIST OF ABBREVIATIONS 
AE 
 
 
 
 
Adverse event 
BP 
Blood Pressure 
BW 
Body Weight 
CI 
confidence interval 
CKD 
Chronic Kidney Disease 
conc. 
concentration 
CTCAE 
Common Terminology Criteria for Adverse Event 
dL 
Deciliter 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture 
e.g. 
for example 
ESA 
Erythropoiesis stimulating agent 
FDA 
Food and Drug Administration 
Fe 
Iron 
g 
Gram 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HMW 
high molecular weight 
IBD 
Inflammatory Bowel Diease 
ICH 
International Conference on Harmonisation 
IDA 
Iron Deficiency Anemia 
i.e. 
that is/ such that 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVP 
Intravenous injection (push) 
kg 
Kilogram 
L 
Liter 
LMW 
low molecular weight 
LOS 
length of stay 
MedDRA 
Medical dictionary for regulatory activities 
mg  
Milligram 
mL 
Milliliter 
ng 
Nanogram 
PET 
positron emission tomography 
p.o. 
by mouth or orally 
RES 
Reticuloendothelial system 
SAE 
Serious adverse event 
t1/2 
Terminal half-life 
t.i.d. 
three times a day 
TSAT 
Transferrin Saturation 
US 
United States 
vs 
Versus 
w/v 
weight / volume 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 12 of 50 
1.0 
INTRODUCTION 
1.1 
Treatment of Iron Deficiency Anemia 
Iron deficiency anemia (“IDA”) remains the most common nutritional deficiency in children in 
the United States.  Rapid growth, insufficient dietary intake, and limited absorption of dietary 
iron combine to place children at increased risk for iron deficiency. Iron deficiency may 
contribute significantly to anemia due to malabsorption, gastrointestinal blood loss, or 
iatrogenically due to repeated blood samplings.  As a result of severe digestive tract disorders, 
some children are unable to tolerate oral iron supplementation or are unresponsive to it.1 Anemia 
may also decrease survival rates in patients (both adults and children) with chronic renal 
impairment where it is a commonly encountered problem2;3 In addition, anemia is a commonly 
encountered manifestation of pediatric inflammatory bowel disease which is associated with a 
decrease in the quality of life and increased hospitalization. 
 
Non-hematologic consequences of iron deficiency include poor weight gain, anorexia, 
irritability, decreased attention span, exercise intolerance and decreased physical activity. 4  
However, IDA in infants and toddlers is associated with long-lasting diminished mental, motor, 
and behavioral functioning.  Although the exact relationship between iron deficiency anemia and 
the developmental effects is not well understood, it appears that these effects do not occur until 
iron deficiency becomes severe and chronic enough to produce anemia. 5 
 
Options for correcting iron deficiency include both oral and parenteral formulations. As 
previously described, some children are unable to tolerate or are non-responsive to oral iron.  
Blood transfusion is an option to treat anemia and restore iron requirements, but the potential risk 
of blood-transmitted virus infection limits its use to severe and badly tolerated anemia. In view 
of the limitations associated with oral iron or blood transfusions, intravenous administration is an 
important option. 
 
Multiple parenteral iron products are available. These vary in complex types which impacts the 
total amount of iron that may be administered in a single administration. Numerous other 
differences differentiate the products; however, all appear to effectively release iron post 
administration and restore the deficit of the patient. There are numerous studies with iron sucrose 
injection (Venofer®) that have been performed in the pediatric population 6-8. Iron doses have 
varied in the studies with demonstrated efficacy and safety in doses up to 7mg iron/kg or 200mg 
given in time frames of 3 min, which was shown to be beneficial to both the child and health care 
facility6.  
Ferric Carboxymaltose has been characterized as a robust and strong type iron complex (Type 1) 
with a molecular mass of about 150,000 Daltons (Da). The solution is a dark brown color with a 
near neutral pH (5.0 to 7.0) and a physiological osmolarity permitting administration of higher 
single doses in short time periods. Although no interventional studies have been conducted with 
Ferric Carboxymaltose in the pediatric population to date, the product has been used in clinical 
practice in markets where it is currently approved for adults to aid correction of iron deficiency 
within the pediatric gastroenterological setting.  A non-interventional/retrospective observational 
data collection has identified in 79 patient’s aged 2 to 18 years with a mean age of 12.7 years.  In 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 13 of 50 
these subjects, Ferric Carboxymaltose showed efficacy with regard to hemoglobin, ferritin, and 
TSAT as well as safety and tolerability (manuscript in preparation).  
Therefore, the proposed studies will assess higher single doses (i.e., 7.5 mg/kg and 15 mg/kg) 
than those used with currently available parenteral iron preparations in iron deficient children 
with anemia to characterize the pharmacokinetics and pharmacodynamics in this younger 
population.  The higher single doses permit fewer overall injections/infusions and may ultimately 
permit fewer visits to the treating facilities positively impacting both the child and family as well 
as health care system. 
1.2 
Ferric Carboxymaltose   
1.2.1 Key features of Ferric Carboxymaltose 
Ferric Carboxymaltose Injection is a stable Type I polynuclear iron (III)-hydroxide carbohydrate 
complex developed as an intravenous iron replacement therapy for the treatment of IDA. After 
intravenous administration, Ferric Carboxymaltose is mainly found in the liver (RES), 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 Ferric Carboxymaltose 
is metabolized by the glycolytic pathway.   
1.2.2 Ferric Carboxymaltose versus Other Parenteral Iron Agents 
There is considerable efficacy and safety experience with the various parenteral iron preparations 
available (3).  However, prior to the approval of non-dextran formulations, the risk of systemic 
adverse reactions restricted their use.  Ferric Carboxymaltose offers significant advantages 
compared to other available intravenous 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% (6).  Over the last 20 years, 30 deaths have been attributed 
to the use of IV iron dextran. The high incidence of anaphylaxis/anaphylactoid reactions is 
believed to be caused by the formation of antibodies to the dextran moiety.   Although some have 
suggested that high molecular weight (HMW) iron dextran is 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 (7).  Iron dextran is limited to second line therapy for treatment of iron 
deficiency.   
More recently approved, non-dextran intravenous 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 IV iron compounds carry a significant risk of bioactive iron reactions at higher doses.  
These reactions are characterized by hypotension (without allergic signs) accompanied by pain in 
the chest, abdomen, flank and/or nausea, vomiting, diarrhea.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment II Date: 08 October 2014 
Page 14 of 50 
 
 
Due to its structure, Ferric Carboxymaltose is more stable than iron gluconate and iron sucrose, 
producing 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 sucrose11 (data on file ).  These 
characteristics of Ferric Carboxymaltose make it possible to administer much higher single doses 
over shorter periods of time than iron gluconate or iron sucrose, resulting in the need for fewer 
administrations to replenish iron stores, consequently making it better suited for outpatient use 
(Table 1.2.2.1).  Another recently approved IV iron is ferumoxytol (AMAG) in which 510 mg 
can be injected rapidly on 2 occasions separated by several days.  This formulation, which is 
currently indicated for IDA associated with CKD, is a modified-dextran derivative and is 
indicated for a 1020 mg repletion dose (see Ferumoxytol PI).  
 
Table 1.2.2.1     Administration of at least 1500 mg of Intravenous Iron with Currently 
Available Iron Preparations and Ferric Carboxymaltose 
Iron 
Preparation 
Test Dose 
Required 
Maximum 
Infusion Dose 
 
Infusion Time 
Number of 
Infusions 
Iron dextran 
Yes 
100 mg* 
2 minutes 
15 + test dose 
Iron gluconate 
No 
125 mg 
10 minutes 
12 
Iron sucrose 
No 
200 mg 
5 minutes 
8 
Iron sucrose 
No 
300mg 
1.5 hours 
5 
Iron sucrose 
No 
400 mg 
2.5 hours 
4 
ferumoxytol 
No 
510 mg 
< 1 minute 
3 
Ferric 
Carboxymaltose 
No 
750 to 1000 mg** 
8 to 15 minutes 
2 
* Higher doses are administered off label and are approved outside the US 
**1000 mg maximum dose is approved in countries outside of the US; 750 mg maximum is the U.S. FDA approved 
dose  
 
The larger Ferric Carboxymaltose and ferumoxytol doses result in less frequent administration of 
intravenous iron that should benefit, in particular, severely iron deficient and anemic 
populations. To be treated with currently available intravenous iron agents, the average 
inflammatory bowel disease, postpartum,  heavy uterine bleeding and non-dialysis dependent 
patient would require an initial test dose, followed by 15 doses of iron dextran as labeled, each 
accompanied by personnel equipped and trained for resuscitation of anaphylaxis; 12 doses of 
ferric gluconate; or either 8 doses of iron sucrose (with 5 minute infusion time) or 5 / 4 doses of 
iron sucrose by prolonged (1.5 to 2.5 hours) intravenous infusion. Ferric gluconate and iron 
sucrose are not approved by the FDA for the treatment of IDA in non chronic kidney disease 
populations and iron dextran is only approved as second line therapy for treatment of iron 
deficiency.  In contrast, most patients treated with Ferric Carboxymaltose would require 2 doses 
administered over 8 to15 minutes one week apart.   
 
1.2.3 Ferric Carboxymaltose Human Experience 
 
The Ferric Carboxymaltose development program demonstrated the safety and effectiveness of 
intravenous Ferric Carboxymaltose in the treatment of IDA.  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 Ferric Carboxymaltose.  


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Amendment II Date: 08 October 2014 
Page 15 of 50 
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 Ferric 
Carboxymaltose 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, compared with 2 to 13% for iron sucrose.  The projected terminal half-life (t½) was 
calculated to approximately 16 hours, compared to 3 to 4 days for iron dextran and 6 hours for 
iron sucrose. An ascending dose pharmacokinetic study (VIT-IV-CL-002), demonstrated that 
following the 500 and 1,000 mg Ferric Carboxymaltose dose, the majority of the Ferric 
Carboxymaltose iron complex was utilized or excreted by 72 hours. 
Phase III studies demonstrated the effectiveness of Ferric Carboxymaltose in treating IDA 
secondary to inflammatory bowel disease, heavy uterine bleeding, chronic kidney disease 
(hemodialysis and non-hemodialysis) and the postpartum state.  Clinically meaningful increases 
in hemoglobin, ferritin, and TSAT were observed in each of the studies. Non-inferiority to full 
therapeutic doses of oral ferrous sulfate was demonstrated in studies of IDA associated with 
inflammatory bowel disease. Superiority to full therapeutic doses of oral ferrous sulfate was 
demonstrated in studies of IDA secondary to heavy uterine bleeding, the postpartum state and 
non-hemodialysis dependent chronic kidney disease.  A head to head comparison of Ferric 
Carboxymaltose to Venofer (Iron sucrose)  in over 2,500 subjects with non-dialysis dependent 
CKD and elevated risk of cardiovascular disease according to the Framingham criteria 
demonstrated that the recommended dose of Ferric Carboxymaltose, 750 mg x 2 (1500 mg total) 
had superior efficacy to the labeled dose of Iron sucrose (200 mg x 5 [1000 mg total]) with 
regard to hemoglobin elevation and had a similar cardiovascular (and overall) safety profile, 
based in part on an independently adjudicated composite cardiovascular safety endpoint (8) . 
 
Important details of pre- and clinical safety and efficacy can be found in the Investigator’s 
Brochure. Ferric carboxymaltose received approval from the UK Medicines and Healthcare 
products Regulatory Agency (MHRA) approval on June 15, 2007 for the use of Ferric 
Carboxymaltose (EU Trade name: Ferinject) in 18 EU (European Union) 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, Ferric Carboxymaltose 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.  
Ferric Carboxymaltose received approved from the Food and Drug Administration (FDA) on 
July 25, 2013 for marketing in the United States. 
2.0 
MAIN TRIAL OBJECTIVE 
The primary objectives of this study are to characterize the pharmacokinetics and determine 
appropriate dosing and safety of Ferric Carboxymaltose for the pediatric population suffering 
from iron deficiency (ID) with anemia.  


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3.0  
OVERALL STUDY DESIGN AND RATIONALE 
3.1 
 Trial Design 
This is a phase II, open-label, non-randomized,  multi-center, single arm study to characterize the 
pharmacokinetic and pharmacodynamics  (PK/PD) profile of Ferric Carboxymaltose dosing in 
pediatric subjects with IDA after receiving either a 7.5 mg/kg or 15 mg/kg dose of Ferric 
Carboxymaltose.  
 
Cohort 1: 16 subjects will be treated with Ferric Carboxymaltose at 7.5 mg/kg 
with a maximum single dose of 750 mg, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have 
completed 4 weeks of therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Ferric Carboxymaltose at 15 mg/kg 
with a maximum single dose of 750 mg, whichever is smaller.   
 
3.2 
Rationale 
3.2.1 Rationale for Trial Design 
Ferric Carboxymaltose is a non-dextran IV iron recently approved by the United States Food and 
Drug Administration (FDA).  This trial is designed to assess the single doses (i.e., 7.5 mg iron/kg 
and 15 mg iron/kg) in iron deficient children with anemia to characterize the pharmacokinetics 
and pharmacodynamics in this younger population.  
3.2.2 Rationale for open label design 
The open-label, single arm trial design is considered appropriate because a control group is not 
required to estimate the PK/PD profile of Ferric Carboxymaltose.  The risk from exposure to 
another form of IV iron is not offset by the minimal scientific benefit. 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 17 of 50 
3.2.3. Schedule of Events 
Visit Day 
Screening 
Period 
(Up to 14 
Days) 
Day 
-1 
Day 
0 
24 and 48 
hours 
post 
dosing 
72 hours 
post 
dosing 
Day 14 
(week 2) 
Day 28 
(week 4) 
Day 35 
(week 5) 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Assess entry 
criteria 
X 
 
X 
 
 
 
 
 
EDC 
X 
 
X 
 
 
 
 
X 
Medical History 
X 
 
X 
 
 
 
 
 
Physical Exam1 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
 
X 
 
X 
X 
X 
X 
Height / Weight 
 
 
X 
 
 
 
 
 
PK/PD Samples 
 
X2 
X3 
X4 
X4 
 
 
 
Hematology, 
Chemistry and 
Iron Indices 
X 
 
 
 
X 
X 
X 
X 
Serum 
pregnancy test 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
 
X 
 
X 
X 
X 
X 
ESA Stability 
X 
 
X 
 
X 
X 
X 
X 
Adverse Event 
Assessments5 
 
 
X 
X 
X 
X 
X 
X 
Ferric 
Carboxymaltose
 
 
X 
 
 
 
 
 
1 Includes clinical assessment of skin, cardiovascular, pulmonary, abdominal, and central nervous system 
2 Blood samples drawn at 8am, 12pm and 8pm for subject iron profile 
3 Blood samples PK/PD should be taken prior to Ferric Carboxymaltose dosing and additional samples for PK/PD 
should be taken at 1, 2, 6 and 12 hours post dosing.  
4 Blood samples should be taken approximately the same time of day as the Day 0 samples were drawn 
5 Adverse event assessments starting at the time of Ferric Carboxymaltose dosing 
6 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-dose only.  Vital signs on non-dosing days 
include sitting heart rate and blood pressure only. 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 18 of 50 
4.0  
SUBJECT SELECTION 
4.1 
Number and Type of Subjects 
Up to thirty two  (32) subjects who have given written informed consent / assent along with 
parent or guardian’s written informed consent with a diagnosis of iron deficiency anemia (IDA) 
who fulfill the inclusion criteria, do not meet any of the exclusion criteria will be registered to 
receive Ferric Carboxymaltose.    
 
4.2 
Screening Phase 
 
Once a subject enters the screening phase, they will be assigned, via the Electronic Data Capture 
(EDC) system, a unique screening number.  From the time of consent until the start of treatment 
of IV Ferric Carboxymaltose, the subject will not receive any form of iron outside of the study 
(intravenous or blood transfusion iron from 4 weeks prior to consent or oral iron including 
multivitamins with iron from time of consent).   
If the subject does not qualify for study entry the subject should be entered into the EDC system 
as a screen failure.  Subjects can be re-screened once, see section 6.2.   
4.2.1  Entry Criteria 
Inclusion Criteria: 
 
1. Male or female subjects 1 to 17 years of age with assent to participation and his/her parent 
or guardian is willing and able to sign the informed consent approved by the Independent 
Review Board / Ethics Committee.  
2. Screening TSAT < 20% 
3. Screening Hemoglobin < 11 g/dL 
4. For subjects who are receiving a erythropoietin stimulating agent (ESA): stable ESA therapy 
(+/- 20% of current dose) for > 8 weeks prior to the qualifying screening visit and no ESA 
dosing or product changes anticipated for the length of the trial. 
 
Exclusion Criteria:    
1. Known hypersensitivity reaction to any component of Ferric Carboxymaltose. 
2. Subject previously randomized and treated in this study or any other  clinical study of Ferric 
Carboxymaltose (FCM, VIT-45). 
3. Body mass index (BMI) ≤ 5th percentile for age (see APPENDIX 2) 
4. Male or Female subject 1 year of age weighing < 12kg. 
5. History of acquired iron overload, hemochromatosis or other iron accumulation disorders. 
6. Chronic kidney disease subjects on hemodialysis. 
7. Screening Ferritin level > 300 ng/mL. 
8. Subjects with significant severe diseases of the liver, hemopoietic system, cardiovascular 
system, psychiatric disorder or other conditions which on the opinion of the investigator 
may place a subject at added risk. 
9. Any active infection.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 19 of 50 
10. Known positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody (HCV) with 
evidence of active hepatitis. 
11. Known positive HIV-1/HIV-2 antibodies (anti-HIV). 
12. Anemia due to reasons other than iron deficiency (i.e. hemoglobinopathy). Subjects treated 
with vitamin B12 or folic acid deficiency are permitted. 
13. Intravenous iron and /or blood transfusion in the 4 weeks prior to screening.  
14. Immunosuppressive therapy that may lead to anemia (i.e. cyclophosphamide, azathioprine, 
mycophenolate mofetil).  Note steroid therapy is permitted. 
15. Administration and / or use of an investigational product (drug or device) within 30 days of 
screening. 
16. Alcohol or drug abuse within the past six months. 
17. Female subject who are pregnant or lactating, or sexually active female who are of 
childbearing potential not willing to use an acceptable form of contraceptive precautions 
during the study. 
18. Subject is unable to comply with study assessments. 
4.3 
Subject Assignment and Registration Process 
Subjects that meet all inclusion requirements and no exclusionary criteria will be offered 
participation in this 7 week study. Cohorts 1 and 2 will be enrolled and treated sequentially.  
Enrollment into Cohort 2 will not begin until  all Cohort 1  subjects have completed 4 weeks of 
therapy and no safety issues with the administration of Ferric Carboxymaltose has been 
confirmed by the DSMB. 
4.4 
Withdrawal from Study 
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.  
At the time of withdrawal, procedures for the Day 35 visit must be performed regardless of 
whether the subject has completed study drug treatment.  In the event the subject has received 
any study drug; the subject should be contacted to assess adverse events 28 days post the last 
dose of Ferric Carboxymaltose, if possible. 
 
In the event a subject withdraws without completing the full PK/PD sampling.  Additional 
subjects may be enrolled to ensure adequate representations of the PK/PD parameters are 
available for analyses.  Conditions for additional enrollment will be defined in more detail in the 
statistical analyses plan. 
 
4.5 
Intervention 
Intervention is defined as follows: 
 Increase in dose of erythropoietin for any reason (Day 0 thru Day 35). 
 Blood transfusion.    
 Use of IV iron outside of protocol.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 20 of 50 
 Use of oral iron outside the protocol.  
When intervention occurs, the date of the intervening event should be recorded in the source 
documents as well as the electronic Case Report Form (eCRF), and the subject should continue 
in the study as scheduled through Day 35. 
5.0 
STUDY DRUG 
5.1 
Formulation Packaging and Storage 
All medication to be used in this study that has been supplied by Vifor Pharma Ltd. will have 
been prepared according to Good Manufacturing Practices (GMP).  
Ferric Carboxymaltose (known in the EU as Ferinject®) will be supplied 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.   
Study drug must be kept in a secure place at the investigational site, and stored at room 
temperature (see: USP).  Ferric Carboxymaltose should not be frozen.  Vials may not be used 
for more than 1 dose or for more than 1 subject.  All Ferric Carboxymaltose vials used and 
unused should be kept by the study staff. 
 
5.2 
Drug Administration / Regimen 
 
The Principal Investigator or designee will supervise administration of the study drug to subjects: 
Cohort 1: 16 subjects will be treated with Ferric Carboxymaltose at 7.5 mg/kg with a 
maximum single dose of 750 mg, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have 
completed 4 weeks of therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Ferric Carboxymaltose at 15 mg/kg with a 
maximum single dose of 750 mg, whichever is smaller.   
Ferric Carboxymaltose will be given on Day 0.  It will be administered as either: 
 
 An undiluted slow IV push at a rate of 100 mg/minute. 
 Doses less than 100 mg should be given as a slow undiluted IV push within a 
minute. 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 21 of 50 
5.3 
IV Iron Precautions 
When administering IV Iron, the following precautions will be taken: 
 The subject will be clinically evaluated prior to drug administration to assess the 
development of clinically significant conditions.   
 The vials will be visually inspected for particulate matter and discoloration before 
each use; if noted, the vial will not be used and the Investigator or his/her designee 
will notify the sponsor, or sponsor’s designee, for replacement of the study drug and 
for directions to return the unused vial.     
 Sitting heart rate and blood pressure will be assessed pre-, 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  
5.4 
Drug Accountability 
Investigators will keep adequate records of the receipt, administration and return of Ferric 
Carboxymaltose.  They will not allow Ferric Carboxymaltose 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 registered 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 Ferric 
Carboxymaltose will be returned to Luitpold Pharmaceuticals, Inc. (or their designee).  All data 
regarding Ferric Carboxymaltose must be recorded on the Drug Accountability Forms provided 
by the sponsor.  
Investigators will keep adequate records of the administration and disposition of IV Ferric 
Carboxymaltose® used for patients selected for the trial.  
5.5 
Concomitant Medication 
 
Concomitant medications along with their route of administration and duration must be recorded 
in the electronic case report form (eCRF) from 30 days prior to consent.  No additional iron 
preparations (IV iron from 4 weeks  prior to consent or oral iron including multivitamins 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 22 of 50 
with iron, from time of consent), will be allowed.  No prophylactic medications may be 
administered prior to Ferric Carboxymaltose administration without prior approval from 
Luitpold Pharmaceuticals, Inc.  
If receiving an Erythropoiesis Stimulating Agent (ESA), a stable (± 20%) dose is required for > 8 
weeks prior to consent.  The ESA type, route, frequency and dose will remain unchanged 
throughout the study unless the dose should be decreased or held per the package label.  Once 
decreased or held, it may not be increased or restarted unless thought necessary by the subject’s 
physician. If the latter event occurs, these data points will be collected and the subject will 
continue for safety analysis. 
 
 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 (who for this trial is 1 -17 years old) 
must assent, if appropriate and his/her legal guardian (who is above age of legal consent) 
voluntarily sign an informed consent statement (Required Elements of Informed Consent, 21 
CFR 50.25).  The Code of Federal Regulations (CFR) is a codification of rules and regulations of 
the United States government.  The subject’s legal guardian will be given a copy of the signed 
consent form. 
6.2 
Screening (up to 14 days)  
Each subject who qualifies for inclusion will undergo the following clinical evaluations to 
confirm their eligibility for the study: 
 Obtain screening number from EDC 
 Medical history, including prior iron therapy use  
 Vitals signs (including sitting heart rate and blood pressure)  
 Hematology, Chemistries and iron indices  
 Serum pregnancy test for female subjects of child bearing potential (negative results must 
be obtained prior to registering the subject for study drug dosing). 
 Concomitant medications assessment 
 ESA therapy stability ( if applicable)  
Subjects who do not meet the entry criteria should be entered into the 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 in 
section 6.2 will need to be repeated. 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 23 of 50 
6.3 
Study Visits  
6.3.1. Day (-1)  
Once it’s confirmed during the screening period that the subject continues meet the entry criteria 
all eligible subjects will return to the clinic on Day – 1, blood samples will be drawn at 8am, 
12pm and 8pm to characterize the subject iron profile.   
6.3.2 Day 0 
On Day 0, prior Ferric Carboxymaltose dosing the following will occur:  
 Re-verify the inclusion and exclusion criteria 
 Update any relevant history 
 Basic physical exam including clinical assessment of skin, cardiovascular, pulmonary, 
abdominal and central nervous system.  
 Height  
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 Log on to the EDC system and register subject for study drug dosing. The EDC system 
will assign the subject into Cohort 1 or 2 treatment group. 
 
After assignment of the treatment group (Cohort 1 and 2) the following will occur: 
 
 Blood samples for PK/PD before start of dose. 
 Weight in kg without shoes 
 Verify amount of single Ferric Carboxymaltose dose (7.5 or 15 mg/kg up to a 
maximum dose of 750 mg whichever is smaller).  
 Document start and stop time of Ferric Carboxymaltose administration, the total dose 
administered. 
 Obtain sitting heart rate and blood pressure immediately pre-dose, immediately post-
dose, and 30 minutes post Ferric Carboxymaltose administration.  Body temperature 
taken pre-dose  
 Adverse event assessment (starting at beginning of Ferric Carboxymaltose injection). 
Blood samples for PK/PD will be drawn at 1, 2, 6 and 12 hours post the Day 0 Ferric 
Carboxymaltose dose. 
 
6.3.2. Days 1 and 2 (24 and 48 hour) 
 
 Blood samples for PK/PD 
 Adverse events assessment 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment II Date: 08 October 2014 
Page 24 of 50 
 
6.3.3.  72 hour, and Days 14 and 28 (weeks 2 and 4) 
 
 Blood samples for PK/PD (72 hour visit only) 
 Vital signs 
 Hematology, Chemistry and iron indices 
 Adverse events assessment 
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 
6.3.4. Day 35 (week 5) End of Study 
 
 Basic physical exam including clinical assessment of skin, cardiovascular, 
pulmonary, abdominal and central nervous system.  
 Vitals signs  
 hematology, chemistries and iron indices  
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 Adverse events assessment 
 Log onto EDC and enter subject as complete 
 
The subject has completed the study after the Day 35 visit is complete.  If for any reason the 
subject does not complete the study the Day 35 procedures should be completed prior to the 
subject exiting from the trial.   
 
6.3.5. Pharmacokinetics and Pharmacodynamics (PK/PD) 
 
Blood samples will be collected for PK/PD assessment pre-dose and at 1, 2, 6, 12, 24, 48 and 72 
hours post dose.  Blood samples should be taken at approximately the same time of day as the 
initial pre-dose sample on Day 0.   
 
Prior to Day 0, subjects will return to the clinic on Day -1 at which time blood samples will be 
drawn at 8am, 12pm and 8pm to characterize the subjects specific iron profile. 
 
Total blood volume (regular hematology, chemistry, iron indices and PK/PD) collected per day 
and during the 35 Day study is provided below: 
 
 
 
Screening 
Day (-
1) 
Day 0 
24hr 
48hr 
72hr 
Day14 
Day 28 
Day 35 
Total 
Blood 
Volume 
Hem/Chem/II 
(4.5ml) 
4.5ml 
 
 
 
 
4.5ml 
4.5ml 
4.5ml 
4.5ml 
PK/PD (2ml) 
 
6ml 
10ml 
2ml 
2ml 
2ml 
 
 
 
 
TOTAL 
4.5ml 
6ml 
10ml 
2ml 
2ml 
6.5ml 
4.5ml 
4.5ml 
4.5ml 
44.5ml / 
approx. 
9.03 
tsps.* 
*4.93 mL = 1 tsp. 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 25 of 50 
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 testing will be provided to the physician 
for review and assessment. If the Investigator wishes to obtain a follow-up of an abnormal Day 
35 laboratory, this laboratory may be obtained after notification of the Sponsor.  The laboratory 
assessments will be determined as listed in Section 3.2.3.  
Hematology: 
Hb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, 
differential count, and reticulocyte count  
Chemistry:  
sodium, potassium, chloride, BUN, creatinine, albumin, alkaline 
phosphatase, total bilirubin, GGT, AST, ALT, LDH, calcium, 
phosphorus, glucose, bicarbonate and magnesium 
      Iron indices: 
serum iron, serum ferritin, and total iron binding capacity (TIBC), 
and percentage serum transferrin saturation (TSAT) 
            Other:                            Serum pregnancy test  
 
 
7.0  
ASSESSMENT OF SAFETY 
 
7.1 
Adverse Events 
 
Any untoward medical event experienced by a subject during the course of this clinical trial, 
whether or not it is related to the investigational product, at any dose, must be recorded on the 
Adverse Event page of the eCRF.  
For any laboratory abnormality, the investigator will make a judgment as to its clinical 
significance.  If the laboratory value is outside the normal 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 eCRF. 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].  All laboratory values at the end of study/Day 35 that have 
been deemed clinical significant by the Investigator should be followed until they are back into 
normal range. 
For the purposes of this study, non-serious anemia (Hb or Hct below the normal range or 
worsened from baseline) or iron deficiency (iron indices below the normal range or worsened 
from baseline) will not be considered adverse events.  Anemia or iron deficiency will be 
considered end points if an intervention is required.   
To quantify the severity of adverse events, the National Cancer Institute (NCI)-Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4 should be used to grade all 
events.  These criteria are provided in the procedure manual.   


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 26 of 50 
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 
Grade 
Adjective 
Description 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (i.e., 
preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.)  
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self care activities of daily living (i.e., bathing, 
dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.)  
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Death 
Results in Death due to the AE 
Timing: Non-serious adverse events will be reported from the initial treatment with Ferric 
Carboxymaltose through the completion of the study Day 35. AE’s will be captured 28 days post 
the last dose of Ferric Carboxymaltose for subjects who early terminate from the trial.  This can 
be completed via a phone call.  All ongoing adverse events related to Ferric Carboxymaltose 
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 Ferric Carboxymaltose as follows: 
 NONE 
There is no evidence of any causal relationship. 
 
 UNLIKELY There is little evidence to suggest there is a causal relationship.  There is 
another reasonable explanation for the event (e.g., the subject’s clinical 
condition, other concomitant treatments). 
 POSSIBLE 
There is some evidence to suggest a causal relationship (i.e. there is a 
reasonable possibility that the adverse experience may have been caused 
by the agent).  However, the influence of other factors may have 
contributed to the event (e.g., the subject’s clinical condition, other 
concomitant events). 
 PROBABLE There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. 
 
*For the purposes of this trial, “study drug” is defined as: Ferric Carboxymaltose  
 
 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 27 of 50 
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 their 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 
Definition: An adverse event is classified as SERIOUS if it meets any one of the following 
criteria:  
 Death 
 Life-Threatening: The subject was at substantial risk of dying at the time of the adverse 
event or it is suspected that the use / continued use of the product would result in the 
subject's death. 
 Hospitalization (initial or prolonged): Required admission to the hospital or 
prolongation of a hospital stay. 
 Disability: Resulted in a significant, persistent, or permanent change, impairment, 
damage or disruption in the subject's body function/structure, physical activities or 
quality of life. 
 Congenital Anomaly/Birth Defect   
 Important medical events: Other medically important events that, in the opinion of the 
investigator, may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed above. 
A distinction should be drawn between SAE and severe AE.  A severe AE is a major experience 
of its type.  A severe AE is not necessarily serious: e.g. nausea, which persists for several hours, 
may be considered severe nausea, but it is not an SAE.  On the other hand 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 initial treatment with Ferric Carboxymaltose 
through the completion of the study Day 35.  SAEs will be captured 28 days post the last dose of 
Ferric Carboxymaltose for subjects who early terminate from the trial.  This can be completed 
via a phone call. 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.   
   


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 28 of 50 
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 
learning 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. 
8.0 
STATISTICS 
No hypothesis testing will be performed for this study. 
8.1 
 Sample Size  
Determination of sample size for this single-arm, pediatric, pharmacokinetic study is a 
compromise between obtaining sufficiently precise estimates of pharmacokinetic parameters and 
the ethics of including a large number of pediatric patients in an experiment. The precision of 
estimation can be quantified as the width of the 95% confidence interval for AUC0-72 from this 
single-arm study (i.e., smaller width indicates better precision). Based on Study VIT-IV-CL-002 
in adults, the standard deviation for total serum iron AUC0-72 following a 500 mg intravenous 
dose is approximately 300 µg◦hour/mL. The width of a 95% confidence interval, using a 
standard deviation of 300 µg◦hour/mL, is presented below for selected sample sizes. As seen in 
the figure, 16 patients appears to be a reasonable compromise between precision and number of 
exposed pediatric patients. 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment II Date: 08 October 2014 
Page 29 of 50 
 
 
Approximately 32 subjects will be enrolled in this study, 16 subjects in cohort I and 16 subjects 
in cohort II.  Within each cohort of 16 subjects will be equally disturbed by age, which will 
include 8 subject’s 1 – 6 years of age and 8 subjects > 6 – 17 year of age.   Subject enrollment 
and ages will be tracked and monitored via interactive web response (IWR) system. 
 
8.2 
Analysis Populations  
 
There will be 2 analysis populations: 
 
 
Safety population: Includes all subjects who receive Ferric Carboxymaltose. 
 
 
PK/PD population: Includes all subjects in the safety population who have evaluable iron 
profiles and no protocol violation that could affect the PK/PD of Ferric Carboxymaltose. 
 
8.3 
Demographic Characteristics 
 
Demographic characteristics will be summarized for the Safety and PK/PD populations.  The 
number and percentage of subject’s who are registered, treated, prematurely discontinue, and 
complete 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.   
 
 
 
0 
100 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1100 
1200 
1300 
1400 
1500 
0 
8 
16 
24 
32 
40 
48 
56 
64 
Width of 95% CI 
Number of Subjects 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
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The number of subjects in each treatment group will be summarized for each investigative site. 
Categorical baseline characteristics (e.g., sex and race) will be summarized with the number and 
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 Clinical Endpoints 
Clinical endpoints include: 
 Efficacy: change from baseline to each scheduled visit for hemoglobin, ferritin, and 
TSAT. 
 Safety: 
 Proportion of subjects reporting treatment-emergent adverse events, overall and 
related, by SOC and preferred term 
 Subjects reporting treatment-emergent serious adverse events, overall and related, 
will be identified 
 Mean change from baseline to each scheduled visit for clinical laboratory values 
 Incidence of treatment-emergent potentially clinically significant (PCS) clinical 
laboratory values 
 Incidence of treatment-emergent PCS vital sign values. 
8.5 
 Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints  
The primary and secondary pharmacokinetic parameters will be determined for each subject as 
appropriate, based on serum concentration. The baseline parameters will be subtracted from all 
measured samples.  
The primary parameters are the maximum serum concentration (Cmax), the area under the serum 
concentration-time curve from time zero to the last sampling time (t) with a quantifiable 
concentration (AUC0-time last measured concentration), the extrapolated area under the serum 
concentration- time curve from time zero to  infinity (AUC0-infinity), and the half-life (T1/2).  Cmax 
is calculated as a non-compartmental variable, which is a more conservative method than if it 
were calculated using a compartmental paradigm.  T1/2 incorporates the calculation of the rate 
elimination constant (Kel). 
 
The secondary parameters are the mean residence time (MRT), the apparent serum clearance 
(Cl), and the apparent volume of distribution (Vd), which includes the initial volume of 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 31 of 50 
distribution following the injection (Vdc), the volume of distribution at the steady state (Vdss), 
and the volume of distribution at the final elimination (Vdarea). 
Pharmacodynamic parameter will include serum ferritin, transferrin, transferrin saturation (TfS) 
UIBC, HGB, reticulocyte count and transferrin receptors. 
The Pharmacokinetic and Pharmacodynamic parameters performed in this study for analysis will 
be outlined in a Statistical and Analytical Plan. 
8.6 
Statistical Analyses of Safety 
The Medical Dictionary for Regulatory Activities (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 system organ class (SOC), the subject will be counted only once for that 
SOC.   
Change in 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 vital signs will be 
summarized for each treatment group. 
8.7 
DSMB Analyses 
A DSMB will review safety information for subjects in Cohort 1 before dosing begins for Cohort 
2.  A Charter will be developed outlining the DSMB processes.  
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 


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Protocol: 1VIT13036 
 
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years following the completion of the study. Permission should be obtained from Luitpold 
Pharmaceuticals, Inc. prior to destroying any study records. 
The investigator must make study data accessible to the monitor, Sponsors, or other authorized 
representatives of the Sponsor and Regulatory Agency (i.e., FDA inspectors.)  A case history for 
each subject must be maintained, that includes the signed Informed Consent form and copies of 
all study documentation related to that subject. The investigator must ensure the availability of 
source documents from which the information on the eCRF was derived.  
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 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 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. 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
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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. 
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 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
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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. Notification of these audits will be sent to all investigators in advance. 
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 
2000 Edinburgh, Scotland 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 
The protocol and the Informed Consent / Assent 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 / Assent 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 / Assent when appropriate must be obtained from each subject prior to study 
participation. The informed consent / assent will be provided to the subject in their native 
language. The consent/assent form must be signed by the subject and/or the subject's legally 
authorized representative.  Each investigational site must provide the Sponsor (or designee) with 
a copy of the Informed Consent / Assent approved by that site's Institutional Review Board. The 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 35 of 50 
original signed consent / assent 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 / 
Assent 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 / assent must be certified by a qualified translator and their use must be documented. 
The Informed Consent / Assent 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 / Assent must be signed and dated by each 
subject and/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 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]. 
 
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. 
(or designee). Source data will be reviewed by the Clinical Monitor 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]. 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
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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, DSMB, 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 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. 
 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 37 of 50 
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 
 
The DSMB will be composed of approximately 3-5 senior academic individuals, including the 
DSMB Chair. They will have high-level expertise in pediatric iron deficiency anemia 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 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 38 of 50 
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 evaluate the safety from both cohorts 1 
and 2 (7.5 or 15 mg/kg of Ferric Carboxymaltose).  Only after all subjects in cohort 1 have 
completed through week 4 and the DSMB has evaluated the safety data as acceptable will 
registration into cohort 2 be granted.  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. 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 39 of 50 
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) 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 40 of 50 
REFERENCES  
1.  Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn's disease. 
Aliment.Pharmacol.Ther. 2006; 24: 1507-1523 
2.  Foley RN, Parfrey PS, Harnett JD et al. Impact of hypertension on cardiomyopathy, 
morbidity and mortality in end-stage renal disease. Kidney Int. 1996; 49: 1379-1385 
3.  Staples AO, Greenbaum LA, Smith JM et al. Association between clinical risk factors and 
progression of chronic kidney disease in children. Clin.J.Am.Soc.Nephrol. 2010; 5: 2172-
2179 
 4.  Wharton BA. Iron deficiency in children: detection and prevention. Br.J.Haematol. 1999; 
106: 270-280 
5.  Kazal LA, Jr. Prevention of iron deficiency in infants and toddlers. Am.Fam.Physician 
2002; 66: 1217-1224 
6.  Michaud L, Guimber D, Mention K et al. Tolerance and efficacy of intravenous iron 
saccharate for iron deficiency anemia in children and adolescents receiving long-term 
parenteral nutrition. Clin.Nutr. 2002; 21: 403-407 
7.  Pinsk V, Levy J, Moser A, Yerushalmi B, Kapelushnik J. Efficacy and safety of 
intravenous iron sucrose therapy in a group of children with iron deficiency anemia. 
Isr.Med.Assoc.J. 2008; 10: 335-338 
8.  Surico G, Muggeo P, Muggeo V et al. Parenteral iron supplementation for the treatment of 
iron deficiency anemia in children. Ann.Hematol. 2002; 81: 154-157 
 
 


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Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
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APPENDIX 1:  FERRIC CARBOXYMALTOSE PACKAGE INSERT 


LPI PI for submission v14 (7-18-2013) trkchng 
 
1
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
Injectafer safely and effectively.  See full prescribing information for 
Injectafer.   
 
INJECTAFER® (ferric carboxymaltose injection)   
For intravenous use 
Initial U.S. Approval: 20XX 
 
----------------------------INDICATIONS AND USAGE--------------------------- 
Injectafer is an iron replacement product indicated for the treatment of iron 
deficiency anemia in adult patients: 
 
who have intolerance to oral iron or have had unsatisfactory 
response to oral iron; 
 
who have non-dialysis dependent chronic kidney disease. 
 
----------------------DOSAGE AND ADMINISTRATION----------------------- 
For patients weighing 50kg (110lb) or more:  Give Injectafer in two doses 
separated by at least 7 days.  Give each dose as 750mg for a total cumulative 
dose of 1500mg of iron per course. 
 
For patients weighing less than 50kg (110lb):  Give Injectafer in two doses 
separated by at least 7 days and give each dose as 15 mg/kg body weight.   
 
Injectafer treatment may be repeated if iron deficiency anemia reoccurs. (2)   
 
 
---------------------DOSAGE FORMS AND STRENGTHS---------------------- 
750 mg iron / 15 mL single-use vial(3) 
 
-------------------------------CONTRAINDICATIONS------------------------------ 
Hypersensitivity to Injectafer or any of its inactive components. (4) 
 
-----------------------WARNINGS AND PRECAUTIONS------------------------ 
 
Hypersensitivity reactions:  Observe for signs and symptoms of 
hypersensitivity during and after Injectafer administration for at least 30 
minutes and until clinically stable following completion of each 
administration. (5.1) 
 
Hypertension:  Monitor patients closely for signs and symptoms of 
hypertension following each Injectafer administration. (5.2) 
 
------------------------------ADVERSE REACTIONS------------------------------- 
The most common adverse reactions (>2%) are nausea, hypertension, 
flushing, hypophosphatemia, and dizziness (6.1) 
 
To report SUSPECTED ADVERSE REACTIONS, contact American 
Regent 
at 
1-800-734-9236 
or 
FDA 
at 
1-800-FDA-1088 
or 
www.fda.gov/medwatch. 
-------------------USE IN SPECIFIC POPULATIONS-------------------
--- 
 
Nursing Mothers: Exercise caution when administered to a nursing 
woman. (8.3) 
 
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling. 
 
 
 
 
Revised:  July 2013 
_____________________________________________________________________________________________________________________________________ 
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 Hypersensitivity Reactions 
5.2 Hypertension 
5.3 Lab test alterations 
6 
ADVERSE REACTIONS 
6.1 Adverse Reactions in Clinical Trials 
6.2 Post-marketing Experience 
7 
DRUG INTERACTIONS 
8 
USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
8.3 Nursing Mothers 
8.4  Pediatric Use 
10  OVERDOSAGE 
11  DESCRIPTION 
12  CLINICAL PHARMACOLOGY 
12.1 
Pharmacodynamics 
12.2 
Pharmacokinetics  
13  
NONCLINICAL TOXICOLOGY 
 
 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 
14  CLINICAL STUDIES 
 14.1 Iron Deficiency Anemia Due to Any Etiology 
 14.2 Non Dialysis Dependent Chronic Kidney Disease  
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
 
 
  8.5 
Geriatric Use 
* Sections or subsections omitted from the full prescribing information are not 
listed.
___________________________________________________________________________________________________________________________________ 
 
Reference ID: 3347006


 
2
FULL PRESCRIBING INFORMATION 
 
1 
INDICATIONS AND USAGE 
Injectafer is indicated for the treatment of iron deficiency anemia in adult patients; 
 
 who have intolerance to oral iron or have had unsatisfactory response to oral iron; 
 who have non-dialysis dependent chronic kidney disease. 
 
2 
DOSAGE AND ADMINISTRATION 
For patients weighing 50 kg (110 lb) or more:  Give Injectafer in two doses separated by 
at least 7 days.  Give each dose as 750 mg for a total cumulative dose not to exceed1500 
mg of iron per course. 
 
For patients weighing less than 50 kg (110 lb):  Give Injectafer in two doses separated by 
at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not 
to exceed 1500 mg of iron per course.   
 
 
The dosage of Injectafer is expressed in mg of elemental iron. Each mL of Injectafer 
contains 50 mg of elemental iron.  Injectafer treatment may be repeated if iron deficiency 
anemia reoccurs.   
 
 
 
Administer Injectafer intravenously, either as an undiluted slow intravenous push or by 
infusion.  When administering as a slow intravenous push, give at the rate of 
approximately 100 mg (2 mL) per minute.  When administered via infusion, dilute up to 
750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, 
such that the concentration of the infusion is not less than 2 mg of iron per mL and 
administer over at least 15 minutes.   
 
When added to an infusion bag containing 0.9% Sodium Chloride Injection, USP, at 
concentrations ranging from 2 mg to 4 mg of iron per mL, Injectafer solution is 
physically and chemically stable for 72 hours when stored at room temperature.  To 
maintain stability, do not dilute to concentrations less than 2 mg iron/mL.  
 
Inspect parenteral drug products visually for the absence of particulate matter and 
discoloration prior to administration.  The product contains no preservatives. Each vial of 
Injectafer is intended for single use only. Any unused drug remaining after injection must 
be discarded. 
 
Avoid extravasation of Injectafer since brown discoloration of the extravasation site may 
be long lasting.  Monitor for extravasation.  If extravasation occurs, discontinue the 
Injectafer administration at that site. 
 
 
 
Reference ID: 3347006


 
3
3 
DOSAGE FORMS AND STRENGTHS 
 
750 mg iron / 15 mL single-use vial  
 
4 
CONTRAINDICATIONS 
Hypersensitivity to Injectafer or any of its components [see Warnings and Precautions 
(5.1)]. 
 
5 
WARNINGS AND PRECAUTIONS 
 
5.1  Hypersensitivity Reactions 
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of 
which have been life-threatening and fatal, have been reported in patients receiving 
Injectafer. Patients may present with shock, clinically significant hypotension, loss 
of consciousness, and/or collapse. Monitor patients for signs and symptoms of 
hypersensitivity during and after Injectafer administration for at least 30 minutes 
and until clinically stable following completion of the infusion. Only administer 
Injectafer when personnel and therapies are immediately available for the 
treatment of serious hypersensitivity reactions. [see Adverse Reactions (6.1 and 6.2)].  
In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% 
(2/1775) of subjects receiving Injectafer. Other serious or severe adverse reactions 
potentially associated with hypersensitivity which included, but not limited to, pruritus, 
rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these 
subjects.  
 
5.2 Hypertension 
In clinical studies, hypertension was reported in 3.8% (67/1,775) of subjects in clinical 
trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with 
facial flushing, dizziness, or nausea were observed in 6% (106/1,775) of subjects in these 
two clinical trials. These elevations generally occurred immediately after dosing and 
resolved within 30 minutes.   Monitor patients for signs and symptoms of hypertension 
following each Injectafer administration [see Dosage and Administration (2)]. 
 
 
5.3 Laboratory Test Alterations 
In the 24 hours following administration of Injectafer, laboratory assays may 
overestimate serum iron and transferrin bound iron by also measuring the iron in 
Injectafer.  
 
6 
ADVERSE REACTIONS   
 
The following adverse reactions are discussed in greater detail in other sections of the 
labeling: 
.  Hypersensitivity Reactions [see Warnings and Precautions (5.1)] 
.  Hypertension [see Warnings and Precautions (5.2)] 
.   Lab test alterations [see Warnings and Precautions (5.3)] 
 
Reference ID: 3347006


 
4
6.1  Adverse Reactions in Clinical Trials 
 
Because clinical trials are conducted under widely varying conditions, the adverse 
reaction rates observed cannot be directly compared to rates in other clinical trials and 
may not reflect the rates observed in clinical practice. 
In two randomized clinical studies [Studies 1 and 2, See Clinical Studies (14)], a total of 
1,775 patients were exposed to Injectafer 15 mg/kg body weight up to a maximum single 
dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative 
dose of 1500 mg of iron. 
 
Adverse reactions reported by ≥ 1% of treated patients are shown in the following table.    
 
Table 1.   Adverse reactions reported in ≥ 1% of Study Patients in Clinical Trials 1 and 
2 
 
 
 
Term 
Injectafer 
 
 
(N=1775) 
% 
Pooled 
Comparatorsa
 
(N=1783) 
% 
Oral 
iron 
 
(N=253) 
% 
Nausea 
7.2 
1.8 
1.2 
Hypertension 
3.8 
1.9 
0.4 
Flushing/Hot Flush 
3.6 
0.2 
0.0 
Blood Phosphorus Decrease 
2.1 
0.1 
0.0 
Dizziness 
2.0 
1.2 
0.0 
Vomiting 
1.7 
0.5 
0.4 
Injection Site Discoloration 
1.4 
0.3 
0.0 
Headache 
1.2 
0.9 
0.0 
Alanine Aminotransferase Increase 
1.1 
0.2 
0.0 
Dysgeusia 
1.1 
2.1 
0.0 
Hypotension 
1.0 
1.9 
0.0 
Constipation 
0.5 
0.9 
3.2 
a Includes oral iron and all formulations of IV iron other than Injectafer 
 
Other adverse reactions reported by ≥ 0.5% of treated patients include abdominal pain, 
diarrhea, gamma glutamyl transferase increased, injection site pain/irritation, rash, 
paraesthesia, sneezing. Transient decreases in laboratory blood phosphorus levels (< 2 
mg/dL) have been observed in 27% (440/1638) patients in clinical trials.  
 
 
 
6.2  Post-marketing Experience 
Because these reactions are reported voluntarily from a population of uncertain size, it is 
not always possible to reliably estimate their frequency or establish a causal relationship 
to drug exposure. The following serious adverse reactions have been most commonly 
reported from the post-marketing spontaneous reports with Injectafer:  urticaria, dyspnea, 
pruritis, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, 
arthralgia,  and syncope. One case of hypophosphatemic osteomalacia was reported in a 
Reference ID: 3347006


 
5
subject who received 500 mg of Injectafer every 2 weeks for a total of 16 weeks.  Partial 
recovery followed discontinuation of Injectafer. 
 
7 
DRUG INTERACTIONS 
Formal drug interaction studies have not been performed with Injectafer .  
 
8 
USE IN SPECIFIC POPULATIONS 
 
8.1  Pregnancy  
Pregnancy Category C  
 
Risk Summary 
 
Adequate and well controlled studies in pregnant women have not been conducted.    
However, animal reproduction studies have been conducted with ferric carboxymaltose. In these 
studies, administration of ferric carboxymaltose to rabbits during the period of 
organogenesis caused fetal malformations and increased implantation loss at maternally 
toxic doses of approximately 12% to 23% of the human weekly dose of 750 mg (based on 
body surface area).  The incidence of major malformations in human pregnancies has not 
been established for Injectafer. However, all pregnancies, regardless of exposure to any 
drug, has a background rate of 2 to 4% for major malformations, and 15 to 20% for 
pregnancy loss. Injectafer should be used during pregnancy only if the potential benefit 
justifies the potential risk to the fetus.   
 
Animal Data 
Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion up to 
30 mg/kg/day iron on gestation days 6 to 17 did not result in adverse embryofetal 
findings.  This daily dose in rats is approximately 40% of the human weekly dose of 750 
mg based on body surface area.  In rabbits, ferric carboxymaltose was administered as a 
one-hour infusion on gestation days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 
mg/kg/day.  Malformations were seen starting at the daily dose of 9 mg/kg (23% of the 
human weekly dose of 750 mg).  Spontaneous abortions occurred starting at the daily 
iron dose of 4.5 mg/kg (12% of the human weekly dose based on body surface area).  
Pre-implantation loss was at the highest dose.  Adverse embryofetal effects were 
observed in the presence of maternal toxicity. 
 
A pre- and post-natal development study was conducted in rats at intravenous doses up to 
18 mg/kg/day of iron (approximately 23% of the weekly human dose of 750 mg on a 
body surface area basis).  There were no adverse effects on survival of offspring, their 
behavior, sexual maturation or reproductive parameters.  
 
8.3  Nursing Mothers 
A study to determine iron concentrations in breast milk after administration of Injectafer 
(n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with 
postpartum iron deficiency anemia.  Mean breast milk iron levels were higher in lactating 
women receiving Injectafer than in lactating women receiving oral ferrous sulfate. 
Reference ID: 3347006


 
6
 
8.4  Pediatric Use 
Safety and effectiveness have not been established in pediatric patients.  
 
8.5  Geriatric Use 
Of the 1775 subjects in clinical studies of Injectafer, 50% were 65 years and over, while 
25% were 75 years and over. No overall differences in safety or effectiveness were 
observed between these subjects and younger subjects, and other reported clinical 
experience has not identified differences in responses between the elderly and younger 
patients, but greater sensitivity of some older individuals cannot be ruled out. 
 
10  OVERDOSAGE 
Excessive dosages of Injectafer may lead to accumulation of iron in storage sites 
potentially leading to hemosiderosis. A patient who received Injectafer 18,000 mg 
over 6 months developed hemosiderosis with multiple joint disorder, walking 
disability and asthenia . Hypophosphatemic osteomalacia was reported in a patient 
who received Injectafer 4000 mg over 4 months. Partial recovery followed 
discontinuation of Injectafer. [see Post-marketing Experience (6.3)].  
 
11 
DESCRIPTION 
Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex 
with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(14)-O--D-
glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. 
It 
has 
a 
relative 
molecular weight of approximately 150,000 Da corresponding to the following empirical 
formula: 
 
[FeOx(OH)y(H2O)z]n [(C6H10O5)m (C6H12O7)l]k,   
 
where n  103, m  8, l 11, and k  4  
(l represents the mean branching degree of the ligand).  
 
The chemical structure is presented below: 
 
Reference ID: 3347006


 
7
 
 
Injectafer (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic 
colloidal solution for intravenous injection. Each mL contains 50 mg iron as ferric 
carboxymaltose in water for injection.  Injectafer is available in 15 mL single-use vials.  
Sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH to 5.0-
7.0.  
 
Vial closure is not made with natural rubber latex
Reference ID: 3347006


 
8
 
12 
CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose, 
a carbohydrate polymer that releases iron. 
 
12.2  Pharmacodynamics 
 
Using positron emission tomography (PET) it was demonstrated that red cell uptake of 
59Fe and 52Fe from Injectafer ranged from 61% to 99%. In patients with iron deficiency, 
red cell uptake of radio-labeled iron ranged from 91% to 99% at 24 days after Injectafer 
dose. In patients with renal anemia red cell uptake of radio-labeled iron ranged from 61% 
to 84% after 24 days Injectafer dose. 
 
12.3 Pharmacokinetics 
After administration of a single dose of Injectafer of 100 to 1000 mg of iron in iron 
deficient patients, maximum iron levels of 37 µg/mL to 333 µg/mL were obtained 
respectively after 15 minutes to 1.21 hours post dose. The volume of distribution was 
estimated to be 3 L. 
 
The iron injected or infused was rapidly cleared from the plasma, the terminal half-life 
ranged from 7 to 12 hours. Renal elimination of iron was negligible. 
 
13 
NONCLINICAL TOXICOLOGY 
13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility  
Carcinogenicity studies have not been performed with ferric carboxymaltose. 
 
Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in 
vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human 
lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma 
L5178Y/TK+/- cells, in vivo mouse micronucleus test at single intravenous doses up to 
500 mg/kg.   
 
In a combined male and female fertility study, ferric carboxymaltose was administered 
intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg.  
Animals were dosed 3 times per week (on Days 0, 3, and 7).  There was no effect on 
mating function, fertility or early embryonic development. The dose of 30 mg/kg in 
animals is approximately 40% of the human dose of 750 mg based on body surface area.  
 
 
 
14 
CLINICAL STUDIES  
The safety and efficacy of Injectafer for treatment of iron deficiency anemia were 
evaluated in two randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In 
these two trials, Injectafer was administered at a dose of 15 mg/kg body weight up to a 
maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up 
to a cumulative dose of 1500 mg of iron.  
Reference ID: 3347006


 
9
 
14.1 Trial 1: Iron Deficiency Anemia in Patients Who Are Intolerant to Oral Iron or 
Have Had Unsatisfactory Response to Oral Iron  
 
Trial 1 was a randomized, open-label, controlled clinical study in patients with iron 
deficiency anemia who had an unsatisfactory response to oral iron (Cohort 1) or who 
were intolerant  to  oral iron (Cohort 2) during the 14 day oral iron run-in period. 
Inclusion criteria prior to randomization included hemoglobin (Hb) <12 g/dL, ferritin ≤ 
100 ng/mL or ferritin ≤ 300 ng/mL when transferrin saturation (TSAT) ≤ 30%. Cohort 1 
subjects were randomized to Injectafer or oral iron for 14 more days.  Cohort 2 subjects 
were randomized to Injectafer or another IV iron per standard of care [90% of subjects 
received iron sucrose]. The mean age of study patients was 43 years (range, 18 to 94); 
94% were female; 42% were Caucasian, 32% were African American, 24% were 
Hispanic, and 2% were other races. The primary etiologies of iron deficiency anemia 
were heavy uterine bleeding (47%) and gastrointestinal disorders (17%).  
 
Table 2 shows the baseline and the change in hemoglobin from baseline to highest value 
between baseline and Day 35 or time of intervention.   
 
Reference ID: 3347006


 
10
 
 
Table 2. Mean Change in Hemoglobin From Baseline to the Highest Value 
Between Day 35 or Time of Intervention (Modified Intent-to-Treat Population) 
 
Hemoglobin (g/dL) 
Mean (SD) 
Cohort 1
Cohort 2
Injectafer 
(N=244) 
Oral Iron 
(N=251) 
Injectafer 
(N=245) 
IV SCa 
(N=237) 
Baseline 
 
10.6 (1.0)
10.6 (1.0)
9.1 (1.6) 
 
9.0 (1.5)
 
Highest Value 
 
 
12.2 (1.1) 
 
11.4 (1.2) 
 
 
12.0 (1.2) 
 
11.2 (1.3) 
 
 
Change (from baseline to 
highest value) 
 
 
 
1.6 (1.2) 
 
 
0.8 (0.8) 
 
 
 
2.9 (1.6) 
 
2.2 (1.3) 
 
 
p-value 
0.001
0.001
SD=standard deviation; a: Intravenous iron per standard of care 
 
Increases from baseline in mean f erritin (264.2±224.2 ng/mL in Cohort 1 and 218.2 
±211.4 ng/mL in Cohort 2), and transferrin saturation (13±16% in Cohort 1 and 
20±15% in Cohort) were  observed  at  Day 35 in Injectafer-treated patients. 
 
14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis Dependent 
Chronic Kidney Disease 
 
Trial 2 was a randomized, open-label, controlled clinical study in patients with non-
dialysis dependent chronic kidney disease. Inclusion criteria included hemoglobin (Hb) ≤ 
11.5 g/dL, ferritin ≤ 100 ng/mL or ferritin ≤ 300 ng/mL when transferrin saturation 
(TSAT) ≤ 30%.Study patients were randomized to either Injectafer or Venofer. The mean 
age of study patients was 67 years (range, 19 to 96); 64% were female; 54% were 
Caucasian, 26% were African American, 18% Hispanics, and 2% were other races.  
 
Table 3 shows the baseline and the change in hemoglobin from baseline to highest value 
between baseline and Day 56 or time of intervention.   
 
 
Reference ID: 3347006


 
11
 
Table 3. Mean Change in Hemoglobin From Baseline to the Highest Value 
Between Baseline  and Day 56 or Time of Intervention (Modified Intent-to-Treat 
Population) 
Hemoglobin (g/dL)
Mean (SD) 
Injectafer 
(N=1249) 
Venofer 
(N=1244) 
 
Baseline 
 
10.3 (0.8) 
10.3 (0.8) 
 
Highest Value  
11.4 (1.2) 
11.3 (1.1) 
 
Change (from baseline to highest 
value) 
1.1 (1.0) 
 
0.9 (0.92) 
 
Treatment Difference (95% CI) 
0.21 (0.13, 0.28)
 
 
 
Increases from baseline in mean f erritin (734.7±337.8 ng/mL), and transferrin 
saturation (30±17%)  were  observed  at  Day 56 in Injectafer-treated patients. 
 
 
16 
HOW SUPPLIED/STORAGE AND HANDLING   
 
 
NDC 0517-0650-01  
750 mg iron/15 mL Single-Use Vial Individually boxed 
NDC 0517-0650-02  
750 mg iron/15 mL Single-Use Vial Packages of 2 
 
 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 
86°F). [See the USP controlled room temperature].  Do not freeze.  
 
 
 
17 
PATIENT COUNSELING INFORMATION 
 
Question patients regarding any prior history of reactions to parenteral iron products. 
 
Advise patients of the risks associated with Injectafer. 
 
Advise patients to report any signs and symptoms of hypersensitivity that may develop during and 
following Injectafer administration, such as rash, itching, dizziness, lightheadedness, swelling and 
breathing problems [see Warnings and Precautions (5)] 
 
Injectafer is manufactured under license from Vifor (International) Inc, Switzerland. 
Reference ID: 3347006


 
12
 
AMERICAN 
REGENT, INC. 
SHIRLEY, NY  11967 
 
IN0602 
Rev. 7/13 
 
Reference ID: 3347006


 
13
Patient Information 
INJECTAFER (ferric carboxymaltose injection) 
 
Please read this information carefully before taking this medication. This summary does 
not tell you everything about INJECTAFER. Speak with your doctor or healthcare 
professional if there is something you do not understand or if you would like to learn 
more about INJECTAFER. Your doctor or healthcare professional is your best source of 
information about this medicine. 
 
What is INJECTAFER? 
 
Iron is a mineral that the body needs to produce red blood cells. When the body does not 
get enough iron, it cannot produce the number of normal red blood cells needed to keep 
you in good health. This condition is called iron deficiency (iron shortage) or iron 
deficiency anemia.  
 
INJECTAFER is used to treat iron deficiency anemia. Iron deficiency anemia may be 
caused by several medical conditions including heavy menstrual bleeding, pregnancy, 
childbirth, inflammatory bowel disease, other malabsorption diseases, bariatric surgery, 
or chronic kidney disease.  
 
General information about using INJECTAFER safely and effectively 
 
Injectable iron is administered only by or under the supervision of your health care 
professional. 
 
Serious or life threatening allergic reactions have been reported with intravenous iron 
products. Tell your health care professional if you have ever had any unusual or allergic 
reaction to any IV iron. 
 
Patients should report to their healthcare professional any signs and symptoms of an 
allergic reaction to INJECTAFER, in particular rashes, shortness of breath and wheezing.  
 
Iron is not easily eliminated from the body, and its build up may be lead to a condition 
called iron overload which may be harmful.  Certain medical conditions such as liver 
disease may also make you more likely to develop iron overload. Ask your doctor or 
healthcare professional. 
 
Who should not take INJECTAFER? 
 
You should not be given INJECTAFER if you have anemia that is not caused by iron 
deficiency, or if you have iron overload. 
 
If you are pregnant or plan to become pregnant please notify your doctor or healthcare 
professional. They will decide whether it is safe for you to receive INJECTAFER.  
 
How should I take INJECTAFER? 
Reference ID: 3347006


 
14
 
INJECTAFER is administered intravenously (into your vein) by your doctor or health 
care professional in two doses.  
 
What should I avoid while taking INJECTAFER? 
 
You should not take iron supplements by mouth if you are receiving iron injections. Tell 
your doctor about all the medicines you take, including prescription and non-prescription 
medicines, vitamins and herbal supplements. 
 
What are the possible side effects of INJECTAFER? 
 
The side effects of INJECTAFER are infrequent, usually mild and generally do not cause 
patients to stop treatment. The most common side effects are nausea, injection site 
reactions (including pain or bruising at the injection site), asymptomatic reductions in 
blood phosphorus, flushing, headache, hypertension, dizziness, and increased alanine 
aminotransferase. Potentially long lasting brown staining of skin near injection site may 
occur.   
 
These are not all the possible side effects of INJECTAFER. For more information ask 
your doctor or healthcare professional.     
 
Talk to your doctor if you think you have side effects from taking INJECTAFER. 
 
 
Reference ID: 3347006


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 43 of 50 
APPENDIX 2:  WEIGHT CHARTS FOR BOYS AND GIRLS 
Boys (White) Weight Chart age 0-36 months (http://www.halls.md/chart/boys-weight-w.htm) 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment II Date: 08 October 2014 
Page 44 of 50 
 
BOYS (WHITE) WEIGHT CHART AGE 2-20 YRS 
(HTTP://WWW.CDC.GOV/GROWTHCHARTS/DATA/SET1CLINICAL/CJ41L021.PDF) 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Amendment II Date: 08 October 2014 
Page 45 of 50 
Girls (White) Weight Chart age 0-36 months (http://www.halls.md/on/girls-weight-w.htm) 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment II Date: 08 October 2014 
Page 46 of 50 
 
GIRLS (WHITE) WEIGHT CHART AGES 2-20 YRS 
(HTTP://WWW.CDC.GOV/GROWTHCHARTS/DATA/SET1CLINICAL/CJ41L022.PDF)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment II Date: 08 October 2014 
Page 47 of 50 
 
APPENDIX 3:  ADMENDMENT I CHANGES 
 
Title Page: 
 
Original 
Wording: 
Protocol Date: 
27 March 2014 
New Wording: 
Protocol Date: 
Amendment 1: 29 July 2014 
Study 
Synopsis and 
8.1 Sample 
Size 
Rationale: 
 
New Wording: 
 
Sample Size: 
 
Determination of sample size for this single-arm, pediatric, pharmacokinetic 
study is a compromise between obtaining sufficiently precise estimates of 
pharmacokinetic parameters and the ethics of including a large number of 
pediatric patients in an experiment. The precision of estimation can be 
quantified as the width of the 95% confidence interval for AUC0-72 from this 
single-arm study (i.e., smaller width indicates better precision). Based on Study 
VIT-IV-CL-002 in adults, the standard deviation for total serum iron AUC0-72 
following a 500 mg intravenous dose is approximately 300 µg◦hour/mL. The 
width of a 95% confidence interval, using a standard deviation of 300 
µg◦hour/mL, is presented below for selected sample sizes. As seen in the figure, 
16 patients appears to be a reasonable compromise between precision and 
number of exposed pediatric patients.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment II Date: 08 October 2014 
Page 48 of 50 
 
 
Approximately 32 subjects will be enrolled in this study, 16 subjects in cohort I 
and 16 subjects in cohort II.  Within each cohort of 16 subjects will be equally 
disturbed by age, which will include 8 subject’s 1 – 6 years of age and 8 
subjects > 6 – 17 year of age.   Subject enrollment and ages will be tracked and 
monitored via interactive web response (IWR) system. 
 
Original 
Wording: 
Exclusion Criteria: 
 
3. Body mass index (BMI) ≤ 95th percentile for age (see APPENDIX 2) 
 
New Wording: 
3. Body mass index (BMI) ≤ 5th percentile for age (see APPENDIX 2) 
 
Original 
Wording: 
Trial design – Phase III 
New Wording: 
Trial Design – Phase II 
Additional 
Wording – 
Sections 7.1 
All laboratory values at the end of study/Day 35 that have been deemed clinical 
significant by the Investigator should be followed until they are back into 
normal range. 
 
 
 
 
 
0 
100 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1100 
1200 
1300 
1400 
1500 
0 
8 
16 
24 
32 
40 
48 
56 
64 
Width of 95% CI 
Number of Subjects 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment II Date: 08 October 2014 
Page 49 of 50 
 
APPENDIX 4:  ADMENDMENT II CHANGES 
 
Title Page: 
 
Original 
Wording: 
Protocol Date: 27 March 2014 
Amendment 1: 29 July 2014 
New Wording: 
Protocol Date: 27 March 2014 
Amendment 1: 29 July 2014 
Amendment II: 08 October 2014 
Signature of 
Agreement 
For Protocol 
Original 
Wording: 
 
Marc Tokars 
 
 
 
   
 
            Date 
Vice President of Clinical Operations 
Luitpold Pharmaceuticals, Inc. 
 
Marsha Simon 
 
 
 
 
 
   
Date 
Sr. Manager-Regulatory Affairs 
Luitpold Pharmaceuticals, Inc. 
 
David Morris, PhD                    
Date 
Senior Director, Statistics 
WebbWrites, LLC 
 
Signature of 
Agreement 
For Protocol 
New Wording: 
 
Sylvan Hurewitz, MD 
 
 
 
 
   
Date 
Medical Director 
Luitpold Pharmaceuticals, Inc. 
 
Syed Quadri, MD 
 
 
 
 
 
   
Date 
Medical Director, Pharmacovigilance 
Luitpold Pharmaceuticals, Inc. 
 
Marsha Simon 
 
 
 
 
 
   
Date 
Sr. Manager-Regulatory Affairs 
Luitpold Pharmaceuticals, Inc. 
 
David Morris, PhD                    
Date 
Senior Director, Statistics 
WebbWrites, LLC 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment II Date: 08 October 2014 
Page 50 of 50 
 
 
New 
Exclusion 
Criteria 
Wording: 
Exclusion Criteria # 4: Male or Female subject 1 year of age weighing < 
12kg. 
Exclusion 
Criteria 
Deletion 
Deleted original criteria number 12.  Significant blood loss (> 100 ml) 
within the last 3 months or any current bleeding disorders or anticipated 
need for surgery that may result in significant blood loss (> 100 ml). 
Original 
Wording 
section 6.3.5 
Blood Volume 
Table: 
Total Blood Volume = 72mL/approx. 14.6 tsps 
New Wording 
section 6.3.5 
Blood Volume 
Table: 
Total Blood Volume = 44.5mL/approx. 9.03 tsps 
New Wording 
Injectafer ® replaced by Ferric Carboxymaltose throughout Protocol 
 




1 
LUITPOLD PHARMACEUTICALS, INC. 
PROTOCOL 
No. 1VIT13036 
 
IND #: 63,243 
 
 
A Multi-center, Open-label, Single Arm Study to Characterize the Pharmacokinetics and 
Pharmacodynamics Profile of Intravenous Ferric Carboxymaltose in Pediatric Subjects 1 – 
17 years old with Iron Deficiency Anemia (IDA) 
 
 
SPONSOR 
Luitpold Pharmaceuticals, Inc. 
Clinical Research and Development 
800 Adams Avenue 
Norristown, PA 19403 
(610) 650-4200 
 
 
 
 
Protocol Date: 27 March 2014 
Amendment I Date: 29 July 2014 
Amendment II Date: 08 October 2014 
Local Protocol Amendment I for Russia: 24 February 2015 
 
 
 


CONFIDENTIAL 
Protocol: I VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
SIGNATURES OF AGREEMENT FOR PROTOCOL 
Sylvan Hurewitz, MD 
Medical Director 
Luitpold Pharmaceuticals, Inc. 
Syed Quadri, MD 
Medical Director, Pharmacovigilance 
Luitpold Pharmaceuticals, Inc. 
M sha Simon 
Sr. Manager-Regulatory Affairs 
Luitpold Pharmaceuticals, Inc. 
David Morris, PhD 
Senior Director, Statistics 
Webb Writes, LLC 
Date 
Date 
Date 
Date 
Page 2 of 51 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 3 of 51 
Study Synopsis 
Protocol No. 1VIT13036 
Title:   
A Multi-center, Open-label, Single Arm Study to Characterize the 
Pharmacokinetics and Pharmacodynamics Profile of Intravenous Ferric 
Carboxymaltose in Pediatric Subjects 1 – 17 years old with Iron Deficiency 
Anemia (IDA). 
Drug:  
Ferric Carboxymaltose 
Objectives:   The primary objectives of this study are to characterize the pharmacokinetics and 
determine appropriate dosing and safety of Ferric Carboxymaltose for the 
pediatric population suffering from iron deficiency (ID) with anemia.  
 
Study Design:This is a Phase II, open-label, non-randomized, multi-center, single arm study to 
characterize the pharmacokinetic and pharmacodynamics  (PK/PD) profile of 
Ferric Carboxymaltose dosing in pediatric subjects with IDA after receiving either 
a 7.5 mg/kg or 15 mg/kg dose of Ferric Carboxymaltose®.  
 
Treatment 
 
Cohort 1: 16 subjects will be treated with Ferric Carboxymaltose at 7.5 mg/kg to a 
maximum single dose of 750 mg iron, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have 
completed 4 weeks of therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Ferric Carboxymaltose at 15 mg/kg to a 
maximum single dose of 750 mg iron, whichever is smaller.   
Inclusion Criteria:  
1. Male or female subjects 1 to 17 years of age (6 to 17 years of age in Russia only) 
with assent to participation and his/her parent or guardian is willing and able to 
sign the informed consent approved by the Independent Review Board / Ethics 
Committee.  
2. Screening TSAT < 20% 
3. Screening Hemoglobin < 11 g/dL 
4. For subjects who are receiving an erythropoietin stimulating agent (ESA): stable 
ESA therapy (+/- 20% of current dose) for > 8 weeks prior to the qualifying 
screening visit and no ESA dosing or product changes anticipated for the length 
of the trial 
 
 


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Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 4 of 51 
Exclusion Criteria:    
1. Known hypersensitivity reaction to any component of Ferric Carboxymaltose. 
2. Subject previously randomized and treated in this study or any other clinical study 
of Ferric Carboxymaltose (FCM or VIT-45). 
3. Body mass index (BMI) ≤ 5th percentile for age (see APPENDIX 2) 
4. Male or Female subject 1 year of age weighing < 12kg. 
5. History of acquired iron overload, hemochromatosis or other iron accumulation 
disorders. 
6. Chronic kidney disease subjects on hemodialysis. 
7. Screening Ferritin level > 300ng/mL 
8. Subjects with significant severe diseases of the liver, hemopoietic system, 
cardiovascular system, psychiatric disorder or other conditions which on the 
opinion of the investigator may place a subject at added risk. 
9. Any active infection.  
10. Known positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody (HCV) 
with evidence of active hepatitis. 
11. Known positive HIV-1/HIV-2 antibodies (anti-HIV). 
12. Anemia due to reasons other than iron deficiency (i.e. hemoglobinopathy). 
Subjects treated with vitamin B12 or folic acid deficiency are permitted. 
13. Intravenous iron and /or blood transfusion in the 4 weeks prior to screening.  
14. Immunosuppressive therapy that may lead to anemia (i.e. cyclophosphamide, 
azathioprine, mycophenolate mofetil).  Note steroid therapy is permitted. 
15. Administration and / or use of an investigational product (drug or device) within 
30 days of screening. 
16. Alcohol or drug abuse within the past six months. 
17. Female subjects who are pregnant or lactating, or sexually active female who are 
of childbearing potential not willing to use an acceptable form of contraceptive 
precautions during the study. 
18. Subject is unable to comply with study assessments. 
 
Subject 
Assessments:  
All subjects that provide informed consent / assent will enter a screening period 
up to 14 days prior to Day 0.  During this time subjects will be evaluated to insure 
they meet the study entry criteria.  Subjects will have vital signs, medical history 
review and laboratory samples to include hematology, chemistries and iron 
indices.  Once it has been determined the subject qualifies for participation the 
subject will be scheduled to return to the clinic 1 day prior to Day 0 (Day -1) at 
which time additional blood samples will be taken (8am, 12pm and 8pm) to 
characterize the subjects iron profile. 
 
Blood samples for PK/PD will also be assessed immediately prior to Ferric 
Carboxymaltose dosing on Day 0, at 1, 2, 6, 12, 24, 48 hours and at 72 hours.  
 
Safety assessments, including vital signs and adverse events, will be assessed 
starting on Day 0 at the time of Ferric Carboxymaltose dosing through Day 35.   


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Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 5 of 51 
Erythropoietin 
Dosage: 
 
If receiving an Erythropoiesis Stimulating Agent (ESA), a stable (± 20%) dose is 
required for > 8 weeks prior to screening.  The ESA type, route, frequency and 
dose will remain unchanged throughout the remainder of the study unless the dose 
should be decreased or held per the package label.  Once decreased or held, it may 
not be increased or restarted unless thought necessary by the subject’s physician. 
If the latter event occurs, the ESA dose changes will be collected and the subject 
will continue for safety analysis. 
Study Duration 
per subject:  up to 9 weeks  
Number of  
Subjects:   
32 subjects 
Sites:   
Approximately 10 
Sample Size: 
 
Determination of sample size for this single-arm, pediatric, pharmacokinetic study 
is a compromise between obtaining sufficiently precise estimates of 
pharmacokinetic parameters and the ethics of including a large number of 
pediatric patients in an experiment. The precision of estimation can be quantified 
as the width of the 95% confidence interval for AUC0-72 from this single-arm 
study (i.e., smaller width indicates better precision). Based on Study VIT-IV-CL-
002 in adults, the standard deviation for total serum iron AUC0-72 following a 500 
mg intravenous dose is approximately 300 µg◦hour/mL. The width of a 95% 
confidence interval, using a standard deviation of 300 µg◦hour/mL, is presented 
below for selected sample sizes. As seen in the figure, 16 patients appears to be a 
reasonable compromise between precision and number of exposed pediatric 
patients.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 6 of 51 
 
 
Approximately 32 subjects will be enrolled in this study, 16 subjects in cohort I 
and 16 subjects in cohort II.  Within each cohort of 16 subjects will be equally 
distributed by age, which will include 8 subject’s 1 – 6 years of age and 8 
subjects > 6 – 17 year of age.   Subject enrollment and ages will be tracked and 
monitored via interactive web response (IWR) system. 
 
0 
100 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1100 
1200 
1300 
1400 
1500 
0 
8 
16 
24 
32 
40 
48 
56 
64 
Width of 95% CI 
Number of Subjects 


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Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 7 of 51 
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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Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 8 of 51 
TABLE OF CONTENTS 
1.0 INTRODUCTION .................................................................................................................... 12 
1.1 
Treatment of Iron Deficiency Anemia ............................................................................ 12 
1.2 
Ferric Carboxymaltose .................................................................................................... 13 
1.2.1 
Key features of Ferric Carboxymaltose ...................................................................... 13 
1.2.2 
Ferric Carboxymaltose versus Other Parenteral Iron Agents ................................... 13 
1.2.3 
Ferric Carboxymaltose Human Experience ............................................................... 14 
2.0 MAIN TRIAL OBJECTIVE ..................................................................................................... 15 
3.0  
OVERALL STUDY DESIGN AND RATIONALE .......................................................... 16 
3.1 
 Trial Design ................................................................................................................... 16 
3.2 
Rationale ......................................................................................................................... 16 
3.2.1 
Rationale for Trial Design .......................................................................................... 16 
4.0  
SUBJECT SELECTION ..................................................................................................... 18 
4.1 
Number and Type of Subjects......................................................................................... 18 
4.2 
Screening Phase .............................................................................................................. 18 
4.2.1  
Entry Criteria .......................................................................................................... 18 
4.3 
Subject Assignment and Registration Process ................................................................ 19 
4.4 
Withdrawal from Study................................................................................................... 19 
4.5 
Intervention ..................................................................................................................... 19 
5.0 STUDY DRUG ......................................................................................................................... 20 
5.1 
Formulation Packaging and Storage ............................................................................... 20 
5.2 
Drug Administration / Regimen...................................................................................... 20 
5.3 
IV Iron Precautions ......................................................................................................... 21 
5.4 
Drug Accountability........................................................................................................ 21 
5.5 
Concomitant Medication ................................................................................................. 21 
6.0 STUDY PROCEDURES .......................................................................................................... 22 
6.1 
Informed Consent............................................................................................................ 22 
6.2 
Screening (up to 14 days) ............................................................................................... 22 
6.3 
Study Visits .................................................................................................................. 23 
6.3.1. 
Day (-1) ................................................................................................................... 23 


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6.3.2 
Day 0 ........................................................................................................................... 23 
6.3.2. 
Days 1 and 2 (24 and 48 hour) ............................................................................... 23 
6.3.3. 
 72 hour, and Days 14 and 28 (weeks 2 and 4)....................................................... 24 
6.3.4. 
Day 35 (week 5) End of Study ................................................................................. 24 
6.3.5. 
Pharmacokinetics and Pharmacodynamics (PK/PD) ............................................. 24 
6.4 
Central Laboratory Assessments..................................................................................... 25 
7.0  
ASSESSMENT OF SAFETY ............................................................................................. 25 
7.1 
Adverse Events ............................................................................................................... 25 
7.2 
Reporting of Adverse Events .......................................................................................... 27 
7.3 
Serious Adverse Events .................................................................................................. 27 
8.0 STATISTICS ............................................................................................................................ 28 
8.1 
 Sample Size .................................................................................................................... 28 
8.2 
Analysis Populations ....................................................................................................... 29 
8.3 
Demographic Characteristics .......................................................................................... 29 
8.4 
Endpoints and Definitions............................................................................................... 30 
8.4.1 
Clinical Endpoints ...................................................................................................... 30 
8.5 
 Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints .................................... 30 
8.6 
Statistical Analyses of Safety .......................................................................................... 31 
8.7 
DSMB Analyses.............................................................................................................. 31 
9.0 ADMINISTRATIVE CONSIDERATIONS ............................................................................. 31 
9.1 
Retention and Availability of Records ............................................................................ 31 
9.2 
Investigator Responsibilities ........................................................................................... 32 
9.3 
Financial Disclosure........................................................................................................ 32 
9.4 
Advertisement for Subject Recruitment.......................................................................... 33 
9.5 
Documents Required for Study Initiation ....................................................................... 33 
9.6 
Quality Control and Quality Assurance .......................................................................... 33 
9.6.1 
Investigator Selection Criteria .................................................................................... 33 
9.6.2 
Clinical Monitoring .................................................................................................... 33 
9.6.3 
Quality Assurance Audit ............................................................................................. 34 
9.7 
Ethics............................................................................................................................... 34 
9.7.1 
Ethical and Legal Issues ............................................................................................. 34 


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9.7.2 
Institutional Review Board ......................................................................................... 34 
9.7.3 
Informed Consent ........................................................................................................ 34 
9.7.4 
Good Clinical Practice ............................................................................................... 35 
9.8 
Data Handling and Record Keeping ............................................................................... 35 
9.8.1 
Electronic Case Report Form (eCRF) ........................................................................ 35 
9.8.2 
Confidentiality............................................................................................................. 35 
9.8.3 
Termination of the Study ............................................................................................. 36 
9.8.4 
Protocol Revisions ...................................................................................................... 36 
9.8.5 
Protocol Administrative Changes ............................................................................... 36 
9.9 
Publication Policy ........................................................................................................... 37 
10.0  GOVERNANCE COMMITTEE ........................................................................................ 37 
10.1 
Data and Safety Monitoring Board............................................................................. 37 
INVESTIGATOR’S ACKNOWLEDGEMENT ............................................................................ 39 
REFERENCES .............................................................................................................................. 40 
APPENDIX 1:  FERRIC CARBOXYMALTOSE PACKAGE INSERT ................................ 42 
APPENDIX 2:  WEIGHT CHARTS FOR BOYS AND GIRLS ................................................... 43 
APPENDIX 3:  ADMENDMENT I CHANGES ........................................................................ 47 
APPENDIX 4:  ADMENDMENT II CHANGES ....................................................................... 49 


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Protocol: 1VIT13036 
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Page 11 of 51 
LIST OF ABBREVIATIONS 
AE 
 
 
 
 
Adverse event 
BP 
Blood Pressure 
BW 
Body Weight 
CI 
confidence interval 
CKD 
Chronic Kidney Disease 
conc. 
concentration 
CTCAE 
Common Terminology Criteria for Adverse Event 
dL 
Deciliter 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture 
e.g. 
for example 
ESA 
Erythropoiesis stimulating agent 
FDA 
Food and Drug Administration 
Fe 
Iron 
g 
Gram 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HMW 
high molecular weight 
IBD 
Inflammatory Bowel Diease 
ICH 
International Conference on Harmonisation 
IDA 
Iron Deficiency Anemia 
i.e. 
that is/ such that 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVP 
Intravenous injection (push) 
kg 
Kilogram 
L 
Liter 
LMW 
low molecular weight 
LOS 
length of stay 
MedDRA 
Medical dictionary for regulatory activities 
mg  
Milligram 
mL 
Milliliter 
ng 
Nanogram 
PET 
positron emission tomography 
p.o. 
by mouth or orally 
RES 
Reticuloendothelial system 
SAE 
Serious adverse event 
t1/2 
Terminal half-life 
t.i.d. 
three times a day 
TSAT 
Transferrin Saturation 
US 
United States 
vs 
Versus 
w/v 
weight / volume 


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Protocol: 1VIT13036 
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Page 12 of 51 
1.0 
INTRODUCTION 
1.1 
Treatment of Iron Deficiency Anemia 
Iron deficiency anemia (“IDA”) remains the most common nutritional deficiency in children in 
the United States.  Rapid growth, insufficient dietary intake, and limited absorption of dietary 
iron combine to place children at increased risk for iron deficiency. Iron deficiency may 
contribute significantly to anemia due to malabsorption, gastrointestinal blood loss, or 
iatrogenically due to repeated blood samplings.  As a result of severe digestive tract disorders, 
some children are unable to tolerate oral iron supplementation or are unresponsive to it.1 Anemia 
may also decrease survival rates in patients (both adults and children) with chronic renal 
impairment where it is a commonly encountered problem2;3 In addition, anemia is a commonly 
encountered manifestation of pediatric inflammatory bowel disease which is associated with a 
decrease in the quality of life and increased hospitalization. 
 
Non-hematologic consequences of iron deficiency include poor weight gain, anorexia, 
irritability, decreased attention span, exercise intolerance and decreased physical activity. 4  
However, IDA in infants and toddlers is associated with long-lasting diminished mental, motor, 
and behavioral functioning.  Although the exact relationship between iron deficiency anemia and 
the developmental effects is not well understood, it appears that these effects do not occur until 
iron deficiency becomes severe and chronic enough to produce anemia. 5 
 
Options for correcting iron deficiency include both oral and parenteral formulations. As 
previously described, some children are unable to tolerate or are non-responsive to oral iron.  
Blood transfusion is an option to treat anemia and restore iron requirements, but the potential risk 
of blood-transmitted virus infection limits its use to severe and badly tolerated anemia. In view 
of the limitations associated with oral iron or blood transfusions, intravenous administration is an 
important option. 
 
Multiple parenteral iron products are available. These vary in complex types which impacts the 
total amount of iron that may be administered in a single administration. Numerous other 
differences differentiate the products; however, all appear to effectively release iron post 
administration and restore the deficit of the patient. There are numerous studies with iron sucrose 
injection (Venofer®) that have been performed in the pediatric population 6-8. Iron doses have 
varied in the studies with demonstrated efficacy and safety in doses up to 7mg iron/kg or 200mg 
given in time frames of 3 min, which was shown to be beneficial to both the child and health care 
facility6.  
Ferric Carboxymaltose has been characterized as a robust and strong type iron complex (Type 1) 
with a molecular mass of about 150,000 Daltons (Da). The solution is a dark brown color with a 
near neutral pH (5.0 to 7.0) and a physiological osmolarity permitting administration of higher 
single doses in short time periods. Although no interventional studies have been conducted with 
Ferric Carboxymaltose in the pediatric population to date, the product has been used in clinical 
practice in markets where it is currently approved for adults to aid correction of iron deficiency 
within the pediatric gastroenterological setting.  A non-interventional/retrospective observational 
data collection has identified in 79 patient’s aged 2 to 18 years with a mean age of 12.7 years.  In 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
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Page 13 of 51 
these subjects, Ferric Carboxymaltose showed efficacy with regard to hemoglobin, ferritin, and 
TSAT as well as safety and tolerability (manuscript in preparation).  
 
Therefore, the proposed studies will assess higher single doses (i.e., 7.5 mg/kg and 15 mg/kg) 
than those used with currently available parenteral iron preparations in iron deficient children 
with anemia to characterize the pharmacokinetics and pharmacodynamics in this younger 
population.  The higher single doses permit fewer overall injections/infusions and may ultimately 
permit fewer visits to the treating facilities positively impacting both the child and family as well 
as health care system. 
 
1.2 
Ferric Carboxymaltose   
1.2.1 Key features of Ferric Carboxymaltose 
Ferric Carboxymaltose Injection is a stable Type I polynuclear iron (III)-hydroxide carbohydrate 
complex developed as an intravenous iron replacement therapy for the treatment of IDA. After 
intravenous administration, Ferric Carboxymaltose is mainly found in the liver (RES), 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 Ferric Carboxymaltose 
is metabolized by the glycolytic pathway.   
1.2.2 Ferric Carboxymaltose versus Other Parenteral Iron Agents 
There is considerable efficacy and safety experience with the various parenteral iron preparations 
available (3).  However, prior to the approval of non-dextran formulations, the risk of systemic 
adverse reactions restricted their use.  Ferric Carboxymaltose offers significant advantages 
compared to other available intravenous 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% (6).  Over the last 20 years, 30 deaths have been attributed 
to the use of IV iron dextran. The high incidence of anaphylaxis/anaphylactoid reactions is 
believed to be caused by the formation of antibodies to the dextran moiety.   Although some have 
suggested that high molecular weight (HMW) iron dextran is 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 (7).  Iron dextran is limited to second line therapy for treatment of iron 
deficiency.   
More recently approved, non-dextran intravenous 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 IV iron compounds carry a significant risk of bioactive iron reactions at higher doses.  
These reactions are characterized by hypotension (without allergic signs) accompanied by pain in 
the chest, abdomen, flank and/or nausea, vomiting, diarrhea.  


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Page 14 of 51 
 
 
Due to its structure, Ferric Carboxymaltose is more stable than iron gluconate and iron sucrose, 
producing 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 sucrose11 (data on file ).  These 
characteristics of Ferric Carboxymaltose make it possible to administer much higher single doses 
over shorter periods of time than iron gluconate or iron sucrose, resulting in the need for fewer 
administrations to replenish iron stores, consequently making it better suited for outpatient use 
(Table 1.2.2.1).  Another recently approved IV iron is ferumoxytol (AMAG) in which 510 mg 
can be injected rapidly on 2 occasions separated by several days.  This formulation, which is 
currently indicated for IDA associated with CKD, is a modified-dextran derivative and is 
indicated for a 1020 mg repletion dose (see Ferumoxytol PI).  
 
Table 1.2.2.1     Administration of at least 1500 mg of Intravenous Iron with Currently 
Available Iron Preparations and Ferric Carboxymaltose 
Iron 
Preparation 
Test Dose 
Required 
Maximum 
Infusion Dose 
 
Infusion Time 
Number of 
Infusions 
Iron dextran 
Yes 
100 mg* 
2 minutes 
15 + test dose 
Iron gluconate 
No 
125 mg 
10 minutes 
12 
Iron sucrose 
No 
200 mg 
5 minutes 
8 
Iron sucrose 
No 
300mg 
1.5 hours 
5 
Iron sucrose 
No 
400 mg 
2.5 hours 
4 
ferumoxytol 
No 
510 mg 
< 1 minute 
3 
Ferric 
Carboxymaltose 
No 
750 to 1000 mg** 
8 to 15 minutes 
2 
* Higher doses are administered off label and are approved outside the US 
**1000 mg maximum dose is approved in countries outside of the US; 750 mg maximum is the U.S. FDA approved 
dose  
 
The larger Ferric Carboxymaltose and ferumoxytol doses result in less frequent administration of 
intravenous iron that should benefit, in particular, severely iron deficient and anemic 
populations. To be treated with currently available intravenous iron agents, the average 
inflammatory bowel disease, postpartum,  heavy uterine bleeding and non-dialysis dependent 
patient would require an initial test dose, followed by 15 doses of iron dextran as labeled, each 
accompanied by personnel equipped and trained for resuscitation of anaphylaxis; 12 doses of 
ferric gluconate; or either 8 doses of iron sucrose (with 5 minute infusion time) or 5 / 4 doses of 
iron sucrose by prolonged (1.5 to 2.5 hours) intravenous infusion. Ferric gluconate and iron 
sucrose are not approved by the FDA for the treatment of IDA in non chronic kidney disease 
populations and iron dextran is only approved as second line therapy for treatment of iron 
deficiency.  In contrast, most patients treated with Ferric Carboxymaltose would require 2 doses 
administered over 8 to15 minutes one week apart.   
 
1.2.3 Ferric Carboxymaltose Human Experience 
 
The Ferric Carboxymaltose development program demonstrated the safety and effectiveness of 
intravenous Ferric Carboxymaltose in the treatment of IDA.  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 Ferric Carboxymaltose.  


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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 Ferric 
Carboxymaltose 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, compared with 2 to 13% for iron sucrose.  The projected terminal half-life (t½) was 
calculated to approximately 16 hours, compared to 3 to 4 days for iron dextran and 6 hours for 
iron sucrose. An ascending dose pharmacokinetic study (VIT-IV-CL-002), demonstrated that 
following the 500 and 1,000 mg Ferric Carboxymaltose dose, the majority of the Ferric 
Carboxymaltose iron complex was utilized or excreted by 72 hours. 
Phase III studies demonstrated the effectiveness of Ferric Carboxymaltose in treating IDA 
secondary to inflammatory bowel disease, heavy uterine bleeding, chronic kidney disease 
(hemodialysis and non-hemodialysis) and the postpartum state.  Clinically meaningful increases 
in hemoglobin, ferritin, and TSAT were observed in each of the studies. Non-inferiority to full 
therapeutic doses of oral ferrous sulfate was demonstrated in studies of IDA associated with 
inflammatory bowel disease. Superiority to full therapeutic doses of oral ferrous sulfate was 
demonstrated in studies of IDA secondary to heavy uterine bleeding, the postpartum state and 
non-hemodialysis dependent chronic kidney disease.  A head to head comparison of Ferric 
Carboxymaltose to Venofer (Iron sucrose)  in over 2,500 subjects with non-dialysis dependent 
CKD and elevated risk of cardiovascular disease according to the Framingham criteria 
demonstrated that the recommended dose of Ferric Carboxymaltose, 750 mg x 2 (1500 mg total) 
had superior efficacy to the labeled dose of Iron sucrose (200 mg x 5 [1000 mg total]) with 
regard to hemoglobin elevation and had a similar cardiovascular (and overall) safety profile, 
based in part on an independently adjudicated composite cardiovascular safety endpoint (8) . 
 
Important details of pre- and clinical safety and efficacy can be found in the Investigator’s 
Brochure. Ferric carboxymaltose received approval from the UK Medicines and Healthcare 
products Regulatory Agency (MHRA) approval on June 15, 2007 for the use of Ferric 
Carboxymaltose (EU Trade name: Ferinject) in 18 EU (European Union) 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, Ferric Carboxymaltose 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.  
Ferric Carboxymaltose received approved from the Food and Drug Administration (FDA) on 
July 25, 2013 for marketing in the United States. 
2.0 
MAIN TRIAL OBJECTIVE 
The primary objectives of this study are to characterize the pharmacokinetics and determine 
appropriate dosing and safety of Ferric Carboxymaltose for the pediatric population suffering 
from iron deficiency (ID) with anemia.  


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3.0  
OVERALL STUDY DESIGN AND RATIONALE 
3.1 
 Trial Design 
This is a phase II, open-label, non-randomized,  multi-center, single arm study to characterize the 
pharmacokinetic and pharmacodynamics  (PK/PD) profile of Ferric Carboxymaltose dosing in 
pediatric subjects with IDA after receiving either a 7.5 mg/kg or 15 mg/kg dose of Ferric 
Carboxymaltose.  
 
Cohort 1: 16 subjects will be treated with Ferric Carboxymaltose at 7.5 mg/kg 
with a maximum single dose of 750 mg, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have 
completed 4 weeks of therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Ferric Carboxymaltose at 15 mg/kg 
with a maximum single dose of 750 mg, whichever is smaller.   
 
3.2 
Rationale 
3.2.1 Rationale for Trial Design 
Ferric Carboxymaltose is a non-dextran IV iron recently approved by the United States Food and 
Drug Administration (FDA).  This trial is designed to assess the single doses (i.e., 7.5 mg iron/kg 
and 15 mg iron/kg) in iron deficient children with anemia to characterize the pharmacokinetics 
and pharmacodynamics in this younger population.  
3.2.2 Rationale for open label design 
The open-label, single arm trial design is considered appropriate because a control group is not 
required to estimate the PK/PD profile of Ferric Carboxymaltose.  The risk from exposure to 
another form of IV iron is not offset by the minimal scientific benefit. 


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3.2.3. Schedule of Events 
Visit Day 
Screening 
Period 
(Up to 14 
Days) 
Day 
-1 
Day 
0 
24 and 48 
hours 
post 
dosing 
72 hours 
post 
dosing 
Day 14 
(week 2) 
Day 28 
(week 4) 
Day 35 
(week 5) 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Assess entry 
criteria 
X 
 
X 
 
 
 
 
 
EDC 
X 
 
X 
 
 
 
 
X 
Medical History 
X 
 
X 
 
 
 
 
 
Physical Exam1 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
 
X 
 
X 
X 
X 
X 
Height / Weight 
 
 
X 
 
 
 
 
 
PK/PD Samples 
 
X2 
X3 
X4 
X4 
 
 
 
Hematology, 
Chemistry and 
Iron Indices 
X 
 
 
 
X 
X 
X 
X 
Serum 
pregnancy test 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
 
X 
 
X 
X 
X 
X 
ESA Stability 
X 
 
X 
 
X 
X 
X 
X 
Adverse Event 
Assessments5 
 
 
X 
X 
X 
X 
X 
X 
Ferric 
Carboxymaltose
 
 
X 
 
 
 
 
 
1 Includes clinical assessment of skin, cardiovascular, pulmonary, abdominal, and central nervous system 
2 Blood samples drawn at 8am, 12pm and 8pm for subject iron profile 
3 Blood samples PK/PD should be taken prior to Ferric Carboxymaltose dosing and additional samples for PK/PD 
should be taken at 1, 2, 6 and 12 hours post dosing.  
4 Blood samples should be taken approximately the same time of day as the Day 0 samples were drawn 
5 Adverse event assessments starting at the time of Ferric Carboxymaltose dosing 
6 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-dose only.  Vital signs on non-dosing days 
include sitting heart rate and blood pressure only. 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 18 of 51 
4.0  
SUBJECT SELECTION 
4.1 
Number and Type of Subjects 
Up to thirty two  (32) subjects who have given written informed consent / assent along with 
parent or guardian’s written informed consent with a diagnosis of iron deficiency anemia (IDA) 
who fulfill the inclusion criteria, do not meet any of the exclusion criteria will be registered to 
receive Ferric Carboxymaltose.    
 
4.2 
Screening Phase 
 
Once a subject enters the screening phase, they will be assigned, via the Electronic Data Capture 
(EDC) system, a unique screening number.  From the time of consent until the start of treatment 
of IV Ferric Carboxymaltose, the subject will not receive any form of iron outside of the study 
(intravenous or blood transfusion iron from 4 weeks prior to consent or oral iron including 
multivitamins with iron from time of consent).   
If the subject does not qualify for study entry the subject should be entered into the EDC system 
as a screen failure.  Subjects can be re-screened once, see section 6.2.   
4.2.1  Entry Criteria 
Inclusion Criteria: 
 
1. Male or female subjects 1 to 17 years of age (6 to 17 years of age in Russia only) with 
assent to participation and his/her parent or guardian is willing and able to sign the informed 
consent approved by the Independent Review Board / Ethics Committee.  
2. Screening TSAT < 20% 
3. Screening Hemoglobin < 11 g/dL 
4. For subjects who are receiving a erythropoietin stimulating agent (ESA): stable ESA therapy 
(+/- 20% of current dose) for > 8 weeks prior to the qualifying screening visit and no ESA 
dosing or product changes anticipated for the length of the trial. 
 
Exclusion Criteria:    
1. Known hypersensitivity reaction to any component of Ferric Carboxymaltose. 
2. Subject previously randomized and treated in this study or any other clinical study of Ferric 
Carboxymaltose (FCM, VIT-45). 
3. Body mass index (BMI) ≤ 5th percentile for age (see APPENDIX 2) 
4. Male or Female subject 1 year of age weighing < 12kg. 
5. History of acquired iron overload, hemochromatosis or other iron accumulation disorders. 
6. Chronic kidney disease subjects on hemodialysis. 
7. Screening Ferritin level > 300 ng/mL. 
8. Subjects with significant severe diseases of the liver, hemopoietic system, cardiovascular 
system, psychiatric disorder or other conditions which on the opinion of the investigator 
may place a subject at added risk. 
9. Any active infection.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 19 of 51 
10. Known positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody (HCV) with 
evidence of active hepatitis. 
11. Known positive HIV-1/HIV-2 antibodies (anti-HIV). 
12. Anemia due to reasons other than iron deficiency (i.e. hemoglobinopathy). Subjects treated 
with vitamin B12 or folic acid deficiency are permitted. 
13. Intravenous iron and /or blood transfusion in the 4 weeks prior to screening.  
14. Immunosuppressive therapy that may lead to anemia (i.e. cyclophosphamide, azathioprine, 
mycophenolate mofetil).  Note steroid therapy is permitted. 
15. Administration and / or use of an investigational product (drug or device) within 30 days of 
screening. 
16. Alcohol or drug abuse within the past six months. 
17. Female subject who are pregnant or lactating, or sexually active female who are of 
childbearing potential not willing to use an acceptable form of contraceptive precautions 
during the study. 
18. Subject is unable to comply with study assessments. 
4.3 
Subject Assignment and Registration Process 
Subjects that meet all inclusion requirements and no exclusionary criteria will be offered 
participation in this 7 week study. Cohorts 1 and 2 will be enrolled and treated sequentially.  
Enrollment into Cohort 2 will not begin until all Cohort 1 subjects have completed 4 weeks of 
therapy and no safety issues with the administration of Ferric Carboxymaltose has been 
confirmed by the DSMB. 
4.4 
Withdrawal from Study 
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.  
At the time of withdrawal, procedures for the Day 35 visit must be performed regardless of 
whether the subject has completed study drug treatment.  In the event the subject has received 
any study drug; the subject should be contacted to assess adverse events 28 days post the last 
dose of Ferric Carboxymaltose, if possible. 
 
In the event a subject withdraws without completing the full PK/PD sampling.  Additional 
subjects may be enrolled to ensure adequate representations of the PK/PD parameters are 
available for analyses.  Conditions for additional enrollment will be defined in more detail in the 
statistical analyses plan. 
 
4.5 
Intervention 
Intervention is defined as follows: 
 Increase in dose of erythropoietin for any reason (Day 0 thru Day 35). 
 Blood transfusion.    
 Use of IV iron outside of protocol.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
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 Use of oral iron outside the protocol.  
When intervention occurs, the date of the intervening event should be recorded in the source 
documents as well as the electronic Case Report Form (eCRF), and the subject should continue 
in the study as scheduled through Day 35. 
5.0 
STUDY DRUG 
5.1 
Formulation Packaging and Storage 
All medication to be used in this study that has been supplied by Vifor Pharma Ltd. will have 
been prepared according to Good Manufacturing Practices (GMP).  
Ferric Carboxymaltose (known in the EU as Ferinject®) will be supplied 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.   
Study drug must be kept in a secure place at the investigational site, and stored at room 
temperature (see: USP).  Ferric Carboxymaltose should not be frozen.  Vials may not be used 
for more than 1 dose or for more than 1 subject.  All Ferric Carboxymaltose vials used and 
unused should be kept by the study staff. 
 
5.2 
Drug Administration / Regimen 
 
The Principal Investigator or designee will supervise administration of the study drug to subjects: 
Cohort 1: 16 subjects will be treated with Ferric Carboxymaltose at 7.5 mg/kg with a 
maximum single dose of 750 mg, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have 
completed 4 weeks of therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Ferric Carboxymaltose at 15 mg/kg with a 
maximum single dose of 750 mg, whichever is smaller.   
Ferric Carboxymaltose will be given on Day 0.  It will be administered as either: 
 
 An undiluted slow IV push at a rate of 100 mg/minute. 
 Doses less than 100 mg should be given as a slow undiluted IV push within a 
minute. 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 21 of 51 
5.3 
IV Iron Precautions 
When administering IV Iron, the following precautions will be taken: 
 The subject will be clinically evaluated prior to drug administration to assess the 
development of clinically significant conditions.   
 The vials will be visually inspected for particulate matter and discoloration before 
each use; if noted, the vial will not be used and the Investigator or his/her designee 
will notify the sponsor, or sponsor’s designee, for replacement of the study drug and 
for directions to return the unused vial.     
 Sitting heart rate and blood pressure will be assessed pre-, 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.  
5.4 
Drug Accountability 
Investigators will keep adequate records of the receipt, administration and return of Ferric 
Carboxymaltose.  They will not allow Ferric Carboxymaltose 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 registered 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 Ferric 
Carboxymaltose will be returned to Luitpold Pharmaceuticals, Inc. (or their designee).  All data 
regarding Ferric Carboxymaltose must be recorded on the Drug Accountability Forms provided 
by the sponsor.  
Investigators will keep adequate records of the administration and disposition of IV Ferric 
Carboxymaltose® used for patients selected for the trial.  
5.5 
Concomitant Medication 
 
Concomitant medications along with their route of administration and duration must be recorded 
in the electronic case report form (eCRF) from 30 days prior to consent.  No additional iron 
preparations (IV iron from 4 weeks  prior to consent or oral iron including multivitamins 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 22 of 51 
with iron, from time of consent), will be allowed.  No prophylactic medications may be 
administered prior to Ferric Carboxymaltose administration without prior approval from 
Luitpold Pharmaceuticals, Inc.  
 
If receiving an Erythropoiesis Stimulating Agent (ESA), a stable (± 20%) dose is required for > 8 
weeks prior to consent.  The ESA type, route, frequency and dose will remain unchanged 
throughout the study unless the dose should be decreased or held per the package label.  Once 
decreased or held, it may not be increased or restarted unless thought necessary by the subject’s 
physician. If the latter event occurs, these data points will be collected and the subject will 
continue for safety analysis. 
 
 
 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 (who for this trial is 1 -17 years old) 
must assent, if appropriate and his/her legal guardian (who is above age of legal consent) 
voluntarily sign an informed consent statement (Required Elements of Informed Consent, 21 
CFR 50.25).  The Code of Federal Regulations (CFR) is a codification of rules and regulations of 
the United States government.  The subject’s legal guardian will be given a copy of the signed 
consent form. 
6.2 
Screening (up to 14 days)  
Each subject who qualifies for inclusion will undergo the following clinical evaluations to 
confirm their eligibility for the study: 
 Obtain screening number from EDC 
 Medical history, including prior iron therapy use  
 Vitals signs (including sitting heart rate and blood pressure)  
 Hematology, Chemistries and iron indices  
 Serum pregnancy test for female subjects of child bearing potential (negative results must 
be obtained prior to registering the subject for study drug dosing). 
 Concomitant medications assessment 
 ESA therapy stability ( if applicable)  
Subjects who do not meet the entry criteria should be entered into the 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 in 
section 6.2 will need to be repeated. 


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Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
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6.3 
Study Visits  
6.3.1. Day (-1)  
Once it’s confirmed during the screening period that the subject continues meet the entry criteria 
all eligible subjects will return to the clinic on Day – 1, blood samples will be drawn at 8am, 
12pm and 8pm to characterize the subject iron profile.   
6.3.2 Day 0 
On Day 0, prior Ferric Carboxymaltose dosing the following will occur:  
 Re-verify the inclusion and exclusion criteria 
 Update any relevant history 
 Basic physical exam including clinical assessment of skin, cardiovascular, pulmonary, 
abdominal and central nervous system.  
 Height  
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 Log on to the EDC system and register subject for study drug dosing.  
After assignment of the treatment group (Cohort 1 and 2, subsequently) the following will occur: 
 Blood samples for PK/PD before start of dose. 
 Weight in kg without shoes 
 Verify amount of single Ferric Carboxymaltose dose (7.5 or 15 mg/kg up to a 
maximum dose of 750 mg whichever is smaller).  
 Document start and stop time of Ferric Carboxymaltose administration, the total dose 
administered. 
 Obtain sitting heart rate and blood pressure immediately pre-dose, immediately post-
dose, and 30 minutes post Ferric Carboxymaltose administration.  Body temperature 
taken pre-dose  
 Adverse event assessment (starting at beginning of Ferric Carboxymaltose injection). 
Blood samples for PK/PD will be drawn at 1, 2, 6 and 12 hours post the Day 0 Ferric 
Carboxymaltose dose. 
 
6.3.2. Days 1 and 2 (24 and 48 hour) 
 
 Blood samples for PK/PD 
 Adverse events assessment 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 24 of 51 
 
6.3.3.  72 hour, and Days 14 and 28 (weeks 2 and 4) 
 
 Blood samples for PK/PD (72 hour visit only) 
 Vital signs 
 Hematology, Chemistry and iron indices 
 Adverse events assessment 
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 
6.3.4. Day 35 (week 5) End of Study 
 
 Basic physical exam including clinical assessment of skin, cardiovascular, 
pulmonary, abdominal and central nervous system.  
 Vitals signs  
 hematology, chemistries and iron indices  
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 Adverse events assessment 
 Log onto EDC and enter subject as complete 
 
The subject has completed the study after the Day 35 visit is complete.  If for any reason the 
subject does not complete the study the Day 35 procedures should be completed prior to the 
subject exiting from the trial.   
 
6.3.5. Pharmacokinetics and Pharmacodynamics (PK/PD) 
 
Blood samples will be collected for PK/PD assessment pre-dose and at 1, 2, 6, 12, 24, 48 and 72 
hours post dose.  Blood samples should be taken at approximately the same time of day as the 
initial pre-dose sample on Day 0.   
 
Prior to Day 0, subjects will return to the clinic on Day -1 at which time blood samples will be 
drawn at 8am, 12pm and 8pm to characterize the subjects specific iron profile. 
 
Total blood volume (regular hematology, chemistry, iron indices and PK/PD) collected per day 
and during the 35 Day study is provided below: 
 
 
 
Screening 
Day (-
1) 
Day 0 
24hr 
48hr 
72hr 
Day14 
Day 28 
Day 35 
Total 
Blood 
Volume 
Hem/Chem/II 
(4.5ml) 
4.5ml 
 
 
 
 
4.5ml 
4.5ml 
4.5ml 
4.5ml 
PK/PD (2ml) 
 
6ml 
10ml 
2ml 
2ml 
2ml 
 
 
 
 
TOTAL 
4.5ml 
6ml 
10ml 
2ml 
2ml 
6.5ml 
4.5ml 
4.5ml 
4.5ml 
44.5ml / 
approx. 
9.03 
tsps.* 
*4.93 mL = 1 tsp. 


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Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 25 of 51 
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 testing will be provided to the physician 
for review and assessment. If the Investigator wishes to obtain a follow-up of an abnormal Day 
35 laboratory, this laboratory may be obtained after notification of the Sponsor.  The laboratory 
assessments will be determined as listed in Section 3.2.3.  
Hematology: 
Hb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, 
differential count, and reticulocyte count  
Chemistry:  
sodium, potassium, chloride, BUN, creatinine, albumin, alkaline 
phosphatase, total bilirubin, GGT, AST, ALT, LDH, calcium, 
phosphorus, glucose, bicarbonate and magnesium 
      Iron indices: 
serum iron, serum ferritin, and total iron binding capacity (TIBC), 
and percentage serum transferrin saturation (TSAT) 
            Other:                            Serum pregnancy test  
 
 
7.0  
ASSESSMENT OF SAFETY 
 
7.1 
Adverse Events 
 
Any untoward medical event experienced by a subject during the course of this clinical trial, 
whether or not it is related to the investigational product, at any dose, must be recorded on the 
Adverse Event page of the eCRF.  
For any laboratory abnormality, the investigator will make a judgment as to its clinical 
significance.  If the laboratory value is outside the normal 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 eCRF. 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].  All laboratory values at the end of study/Day 35 that have 
been deemed clinical significant by the Investigator should be followed until they are back into 
normal range. 
For the purposes of this study, non-serious anemia (Hb or Hct below the normal range or 
worsened from baseline) or iron deficiency (iron indices below the normal range or worsened 
from baseline) will not be considered adverse events.  Anemia or iron deficiency will be 
considered end points if an intervention is required.   
To quantify the severity of adverse events, the National Cancer Institute (NCI)-Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4 should be used to grade all 
events.  These criteria are provided in the procedure manual.   


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Protocol: 1VIT13036 
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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 
Grade 
Adjective 
Description 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (i.e., 
preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.)  
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self care activities of daily living (i.e., bathing, 
dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.)  
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Death 
Results in Death due to the AE 
Timing: Non-serious adverse events will be reported from the initial treatment with Ferric 
Carboxymaltose through the completion of the study Day 35. AE’s will be captured 28 days post 
the last dose of Ferric Carboxymaltose for subjects who early terminate from the trial.  This can 
be completed via a phone call.  All ongoing adverse events related to Ferric Carboxymaltose 
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 Ferric Carboxymaltose as follows: 
 NONE 
There is no evidence of any causal relationship. 
 
 UNLIKELY There is little evidence to suggest there is a causal relationship.  There is 
another reasonable explanation for the event (e.g., the subject’s clinical 
condition, other concomitant treatments). 
 POSSIBLE 
There is some evidence to suggest a causal relationship (i.e. there is a 
reasonable possibility that the adverse experience may have been caused 
by the agent).  However, the influence of other factors may have 
contributed to the event (e.g., the subject’s clinical condition, other 
concomitant events). 
 PROBABLE There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. 
 
*For the purposes of this trial, “study drug” is defined as: Ferric Carboxymaltose  
 
 


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Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 27 of 51 
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 their 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 
Definition: An adverse event is classified as SERIOUS if it meets any one of the following 
criteria:  
 Death 
 Life-Threatening: The subject was at substantial risk of dying at the time of the adverse 
event or it is suspected that the use / continued use of the product would result in the 
subject's death. 
 Hospitalization (initial or prolonged): Required admission to the hospital or 
prolongation of a hospital stay. 
 Disability: Resulted in a significant, persistent, or permanent change, impairment, 
damage or disruption in the subject's body function/structure, physical activities or 
quality of life. 
 Congenital Anomaly/Birth Defect   
 Important medical events: Other medically important events that, in the opinion of the 
investigator, may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed above. 
A distinction should be drawn between SAE and severe AE.  A severe AE is a major experience 
of its type.  A severe AE is not necessarily serious: e.g. nausea, which persists for several hours, 
may be considered severe nausea, but it is not an SAE.  On the other hand 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 initial treatment with Ferric Carboxymaltose 
through the completion of the study Day 35.  SAEs will be captured 28 days post the last dose of 
Ferric Carboxymaltose for subjects who early terminate from the trial.  This can be completed 
via a phone call. 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.   
   


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Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
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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 
learning 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. 
8.0 
STATISTICS 
No hypothesis testing will be performed for this study. 
8.1 
 Sample Size  
Determination of sample size for this single-arm, pediatric, pharmacokinetic study is a 
compromise between obtaining sufficiently precise estimates of pharmacokinetic parameters and 
the ethics of including a large number of pediatric patients in an experiment. The precision of 
estimation can be quantified as the width of the 95% confidence interval for AUC0-72 from this 
single-arm study (i.e., smaller width indicates better precision). Based on Study VIT-IV-CL-002 
in adults, the standard deviation for total serum iron AUC0-72 following a 500 mg intravenous 
dose is approximately 300 µg◦hour/mL. The width of a 95% confidence interval, using a 
standard deviation of 300 µg◦hour/mL, is presented below for selected sample sizes. As seen in 
the figure, 16 patients appears to be a reasonable compromise between precision and number of 
exposed pediatric patients. 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
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Page 29 of 51 
 
 
Approximately 32 subjects will be enrolled in this study, 16 subjects in cohort I and 16 subjects 
in cohort II.  Within each cohort of 16 subjects will be equally disturbed by age, which will 
include 8 subject’s 1 – 6 years of age and 8 subjects > 6 – 17 year of age.   Subject enrollment 
and ages will be tracked and monitored via interactive web response (IWR) system. 
 
8.2 
Analysis Populations  
 
There will be 2 analysis populations: 
 
 
Safety population: Includes all subjects who receive Ferric Carboxymaltose. 
 
 
PK/PD population: Includes all subjects in the safety population who have evaluable iron 
profiles and no protocol violation that could affect the PK/PD of Ferric Carboxymaltose. 
 
8.3 
Demographic Characteristics 
 
Demographic characteristics will be summarized for the Safety and PK/PD populations.  The 
number and percentage of subject’s who are registered, treated, prematurely discontinue, and 
complete 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.   
 
 
 
0 
100 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1100 
1200 
1300 
1400 
1500 
0 
8 
16 
24 
32 
40 
48 
56 
64 
Width of 95% CI 
Number of Subjects 


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The number of subjects in each treatment group will be summarized for each investigative site. 
Categorical baseline characteristics (e.g., sex and race) will be summarized with the number and 
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 Clinical Endpoints 
Clinical endpoints include: 
 Efficacy: change from baseline to each scheduled visit for hemoglobin, ferritin, and 
TSAT. 
 Safety: 
 Proportion of subjects reporting treatment-emergent adverse events, overall and 
related, by SOC and preferred term 
 Subjects reporting treatment-emergent serious adverse events, overall and related, 
will be identified 
 Mean change from baseline to each scheduled visit for clinical laboratory values 
 Incidence of treatment-emergent potentially clinically significant (PCS) clinical 
laboratory values 
 Incidence of treatment-emergent PCS vital sign values. 
8.5 
 Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints  
The primary and secondary pharmacokinetic parameters will be determined for each subject as 
appropriate, based on serum concentration. The baseline parameters will be subtracted from all 
measured samples.  
The primary parameters are the maximum serum concentration (Cmax), the area under the serum 
concentration-time curve from time zero to the last sampling time (t) with a quantifiable 
concentration (AUC0-time last measured concentration), the extrapolated area under the serum 
concentration- time curve from time zero to  infinity (AUC0-infinity), and the half-life (T1/2).  Cmax 
is calculated as a non-compartmental variable, which is a more conservative method than if it 
were calculated using a compartmental paradigm.  T1/2 incorporates the calculation of the rate 
elimination constant (Kel). 
 
The secondary parameters are the mean residence time (MRT), the apparent serum clearance 
(Cl), and the apparent volume of distribution (Vd), which includes the initial volume of 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 31 of 51 
distribution following the injection (Vdc), the volume of distribution at the steady state (Vdss), 
and the volume of distribution at the final elimination (Vdarea). 
Pharmacodynamic parameter will include serum ferritin, transferrin, transferrin saturation (TfS) 
UIBC, HGB, reticulocyte count and transferrin receptors. 
The Pharmacokinetic and Pharmacodynamic parameters performed in this study for analysis will 
be outlined in a Statistical and Analytical Plan. 
8.6 
Statistical Analyses of Safety 
The Medical Dictionary for Regulatory Activities (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 system organ class (SOC), the subject will be counted only once for that 
SOC.   
Change in 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 vital signs will be 
summarized for each treatment group. 
8.7 
DSMB Analyses 
A DSMB will review safety information for subjects in Cohort 1 before dosing begins for Cohort 
2.  A Charter will be developed outlining the DSMB processes.  
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 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
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years following the completion of the study. Permission should be obtained from Luitpold 
Pharmaceuticals, Inc. prior to destroying any study records. 
The investigator must make study data accessible to the monitor, Sponsors, or other authorized 
representatives of the Sponsor and Regulatory Agency (i.e., FDA inspectors.)  A case history for 
each subject must be maintained, that includes the signed Informed Consent form and copies of 
all study documentation related to that subject. The investigator must ensure the availability of 
source documents from which the information on the eCRF was derived.  
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 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 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. 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
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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. 
 
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 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
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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. Notification of these audits will be sent to all investigators in advance. 
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 Declaration of Helsinki, all applicable local and state regulations, 21 
CFR Part 312 and applicable ICH guidelines. 
9.7.2 Institutional Review Board 
The protocol and the Informed Consent / Assent 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 / Assent 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 / Assent when appropriate must be obtained from each subject prior to study 
participation. The informed consent / assent will be provided to the subject in their native 
language. The consent/assent form must be signed by the subject and/or the subject's legally 
authorized representative.  Each investigational site must provide the Sponsor (or designee) with 
a copy of the Informed Consent / Assent approved by that site's Institutional Review Board. The 


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Protocol: 1VIT13036 
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original signed consent / assent 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 / 
Assent 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 / assent must be certified by a qualified translator and their use must be documented. 
The Informed Consent / Assent 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 / Assent must be signed and dated by each 
subject and/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 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]. 
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. 
(or designee). Source data will be reviewed by the Clinical Monitor 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]. 


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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, DSMB, 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 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. 
 


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Protocol: 1VIT13036 
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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 
The DSMB will be composed of approximately 3-5 senior academic individuals, including the 
DSMB Chair. They will have high-level expertise in pediatric iron deficiency anemia 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 


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Protocol: 1VIT13036 
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Page 38 of 51 
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 evaluate the safety from both cohorts 1 
and 2 (7.5 or 15 mg/kg of Ferric Carboxymaltose).  Only after all subjects in cohort 1 have 
completed through week 4 and the DSMB has evaluated the safety data as acceptable will 
registration into cohort 2 be granted.  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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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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Protocol: 1VIT13036 
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REFERENCES  
1.  Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn's disease. 
Aliment.Pharmacol.Ther. 2006; 24: 1507-1523 
2.  Foley RN, Parfrey PS, Harnett JD et al. Impact of hypertension on cardiomyopathy, 
morbidity and mortality in end-stage renal disease. Kidney Int. 1996; 49: 1379-1385 
3.  Staples AO, Greenbaum LA, Smith JM et al. Association between clinical risk factors and 
progression of chronic kidney disease in children. Clin.J.Am.Soc.Nephrol. 2010; 5: 2172-
2179 
 4.  Wharton BA. Iron deficiency in children: detection and prevention. Br.J.Haematol. 1999; 
106: 270-280 
5.  Kazal LA, Jr. Prevention of iron deficiency in infants and toddlers. Am.Fam.Physician 
2002; 66: 1217-1224 
6.  Michaud L, Guimber D, Mention K et al. Tolerance and efficacy of intravenous iron 
saccharate for iron deficiency anemia in children and adolescents receiving long-term 
parenteral nutrition. Clin.Nutr. 2002; 21: 403-407 
7.  Pinsk V, Levy J, Moser A, Yerushalmi B, Kapelushnik J. Efficacy and safety of 
intravenous iron sucrose therapy in a group of children with iron deficiency anemia. 
Isr.Med.Assoc.J. 2008; 10: 335-338 
8.  Surico G, Muggeo P, Muggeo V et al. Parenteral iron supplementation for the treatment of 
iron deficiency anemia in children. Ann.Hematol. 2002; 81: 154-157 
 
 


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APPENDIX 1:  FERRIC CARBOXYMALTOSE PACKAGE INSERT 


LPI PI for submission v14 (7-18-2013) trkchng 
 
1
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
Injectafer safely and effectively.  See full prescribing information for 
Injectafer.   
 
INJECTAFER® (ferric carboxymaltose injection)   
For intravenous use 
Initial U.S. Approval: 20XX 
 
----------------------------INDICATIONS AND USAGE--------------------------- 
Injectafer is an iron replacement product indicated for the treatment of iron 
deficiency anemia in adult patients: 
 
who have intolerance to oral iron or have had unsatisfactory 
response to oral iron; 
 
who have non-dialysis dependent chronic kidney disease. 
 
----------------------DOSAGE AND ADMINISTRATION----------------------- 
For patients weighing 50kg (110lb) or more:  Give Injectafer in two doses 
separated by at least 7 days.  Give each dose as 750mg for a total cumulative 
dose of 1500mg of iron per course. 
 
For patients weighing less than 50kg (110lb):  Give Injectafer in two doses 
separated by at least 7 days and give each dose as 15 mg/kg body weight.   
 
Injectafer treatment may be repeated if iron deficiency anemia reoccurs. (2)   
 
 
---------------------DOSAGE FORMS AND STRENGTHS---------------------- 
750 mg iron / 15 mL single-use vial(3) 
 
-------------------------------CONTRAINDICATIONS------------------------------ 
Hypersensitivity to Injectafer or any of its inactive components. (4) 
 
-----------------------WARNINGS AND PRECAUTIONS------------------------ 
 
Hypersensitivity reactions:  Observe for signs and symptoms of 
hypersensitivity during and after Injectafer administration for at least 30 
minutes and until clinically stable following completion of each 
administration. (5.1) 
 
Hypertension:  Monitor patients closely for signs and symptoms of 
hypertension following each Injectafer administration. (5.2) 
 
------------------------------ADVERSE REACTIONS------------------------------- 
The most common adverse reactions (>2%) are nausea, hypertension, 
flushing, hypophosphatemia, and dizziness (6.1) 
 
To report SUSPECTED ADVERSE REACTIONS, contact American 
Regent 
at 
1-800-734-9236 
or 
FDA 
at 
1-800-FDA-1088 
or 
www.fda.gov/medwatch. 
-------------------USE IN SPECIFIC POPULATIONS-------------------
--- 
 
Nursing Mothers: Exercise caution when administered to a nursing 
woman. (8.3) 
 
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling. 
 
 
 
 
Revised:  July 2013 
_____________________________________________________________________________________________________________________________________ 
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 Hypersensitivity Reactions 
5.2 Hypertension 
5.3 Lab test alterations 
6 
ADVERSE REACTIONS 
6.1 Adverse Reactions in Clinical Trials 
6.2 Post-marketing Experience 
7 
DRUG INTERACTIONS 
8 
USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
8.3 Nursing Mothers 
8.4  Pediatric Use 
10  OVERDOSAGE 
11  DESCRIPTION 
12  CLINICAL PHARMACOLOGY 
12.1 
Pharmacodynamics 
12.2 
Pharmacokinetics  
13  
NONCLINICAL TOXICOLOGY 
 
 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 
14  CLINICAL STUDIES 
 14.1 Iron Deficiency Anemia Due to Any Etiology 
 14.2 Non Dialysis Dependent Chronic Kidney Disease  
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
 
 
  8.5 
Geriatric Use 
* Sections or subsections omitted from the full prescribing information are not 
listed.
___________________________________________________________________________________________________________________________________ 
 
Reference ID: 3347006


 
2
FULL PRESCRIBING INFORMATION 
 
1 
INDICATIONS AND USAGE 
Injectafer is indicated for the treatment of iron deficiency anemia in adult patients; 
 
 who have intolerance to oral iron or have had unsatisfactory response to oral iron; 
 who have non-dialysis dependent chronic kidney disease. 
 
2 
DOSAGE AND ADMINISTRATION 
For patients weighing 50 kg (110 lb) or more:  Give Injectafer in two doses separated by 
at least 7 days.  Give each dose as 750 mg for a total cumulative dose not to exceed1500 
mg of iron per course. 
 
For patients weighing less than 50 kg (110 lb):  Give Injectafer in two doses separated by 
at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not 
to exceed 1500 mg of iron per course.   
 
 
The dosage of Injectafer is expressed in mg of elemental iron. Each mL of Injectafer 
contains 50 mg of elemental iron.  Injectafer treatment may be repeated if iron deficiency 
anemia reoccurs.   
 
 
 
Administer Injectafer intravenously, either as an undiluted slow intravenous push or by 
infusion.  When administering as a slow intravenous push, give at the rate of 
approximately 100 mg (2 mL) per minute.  When administered via infusion, dilute up to 
750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, 
such that the concentration of the infusion is not less than 2 mg of iron per mL and 
administer over at least 15 minutes.   
 
When added to an infusion bag containing 0.9% Sodium Chloride Injection, USP, at 
concentrations ranging from 2 mg to 4 mg of iron per mL, Injectafer solution is 
physically and chemically stable for 72 hours when stored at room temperature.  To 
maintain stability, do not dilute to concentrations less than 2 mg iron/mL.  
 
Inspect parenteral drug products visually for the absence of particulate matter and 
discoloration prior to administration.  The product contains no preservatives. Each vial of 
Injectafer is intended for single use only. Any unused drug remaining after injection must 
be discarded. 
 
Avoid extravasation of Injectafer since brown discoloration of the extravasation site may 
be long lasting.  Monitor for extravasation.  If extravasation occurs, discontinue the 
Injectafer administration at that site. 
 
 
 
Reference ID: 3347006


 
3
3 
DOSAGE FORMS AND STRENGTHS 
 
750 mg iron / 15 mL single-use vial  
 
4 
CONTRAINDICATIONS 
Hypersensitivity to Injectafer or any of its components [see Warnings and Precautions 
(5.1)]. 
 
5 
WARNINGS AND PRECAUTIONS 
 
5.1  Hypersensitivity Reactions 
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of 
which have been life-threatening and fatal, have been reported in patients receiving 
Injectafer. Patients may present with shock, clinically significant hypotension, loss 
of consciousness, and/or collapse. Monitor patients for signs and symptoms of 
hypersensitivity during and after Injectafer administration for at least 30 minutes 
and until clinically stable following completion of the infusion. Only administer 
Injectafer when personnel and therapies are immediately available for the 
treatment of serious hypersensitivity reactions. [see Adverse Reactions (6.1 and 6.2)].  
In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% 
(2/1775) of subjects receiving Injectafer. Other serious or severe adverse reactions 
potentially associated with hypersensitivity which included, but not limited to, pruritus, 
rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these 
subjects.  
 
5.2 Hypertension 
In clinical studies, hypertension was reported in 3.8% (67/1,775) of subjects in clinical 
trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with 
facial flushing, dizziness, or nausea were observed in 6% (106/1,775) of subjects in these 
two clinical trials. These elevations generally occurred immediately after dosing and 
resolved within 30 minutes.   Monitor patients for signs and symptoms of hypertension 
following each Injectafer administration [see Dosage and Administration (2)]. 
 
 
5.3 Laboratory Test Alterations 
In the 24 hours following administration of Injectafer, laboratory assays may 
overestimate serum iron and transferrin bound iron by also measuring the iron in 
Injectafer.  
 
6 
ADVERSE REACTIONS   
 
The following adverse reactions are discussed in greater detail in other sections of the 
labeling: 
.  Hypersensitivity Reactions [see Warnings and Precautions (5.1)] 
.  Hypertension [see Warnings and Precautions (5.2)] 
.   Lab test alterations [see Warnings and Precautions (5.3)] 
 
Reference ID: 3347006


 
4
6.1  Adverse Reactions in Clinical Trials 
 
Because clinical trials are conducted under widely varying conditions, the adverse 
reaction rates observed cannot be directly compared to rates in other clinical trials and 
may not reflect the rates observed in clinical practice. 
In two randomized clinical studies [Studies 1 and 2, See Clinical Studies (14)], a total of 
1,775 patients were exposed to Injectafer 15 mg/kg body weight up to a maximum single 
dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative 
dose of 1500 mg of iron. 
 
Adverse reactions reported by ≥ 1% of treated patients are shown in the following table.    
 
Table 1.   Adverse reactions reported in ≥ 1% of Study Patients in Clinical Trials 1 and 
2 
 
 
 
Term 
Injectafer 
 
 
(N=1775) 
% 
Pooled 
Comparatorsa
 
(N=1783) 
% 
Oral 
iron 
 
(N=253) 
% 
Nausea 
7.2 
1.8 
1.2 
Hypertension 
3.8 
1.9 
0.4 
Flushing/Hot Flush 
3.6 
0.2 
0.0 
Blood Phosphorus Decrease 
2.1 
0.1 
0.0 
Dizziness 
2.0 
1.2 
0.0 
Vomiting 
1.7 
0.5 
0.4 
Injection Site Discoloration 
1.4 
0.3 
0.0 
Headache 
1.2 
0.9 
0.0 
Alanine Aminotransferase Increase 
1.1 
0.2 
0.0 
Dysgeusia 
1.1 
2.1 
0.0 
Hypotension 
1.0 
1.9 
0.0 
Constipation 
0.5 
0.9 
3.2 
a Includes oral iron and all formulations of IV iron other than Injectafer 
 
Other adverse reactions reported by ≥ 0.5% of treated patients include abdominal pain, 
diarrhea, gamma glutamyl transferase increased, injection site pain/irritation, rash, 
paraesthesia, sneezing. Transient decreases in laboratory blood phosphorus levels (< 2 
mg/dL) have been observed in 27% (440/1638) patients in clinical trials.  
 
 
 
6.2  Post-marketing Experience 
Because these reactions are reported voluntarily from a population of uncertain size, it is 
not always possible to reliably estimate their frequency or establish a causal relationship 
to drug exposure. The following serious adverse reactions have been most commonly 
reported from the post-marketing spontaneous reports with Injectafer:  urticaria, dyspnea, 
pruritis, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, 
arthralgia,  and syncope. One case of hypophosphatemic osteomalacia was reported in a 
Reference ID: 3347006


 
5
subject who received 500 mg of Injectafer every 2 weeks for a total of 16 weeks.  Partial 
recovery followed discontinuation of Injectafer. 
 
7 
DRUG INTERACTIONS 
Formal drug interaction studies have not been performed with Injectafer .  
 
8 
USE IN SPECIFIC POPULATIONS 
 
8.1  Pregnancy  
Pregnancy Category C  
 
Risk Summary 
 
Adequate and well controlled studies in pregnant women have not been conducted.    
However, animal reproduction studies have been conducted with ferric carboxymaltose. In these 
studies, administration of ferric carboxymaltose to rabbits during the period of 
organogenesis caused fetal malformations and increased implantation loss at maternally 
toxic doses of approximately 12% to 23% of the human weekly dose of 750 mg (based on 
body surface area).  The incidence of major malformations in human pregnancies has not 
been established for Injectafer. However, all pregnancies, regardless of exposure to any 
drug, has a background rate of 2 to 4% for major malformations, and 15 to 20% for 
pregnancy loss. Injectafer should be used during pregnancy only if the potential benefit 
justifies the potential risk to the fetus.   
 
Animal Data 
Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion up to 
30 mg/kg/day iron on gestation days 6 to 17 did not result in adverse embryofetal 
findings.  This daily dose in rats is approximately 40% of the human weekly dose of 750 
mg based on body surface area.  In rabbits, ferric carboxymaltose was administered as a 
one-hour infusion on gestation days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 
mg/kg/day.  Malformations were seen starting at the daily dose of 9 mg/kg (23% of the 
human weekly dose of 750 mg).  Spontaneous abortions occurred starting at the daily 
iron dose of 4.5 mg/kg (12% of the human weekly dose based on body surface area).  
Pre-implantation loss was at the highest dose.  Adverse embryofetal effects were 
observed in the presence of maternal toxicity. 
 
A pre- and post-natal development study was conducted in rats at intravenous doses up to 
18 mg/kg/day of iron (approximately 23% of the weekly human dose of 750 mg on a 
body surface area basis).  There were no adverse effects on survival of offspring, their 
behavior, sexual maturation or reproductive parameters.  
 
8.3  Nursing Mothers 
A study to determine iron concentrations in breast milk after administration of Injectafer 
(n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with 
postpartum iron deficiency anemia.  Mean breast milk iron levels were higher in lactating 
women receiving Injectafer than in lactating women receiving oral ferrous sulfate. 
Reference ID: 3347006


 
6
 
8.4  Pediatric Use 
Safety and effectiveness have not been established in pediatric patients.  
 
8.5  Geriatric Use 
Of the 1775 subjects in clinical studies of Injectafer, 50% were 65 years and over, while 
25% were 75 years and over. No overall differences in safety or effectiveness were 
observed between these subjects and younger subjects, and other reported clinical 
experience has not identified differences in responses between the elderly and younger 
patients, but greater sensitivity of some older individuals cannot be ruled out. 
 
10  OVERDOSAGE 
Excessive dosages of Injectafer may lead to accumulation of iron in storage sites 
potentially leading to hemosiderosis. A patient who received Injectafer 18,000 mg 
over 6 months developed hemosiderosis with multiple joint disorder, walking 
disability and asthenia . Hypophosphatemic osteomalacia was reported in a patient 
who received Injectafer 4000 mg over 4 months. Partial recovery followed 
discontinuation of Injectafer. [see Post-marketing Experience (6.3)].  
 
11 
DESCRIPTION 
Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex 
with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(14)-O--D-
glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. 
It 
has 
a 
relative 
molecular weight of approximately 150,000 Da corresponding to the following empirical 
formula: 
 
[FeOx(OH)y(H2O)z]n [(C6H10O5)m (C6H12O7)l]k,   
 
where n  103, m  8, l 11, and k  4  
(l represents the mean branching degree of the ligand).  
 
The chemical structure is presented below: 
 
Reference ID: 3347006


 
7
 
 
Injectafer (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic 
colloidal solution for intravenous injection. Each mL contains 50 mg iron as ferric 
carboxymaltose in water for injection.  Injectafer is available in 15 mL single-use vials.  
Sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH to 5.0-
7.0.  
 
Vial closure is not made with natural rubber latex
Reference ID: 3347006


 
8
 
12 
CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose, 
a carbohydrate polymer that releases iron. 
 
12.2  Pharmacodynamics 
 
Using positron emission tomography (PET) it was demonstrated that red cell uptake of 
59Fe and 52Fe from Injectafer ranged from 61% to 99%. In patients with iron deficiency, 
red cell uptake of radio-labeled iron ranged from 91% to 99% at 24 days after Injectafer 
dose. In patients with renal anemia red cell uptake of radio-labeled iron ranged from 61% 
to 84% after 24 days Injectafer dose. 
 
12.3 Pharmacokinetics 
After administration of a single dose of Injectafer of 100 to 1000 mg of iron in iron 
deficient patients, maximum iron levels of 37 µg/mL to 333 µg/mL were obtained 
respectively after 15 minutes to 1.21 hours post dose. The volume of distribution was 
estimated to be 3 L. 
 
The iron injected or infused was rapidly cleared from the plasma, the terminal half-life 
ranged from 7 to 12 hours. Renal elimination of iron was negligible. 
 
13 
NONCLINICAL TOXICOLOGY 
13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility  
Carcinogenicity studies have not been performed with ferric carboxymaltose. 
 
Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in 
vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human 
lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma 
L5178Y/TK+/- cells, in vivo mouse micronucleus test at single intravenous doses up to 
500 mg/kg.   
 
In a combined male and female fertility study, ferric carboxymaltose was administered 
intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg.  
Animals were dosed 3 times per week (on Days 0, 3, and 7).  There was no effect on 
mating function, fertility or early embryonic development. The dose of 30 mg/kg in 
animals is approximately 40% of the human dose of 750 mg based on body surface area.  
 
 
 
14 
CLINICAL STUDIES  
The safety and efficacy of Injectafer for treatment of iron deficiency anemia were 
evaluated in two randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In 
these two trials, Injectafer was administered at a dose of 15 mg/kg body weight up to a 
maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up 
to a cumulative dose of 1500 mg of iron.  
Reference ID: 3347006


 
9
 
14.1 Trial 1: Iron Deficiency Anemia in Patients Who Are Intolerant to Oral Iron or 
Have Had Unsatisfactory Response to Oral Iron  
 
Trial 1 was a randomized, open-label, controlled clinical study in patients with iron 
deficiency anemia who had an unsatisfactory response to oral iron (Cohort 1) or who 
were intolerant  to  oral iron (Cohort 2) during the 14 day oral iron run-in period. 
Inclusion criteria prior to randomization included hemoglobin (Hb) <12 g/dL, ferritin ≤ 
100 ng/mL or ferritin ≤ 300 ng/mL when transferrin saturation (TSAT) ≤ 30%. Cohort 1 
subjects were randomized to Injectafer or oral iron for 14 more days.  Cohort 2 subjects 
were randomized to Injectafer or another IV iron per standard of care [90% of subjects 
received iron sucrose]. The mean age of study patients was 43 years (range, 18 to 94); 
94% were female; 42% were Caucasian, 32% were African American, 24% were 
Hispanic, and 2% were other races. The primary etiologies of iron deficiency anemia 
were heavy uterine bleeding (47%) and gastrointestinal disorders (17%).  
 
Table 2 shows the baseline and the change in hemoglobin from baseline to highest value 
between baseline and Day 35 or time of intervention.   
 
Reference ID: 3347006


 
10
 
 
Table 2. Mean Change in Hemoglobin From Baseline to the Highest Value 
Between Day 35 or Time of Intervention (Modified Intent-to-Treat Population) 
 
Hemoglobin (g/dL) 
Mean (SD) 
Cohort 1
Cohort 2
Injectafer 
(N=244) 
Oral Iron 
(N=251) 
Injectafer 
(N=245) 
IV SCa 
(N=237) 
Baseline 
 
10.6 (1.0)
10.6 (1.0)
9.1 (1.6) 
 
9.0 (1.5)
 
Highest Value 
 
 
12.2 (1.1) 
 
11.4 (1.2) 
 
 
12.0 (1.2) 
 
11.2 (1.3) 
 
 
Change (from baseline to 
highest value) 
 
 
 
1.6 (1.2) 
 
 
0.8 (0.8) 
 
 
 
2.9 (1.6) 
 
2.2 (1.3) 
 
 
p-value 
0.001
0.001
SD=standard deviation; a: Intravenous iron per standard of care 
 
Increases from baseline in mean f erritin (264.2±224.2 ng/mL in Cohort 1 and 218.2 
±211.4 ng/mL in Cohort 2), and transferrin saturation (13±16% in Cohort 1 and 
20±15% in Cohort) were  observed  at  Day 35 in Injectafer-treated patients. 
 
14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis Dependent 
Chronic Kidney Disease 
 
Trial 2 was a randomized, open-label, controlled clinical study in patients with non-
dialysis dependent chronic kidney disease. Inclusion criteria included hemoglobin (Hb) ≤ 
11.5 g/dL, ferritin ≤ 100 ng/mL or ferritin ≤ 300 ng/mL when transferrin saturation 
(TSAT) ≤ 30%.Study patients were randomized to either Injectafer or Venofer. The mean 
age of study patients was 67 years (range, 19 to 96); 64% were female; 54% were 
Caucasian, 26% were African American, 18% Hispanics, and 2% were other races.  
 
Table 3 shows the baseline and the change in hemoglobin from baseline to highest value 
between baseline and Day 56 or time of intervention.   
 
 
Reference ID: 3347006


 
11
 
Table 3. Mean Change in Hemoglobin From Baseline to the Highest Value 
Between Baseline  and Day 56 or Time of Intervention (Modified Intent-to-Treat 
Population) 
Hemoglobin (g/dL)
Mean (SD) 
Injectafer 
(N=1249) 
Venofer 
(N=1244) 
 
Baseline 
 
10.3 (0.8) 
10.3 (0.8) 
 
Highest Value  
11.4 (1.2) 
11.3 (1.1) 
 
Change (from baseline to highest 
value) 
1.1 (1.0) 
 
0.9 (0.92) 
 
Treatment Difference (95% CI) 
0.21 (0.13, 0.28)
 
 
 
Increases from baseline in mean f erritin (734.7±337.8 ng/mL), and transferrin 
saturation (30±17%)  were  observed  at  Day 56 in Injectafer-treated patients. 
 
 
16 
HOW SUPPLIED/STORAGE AND HANDLING   
 
 
NDC 0517-0650-01  
750 mg iron/15 mL Single-Use Vial Individually boxed 
NDC 0517-0650-02  
750 mg iron/15 mL Single-Use Vial Packages of 2 
 
 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 
86°F). [See the USP controlled room temperature].  Do not freeze.  
 
 
 
17 
PATIENT COUNSELING INFORMATION 
 
Question patients regarding any prior history of reactions to parenteral iron products. 
 
Advise patients of the risks associated with Injectafer. 
 
Advise patients to report any signs and symptoms of hypersensitivity that may develop during and 
following Injectafer administration, such as rash, itching, dizziness, lightheadedness, swelling and 
breathing problems [see Warnings and Precautions (5)] 
 
Injectafer is manufactured under license from Vifor (International) Inc, Switzerland. 
Reference ID: 3347006


 
12
 
AMERICAN 
REGENT, INC. 
SHIRLEY, NY  11967 
 
IN0602 
Rev. 7/13 
 
Reference ID: 3347006


 
13
Patient Information 
INJECTAFER (ferric carboxymaltose injection) 
 
Please read this information carefully before taking this medication. This summary does 
not tell you everything about INJECTAFER. Speak with your doctor or healthcare 
professional if there is something you do not understand or if you would like to learn 
more about INJECTAFER. Your doctor or healthcare professional is your best source of 
information about this medicine. 
 
What is INJECTAFER? 
 
Iron is a mineral that the body needs to produce red blood cells. When the body does not 
get enough iron, it cannot produce the number of normal red blood cells needed to keep 
you in good health. This condition is called iron deficiency (iron shortage) or iron 
deficiency anemia.  
 
INJECTAFER is used to treat iron deficiency anemia. Iron deficiency anemia may be 
caused by several medical conditions including heavy menstrual bleeding, pregnancy, 
childbirth, inflammatory bowel disease, other malabsorption diseases, bariatric surgery, 
or chronic kidney disease.  
 
General information about using INJECTAFER safely and effectively 
 
Injectable iron is administered only by or under the supervision of your health care 
professional. 
 
Serious or life threatening allergic reactions have been reported with intravenous iron 
products. Tell your health care professional if you have ever had any unusual or allergic 
reaction to any IV iron. 
 
Patients should report to their healthcare professional any signs and symptoms of an 
allergic reaction to INJECTAFER, in particular rashes, shortness of breath and wheezing.  
 
Iron is not easily eliminated from the body, and its build up may be lead to a condition 
called iron overload which may be harmful.  Certain medical conditions such as liver 
disease may also make you more likely to develop iron overload. Ask your doctor or 
healthcare professional. 
 
Who should not take INJECTAFER? 
 
You should not be given INJECTAFER if you have anemia that is not caused by iron 
deficiency, or if you have iron overload. 
 
If you are pregnant or plan to become pregnant please notify your doctor or healthcare 
professional. They will decide whether it is safe for you to receive INJECTAFER.  
 
How should I take INJECTAFER? 
Reference ID: 3347006


 
14
 
INJECTAFER is administered intravenously (into your vein) by your doctor or health 
care professional in two doses.  
 
What should I avoid while taking INJECTAFER? 
 
You should not take iron supplements by mouth if you are receiving iron injections. Tell 
your doctor about all the medicines you take, including prescription and non-prescription 
medicines, vitamins and herbal supplements. 
 
What are the possible side effects of INJECTAFER? 
 
The side effects of INJECTAFER are infrequent, usually mild and generally do not cause 
patients to stop treatment. The most common side effects are nausea, injection site 
reactions (including pain or bruising at the injection site), asymptomatic reductions in 
blood phosphorus, flushing, headache, hypertension, dizziness, and increased alanine 
aminotransferase. Potentially long lasting brown staining of skin near injection site may 
occur.   
 
These are not all the possible side effects of INJECTAFER. For more information ask 
your doctor or healthcare professional.     
 
Talk to your doctor if you think you have side effects from taking INJECTAFER. 
 
 
Reference ID: 3347006


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 43 of 51 
APPENDIX 2:  WEIGHT CHARTS FOR BOYS AND GIRLS 
Boys (White) Weight Chart age 0-36 months (http://www.halls.md/chart/boys-weight-w.htm) 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 44 of 51 
 
BOYS (WHITE) WEIGHT CHART AGE 2-20 YRS 
(HTTP://WWW.CDC.GOV/GROWTHCHARTS/DATA/SET1CLINICAL/CJ41L021.PDF) 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 45 of 51 
Girls (White) Weight Chart age 0-36 months (http://www.halls.md/on/girls-weight-w.htm) 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 46 of 51 
 
GIRLS (WHITE) WEIGHT CHART AGES 2-20 YRS 
(HTTP://WWW.CDC.GOV/GROWTHCHARTS/DATA/SET1CLINICAL/CJ41L022.PDF)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 47 of 51 
 
APPENDIX 3:  ADMENDMENT I CHANGES 
 
Title Page: 
 
Original 
Wording: 
Protocol Date: 
27 March 2014 
New Wording: 
Protocol Date: 
Amendment 1: 29 July 2014 
Study 
Synopsis and 
8.1 Sample 
Size 
Rationale: 
 
New Wording: 
 
Sample Size: 
 
Determination of sample size for this single-arm, pediatric, pharmacokinetic 
study is a compromise between obtaining sufficiently precise estimates of 
pharmacokinetic parameters and the ethics of including a large number of 
pediatric patients in an experiment. The precision of estimation can be 
quantified as the width of the 95% confidence interval for AUC0-72 from this 
single-arm study (i.e., smaller width indicates better precision). Based on Study 
VIT-IV-CL-002 in adults, the standard deviation for total serum iron AUC0-72 
following a 500 mg intravenous dose is approximately 300 µg◦hour/mL. The 
width of a 95% confidence interval, using a standard deviation of 300 
µg◦hour/mL, is presented below for selected sample sizes. As seen in the figure, 
16 patients appears to be a reasonable compromise between precision and 
number of exposed pediatric patients.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 48 of 51 
 
 
Approximately 32 subjects will be enrolled in this study, 16 subjects in cohort I 
and 16 subjects in cohort II.  Within each cohort of 16 subjects will be equally 
disturbed by age, which will include 8 subject’s 1 – 6 years of age and 8 
subjects > 6 – 17 year of age.   Subject enrollment and ages will be tracked and 
monitored via interactive web response (IWR) system. 
 
Original 
Wording: 
Exclusion Criteria: 
 
3. Body mass index (BMI) ≤ 95th percentile for age (see APPENDIX 2) 
 
New Wording: 
3. Body mass index (BMI) ≤ 5th percentile for age (see APPENDIX 2) 
 
Original 
Wording: 
Trial design – Phase III 
New Wording: 
Trial Design – Phase II 
Additional 
Wording – 
Sections 7.1 
All laboratory values at the end of study/Day 35 that have been deemed clinical 
significant by the Investigator should be followed until they are back into 
normal range. 
 
 
 
 
 
0 
100 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1100 
1200 
1300 
1400 
1500 
0 
8 
16 
24 
32 
40 
48 
56 
64 
Width of 95% CI 
Number of Subjects 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 49 of 51 
 
APPENDIX 4:  ADMENDMENT II CHANGES 
 
Title Page: 
 
Original 
Wording: 
Protocol Date: 27 March 2014 
Amendment 1: 29 July 2014 
New Wording: 
Protocol Date: 27 March 2014 
Amendment 1: 29 July 2014 
Amendment II: 08 October 2014 
Signature of 
Agreement 
For Protocol 
Original 
Wording: 
 
Marc Tokars 
 
 
 
   
 
            Date 
Vice President of Clinical Operations 
Luitpold Pharmaceuticals, Inc. 
 
Marsha Simon 
 
 
 
 
 
   
Date 
Sr. Manager-Regulatory Affairs 
Luitpold Pharmaceuticals, Inc. 
 
David Morris, PhD                    
Date 
Senior Director, Statistics 
WebbWrites, LLC 
 
Signature of 
Agreement 
For Protocol 
New Wording: 
 
Sylvan Hurewitz, MD 
 
 
 
 
   
Date 
Medical Director 
Luitpold Pharmaceuticals, Inc. 
 
Syed Quadri, MD 
 
 
 
 
 
   
Date 
Medical Director, Pharmacovigilance 
Luitpold Pharmaceuticals, Inc. 
 
Marsha Simon 
 
 
 
 
 
   
Date 
Sr. Manager-Regulatory Affairs 
Luitpold Pharmaceuticals, Inc. 
 
David Morris, PhD                    
Date 
Senior Director, Statistics 
WebbWrites, LLC 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 50 of 51 
 
 
New 
Exclusion 
Criteria 
Wording: 
Exclusion Criteria # 4: Male or Female subject 1 year of age weighing < 
12kg. 
Exclusion 
Criteria 
Deletion 
Deleted original criteria number 12.  Significant blood loss (> 100 ml) 
within the last 3 months or any current bleeding disorders or anticipated 
need for surgery that may result in significant blood loss (> 100 ml). 
Original 
Wording 
section 6.3.5 
Blood Volume 
Table: 
Total Blood Volume = 72mL/approx. 14.6 tsps 
New Wording 
section 6.3.5 
Blood Volume 
Table: 
Total Blood Volume = 44.5mL/approx. 9.03 tsps 
New Wording 
Injectafer ® replaced by Ferric Carboxymaltose throughout Protocol 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Local Protocol Amendment I for Russia: 24 February 2015 
Page 51 of 51 
 
APPENDIX 5:  Local Protocol Amendment I for Russia 
 
 
Title Page: 
 
Original 
Wording: 
Protocol Date: 27 March 2014 
Amendment 1: 29 July 2014 
Amendment II: 08 October 2014 
New Wording: 
Protocol Date: 27 March 2014 
Amendment 1: 29 July 2014 
Amendment II: 08 October 2014 
Local Protocol Amendment I for Russia: 24 February 2015 
 
 
Inclusion 
Criteria: 
Additional wording Inclusion criteria #1: 
1. Male or female subjects 1 to 17 years of age (6 to 17 years of age in 
Russia only) with assent to participation and his/her parent or 
guardian is willing and able to sign the informed consent approved 
by the Independent Review Board / Ethics Committee.  
 
 
 
6.3.2 Day 0 
 
Log on to the EDC system and register subject for study drug dosing. 
The EDC system will assign the subject into Cohort 1 or 2 treatment 
group. 
 
After assignment of the treatment group (Cohort 1 and 2) the following will 
occur: 
 
 
Updated wording: 
 
Log on to the EDC system and register subject for study drug dosing.  
 
After assignment of the treatment group (Cohort 1 and 2, subsequently) the 
following will occur: 
 
 




1 
 
 
LUITPOLD PHARMACEUTICALS, INC. 
 
PROTOCOL 
No. 1VIT13036 
 
IND #: 63,243 
 
 
A Multi-center, Open-label, Single Arm Study to Characterize the Pharmacokinetics and 
Pharmacodynamics Profile of Intravenous Injectafer® (Ferric Carboxymaltose) in Pediatric Subjects 1 – 
17 years old with Iron Deficiency Anemia (IDA) 
 
 
SPONSOR 
Luitpold Pharmaceuticals, Inc. 
Clinical Research and Development 
800 Adams Avenue 
Norristown, PA 19403 
(610) 650-4200 
 
 
 
 
Protocol Date: 27 March 2014 
Amendment I Date: 29 July 2014 
 
 
 


CONFIDENTIAL
Protocoh 1VIT13036
Amendment I Date: 29 July 2014
Date
SIGNATURES OT AGREBMENT FOR PROTOCOL
Marc Tokars
Vice President of Clinical Operations
Luitpold Pharmaceuticals, Inc.
Sr. Manager-Regulatory Affairs
Luitpold Pharmaceutical s, fnc.
"C , 
',( a 
- 
- -.,,, *z Yu+ 2o(+
David Morris, PhD
Senior Director, Statistics
Webb\Mrites, LLC
Marsha Simon
Page 2 of 44


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 3 of 44 
Study Synopsis 
Protocol No. 1VIT13036 
Title:   
A Multi-center, Open-label, Single Arm Study to Characterize the Pharmacokinetics and 
Pharmacodynamics Profile of Intravenous Injectafer® (Ferric Carboxymaltose) in Pediatric 
Subjects 1 – 17 years old with Iron Deficiency Anemia (IDA). 
Drugs:  
Injectafer® (Ferric Carboxymaltose) 
Objectives:   The primary objectives of this study are to characterize the pharmacokinetics and determine 
appropriate dosing and safety of Injectafer® for the pediatric population suffering from iron 
deficiency (ID) with anemia.  
 
Study Design:This is a Phase II, open-label, non-randomized, multi-center, single arm study to characterize the 
pharmacokinetic and pharmacodynamics  (PK/PD) profile of Injectafer® dosing in pediatric 
subjects with IDA after receiving either a 7.5 mg/kg or 15 mg/kg dose of Injectafer®.  
 
Treatment 
 
Cohort 1: 16 subjects will be treated with Injectafer® at 7.5 mg/kg to a maximum single dose of 
750 mg iron, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have completed 4 weeks of 
therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Injectafer® at 15 mg/kg to a maximum single dose of 
750 mg iron, whichever is smaller.   
Inclusion Criteria:  
1. Male or female subjects 1 to 17 years of age with assent to participation and his/her parent or 
guardian is willing and able to sign the informed consent approved by the Independent Review 
Board / Ethics Committee.  
2. Screening TSAT < 20% 
3. Screening Hemoglobin < 11 g/dL 
4. For subjects who are receiving an erythropoietin stimulating agent (ESA): stable ESA therapy 
(+/- 20% of current dose) for > 8 weeks prior to the qualifying screening visit and no ESA 
dosing or product changes anticipated for the length of the trial 
 
Exclusion Criteria:    
1. Known hypersensitivity reaction to any component of Injectafer®. 
2. Subject previously randomized and treated in this study or any other clinical study of Injectafer® 
(FCM or VIT-45). 
3. Body mass index (BMI) ≤ 5th percentile for age (see APPENDIX 2) 
4. History of acquired iron overload, hemochromatosis or other iron accumulation disorders. 
5. Chronic kidney disease subjects on hemodialysis. 
6. Screening Ferritin level > 300ng/mL 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 4 of 44 
7. Subjects with significant severe diseases of the liver, hemopoietic system, cardiovascular system, 
psychiatric disorder or other conditions which on the opinion of the investigator may place a 
subject at added risk. 
8. Any active infection.  
9. Known positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody (HCV) with evidence 
of active hepatitis. 
10. Known positive HIV-1/HIV-2 antibodies (anti-HIV). 
11. Anemia due to reasons other than iron deficiency (i.e. hemoglobinopathy). Subjects treated with 
vitamin B12 or folic acid deficiency are permitted. 
12. Significant blood loss (> 100 ml) within the last 3 months or any current bleeding disorders or 
anticipated need for surgery that may result in significant blood loss (> 100 ml). 
13. Intravenous iron and /or blood transfusion in the 4 weeks prior to screening.  
14. Immunosuppressive therapy that may lead to anemia (i.e. cyclophosphamide, azathioprine, 
mycophenolate mofetil).  Note steroid therapy is permitted. 
15. Administration and / or use of an investigational product (drug or device) within 30 days of 
screening. 
16. Alcohol or drug abuse within the past six months. 
17. Female subjects who are pregnant or lactating, or sexually active female who are of childbearing 
potential not willing to use an acceptable form of contraceptive precautions during the study. 
18. Subject is unable to comply with study assessments. 
 
Subject 
Assessments:  
All subjects that provide informed consent / assent will enter a screening period up to 14 days 
prior to Day 0.  During this time subjects will be evaluated to insure they meet the study entry 
criteria.  Subjects will have vital signs, medical history review and laboratory samples to include 
hematology, chemistries and iron indices.  Once it has been determine the subject qualifies for 
participation the subject will be scheduled to return to the clinic 1 day prior to Day 0 (Day -1) at 
which time additional blood samples will be taken (8am, 12pm and 8pm) to characterize the 
subjects iron profile. 
 
Blood samples for PK/PD will also be assessed immediately prior to Injectafer® dosing on Day 
0, at 1, 2, 6, 12, 24, 48 hours and at 72 hours.  
 
Safety assessments, including vital signs and adverse events, will be assessed starting on Day 0 
at the time of Injectafer® dosing through Day 35.   
 
Erythropoietin 
Dosage: 
 
 
If receiving an Erythropoiesis Stimulating Agent (ESA), a stable (± 20%) dose is required for > 8 
weeks prior to screening.  The ESA type, route, frequency and dose will remain unchanged 
throughout the remainder of the study unless the dose should be decreased or held per the 
package label.  Once decreased or held, it may not be increased or restarted unless thought 
necessary by the subject’s physician. If the latter event occurs, the ESA dose changes will be 
collected and the subject will continue for safety analysis. 
Study Duration 
per subject:  up to 9 weeks  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 5 of 44 
Number of  
Subjects:   
32 subjects 
Sites:   
Approximately 10 
Sample Size: 
 
Determination of sample size for this single-arm, pediatric, pharmacokinetic study is a 
compromise between obtaining sufficiently precise estimates of pharmacokinetic parameters and 
the ethics of including a large number of pediatric patients in an experiment. The precision of 
estimation can be quantified as the width of the 95% confidence interval for AUC0-72 from this 
single-arm study (i.e., smaller width indicates better precision). Based on Study VIT-IV-CL-002 
in adults, the standard deviation for total serum iron AUC0-72 following a 500 mg intravenous 
dose is approximately 300 µg◦hour/mL. The width of a 95% confidence interval, using a 
standard deviation of 300 µg◦hour/mL, is presented below for selected sample sizes. As seen in 
the figure, 16 patients appears to be a reasonable compromise between precision and number of 
exposed pediatric patients.  
 
 
Approximately 32 subjects will be enrolled in this study, 16 subjects in cohort I and 16 subjects 
in cohort II.  Within each cohort of 16 subjects will be equally disturbed by age, which will 
include 8 subject’s 1 – 6 years of age and 8 subjects > 6 – 17 year of age.   Subject enrollment 
and ages will be tracked and monitored via interactive web response (IWR) system. 
 
0 
100 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1100 
1200 
1300 
1400 
1500 
0 
8 
16 
24 
32 
40 
48 
56 
64 
Width of 95% CI 
Number of Subjects 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 6 of 44 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 7 of 44 
TABLE OF CONTENTS 
1.0 INTRODUCTION .................................................................................................................... 11 
1.1 
Treatment of Iron Deficiency Anemia ............................................................................ 11 
1.2 
Injectafer ......................................................................................................................... 12 
1.2.1 
Key features of Injectafer ............................................................................................ 12 
1.2.2 
Injectafer versus Other Parenteral Iron Agents ......................................................... 12 
1.2.3 
Injectafer Human Experience ..................................................................................... 13 
2.0 MAIN TRIAL OBJECTIVE ..................................................................................................... 14 
3.0  
OVERALL STUDY DESIGN AND RATIONALE .......................................................... 14 
3.1 
 Trial Design ................................................................................................................... 14 
3.2 
Rationale ......................................................................................................................... 14 
3.2.1 
Rationale for Trial Design .......................................................................................... 14 
3.2.2 
Rationale for open label design .................................................................................. 15 
3.2.3. 
Schedule of Events .................................................................................................. 16 
4.0  
SUBJECT SELECTION ..................................................................................................... 17 
4.1 
Number and Type of Subjects......................................................................................... 17 
4.2 
Screening Phase .............................................................................................................. 17 
4.2.1  
Entry Criteria .......................................................................................................... 17 
4.3 
Subject Assignment and Registration Process ................................................................ 18 
4.4 
Withdrawal from Study................................................................................................... 18 
4.5 
Intervention ..................................................................................................................... 18 
5.0 STUDY DRUG ......................................................................................................................... 19 
5.1 
Formulation Packaging and Storage ............................................................................... 19 
5.2 
Drug Administration / Regimen...................................................................................... 19 
5.3 
IV Iron Precautions ......................................................................................................... 19 
5.4 
Drug Accountability........................................................................................................ 20 
5.5 
Concomitant Medication ................................................................................................. 20 
6.0 STUDY PROCEDURES .......................................................................................................... 20 
6.1 
Informed Consent............................................................................................................ 20 
6.2 
Screening (up to 14 days) ............................................................................................... 21 
6.3 
Study Visits .................................................................................................................. 21 
6.3.1. 
Day (-1) ................................................................................................................... 21 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 8 of 44 
6.3.2 
Day 0 ........................................................................................................................... 21 
6.3.2. 
Days 1 and 2 (24 and 48 hour) ............................................................................... 22 
6.3.3. 
 72 hour, and Days 14 and 28 (weeks 2 and 4)....................................................... 22 
6.3.4. 
Day 35 (week 5) End of Study ................................................................................. 22 
6.3.5. 
Pharmacokinetics and Pharmacodynamics (PK/PD) ............................................. 22 
6.4 
Central Laboratory Assessments..................................................................................... 23 
7.0  
ASSESSMENT OF SAFETY ............................................................................................. 23 
7.1 
Adverse Events ............................................................................................................... 23 
7.2 
Reporting of Adverse Events .......................................................................................... 25 
7.3 
Serious Adverse Events .................................................................................................. 25 
8.0 STATISTICS ............................................................................................................................ 26 
8.1 
 Sample Size .................................................................................................................... 26 
8.2 
Analysis Populations ....................................................................................................... 27 
8.3 
Demographic Characteristics .......................................................................................... 27 
8.4 
Endpoints and Definitions............................................................................................... 27 
8.4.1 
Clinical Endpoints ...................................................................................................... 27 
8.5 
 Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints .................................... 28 
8.6 
Statistical Analyses of Safety .......................................................................................... 28 
8.7 
DSMB Analyses.............................................................................................................. 28 
9.0 ADMINISTRATIVE CONSIDERATIONS ............................................................................. 29 
9.1 
Retention and Availability of Records ............................................................................ 29 
9.2 
Investigator Responsibilities ........................................................................................... 29 
9.3 
Financial Disclosure........................................................................................................ 30 
9.4 
Advertisement for Subject Recruitment.......................................................................... 30 
9.5 
Documents Required for Study Initiation ....................................................................... 30 
9.6 
Quality Control and Quality Assurance .......................................................................... 30 
9.6.1 
Investigator Selection Criteria .................................................................................... 30 
9.6.2 
Clinical Monitoring .................................................................................................... 30 
9.6.3 
Quality Assurance Audit ............................................................................................. 31 
9.7 
Ethics............................................................................................................................... 31 
9.7.1 
Ethical and Legal Issues ............................................................................................. 31 
9.7.2 
Institutional Review Board ......................................................................................... 31 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 9 of 44 
9.7.3 
Informed Consent ........................................................................................................ 31 
9.7.4 
Good Clinical Practice ............................................................................................... 32 
9.8 
Data Handling and Record Keeping ............................................................................... 32 
9.8.1 
Electronic Case Report Form (eCRF) ........................................................................ 32 
9.8.2 
Confidentiality............................................................................................................. 33 
9.8.3 
Termination of the Study ............................................................................................. 33 
9.8.4 
Protocol Revisions ...................................................................................................... 33 
9.8.5 
Protocol Administrative Changes ............................................................................... 33 
9.9 
Publication Policy ........................................................................................................... 34 
10.0  GOVERNANCE COMMITTEE ........................................................................................ 34 
10.1 
Data and Safety Monitoring Board............................................................................. 34 
INVESTIGATOR’S ACKNOWLEDGEMENT ............................................................................ 36 
REFERENCES .............................................................................................................................. 37 
APPENDIX 1:  INJECTAFER® PACKAGE INSERT ............................................................ 38 
APPENDIX 2:  WEIGHT CHARTS FOR BOYS AND GIRLS .................................................. 39 
APPENDIX 3:  ADMENDMENT I CHANGES ........................................................................ 43 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 10 of 44 
 
LIST OF ABBREVIATIONS 
AE 
 
 
 
 
Adverse event 
BP 
Blood Pressure 
BW 
Body Weight 
CI 
confidence interval 
CKD 
Chronic Kidney Disease 
conc. 
concentration 
CTCAE 
Common Terminology Criteria for Adverse Event 
dL 
Deciliter 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture 
e.g. 
for example 
ESA 
Erythropoiesis stimulating agent 
FDA 
Food and Drug Administration 
Fe 
Iron 
g 
Gram 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HMW 
high molecular weight 
IBD 
Inflammatory Bowel Diease 
ICH 
International Conference on Harmonisation 
IDA 
Iron Deficiency Anemia 
i.e. 
that is/ such that 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVP 
Intravenous injection (push) 
kg 
Kilogram 
L 
Liter 
LMW 
low molecular weight 
LOS 
length of stay 
MedDRA 
Medical dictionary for regulatory activities 
mg  
Milligram 
mL 
Milliliter 
ng 
Nanogram 
PET 
positron emission tomography 
p.o. 
by mouth or orally 
RES 
Reticuloendothelial system 
SAE 
Serious adverse event 
t1/2 
Terminal half-life 
t.i.d. 
three times a day 
TSAT 
Transferrin Saturation 
US 
United States 
vs 
Versus 
w/v 
weight / volume 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 11 of 44 
 
1.0 
INTRODUCTION 
 
1.1 
Treatment of Iron Deficiency Anemia 
 
Iron deficiency anemia (“IDA”) remains the most common nutritional deficiency in children in the United 
States.  Rapid growth, insufficient dietary intake, and limited absorption of dietary iron combine to place 
children at increased risk for iron deficiency. Iron deficiency may contribute significantly to anemia due to 
malabsorption, gastrointestinal blood loss, or iatrogenically due to repeated blood samplings.  As a result of 
severe digestive tract disorders, some children are unable to tolerate oral iron supplementation or are 
unresponsive to it.1 Anemia may also decrease survival rates in patients (both adults and children) with chronic 
renal impairment where it is a commonly encountered problem2;3 In addition, anemia is a commonly 
encountered manifestation of pediatric inflammatory bowel disease which is associated with a decrease in the 
quality of life and increased hospitalization. 
 
Non-hematologic consequences of iron deficiency include poor weight gain, anorexia, irritability, decreased 
attention span, exercise intolerance and decreased physical activity. 4  However, IDA in infants and toddlers is 
associated with long-lasting diminished mental, motor, and behavioral functioning.  Although the exact 
relationship between iron deficiency anemia and the developmental effects is not well understood, it appears 
that these effects do not occur until iron deficiency becomes severe and chronic enough to produce anemia. 5 
 
Options for correcting iron deficiency include both oral and parenteral formulations. As previously described, 
some children are unable to tolerate or are non-responsive to oral iron.  Blood transfusion is an option to treat 
anemia and restore iron requirements, but the potential risk of blood-transmitted virus infection limits its use to 
severe and badly tolerated anemia. In view of the limitations associated with oral iron or blood transfusions, 
intravenous administration is an important option. 
 
Multiple parenteral iron products are available. These vary in complex types which impacts the total amount of 
iron that may be administered in a single administration. Numerous other differences differentiate the products; 
however, all appear to effectively release iron post administration and restore the deficit of the patient. There 
are numerous studies with iron sucrose injection (Venofer®) that have been performed in the pediatric 
population 6-8. Iron doses have varied in the studies with demonstrated efficacy and safety in doses up to 7mg 
iron/kg or 200mg given in time frames of 3 min, which was shown to be beneficial to both the child and health 
care facility6.  
 
Injectafer® has been characterized as a robust and strong type iron complex (Type 1) with a molecular mass of 
about 150,000 Daltons (Da). The solution is a dark brown color with a near neutral pH (5.0 to 7.0) and a 
physiological osmolarity permitting administration of higher single doses in short time periods. Although no 
interventional studies have been conducted with Injectafer® in the pediatric population to date, the product has 
been used in clinical practice in markets where it is currently approved for adults to aid correction of iron 
deficiency within the pediatric gastroenterological setting.  A non-interventional/retrospective observational 
data collection has identified in 79 patient’s aged 2 to 18 years with a mean age of 12.7 years.  In these subjects, 
Injectafer® showed efficacy with regard to hemoglobin, ferritin, and TSAT as well as safety and tolerability 
(manuscript in preparation).  
 
Therefore, the proposed studies will assess higher single doses (i.e., 7.5 mg/kg and 15 mg/kg) than those used 
with currently available parenteral iron preparations in iron deficient children with anemia to characterize the 
pharmacokinetics and pharmacodynamics in this younger population.  The higher single doses permit fewer 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 12 of 44 
 
overall injections/infusions and may ultimately permit fewer visits to the treating facilities positively impacting 
both the child and family as well as health care system. 
 
1.2 
Injectafer   
 
1.2.1 Key features of Injectafer 
 
Injectafer (Ferric Carboxymaltose Injection) is a stable Type I polynuclear iron (III)-hydroxide carbohydrate 
complex developed as an intravenous iron replacement therapy for the treatment of IDA. After intravenous 
administration, Injectafer is mainly found in the liver (RES), 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.   
 
1.2.2 Injectafer versus Other Parenteral Iron Agents 
 
There is considerable efficacy and safety experience with the various parenteral iron preparations available (3).  
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 intravenous 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% (6).  Over the last 20 years, 30 deaths have been attributed to the use of IV iron dextran. The high incidence 
of anaphylaxis/anaphylactoid reactions is believed to be caused by the formation of antibodies to the dextran 
moiety.   Although some have suggested that high molecular weight (HMW) iron dextran is 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 (7).  
Iron dextran is limited to second line therapy for treatment of iron deficiency.   
 
More recently approved, non-dextran intravenous 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 IV iron compounds carry a significant risk of bioactive iron reactions 
at higher doses.  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, producing 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 sucrose11 (data on file ).  These characteristics of Injectafer make it possible to administer much higher 
single doses over shorter periods of time than iron gluconate or iron sucrose, resulting in the need for fewer 
administrations to replenish iron stores, consequently making it better suited for outpatient use (Table 1.2.2.1).  
Another recently approved IV iron is ferumoxytol (AMAG) in which 510 mg can be injected rapidly on 2 
occasions separated by several days.  This formulation, which is currently indicated for IDA associated with 
CKD, is a modified-dextran derivative and is indicated for a 1020 mg repletion dose (see Ferumoxytol PI).  
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 13 of 44 
 
Table 1.2.2.1     Administration of at least 1500 mg of Intravenous Iron with Currently Available Iron 
Preparations and Injectafer 
Iron 
Preparation 
Test Dose 
Required 
Maximum 
Infusion Dose 
 
Infusion Time 
Number of 
Infusions 
Iron dextran 
Yes 
100 mg* 
2 minutes 
15 + test dose 
Iron gluconate 
No 
125 mg 
10 minutes 
12 
Iron sucrose 
No 
200 mg 
5 minutes 
8 
Iron sucrose 
No 
300mg 
1.5 hours 
5 
Iron sucrose 
No 
400 mg 
2.5 hours 
4 
ferumoxytol 
No 
510 mg 
< 1 minute 
3 
Injectafer 
No 
750 to 1000 mg** 
8 to 15 minutes 
2 
* Higher doses are administered off label and are approved outside the US 
**1000 mg maximum dose is approved in countries outside of the US; 750 mg maximum is the U.S. FDA approved dose  
 
The larger Injectafer and ferumoxytol doses result in less frequent administration of intravenous iron that should 
benefit, in particular, severely iron deficient and anemic populations. To be treated with currently available 
intravenous iron agents, the average inflammatory bowel disease, postpartum,  heavy uterine bleeding and non-
dialysis dependent patient would require an initial test dose, followed by 15 doses of iron dextran as labeled, 
each accompanied by personnel equipped and trained for resuscitation of anaphylaxis; 12 doses of ferric 
gluconate; or either 8 doses of iron sucrose (with 5 minute infusion time) or 5 / 4 doses of iron sucrose by 
prolonged (1.5 to 2.5 hours) intravenous infusion. Ferric gluconate and iron sucrose are not approved by the 
FDA for the treatment of IDA in non chronic kidney disease populations and iron dextran is only approved as 
second line therapy for treatment of iron deficiency.  In contrast, most patients treated with Injectafer would 
require 2 doses administered over 8 to15 minutes one week apart.   
 
1.2.3 Injectafer Human Experience 
 
The Injectafer development program demonstrated the safety and effectiveness of intravenous Injectafer in the 
treatment of IDA.  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.  
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, compared with 2 to 13% for iron sucrose.  The projected terminal 
half-life (t½) was calculated to approximately 16 hours, compared to 3 to 4 days for iron dextran and 6 hours for 
iron sucrose. An ascending dose pharmacokinetic study (VIT-IV-CL-002), demonstrated that following the 500 
and 1,000 mg Injectafer dose, the majority of the Injectafer iron complex was utilized or excreted by 72 hours. 
 
Phase III studies demonstrated the effectiveness of Injectafer in treating IDA secondary to inflammatory bowel 
disease, heavy uterine bleeding, chronic kidney disease (hemodialysis and non-hemodialysis) and the 
postpartum state.  Clinically meaningful increases in hemoglobin, ferritin, and TSAT were observed in each of 
the studies. Non-inferiority to full therapeutic doses of oral ferrous sulfate was demonstrated in studies of IDA 
associated with inflammatory bowel disease. Superiority to full therapeutic doses of oral ferrous sulfate was 
demonstrated in studies of IDA secondary to heavy uterine bleeding, the postpartum state and non-hemodialysis 
dependent chronic kidney disease.  A head to head comparison of Injectafer (Ferric carboxymaltose) to Venofer 
(Iron sucrose)  in over 2,500 subjects with non-dialysis dependent CKD and elevated risk of cardiovascular 
disease according to the Framingham criteria demonstrated that the recommended dose of Injectafer, 750 mg x 
2 (1500 mg total) had superior efficacy to the labeled dose of Iron sucrose (200 mg x 5 [1000 mg total]) with 
regard to hemoglobin elevation and had a similar cardiovascular (and overall) safety profile, based in part on an 
independently adjudicated composite cardiovascular safety endpoint (8) . 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 14 of 44 
 
 
Important details of pre- and clinical safety and efficacy can be found in the Investigator’s Brochure. Ferric 
carboxymaltose received approval from the UK Medicines and Healthcare products Regulatory Agency 
(MHRA) approval on June 15, 2007 for the use of Injectafer (EU Trade name: Ferinject) in 18 EU (European 
Union) 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 approved from the Food and Drug Administration (FDA) on July 25, 2013 for marketing 
in the United States. 
 
2.0 
MAIN TRIAL OBJECTIVE 
 
The primary objectives of this study are to characterize the pharmacokinetics and determine appropriate dosing 
and safety of Injectafer® for the pediatric population suffering from iron deficiency (ID) with anemia.  
 
 
3.0  
OVERALL STUDY DESIGN AND RATIONALE 
 
3.1 
 Trial Design 
 
This is a phase II, open-label, non-randomized,  multi-center, single arm study to characterize the 
pharmacokinetic and pharmacodynamics  (PK/PD) profile of Injectafer® dosing in pediatric subjects with IDA 
after receiving either a 7.5 mg/kg or 15 mg/kg dose of Injectafer®.  
 
Cohort 1: 16 subjects will be treated with Injectafer® at 7.5 mg/kg with a maximum single dose 
of 750 mg, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have completed 4 weeks of 
therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Injectafer® at 15 mg/kg with a maximum single dose 
of 750 mg, whichever is smaller.   
 
3.2 
Rationale 
 
3.2.1 Rationale for Trial Design 
 
Injectafer is a non-dextran IV iron recently approved by the United States Food and Drug Administration 
(FDA).  This trial is designed to assess the single doses (i.e., 7.5 mg iron/kg and 15 mg iron/kg) in iron deficient 
children with anemia to characterize the pharmacokinetics and pharmacodynamics in this younger population.  
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 15 of 44 
 
3.2.2 Rationale for open label design 
 
The open-label, single arm trial design is considered appropriate because a control group is not required to 
estimate the PK/PD profile of Injectafer®.  The risk from exposure to another form of IV iron is not offset by 
the minimal scientific benefit. 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 16 of 44 
 
3.2.3. Schedule of Events 
Visit Day 
Screening 
Period 
(Up to 14 
Days) 
Day 
-1 
Day 
0 
24 and 48 
hours 
post 
dosing 
72 hours 
post 
dosing 
Day 14 
(week 2) 
Day 28 
(week 4) 
Day 35 
(week 5) 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Assess entry 
criteria 
X 
 
X 
 
 
 
 
 
EDC 
X 
 
X 
 
 
 
 
X 
Medical History 
X 
 
X 
 
 
 
 
 
Physical Exam1 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
 
X 
 
X 
X 
X 
X 
Height / Weight 
 
 
X 
 
 
 
 
 
PK/PD Samples 
 
X2 
X3 
X4 
X4 
 
 
 
Hematology, 
Chemistry and 
Iron Indices 
X 
 
 
 
X 
X 
X 
X 
Serum 
pregnancy test 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
 
X 
 
X 
X 
X 
X 
ESA Stability 
X 
 
X 
 
X 
X 
X 
X 
Adverse Event 
Assessments5 
 
 
X 
X 
X 
X 
X 
X 
Injectafer® 
Dosing6 
 
 
X 
 
 
 
 
 
 
1 Includes clinical assessment of skin, cardiovascular, pulmonary, abdominal and central nervous system 
2 Blood samples drawn at 8am, 12pm and 8pm for subject iron profile 
3 Blood samples PK/PD should be taken prior to Injectafer® dosing and additional samples for PK/PD should be taken at 1, 2, 6 and 
12 hours post dosing.  
4 Blood samples should be taken approximately the same time of day as the Day 0 samples were drawn 
5 Adverse event assessments starting at the time of Injectafer® dosing 
6 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-dose only.  Vital signs on non-dosing days include sitting heart rate and 
blood pressure only. 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 17 of 44 
 
4.0  
SUBJECT SELECTION 
 
4.1 
Number and Type of Subjects 
 
Up to thirty two  (32) subjects who have given written informed consent / assent along with parent or guardian’s 
written informed consent with a diagnosis of iron deficiency anemia (IDA) who fulfill the inclusion criteria, do 
not meet any of the exclusion criteria will be registered to receive Injectafer®.    
 
4.2 
Screening Phase 
 
Once a subject enters the screening phase, they will be assigned, via the Electronic Data Capture (EDC) system, 
a unique screening number.  From the time of consent until the start of treatment of IV Injectafer®, the subject 
will not receive any form of iron outside of the study (intravenous or blood transfusion iron from 4 weeks prior 
to consent or oral iron including multivitamins with iron from time of consent).   
 
If the subject does not qualify for study entry the subject should be entered into the EDC system as a screen 
failure.  Subjects can be re-screened once, see section 6.2.   
 
4.2.1  Entry Criteria 
 
Inclusion Criteria: 
 
1. Male or female subjects 1 to 17 years of age with assent to participation and his/her parent or guardian is 
willing and able to sign the informed consent approved by the Independent Review Board / Ethics 
Committee.  
2. Screening TSAT < 20% 
3. Screening Hemoglobin < 11 g/dL 
4. For subjects who are receiving a erythropoietin stimulating agent (ESA): stable ESA therapy (+/- 20% of 
current dose) for > 8 weeks prior to the qualifying screening visit and no ESA dosing or product changes 
anticipated for the length of the trial. 
 
Exclusion Criteria:    
 
1. Known hypersensitivity reaction to any component of Injectafer®. 
2. Subject previously randomized and treated in this study or any other  clinical study of Injectafer® (FCM, 
VIT-45). 
3. Body mass index (BMI) ≤ 5th percentile for age (see APPENDIX 2) 
4. History of acquired iron overload, hemochromatosis or other iron accumulation disorders. 
5. Chronic kidney disease subjects on hemodialysis. 
6. Screening Ferritin level > 300 ng/mL. 
7. Subjects with significant severe diseases of the liver, hemopoietic system, cardiovascular system, 
psychiatric disorder or other conditions which on the opinion of the investigator may place a subject at 
added risk. 
8. Any active infection.  
9. Known positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody (HCV) with evidence of active 
hepatitis. 
10. Known positive HIV-1/HIV-2 antibodies (anti-HIV). 


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
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11. Anemia due to reasons other than iron deficiency (i.e. hemoglobinopathy). Subjects treated with vitamin 
B12 or folic acid deficiency are permitted. 
12. Significant blood loss (> 100 ml) within the last 3 months or any current bleeding disorders or anticipated 
need for surgery that may result in significant blood loss (> 100 ml). 
13. Intravenous iron and /or blood transfusion in the 4 weeks prior to screening.  
14. Immunosuppressive therapy that may lead to anemia (i.e. cyclophosphamide, azathioprine, mycophenolate 
mofetil).  Note steroid therapy is permitted. 
15. Administration and / or use of an investigational product (drug or device) within 30 days of screening. 
16. Alcohol or drug abuse within the past six months. 
17. Female subject who are pregnant or lactating, or sexually active female who are of childbearing potential 
not willing to use an acceptable form of contraceptive precautions during the study. 
18. Subject is unable to comply with study assessments. 
 
4.3 
Subject Assignment and Registration Process 
Subjects that meet all inclusion requirements and no exclusionary criteria will be offered participation in this 7 
week study. Cohorts 1 and 2 will be enrolled and treated sequentially.  Enrollment into Cohort 2 will not begin 
until  all Cohort 1  subjects have completed 4 weeks of therapy and no safety issues with the administration of 
Injectafer® has been confirmed by the DSMB. 
 
4.4 
Withdrawal from Study 
 
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.  
 
At the time of withdrawal, procedures for the Day 35 visit must be performed regardless of whether the subject 
has completed study drug treatment.  In the event the subject has received any study drug; the subject should be 
contacted to assess adverse events 28 days post the last dose of Injectafer®, if possible. 
 
In the event a subject withdraws without completing the full PK/PD sampling.  Additional subjects may be 
enrolled to ensure adequate representations of the PK/PD parameters are available for analyses.  Conditions for 
additional enrollment will be defined in more detail in the statistical analyses plan. 
 
4.5 
Intervention 
 
 Intervention is defined as follows: 
 Increase in dose of erythropoietin for any reason (Day 0 thru Day 35). 
 Blood transfusion.    
 Use of IV iron outside of protocol.  
 Use of oral iron outside the protocol.  
 
When intervention occurs, the date of the intervening event should be recorded in the source documents as well 
as the electronic Case Report Form (eCRF), and the subject should continue in the study as scheduled through 
Day 35. 
 
 
 


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
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5.0 
STUDY DRUG 
 
5.1 
Formulation Packaging and Storage 
 
All medication to be used in this study that has been supplied by Vifor Pharma Ltd. will have been prepared 
according to Good Manufacturing Practices (GMP).  
 
Injectafer® (known in the EU as Ferinject®) will be supplied 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.   
 
Study drug 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 Injectafer® vials used and unused should be kept by the study staff and returned to Vifor Pharma 
Ltd., after drug accountability has been completed by the monitor. 
 
5.2 
Drug Administration / Regimen 
 
The Principal Investigator or designee will supervise administration of the study drug to subjects: 
 
Cohort 1: 16 subjects will be treated with Injectafer® at 7.5 mg/kg with a maximum single dose of 750 
mg, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have completed 4 weeks of 
therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Injectafer® at 15 mg/kg with a maximum single dose of 750 
mg, whichever is smaller.   
 
Injectafer® will be given on Day 0.  It will be administered as either: 
 
 An undiluted slow IV push at a rate of 100 mg/minute. 
 Doses less than 100 mg should be given as a slow undiluted IV push within a minute. 
 
5.3 
IV Iron Precautions 
 
When administering IV Iron, the following precautions will be taken: 
 
 The subject will be clinically evaluated prior to drug administration to assess the development of 
clinically significant conditions.   
 The vials will be visually inspected for particulate matter and discoloration before each use; if noted, 
the vial will not be used and the Investigator or his/her designee will notify the sponsor, or sponsor’s 
designee, for replacement of the study drug and for directions to return the unused vial.     
 Sitting heart rate and blood pressure will be assessed pre-, immediately post, and 30 minutes post 
administration.  If the subject is an outpatient, they will be discharged from the site by the 


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
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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  
 
5.4 
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 registered 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. (or their designee).  All data regarding Injectafer® must be 
recorded on the Drug Accountability Forms provided by the sponsor.  
 
Investigators will keep adequate records of the administration and disposition of IV Injectafer® used for 
patients selected for the trial.  
 
5.5 
Concomitant Medication 
 
Concomitant medications along with their route of administration and duration must be recorded in the 
electronic case report form (eCRF) from 30 days prior to consent.  No additional iron preparations (IV iron 
from 4 weeks  prior to consent or oral iron including multivitamins with iron, from time of consent), will 
be allowed.  No prophylactic medications may be administered prior to Injectafer® administration 
without prior approval from Luitpold Pharmaceuticals, Inc.  
 
If receiving an Erythropoiesis Stimulating Agent (ESA), a stable (± 20%) dose is required for > 8 weeks prior to 
consent.  The ESA type, route, frequency and dose will remain unchanged throughout the study unless the dose 
should be decreased or held per the package label.  Once decreased or held, it may not be increased or restarted 
unless thought necessary by the subject’s physician. If the latter event occurs, these data points will be collected 
and the subject will continue for safety analysis. 
 
 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 (who for this trial is 1 -17 years old) must assent, if appropriate and his/her legal 
guardian (who is above age of legal consent) voluntarily sign an informed consent statement (Required 
Elements of Informed Consent, 21 CFR 50.25).  The Code of Federal Regulations (CFR) is a codification of 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 21 of 44 
 
rules and regulations of the United States government.  The subject’s legal guardian will be given a copy of the 
signed consent form. 
 
6.2 
Screening (up to 14 days)  
 
Each subject who qualifies for inclusion will undergo the following clinical evaluations to confirm their 
eligibility for the study: 
 
 Obtain screening number from EDC 
 Medical history, including prior iron therapy use  
 Vitals signs (including sitting heart rate and blood pressure)  
 Hematology, Chemistries and iron indices  
 Serum pregnancy test for female subjects of child bearing potential (negative results must be obtained 
prior to registering the subject for study drug dosing). 
 Concomitant medications assessment 
 ESA therapy stability ( if applicable)  
 
Subjects who do not meet the entry criteria should be entered into the 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 in section 6.2 will need to be repeated. 
 
6.3 
Study Visits  
 
6.3.1. Day (-1)  
 
Once it’s confirmed during the screening period that the subject continues meet the entry criteria all eligible 
subjects will return to the clinic on Day – 1, blood samples will be drawn at 8am, 12pm and 8pm to characterize 
the subject iron profile.   
 
6.3.2 Day 0 
 
On Day 0, prior Injectafer® dosing the following will occur:  
 
 Re-verify the inclusion and exclusion criteria 
 Update any relevant history 
 Basic physical exam including clinical assessment of skin, cardiovascular, pulmonary, abdominal and 
central nervous system.  
 Height  
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 Log on to the EDC system and register subject for study drug dosing. The EDC system will assign the 
subject into Cohort 1 or 2 treatment group. 
 
After assignment of the treatment group (Cohort 1 and 2) the following will occur: 
 
 Blood samples for PK/PD before start of dose. 
 Weight in kg without shoes 


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 22 of 44 
 
 Verify amount of single Injectafer® dose (7.5 or 15 mg/kg up to a maximum dose of 750 mg 
whichever is smaller).  
 Document start and stop time of Injectafer® administration, the total dose administered and if 
diluted. 
 Obtain sitting heart rate and blood pressure immediately pre-dose, immediately post-dose, and 30 
minutes post Injectafer® administration.  Body temperature taken pre-dose  
 Adverse event assessment (starting at beginning of Injectafer® injection). 
 
Blood samples for PK/PD will be drawn at 1, 2, 6 and 12 hours post the Day 0 Injectafer® dose. 
 
6.3.2. Days 1 and 2 (24 and 48 hour) 
 
 Blood samples for PK/PD 
 Adverse events assessment 
 
6.3.3.  72 hour, and Days 14 and 28 (weeks 2 and 4) 
 
 Blood samples for PK/PD (72 hour visit only) 
 Vital signs 
 Hematology, chemistries and iron indices 
 Adverse events assessment 
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 
6.3.4. Day 35 (week 5) End of Study 
 
 Basic physical exam including clinical assessment of skin, cardiovascular, pulmonary, abdominal 
and central nervous system.  
 Vitals signs  
 hematology, chemistries and iron indices  
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 Adverse events assessment 
 Log onto EDC and enter subject as complete 
 
The subject has completed the study after the Day 35 visit is complete.  If for any reason the subject does not 
complete the study the Day 35 procedures should be completed prior to the subject exiting from the trial.   
 
6.3.5. Pharmacokinetics and Pharmacodynamics (PK/PD) 
 
Blood samples will be collected for PK/PD assessment pre-dose and at 1, 2, 6, 12, 24, 48 and 72 hours post 
dose.  Blood samples should be taken at approximately the same time of day as the initial pre-dose sample on 
Day 0.   
 
Prior to Day 0, subjects will return to the clinic on Day -1 at which time blood samples will be drawn at 8am, 
12pm and 8pm to characterize the subjects specific iron profile. 
 


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
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Total blood volume (regular hematology, chemistry, iron indices and PK/PD) collected per day and during the 
35 Day study is provided below: 
 
 
Screening 
Day (-1) 
Day 0 
24hr 
48hr 
72hr 
Day14 
Day 28 
Day 35 
Total 
Blood 
Volume 
Hem/Chem/II 
(10ml) 
10ml 
 
 
 
 
10ml 
10ml 
10ml 
10ml 
PK/PD (2ml) 
 
6ml 
10ml 
2ml 
2ml 
2ml 
 
 
 
 
TOTAL 
10ml 
6ml 
10ml 
2ml 
2ml 
12ml 
10ml 
10ml 
10ml 
72ml / 
approx. 
14.6 
tsps.* 
*4.93 mL = 1 tsp. 
 
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 testing will be provided to the physician for review and assessment. If 
the Investigator wishes to obtain a follow-up of an abnormal Day 35 laboratory, this laboratory may be obtained 
after notification of the Sponsor.  The laboratory assessments will be determined as listed in Section 3.2.3.  
 
Hematology: 
Hb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, differential count, 
and reticulocyte count  
Chemistry:  
sodium, potassium, chloride, BUN, creatinine, albumin, alkaline phosphatase, 
total bilirubin, GGT, AST, ALT, LDH, calcium, phosphorus, glucose, 
bicarbonate and magnesium 
      Iron indices: 
serum iron, serum ferritin, and total iron binding capacity (TIBC), and 
percentage serum transferrin saturation (TSAT) 
            Other:                            Serum pregnancy test  
 
 
7.0  
ASSESSMENT OF SAFETY 
 
7.1 
Adverse Events 
 
Any untoward medical event experienced by a subject during the course of this clinical trial, whether or not it is 
related to the investigational product, at any dose, must be recorded on the Adverse Event page of the eCRF.  
 
For any laboratory abnormality, the investigator will make a judgment as to its clinical significance.  If the 
laboratory value is outside the normal 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 eCRF. 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].  All laboratory values at the end of study/Day 35 that have been deemed 
clinical significant by the Investigator should be followed until they are back into normal range. 
 
For the purposes of this study, non-serious anemia (Hb or Hct below the normal range or worsened from 
baseline) or iron deficiency (iron indices below the normal range or worsened from baseline) will not be 
considered adverse events.  Anemia or iron deficiency will be considered end points if an intervention is 
required.   


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
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To quantify the severity of adverse events, the National Cancer Institute (NCI)-Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4 should be used to grade all events.  These criteria are provided in the 
procedure manual.   
 
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 
Grade 
Adjective 
Description 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (i.e., 
preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.)  
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self care activities of daily living (i.e., bathing, 
dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.)  
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Death 
Results in Death due to the AE 
 
Timing: Non-serious adverse events will be reported from the initial treatment with Injectafer® through the 
completion of the study Day 35. AE’s will be captured 28 days post the last dose of Injectafer® for subjects 
who early terminate from the trial.  This can be completed via a phone call.  All ongoing adverse events related 
to Injectafer® 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 Injectafer® as follows: 
 
 NONE 
There is no evidence of any causal relationship. 
 
 UNLIKELY There is little evidence to suggest there is a causal relationship.  There is another 
reasonable explanation for the event (e.g., the subject’s clinical condition, other 
concomitant treatments). 
 
 POSSIBLE 
There is some evidence to suggest a causal relationship (i.e. there is a reasonable 
possibility that the adverse experience may have been caused by the agent).  However, 
the influence of other factors may have contributed to the event (e.g., the subject’s 
clinical condition, other concomitant events). 
 
 PROBABLE There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. 
 
 
*For the purposes of this trial, “study drug” is defined as: Injectafer® (known in the EU as Ferinject®) 
 
 


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
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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 their 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 
 
Definition: An adverse event is classified as SERIOUS if it meets any one of the following criteria:  
 Death 
 Life-Threatening: The subject was at substantial risk of dying at the time of the adverse event or it is 
suspected that the use / continued use of the product would result in the subject's death. 
 Hospitalization (initial or prolonged): Required admission to the hospital or prolongation of a hospital 
stay. 
 Disability: Resulted in a significant, persistent, or permanent change, impairment, damage or disruption 
in the subject's body function/structure, physical activities or quality of life. 
 Congenital Anomaly/Birth Defect   
 Important medical events: Other medically important events that, in the opinion of the investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes listed 
above. 
 
A distinction should be drawn between SAE and severe AE.  A severe AE is a major experience of its type.  A 
severe AE is not necessarily serious: e.g. nausea, which persists for several hours, may be considered severe 
nausea, but it is not an SAE.  On the other hand 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 initial treatment with Injectafer® through the completion of the 
study Day 35.  SAEs will be captured 28 days post the last dose of Injectafer® for subjects who early terminate 
from the trial.  This can be completed via a phone call. 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 learning 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 


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 26 of 44 
 
 
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. 
 
8.0 
STATISTICS 
 
No hypothesis testing will be performed for this study. 
 
8.1 
 Sample Size  
 
Determination of sample size for this single-arm, pediatric, pharmacokinetic study is a compromise between 
obtaining sufficiently precise estimates of pharmacokinetic parameters and the ethics of including a large 
number of pediatric patients in an experiment. The precision of estimation can be quantified as the width of the 
95% confidence interval for AUC0-72 from this single-arm study (i.e., smaller width indicates better precision). 
Based on Study VIT-IV-CL-002 in adults, the standard deviation for total serum iron AUC0-72 following a 500 
mg intravenous dose is approximately 300 µg◦hour/mL. The width of a 95% confidence interval, using a 
standard deviation of 300 µg◦hour/mL, is presented below for selected sample sizes. As seen in the figure, 16 
patients appears to be a reasonable compromise between precision and number of exposed pediatric patients. 
 
 
Approximately 32 subjects will be enrolled in this study, 16 subjects in cohort I and 16 subjects in cohort II.  
Within each cohort of 16 subjects will be equally disturbed by age, which will include 8 subject’s 1 – 6 years of 
age and 8 subjects > 6 – 17 year of age.   Subject enrollment and ages will be tracked and monitored via 
interactive web response (IWR) system. 
0 
100 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1100 
1200 
1300 
1400 
1500 
0 
8 
16 
24 
32 
40 
48 
56 
64 
Width of 95% CI 
Number of Subjects 


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
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8.2 
Analysis Populations  
 
There will be 2 analysis populations: 
 
 
Safety population: Includes all subjects who receive Injectafer®. 
 
 
PK/PD population: Includes all subjects in the safety population who have evaluable iron profiles and no 
protocol violation that could affect the PK/PD of Injectafer®. 
 
8.3 
Demographic Characteristics 
 
Demographic characteristics will be summarized for the Safety and PK/PD populations.  The number and 
percentage of subject’s who are registered, treated, prematurely discontinue, and complete 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. 
Categorical baseline characteristics (e.g., sex and race) will be summarized with the number and 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 Clinical Endpoints 
 
Clinical endpoints include: 
 
 Efficacy: change from baseline to each scheduled visit for hemoglobin, ferritin, and TSAT. 
 Safety: 
 
 Proportion of subjects reporting treatment-emergent adverse events, overall and related, by SOC 
and preferred term 
 Subjects reporting treatment-emergent serious adverse events, overall and related, will be 
identified 
 Mean change from baseline to each scheduled visit for clinical laboratory values 
 Incidence of treatment-emergent potentially clinically significant (PCS) clinical laboratory 
values 
 Incidence of treatment-emergent PCS vital sign values. 
 


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
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8.5 
 Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints  
 
The primary and secondary pharmacokinetic parameters will be determined for each subject as appropriate, 
based on serum concentration. The baseline parameters will be subtracted from all measured samples.  
 
The primary parameters are the maximum serum concentration (Cmax), the area under the serum concentration-
time curve from time zero to the last sampling time (t) with a quantifiable concentration (AUC0-time last measured 
concentration), the extrapolated area under the serum concentration- time curve from time zero to  infinity (AUC0-
infinity), and the half-life (T1/2).  Cmax is calculated as a non-compartmental variable, which is a more 
conservative method than if it were calculated using a compartmental paradigm.  T1/2 incorporates the 
calculation of the rate elimination constant (Kel
 
). 
The secondary parameters are the mean residence time (MRT), the apparent serum clearance (Cl), and the 
apparent volume of distribution (Vd), which includes the initial volume of distribution following the injection 
(Vdc), the volume of distribution at the steady state (Vdss), and the volume of distribution at the final 
elimination (Vdarea). 
 
Pharmacodynamic parameter will include serum ferritin, transferrin, transferrin saturation (TfS) UIBC, HGB, 
reticulocyte count and transferrin receptors. 
 
The Pharmacokinetic and Pharmacodynamic parameters performed in this study for analysis will be outlined in 
a Statistical and Analytical Plan. 
 
8.6 
Statistical Analyses of Safety 
 
The Medical Dictionary for Regulatory Activities (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 system organ class (SOC), the 
subject will be counted only once for that SOC.   
 
Change in 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 vital signs will be summarized for each treatment group. 
 
8.7 
DSMB Analyses 
 
A DSMB will review safety information for subjects in Cohort 1 before dosing begins for Cohort 2.  A Charter 
will be developed outlining the DSMB processes.  


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Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 29 of 44 
 
 
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. 
 
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 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 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. 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 30 of 44 
 
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. 
 
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 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 31 of 44 
 
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. Notification of these audits will be 
sent to all investigators in advance. 
 
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 2000 Edinburgh, Scotland 
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 
 
The protocol and the Informed Consent / Assent 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 / Assent 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 / Assent when appropriate must be obtained from each subject prior to study participation. 
The informed consent / assent will be provided to the subject in their native language. The consent/assent form 
must be signed by the subject and/or the subject's legally authorized representative.  Each investigational site 
must provide the Sponsor (or designee) with a copy of the Informed Consent / Assent approved by that site's 
Institutional Review Board. The original signed consent / assent 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 / Assent meets the requirements of Parts 50.20 and 50.25 of Title 21 of the CFR, which outlines the 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 32 of 44 
 
basic elements of informed consent and ICH guidelines.  Translations of the informed consent / assent must be 
certified by a qualified translator and their use must be documented. 
 
The Informed Consent / Assent 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 / Assent must be signed and dated by each subject and/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 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]. 
 
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. (or designee). 
Source data will be reviewed by the Clinical Monitor to insure accuracy, completeness and compliance 
with the protocol.  
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 33 of 44 
 
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, DSMB, 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 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. 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 34 of 44 
 
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 
 
The DSMB will be composed of approximately 3-5 senior academic individuals, including the DSMB Chair. 
They will have high-level expertise in pediatric iron deficiency anemia 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 Injectafer®, 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 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 35 of 44 
 
will evaluate the safety from both cohorts 1 and 2 (7.5 or 15 mg/kg of Injectafer®).  Only after all subjects in 
cohort 1 have completed through week 4 and the DSMB has evaluated the safety data as acceptable will 
registration into cohort 2 be granted.  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. 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 36 of 44 
 
 
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) 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 37 of 44 
 
REFERENCES  
 
1.  Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn's disease. Aliment.Pharmacol.Ther. 
2006; 24: 1507-1523 
 2.  Foley RN, Parfrey PS, Harnett JD et al. Impact of hypertension on cardiomyopathy, morbidity and 
mortality in end-stage renal disease. Kidney Int. 1996; 49: 1379-1385 
 3.  Staples AO, Greenbaum LA, Smith JM et al. Association between clinical risk factors and progression of 
chronic kidney disease in children. Clin.J.Am.Soc.Nephrol. 2010; 5: 2172-2179 
 4.  Wharton BA. Iron deficiency in children: detection and prevention. Br.J.Haematol. 1999; 106: 270-280 
 5.  Kazal LA, Jr. Prevention of iron deficiency in infants and toddlers. Am.Fam.Physician 2002; 66: 1217-
1224 
 6.  Michaud L, Guimber D, Mention K et al. Tolerance and efficacy of intravenous iron saccharate for iron 
deficiency anemia in children and adolescents receiving long-term parenteral nutrition. Clin.Nutr. 2002; 
21: 403-407 
 7.  Pinsk V, Levy J, Moser A, Yerushalmi B, Kapelushnik J. Efficacy and safety of intravenous iron sucrose 
therapy in a group of children with iron deficiency anemia. Isr.Med.Assoc.J. 2008; 10: 335-338 
 8.  Surico G, Muggeo P, Muggeo V et al. Parenteral iron supplementation for the treatment of iron deficiency 
anemia in children. Ann.Hematol. 2002; 81: 154-157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 38 of 44 
 
APPENDIX 1:  INJECTAFER® PACKAGE INSERT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


HIGHLIGHTS OF PRESCRIBL'\G L'\FOIHL\TIOi\ 
These highlights do not include all the information nel'dl'd to usl' 
lnjectafl'r safl'ly and effl'cliwly. Sel' full prescribing information for 
lnjectafl'r. 
li\.JECL\FERE (fl'rric earboxymaltosl' injl'elion) 
For intnn·l'nous usl' 
Initial l '.S. Approval: 20XX 
----------------------------1 i\D I C.-\ TIO :\ S AND LTSA G E---------------------------
lnjectafer is an iron replacement product indicated for the treatment of iron 
dctlciency anemia in adult patients: 
who have intohnance to oral iron or have had unsatisfactory 
response to oral iron: 
who have non-dialysis dependent chronic kidney disease 
----------------------DOS.-\G E .-\!\'D .-\ D\l INISTIU TION-----------------------
For patients \\eighing 50kg ( IIOib) or more: Give lnjectafer in two doses 
separated by at least 7 
s Give each dose as 750mg for a total cumulative 
dose or 1500mg of iron per course. 
For patients weighing less than 50kg {I I Olb): Give lnjectater in two doses 
separated by at least 7 days and give each dose as I 5 mglkg body weight. 
lnjectafer treatment may be repeated if iron deficiency anemia reoccurs. (2) 
---------------------DOS.-\G E FOR \IS A\'D STRENGTIIS----------------------
7 50 mg iron/ 15 mL single-use via1(3} 
J·TLL PRESCRIBii\G INFORM.-\TlON: CONTENTS* 
I 
INDICATIONS .-\i\D USAGE 
2 
DOSAGE AND AD\IINISTRATION 
3 
DOSAGE FOR:\IS AND STRENGTIIS 
4 
CONTRAINDICATIO\'S 
5 
W.-\RJ\1.'\GS .-\ND PREC-\FfiONS 
5.1 
Hypersensitivity Reactions 
5.2 
Hypertension 
5.3 
Lab test alterations 
6 
ADVERSE REACTIONS 
6.1 
Adverse Reactions in Clinical Trials 
6.2 
Post-marketing Experience 
7 
DRUG INTERACTIONS 
8 
l!SE IN SPECIFIC POPULATIONS 
8. I 
Pregnancy 
8.5 
Geriatric Use 
Reference 10: 3347006 
-------------------------------C Oi\TR-\ I J\ D I C.\ Tl 0 !\ S------------------------------
Hypersensitivity to fn_1ectater or any of its inactive components_ ( 4) 
-----------------------\\" .-\ Ri\ [\ G S .-\:\ D PRE CAl T I 0 i\ S------------------------
reactions: 
Observe tor signs and symptoms of 
hypersensitivity during and alter lnjectafer administration tor at least 30 
minutes and until clinically stable following completion of each 
administration (5.1) 
H!'llertension: 
Monitor patients closely lor signs and sympwms of 
hypertension lollowing each lnjectafer administration (5.2) 
------------------------------.-\ D VERSE REACT I 0!\S-------------------------------
The most common adverse reactions {_:::2%) are nausea. hypertension. 
11ushing. hypophosphatemia. and dizziness (61) 
To r·e1mr1 Sl"SPECTED ADVERSE RL\CTIO.'\S, eontnct American 
at 
1-800-734-9236 
or 
FI)A 
at 
1-800-FIH-1088 
or 
-------------------l'SE E\ SPECIFIC POPl;L\TIONS-------------------
Nursmg Mothers: Exercise caution when administered to a nursing 
woman. (83) 
Sl'e 17 for PATIE!\T COUNSELING INFORMATION and FDA-
apiH"O\'ed 1mtil'nt labeling. 
83 
Nursing Mothers 
8.4 
Pediatric Use 
IO 
OVERDOSAGE 
II 
DESCRIPTIO:\ 
12 
CU:"iiCAL PHAR\IACOLOGY 
I 2. I 
Pharmacodynamics 
12.2 
Pharmacokinetics 
13 
:"iO:\CLINICAL TOXICOLOGY 
Revised: July 2013 
13.! Carcinogenesis, Mutagenesis, and Impairment of Fertility 
14 CLINICAL SlTDIES 
14.1 
Iron Deficiency Anemia Due to Any Etiology 
14.2 
Non Dialysis Dependent Chronic Kidney Disease 
16 110\Y SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COl'NSELING INFORMATION 
*Sections or subsections omitted from the full prescribing information are not 
listed. 
LPI PI for submission vl4 (7-18-2013) trkchng 


FULL PRESCRIBING INFORl\1ATION 
1 
INDICATIONS AND USAGE 
Injectafer is indicated for the treatment of iron deficiency anemia in adult patients; 
• 
who have intolerance to oral iron or have had unsatisfactory response to oral iron; 
• 
who have non-dialysis dependent chronic kidney disease. 
2 
DOSAGE AND ADl\1INISTRATION 
For patients weighing 50 kg (II 0 lb) or more: Give lnjectafer in two doses separated by 
at least 7 days. Give each dose as 750 mg for a total cumulative dose not to exceed 1500 
mg of iron per course. 
For patients weighing less than 50 kg ( J 10 lb ): Give Injectafer in two doses separated by 
at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not 
to exceed 1500 mg of iron per course. 
The dosage of lnjectafer is expressed in mg of elemental iron. Each mL of Injectafer 
contains 50 mg of elemental iron. Injectafer treatment may be repeated if iron deficiency 
anemia reoccurs. 
Administer 1njectafer intravenously, either as an undiluted slow intravenous push or by 
infusion. When administering as a slow intravenous push, give at the rate of 
approximately I 00 mg (2 mL) per minute. When administered via infusion, dilute up to 
750 mg of iron in no more than 250 mL of sterile 0.9%sodium chloride injection, USP, 
such that the concentration of the infusion is not less than 2 mg of iron per mL and 
administer over at least 15 minutes. 
When added to an infusion bag containing 0.9% Sodium Chloride Injection, USP, at 
concentrations ranging from 2 mg to 4 mg of iron per mL, Injectafer solution is 
physically and chemically stable for 72 hours when stored at room temperature. To 
maintain stability, do not dilute to concentrations less than 2 mg iron/mL. 
Inspect parenteral drug products visually for the absence of particulate matter and 
discoloration prior to administration. The product contains no preservatives. Each vial of 
Injectafer is intended for single use only. Any unused drug remaining after injection must 
be discarded. 
Avoid extravasation oflnjectafer since brown discoloration of the extravasation site may 
be long lasting. Monitor for extravasation. If extravasation occurs, discontinue the 
Injectafer administration at that site. 
2 
Reference ID: 3347006 


3 
DOSAGEFORMSANDSTRENGTHS 
750 mg iron I 15 mL single-use vial 
4 
CONTRAINDICATIONS 
Hypersensitivity to lnjectafer or any of its components [see rVarnings and Precautions 
(5.1)]. 
5 
WARNINGS AND PRECAUTIONS 
5.1 Hypersensitivity Reactions 
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of 
which have been life-threatening and fatal, have been reported in patients receiving 
Injectafer. Patients may present with shock, clinically significant hypotension, loss 
of consciousness, and/or collapse. Monitor patients for signs and symptoms of 
hypersensitivity during and after Injectafer administration for at least 30 minutes 
and until clinically stable following completion of the infusion. Only administer 
Injectafer when personnel and therapies are immediately available for the 
treatment of serious hypersensitivity reactions. [see Adverse Reactions (6.1 and 6.2)]. 
In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% 
(2/1775) of subjects receiving Injectafer. Other serious or severe adverse reactions 
potentially associated \vith hypersensitivity \Vhich included, but not limited to, pruritus, 
rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these 
subjects. 
5.2 Hypertension 
In clinical studies, hypertension was reported in 3.8% (67 /I, 775) of subjects in clinical 
trials I and 2. Transient elevations in systolic blood pressure, sometimes occurring with 
facial flushing, dizziness, or nausea were observed in 6% ( 106/1, 775) of subjects in these 
two clinical trials. These elevations generally occurred immediately after dosing and 
resolved within 30 minutes. 
Monitor patients for signs and symptoms of hypertension 
following each Injectafer administration [see Dosage and Administration (2)]. 
5.3 Laboratory Test Alterations 
In the 24 hours following administration of Injectafer, laboratory assays may 
overestimate serum iron and transferrin bound iron by also measuring the iron in 
Injectafer. 
6 
ADVERSE REACTIONS 
The following adverse reactions are discussed in greater detail in other sections of the 
labeling: 
Hypersensitivity Reactions {see Warnings and Precautions (5.1)] 
Hypertension {see Warnings and Precautions (5.2)] 
Lab test alterations {see Warnings and Precautions (5.3)] 
3 
Reference ID: 3347006 


6.1 Adverse Reactions in Clinical Trials 
Because clinical trials are conducted under widely varying conditions, the adverse 
reaction rates observed cannot be directly compared to rates in other clinical trials and 
may not reflect the rates observed in clinical practice. 
In two randomized clinical studies [Studies I and 2, See Clinical Studies 
a total of 
775 patients were exposed to Injectafer I 5 mg/kg body weight up to a maximum single 
dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative 
dose of 1500 mg of iron. 
Adverse reactions reported by 2': l% of treated patients are shown in the following table. 
Table 1. Adverse reactions reported in 2:: I 0/o of Study Patients in Clinical Trials 1 and 
2 
Injectafer 
Pooled 
Oral 
iron 
Term 
{N=1775) 
(N=1783) 
(N=253) 
% 
o;o 
% 
Nausea 
7.2 
1.8 
1.2 
Hypertension 
3.8 
l.9 
0.4 
Flushing/Hot Flush 
3.6 
0.2 
0.0 
Blood Phosphorus Decrease 
2.1 
0.1 
0.0 
Dizziness 
2.0 
1.2 
0.0 
Vomiting 
1.7 
0.5 
0.4 
Injection Site Discoloration 
1.4 
0.3 
0.0 
Headache 
1.2 
0.9 
0.0 
Alanine Aminotransferase Increase 
1.1 
0.2 
0.0 
Dysgeusia 
l.l 
2.1 
0.0 
Hypotension 
1.0 
1.9 
0.0 
Constipation 
0.5 
0.9 
3.2 
a Includes oral Iron and all formulations of IV 1ron other than lnJectafer 
Other adverse reactions reported by 2': 0.5% of treated patients include abdominal pain, 
diarrhea, gamma glutamyl transferase increased, injection site pain/irritation, rash, 
paraesthesia, sneezing. Transient decreases in laboratory blood phosphorus levels ( < 2 
mg/dL) have been observed in 27o/o { 44011638) patients in clinical trials. 
6.2 Post-marketing Experience 
Because these reactions are reported voluntarily from a population of uncertain size, it is 
not always possible to reliably estimate their frequency or establish a causal relationship 
to drug exposure. The following serious adverse reactions have been most commonly 
reported from the post-marketing spontaneous reports with Injectafer: urticaria, dyspnea, 
pruritis, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, 
arthralgia, and syncope. One case of hypophosphatemic osteomalacia was reported in a 
4 
Reference ID: 3347006 


subject who received 500 mg of lnjectafer every 2 weeks for a total of 16 weeks. Partial 
recovery followed discontinuation of Injectafer. 
7 
DRUG INTERACTIONS 
Formal drug interaction studies have not been performed with lnjectater. 
8 
USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Pregnancy Category C 
Risk Summary 
Adequate and well controlled studies in pregnant women have not been conducted. 
However, animal reproduction studies have been conducted with ferric carboxymaltose. ln these 
studies, administration of ferric carboxymaltose to rabbits during the period of 
organogenesis caused fetal malformations and increased implantation loss at maternally 
toxic doses of approximately 12% to 23% ofthe human weekly dose of750 mg (based on 
body surface area). The incidence of major malformations in human pregnancies has not 
been established for lnjectafer. However, all pregnancies, regardless of exposure to any 
drug, has a background rate of 2 to 4o/o for major malformations, and 15 to 20o/o for 
pregnancy loss. Injectafer should be used during pregnancy only if the potential benefit 
justifies the potential risk to the fetus. 
Animal Data 
Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion up to 
30 mg/kg/day iron on gestation days 6 to 17 did not result in adverse embryofetal 
findings. This daily dose in rats is approximately 40o/o of the human weekly dose of750 
mg based on body surface area. In rabbits, ferric carboxymaltose was administered as a 
one-hour infusion on gestation days 6 to 19 at iron doses of 4.5, 9, I 3.5, and 18 
mg/kg/day. Malformations were seen starting at the daily dose of9 mg/kg (23% of the 
human weekly dose of750 mg). Spontaneous abortions occurred stm1ing at the daily 
iron dose of 4.5 mg/kg (12% of the human weekly dose based on body surface area). 
Pre-implantation loss was at the highest dose. Adverse embryofetal effects were 
observed in the presence of maternal toxicity. 
A pre- and post-natal development study was conducted in rats at intravenous doses up to 
18 mg/kg/day of iron (approximately 23% of the weekly human dose of 750 mg on a 
body surface area basis). There were no adverse effects on survival of offspring, their 
behavior, sexual maturation or reproductive parameters. 
8.3 Nursing Mothers 
A study to determine iron concentrations in breast milk after administration of Injectafer 
(n=l 1) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with 
postpartum iron deficiency anemia. Mean breast milk iron levels were higher in lactating 
women receiving Injectafer than in lactating women receiving oral ferrous sulfate. 
5 
Reference ID: 3347006 


8.4 Pediatric Use 
Safety and effectiveness have not been established in pediatric patients. 
8.5 Geriatric Use 
Of the 1775 subjects in clinical studies of InjectafeL 50% were 65 years and over, while 
25o/o were 75 years and over. No overall differences in safety or effectiveness were 
observed between these subjects and younger subjects. and other reported clinical 
experience has not identified differences in responses between the elderly and younger 
patients, but greater sensitivity of some older individuals cannot be ruled out. 
10 OVERDOSAGE 
Excessive dosages of Injectafer may lead to accumulation of iron in storage sites 
potentially leading to hemosiderosis. A patient who received lnjectafer 18,000 mg 
over 6 months developed hemosiderosis with multiple joint disorder, walking 
disability and asthenia. Hypophosphatemic osteomalacia was reported in a patient 
who received lnjectafer 4000 mg over 4 months. Partial recovery followed 
discontinuation of Injectafer. [see Post-marketing Experience (6.3)]. 
11 
DESCRIPTION 
Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex 
with the chemical name of polynuclear iron (II I) hydroxide 4(R)-(poly-(l--74)-0-a-D-
glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. 
It 
has 
a 
relative 
molecular weight of approximately J 50,000 Da corresponding to the following empirical 
formula: 
' 
where n :::::: 103, m 
8, 
11, and k:::::: 4 
(I represents the mean branching degree of the ligand). 
The chemical structure is presented below: 
6 
Reference 10: 3347006 


O 
(91:::-L; 
0 
Of< 
0>< 
' OH 
0 o' 
e 
H,O 
glc 
glucos-e 
•••• h;'drogenbond 
/ 0>-r_l'' (Ori 
y ' ·*o(""' Yo" 
0 
0 
. 
0 
[!f{: 
C-?-! 
o •• 
Ott 
lnjectafer (ferric carboxymaltose injection} is a dark brown, sterile, aqueous, isotonic 
colloidal solution for intravenous injection. Each mL contains 50 mg iron as ferric 
carboxymaltose in water for injection. lnjectafer is available in 15 mL single-use vials. 
Sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH to 5.0-
7.0. 
Vial closure is not made with natural rubber latex 
7 
Reference ID: 3347006 


12 
CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Ferric carboxymaltose is a colloidal iron (Ill) hydroxide in complex with carboxymaltose, 
a carbohydrate polymer that releases iron. 
12.2 Pharmacodynamics 
Using positron emission tomography (PET) it was demonstrated that red cell uptake of 
59Fe and 52 Fe from lnjectafer ranged from 61% to 99%. In patients with iron deficiency. 
red cell uptake of radio-labeled iron ranged fi·om 91% to 99o/o at 24 days after lnjectafer 
dose. In patients with renal anemia red cell uptake of radio-labeled iron ranged from 61 o/o 
to 84% after 24 days lnjectafer dose. 
12.3 Pharmacokinetics 
After administration of a single dose of lnjectafer of I 00 to 1000 mg of iron in iron 
deficient 
maximum iron levels of 37 11g/mL to 333 Jlg/mL were obtained 
respectively after 15 minutes to 1.21 hours post dose. The volume of distribution was 
estimated to be 3 L. 
The iron injected or infused was rapidly cleared from the plasma, the terminal half-life 
ranged from 7 to 12 hours. Renal elimination of iron was negligible. 
13 
NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been performed with ferric carboxymaJtose. 
Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in 
vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human 
lymphocytes, in 
vitro mammalian cell 
mutation assay 
in 
mouse 
lymphoma 
L5178Y /TK +I- cells, in vivo mouse micronucleus test at single intravenous doses up to 
500 mg/kg. 
In a combined male and female fertility study, ferric carboxymaltose was administered 
intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg. 
Animals were dosed 3 times per week (on Days 0, 3, and 7). There was no effect on 
mating function, fertility or early embryonic development. The dose of30 mg/kg in 
animals is approximately 40% ofthe human dose of750 mg based on body surface area. 
14 
CLINICAL STUDIES 
The safety and efficacy ofinjectafer for treatment of iron deficiency anemia were 
evaluated in two randomized, open-label, controlled clinical trials {Trial 1 and Trial2). In 
these two trials, Injectafer was administered at a dose of 15 mg/kg body weight up to a 
maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up 
to a cumulative dose of 1500 mg of iron. 
8 
Reference ID: 3347006 


14.1 Triall: Iron Deficiency Anemia in Patients Who Are Intolerant to Oral Iron or 
Have Had Unsatisfactory Response to Oral Iron 
Trial I \Vas a randomized, open-label, controlled clinical study in patients with iron 
deficiency anemia \Vho had an unsatisfactory response to oral iron (Cohort I) or who 
were intolerant to oral iron (Cohort 2) during the 14 day oral iron run-in period. 
Inclusion criteria prior to randomization included hemoglobin (Hb) <12 g/dL, ferritin ::S 
100 ng/mL or ferritin ::S 300 ng/mL when transferrin saturation (TSA T) :::; 30%. Cohort I 
subjects were randomized to lnjectafer or oral iron for 14 more days. Cohort 2 subjects 
were randomized to lnjectafer or another IV iron per standard of care [90% of subjects 
received iron sucrose]. The mean age of study patients was 43 years (range, 18 to 94 ); 
94% were female; 42% were Caucasian, 32o/o were Afi·ican American, 24% were 
Hispanic, and 2% were other races. The primary etiologies of iron deficiency anemia 
were heavy uterine bleeding (47%) and gastrointestinal disorders ( l7o/o). 
Table 2 shows the baseline and the change in hemoglobin from baseline to highest value 
bet\veen baseline and Day 35 or time of intervention. 
9 
Reference 10: 3347006 


Table 2. Mean Change in Hemoglobin From Baseline to the Highest Value 
Between Day 35 or Time of Intervention (Modified Intent-to-Treat Population) 
Hemoglobin (g/dL) 
Cohort 1 
Cohort 2 
Mean (SD) 
Injectafer 
Oral Iron 
Injectafer 
(N=244) 
(N=251) 
(N=245) 
Baseline 
l 0.6 ( l.O) 
10.6 ( 1.0) 
9. I ( 1.6) 
Highest Value 
12.2 ( 1.1) 
l 1.4 ( 1.2) 
12.0 ( 1.2) 
Change (from baseline to 
1.6 ( 1.2) 
0.8 (0.8) 
2.9 ( 1.6) 
highest value) 
p-value 
0.001 
0.001 
SD=standard deviatiOn; a: Intravenous Iron per standard of care 
Increases from baseline in mean ferritin (264.2±224.2 ng/mL in Cohort 1 and 218.2 
±211.4 ng/mL in Cohort 2), and transferrin saturation ( 13± 16% in Cohort I and 
20±15% in Cohort) were observed at Day 35 in Injectafer-treated patients. 
14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis Dependent 
Chronic Kidney Disease 
Trial 2 was a randomized, open-label, controlled clinical study in patients with non-
dialysis dependent chronic kidney disease. Inclusion criteria included hemoglobin (Hb) 
11.5 g/dL, ferritin :S 100 ng/mL or ferritin :S 300 ng/mL when transferrin saturation 
(TSA T) 
30%.Study patients were randomized to either lnjectafer or Venofer. The mean 
age of study patients was 67 years (range, 19 to 96); 64% were female; 54% were 
Caucasian, 26% were African American, 18% Hispanics, and 2% were other races. 
Table 3 shows the baseline and the change in hemoglobin from baseline to highest value 
between baseline and Day 56 or time of intervention. 
10 
Reference 10: 3347006 
IVSCa 
(N=237) 
9.0 (1.5) 
11.2 ( 1.3) 
2.2 (1.3) 


Table 3. Mean Change in Hemoglobin From Baseline to the Highest Value 
Between Baseline and Day 56 or Time of Intervention (Modified Intent-to-Treat 
Population) 
Hemoglobin (g/dL) 
lnjectafer 
Venofer 
Mean (SD) 
(N=l249) 
(N=l244) 
Baseline 
10.3 (0.8) 
10.3 (0.8) 
Highest Value 
I 1.4 ( 1.2) 
11.3 (1.1) 
Change (from baseline to highest 
l.l ( 1.0) 
0.9 (0.92) 
value) 
Treatment Difference (95o/o CI) 
0.21 (0.13, 0.28) 
Increases from baseline in mean ferritin (734.7±337.8 ng/mL), and transferrin 
saturation (30±17%) were observed at Day 56 in Injectafer-treated patients. 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
NDC 0517-0650-01 
NDC 0517-0650-02 
750 mg iron/15 mL Single-Use Vial Individually boxed 
750 mg iron/15 mL Single-Use Vial Packages of2 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to l5°C to 30°C (59°F to 
86°F). [See the USP controlled room temperature]. Do not freeze. 
17 
PATIENT COUNSELING INFORMATION 
• 
Question patients regarding any prior history of reactions to parenteral iron products. 
• 
Advise patients of the risks associated with lnjectafer. 
• 
Advise patients to report any signs and symptoms of hypersensitivity that may develop during and 
following lnjectafer administration, such as rash, itching, dizziness, lightheadedness, swelling and 
breathing problems [see Warnings and Precautions (5)] 
lnjectafer is manufactured under license from Vifor (International) lnc, Switzerland. 
11 
Reference ID: 334 7006 


AMERICAN 
REGENT, INC. 
SHIRLEY, NY 11967 
IN0602 
Rev. 7113 
Reference ID: 3347006 
12 


Patient Information 
INJECTAFER (ferric carboxymaltose injection) 
Please read this information carefully before taking this medication. This summary does 
not tell you everything about INJECTAFER. Speak with your doctor or healthcare 
professional if there is something you do not understand or if you would like to learn 
more about INJECT AFER. Your doctor or healthcare professional is your best source of 
information about this medicine. 
What is INJECT AFER? 
Iron is a mineral that the body needs to produce red blood cells. When the body does not 
get enough iron, it cannot produce the number of normal red blood cells needed to keep 
you in good health. This condition is called iron deficiency (iron shortage) or iron 
deficiency anemia. 
INJECTAFER is used to treat iron deficiency anemia. Iron deficiency anemia may be 
caused by several medical conditions including heavy menstrual bleeding, pregnancy, 
childbirth, inflammatory bowel disease, other malabsorption diseases, bariatric surgery, 
or chronic kidney disease. 
General information about using INJECT AFER safely and effectively 
Injectable iron is administered only by or under the supervision of your health care 
professional. 
Serious or life threatening allergic reactions have been reported with intravenous iron 
products. Tell your health care professional if you have ever had any unusual or allergic 
reaction to any IV iron. 
Patients should report to their healthcare professional any signs and symptoms of an 
allergic reaction to INJECTAFER, in particular rashes, shortness of breath and wheezing. 
Iron is not easily eliminated from the body, and its build up may be lead to a condition 
called iron overload which may be harmfuL Certain medical conditions such as liver 
disease may also make you more likely to develop iron overload. Ask your doctor or 
healthcare professional. 
Who should not take INJECT AFER? 
You should not be given INJECT AFER if you have anemia that is not caused by iron 
deficiency, or if you have iron overload. 
If you are pregnant or plan to become pregnant please notify your doctor or healthcare 
professional. They will decide whether it is safe for you to receive INJECTAFER. 
How should I take INJECTAFER? 
13 
Reference ID: 3347006 


INJECT AFER is administered intravenously (into your vein) by your doctor or health 
care professional in two doses. 
What should I avoid while taking INJECT AFER? 
You should not take iron supplements by mouth if you are receiving iron injections. Tell 
your doctor about all the medicines you take, including prescription and non-prescription 
medicines, vitamins and herbal supplements. 
What are the possible side effects of INJECT AFER? 
The side effects of INJECT AFER are infi·equent. usually mild and generally do not cause 
patients to stop treatment. The most common side effects are nausea, injection site 
reactions (including pain or bruising at the injection site), asymptomatic reductions in 
blood phosphorus, flushing, headache, hypertension, dizziness, and increased alanine 
aminotransferase. Potentially long lasting brown staining of skin near injection site may 
occur. 
These are not all the possible side effects of INJECT AFER. For more information ask 
your doctor or healthcare professional. 
Talk to your doctor if you think you have side effects fi·om taking INJECTAFER. 
14 
Reference ID: 3347006 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 39 of 44 
 
APPENDIX 2:  WEIGHT CHARTS FOR BOYS AND GIRLS 
 
Boys (White) Weight Chart age 0-36 months (http://www.halls.md/chart/boys-weight-w.htm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 40 of 44 
 
BOYS (WHITE) WEIGHT CHART AGE 2-20 YRS 
(HTTP://WWW.CDC.GOV/GROWTHCHARTS/DATA/SET1CLINICAL/CJ41L021.PDF) 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 41 of 44 
 
Girls (White) Weight Chart age 0-36 months (http://www.halls.md/on/girls-weight-w.htm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 42 of 44 
 
GIRLS (WHITE) WEIGHT CHART AGES 2-20 YRS 
(HTTP://WWW.CDC.GOV/GROWTHCHARTS/DATA/SET1CLINICAL/CJ41L022.PDF)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 43 of 44 
 
APPENDIX 3:  ADMENDMENT I CHANGES 
 
Title Page: 
 
Original 
Wording: 
Protocol Date: 
27 March 2014 
New Wording: 
Protocol Date: 
Amendment 1: 29 July 2014 
Study 
Synopsis and 
8.1 Sample 
Size 
Rationale: 
 
New Wording: 
 
Sample Size: 
 
Determination of sample size for this single-arm, pediatric, pharmacokinetic 
study is a compromise between obtaining sufficiently precise estimates of 
pharmacokinetic parameters and the ethics of including a large number of 
pediatric patients in an experiment. The precision of estimation can be 
quantified as the width of the 95% confidence interval for AUC0-72 from this 
single-arm study (i.e., smaller width indicates better precision). Based on Study 
VIT-IV-CL-002 in adults, the standard deviation for total serum iron AUC0-72 
following a 500 mg intravenous dose is approximately 300 µg◦hour/mL. The 
width of a 95% confidence interval, using a standard deviation of 300 
µg◦hour/mL, is presented below for selected sample sizes. As seen in the figure, 
16 patients appears to be a reasonable compromise between precision and 
number of exposed pediatric patients.  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Amendment I Date: 29 July 2014 
Page 44 of 44 
 
 
Approximately 32 subjects will be enrolled in this study, 16 subjects in cohort I 
and 16 subjects in cohort II.  Within each cohort of 16 subjects will be equally 
disturbed by age, which will include 8 subject’s 1 – 6 years of age and 8 
subjects > 6 – 17 year of age.   Subject enrollment and ages will be tracked and 
monitored via interactive web response (IWR) system. 
 
Original 
Wording: 
Exclusion Criteria: 
 
3. Body mass index (BMI) ≤ 95th percentile for age (see APPENDIX 2) 
 
New Wording: 
3. Body mass index (BMI) ≤ 5th percentile for age (see APPENDIX 2) 
 
Original 
Wording: 
Trial design – Phase III 
New Wording: 
Trial Design – Phase II 
Additional 
Wording – 
Sections 7.1 
All laboratory values at the end of study/Day 35 that have been deemed clinical 
significant by the Investigator should be followed until they are back into 
normal range. 
 
 
 
0 
100 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1100 
1200 
1300 
1400 
1500 
0 
8 
16 
24 
32 
40 
48 
56 
64 
Width of 95% CI 
Number of Subjects 




CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 1 of 41 
 
 
LUITPOLD PHARMACEUTICALS, INC. 
 
PROTOCOL 
No. 1VIT13036 
 
IND #: 63,243 
 
 
A Multi-center, Open-label, Single Arm Study to Characterize the Pharmacokinetics and 
Pharmacodynamics Profile of Intravenous Injectafer® (Ferric Carboxymaltose) in Pediatric Subjects 1 – 
17 years old with Iron Deficiency Anemia (IDA) 
 
 
SPONSOR 
Luitpold Pharmaceuticals, Inc. 
Clinical Research and Development 
800 Adams Avenue 
Norristown, PA 19403 
(610) 650-4200 
 
 
 
 
Protocol Date: 27 March 2014 
 
 
 


CONFIDENTIAL
SIGNATURES OF AGREEMENT FOR PROTOCOL
el Abreu,
Meclical Director, Pharrnacovigilance
Luitpold Pha
ticals, lnc.
Mzu$ha Simon
Sr. Manager-Regulatory Aftairs
Luitpold Pharrnaceuticals, Inc.
,1
q
Protocol: lVITl3036
Date: 2'l March 2014
{7
Date
Date
/b"" / gzt +
David Morris, PhD
Senior Director, Statistics
V/ebbwrites, LLC
Date
Page 2 of 4l


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Date: 27 March 2014 
Page 3 of 41 
Study Synopsis 
Protocol No. 1VIT13036 
Title:   
A Multi-center, Open-label, Single Arm Study to Characterize the Pharmacokinetics and 
Pharmacodynamics Profile of Intravenous Injectafer® (Ferric Carboxymaltose) in Pediatric 
Subjects 1 – 17 years old with Iron Deficiency Anemia (IDA). 
Drugs:  
Injectafer® (Ferric Carboxymaltose) 
Objectives:   The primary objectives of this study are to characterize the pharmacokinetics and determine 
appropriate dosing and safety of Injectafer® for the pediatric population suffering from iron 
deficiency (ID) with anemia.  
 
Study Design:This is a Phase III, open-label, non-randomized, multi-center, single arm study to characterize 
the pharmacokinetic and pharmacodynamics  (PK/PD) profile of Injectafer® dosing in pediatric 
subjects with IDA after receiving either a 7.5 mg/kg or 15 mg/kg dose of Injectafer®.  
 
Treatment 
 
Cohort 1: 16 subjects will be treated with Injectafer® at 7.5 mg/kg to a maximum single dose of 
750 mg iron, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have completed 4 weeks of 
therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Injectafer® at 15 mg/kg to a maximum single dose of 
750 mg iron, whichever is smaller.   
Inclusion Criteria:  
1. Male or female subjects 1 to 17 years of age with assent to participation and his/her parent or 
guardian is willing and able to sign the informed consent approved by the Independent Review 
Board / Ethics Committee.  
2. Screening TSAT < 20% 
3. Screening Hemoglobin < 11 g/dL 
4. For subjects who are receiving an erythropoietin stimulating agent (ESA): stable ESA therapy 
(+/- 20% of current dose) for > 8 weeks prior to the qualifying screening visit and no ESA 
dosing or product changes anticipated for the length of the trial 
 
Exclusion Criteria:    
1. Known hypersensitivity reaction to any component of Injectafer®. 
2. Subject previously randomized and treated in this study or any other clinical study of Injectafer® 
(FCM or VIT-45). 
3. Body mass index (BMI) ≤ 95th percentile for age (see APPENDIX 2) 
4. History of acquired iron overload, hemochromatosis or other iron accumulation disorders. 
5. Chronic kidney disease subjects on hemodialysis. 
6. Screening Ferritin level > 300ng/mL 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Date: 27 March 2014 
Page 4 of 41 
7. Subjects with significant severe diseases of the liver, hemopoietic system, cardiovascular system, 
psychiatric disorder or other conditions which on the opinion of the investigator may place a 
subject at added risk. 
8. Any active infection.  
9. Known positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody (HCV) with evidence 
of active hepatitis. 
10. Known positive HIV-1/HIV-2 antibodies (anti-HIV). 
11. Anemia due to reasons other than iron deficiency (i.e. hemoglobinopathy). Subjects treated with 
vitamin B12 or folic acid deficiency are permitted. 
12. Significant blood loss (> 100 ml) within the last 3 months or any current bleeding disorders or 
anticipated need for surgery that may result in significant blood loss (> 100 ml). 
13. Intravenous iron and /or blood transfusion in the 4 weeks prior to screening.  
14. Immunosuppressive therapy that may lead to anemia (i.e. cyclophosphamide, azathioprine, 
mycophenolate mofetil).  Note steroid therapy is permitted. 
15. Administration and / or use of an investigational product (drug or device) within 30 days of 
screening. 
16. Alcohol or drug abuse within the past six months. 
17. Female subjects who are pregnant or lactating, or sexually active female who are of childbearing 
potential not willing to use an acceptable form of contraceptive precautions during the study. 
18. Subject is unable to comply with study assessments. 
 
Subject 
Assessments:  
All subjects that provide informed consent / assent will enter a screening period up to 14 days 
prior to Day 0.  During this time subjects will be evaluated to insure they meet the study entry 
criteria.  Subjects will have vital signs, medical history review and laboratory samples to include 
hematology, chemistries and iron indices.  Once it has been determine the subject qualifies for 
participation the subject will be scheduled to return to the clinic 1 day prior to Day 0 (Day -1) at 
which time additional blood samples will be taken (8am, 12pm and 8pm) to characterize the 
subjects iron profile. 
 
Blood samples for PK/PD will also be assessed immediately prior to Injectafer® dosing on Day 
0, at 1, 2, 6, 12, 24, 48 hours and at 72 hours.  
 
Safety assessments, including vital signs and adverse events, will be assessed starting on Day 0 
at the time of Injectafer® dosing through Day 35.   
 
Erythropoietin 
Dosage: 
 
 
If receiving an Erythropoiesis Stimulating Agent (ESA), a stable (± 20%) dose is required for > 8 
weeks prior to screening.  The ESA type, route, frequency and dose will remain unchanged 
throughout the remainder of the study unless the dose should be decreased or held per the 
package label.  Once decreased or held, it may not be increased or restarted unless thought 
necessary by the subject’s physician. If the latter event occurs, the ESA dose changes will be 
collected and the subject will continue for safety analysis. 
  


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Date: 27 March 2014 
Page 5 of 41 
Study Duration 
per subject:  up to 9 weeks  
Number of  
Subjects:   
32 subjects 
Sites:   
Approximately 10 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Date: 27 March 2014 
Page 6 of 41 
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: 610-6507781 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Date: 27 March 2014 
Page 7 of 41 
TABLE OF CONTENTS 
1.0 INTRODUCTION .................................................................................................................... 11 
1.1 
Treatment of Iron Deficiency Anemia ............................................................................ 11 
1.2 
Injectafer ......................................................................................................................... 12 
1.2.1 
Key features of Injectafer ............................................................................................ 12 
1.2.2 
Injectafer versus Other Parenteral Iron Agents ......................................................... 12 
1.2.3 
Injectafer Human Experience ..................................................................................... 13 
2.0 MAIN TRIAL OBJECTIVE ..................................................................................................... 14 
3.0  
OVERALL STUDY DESIGN AND RATIONALE .......................................................... 14 
3.1 
 Trial Design ................................................................................................................... 14 
3.2 
Rationale ......................................................................................................................... 14 
3.2.1 
Rationale for Trial Design .......................................................................................... 14 
3.2.2 
Rationale for open label design .................................................................................. 15 
3.2.3. 
Schedule of Events .................................................................................................. 16 
4.0  
SUBJECT SELECTION ..................................................................................................... 17 
4.1 
Number and Type of Subjects......................................................................................... 17 
4.2 
Screening Phase .............................................................................................................. 17 
4.2.1  
Entry Criteria .......................................................................................................... 17 
4.3 
Subject Assignment and Registration Process ................................................................ 18 
4.4 
Withdrawal from Study................................................................................................... 18 
4.5 
Intervention ..................................................................................................................... 18 
5.0 STUDY DRUG ......................................................................................................................... 19 
5.1 
Formulation Packaging and Storage ............................................................................... 19 
5.2 
Drug Administration / Regimen...................................................................................... 19 
5.3 
IV Iron Precautions ......................................................................................................... 19 
5.4 
Drug Accountability........................................................................................................ 20 
5.5 
Concomitant Medication ................................................................................................. 20 
6.0 STUDY PROCEDURES .......................................................................................................... 20 
6.1 
Informed Consent............................................................................................................ 20 
6.2 
Screening (up to 14 days) ............................................................................................... 21 
6.3 
Study Visits .................................................................................................................. 21 
6.3.1. 
Day (-1) ................................................................................................................... 21 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
Date: 27 March 2014 
Page 8 of 41 
6.3.2 
Day 0 ........................................................................................................................... 21 
6.3.2. 
Days 1 and 2 (24 and 48 hour) ............................................................................... 22 
6.3.3. 
 72 hour, and Days 14 and 28 (weeks 2 and 4)....................................................... 22 
6.3.4. 
Day 35 (week 5) End of Study ................................................................................. 22 
6.3.5. 
Pharmacokinetics and Pharmacodynamics (PK/PD) ............................................. 22 
6.4 
Central Laboratory Assessments..................................................................................... 23 
7.0  
ASSESSMENT OF SAFETY ............................................................................................. 23 
7.1 
Adverse Events ............................................................................................................... 23 
7.2 
Reporting of Adverse Events .......................................................................................... 25 
7.3 
Serious Adverse Events .................................................................................................. 25 
8.0 STATISTICS ............................................................................................................................ 26 
8.1 
 Sample Size Rationale ................................................................................................... 26 
8.2 
Analysis Populations ....................................................................................................... 26 
8.3 
Demographic Characteristics .......................................................................................... 26 
8.4 
Endpoints and Definitions............................................................................................... 27 
8.4.1 
Clinical Endpoints ...................................................................................................... 27 
8.5 
 Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints .................................... 27 
8.6 
Statistical Analyses of Safety .......................................................................................... 27 
8.7 
DSMB Analyses.............................................................................................................. 28 
9.0 ADMINISTRATIVE CONSIDERATIONS ............................................................................. 28 
9.1 
Retention and Availability of Records ............................................................................ 28 
9.2 
Investigator Responsibilities ........................................................................................... 28 
9.3 
Financial Disclosure........................................................................................................ 29 
9.4 
Advertisement for Subject Recruitment.......................................................................... 29 
9.5 
Documents Required for Study Initiation ....................................................................... 29 
9.6 
Quality Control and Quality Assurance .......................................................................... 29 
9.6.1 
Investigator Selection Criteria .................................................................................... 29 
9.6.2 
Clinical Monitoring .................................................................................................... 30 
9.6.3 
Quality Assurance Audit ............................................................................................. 30 
9.7 
Ethics............................................................................................................................... 30 
9.7.1 
Ethical and Legal Issues ............................................................................................. 30 
9.7.2 
Institutional Review Board ......................................................................................... 30 


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Protocol: 1VIT13036 
 
Date: 27 March 2014 
Page 9 of 41 
9.7.3 
Informed Consent ........................................................................................................ 31 
9.7.4 
Good Clinical Practice ............................................................................................... 31 
9.8 
Data Handling and Record Keeping ............................................................................... 31 
9.8.1 
Electronic Case Report Form (eCRF) ........................................................................ 31 
9.8.2 
Confidentiality............................................................................................................. 32 
9.8.3 
Termination of the Study ............................................................................................. 32 
9.8.4 
Protocol Revisions ...................................................................................................... 32 
9.8.5 
Protocol Administrative Changes ............................................................................... 32 
9.9 
Publication Policy ........................................................................................................... 33 
10.0  GOVERNANCE COMMITTEE ........................................................................................ 33 
10.1 
Data and Safety Monitoring Board............................................................................. 33 
INVESTIGATOR’S ACKNOWLEDGEMENT ............................................................................ 35 
REFERENCES .............................................................................................................................. 36 
APPENDIX 1:  INJECTAFER® PACKAGE INSERT ............................................................ 37 
APPENDIX 2:  WEIGHT CHARTS FOR BOYS AND GIRLS .................................................. 38 


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Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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LIST OF ABBREVIATIONS 
AE 
 
 
 
 
Adverse event 
BP 
Blood Pressure 
BW 
Body Weight 
CI 
confidence interval 
CKD 
Chronic Kidney Disease 
conc. 
concentration 
CTCAE 
Common Terminology Criteria for Adverse Event 
dL 
Deciliter 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture 
e.g. 
for example 
ESA 
Erythropoiesis stimulating agent 
FDA 
Food and Drug Administration 
Fe 
Iron 
g 
Gram 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HMW 
high molecular weight 
IBD 
Inflammatory Bowel Diease 
ICH 
International Conference on Harmonisation 
IDA 
Iron Deficiency Anemia 
i.e. 
that is/ such that 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVP 
Intravenous injection (push) 
kg 
Kilogram 
L 
Liter 
LMW 
low molecular weight 
LOS 
length of stay 
MedDRA 
Medical dictionary for regulatory activities 
mg  
Milligram 
mL 
Milliliter 
ng 
Nanogram 
PET 
positron emission tomography 
p.o. 
by mouth or orally 
RES 
Reticuloendothelial system 
SAE 
Serious adverse event 
t1/2 
Terminal half-life 
t.i.d. 
three times a day 
TSAT 
Transferrin Saturation 
US 
United States 
vs 
Versus 
w/v 
weight / volume 


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Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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1.0 
INTRODUCTION 
 
1.1 
Treatment of Iron Deficiency Anemia 
 
Iron deficiency anemia (“IDA”) remains the most common nutritional deficiency in children in the United 
States.  Rapid growth, insufficient dietary intake, and limited absorption of dietary iron combine to place 
children at increased risk for iron deficiency. Iron deficiency may contribute significantly to anemia due to 
malabsorption, gastrointestinal blood loss, or iatrogenically due to repeated blood samplings.  As a result of 
severe digestive tract disorders, some children are unable to tolerate oral iron supplementation or are 
unresponsive to it.1 Anemia may also decrease survival rates in patients (both adults and children) with chronic 
renal impairment where it is a commonly encountered problem2;3 In addition, anemia is a commonly 
encountered manifestation of pediatric inflammatory bowel disease which is associated with a decrease in the 
quality of life and increased hospitalization. 
 
Non-hematologic consequences of iron deficiency include poor weight gain, anorexia, irritability, decreased 
attention span, exercise intolerance and decreased physical activity. 4  However, IDA in infants and toddlers is 
associated with long-lasting diminished mental, motor, and behavioral functioning.  Although the exact 
relationship between iron deficiency anemia and the developmental effects is not well understood, it appears 
that these effects do not occur until iron deficiency becomes severe and chronic enough to produce anemia. 5 
 
Options for correcting iron deficiency include both oral and parenteral formulations. As previously described, 
some children are unable to tolerate or are non-responsive to oral iron.  Blood transfusion is an option to treat 
anemia and restore iron requirements, but the potential risk of blood-transmitted virus infection limits its use to 
severe and badly tolerated anemia. In view of the limitations associated with oral iron or blood transfusions, 
intravenous administration is an important option. 
 
Multiple parenteral iron products are available. These vary in complex types which impacts the total amount of 
iron that may be administered in a single administration. Numerous other differences differentiate the products; 
however, all appear to effectively release iron post administration and restore the deficit of the patient. There 
are numerous studies with iron sucrose injection (Venofer®) that have been performed in the pediatric 
population 6-8. Iron doses have varied in the studies with demonstrated efficacy and safety in doses up to 7mg 
iron/kg or 200mg given in time frames of 3 min, which was shown to be beneficial to both the child and health 
care facility6.  
 
Injectafer® has been characterized as a robust and strong type iron complex (Type 1) with a molecular mass of 
about 150,000 Daltons (Da). The solution is a dark brown color with a near neutral pH (5.0 to 7.0) and a 
physiological osmolarity permitting administration of higher single doses in short time periods. Although no 
interventional studies have been conducted with Injectafer® in the pediatric population to date, the product has 
been used in clinical practice in markets where it is currently approved for adults to aid correction of iron 
deficiency within the pediatric gastroenterological setting.  A non-interventional/retrospective observational 
data collection has identified in 79 patient’s aged 2 to 18 years with a mean age of 12.7 years.  In these subjects, 
Injectafer® showed efficacy with regard to hemoglobin, ferritin, and TSAT as well as safety and tolerability 
(manuscript in preparation).  
 
Therefore, the proposed studies will assess higher single doses (i.e., 7.5 mg/kg and 15 mg/kg) than those used 
with currently available parenteral iron preparations in iron deficient children with anemia to characterize the 
pharmacokinetics and pharmacodynamics in this younger population.  The higher single doses permit fewer 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 12 of 41 
 
overall injections/infusions and may ultimately permit fewer visits to the treating facilities positively impacting 
both the child and family as well as health care system. 
 
1.2 
Injectafer   
 
1.2.1 Key features of Injectafer 
 
Injectafer (Ferric Carboxymaltose Injection) is a stable Type I polynuclear iron (III)-hydroxide carbohydrate 
complex developed as an intravenous iron replacement therapy for the treatment of IDA. After intravenous 
administration, Injectafer is mainly found in the liver (RES), 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.   
 
1.2.2 Injectafer versus Other Parenteral Iron Agents 
 
There is considerable efficacy and safety experience with the various parenteral iron preparations available (3).  
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 intravenous 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% (6).  Over the last 20 years, 30 deaths have been attributed to the use of IV iron dextran. The high incidence 
of anaphylaxis/anaphylactoid reactions is believed to be caused by the formation of antibodies to the dextran 
moiety.   Although some have suggested that high molecular weight (HMW) iron dextran is 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 (7).  
Iron dextran is limited to second line therapy for treatment of iron deficiency.   
 
More recently approved, non-dextran intravenous 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 IV iron compounds carry a significant risk of bioactive iron reactions 
at higher doses.  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, producing 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 sucrose11 (data on file ).  These characteristics of Injectafer make it possible to administer much higher 
single doses over shorter periods of time than iron gluconate or iron sucrose, resulting in the need for fewer 
administrations to replenish iron stores, consequently making it better suited for outpatient use (Table 1.2.2.1).  
Another recently approved IV iron is ferumoxytol (AMAG) in which 510 mg can be injected rapidly on 2 
occasions separated by several days.  This formulation, which is currently indicated for IDA associated with 
CKD, is a modified-dextran derivative and is indicated for a 1020 mg repletion dose (see Ferumoxytol PI).  
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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Table 1.2.2.1     Administration of at least 1500 mg of Intravenous Iron with Currently Available Iron 
Preparations and Injectafer 
Iron 
Preparation 
Test Dose 
Required 
Maximum 
Infusion Dose 
 
Infusion Time 
Number of 
Infusions 
Iron dextran 
Yes 
100 mg* 
2 minutes 
15 + test dose 
Iron gluconate 
No 
125 mg 
10 minutes 
12 
Iron sucrose 
No 
200 mg 
5 minutes 
8 
Iron sucrose 
No 
300mg 
1.5 hours 
5 
Iron sucrose 
No 
400 mg 
2.5 hours 
4 
ferumoxytol 
No 
510 mg 
< 1 minute 
3 
Injectafer 
No 
750 to 1000 mg** 
8 to 15 minutes 
2 
* Higher doses are administered off label and are approved outside the US 
**1000 mg maximum dose is approved in countries outside of the US; 750 mg maximum is the U.S. FDA approved dose  
 
The larger Injectafer and ferumoxytol doses result in less frequent administration of intravenous iron that should 
benefit, in particular, severely iron deficient and anemic populations. To be treated with currently available 
intravenous iron agents, the average inflammatory bowel disease, postpartum,  heavy uterine bleeding and non-
dialysis dependent patient would require an initial test dose, followed by 15 doses of iron dextran as labeled, 
each accompanied by personnel equipped and trained for resuscitation of anaphylaxis; 12 doses of ferric 
gluconate; or either 8 doses of iron sucrose (with 5 minute infusion time) or 5 / 4 doses of iron sucrose by 
prolonged (1.5 to 2.5 hours) intravenous infusion. Ferric gluconate and iron sucrose are not approved by the 
FDA for the treatment of IDA in non chronic kidney disease populations and iron dextran is only approved as 
second line therapy for treatment of iron deficiency.  In contrast, most patients treated with Injectafer would 
require 2 doses administered over 8 to15 minutes one week apart.   
 
1.2.3 Injectafer Human Experience 
 
The Injectafer development program demonstrated the safety and effectiveness of intravenous Injectafer in the 
treatment of IDA.  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.  
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, compared with 2 to 13% for iron sucrose.  The projected terminal 
half-life (t½) was calculated to approximately 16 hours, compared to 3 to 4 days for iron dextran and 6 hours for 
iron sucrose. An ascending dose pharmacokinetic study (VIT-IV-CL-002), demonstrated that following the 500 
and 1,000 mg Injectafer dose, the majority of the Injectafer iron complex was utilized or excreted by 72 hours. 
 
Phase III studies demonstrated the effectiveness of Injectafer in treating IDA secondary to inflammatory bowel 
disease, heavy uterine bleeding, chronic kidney disease (hemodialysis and non-hemodialysis) and the 
postpartum state.  Clinically meaningful increases in hemoglobin, ferritin, and TSAT were observed in each of 
the studies. Non-inferiority to full therapeutic doses of oral ferrous sulfate was demonstrated in studies of IDA 
associated with inflammatory bowel disease. Superiority to full therapeutic doses of oral ferrous sulfate was 
demonstrated in studies of IDA secondary to heavy uterine bleeding, the postpartum state and non-hemodialysis 
dependent chronic kidney disease.  A head to head comparison of Injectafer (Ferric carboxymaltose) to Venofer 
(Iron sucrose)  in over 2,500 subjects with non-dialysis dependent CKD and elevated risk of cardiovascular 
disease according to the Framingham criteria demonstrated that the recommended dose of Injectafer, 750 mg x 
2 (1500 mg total) had superior efficacy to the labeled dose of Iron sucrose (200 mg x 5 [1000 mg total]) with 
regard to hemoglobin elevation and had a similar cardiovascular (and overall) safety profile, based in part on an 
independently adjudicated composite cardiovascular safety endpoint (8) . 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 14 of 41 
 
 
Important details of pre- and clinical safety and efficacy can be found in the Investigator’s Brochure. Ferric 
carboxymaltose received approval from the UK Medicines and Healthcare products Regulatory Agency 
(MHRA) approval on June 15, 2007 for the use of Injectafer (EU Trade name: Ferinject) in 18 EU (European 
Union) 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 approved from the Food and Drug Administration (FDA) on July 25, 2013 for marketing 
in the United States. 
 
2.0 
MAIN TRIAL OBJECTIVE 
 
The primary objectives of this study are to characterize the pharmacokinetics and determine appropriate dosing 
and safety of Injectafer® for the pediatric population suffering from iron deficiency (ID) with anemia.  
 
 
3.0  
OVERALL STUDY DESIGN AND RATIONALE 
 
3.1 
 Trial Design 
 
This is a phase III, open-label, non-randomized,  multi-center, single arm study to characterize the 
pharmacokinetic and pharmacodynamics  (PK/PD) profile of Injectafer® dosing in pediatric subjects with IDA 
after receiving either a 7.5 mg/kg or 15 mg/kg dose of Injectafer®.  
 
Cohort 1: 16 subjects will be treated with Injectafer® at 7.5 mg/kg with a maximum single dose 
of 750 mg, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have completed 4 weeks of 
therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Injectafer® at 15 mg/kg with a maximum single dose 
of 750 mg, whichever is smaller.   
 
3.2 
Rationale 
 
3.2.1 Rationale for Trial Design 
 
Injectafer is a non-dextran IV iron recently approved by the United States Food and Drug Administration 
(FDA).  This trial is designed to assess the single doses (i.e., 7.5 mg iron/kg and 15 mg iron/kg) in iron deficient 
children with anemia to characterize the pharmacokinetics and pharmacodynamics in this younger population.  
 
 
 


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3.2.2 Rationale for open label design 
 
The open-label, single arm trial design is considered appropriate because a control group is not required to 
estimate the PK/PD profile of Injectafer®.  The risk from exposure to another form of IV iron is not offset by 
the minimal scientific benefit. 
 
 
 


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Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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3.2.3. Schedule of Events 
Visit Day 
Screening 
Period 
(Up to 14 
Days) 
Day 
-1 
Day 
0 
24 and 48 
hours 
post 
dosing 
72 hours 
post 
dosing 
Day 14 
(week 2) 
Day 28 
(week 4) 
Day 35 
(week 5) 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Assess entry 
criteria 
X 
 
X 
 
 
 
 
 
EDC 
X 
 
X 
 
 
 
 
X 
Medical History 
X 
 
X 
 
 
 
 
 
Physical Exam1 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
 
X 
 
X 
X 
X 
X 
Height / Weight 
 
 
X 
 
 
 
 
 
PK/PD Samples 
 
X2 
X3 
X4 
X4 
 
 
 
Hematology, 
Chemistry and 
Iron Indices 
X 
 
 
 
X 
X 
X 
X 
Serum 
pregnancy test 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
 
X 
 
X 
X 
X 
X 
ESA Stability 
X 
 
X 
 
X 
X 
X 
X 
Adverse Event 
Assessments5 
 
 
X 
X 
X 
X 
X 
X 
Injectafer® 
Dosing6 
 
 
X 
 
 
 
 
 
 
1 Includes clinical assessment of skin, cardiovascular, pulmonary, abdominal and central nervous system 
2 Blood samples drawn at 8am, 12pm and 8pm for subject iron profile 
3 Blood samples PK/PD should be taken prior to Injectafer® dosing and additional samples for PK/PD should be taken at 1, 2, 6 and 
12 hours post dosing.  
4 Blood samples should be taken approximately the same time of day as the Day 0 samples were drawn 
5 Adverse event assessments starting at the time of Injectafer® dosing 
6 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-dose only.  Vital signs on non-dosing days include sitting heart rate and 
blood pressure only. 
 
 
 
 
 
 


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Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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4.0  
SUBJECT SELECTION 
 
4.1 
Number and Type of Subjects 
 
Up to thirty two  (32) subjects who have given written informed consent / assent along with parent or guardian’s 
written informed consent with a diagnosis of iron deficiency anemia (IDA) who fulfill the inclusion criteria, do 
not meet any of the exclusion criteria will be registered to receive Injectafer®.    
 
4.2 
Screening Phase 
 
Once a subject enters the screening phase, they will be assigned, via the Electronic Data Capture (EDC) system, 
a unique screening number.  From the time of consent until the start of treatment of IV Injectafer®, the subject 
will not receive any form of iron outside of the study (intravenous or blood transfusion iron from 4 weeks prior 
to consent or oral iron including multivitamins with iron from time of consent).   
 
If the subject does not qualify for study entry the subject should be entered into the EDC system as a screen 
failure.  Subjects can be re-screened once, see section 6.2.   
 
4.2.1  Entry Criteria 
 
Inclusion Criteria: 
 
1. Male or female subjects 1 to 17 years of age with assent to participation and his/her parent or guardian is 
willing and able to sign the informed consent approved by the Independent Review Board / Ethics 
Committee.  
2. Screening TSAT < 20% 
3. Screening Hemoglobin < 11 g/dL 
4. For subjects who are receiving a erythropoietin stimulating agent (ESA): stable ESA therapy (+/- 20% of 
current dose) for > 8 weeks prior to the qualifying screening visit and no ESA dosing or product changes 
anticipated for the length of the trial. 
 
Exclusion Criteria:    
 
1. Known hypersensitivity reaction to any component of Injectafer®. 
2. Subject previously randomized and treated in this study or any other  clinical study of Injectafer® (FCM, 
VIT-45). 
3. Body mass index (BMI) ≤ 95th percentile for age (see APPENDIX 2) 
4. History of acquired iron overload, hemochromatosis or other iron accumulation disorders. 
5. Chronic kidney disease subjects on hemodialysis. 
6. Screening Ferritin level > 300 ng/mL. 
7. Subjects with significant severe diseases of the liver, hemopoietic system, cardiovascular system, 
psychiatric disorder or other conditions which on the opinion of the investigator may place a subject at 
added risk. 
8. Any active infection.  
9. Known positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody (HCV) with evidence of active 
hepatitis. 
10. Known positive HIV-1/HIV-2 antibodies (anti-HIV). 
11. Anemia due to reasons other than iron deficiency (i.e. hemoglobinopathy). Subjects treated with vitamin 
B12 or folic acid deficiency are permitted. 


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Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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12. Significant blood loss (> 100 ml) within the last 3 months or any current bleeding disorders or anticipated 
need for surgery that may result in significant blood loss (> 100 ml). 
13. Intravenous iron and /or blood transfusion in the 4 weeks prior to screening.  
14. Immunosuppressive therapy that may lead to anemia (i.e. cyclophosphamide, azathioprine, mycophenolate 
mofetil).  Note steroid therapy is permitted. 
15. Administration and / or use of an investigational product (drug or device) within 30 days of screening. 
16. Alcohol or drug abuse within the past six months. 
17. Female subject who are pregnant or lactating, or sexually active female who are of childbearing potential 
not willing to use an acceptable form of contraceptive precautions during the study. 
18. Subject is unable to comply with study assessments. 
 
4.3 
Subject Assignment and Registration Process 
Subjects that meet all inclusion requirements and no exclusionary criteria will be offered participation in this 7 
week study. Cohorts 1 and 2 will be enrolled and treated sequentially.  Enrollment into Cohort 2 will not begin 
until  all Cohort 1  subjects have completed 4 weeks of therapy and no safety issues with the administration of 
Injectafer® has been confirmed by the DSMB. 
 
4.4 
Withdrawal from Study 
 
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.  
 
At the time of withdrawal, procedures for the Day 35 visit must be performed regardless of whether the subject 
has completed study drug treatment.  In the event the subject has received any study drug; the subject should be 
contacted to assess adverse events 28 days post the last dose of Injectafer®, if possible. 
 
In the event a subject withdraws without completing the full PK/PD sampling.  Additional subjects may be 
enrolled to ensure adequate representations of the PK/PD parameters are available for analyses.  Conditions for 
additional enrollment will be defined in more detail in the statistical analyses plan. 
 
4.5 
Intervention 
 
 Intervention is defined as follows: 
 Increase in dose of erythropoietin for any reason (Day 0 thru Day 35). 
 Blood transfusion.    
 Use of IV iron outside of protocol.  
 Use of oral iron outside the protocol.  
 
When intervention occurs, the date of the intervening event should be recorded in the source documents as well 
as the electronic Case Report Form (eCRF), and the subject should continue in the study as scheduled through 
Day 35. 
 
 
 


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Protocol: 1VIT13036 
 
 
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5.0 
STUDY DRUG 
 
5.1 
Formulation Packaging and Storage 
 
All medication to be used in this study that has been supplied by Vifor Pharma Ltd. will have been prepared 
according to Good Manufacturing Practices (GMP).  
 
Injectafer® (known in the EU as Ferinject®) will be supplied 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.   
 
Study drug 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 Injectafer® vials used and unused should be kept by the study staff and returned to Vifor Pharma 
Ltd., after drug accountability has been completed by the monitor. 
 
5.2 
Drug Administration / Regimen 
 
The Principal Investigator or designee will supervise administration of the study drug to subjects: 
 
Cohort 1: 16 subjects will be treated with Injectafer® at 7.5 mg/kg with a maximum single dose of 750 
mg, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have completed 4 weeks of 
therapy and a DSMB approves continuation. 
 
Cohort 2: 16 subjects will be treated with Injectafer® at 15 mg/kg with a maximum single dose of 750 
mg, whichever is smaller.   
 
Injectafer® will be given on Day 0.  It will be administered as either: 
 
 An undiluted slow IV push at a rate of 100 mg/minute. 
 Doses less than 100 mg should be given as a slow undiluted IV push within a minute. 
 
5.3 
IV Iron Precautions 
 
When administering IV Iron, the following precautions will be taken: 
 
 The subject will be clinically evaluated prior to drug administration to assess the development of 
clinically significant conditions.   
 The vials will be visually inspected for particulate matter and discoloration before each use; if noted, 
the vial will not be used and the Investigator or his/her designee will notify the sponsor, or sponsor’s 
designee, for replacement of the study drug and for directions to return the unused vial.     
 Sitting heart rate and blood pressure will be assessed pre-, immediately post, and 30 minutes post 
administration.  If the subject is an outpatient, they will be discharged from the site by the 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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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  
 
5.4 
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 registered 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. (or their designee).  All data regarding Injectafer® must be 
recorded on the Drug Accountability Forms provided by the sponsor.  
 
Investigators will keep adequate records of the administration and disposition of IV Injectafer® used for 
patients selected for the trial.  
 
5.5 
Concomitant Medication 
 
Concomitant medications along with their route of administration and duration must be recorded in the 
electronic case report form (eCRF) from 30 days prior to consent.  No additional iron preparations (IV iron 
from 4 weeks  prior to consent or oral iron including multivitamins with iron, from time of consent), will 
be allowed.  No prophylactic medications may be administered prior to Injectafer® administration 
without prior approval from Luitpold Pharmaceuticals, Inc.  
 
If receiving an Erythropoiesis Stimulating Agent (ESA), a stable (± 20%) dose is required for > 8 weeks prior to 
consent.  The ESA type, route, frequency and dose will remain unchanged throughout the study unless the dose 
should be decreased or held per the package label.  Once decreased or held, it may not be increased or restarted 
unless thought necessary by the subject’s physician. If the latter event occurs, these data points will be collected 
and the subject will continue for safety analysis. 
 
 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 (who for this trial is 1 -17 years old) must assent, if appropriate and his/her legal 
guardian (who is above age of legal consent) voluntarily sign an informed consent statement (Required 
Elements of Informed Consent, 21 CFR 50.25).  The Code of Federal Regulations (CFR) is a codification of 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 21 of 41 
 
rules and regulations of the United States government.  The subject’s legal guardian will be given a copy of the 
signed consent form. 
 
6.2 
Screening (up to 14 days)  
 
Each subject who qualifies for inclusion will undergo the following clinical evaluations to confirm their 
eligibility for the study: 
 
 Obtain screening number from EDC 
 Medical history, including prior iron therapy use  
 Vitals signs (including sitting heart rate and blood pressure)  
 Hematology, Chemistries and iron indices  
 Serum pregnancy test for female subjects of child bearing potential (negative results must be obtained 
prior to registering the subject for study drug dosing). 
 Concomitant medications assessment 
 ESA therapy stability ( if applicable)  
 
Subjects who do not meet the entry criteria should be entered into the 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 in section 6.2 will need to be repeated. 
 
6.3 
Study Visits  
 
6.3.1. Day (-1)  
 
Once it’s confirmed during the screening period that the subject continues meet the entry criteria all eligible 
subjects will return to the clinic on Day – 1, blood samples will be drawn at 8am, 12pm and 8pm to characterize 
the subject iron profile.   
 
6.3.2 Day 0 
 
On Day 0, prior Injectafer® dosing the following will occur:  
 
 Re-verify the inclusion and exclusion criteria 
 Update any relevant history 
 Basic physical exam including clinical assessment of skin, cardiovascular, pulmonary, abdominal and 
central nervous system.  
 Height  
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 Log on to the EDC system and register subject for study drug dosing. The EDC system will assign the 
subject into Cohort 1 or 2 treatment group. 
 
After assignment of the treatment group (Cohort 1 and 2) the following will occur: 
 
 Blood samples for PK/PD before start of dose. 
 Weight in kg without shoes 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 22 of 41 
 
 Verify amount of single Injectafer® dose (7.5 or 15 mg/kg up to a maximum dose of 750 mg 
whichever is smaller).  
 Document start and stop time of Injectafer® administration, the total dose administered and if 
diluted. 
 Obtain sitting heart rate and blood pressure immediately pre-dose, immediately post-dose, and 30 
minutes post Injectafer® administration.  Body temperature taken pre-dose  
 Adverse event assessment (starting at beginning of Injectafer® injection). 
 
Blood samples for PK/PD will be drawn at 1, 2, 6 and 12 hours post the Day 0 Injectafer® dose. 
 
6.3.2. Days 1 and 2 (24 and 48 hour) 
 
 Blood samples for PK/PD 
 Adverse events assessment 
 
6.3.3.  72 hour, and Days 14 and 28 (weeks 2 and 4) 
 
 Blood samples for PK/PD (72 hour visit only) 
 Vital signs 
 Hematology, chemistries and iron indices 
 Adverse events assessment 
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 
6.3.4. Day 35 (week 5) End of Study 
 
 Basic physical exam including clinical assessment of skin, cardiovascular, pulmonary, abdominal 
and central nervous system.  
 Vitals signs  
 hematology, chemistries and iron indices  
 Concomitant medications assessment 
 ESA stability/use ( if applicable)  
 Adverse events assessment 
 Log onto EDC and enter subject as complete 
 
The subject has completed the study after the Day 35 visit is complete.  If for any reason the subject does not 
complete the study the Day 35 procedures should be completed prior to the subject exiting from the trial.   
 
6.3.5. Pharmacokinetics and Pharmacodynamics (PK/PD) 
 
Blood samples will be collected for PK/PD assessment pre-dose and at 1, 2, 6, 12, 24, 48 and 72 hours post 
dose.  Blood samples should be taken at approximately the same time of day as the initial pre-dose sample on 
Day 0.   
 
Prior to Day 0, subjects will return to the clinic on Day -1 at which time blood samples will be drawn at 8am, 
12pm and 8pm to characterize the subjects specific iron profile. 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 23 of 41 
 
Total blood volume (regular hematology, chemistry, iron indices and PK/PD) collected per day and during the 
35 Day study is provided below: 
 
 
Screening 
Day (-1) 
Day 0 
24hr 
48hr 
72hr 
Day14 
Day 28 
Day 35 
Total 
Blood 
Volume 
Hem/Chem/II 
(10ml) 
10ml 
 
 
 
 
10ml 
10ml 
10ml 
10ml 
PK/PD (2ml) 
 
6ml 
10ml 
2ml 
2ml 
2ml 
 
 
 
 
TOTAL 
10ml 
6ml 
10ml 
2ml 
2ml 
12ml 
10ml 
10ml 
10ml 
72ml / 
approx. 
14.6 
tsps.* 
*4.93 mL = 1 tsp. 
 
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 testing will be provided to the physician for review and assessment. If 
the Investigator wishes to obtain a follow-up of an abnormal Day 35 laboratory, this laboratory may be obtained 
after notification of the Sponsor.  The laboratory assessments will be determined as listed in Section 3.2.3.  
 
Hematology: 
Hb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, differential count, 
and reticulocyte count  
Chemistry:  
sodium, potassium, chloride, BUN, creatinine, albumin, alkaline phosphatase, 
total bilirubin, GGT, AST, ALT, LDH, calcium, phosphorus, glucose, 
bicarbonate and magnesium 
      Iron indices: 
serum iron, serum ferritin, and total iron binding capacity (TIBC), and 
percentage serum transferrin saturation (TSAT) 
            Other:                            Serum pregnancy test  
 
 
7.0  
ASSESSMENT OF SAFETY 
 
7.1 
Adverse Events 
 
Any untoward medical event experienced by a subject during the course of this clinical trial, whether or not it is 
related to the investigational product, at any dose, must be recorded on the Adverse Event page of the eCRF.  
 
For any laboratory abnormality, the investigator will make a judgment as to its clinical significance.  If the 
laboratory value is outside the normal 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 eCRF. 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, non-serious anemia (Hb or Hct below the normal range or worsened from 
baseline) or iron deficiency (iron indices below the normal range or worsened from baseline) will not be 
considered adverse events.  Anemia or iron deficiency will be considered end points if an intervention is 
required.   
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 24 of 41 
 
To quantify the severity of adverse events, the National Cancer Institute (NCI)-Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4 should be used to grade all events.  These criteria are provided in the 
procedure manual.   
 
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 
Grade 
Adjective 
Description 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (i.e., 
preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.)  
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self care activities of daily living (i.e., bathing, 
dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.)  
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Death 
Results in Death due to the AE 
 
Timing: Non-serious adverse events will be reported from the initial treatment with Injectafer® through the 
completion of the study Day 35. AE’s will be captured 28 days post the last dose of Injectafer® for subjects 
who early terminate from the trial.  This can be completed via a phone call.  All ongoing adverse events related 
to Injectafer® 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 Injectafer® as follows: 
 
 NONE 
There is no evidence of any causal relationship. 
 
 UNLIKELY There is little evidence to suggest there is a causal relationship.  There is another 
reasonable explanation for the event (e.g., the subject’s clinical condition, other 
concomitant treatments). 
 
 POSSIBLE 
There is some evidence to suggest a causal relationship (i.e. there is a reasonable 
possibility that the adverse experience may have been caused by the agent).  However, 
the influence of other factors may have contributed to the event (e.g., the subject’s 
clinical condition, other concomitant events). 
 
 PROBABLE There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. 
 
 
*For the purposes of this trial, “study drug” is defined as: Injectafer® (known in the EU as Ferinject®) 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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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 their 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 
 
Definition: An adverse event is classified as SERIOUS if it meets any one of the following criteria:  
 Death 
 Life-Threatening: The subject was at substantial risk of dying at the time of the adverse event or it is 
suspected that the use / continued use of the product would result in the subject's death. 
 Hospitalization (initial or prolonged): Required admission to the hospital or prolongation of a hospital 
stay. 
 Disability: Resulted in a significant, persistent, or permanent change, impairment, damage or disruption 
in the subject's body function/structure, physical activities or quality of life. 
 Congenital Anomaly/Birth Defect   
 Important medical events: Other medically important events that, in the opinion of the investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes listed 
above. 
 
A distinction should be drawn between SAE and severe AE.  A severe AE is a major experience of its type.  A 
severe AE is not necessarily serious: e.g. nausea, which persists for several hours, may be considered severe 
nausea, but it is not an SAE.  On the other hand 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 initial treatment with Injectafer® through the completion of the 
study Day 35.  SAEs will be captured 28 days post the last dose of Injectafer® for subjects who early terminate 
from the trial.  This can be completed via a phone call. 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 learning 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 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 26 of 41 
 
 
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. 
 
8.0 
STATISTICS 
 
No hypothesis testing will be performed for this study. 
 
8.1 
 Sample Size Rationale 
 
Sixteen subjects per cohort will provide adequate data to estimate the primary PK parameters. 
 
8.2 
Analysis Populations  
 
There will be 2 analysis populations: 
 
 
Safety population: Includes all subjects who receive Injectafer®. 
 
 
PK/PD population: Includes all subjects in the safety population who have evaluable iron profiles and no 
protocol violation that could affect the PK/PD of Injectafer®. 
 
8.3 
Demographic Characteristics 
 
Demographic characteristics will be summarized for the Safety and PK/PD populations.  The number and 
percentage of subject’s who are registered, treated, prematurely discontinue, and complete 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. 
Categorical baseline characteristics (e.g., sex and race) will be summarized with the number and 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. 
 
 
 


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Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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8.4 
Endpoints and Definitions 
 
8.4.1 Clinical Endpoints 
 
Clinical endpoints include: 
 
 Efficacy: change from baseline to each scheduled visit for hemoglobin, ferritin, and TSAT. 
 Safety: 
 
 Proportion of subjects reporting treatment-emergent adverse events, overall and related, by SOC 
and preferred term 
 Subjects reporting treatment-emergent serious adverse events, overall and related, will be 
identified 
 Mean change from baseline to each scheduled visit for clinical laboratory values 
 Incidence of treatment-emergent potentially clinically significant (PCS) clinical laboratory 
values 
 Incidence of treatment-emergent PCS vital sign values. 
 
8.5 
 Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints  
 
The primary and secondary pharmacokinetic parameters will be determined for each subject as appropriate, 
based on serum concentration. The baseline parameters will be subtracted from all measured samples.  
 
The primary parameters are the maximum serum concentration (Cmax), the area under the serum concentration-
time curve from time zero to the last sampling time (t) with a quantifiable concentration (AUC0-time last measured 
concentration), the extrapolated area under the serum concentration- time curve from time zero to  infinity (AUC0-
infinity), and the half-life (T1/2).  Cmax is calculated as a non-compartmental variable, which is a more 
conservative method than if it were calculated using a compartmental paradigm.  T1/2 incorporates the 
calculation of the rate elimination constant (Kel
 
). 
The secondary parameters are the mean residence time (MRT), the apparent serum clearance (Cl), and the 
apparent volume of distribution (Vd), which includes the initial volume of distribution following the injection 
(Vdc), the volume of distribution at the steady state (Vdss), and the volume of distribution at the final 
elimination (Vdarea). 
 
Pharmacodynamic parameter will include serum ferritin, transferrin, transferrin saturation (TfS) UIBC, HGB, 
reticulocyte count and transferrin receptors. 
 
The Pharmacokinetic and Pharmacodynamic parameters performed in this study for analysis will be outlined in 
a Statistical and Analytical Plan. 
 
8.6 
Statistical Analyses of Safety 
 
The Medical Dictionary for Regulatory Activities (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. 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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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 system organ class (SOC), the 
subject will be counted only once for that SOC.   
 
Change in 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 vital signs will be summarized for each treatment group. 
 
8.7 
DSMB Analyses 
 
A DSMB will review safety information for subjects in Cohort 1 before dosing begins for Cohort 2.  A Charter 
will be developed outlining the DSMB processes.  
 
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. 
 
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 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. 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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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 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. 
 
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. 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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 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. Notification of these audits will be 
sent to all investigators in advance. 
 
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 2000 Edinburgh, Scotland 
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 
 
The protocol and the Informed Consent / Assent 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 / Assent 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. 


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Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
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 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 / Assent when appropriate must be obtained from each subject prior to study participation. 
The informed consent / assent will be provided to the subject in their native language. The consent/assent form 
must be signed by the subject and/or the subject's legally authorized representative.  Each investigational site 
must provide the Sponsor (or designee) with a copy of the Informed Consent / Assent approved by that site's 
Institutional Review Board. The original signed consent / assent 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 / Assent 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 / assent must be 
certified by a qualified translator and their use must be documented. 
 
The Informed Consent / Assent 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 / Assent must be signed and dated by each subject and/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 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]. 
 
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. (or designee). 
Source data will be reviewed by the Clinical Monitor to insure accuracy, completeness and compliance 
with the protocol.  
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 32 of 41 
 
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, DSMB, 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 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. 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 33 of 41 
 
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 
 
The DSMB will be composed of approximately 3-5 senior academic individuals, including the DSMB Chair. 
They will have high-level expertise in pediatric iron deficiency anemia 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 Injectafer®, 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 evaluate the safety from both cohorts 1 and 2 (7.5 or 15 mg/kg of Injectafer®).  Only after all subjects in 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 34 of 41 
 
cohort 1 have completed through week 4 and the DSMB has evaluated the safety data as acceptable will 
registration into cohort 2 be granted.  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. 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 35 of 41 
 
 
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) 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 36 of 41 
 
REFERENCES  
 
1.  Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn's disease. Aliment.Pharmacol.Ther. 
2006; 24: 1507-1523 
 2.  Foley RN, Parfrey PS, Harnett JD et al. Impact of hypertension on cardiomyopathy, morbidity and 
mortality in end-stage renal disease. Kidney Int. 1996; 49: 1379-1385 
 3.  Staples AO, Greenbaum LA, Smith JM et al. Association between clinical risk factors and progression of 
chronic kidney disease in children. Clin.J.Am.Soc.Nephrol. 2010; 5: 2172-2179 
 4.  Wharton BA. Iron deficiency in children: detection and prevention. Br.J.Haematol. 1999; 106: 270-280 
 5.  Kazal LA, Jr. Prevention of iron deficiency in infants and toddlers. Am.Fam.Physician 2002; 66: 1217-
1224 
 6.  Michaud L, Guimber D, Mention K et al. Tolerance and efficacy of intravenous iron saccharate for iron 
deficiency anemia in children and adolescents receiving long-term parenteral nutrition. Clin.Nutr. 2002; 
21: 403-407 
 7.  Pinsk V, Levy J, Moser A, Yerushalmi B, Kapelushnik J. Efficacy and safety of intravenous iron sucrose 
therapy in a group of children with iron deficiency anemia. Isr.Med.Assoc.J. 2008; 10: 335-338 
 8.  Surico G, Muggeo P, Muggeo V et al. Parenteral iron supplementation for the treatment of iron deficiency 
anemia in children. Ann.Hematol. 2002; 81: 154-157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 37 of 41 
 
APPENDIX 1:  INJECTAFER® PACKAGE INSERT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LPI PI for submission v14 (7-18-2013) trkchng 
 
1
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
Injectafer safely and effectively.  See full prescribing information for 
Injectafer.   
 
INJECTAFER® (ferric carboxymaltose injection)   
For intravenous use 
Initial U.S. Approval: 20XX 
 
----------------------------INDICATIONS AND USAGE--------------------------- 
Injectafer is an iron replacement product indicated for the treatment of iron 
deficiency anemia in adult patients: 
 
who have intolerance to oral iron or have had unsatisfactory 
response to oral iron; 
 
who have non-dialysis dependent chronic kidney disease. 
 
----------------------DOSAGE AND ADMINISTRATION----------------------- 
For patients weighing 50kg (110lb) or more:  Give Injectafer in two doses 
separated by at least 7 days.  Give each dose as 750mg for a total cumulative 
dose of 1500mg of iron per course. 
 
For patients weighing less than 50kg (110lb):  Give Injectafer in two doses 
separated by at least 7 days and give each dose as 15 mg/kg body weight.   
 
Injectafer treatment may be repeated if iron deficiency anemia reoccurs. (2)   
 
 
---------------------DOSAGE FORMS AND STRENGTHS---------------------- 
750 mg iron / 15 mL single-use vial(3) 
 
-------------------------------CONTRAINDICATIONS------------------------------ 
Hypersensitivity to Injectafer or any of its inactive components. (4) 
 
-----------------------WARNINGS AND PRECAUTIONS------------------------ 
 
Hypersensitivity reactions:  Observe for signs and symptoms of 
hypersensitivity during and after Injectafer administration for at least 30 
minutes and until clinically stable following completion of each 
administration. (5.1) 
 
Hypertension:  Monitor patients closely for signs and symptoms of 
hypertension following each Injectafer administration. (5.2) 
 
------------------------------ADVERSE REACTIONS------------------------------- 
The most common adverse reactions (>2%) are nausea, hypertension, 
flushing, hypophosphatemia, and dizziness (6.1) 
 
To report SUSPECTED ADVERSE REACTIONS, contact American 
Regent 
at 
1-800-734-9236 
or 
FDA 
at 
1-800-FDA-1088 
or 
www.fda.gov/medwatch. 
-------------------USE IN SPECIFIC POPULATIONS-------------------
--- 
 
Nursing Mothers: Exercise caution when administered to a nursing 
woman. (8.3) 
 
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling. 
 
 
 
 
Revised:  July 2013 
_____________________________________________________________________________________________________________________________________ 
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 Hypersensitivity Reactions 
5.2 Hypertension 
5.3 Lab test alterations 
6 
ADVERSE REACTIONS 
6.1 Adverse Reactions in Clinical Trials 
6.2 Post-marketing Experience 
7 
DRUG INTERACTIONS 
8 
USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
8.3 Nursing Mothers 
8.4  Pediatric Use 
10  OVERDOSAGE 
11  DESCRIPTION 
12  CLINICAL PHARMACOLOGY 
12.1 
Pharmacodynamics 
12.2 
Pharmacokinetics  
13  
NONCLINICAL TOXICOLOGY 
 
 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 
14  CLINICAL STUDIES 
 14.1 Iron Deficiency Anemia Due to Any Etiology 
 14.2 Non Dialysis Dependent Chronic Kidney Disease  
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
 
 
  8.5 
Geriatric Use 
* Sections or subsections omitted from the full prescribing information are not 
listed.
___________________________________________________________________________________________________________________________________ 
 
Reference ID: 3347006


 
2
FULL PRESCRIBING INFORMATION 
 
1 
INDICATIONS AND USAGE 
Injectafer is indicated for the treatment of iron deficiency anemia in adult patients; 
 
 who have intolerance to oral iron or have had unsatisfactory response to oral iron; 
 who have non-dialysis dependent chronic kidney disease. 
 
2 
DOSAGE AND ADMINISTRATION 
For patients weighing 50 kg (110 lb) or more:  Give Injectafer in two doses separated by 
at least 7 days.  Give each dose as 750 mg for a total cumulative dose not to exceed1500 
mg of iron per course. 
 
For patients weighing less than 50 kg (110 lb):  Give Injectafer in two doses separated by 
at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not 
to exceed 1500 mg of iron per course.   
 
 
The dosage of Injectafer is expressed in mg of elemental iron. Each mL of Injectafer 
contains 50 mg of elemental iron.  Injectafer treatment may be repeated if iron deficiency 
anemia reoccurs.   
 
 
 
Administer Injectafer intravenously, either as an undiluted slow intravenous push or by 
infusion.  When administering as a slow intravenous push, give at the rate of 
approximately 100 mg (2 mL) per minute.  When administered via infusion, dilute up to 
750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, 
such that the concentration of the infusion is not less than 2 mg of iron per mL and 
administer over at least 15 minutes.   
 
When added to an infusion bag containing 0.9% Sodium Chloride Injection, USP, at 
concentrations ranging from 2 mg to 4 mg of iron per mL, Injectafer solution is 
physically and chemically stable for 72 hours when stored at room temperature.  To 
maintain stability, do not dilute to concentrations less than 2 mg iron/mL.  
 
Inspect parenteral drug products visually for the absence of particulate matter and 
discoloration prior to administration.  The product contains no preservatives. Each vial of 
Injectafer is intended for single use only. Any unused drug remaining after injection must 
be discarded. 
 
Avoid extravasation of Injectafer since brown discoloration of the extravasation site may 
be long lasting.  Monitor for extravasation.  If extravasation occurs, discontinue the 
Injectafer administration at that site. 
 
 
 
Reference ID: 3347006


 
3
3 
DOSAGE FORMS AND STRENGTHS 
 
750 mg iron / 15 mL single-use vial  
 
4 
CONTRAINDICATIONS 
Hypersensitivity to Injectafer or any of its components [see Warnings and Precautions 
(5.1)]. 
 
5 
WARNINGS AND PRECAUTIONS 
 
5.1  Hypersensitivity Reactions 
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of 
which have been life-threatening and fatal, have been reported in patients receiving 
Injectafer. Patients may present with shock, clinically significant hypotension, loss 
of consciousness, and/or collapse. Monitor patients for signs and symptoms of 
hypersensitivity during and after Injectafer administration for at least 30 minutes 
and until clinically stable following completion of the infusion. Only administer 
Injectafer when personnel and therapies are immediately available for the 
treatment of serious hypersensitivity reactions. [see Adverse Reactions (6.1 and 6.2)].  
In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% 
(2/1775) of subjects receiving Injectafer. Other serious or severe adverse reactions 
potentially associated with hypersensitivity which included, but not limited to, pruritus, 
rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these 
subjects.  
 
5.2 Hypertension 
In clinical studies, hypertension was reported in 3.8% (67/1,775) of subjects in clinical 
trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with 
facial flushing, dizziness, or nausea were observed in 6% (106/1,775) of subjects in these 
two clinical trials. These elevations generally occurred immediately after dosing and 
resolved within 30 minutes.   Monitor patients for signs and symptoms of hypertension 
following each Injectafer administration [see Dosage and Administration (2)]. 
 
 
5.3 Laboratory Test Alterations 
In the 24 hours following administration of Injectafer, laboratory assays may 
overestimate serum iron and transferrin bound iron by also measuring the iron in 
Injectafer.  
 
6 
ADVERSE REACTIONS   
 
The following adverse reactions are discussed in greater detail in other sections of the 
labeling: 
.  Hypersensitivity Reactions [see Warnings and Precautions (5.1)] 
.  Hypertension [see Warnings and Precautions (5.2)] 
.   Lab test alterations [see Warnings and Precautions (5.3)] 
 
Reference ID: 3347006


 
4
6.1  Adverse Reactions in Clinical Trials 
 
Because clinical trials are conducted under widely varying conditions, the adverse 
reaction rates observed cannot be directly compared to rates in other clinical trials and 
may not reflect the rates observed in clinical practice. 
In two randomized clinical studies [Studies 1 and 2, See Clinical Studies (14)], a total of 
1,775 patients were exposed to Injectafer 15 mg/kg body weight up to a maximum single 
dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative 
dose of 1500 mg of iron. 
 
Adverse reactions reported by ≥ 1% of treated patients are shown in the following table.    
 
Table 1.   Adverse reactions reported in ≥ 1% of Study Patients in Clinical Trials 1 and 
2 
 
 
 
Term 
Injectafer 
 
 
(N=1775) 
% 
Pooled 
Comparatorsa
 
(N=1783) 
% 
Oral 
iron 
 
(N=253) 
% 
Nausea 
7.2 
1.8 
1.2 
Hypertension 
3.8 
1.9 
0.4 
Flushing/Hot Flush 
3.6 
0.2 
0.0 
Blood Phosphorus Decrease 
2.1 
0.1 
0.0 
Dizziness 
2.0 
1.2 
0.0 
Vomiting 
1.7 
0.5 
0.4 
Injection Site Discoloration 
1.4 
0.3 
0.0 
Headache 
1.2 
0.9 
0.0 
Alanine Aminotransferase Increase 
1.1 
0.2 
0.0 
Dysgeusia 
1.1 
2.1 
0.0 
Hypotension 
1.0 
1.9 
0.0 
Constipation 
0.5 
0.9 
3.2 
a Includes oral iron and all formulations of IV iron other than Injectafer 
 
Other adverse reactions reported by ≥ 0.5% of treated patients include abdominal pain, 
diarrhea, gamma glutamyl transferase increased, injection site pain/irritation, rash, 
paraesthesia, sneezing. Transient decreases in laboratory blood phosphorus levels (< 2 
mg/dL) have been observed in 27% (440/1638) patients in clinical trials.  
 
 
 
6.2  Post-marketing Experience 
Because these reactions are reported voluntarily from a population of uncertain size, it is 
not always possible to reliably estimate their frequency or establish a causal relationship 
to drug exposure. The following serious adverse reactions have been most commonly 
reported from the post-marketing spontaneous reports with Injectafer:  urticaria, dyspnea, 
pruritis, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, 
arthralgia,  and syncope. One case of hypophosphatemic osteomalacia was reported in a 
Reference ID: 3347006


 
5
subject who received 500 mg of Injectafer every 2 weeks for a total of 16 weeks.  Partial 
recovery followed discontinuation of Injectafer. 
 
7 
DRUG INTERACTIONS 
Formal drug interaction studies have not been performed with Injectafer .  
 
8 
USE IN SPECIFIC POPULATIONS 
 
8.1  Pregnancy  
Pregnancy Category C  
 
Risk Summary 
 
Adequate and well controlled studies in pregnant women have not been conducted.    
However, animal reproduction studies have been conducted with ferric carboxymaltose. In these 
studies, administration of ferric carboxymaltose to rabbits during the period of 
organogenesis caused fetal malformations and increased implantation loss at maternally 
toxic doses of approximately 12% to 23% of the human weekly dose of 750 mg (based on 
body surface area).  The incidence of major malformations in human pregnancies has not 
been established for Injectafer. However, all pregnancies, regardless of exposure to any 
drug, has a background rate of 2 to 4% for major malformations, and 15 to 20% for 
pregnancy loss. Injectafer should be used during pregnancy only if the potential benefit 
justifies the potential risk to the fetus.   
 
Animal Data 
Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion up to 
30 mg/kg/day iron on gestation days 6 to 17 did not result in adverse embryofetal 
findings.  This daily dose in rats is approximately 40% of the human weekly dose of 750 
mg based on body surface area.  In rabbits, ferric carboxymaltose was administered as a 
one-hour infusion on gestation days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 
mg/kg/day.  Malformations were seen starting at the daily dose of 9 mg/kg (23% of the 
human weekly dose of 750 mg).  Spontaneous abortions occurred starting at the daily 
iron dose of 4.5 mg/kg (12% of the human weekly dose based on body surface area).  
Pre-implantation loss was at the highest dose.  Adverse embryofetal effects were 
observed in the presence of maternal toxicity. 
 
A pre- and post-natal development study was conducted in rats at intravenous doses up to 
18 mg/kg/day of iron (approximately 23% of the weekly human dose of 750 mg on a 
body surface area basis).  There were no adverse effects on survival of offspring, their 
behavior, sexual maturation or reproductive parameters.  
 
8.3  Nursing Mothers 
A study to determine iron concentrations in breast milk after administration of Injectafer 
(n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with 
postpartum iron deficiency anemia.  Mean breast milk iron levels were higher in lactating 
women receiving Injectafer than in lactating women receiving oral ferrous sulfate. 
Reference ID: 3347006


 
6
 
8.4  Pediatric Use 
Safety and effectiveness have not been established in pediatric patients.  
 
8.5  Geriatric Use 
Of the 1775 subjects in clinical studies of Injectafer, 50% were 65 years and over, while 
25% were 75 years and over. No overall differences in safety or effectiveness were 
observed between these subjects and younger subjects, and other reported clinical 
experience has not identified differences in responses between the elderly and younger 
patients, but greater sensitivity of some older individuals cannot be ruled out. 
 
10  OVERDOSAGE 
Excessive dosages of Injectafer may lead to accumulation of iron in storage sites 
potentially leading to hemosiderosis. A patient who received Injectafer 18,000 mg 
over 6 months developed hemosiderosis with multiple joint disorder, walking 
disability and asthenia . Hypophosphatemic osteomalacia was reported in a patient 
who received Injectafer 4000 mg over 4 months. Partial recovery followed 
discontinuation of Injectafer. [see Post-marketing Experience (6.3)].  
 
11 
DESCRIPTION 
Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex 
with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(14)-O--D-
glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. 
It 
has 
a 
relative 
molecular weight of approximately 150,000 Da corresponding to the following empirical 
formula: 
 
[FeOx(OH)y(H2O)z]n [(C6H10O5)m (C6H12O7)l]k,   
 
where n  103, m  8, l 11, and k  4  
(l represents the mean branching degree of the ligand).  
 
The chemical structure is presented below: 
 
Reference ID: 3347006


 
7
 
 
Injectafer (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic 
colloidal solution for intravenous injection. Each mL contains 50 mg iron as ferric 
carboxymaltose in water for injection.  Injectafer is available in 15 mL single-use vials.  
Sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH to 5.0-
7.0.  
 
Vial closure is not made with natural rubber latex
Reference ID: 3347006


 
8
 
12 
CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose, 
a carbohydrate polymer that releases iron. 
 
12.2  Pharmacodynamics 
 
Using positron emission tomography (PET) it was demonstrated that red cell uptake of 
59Fe and 52Fe from Injectafer ranged from 61% to 99%. In patients with iron deficiency, 
red cell uptake of radio-labeled iron ranged from 91% to 99% at 24 days after Injectafer 
dose. In patients with renal anemia red cell uptake of radio-labeled iron ranged from 61% 
to 84% after 24 days Injectafer dose. 
 
12.3 Pharmacokinetics 
After administration of a single dose of Injectafer of 100 to 1000 mg of iron in iron 
deficient patients, maximum iron levels of 37 µg/mL to 333 µg/mL were obtained 
respectively after 15 minutes to 1.21 hours post dose. The volume of distribution was 
estimated to be 3 L. 
 
The iron injected or infused was rapidly cleared from the plasma, the terminal half-life 
ranged from 7 to 12 hours. Renal elimination of iron was negligible. 
 
13 
NONCLINICAL TOXICOLOGY 
13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility  
Carcinogenicity studies have not been performed with ferric carboxymaltose. 
 
Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in 
vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human 
lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma 
L5178Y/TK+/- cells, in vivo mouse micronucleus test at single intravenous doses up to 
500 mg/kg.   
 
In a combined male and female fertility study, ferric carboxymaltose was administered 
intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg.  
Animals were dosed 3 times per week (on Days 0, 3, and 7).  There was no effect on 
mating function, fertility or early embryonic development. The dose of 30 mg/kg in 
animals is approximately 40% of the human dose of 750 mg based on body surface area.  
 
 
 
14 
CLINICAL STUDIES  
The safety and efficacy of Injectafer for treatment of iron deficiency anemia were 
evaluated in two randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In 
these two trials, Injectafer was administered at a dose of 15 mg/kg body weight up to a 
maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up 
to a cumulative dose of 1500 mg of iron.  
Reference ID: 3347006


 
9
 
14.1 Trial 1: Iron Deficiency Anemia in Patients Who Are Intolerant to Oral Iron or 
Have Had Unsatisfactory Response to Oral Iron  
 
Trial 1 was a randomized, open-label, controlled clinical study in patients with iron 
deficiency anemia who had an unsatisfactory response to oral iron (Cohort 1) or who 
were intolerant  to  oral iron (Cohort 2) during the 14 day oral iron run-in period. 
Inclusion criteria prior to randomization included hemoglobin (Hb) <12 g/dL, ferritin ≤ 
100 ng/mL or ferritin ≤ 300 ng/mL when transferrin saturation (TSAT) ≤ 30%. Cohort 1 
subjects were randomized to Injectafer or oral iron for 14 more days.  Cohort 2 subjects 
were randomized to Injectafer or another IV iron per standard of care [90% of subjects 
received iron sucrose]. The mean age of study patients was 43 years (range, 18 to 94); 
94% were female; 42% were Caucasian, 32% were African American, 24% were 
Hispanic, and 2% were other races. The primary etiologies of iron deficiency anemia 
were heavy uterine bleeding (47%) and gastrointestinal disorders (17%).  
 
Table 2 shows the baseline and the change in hemoglobin from baseline to highest value 
between baseline and Day 35 or time of intervention.   
 
Reference ID: 3347006


 
10
 
 
Table 2. Mean Change in Hemoglobin From Baseline to the Highest Value 
Between Day 35 or Time of Intervention (Modified Intent-to-Treat Population) 
 
Hemoglobin (g/dL) 
Mean (SD) 
Cohort 1
Cohort 2
Injectafer 
(N=244) 
Oral Iron 
(N=251) 
Injectafer 
(N=245) 
IV SCa 
(N=237) 
Baseline 
 
10.6 (1.0)
10.6 (1.0)
9.1 (1.6) 
 
9.0 (1.5)
 
Highest Value 
 
 
12.2 (1.1) 
 
11.4 (1.2) 
 
 
12.0 (1.2) 
 
11.2 (1.3) 
 
 
Change (from baseline to 
highest value) 
 
 
 
1.6 (1.2) 
 
 
0.8 (0.8) 
 
 
 
2.9 (1.6) 
 
2.2 (1.3) 
 
 
p-value 
0.001
0.001
SD=standard deviation; a: Intravenous iron per standard of care 
 
Increases from baseline in mean f erritin (264.2±224.2 ng/mL in Cohort 1 and 218.2 
±211.4 ng/mL in Cohort 2), and transferrin saturation (13±16% in Cohort 1 and 
20±15% in Cohort) were  observed  at  Day 35 in Injectafer-treated patients. 
 
14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis Dependent 
Chronic Kidney Disease 
 
Trial 2 was a randomized, open-label, controlled clinical study in patients with non-
dialysis dependent chronic kidney disease. Inclusion criteria included hemoglobin (Hb) ≤ 
11.5 g/dL, ferritin ≤ 100 ng/mL or ferritin ≤ 300 ng/mL when transferrin saturation 
(TSAT) ≤ 30%.Study patients were randomized to either Injectafer or Venofer. The mean 
age of study patients was 67 years (range, 19 to 96); 64% were female; 54% were 
Caucasian, 26% were African American, 18% Hispanics, and 2% were other races.  
 
Table 3 shows the baseline and the change in hemoglobin from baseline to highest value 
between baseline and Day 56 or time of intervention.   
 
 
Reference ID: 3347006


 
11
 
Table 3. Mean Change in Hemoglobin From Baseline to the Highest Value 
Between Baseline  and Day 56 or Time of Intervention (Modified Intent-to-Treat 
Population) 
Hemoglobin (g/dL)
Mean (SD) 
Injectafer 
(N=1249) 
Venofer 
(N=1244) 
 
Baseline 
 
10.3 (0.8) 
10.3 (0.8) 
 
Highest Value  
11.4 (1.2) 
11.3 (1.1) 
 
Change (from baseline to highest 
value) 
1.1 (1.0) 
 
0.9 (0.92) 
 
Treatment Difference (95% CI) 
0.21 (0.13, 0.28)
 
 
 
Increases from baseline in mean f erritin (734.7±337.8 ng/mL), and transferrin 
saturation (30±17%)  were  observed  at  Day 56 in Injectafer-treated patients. 
 
 
16 
HOW SUPPLIED/STORAGE AND HANDLING   
 
 
NDC 0517-0650-01  
750 mg iron/15 mL Single-Use Vial Individually boxed 
NDC 0517-0650-02  
750 mg iron/15 mL Single-Use Vial Packages of 2 
 
 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 
86°F). [See the USP controlled room temperature].  Do not freeze.  
 
 
 
17 
PATIENT COUNSELING INFORMATION 
 
Question patients regarding any prior history of reactions to parenteral iron products. 
 
Advise patients of the risks associated with Injectafer. 
 
Advise patients to report any signs and symptoms of hypersensitivity that may develop during and 
following Injectafer administration, such as rash, itching, dizziness, lightheadedness, swelling and 
breathing problems [see Warnings and Precautions (5)] 
 
Injectafer is manufactured under license from Vifor (International) Inc, Switzerland. 
Reference ID: 3347006


 
12
 
AMERICAN 
REGENT, INC. 
SHIRLEY, NY  11967 
 
IN0602 
Rev. 7/13 
 
Reference ID: 3347006


 
13
Patient Information 
INJECTAFER (ferric carboxymaltose injection) 
 
Please read this information carefully before taking this medication. This summary does 
not tell you everything about INJECTAFER. Speak with your doctor or healthcare 
professional if there is something you do not understand or if you would like to learn 
more about INJECTAFER. Your doctor or healthcare professional is your best source of 
information about this medicine. 
 
What is INJECTAFER? 
 
Iron is a mineral that the body needs to produce red blood cells. When the body does not 
get enough iron, it cannot produce the number of normal red blood cells needed to keep 
you in good health. This condition is called iron deficiency (iron shortage) or iron 
deficiency anemia.  
 
INJECTAFER is used to treat iron deficiency anemia. Iron deficiency anemia may be 
caused by several medical conditions including heavy menstrual bleeding, pregnancy, 
childbirth, inflammatory bowel disease, other malabsorption diseases, bariatric surgery, 
or chronic kidney disease.  
 
General information about using INJECTAFER safely and effectively 
 
Injectable iron is administered only by or under the supervision of your health care 
professional. 
 
Serious or life threatening allergic reactions have been reported with intravenous iron 
products. Tell your health care professional if you have ever had any unusual or allergic 
reaction to any IV iron. 
 
Patients should report to their healthcare professional any signs and symptoms of an 
allergic reaction to INJECTAFER, in particular rashes, shortness of breath and wheezing.  
 
Iron is not easily eliminated from the body, and its build up may be lead to a condition 
called iron overload which may be harmful.  Certain medical conditions such as liver 
disease may also make you more likely to develop iron overload. Ask your doctor or 
healthcare professional. 
 
Who should not take INJECTAFER? 
 
You should not be given INJECTAFER if you have anemia that is not caused by iron 
deficiency, or if you have iron overload. 
 
If you are pregnant or plan to become pregnant please notify your doctor or healthcare 
professional. They will decide whether it is safe for you to receive INJECTAFER.  
 
How should I take INJECTAFER? 
Reference ID: 3347006


 
14
 
INJECTAFER is administered intravenously (into your vein) by your doctor or health 
care professional in two doses.  
 
What should I avoid while taking INJECTAFER? 
 
You should not take iron supplements by mouth if you are receiving iron injections. Tell 
your doctor about all the medicines you take, including prescription and non-prescription 
medicines, vitamins and herbal supplements. 
 
What are the possible side effects of INJECTAFER? 
 
The side effects of INJECTAFER are infrequent, usually mild and generally do not cause 
patients to stop treatment. The most common side effects are nausea, injection site 
reactions (including pain or bruising at the injection site), asymptomatic reductions in 
blood phosphorus, flushing, headache, hypertension, dizziness, and increased alanine 
aminotransferase. Potentially long lasting brown staining of skin near injection site may 
occur.   
 
These are not all the possible side effects of INJECTAFER. For more information ask 
your doctor or healthcare professional.     
 
Talk to your doctor if you think you have side effects from taking INJECTAFER. 
 
 
Reference ID: 3347006


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 38 of 41 
 
APPENDIX 2:  WEIGHT CHARTS FOR BOYS AND GIRLS 
 
Boys (White) Weight Chart age 0-36 months (http://www.halls.md/chart/boys-weight-w.htm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 39 of 41 
 
BOYS (WHITE) WEIGHT CHART AGE 2-20 YRS 
(HTTP://WWW.CDC.GOV/GROWTHCHARTS/DATA/SET1CLINICAL/CJ41L021.PDF) 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 40 of 41 
 
Girls (White) Weight Chart age 0-36 months (http://www.halls.md/on/girls-weight-w.htm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Protocol: 1VIT13036 
 
 
Date: 27 March 2014 
Page 41 of 41 
 
GIRLS (WHITE) WEIGHT CHART AGES 2-20 YRS 
(HTTP://WWW.CDC.GOV/GROWTHCHARTS/DATA/SET1CLINICAL/CJ41L022.PDF)  
 
 
 
 
 
 

SAP_001.pdf: 
Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 1 of 12 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol 1VIT13036 
 
 
A Multi-center, Open-Label, Single Arm Study to Characterize the 
Pharmacokinetics and Pharmacodynamics Profile of Intravenous Ferric 
Carboxymaltose in Pediatric Subjects 1-17 years old with Iron Deficiency 
Anemia (IDA) 
 
Prepared for: 
Luitpold Pharmaceuticals, Inc. 
Clinical Research and Development 
800 Adams Avenue, Suite 100 
Norristown, PA  19403 
(610) 650-4200 
 
Prepared by: 
MedTrials, Inc. 
1400 N. Providence Road 
Building 1, Suite 212 
Media, PA 19063 
 
 


Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 2 of 12 
 
Document Version History: 
Version 
Date 
Author 
Comments 
1.0 
6/8/15 
Michelle Secic 
Original 
2.0 
7/14/15 
Michelle Secic 
Revisions based on initial review from 
Luitpold 
2.1 
2/4/17 
Michelle Secic 
Excluded summary of potentially clinically 
significant (PCS) Vital Signs 
 


Luitpold Pharmaceuticals, Inc. 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 Protocol No. 1VIT13036 
Page 3 of 12 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..............................................................................................4 
1.
INTRODUCTION ........................................................................................................5 
2.
STUDY OBJECTIVES ................................................................................................5 
3.
STUDY DESIGN .........................................................................................................5 
3.1. 
Inclusion/Exclusion Criteria .............................................................................5 
3.2. 
Schedule of Visits .............................................................................................7 
4.
PLANNED ANALYSES ..............................................................................................8 
4.1. 
Interim Analyses ...............................................................................................8 
4.2. 
Final Analysis ...................................................................................................8 
4.3. 
Populations .......................................................................................................8 
5.
SAMPLE SIZE CONSIDERATIONS .........................................................................8 
6.
REPORTING CONVENTIONS ..................................................................................9 
7.
STATISTICAL ANALYSES AND SUMMARIES.....................................................9 
7.1. 
General Statistical Considerations ....................................................................9 
7.2. 
Baseline Definitions..........................................................................................9 
7.3. 
Subject Disposition .........................................................................................10 
7.4. 
Demographic Characteristics ..........................................................................10 
7.5. 
Medical/Surgical History ................................................................................10 
7.6. 
Efficacy ...........................................................................................................10 
7.7. 
Adverse Events ...............................................................................................10 
7.8. 
Laboratory Values ..........................................................................................10 
7.9. 
Vital Signs ......................................................................................................11 
APPENDIX A – TABLE SHELLS ...................................................................................11 
APPENDIX B – LISTING SHELLS .................................................................................11 


Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 4 of 12 
 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
DSMB 
Data and Safety Monitoring Board 
EDC 
Electronic Data Capture 
ESA 
Erythropoiesis stimulating agent 
FCM 
Ferric Carboxymaltose 
HBsAg 
Hepatitis B antigen 
HCV 
Hepatitis C viral antibody 
HIV 
Human Immunodeficiency Virus 
ID 
Iron deficiency 
IDA 
Iron deficiency anemia 
IV 
Intravenous 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
TEAE 
Treatment emergent adverse event 
TSAT 
Transferrin Saturation 
 
 


Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 5 of 12 
 
1. 
INTRODUCTION 
Rapid growth, insufficient dietary intake, and limited absorption of dietary iron combine to 
place children at increased risk for iron deficiency. In addition, iron deficiency may 
contribute significantly to anemia due to malabsorption, gastrointestinal blood loss, or 
iatrogenically due to repeated blood samplings. As a result, iron deficiency anemia (IDA) 
remains the most common nutritional deficiency in children in the United States.   
  
2. 
STUDY OBJECTIVES  
The main objectives of this study are to characterize the pharmacokinetics and determine 
appropriate dosing and safety of Ferric Carboxymaltose for the pediatric population suffering 
from iron deficiency (ID) with anemia.   
 
The pharmacokinetics component has its own separate statistical analysis plan (SAP).  This 
SAP is intended to provide details on the dosing and safety components of the study, including 
the statistical methodology and associated tables and listings.   
 
3. 
STUDY DESIGN 
This is a phase II, open-label, non-randomized, multi-center, single arm study with two 
cohorts: 
 
Cohort 1: 16 subjects will be treated with Ferric Carboxymaltose at 7.5 mg/kg with a 
maximum single dose of 750 mg, whichever is smaller. 
 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have completed 4 weeks 
of therapy and a Data and Safety Monitoring Board (DSMB) approves continuation. 
 
Cohort 2: 16 subjects will be treated with Ferric Carboxymaltose at 15 mg/kg with a 
maximum single dose of 750 mg, whichever is smaller. 
 
3.1. 
Inclusion/Exclusion Criteria  
As per section 4.2.1 in the protocol, the following are the study inclusion and exclusion criteria. 
 
 
 
 


Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 6 of 12 
 
 
 
 
 
 
 
 
 
 


Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 7 of 12 
 
3.2. 
Schedule of Visits  
Subjects will have a screening period, baseline visit, 24, 48 and 72 hours post dosing visits, and 
visits at day 14, 28 and 35.  The schedule of visits is summarized below: 
 
 


Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 8 of 12 
 
4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
An interim analysis of the safety data is planned after the first cohort of 16 patients have 
completed through week 4 of the study.  The purpose of the interim analysis is for the DSMB to 
review the interim data and to make recommendations to Luitpold Pharmaceuticals concerning 
the merits of continuing the study and the safety of continuing enrollment into cohort 2.   
Refer to the DSMB Charter to details on the planned review of the interim data. 
4.2. 
Final Analysis 
The final planned data analyses will be performed after all subjects have completed the study and 
after the database is locked. 
4.3. 
Populations 
There will be two analysis populations: 
- 
The Safety Population: The safety population includes all subjects who receive Ferric 
Carboxymaltose.   
- 
The Pharmacokinetics and Pharmacodynamics (PK/PD) Population: The PK/PD population 
includes all subjects in the safety population who have evaluable iron profiles and no protocol 
violation that could affect the PK/PD of Ferric Carboxymaltose. 
 
All summaries will be presented for the safety population.  Only demographic characteristics will 
be summarized for the PK/PD population. 
5. 
SAMPLE SIZE CONSIDERATIONS 
Determination of sample size for this study was a compromise between obtaining sufficiently 
precise estimates of pharmacokinetic parameters and the ethics of including a large number of 
pediatric patients in an experiment.  The precision of estimation can be quantified as the width of 
the 95% confidence interval for area under the curve (AUC) from 0 to 72 (AUC0-72) from this 
single-arm study (i.e., smaller width indicates better precision).  Based on Study VIT-IV-CL-002 
in adults, the standard deviation for total serum iron AUC0-72 following a 500 mg intravenous 
dose is approximately 300 mg-hour/mL.  The width of a 95% confidence interval, using a 
standard deviation of 300 mg-hour/mL, is presented below for selected sample sizes.   
 
As seen in the figure below, 16 patients appears to be a reasonable compromise between 
precision and number of exposed pediatric patients.  Therefore, 32 subjects will be enrolled, with 
16 subjects in each cohort.  Within each cohort of 16 subjects there will be 8 subjects 1 to 6 years 
of age and 8 subjects >6 to 17 years of age.  Subject enrollment and ages will be tracked and 
monitored via interactive web response (IWR) system. 
 


Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 9 of 12 
 
 
 
6. 
REPORTING CONVENTIONS 
 
Unless otherwise specified, standard descriptive statistics will be computed for measurements 
presented in summary tables. The standard descriptive statistics for continuous variables include:  
number of observations analyzed, mean, standard deviation, median, and range (minimum, and 
maximum). The standard descriptive statistics for categorical variables include: frequency 
distribution with the number and percent of subjects included in each category. 
 
Calculation of percentage will use the denominator of the total number of subjects with 
non-missing data in the particular group of analysis population used in the data display unless 
otherwise specified. 
 
All data listings, summaries, and statistical analyses will be generated using SAS® Version 9.1 or 
higher (SAS is registered trademarks of the SAS Institute Inc., Cary, NC, USA.)  
 
7. 
STATISTICAL ANALYSES AND SUMMARIES 
7.1. 
General Statistical Considerations 
No formal hypothesis testing is planned for this study.  Only descriptive, summary statistics are 
planned for assessment of dosing and safety.   
7.2. 
Baseline Definitions 
Baseline for this study is defined as Day 0.  If the data is not captured at Day 0, or if the data at 
Day 0 is missing, the screening value will be used.   


Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 10 of 12 
 
7.3. 
Subject Disposition 
Subject disposition will be summarized as: enrolled/registered, treated, completed or 
discontinued.  For those discontinued, the reason for discontinuation will be summarized. 
7.4. 
Demographic Characteristics 
Demographic characteristics will be summarized separately for the treatment groups, and 
separately for the two study populations (safety and PK/PD).  Demographic characteristics will 
include: age, gender, ethnicity and race. 
7.5. 
Medical/Surgical History 
Medical/surgical histories will be summarized separately for the treatment groups.  System organ 
class and condition/surgery will be coded with the Medical Dictionary for Regulatory Activities 
(MedDRA) Terminology. 
7.6. 
Efficacy 
Hemoglobin, ferritin and TSAT will be summarized at each visit, and for each treatment group.  
In addition, the change from baseline to each visit will be summarized for each treatment group.   
7.7. 
Adverse Events 
Adverse events (AEs) will be summarized for treatment emergent adverse events (TEAEs).  TEAEs 
are defined as AEs that occur on or after the day of the first dose.  MedDRA terminology will be 
used to classify all AEs with respect to system organ class (SOC) and preferred term (PT). 
A summary of subjects with TEAEs will be presented for each treatment group.  The summary will 
include counts and percentages for subjects who experience at least one AE, overall and by SOC and 
PT.  This will be repeated for severe TEAEs, related TEAEs and serious TEAEs.  Severity will be 
captured as Grade 1 through Grade 5 with Grades 3-5 categorized as severe.  Related will be 
captured as: none, unlikely, possibly or probably, with related = possibly or probably.  Serious will 
be captured with the standard serious adverse event (SAE) criteria.  
Subjects who report the same PT on multiple occasions will be counted once for the preferred term 
under the highest severity when summarizing by severity, under the closest relationship to the drug 
when summarizing by relationship, under most serious when summarizing by seriousness. 
7.8. 
Laboratory Values 
Laboratory values will be summarized at each visit, and for each treatment group.  In addition, 
the change from baseline to each visit, and the incidence of treatment-emergent potentially 
clinically significant (PCS) laboratory values will be summarized for each treatment group. 


Luitpold Pharmaceuticals, Inc. 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 Protocol No. 1VIT13036 
Page 11 of 12 
7.9. 
Vital Signs 
Vital signs will be summarized at each visit, and for each treatment group and by age groups (1 - 
< 6 years, and 6-17 years).  Height and weight will be summarized at Day 0 only.  Blood 
pressure and heart rate will be summarized at all visits and as the change from pre to 
immediately post treatment and the change from pre to 30 minutes post-treatment.  . 
APPENDIX A – TABLE SHELLS 
Table 14.1.1 Site and Population Summaries  
Table 14.1.1 Subject Disposition – Safety Population 
Table 14.1.2.1 Demographic Characteristics – Safety Population 
Table 14.1.2.2 Demographic Characteristics – PK/PD Population 
Table 14.1.3 Medical/Surgical History – Safety Population  
Table 14.2.1 Efficacy – Safety Population 
Table 14.2.2 Summary of Intolerance and ESA – Safety Population  
Table 14.3.1.1 Summary of Subjects with TEAEs – Safety Population 
Table 14.3.1.2 Occurrence of TEAEs – Safety Population 
Table 14.3.1.3 Occurrence of Severe TEAEs – Safety Population 
Table 14.3.1.4 Occurrence of Related TEAEs – Safety Population  
Table 14.3.1.5 Occurrence of Serious TEAEs – Safety Population  
Table 14.3.2.1 Laboratory Values – Safety Population 
Table 14.3.2.2 Incidence of Potentially Clinically Significant (PCS) Laboratory Values 
Table 14.3.3.1 Vital Signs – Safety Population 
APPENDIX B – LISTING SHELLS 
Listing 16.2.1.1 Completion/Discontinuation  
Listing 16.2.1.2 Identification of Subjects with Clinically Important Protocol Violations 
Listing 16.2.1.3 Inclusion/Exclusion Criteria  
Listing 16.2.1.4 Patient Populations  
Listing 16.2.1.5 Demographics 
Listing 16.2.1.6 Medical/Surgical History 
Listing 16.2.1.7 Drug Allergy/Intolerance at Screening 
Listing 16.2.1.8 IV Iron Intolerance  
Listing 16.2.1.9 Physical Examination 
Listing 16.2.1.10 Iron Deficiency 
Listing 16.2.2.1 Erythropoiesis Stimulating Agent 
Listing 16.2.2.2 Ferric Carboxymaltoses Administration 
Listing 16.2.2.3 Pharmacokinetic Samples 
Listing 16.2.3.1 Concomitant Medications 
Listing 16.2.3.2.1 Central Laboratory Values - CFR  
Listing 16.2.3.2.2 Central Laboratory Values – Lab Transfer 


Luitpold Pharmaceuticals, Inc. 
 
Statistical Analysis Plan – 2.1 
CONFIDENTIAL 
 
 
 Protocol No. 1VIT13036 
 
 
Page 12 of 12 
 
Listing 16.2.3.2.3 Potentially Clinically Significant Central Laboratory Values – Lab Transfer 
 
Listing 16.2.3.3.1 Vital Signs  
Listing 16.2.3.4 Adverse Event Details 
 
 




Luitpold Pharmaceuticals, Inc. 
Statistical Analysis Plan - FINAL 
Protocol No. I VlT 13036 
ONFTDENTTAL 
STATISTICAL ANALYSIS PLAN 
Protocol 1 VIT13036
A Multi-center, Open-Label, Single Arm Study to Characterize the 
Pharmacokinetics and Pharmacodynamics Profile of Intravenous Ferric 
Carboxymaltose in Pediatric Subjects 1-17 years old with Iron Deficiency 
Anemia (IDA) 
Prepared for: 
Luitpold Pharmaceuticals, Inc. 
Clinical Research and Development 
800 Adams Avenue, Suite 100 
Norristown, PA 19403 
(610) 650-4200
Prepared by: 
MedTrials, Inc. 
1400 N. Providence Road 
Building 1, Suite 212 
Media, PA 19063 
Page 1 


Luitpold Pharmaceuticals, Inc. 
. ONFIDENTlAL 
Document Version History: 
Version 
Date 
1.0 
6/8/15 
2.0 
7/14/15 
2.1 
6/17/16 
2.2 
6/21/16 
2.3 
6/23/16 
2.4 
6/23/16 
2.5 
6/24/16 
FINAL 
7/7/16 
Author 
Michelle Secic 
Michelle Secic 
Michelle Secic 
Michelle Secic 
Michelle Secic 
Michelle Secic 
Michelle Secic 
Michelle Secic 
Statistical Analysis Plan - FINAL 
Protocol No. I VIT.13036 
Comments 
Original 
Revisions based on initial review from 
Luitpold 
Revised to exclude PCS vitals and stratify by 
age instead 
Revised section 7.9 as per Luitpold 
comments 
Revised sections 7.5 and 7.8 as per Luitpold 
Revised vital signs table to include additional 
changes over time 
Split vital signs table 
Finalized date and version 
Page 2 


Luitpold Pharmaceuticals, Inc. 
ONFIDENTIAL 
Statistical Analysis Plan - FINAL 
Protocol No. I VITI 3036 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................. 4 
1.
INTRODUCTION ....................................................................................................... 5 
2.
STUDY OBJECTIVES ............................................................................................... 5 
3.
STUDY DESIGN ........................................................................................................ 5 
3 .1. 
Inclusion/Exclusion Criteria ............................................................................ 5 
3.2. 
Schedule of Visits ............................................................................................ 7 
4.
PLANNED ANALYSES ............................................................................................. 8 
4.1. 
Interim Analyses .............................................................................................. 8 
4.2. 
Final Analysis .................................................................................................. 8 
4.3. 
Populations ...................................................................................................... 8 
5.
SAMPLE SIZE CONS ID ERA TIO NS ........................................................................ 8 
6.
REPORTING CONVENTIONS ................................................................................. 9 
7.
STATISTICAL ANALYSES AND SUMMARIES .................................................... 9 
7.1. 
General Statistical Considerations ................................................................... 9 
7.2. 
Baseline Definitions ......................................................................................... 9 
7 .3. 
Subject Disposition ........................................................................................ 10 
7.4. 
Demographic Characteristics ......................................................................... 10 
7.5. 
Medical/Surgical History ............................................................................... 10 
7.6. 
Efficacy .......................................................................................................... 10 
7. 7.
Adverse Events .............................................................................................. 10 
7.8. 
Laboratory Values ......................................................................................... 10 
7.9. 
Vital Signs ..................................................................................................... 11 
APPENDIX A - TABLE SHELLS .................................................................................. 12 
APPENDIX B -LISTING SHELLS ................................................................................ 12 
Page 3 


Luitpold Pharmaceuticals, Inc. 
CONFlDENTIA L 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
DSMB 
Data and Safety Monitoring Board 
EDC 
Electronic Data Capture 
ESA 
Erythroooiesis stimulating agent 
FCM 
Ferric Carboxymaltose 
HBsAg 
Hepatitis B antigen 
HCV 
Hepatitis C viral antibody 
HIV 
Human Immunodeficiency Virus 
ID 
Ir011 deficiency 
IDA 
Iron deficiency anemia 
IV 
Intravenous 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
soc 
System Organ Class 
TEAE 
Treatment emergent adverse event 
TSAT 
Transferrin Saturation 
Statistical Analysis Plan - FINAL 
Protocol No. I VITI 036 
Page 4 


Luitpold Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan - FINAL 
Protocol No. l VJTl3036 
1.
INTRODUCTION
Rapid growth, insufficient dietary intake, and limited absorption of dietary iron combine to 
place children at increased risk for iron deficiency. In addition, iron deficiency may 
contribute significantly to anemia due to malabsorption, gastrointestinal blood loss, or 
iatrogenically due to repeated blood samplings. As a result, iron deficiency anemia (IDA) 
remains the most common nutritional deficiency in children in the United States. 
2.
STUDY OBJECTIVES
The main objectives of this study are to characterize the pharmacokinetics and determine 
appropriate dosing and safety of Ferric Carboxymaltose for the pediatric population suffering 
from iron deficiency (ID) with anemia. 
The pharmacokinetics component has its own separate statistical analysis plan (SAP). This 
SAP is intended to provide details on the dosing and safety components of the study, including 
the statistical methodology and associated tables and listings. 
3.
STUDY DESIGN
This is a phase II, open-label, non-randomized, multi-center, single arm study with two 
cohorts: 
Cohort 1: 16 subjects will be treated with Ferric Carboxymaltose at 7.5 mg/kg with a 
maximum single dose of 750 mg, whichever is smaller. 
Cohort 2 will initiate enrollment only after all subjects in Cohort 1 have completed 4 weeks 
of therapy and a Data and Safety Monitoring Board (DSMB) approves continuation. 
Cohort 2: 16 subjects will be treated with Ferric Carboxymaltose at 15 mg/kg with a 
maximum single dose of 750 mg, whichever is smaller. 
3.1. 
Inclusion/Exclusion Criteria 
As per section 4.2.1 in the protocol, the following are the study inclusion and exclusion criteria. 
Page 5 


Luitpold Pharmaceuticals, Inc. 
ONFlDENTIAL 
Statistical Analysis Plan - FINAL 
Protocol No. 1 vrr 13036 
Jndusion Criteria: 
l. M,1le or Jeima.le subjecLܴ I to J 7 yܵ 11s uJ' ag ܶ 10 17 yܷܸ1r.' of llge in Russia ouly)
wllh a· (}[11. t 1ܹ111.lc:l1>aii\ 1i and hi· 'hܺ purcnܻ or guanlinn ls willing and able o
isi •n tlho i11fo1111t:d cciuNC-nl apJ,ro eel y 1hc fndcJ ·ndcml Rc,•i \, Bo31'lJ / E•l1ics
ܼommitree.
2. Screening TSAT < 211'/2
3. Screening Hemoglobin< 11 gldL
4. F.1>r subjt:cls who nrc rec iving 11n "'rylhropoiclin :,umul ,Lin , ngcul 
SA ; stuble
I!$/\ lhc:nlr>Y (+/- W¾ of current dost) for 
8 weeks prior Lo thܽ qu(l]U'yinG
1JC1-ci::ning vrsit and JIO E.' d0 ܾ r proJ: l clumg anticiJmted fur the tength
<) lh trial
.Exclusion Crit.erjm 
I. KnowIJ hypcl'sensllivily reaction lo ru_1y component o Ferric ܿrboxy U11!ose.
2. Su1݀jocL previously l'Oildomii.cd a11<l Lrcate<I In tbi study or nu other clinical study
of.Ferric Garb xym!lltose (F0.1 or Vfr-4j) .
... 
3, Bo<l r llla.!iS illdex (BMl) < 5 I 1>e1ce11Lile foi" ;ig 
4.
?v1· l·e OJ' Pemalesubjecl I year'ofil e welijhi.ng < l2:g..
5.
Hist 1·y nf.actp.utcd ii n uV'l!Tload, honmd1.romutosi݁ 01 other l1w1 accumuiation
disol'ders.
6. Chroni:o kidn݂y di5ease StLbje.cts on hemodinl)·݃i݄.
7. &n..'t':tti , F r itin Ji;rveP· 300ng/mL
$, , uhjec݅ wUI· :ig11,lfiu,111t :iev 
i; tJI.݆ uses of tb 1i t:r, heo\1)JR'leti݇ .s sleo,,
ct1nH vu.s1..uJ4r ·݈ ·1em, p݉yohi tri di!iur<ler <1r ther c mJition' whicb ill\ the 
opl11ion C)f the investig11tor miiy ))lace a 1;ubjecJ ut added tisk. 
9. Arty ncfr.,,e illfeotion.
10. Known positive bopa iti O m1tigcn O f
flsAg) or hepatitis C viral antibody (HCV)
with c ridcn<.io of t1ctlve htt11uti1·s,
I l. Known p<1sitivc mv݊ttHIV-2 antibodies (nnli-HJV). 
12. Ancini.:i di.1݋ to rel݌sons otb r than ir u d !iciency i. . heruogloblnopatlly).
ubjects tmi d with vitamjr BL r lbJic aci<l tlelidݍ1cy ;u- permlU .d.
I • lntmv ·nou · iro and /or bl ti transl't1si n i1l u, 4 we ·s p, l r lo 
reening. 
14. lnrniunosupfl • .iv thmpy tb, t m 
J d t;, 1memfo 'Le. ydoph spl mfrle
87.ath101}ru c, rn. co1>hcnol e 1no til), Note ݎtcr id tllel' ti is pen:nitt-cd.
LS . .'\dmilt'strat:ion tmd / or 11se ofm1 iuve. lig,utfonal prooucr (clrug > J •vioo) with.in 
3 days ,f · 1·ecnt,rn. 
I 6. Alcoho[ or dmg abuse witllln the 1ݏs.1 six 111onths. 
J 7. Fcmalݐ .'it1l1,iecls WI \J un.: p::tgtiaill or ltict1Lli11g, lH' .ݑc:<\uil ly Hcli"c.: Jc1nulݒ who 1we 
of ullildh ·tiril1}ݓ pmooti1tl 11.01. 'Wilfing lf use u11 ݔcc.c.,11,16 e forr of contrnccpth· • 
preݕ;. uCion. ,lurinJ!, lh -;l:ud.y. 
18. Subjecl ls: umtblc to comply ,vith sHv.Jy asscss.mcnt'>.
Page 6 


Luitpold Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan - FINAL 
Protocol No. I VIT13036 
3.2. 
Schedule of Visits 
Subjects will have a screening period, baseline visit, 24, 48 and 72 hours post dosing visits, and 
visits at day 14, 28 and 35. The schedule of visits is summarized below: 
Screening 
24and48 
72 hours 
Visit Day 
Period 
Day 
Day 
hours 
post 
Day 14 
Duy28 
Day 35 
(Up to 14 
-J
0 
post 
dosing 
(week 2) 
(week4) 
(week 5) 
bays) 
dosing 
Informed 
X 
Consent 
Assess entry 
X 
X 
criteria 
EDC 
X 
X 
X 
Medical History 
X 
X 
Physical Exam1 
X 
X 
Vital Signs" 
X 
X 
X 
X 
X 
X 
Height·/ Weight 
X 
PK/PD Samples 
X' 
XJ 
x• 
x4 
Hematology, 
X 
X 
X 
X 
X 
Chemistry aud 
Tron lnill,.,.ρ 
Serum 
X 
preg,mmcy test 
Concomitant 
X 
X 
X 
X 
X 
X 
Metlicaliom 
ESA Stability 
X 
X 
X 
X 
X 
X 
Adverse Bvent 
X 
X 
X 
X 
X 
Assessments
.l 
Fenic 
X 
Carbox:ymaltose 
1 Includes c:linfonl assessment of skin, cardiovascular, pulmoJJHlY, abdominal, aud centrnl neTVous system
z Blood samples drnwn 11.c R11m t2r,m and 8pm for, ubjecl iron profile 
3 Blood samples PK/l>D famld be t.ukeu prior to Fcrriu Carboxymaltose <losing and additior1al sςmple., fot PK/PD 
should be tak.en at 1, 2, 6 and 12 hours post dosing. 
• Blood samples should be taken approximat.ely the sume time of day as the Day O sa1npl1:s w<:rc drawn
5 Adverse even( as.sessmentll starting at the time of Ferric Carboxymaltosc dosing 
6Sitting vital signs including blood pressure and he.irt rate should be collected immediately pre-<losing, immediately 
and 30 minuies post dosing. Body temperature will also be collected pre-dose only. Yilal. signs on non-dosing days 
include sitting .be-.irt rate and blood pressure only. 
Page 7 


Luitpold Pharmaceuticals, Inc. 
ONFIDENTIAL 
Statistical Analysis Plan - FINAL 
Protocol No. 1 VTT13036 
4.
PLANNED ANALYSES
4.1. 
Interim Analyses
An interim analysis of the safety data is planned after the first cohort of 16 patients have 
completed through week 4 of the study. The purpose of the interim analysis is for the DSMB to 
review the interim data and to make recommendations to Luitpold Pharmaceuticals concerning 
the merits of continuing the study and the safety of continuing enrollment into cohort 2. 
Refer to the DSMB Charter to details on the planned review of the interim data. 
4.2. 
Final Analysis 
The final planned data analyses will be performed after all subjects have completed the study and 
after the database is locked. 
4.3. 
Populations 
There will be two analysis populations: 
The Safety Population: The safety population includes all subjects who receive Ferric 
Carboxymaltose. 
The Pharmacokinetics and Pharmacodynamics (PK/PD) Population: The PK/PD population 
includes all subjects in the safety population who have evaluable iron profiles and no protocol 
violation that could affect the PK/PD of Ferric Carboxymaltose. 
All summaries will be presented for the safety population. Only demographic characteristics will 
be summarized for the PK/PD population. 
5.
SAMPLE SIZE CONSIDERATIONS
Determination of sample size for this study was a compromise between obtaining sufficiently 
precise estimates of pharmacokinetic parameters and the ethics of including a large number of 
pediatric patients in an experiment. The precision of estimation can be quantified as the width of 
the 95% confidence interval for area under the curve (AUC) from Oto 72 (AUCo.n) from this 
single-arm study (i.e., smaller width indicates better precision). Based on Study VIT-IV-CL-002 
in adults, the standard deviation for total serum iron AUCo-72 following a 500 mg intravenous 
dose is approximately 300 mg-hour/mL. The width of a 95% confidence interval, using a 
standard deviation of 300 mg-hour/mL, is presented below for selected sample sizes. 
As seen in the figure below, 16 patients appears to be a reasonable compromise between 
precision and number of exposed pediatric patients. Therefore, 32 subjects will be enrolled, with 
16 subjects in each cohort. Within each cohort of 16 subjects there will be 8 subjects 1 to 6 years 
of age and 8 subjects >6 to 17 years of age. Subject enrollment and ages will be tracked and 
monitored via interactive web response (IWR) system. 
Page 8 


Luitpold Pharmaceuticals, Inc. 
CONFIDENTIAL 
1500 
1400 
1300 
1200 -
1100 -
1000 
W 900 
ro 800 · 
Cl\ 
'a 700 
,a 600 · 
:i 500
400 
300 
200 
100 
0+---
--
-;---,,---.----,------, 
D 
6. 
8 
16 
2.4 
32 
40 
N111nh1rr of Suhjccl/1 
48 
REPORTING CONVENTIONS 
56 
64 
Statistical Analysis Plan - FINAL 
Protocol No. 1 VIT13036 
Unless otherwise specified, standard descriptive statistics will be computed for measurements 
presented in summary tables. The standard descriptive statistics for continuous variables include: 
number of observations analyzed, mean, standard deviation, median, and range (minimum, and 
maximum). The standard descriptive statistics for categorical variables include: frequency 
distribution with the number and percent of subjects included in each category. 
Calculation of percentage will use the denominator of the total number of subjects with 
non-missing data in the particular group of analysis population used in the data display unless 
otherwise specified. 
All data listings, summaries, and statistical analyses will be generated using SAS® Version 9 .1 or 
higher (SAS is registered trademarks of the SAS Institute Inc., Cary, NC, USA.) 
7.
STATISTICAL ANALYSES AND SUMMARIES
7.1. 
General Statistical Considerations
No formal hypothesis testing is planned for this study. Only descriptive, summary statistics are 
planned for assessment of dosing and safety. 
7 .2. 
Baseline Definitions 
Baseline for this study is defined as Day 0. If the data is not captured at Day 0, or if the data at 
Day O is missing, the screening value will be used. 
Page 9 


Luitpold Pharmaceuticals, Inc. 
CONFID NTIAL 
7.3. 
Subject Disposition 
Statistical Analysis Plan - FINAL 
Protocol No. 1 VJT 13036 
Subject disposition will be summarized as: enrolled/registered, treated, completed or 
discontinued. For those discontinued, the reason for discontinuation will be summarized. 
7 .4. 
Demographic Characteristics 
Demographic characteristics will be summarized separately for the treatment groups, and 
separately for the two study populations (safety and PK/PD). Demographic characteristics will 
include: age, gender, ethnicity and race. 
7.5. 
Medical/Surgical History 
Medical/surgical histories will be summarized separately for the treatment groups. System organ 
class and condition/surgery will be coded with the Medical Dictionary for Regulatory Activities 
(MedDRA) Terminology. 
7.6. 
Efficacy 
Hemoglobin, ferritin and TSA T will be summarized at each visit, and for each treatment group. 
In addition, the change from baseline to each visit will be summarized for each treatment group. 
7.7. 
Adverse Events 
Adverse events (AEs) will be summarized for treatment emergent adverse events (TRARs). TF.AEs 
are defined as AEs that occur on or after the day of the first dose. MedDRA terminology will be 
used to classify all AEs with respect to system organ class (SOC) and preferred term (PT). 
A summary of subjects with TEAEs will be presented for each treatment group. The summary will 
include counts and percentages for subjects who experience at least one AE, overall and by SOC and 
PT. This will be repeated for severe TEAEs, related TEAEs and serious TEAEs. Severity will be 
captured as Grade 1 through Grade 5 with Grades 3-5 categorized as severe. Related will be 
captured as: none, unlikely, possibly or probably, with related= possibly or probably. Serious will 
be captured with the standard serious adverse event (SAE) criteria. 
Subjects who report the same PT on multiple occasions will be counted once for the preferred term 
under the highest severity when summarizing by severity, under the closest relationship to the drug 
when summarizing by relationship, under most serious when summarizing by seriousness. 
7.8. 
Laboratory Values 
Laboratory values will be summarized at each visit, and for each treatment group. In addition, 
the change from baseline to each visit, and the incidence of treatment-emergent potentially 
clinically significant (PCS) laboratory values will be summarized for each treatment group. The 
denominator is all subjects with normal baseline ( < Grade III value) and at least one post 
baseline assessment in the safety population and the numerator is the number of subjects with 
Page 10 


Luitpold Pharmaceuticals, Inc. 
CONFTDENTfAL 
Statistical Analysis Plan - FINAL 
Protocol No. lVJT 13036 
PCS (i.e., meets Grade III or Grade IV toxicity criteria from the National Cancer Institute 
Common Terminology Criteria) at post-baseline. 
7.9. 
Vital Signs 
Vital signs will be summarized for dosing day (Day 0), at each visit and for each treatment 
group. The change from baseline to each visit, will be summarized for each treatment group. In 
addition, summary statistics for vital signs will be stratified by age groups: 1 - <6years, and 6 to 
17 years. 
Page 11 


Luitpold Pharmaceuticals, Inc. 
CON FlD'ENTIAL 
Statistical Analysis Plan - FINAL 
Protocol No. I VITl3036 
APPENDIX A - TABLE SHELLS 
Table 14.1.1 Site and Population Summaries 
Table 14.1.1 Subject Disposition - Safety Population 
Table 14.1.2.1 Demographic Characteristics - Safety Population 
Table 14.1.2.2 Demographic Characteristics - PK/PD Population 
Table 14.1.3 Medical/Surgical History - Safety Population 
Table 14.2.1 Efficacy -Safety Population 
Table 14.2.2 Summary of Intolerance and ESA -Safety Population 
Table 14.3 .1.1 Summary of Subjects with TEAEs -Safety Population 
Table 14.3.1.2 Occurrence ofTEAEs -Safety Population 
Table 14.3 .1.3 Occurrence of Severe TEAEs - Safety Population 
Table 14.3 .1.4 Occurrence of Related TEAEs - Safety Population 
Table 14.3 .1.5 Occurrence of Serious TEAEs -Safety Population 
Table 14.3.2.1 Laboratory Values -Safety Population 
Table 14.3 .2.2 Incidence of Potentially Clinically Significant (PCS) Laboratory Values 
Table 14.3.3.1 Vital Signs - Day O - Safety Population 
Table 14.3.3.2 Vital Signs -All Visits -Safety Population 
APPENDIX B - LISTING SHELLS 
Listing 16.2.1.1 Completion/Discontinuation 
Listing 16.2.1.2 Identification of Subjects with Clinically Important Protocol Violations 
Listing 16.2.1.3 Inclusion/Exclusion Criteria 
Listing 16.2.1.4 Patient Populations 
Listing 16.2.1.5 Demographics 
Listing 16.2.1.6 Medical/Surgical History 
Listing 16.2.1. 7 Drug Allergy/Intolerance at Screening 
Listing 16.2.1.8 IV Iron Intolerance 
Listing 16.2.1.9 Physical Examination 
Listing 16.2.1.10 Iron Deficiency 
Listing 16.2.2.1 Erythropoiesis Stimulating Agent 
Listing 16.2.2.2 Ferric Carboxymaltose Administration 
Listing 16.2.2.3 Pharmacokinetic Samples 
Listing 16.2.3 .1 Concomitant Medications 
Listing 16.2.3 .2.1 Central Laboratory Values - CFR 
Listing 16.2.3.2.2 Central Laboratory Values - Lab Transfer 
Listing 16.2.3.2.3 Potentially Clinically Significant Central Laboratory Values- Lab Transfer 
Listing 16.2.3.3.1 Vital Signs 
Listing 16.2.3.4 Adverse Event Details 
Page 12 


Luitpold Pharmaceuticals, Inc. 
SAP Version F!NAL 
Protocol I VITJ3036 
Appendix A - Shells for Study Tables 
Table of Contents 
Table 14.1.1 Site and Population Summaries 
Table 14.1.1 Subject Disposition - Safety Population 
Table 14.1.2.1 Demographic Characteristics -Safety Population 
Table 14.1.2.2 Demographic Characteristics - PK/PD Population 
Table 14.1.3 Medical/Surgical History - Safety Population 
Table 14.2.1 Efficacy - Safety Population 
Table 14.2.2 Summary oflntolerance and ESA -Safety Population 
Table 14.3.1.1 Summary of Subjects with TEAEs - Safety Population 
Table 14.3 .1.2 Occurrence of TEAEs - Safety Population 
Table 14.3.1.3 Occurrence of Severe TEAEs - Safety Population 
Table 14.3 .1.4 Occurrence of Related TEAEs - Safety Population 
Table 14.3 .1.5 Occurrence of Serious TEAEs - Safety Population 
Table 14.3.2.1 Laboratory Values - Safety Population 
Table 14.3.2.2 Incidence of Potentially Clinically Significant (PCS) Laboratory Values 
Table 14.3 .3 .1 Vital Signs -Day O - Safety Population 
Table 14.3.3.2 Vital Signs -All Visits - Safety Population 
Confidential 
2 
3 
4 
5 
6 
7 
10 
11 
12 
13 
14 
15 
16 
18 
20 
21 
Page I of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FfNAL 
Protocol l VlTJ 3036 
Table 14.1.J Site and Population Summaries 
Site 
Site #1 
Site #2 
Etc. 
In Safety Population 
In PK Population 
Confidential 
Cohort I 
Cohort 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 2 of22 


Luitpold Phannaceuticals, Inc. 
SAP Version FINAL 
Protocol l VITI 3036 
Table 14.1.1 Su{iect Disposition - Safety Populntion 
Disposition 
Registered/Enrolled 
Completed Study 
Discontinued due to: 
Adverse Event 
Intervention 
Lost to Follow-up 
Physician Decision 
Withdrawal by Subject 
Death 
Study Tenninated by Sponsor 
Other 
Confidential 
Cohort I 
Cohort 2 
(N=XXX) 
(N=XXX) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
X (XX.X) 
X(XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
Page 3 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Table 14.1.2. I Demographic Characteristics - Safety Population 
Baseline Characteristic 
Statistic 
Age 
N 
Mean (SD) 
Median 
Range 
Gender 
Male 
Female 
Ethnicity 
Hispanic or Latino 
Not Hispanic or Latino 
Race [I] 
American Indian/Alaska Native 
Asian 
Black/ African American 
Native Hawaiian/Other Pacific Islander 
White 
[I] Total may be more than 100% as this category is "check all that apply."
Confidential 
Cohort I 
Cohort 2 
(N=XXX) 
(N=XXX) 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
X(XX.X) 
X (XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
Page 4 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITl3036 
Table 14.1.2.2 Demographic Characteristics - PK/PD Population 
Baseline Characteristic 
Statistic 
Age 
N 
Mean (SD) 
Median 
Range 
Gender 
Male 
Female 
Ethnicity 
Hispanic or Latino 
Not Hispanic or Latino 
Race [I) 
American Indian/Alaska Native 
Asian 
Black/African American 
Native Hawaiian/Other Pacific Islander 
White 
[I) Total may be more than 100% as this category is "check all that apfllY" 
Confidential 
Cohort 1 
Cohort 2 
(N=XXX) 
(N=XXX) 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx.xx
xx.xx
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
Page 5 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol 1 VITI 3036 
Table 14.1.3 Mcdic,11/Surgical History-Safety Population 
System Organ Class 
System Organ Class #1 
System Organ Class #2 
Etc. 
Confidential 
Condition/Surgery 
Condition/Surgery# I 
<;:ondit!oryur_ge_ry #2 
Etc. 
Condition/Surgery# I 
Condition/Surgery #2 
Etc. 
Condition/Surgery # I 
Condition/Surgery #2 
Etc. 
Cohort 1 
ohorl 2 
(N=XXX) 
(N6XXX) 
X( X.X) 
X(XX.X) 
I (XX.X) 
X(XX..J,C) 
X(XXX) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
(, .X) 
(XX.X) 
(X.X.X) 
X (XX.X) 
Page6 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITl3036 
Table 14.2.1 Efficacy- Safety Population 
Parameter 
Visit 
Hemoglobin 
Screening 
72 hours post-dose 
Change from Screening to 72 hours post-dose 
Day 14 
Change from Screening to Day 14 
Day 28 
Change from Screening to Day 28 
Day 35 
Change from Screening to Day 35 
Ferritin 
Screening 
72 hours post-dose 
Change from Screening to 72 hours post-dose 
Confidential 
Shlli 1icl I j 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
Cohort I 
Cohort 2 
(N=XXX) 
(N=XXX) 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx,xx 
XX,XX 
xx 
xx 
XX(XX.X) 
XX (XX.X) 
xx 
xx 
XX,XX 
XX,XX 
Page 7 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol IVITl3036 
Table 14.2.1 Efficacy - Safety Population 
Parameter 
Visit 
Day 14 
Change from Screening to Day 14 
Day28 
Change from Screening to Day 28 
Day35 
Change from Screening to Day 35 
TSAT 
Scrnening 
72 hours post-dose 
Change from Screening to 72 hours post-dose 
Day 14 
Change from Screening to Day 14 
Day28 
Change from Screening to Day 28 
Confidential 
Statistic[!] 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
Cohort 1 
Cohort 2 
(N=XXX) 
(N=XXX) 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx.xx
xx.xx
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx.xx
xx.xx
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx.xx
xx.xx
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx,xx 
xx.xx
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX X) 
xx 
xx 
xx.xx
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx,xx 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx,xx 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
xx.xx
xx 
xx
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx.xx
XX,XX 
xx
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx.xx
XX,XX 
xx
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
Page 8 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Table 14.2.1 Efficacy- Safety Population 
Parameter 
Visit 
Day 35 
Change from Screening to Day 35 
Confidential 
Statistic[!] 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
Cohort I 
Cohort 2 
(N=XXX) 
(N=XXX) 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
Page 9 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VIT13036 
Table 14.2.2 Summary of Intolerance and ESA- Safety Population 
Drug Allergy Intolerance 
IV Iron Intolerance 
ESA 
Confidential 
Cohort 1 
(N=XXX) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
Cohort 2 
(N=XXX) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
Page 10 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol 1 VIT13036 
Table 14.3.1.1 Summary of Subjects with TEAEs - Safety Population 
Any Treatment-Emergent Adverse Event [I] 
Serious 
Severe [2] 
Related to Study Drug [3] 
Cohort 1 
(N=XXX) 
X(>..'XX) 
X(XX.X,) 
X(XX.XJ 
X (XX.X) 
Cohort 2 
(N=XXX) 
X (XX.X) 
X (XX.X) 
X(XX.X) 
X (XXX) 
[l] !fa subject experiences the same event more than once, the first occurrence is tabulated
[2] Refers to CTCAE grade 3, 4, or 5.
[3] Related includes Possibly or Probably related to study drug.
Confidential 
Page 11 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VJT13036 
Table I 4.3.1.2 Occurrence ofTEAEs - Safety PopuJa1i1:m 
MedDRA System Organ Class 
MedDRA Preferred Tenn 
SOC#! 
Any 
PT#l 
PT#2 
PT#3 
Etc. 
soc #2 
Any 
PT#! 
PT#2 
PT#3 
Etc. 
Etc. 
Cohort I 
Cohort 2 
(N=XXX) 
(N=XXX) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
All AEs in this table are treatment-emergent. The denominator for the calculation of the percentage is the number of subjects in the group and the numerator 
is the number of subjects in the group with at least one TEAE in the given system organ class or with the given preferred term. If a subject experiences the 
same event more than once, the first occurrence is tabulated. 
Confidential 
Page 12 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITl3036 
Table 14.3.1.3 Occurrence of Severe TEAEs - Safety Population 
MedDRA System Organ Class 
MedDRA Preferred Term 
SOC#! 
Any 
PT#! 
PT#2 
PT#3 
Etc. 
SOC#2 
Any 
PT#! 
PT#2 
PT#3 
Etc. 
Etc. 
Cohort I 
Cohort 2 
(N=XXX) 
(N=XXX) 
X(XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
All AEs in this table are severe (Grade 3, 4 or 5) and treatment-emergent. The denominator for the calculation of the percentage is the number of subjects in 
the group and the numerator is the number of subjects in the group with at least one TEAE in the given system organ class or with the given preferred term. 
If a subject experiences the same event more than once, the first occurrence is tabulated. 
Confidential 
Page 13 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Table 14.3.1.4 Occurrence of Related TEAEs - Safety Population 
MedDRA System Organ Class 
MedDRA Preferred Term 
SOC#I 
Any 
PT#! 
PT#2 
PT#3 
Etc. 
SOC#2 
Any 
PT#! 
PT#2 
PT#3 
Etc. 
Etc. 
Cohort I 
Cohort 2 
(N=XX C) 
(N=XXX) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
All AEs in this table are related (possibly or probably) to study drug and treatment-emergent. The denominator for the calculation of the percentage is the 
number of subjects in the group and the numerator is the number of subjects in the group with at least one TEAE in the given system organ class or with the 
given preferred term. If a subject experiences the same event more than once, the first occurrence is tabulated. 
Confidential 
Page 14 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Table 14.3 .1.5 Occurrence of Serious TEAEs - Safetv Population 
MedDRA System Organ Class 
MedDRA Preferred Term 
SOC#I 
Any 
PT#I 
PT#2 
PT#3 
Etc. 
SOC#2 
Any 
PT#! 
PT#2 
PT 113 
Etc. 
Etc. 
Cohort I 
Cohort 2 
(N=XXX) 
(N=XXX) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
X(XX.X) 
X(XX.X) 
All AEs in this table are serious and treatment-emergent. The denominator for the calculation of the percentage is the number of subjects in the group and 
the numerator is the number of subjects in the group with at least one TEAE in the given system organ class or with the given preferred term. If a subject 
experiences the same event more than once, the first occurrence is tabulated. 
Confidential 
Page 15 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Table 14.3.2.1 Laboratory Values - Safety Population 
Parameter 
Visit 
Lab#! 
Screening 
72 hours post-dose 
Change from Screening to 72 
hours post-dose 
Day 14 
Change from Screening to Day 
14 
Day28 
Change from Screening to Day 
28 
Day 35 
Change from Screening to Day 
35 
Lab #2 
Screening 
72 hours post-dose 
Change from Screening to 72 
hours post-dose 
Confidential 
Statistic[!] 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
Cohort 1 
Cohort 2 
(N=XXX) 
(N=XXX) 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
xx,xx 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx,xx 
XX,XX 
xx 
xx 
XX(XX.X) 
XX (XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx,xx 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
xx,xx 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx,xx 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
xx,xx 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
xx,xx 
Page 16 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VIT13036 
Table 14.3.2.1 Laboratory Values - Safety Population 
Parameter 
Visit 
Day 14 
Change from Screening to Day 
14 
Day28 
Change from Screening to Day 
28 
Day 35 
Change from Screening to Day 
35 
Etc. 
Etc. 
Confidential 
Stutisticl'I'] 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
N 
Mean (SD) 
Median 
Range 
Cohort 1 
Cohort 2 
(N=XXX) 
(N·•XXX) 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
xx 
xx 
XX(XX.X) 
XX(XX.X) 
xx 
xx 
XX,XX 
XX,XX 
Page 17 of22 


Luitpold Pharnrnceuticals, Inc. 
SAP Version FINAL 
Protocol lVITl3036 
Table 14.3.2.2 Incidence of Potentially Clinically Significant (PCS) Laboratory Values 
Lab Test/Category 
Lab #I 
Lab 112 
Etc. 
Conlidential 
PCS 
No 
Y-,s 
No 
Yes 
Cohort I 
Cohort 2 
(N=XXX) 
(N=XXX) 
X (XX.X) 
X (XX.X) 
X (XX.X) 
X (XXX) 
X(XX.X) 
X(XX.X) 
X (XX.X) 
X(XX.X) 
Page 18 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITl3036 
Confidential 
Page 19 of22 


Luitpold Phannaceuticals, Inc. 
SAP Version FINAL 
Protocol I VIT13036 
Table 14.3.3.1 Vital Signs - Day 0-Safcty Population 
Statistic/ 
Cohort I 
Cohort 2 
Age Group 
Vital Sign 
Time Point 
Category 
(n=XXX) 
(n=XXX) 
All Subjects 
Sitting Diastolic BP (mmHg) 
Day 0 Pre-Treatment 
N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
xx.xx
xx,xx 
Day 0 Immediately Post-Treatment N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
xx.xx
xx.xx
Change from Pre-Treatment to 
N 
xx 
xx 
Immediately Post-Treatment 
Mean (SD) 
XX(XX.X) 
XX (XX.X) 
Median 
xx 
xx 
Range 
xx.xx
xx.xx
Day 0 30 Minutes Post-Treatment 
N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
xx.xx
xx.xx
Change from Pre-Treatment to 30 
N 
xx 
xx 
Minutes Post-Treatment 
Mean (SD) 
XX (XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
xx.xx
xx.xx
Note to programmer, re pcm above for all Systolic BP and Heart Rate and for two age stratum: I - < 6 years, and 6 - 17 years 
Confidential 
Page 20 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITl3036 
Table 14. 3.3.2 Vital Si!;lns -All Visits -Safetl'. Poeulation 
Statistic/ 
Cohort I 
Cohort 2 
Age Group 
Vital Sign 
Time Point 
Category 
(n=XXX) 
(n=XXX) 
All Subjects 
Sitting Diastolic BP (mmHg) 
Screening 
N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
Day O Initial (Baseline) 
N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
72hr / Day 3 
N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
Change from Baseline at 72hr / Day 3 
N 
xx 
xx 
Mean (SD) 
XX (XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
Day 14 
N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
Change from Baseline at Day 14 
N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
Day28 
N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
Change from Baseline at Day 28 
N 
xx 
xx 
Mean (SD) 
XX(XX. X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
Day 35 (End of Study) 
N 
xx 
xx 
Mean (SD) 
XX(XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
Change from Baseline at Day 35 (End of Study) 
N 
xx 
xx 
Mean (SD) 
XX (XX.X) 
XX(XX.X) 
Median 
xx 
xx 
Range 
XX,XX 
XX,XX 
Confidential 
Page 21 of22 


Luitpold Phannaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Statistic/ 
Age Group 
Vital Sign 
Time Point 
Category 
Note to programmer, repeat above for Systolic BP, Heart Rate, and for two age stratum: I - < 6 years, and 6 - 17 years. 
weight are only measured at Day 0. 
Confidential 
Cohort I 
(n=XXX) 
Cohort 2 
(n=XXX) 
Note also that height and 
Page 22 of22 


Luitpold Pharmaceuticals, Inc. 
SAP Version FfNAL 
Protocol l VITI3036 
Table of Contents 
Listing 16.2.1.1 Completion/Discontinuation ....................................................................................................................... 2
Listing 16.2.1.2 Identification of Subjects with Clinically Important Protocol Violations .............................. , .......................... 2
Listing 16.2.1.3 Inclusion/Exclusion Criteria ....................................................................................................................... 3 
Listing 16.2.1.4 Patient Populations .................................................................................................................................... 3 
Listing 16.2.1.5 Demographics ........................................................................................................................................... 3 
Listing 16.2.1.6 Medical/Surgical History .......................................................................................................................... .4
Listing 16.2.1.7 Drug Allergy/Intolerance at Screening ........................................................................................................ .4 
Listing 16 .2 .1. 8 IV Iron Intolerance .................................................................................................................................... 5 
Listing 16.2.1.9 Physical Examination ................................................................................................................................ 5
Listing 16.2.1.10 Iron Deficiency ....................................................................................................................................... 5
Listing 16.2.2.1 Erythropoiesis Stimulating Agent ............................................................................................................... 6
Listing 16.2.2.2 Ferric Carboxymaltose Administration ........................................................................................................ 6
Listing 16.2.2.3 Pharmacokinetic Samples .......................................................................................................................... 6
Listing 16.2.3.1 Concomitant Medications .......................................................................................................................... 7 
Listing 16.2.3.2.1 Central Laboratory Values - CFR ............................................................................................ , ................ 7 
Listing 16.2.3.2.2 Central Laboratory Values - Lab Transfer. ................................................................................................ 8 
Listing 16.2.3.2.3 Potentially Clinically Significant Central Laboratory Values - Lab Transfer ................................................. 8 
Listing 16.2.3 .3 .1 Vital Signs ............................................................................................................................................. 9
Listing 16.2.3.4 Adverse Event Details ............................................................................................................................... 9
CONFIDENTIAL 
Page 1 of 9 


,ite/ 
bject 
Safe!}'_ 
Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol 1 VITI 3036 
PK 
Group_ 
Site/ Sub.iect 
Safet}. 
CONFIDENTIAL 
Date of 
First 
Dose 
PK 
Date of 
Completion or 
Discontin­
uation 
(RXDB)) 
Grou.e. 
Listing 16.2.1.1 Completion/Discontinuation 
Subject 
Status 
Physician 
Decision, 
Specify 
If 
Other, 
s
 
Date of 
Death 
(RxDay) 
Auto 
Primary 
Cause of 
Death 
Pregnant 
During 
Stud}'. 
Lactation 
Ex.e.osure 
Inter­
vention 
Listing 16.2.1.2 Identification of Subjects with Clinically Important Protocol Violations 
Clinically Important Protocol Violation 
Page 2 of 9 
Date 
Increase 
in Dose of 
Erythrop­
oletin for 
any 
Reason 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITl3036 
Site/ Subject 
Safe_ty 
PK 
Site/ Subiect 
Safety 
CONFIDENTIAL 
Group_ 
PK 
Did subject meet all 
inclusion and 
exclusion criteria? 
Listing 16.2.1.3 Inclusion/Exclusion Criteria 
Inclusion/Exclusion Category 
Not Met 
Inclusion/Exclusion Number 
Not Met 
Listing 16.2.1.4 Patient Populations 
Site/ Subject 
Group 
Safety Population 
PK/PD Population 
Listing 16.2.1.5 Demographics 
Ethnicity 
Age (yrs) 
(Hispanic 
American 
at Date of 
or 
Indian/ Alaska 
Group_ 
Birth Date 
Screening 
Sex 
Latino) 
Native 
Asian 
Waiver 
Granted? 
YIN 
Waiver Date 
Waiver 
Granted by: 
Native 
Black/ African 
Hawaiian/Other 
American 
Pacific Islander 
White 
Page 3 of9 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITl3036 
CONFIDENTIAL 
Listing 16.2.1.6 Medical/Surgical History 
Site/ Subject 
Safety 
PK 
Group 
Body System 
Medical Condition/Past Surgery 
Start Date 
End Date 
Ongoing? 
Listing 16.2.1.7 Drug Allergy/lntolerance at Screening 
Site/ Subject 
Safety 
PK 
Group 
Does the subject have any drug allergies/intolerance 
Drug/Drug Class 
Reaction Symptom 
Page 4 of 9 


Site/ Subject 
Site/ 
Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Safe_ty 
PK 
Group_ 
Heavy 
Uterine 
Bleeding 
Subject Safety PK Group 
T:i::pe 
CONFIDENTIAL 
Does the subject have any 
known IV iron intolerance? 
Listing 16.2.1.8 IV Iron Intolerance 
If_yes, Name 
Itchin_g 
Rash 
Listing 16.2.1.9 Physical Examination 
Bronchos_p_asm 
Hypotension 
Site/ Subject 
Group 
Visit 
Exam Performed? 
Bodv Svstem 
Not Done 
Result 
Specify Abnormalities 
Listing 16.2.1.10 Iron Deficiency 
Heavy 
Heavy 
Gastro-
Gastro-
Gastro-
Endo-
Uterine 
Uterine 
intestinal 
Mal-
GI 
intestinal 
intestinal 
crine Dys-
Bleeding 
Bleeding 
Related 
absorp-
Celiac 
Bleed-
Other 
Specify 
Polvps 
function 
Other 
Specify 
Symptom 
tion 
Disease 
ing 
Cancer 
Specify 
Page 5 of 9 
Other 
Trauma 
Specify 
Sodium Ferric Gluconate 
Other Symptom, Specify 
Surgery 
Other 
Specify 
Specify 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Site/ 
Subject 
Safety 
PK 
Group 
Site/ Subject 
Safety 
Site/ 
Subject 
CONFIDENTIAL 
PK 
GrouE 
Safe_!y 
Date 
PK 
Listing 16.2.2.1 Erythropoiesis Stimulating Agent 
Is subject using 3rythropoiesis Stimulating Agent (ESA)? 
Listing 16.2.2.2 Ferric Carboxymaltose Administration 
Total Dose Required 
for Injeotion 
Start Time 
Stop 
Time 
Total Dose of 
Elemental Iron 
Administered 
Has the dose been stable per 
inclusion criteria? 
IV 
Reason Not 
Administration 
Administered 
Other Specify 
Listing 16.2.2.3 Pharmacokinetic Samples 
Grou_p_ 
Time_p_oint Not Done 
Date (RxDay) 
Time 
Page 6 of 9 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Site/ 
Subject 
Safe_!l 
CONFIDENTIAL 
PK 
Site/ 
Subject 
Group_ 
Safe_!l 
Were any 
medications taken 
from 30 days prior to 
consent through end 
of study or Day 35? 
PK 
GrouE 
Visit 
Drug 
Name 
Listing 16.2.3.1 Concomitant Medications 
Dose 
Unit 
Route 
Other 
Route 
Indication 
Listing 16.2.3.2.1 Central Laboratory Values - CFR 
Start Date 
(RxDay) 
Stop Date 
(RxDay) 
Were labs 
.e_erformed? 
Collection 
Accession 
Date (RxDa2')_ 
Time 
# 
Page 7 of9 
Ongoing 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VIT13036 
CONFIDENTIAL 
Site/ 
Subject 
Site/ 
Subject 
Safe_!y 
PK 
Safe_!y 
PK 
Listing 16.2.3.2.2 Central Laboratory Values - Lab Transfer 
Grou_!l_ 
Visit 
Date {RxDay) 
Lab 
Result 
Normal 
H/L 
Range 
Flag 
Listing 16.2.3.2.3 Potentially Clinically Significant Central Laboratory Values - Lab Transfer 
Grou_!l_ 
Visit 
Date (RxDay) 
Lab 
Result 
Normal 
H/L 
Range 
Flag 
Page 8 of9 


Luitpold Pharmaceuticals, Inc. 
SAP Version FINAL 
Protocol I VITI 3036 
Site/ 
Subject 
Site/ 
Safe_ty 
Subject Safety 
PK 
CONFIDENTIAL 
PK 
Group_ 
Visit 
Any Verbatim 
Grou_!)_ AE? Term 
Listing 16.2.3.3.1 Vital Signs 
Vital Signs Collected? 
Date (RxDay)!Time 
Test 
Listing 16.2.3.4 Adverse Event Details 
Onset 
Resolution 
CTC 
Date 
Date 
Toxicity 
Action 
(RxDay) (RxDay) I
Criteria 
Taken With 
Serious /Time 
Time 
Continuing 
Grade 
Study Drug 
Treatment 
Not 
Done 
Other 
Treatment, 
Seecify 
Result 
Units 
Did ihe AE result in the 
subject being 
Final 
discontinued form the 
Out;;ome Causality 
study? 
Page 9 of9