Clinical trial NCT03523117
Conditions: Iron Deficiency Anemia
Sponsor: American Regent, Inc.
Start date: 2019-01-31; Completion date: 2021-01-29
Enrollment: 79 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to demonstrate the efficacy and safety of intravenous ferric carboxymaltose (FCM), compared to oral iron, in pediatric participants who have iron deficiency anemia.

Detailed description:
This is a Phase III, multicenter, randomized, active-controlled study that compares the efficacy and safety of FCM to oral iron in pediatric participants with IDA and a documented history of an inadequate response to oral iron therapy at least 8 weeks (56 days) prior to randomization.

Participants who satisfy the inclusion requirements and no exclusion criteria will be eligible to participate in this study and enter into a screening phase to confirm eligibility. Randomization will occur via the Interactive Response Technology (IRT) system in a 1:1 ratio to either Group A, participants receiving FCM, or Group B, participants receiving oral iron (oral solution drops, elixir or oral tablets). Randomization will be stratified by baseline Hgb (\<10, ≥10 g/dL) and age (1 to \<12 years and ≥12 to 17 years).

The oral ferrous sulfate formulation received will be based on the participant's age, such that infants and children (1 to \<4 years of age) will receive ferrous sulfate drops, children (≥4 to \<12 years of age) will receive ferrous sulfate elixir, and adolescents (≥12 to 17 years of age) will receive ferrous sulfate tablets. Participants who experience adverse clinical symptoms due to the oral iron during the treatment phase may have a weight-based dose of ferrous sulfate reduced from 6 mg/kg to 3 mg/kg. If the participant is receiving tablets, the dose will be reduced from one tablet taken twice daily to one tablet per day.

Once randomized, all participants will return for efficacy and safety evaluations, including adverse events and laboratory assessments, on Days 7, 14, 28, and 35. Additional pharmacokinetic sampling and analyses will be performed for participants receiving FCM on Days 0 and 7.

Arms: arm 1: Ferric Carboxymaltose - 2 doses (day 0 and day 7) at 15 mg/kg to a maximum single dose of 750 mg (whichever is smaller) up to a maximum of total dose of 1500 mg administered as either an undiluted IV push at a rate of 100 mg (2mL)/minute OR in no more than 250 mL of normal saline and infused over 15 minutes. arm 2: Oral Ferrous Sulfate - will receive an age-dependent formulation of oral ferrous sulfate daily for 28 days as follows: participants \<12 years of age will receive 6 mg (elemental iron)/kg/day divided into 2 daily doses of an oral liquid formulation, either drops or elixir, and participants ≥12 will receive 2 daily doses of oral tablets. Infants and children (ages 1 to \<4 years) will receive oral ferrous sulfate drops, while children (ages ≥4 to \<12 years) will receive oral ferrous sulfate elixir. Adolescents (ages ≥12 to 17 years) will receive an oral ferrous sulfate tablet (65 mg of elemental iron/tablet/dose) twice a day (BID). The maximum daily dose for all participants is 130 mg of elemental iron.
Interventions: intervention 1: Ferric carboxymaltose intervention 2: Ferrous Sulfate
Intervention descriptions: intervention 1: Intravenous iron intervention 2: oral iron therapy

Protocol documents:
Prot_003.pdf: 
NCT03523117 
1VIT17044   Multicenter Randomized 
Active-controlled Study to Investigate 
Efficacy & Safety of IV FCM in 
Pediatric Patients With IDA 
Protocol dated 26SEP2019 


American Regent, Inc. 
Protocol No.: 1VIT17044 
CONFIDENTIAL  
 Administrative Change 1 Date: Final 26 September 2019
Page 1 of 93 
AMERICAN REGENT, INC. 
PROTOCOL 
No. 1VIT17044 
IND #: 63,243 
A Multicenter, Multinational, Randomized, Active-Controlled Study to Investigate 
the Efficacy and Safety of Intravenous Ferric Carboxymaltose in Pediatric Patients 
with Iron Deficiency Anemia 
SPONSOR 
American Regent, Inc. 
Clinical Research and Development 
800 Adams Avenue 
Norristown, PA 19403 
610-650-4200
Protocol Date: 20 April 2017 
Amendment 1 Protocol Date: 14 September 2017 
Amendment 2 Protocol Date: 13 March 2019 
Administrative Change 1 Date: 26 September 2019 




American Regent, Inc. 
 
Protocol No.: 1VIT17044 
CONFIDENTIAL  
 Administrative Change 1 Date: Final 26 September 2019 
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Study Synopsis 
Protocol No. 1VIT17044 
Title: 
A Multicenter, Multinational, Randomized, Active-Controlled 
Study to Investigate the Efficacy and Safety of Intravenous 
Ferric Carboxymaltose in Pediatric Patients with Iron 
Deficiency Anemia  
Study Drug:  
Ferric carboxymaltose (Injectafer®) 
 
 
 
Oral Iron (Ferrous sulfate) 
Objective: 
The primary objective of this study is to demonstrate the efficacy and 
safety of intravenous (IV) ferric carboxymaltose (FCM), compared 
to oral iron, in pediatric participants who have iron deficiency anemia 
(IDA). 
Design: 
This is a Phase III, multicenter, multinational, randomized, active-
controlled study that compares the efficacy and safety of FCM to oral 
iron in pediatric participants with IDA and a documented history of 
an inadequate response to oral iron therapy at least 8 weeks (56 days) 
prior to randomization.   
Participants who satisfy the inclusion requirements and no exclusion 
criteria will be eligible to participate in this study and enter into a 
screening phase to confirm eligibility. Randomization will occur via 
the Interactive Response Technology (IRT) system in a 1:1 ratio to 
either Group A, participants receiving FCM, or Group B, participants 
receiving oral iron (oral solution drops, elixir or oral tablets). 
Randomization will be stratified by baseline Hgb (<10, ≥10 g/dL) 
and age (1 to <12 years and ≥12 to 17 years).   
The oral ferrous sulfate formulation received will be based on the 
participant’s age, such that infants and children (1 to <4 years of age) 
will receive ferrous sulfate drops, children (≥4 to <12 years of age) 
will have the option to receive ferrous sulfate elixir or ferrous sulfate 
tablets, and adolescents (≥12 to 17 years of age) will receive ferrous 
sulfate tablets. Participants who experience adverse clinical 
symptoms due to the oral iron during the treatment phase may have 
a weight-based dose of ferrous sulfate reduced from 6 mg/kg to 3 
mg/kg. If the participant is receiving tablets, the dose will be reduced 
from one tablet taken twice daily to one tablet per day.  
Once randomized, all participants will return for efficacy and safety 
evaluations, including adverse events and laboratory assessments, on 
Days 7, 14, 28, and 35. Additional pharmacokinetic sampling and 
analyses will be performed for participants receiving FCM on Days 
0 and 7. 


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Protocol No.: 1VIT17044 
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 Administrative Change 1 Date: Final 26 September 2019 
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Inclusion Criteria: 
 
1. Male or female participants 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 Hgb <11 g/dL. 
3. Screening ferritin ≤300 ng/mL and transferrin saturation (TSAT) <30%. 
4. Participants must have a documented history of an inadequate response to any oral 
iron therapy for at least 8 weeks (56 days) prior to randomization.   
5. For participants who are receiving an erythropoietin stimulating agent (ESA): stable 
ESA therapy (+/- 20% of current dose) for at least 8 weeks prior to the qualifying 
screening visit and no ESA dosing or product changes anticipated for the length of the 
trial. 
6. Participants undergoing treatment for inflammatory bowel disease (IBD) must be on 
stable therapy for at least 8 weeks prior to consent. 
 
Exclusion Criteria:    
1. Known history of hypersensitivity reaction to any component of FCM. 
2. Previous randomization and treatment in this study or any other clinical study of FCM. 
3. History of acquired iron overload, hemochromatosis, or other iron accumulation 
disorders. 
4. History of significant diseases of the liver, hematopoietic system, cardiovascular 
system, psychiatric disorder, or other conditions which, on the opinion of the 
investigator, may place a subject at added risk for participation in the study. 
5. Any existing non-viral infection.  
6. Known history of positive hepatitis B antigen (HBsAg) or hepatitis C viral antibody 
(HCV) with evidence of active hepatitis. 
7. Known history of positive HIV-1/HIV-2 antibodies (anti-HIV). 
8. Anemia due to reasons other than iron deficiency (e.g., hemoglobinopathy and vitamin 
B12 or folic acid deficiency) that has not been corrected.  
9. Intravenous iron and /or blood transfusion in the 4 weeks prior to consent.  
10. Administration and / or use of an investigational product (drug or device) within 30 
days of screening. 
11. Alcohol or drug abuse within the past six months. 
12. Female participant who is 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. 
13. Unable to comply with study procedures and assessments. 
Study Drug  
Administration 
Group A (FCM) will receive 2 doses (Day 0 and Day 7) of FCM at 
15 mg/kg to a maximum single dose of 750 mg (whichever is 
smaller) up to a maximum total dose of 1500 mg. FCM will be 
administered as either an undiluted IV push at a rate of 100 mg (2 
mL)/minute OR in no more than 250 mL of normal saline and infused 
over 15 minutes. 


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Protocol No.: 1VIT17044 
CONFIDENTIAL  
 Administrative Change 1 Date: Final 26 September 2019 
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Group B (Oral ferrous sulfate) will receive an age-dependent 
formulation of oral ferrous sulfate daily for 28 days as follows: 
participants <12 years of age will receive 6 mg (elemental 
iron)/kg/day divided into 2 daily doses of an oral liquid formulation, 
either drops or elixir, and participants ≥12 will receive 2 daily doses 
of oral tablets. Infants and children (ages 1 to <4 years) will receive 
oral ferrous sulfate drops, while children (ages ≥4 to <12 years) will 
have the option to receive oral ferrous sulfate elixir or oral ferrous 
sulfate tablets. Adolescents (ages ≥12 to 17 years) will receive an 
oral ferrous sulfate tablet (65 mg of elemental iron/tablet/dose) twice 
a day (BID). The maximum daily dose for all participants is 130 mg 
of elemental iron. 
Patient 
Assessments              All participants who provide informed consent/assent, meet 
inclusion criteria, and do not meet exclusion criteria will be 
randomized. Starting on Day 0 (the time of study drug dosing) 
through Day 35, all randomized participants will be subject to safety 
assessments including vital signs (including sitting heart rate and 
blood pressure), laboratory samples include hematology, chemistries 
and iron indices, and adverse event queries. Participants receiving 
oral iron treatment will be assessed for degree of compliance. 
Primary 
Endpoint: 
       
Change in hemoglobin from baseline to Day 35.       
Secondary 
Endpoints:                 Change in ferritin from baseline to Day 35 
Change in TSAT from baseline to Day 35  
Changes from baseline in hemoglobin, ferritin, TSAT, and 
reticulocyte hemoglobin content throughout the study. 
Pharmacokinetic assessments, including Cmax, Tmax, AUC0-time last 
measured concentration, AUC0-infinity, T1/2, MRT, Cl, VD, VDc, VDss, and 
VDarea. 
Study duration  
 
per participant: 
Approximately 6 weeks 
 
Study Sites:  
Approximately 30 
Participant Number: Approximately 72 randomized (N=36 FCM / N=36 Oral Iron) 
Sample Size Rationale:  
A total of 60 participants (30 per treatment group) are required to 
detect an expected difference in Hgb of 1.0 g/dL (common standard 
deviation = 1.16 g/dL) at two-sided alpha = 0.05 with 90% power.  


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CONFIDENTIAL  
 Administrative Change 1 Date: Final 26 September 2019 
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Assuming 20% attrition of subjects not meeting the definition of 
modified intention to treat (mITT), approximately 72 participants 
will be randomized. 


American Regent, Inc. 
 
Protocol No.: 1VIT17044 
CONFIDENTIAL  
 Administrative Change 1 Date: Final 26 September 2019 
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Figure 1. Study Diagram 


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CONFIDENTIAL 
Protocol No.: 1VIT17044 
Administrative Change 1 Date: Final 26 September 2019 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................................... 11 
1.0 INTRODUCTION .................................................................................................................... 13 
1.1 TREATMENT OF IRON DEFICIENCY ANEMIA .......................................................................................................... 13 
1.2 FERRIC CARBOXYMALTOSE ........................................................................................................................................ 14 
1.2.1 
KEY FEATURES OF FERRIC CARBOXYMALTOSE ........................................................................................ 14 
1.2.2 
FERRIC CARBOXYMALTOSE VERSUS OTHER PARENTERAL IRON AGENTS ....................................... 14 
2.0 TRIAL OBJECTIVE ................................................................................................................. 15 
2.1 PRIMARY OBJECTIVE .................................................................................................................................................... 15 
3.0 OVERALL STUDY DESIGN AND RATIONALE ................................................................. 15 
3.1 OVERALL STUDY DESIGN ............................................................................................................................................ 15 
3.2 RATIONALE OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS ............................................................. 15 
3.3 RATIONALE FOR SPARSE PHARMACOKINETIC SAMPLING ................................................................................ 17 
3.4 
SCHEDULE OF EVENTS ...................................................................................................................................... 18 
4.0 PARTICIPANT SELECTION .................................................................................................. 19 
4.1 NUMBER AND TYPE OF PARTICIPANTS .................................................................................................................... 19 
4.2 SCREENING PHASE ......................................................................................................................................................... 19 
4.2.1 Inclusion Criteria ......................................................................................................................... 19 
4.2.2 Exclusion Criteria ........................................................................................................................ 19 
4.3 PARTICIPANT ASSIGNMENT AND RANDOMIZATION PROCESS ......................................................................... 20 
4.4 WITHDRAWAL FROM STUDY ...................................................................................................................................... 20 
4.5 DISCONTINUATION FROM STUDY DRUG ................................................................................................................. 20 
4.6 CONCOMITANT INTERVENTION ................................................................................................................................. 20 
5.0 STUDY DRUG ......................................................................................................................... 21 
5.1 FORMULATION, PACKAGING AND STORAGE ......................................................................................................... 21 
5.2 DRUG ADMINISTRATION/REGIMEN .......................................................................................................................... 21 
5.3 IV MEDICATION PRECAUTIONS ................................................................................................................................. 22 
5.4 DRUG ACCOUNTABILITY ............................................................................................................................................. 22 
5.5 CONCOMITANT MEDICATION ..................................................................................................................................... 22 
6.0 STUDY PROCEDURES ........................................................................................................... 23 
6.1 INFORMED CONSENT ..................................................................................................................................................... 23 
6.2 SCREENING PHASE ......................................................................................................................................................... 23 
6.2.1 Screening Visit 1 (Day -7 ± 1)...................................................................................................... 23 
6.3 TREATMENT PHASE (DAY 0 TO DAY 35) .......................................................................................... 24 
6.3.1 Day 0 Visit .................................................................................................................................... 24 
6.3.2 Day 7 and Day 14 Visit ................................................................................................................ 26 


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6.3.3 Day 28 .......................................................................................................................................... 27 
6.3.4 Day 35 (End of Study / Early Termination).................................................................................. 27 
6.3.5 ORAL IRON DOSE REDUCTION DURING THE TREATMENT PHASE ............................................................... 27 
6.3.6 PHARMACOKINETIC SAMPLING ............................................................................................................................. 27 
6.4 CENTRAL LABORATORY ASSESSMENTS ................................................................................................................. 28 
7.0 ASSESSMENT OF SAFETY ................................................................................................... 28 
7.1 ADVERSE EVENTS .......................................................................................................................................................... 28 
7.2 REPORTING OF ADVERSE EVENTS ............................................................................................................................ 30 
7.3 SERIOUS ADVERSE EVENTS ........................................................................................................................................ 30 
8.0 STATISTICS ............................................................................................................................. 31 
8.1 STRATIFICATION/RANDOMIZATION ......................................................................................................................... 32 
8.2 ANALYSIS POPULATIONS ............................................................................................................................................. 32 
8.3 DISPOSITION AND BASELINE CHARACTERISTICS ................................................................................................. 33 
8.4 ENDPOINTS AND DEFINITIONS ................................................................................................................................... 33 
8.4.1 Primary Endpoint ......................................................................................................................... 33 
8.4.2 Secondary Endpoints .................................................................................................................... 33 
8.4.3 Missing Data ................................................................................................................................ 34 
8.5 ANALYSES OF SAFETY .................................................................................................................................................. 34 
8.5.1 STUDY DRUG EXPOSURE ......................................................................................................................................... 34 
8.5.2 ADVERSE EVENTS ...................................................................................................................................................... 34 
8.5.3 ADVERSE EVENTS OF SPECIAL INTEREST ........................................................................................................... 35 
8.5.4 CLINICAL LABORATORY FINDINGS ...................................................................................................................... 35 
8.5.5 VITAL SIGNS ................................................................................................................................................................ 36 
8.6 SAMPLE SIZE RATIONALE ........................................................................................................................................... 36 
9.0 ADMINISTRATIVE CONSIDERATIONS ............................................................................. 36 
9.1 RETENTION AND AVAILABILITY OF RECORDS ...................................................................................................... 36 
9.2 INVESTIGATOR RESPONSIBILITIES ............................................................................................................................ 36 
9.3 FINANCIAL DISCLOSURE .............................................................................................................................................. 37 
9.4 ADVERTISEMENT FOR PARTICIPANT RECRUITMENT .......................................................................................... 37 
9.5 DOCUMENTS REQUIRED FOR STUDY INITIATION ................................................................................................. 37 
9.6 QUALITY CONTROL AND QUALITY ASSURANCE ................................................................................................. 38 
9.6.1 Investigator Selection Criteria ..................................................................................................... 38 
9.6.2 Clinical Monitoring ...................................................................................................................... 38 
9.6.3 Quality Assurance Audit .............................................................................................................. 38 
9.7 ETHICS ............................................................................................................................................................................... 38 
9.7.1 Ethical and Legal Issues .............................................................................................................. 38 
9.7.2 Institutional Review Board ........................................................................................................... 39 


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9.7.3 Informed Consent ......................................................................................................................... 39 
9.7.4 Good Clinical Practice ................................................................................................................ 39 
9.8 DATA HANDLING AND RECORD KEEPING .............................................................................................................. 40 
9.8.1 Case Report Form ........................................................................................................................ 40 
9.8.2 Confidentiality .............................................................................................................................. 40 
9.8.3 Termination of the Study .............................................................................................................. 40 
9.8.4 Protocol Revisions ....................................................................................................................... 41 
9.8.5 Protocol Administrative Changes ................................................................................................ 41 
9.9 PUBLICATION POLICY ................................................................................................................................................... 41 
10.0 GOVERNANCE COMMITTEES .......................................................................................... 41 
10.1 DATA AND SAFETY MONITORING BOARD (DSMB) ....................................................................... 41 
INVESTIGATOR’S ACKNOWLEDGEMENT ............................................................................. 43 
REFERENCES 44 
APPENDIX 1: AMENDMENT CHANGES .................................................................................. 45 
AMENDMENT 1 CHANGES ............................................................................................................... 45 
AMENDMENT 2 CHANGES ............................................................................................................... 78 
ADMINISTRATIVE CHANGE 1 ......................................................................................................... 92 


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CONFIDENTIAL  
 Administrative Change 1 Date: Final 26 September 2019 
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LIST OF ABBREVIATIONS 
AE 
 
 
 
 
Adverse event 
ALT 
 
 
 
 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC0-infinity 
Extrapolated Area Under the Serum Concentration-
Time Curve from Time Zero to Infinity 
AUC0-time last measured concentration 
Area Under the Serum Concentration-Time Curve 
from Time Zero to the Last Sampling Time with a 
Quantifiable Concentration 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR  
Code of Federal Regulations 
CHr 
 
 
 
 
reticulocyte hemoglobin content  
CI 
Confidence interval 
Cl 
Apparent Serum Clearance 
Cmax 
Maximum Serum Concentration 
CKD 
Chronic Kidney Disease 
cm 
Centimeter 
CRF 
Case Report Form  
CTCAE 
Common Terminology Criteria for Adverse Events 
dL 
Deciliter 
DSMB 
Data and Safety Monitoring Committee 
EC 
Ethics Committee  
eCRF 
Electronic Case Report Form 
e.g. 
For exampleEOS 
End of Study 
ESA 
Erythropoiesis-Stimulating Agent 
FCM 
Ferric carboxymaltose 
FDA 
Food and Drug Administration 
Fe 
Iron 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
IBD 
Inflammatory Bowel Disease 
ICH 
International Conference on Harmonisation 
IDA 
Iron deficiency anemia 
i.e. 
that is 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 


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 Administrative Change 1 Date: Final 26 September 2019 
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kg 
Kilogram 
L 
Liter 
LDH 
Lactic dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
mITT 
Modified Intent-to-Treat 
MRT 
Mean Residence Time 
m 
Meter 
mg  
Milligram 
mL 
Milliliter 
ng 
Nanogram 
NS 
Normal saline 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
RBC 
Red Blood Cell 
RDW 
Red (cell) Distribution Width 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
T1/2 
Half-Life 
Tmax 
The time at maximum serum concentration 
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
TSI 
Total Serum Iron 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
White Blood Cell 
w/v 
weight / volume 
VD 
Apparent Volume of Distribution 
VDc 
Initial Volume of Distribution following injection 
VDss 
Volume of distribtion at the steady state 
VDarea 
Volume of distribution at the final elimination 


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 Administrative Change 1 Date: Final 26 September 2019 
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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 (US).1 Rapid growth, insufficient dietary intake, and limited absorption 
of dietary iron combine to place children at increased risk for iron deficiency. Iron 
malabsorption, gastrointestinal blood loss, or iatrogenesis due to repeated blood sampling 
all represent common clinical mechanisms that can result in IDA.  Even when recognized, 
some children are unable to tolerate prescribed oral iron supplementation or are 
unresponsive to it.2 Anemia may also decrease survival rates in adults and children with 
chronic renal impairment where it is a commonly encountered problem.3,4 In addition, 
under-recognized or inadequately treated anemia is likely the most common extra-intestinal  
manifestation of IBD in children, and it can result in a  decrease in quality of life and 
increased morbidity, inclusive of hospitalization,  in affected patients.2 
Non-hematologic consequences of iron deficiency in children include poor weight gain, 
anorexia, irritability, decreased attention span, exercise intolerance, and decreased physical 
activity.5 Existing data suggests that chronic IDA in infants and toddlers is associated with 
long-term diminished mental, motor, and behavioral functioning.  Although the exact 
relationship between iron deficiency and its detrimental effects on growth and development 
is not well-understood, it appears that these effects do not occur until iron deficiency 
becomes severe and chronic enough to produce anemia.6 
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 replete iron stores, but often scarce 
supply, as well as the potential risk of blood-borne pathogens, limits its use to severely ill 
or clinically unstable patients.2 In view of the limitations associated with oral iron 
administration or blood transfusions, IV iron administration is an important therapeutic 
option for use in patients with IDA.10 
Multiple parenteral iron products are available. These products vary in the way that iron is 
complexed, which influences the total amount of iron that may be administered during a 
single administration. Numerous other differences differentiate the products.  However, all 
appear to effectively release iron post administration and can restore iron deficit in the 
patient. Previous studies with parenteral iron sucrose (Venofer®) have been performed in 
the pediatric population.7-9 Iron doses have varied in these studies, and the data 
demonstrates the efficacy and safety of Venofer® in doses up to 7 mg iron/kg (or 200 mg) 
administered over 3 minutes, which was shown to be beneficial to both the child and health 
care facility.7 
FCM has been characterized as an 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 randomized interventional studies have been conducted with 
FCM in the pediatric population to date, the product has been used successfully to address 
iron deficiency in pediatric patients with ulcerative colitis and Crohn’s disease. A non-


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interventional, retrospective observational data collection reported FCM exposure in 79 
patients aged 2 to 18 years with a mean age of 12.7 years.  In these patients, FCM was found 
to be safe, well-tolerated, and effective in increasing hemoglobin, ferritin, and TSAT.18 
The proposed study will provide safety and efficacy data on the use of FCM in pediatric 
patients (aged between 1 and 17 years) with IDA. FCM will be administered in 2 doses at 
15 mg/kg maximum single dose of 750 mg with a total maximum cumulative dose of 1500 
mg.  The ability to infuse higher doses of elemental iron should permit repletion in fewer 
overall infusions, and in doing so may ultimately permit fewer visits to the treating facilities. 
1.2 Ferric Carboxymaltose 
1.2.1 Key features of Ferric Carboxymaltose 
FCM injection is a stable, non-dextran, Type I polynuclear iron (III)-hydroxide 
carbohydrate complex developed as an IV iron replacement therapy for the treatment of 
IDA. After IV administration, FCM is mainly found in the liver, spleen, and bone marrow.  
The iron slowly dissociates from the complex and can be efficiently used in the bone 
marrow for hemoglobin synthesis.  The carbohydrate moiety of FCM is metabolized by the 
glycolytic pathway.   
1.2.2 Ferric Carboxymaltose versus Other Parenteral Iron Agents 
There is considerable efficacy and safety data in the literature with respect to existing 
parenteral iron formulations.4 However, prior to the approval of non-dextran formulations, 
the risk of systemic adverse reactions restricted their use. FCM offers significant advantages 
compared to other available IV iron preparations.  
Iron dextran, the first parenteral iron product available in the US, has been associated with 
an incidence of anaphylaxis/anaphylactoid reactions (i.e., dyspnea, wheezing, hypotension, 
urticaria, angioedema) as high as 1.7%.7   Over the last 20 years, 30 deaths have been 
attributed to the use of IV iron dextran.17   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.8  Iron dextran is 
limited to second line therapy for treatment of iron deficiency.   
More recently approved intravenous iron formulations, including iron sucrose and iron 
gluconate, do not contain the dextran moiety.  However, they too have significant dosage 
and administration rate limitations.  If the body’s ability to sequester, store, and transport 
infused iron is overwhelmed, a reaction to excess free iron in circulation, referred to as a 
bioactive iron reaction, may occur.  Iron sucrose and iron gluconate preparations carry a 
significant risk of inducing a bioactive iron reaction when delivered at higher doses. These 
reactions are characterized by hypotension (without allergic signs) accompanied by pain in 
the chest, abdomen, flank and/or nausea, vomiting, and diarrhea.19  


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Due to its structure, FCM is more stable than iron gluconate and iron sucrose, and this 
results in a slower delivery of the complexed iron to endogenous iron binding sites.  FCM 
has an acute toxicity in animals approximately 1/5 that of iron sucrose.16 These 
characteristics of FCM 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 replete iron stores.   
2.0 TRIAL OBJECTIVE 
2.1 Primary Objective 
The primary objective of this study is to demonstrate the efficacy and safety of IV FCM 
compared to oral iron in pediatric participants who have IDA. 
3.0 OVERALL STUDY DESIGN AND RATIONALE 
3.1 Overall Study Design  
This is a Phase III, multicenter, multinational, randomized, active-controlled study that 
compares the efficacy and safety of FCM to oral iron in pediatric participants with IDA and 
a documented history of an inadequate response to oral iron at least 8 weeks (56 days) prior 
to randomization.   
Participants who satisfy the inclusion requirements and no exclusionary criteria will be 
eligible to participate in this study and enter into a screening phase to confirm eligibility. 
Randomization will occur via the IRT system in a 1:1 ratio to either Group A, participants 
receiving FCM, or Group B, participants receiving oral iron (oral solution drops, elixir or 
oral tablets) up to Day 28. Randomization will be stratified by baseline hemoglobin (<10, 
≥10 g/dL) and age (1 to <12 and ≥12 to 17 years).   
The oral ferrous sulfate formulation received will be based on the participant’s age, such 
that: infants and children (1 to <4 years of age) will receive ferrous sulfate drops, children 
(≥4 to <12 years of age) will have the option to receive ferrous sulfate elixir or ferrous 
sulfate tablets, and adolescents (≥12 to 17 years of age) will receive ferrous sulfate tablets. 
Participants who experience adverse clinical symptoms due to the oral iron during the 
treatment phase may have the weight-based dose of ferrous sulfate reduced from 6 mg/kg 
to 3 mg/kg. If the participant is receiving tablets, the dose will be reduced from one tablet 
taken twice daily to one tablet per day. 
Once randomized, all participants will return for efficacy and safety evaluations, including 
adverse events and laboratory assessments, on Days 7, 14, 28, and 35. Additional 
pharmacokinetic sampling and analyses will be performed for participants receiving FCM 
on Days 0 and 7. 
3.2 Rationale of Study Design and Choice of Control Groups  
Oral ferrous sulfate was selected as the active comparator because in addition to tablets, 
liquid formulations suitable for administration to pediatric participants in different age 


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groups are available. This iron salt is the most widely prescribed oral iron preparation for 
use in the treatment of pediatric IDA, relative to other preparations, according to a survey 
of pediatric hematology/oncology specialists.11 Ferrous sulfate drops, (15 mg elemental 
iron/mL), may be used as an iron supplement for infants and children up to 4 years of age, 
per manufacturer labeling.15 Oral ferrous sulfate elixir will be provided as an alternative 
preparation to oral tablets in order to ameliorate the difficulty of swallowing tablets with 
children. Per the recommended total daily dose of oral elemental iron for the treatment of 
IDA in pediatric patients ranges between 3-6 mg/kg/day divided into one to three doses, a 
total daily dose of 6 mg/kg/day divided into 2 doses (maximum daily dose of 130 mg of 
elemental iron) was selected for all ages based on the most common practice of pediatric 
hematology physicians in the United States.11 Additionally, the simplified regimen may 
minimize adverse effects associated with high-dose oral iron therapy and thus improve 
medication adherence.13  
With respect to FCM, doses of 15 mg/kg with a maximum of 750 mg per dose have been 
selected based off evidence generated from American Regent’s Phase II dose-finding 
PK/PD study in which cohorts received single, weight-based doses of FCM at either 7.5 
mg/kg or 15 mg/kg.16 Results from this study demonstrate that the higher weight-based dose 
is both efficacious and safe. The mean increase from baseline to Day 35 was larger for 
participants in Cohort 2 receiving 15 mg/kg (2.8 ± 1.15 g/dL) than those in Cohort 1 
receiving 7.5 mg/kg (1.9 ± 1.38 g/dL). The mean increase in ferritin and TSAT at Day 35 
was 35.1 ± 98.22 ng/mL and 9.9 ± 11.54%, respectively, for Cohort 1 (N=16) and 52.4 ± 
31.7 ng/mL and 13.5 ± 6.88%, respectively, for Cohort 2 (N=18), respectively.  (Table 1)  
Table 1. Mean Change from Screening in Hemoglobin, Ferritin, and TSAT (Safety 
Population) in 1VIT13036   
Parameter 
Cohort 1 (N=16) 
Cohort 2 (N=19) 
Hemoglobin, g/dL 
Screening mean (SD) 
Mean change at Day 35 (SD) 
 
 
 
9.2 (1.20) 
1.9 (1.38) 
 
 
9.5 (0.81) 
2.8 (1.15) 
Ferritin, ng/mL 
   Screening mean (SD) 
   Mean change at Day 35 (SD)  
 
 
8.9 (9.94) 
 
35.1 (98.22) 
 
 
20.2 (67.37) 
N=18 
52.4 (31.70) 
TSAT, % 
  Screening mean (SD) 
  Mean change at Day 35 (SD) 
 
 
7.5 (4.64) 
9.9 (11.54) 
 
 
3.4 (1.61) 
N=18 
13.5 (6.88) 
SD = standard deviation. 


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Similar percentages of participants in Cohort 1 (56.3%) and Cohort 2 (63.2%) reported at 
least 1 treatment-emergent adverse event (TEAE). At least 1 drug-related treatment-
emergent adverse event was reported by 3 of 16 (18.8%) participants in Cohort 1 and 6 of 
19 (31.6%) participants in Cohort 2. Specifically, the only TEAE considered related to study 
drug that was experienced by >1 participant was urticaria (3 participants in Cohort 2). Other 
TEAEs considered related to study drug and experienced by 1 participant each included 
infusion site pruritus, thirst, and hot flush in Cohort 1 and abdominal pain upper, 
gastroduodenitis, hyperthermia, injection site pain, alanine aminotransferase increased, 
headache, pruritus, rash, and hypertension in Cohort 2.  Two participants in Cohort 1 
experienced a serious adverse event. (Table 2) 
Table 2. Overview of Treatment-Emergent Adverse Events (Safety Population) in 35 
Study Subjects 
Type of Treatment-Emergent Adverse 
Event 
Cohort 1 (N=16) 
No. (%) 
Cohort 2 (N=19) 
No (%) 
Anya 
9 (56.3) 
12 (63.2) 
At least 1 serious event 
At least 1 severe eventb 
At least 1 related to study drugc 
2 (12.5) 
1 (6.3) 
3 (18.8) 
0 
0 
6 (31.6) 
CTCAE = Common Terminology Criteria for Adverse Event 
a If a subject experienced the same event more than once, the first occurrence was tabulated. 
b CTCAE Grade 3, 4, or 5. 
c Possibly or probably related to study drug. 
Further justification for the 15 mg/kg dose is provided by internal modeling data, which 
demonstrated comparable total serum iron clearance profiles between pediatric and adult 
populations.14  Lastly, a retrospective cohort study of 72 pediatric patients with IDA 
refractory to oral iron treatment ranging in age from 9 months to 18 years treated with 15 
mg/kg of FCM (maximum single dose of 750 mg; median dose 750 mg) supports this 
dosing.12 
3.3 Rationale for Sparse Pharmacokinetic Sampling: 
Population-based PK/PD modelling describing the time course of total serum iron (TSI) 
concentrations and the relationship between TSI and changes of hemoglobin following a 
single dose of intravenous FCM in pediatric subjects with IDA has been performed using 
intensively sampled data from Study 1VIT13036.16  It is proposed to supplement this initial 
modelling with additional sparsely sampled PK data from this study. Based on the 
anticipated visit duration on the 2 FCM administration days in this study, the following 
sparse PK sampling scheme is proposed: pre-dose, immediately (within 5 minutes) post-
infusion and 60 minutes post-dose on Days 0 and 7, on which subjects will receive 15 mg/kg 
(up to a maximum dose of 750 mg). This pragmatic approach, which minimizes the number 
of blood draws compared to a full PK profile, is expected to facilitate exposure-response 
analysis for the proposed FCM regimen. 


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3.4  
Schedule of Events 
1For a full description of central laboratory assessments, refer to Protocol Section 6.4. 
2 Blood samples for pharmacokinetic analysis will be collected pre-dose, immediately (within 5 minutes) post-
dose, and 60 minutes post-dose for participants receiving FCM. For a full description of the pharmacokinetic 
parameters, refer to Protocol section 6.3.6. 
Visit Day 
Screening  
(Day -7 + 
1) 
Day 0 
Day 7 
Day 14 
Day 28 
Day 35 
Informed Consent / 
Assent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Exam 
 
X 
 
 
 
X 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
IRT 
X 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
Temperature 
 
X 
X 
 
 
 
Hematology, Chemistry 
and Iron Indices1 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test 
X 
 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
IBD Treatment / ESA 
Stability (if applicable) 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessments 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
Injectafer® Dosing 
 
X 
X 
 
 
 
Pharmacokinetic 
Sampling2 
 
X 
X 
 
 
 
Oral Iron Dosing 
 
X 
X 
X 
X 
 
Oral Iron Dispensing 
 
X 
X 
X 
 
 
Oral Iron Compliance 
Assessment 
 
 
X 
X 
X 
 


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4.0 PARTICIPANT SELECTION 
4.1 Number and Type of Participants 
Approximately 72 participants who have given written informed consent/assent with a 
diagnosis of IDA who fulfill the inclusion criteria and do not meet any of the exclusion 
criteria will be randomized to receive either FCM or Oral Iron.  
4.2 Screening Phase 
A subject who enters the screening phase will be assigned, via the IRT system, a unique 
screening number. From the time of consent until the start of treatment with study drug, the 
participant will not receive any form of supplemental 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).  Dietary iron intake will not be restricted during 
participation in the study. 
If the participant does not qualify for study entry, the participant should be entered into the 
IRT system as a screen failure.  Participants can be re-screened once (See section 6.2).   
4.2.1 Inclusion Criteria  
1. Male or female participants 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 hemoglobin <11 g/dL. 
3. Screening ferritin ≤ 300 ng/mL and TSAT <30%. 
4. Documented history of an inadequate response to any oral iron therapy for at least 
8 weeks (56 days) prior to randomization.   
5. If receiving an ESA: stable ESA therapy (+/- 20% of current dose) for at least 8 
weeks prior to the qualifying screening visit and no ESA dosing or product 
changes anticipated for the length of the trial. 
6. If undergoing treatment for IBD must be on stable therapy for at least 8 weeks 
prior to consent. 
4.2.2 Exclusion Criteria 
1. Known history of hypersensitivity reaction to any component of FCM. 
2. Previous randomization and treatment in this study or any other clinical study of 
FCM. 
3. History of acquired iron overload, hemochromatosis, or other iron accumulation 
disorders. 
4. Significant severe diseases of the liver, hematopoietic system, cardiovascular 
system, psychiatric disorder, or other conditions which on the opinion of the 
investigator may place a subject at added risk. 
5. Any existing non-viral infection.  
6. Known history of positive hepatitis B antigen (HBsAg) or hepatitis C viral 
antibody (HCV) with evidence of active hepatitis. 


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7. Known history of positive HIV-1/HIV-2 antibodies (anti-HIV). 
8. Anemia due to reasons other than iron deficiency (e.g., hemoglobinopathy and 
vitamin B12 or folic acid deficiency) that have not been corrected. 
9. Intravenous iron and /or blood transfusion in the 4 weeks prior to consent.  
10. Administration and / or use of an investigational product (drug or device) within 
30 days of screening. 
11. Alcohol or drug abuse within the past six months. 
12. Female participant who is pregnant or lactating, or sexually active female of 
childbearing potential not willing to use an acceptable form of contraceptive 
precautions during the study. 
13. Unable to comply with study procedures and assessments. 
4.3 Participant Assignment and Randomization Process 
Participants who satisfy the inclusion requirements and no exclusionary criteria will be 
eligible to participate in this study and entered into the IRT system. Randomization will 
occur in a 1:1 ratio to either Group A, participants receiving FCM, or Group B, participants 
receiving oral iron (oral solution drops, elixir or oral tablets). Randomization will be 
stratified by baseline hemoglobin (<10, ≥10 g/dL) and age (1 to <12 and ≥12 to 17 years).   
The oral ferrous sulfate formulation received will be based on the participant’s age, such 
that: infants and children (1 to <4 years of age) will receive ferrous sulfate drops, children 
(≥4 to <12 years of age) will receive ferrous sulfate elixir or ferrous sulfate tablets, and 
adolescents (≥12 to 17 years of age) will receive ferrous sulfate tablets. Participants who 
experience adverse clinical symptoms due to the oral iron during the treatment phase may 
have their weight-based dose of ferrous sulfate reduced from 6 mg/kg to 3 mg/kg. If the 
participant is receiving tablets, the dose will be reduced from one tablet taken twice daily 
to one tablet per day. 
4.4 Withdrawal from Study 
Any participant 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 participant from active study 
treatment at any time if it is felt to be in the best interest of the participant.  
4.5 Discontinuation from Study Drug 
Participants may elect to discontinue study drug, but wish to remain in the study for follow-
up. In those situations, patients will be asked to continue the normal clinical trial schedule 
for ascertainment of safety events. 
4.6 Concomitant Intervention 
Concomitant intervention is defined as follows: 
 Blood transfusion. 
 Use of IV or oral iron outside of protocol. 
 Increase in erythropoietin for any reason (Day 0 thru Day 35). 


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 Change in IBD treatment  
When concomitant intervention occurs, the date of the intervening event should be recorded 
in the source documents, and the electronic Case Report Form (eCRF).  The participant 
should continue in the study as scheduled. 
5.0 STUDY DRUG  
5.1 Formulation, Packaging and Storage 
All investigational medication to be used in this study [supplied by American Regent, Inc.] 
will have been prepared according to Good Manufacturing Practices (GMP). 
FCM (trade name, Injectafer®) will be supplied as 15 ml vials, containing 750 mg of iron 
as 5% w/v iron containing a polynuclear iron(III)-hydroxide 4(R)–(poly-(14)-O  -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.   
Oral iron will be provided depending on participant’s age as either blister packs of oral iron 
tablets or oral liquid formulation (drops or elixir) in pre-filled syringes. 
All study drugs (FCM and ferrous sulfate) must be kept in a secure place at the 
investigational site, and stored at room temperature (See USP).  The study medication 
should not be frozen.  Vials of FCM may not be used for more than 1 dose, or for more than 
1 participant.  All FCM vials, oral iron blister packs and syringes (used and unused) should 
be kept by the study staff for reconciliation by the monitor. Following reconciliation, sites 
may destroy used and unused study drug on site using local procedures, provided a drug 
destruction policy is in place, or it may be returned to American Regent, Inc.  
5.2 Drug Administration/Regimen  
The Principal Investigator or designee will supervise administration of the study drug to 
participants.  Group B (Ferrous sulfate) the first dose of will be administered before the end 
of the Day 0 visit. 
Group A:  
Group A (FCM) will receive a dose of FCM at 15 mg/kg to a maximum 
single dose of 750 mg (whichever is smaller) on Days 0 and 7 for a maximum 
total dose of 1500 mg. FCM will be administered as either an undiluted IV 
push at a rate of 100 mgs (2 mL)/minute OR in no more than 250 mL of 
normal saline and infused over 15 minutes. 
Group B:  
Group B (Oral Ferrous sulfate) will receive an age-dependent formulation of 
oral ferrous sulfate daily for 28 days as follows: participants <12 years of 
age will receive 6 mg (elemental iron)/kg/day divided into 2 daily doses of 
an oral liquid formulation, either drops or elixir, and participants ≥12 will 
receive 2 daily doses of oral tablets. Infants and children (ages 1 to <4 years) 
will receive oral ferrous sulfate drops, while children (ages ≥4 to <12 years) 


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will have the option to receive oral ferrous sulfate elixir or oral ferrous 
sulfate tablets. Adolescents (ages ≥12 to 17 years) will receive an oral 
ferrous sulfate tablet (65 mg of elemental iron/tablet/dose) twice a day 
(BID). The maximum daily dose for all participants is 130 mg of elemental 
iron. 
5.3 IV Medication Precautions 
When administering FCM, the following precautions will be taken: 
 The participant will be evaluated clinically prior to drug administration to assess 
the development of clinically-significant conditions.   
 The vials will be visually inspected for particulate matter and discoloration 
before use.  If noted, the vial will not be used, and the Investigator or his designee 
will notify the sponsor or sponsor’s designee for replacement of the study drug, 
and for direction on the return of the unused vial. 
 Heart rate and blood pressure will be assessed pre-, immediately (within 5 
minutes) post, and 30 minutes post administration.  Participants will be 
discharged from the site by the Investigator or his or her designee only if there 
are no significant signs or symptoms 30 minutes after the administration is 
completed. 
 The participant will be monitored for at least 30 minutes for serious acute 
reactions as hypersensitivity or bioactive (labile) iron reactions to non-dextran 
IV iron products have rarely been reported. The reactions include: hypotension, 
loss of consciousness, bronchospasm with dyspnea, shortness of breath, and 
seizures. 
o In the event a serious acute reaction is seen, the site must have the 
capability to provide appropriate resuscitation measures. These may 
include IV NS, IV epinephrine, steroids, and/or antihistamines. 
5.4 Drug Accountability 
Investigators will keep records of the receipt, administration and return of the study drug 
(FCM and ferrous sulfate).  They will not allow the study drug 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 enrolled 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 the unused 
study drug will be returned to American Regent, Inc., or destroyed on site, per the site’s 
documented locally accepted policies. All data regarding the study drug must be recorded 
as per the Monitoring Plan.   
5.5 Concomitant Medication 
All concomitant medications will be recorded in the eCRF from 30 days prior to consent.  
No additional iron preparations (IV iron from 4 weeks prior to consent or oral iron 


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Protocol No.: 1VIT17044 
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including multivitamins with iron, from time of consent) will be allowed.  No 
prophylactic medications may be administered prior to FCM administration without 
prior approval from American Regent, Inc. 
If receiving an ESA, a stable (± 20%) dose is required for at least 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. 
If receiving treatment for IBD, therapy must be stable for at least 8 weeks prior to consent 
and remain stable through the duration of the study. 
6.0 STUDY PROCEDURES 
6.1 Informed Consent 
Prior to any study specific procedures, the investigator must explain to each participant 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 participant (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 US government. Subjects who are too young 
to sign an ICF, but mature enough to understand the study, will provide informed assent per 
local law.  The subject must be able to understand that he or she can withdraw from the trial 
at any time and for any reason.  The participant’s legal guardian will be given a copy of the 
signed consent form. 
6.2 Screening Phase  
6.2.1 Screening Visit 1 (Day -7 ± 1) 
Each participant who qualifies for inclusion will undergo the following clinical 
evaluations to confirm their eligibility for the study: 
 Obtain screening number from IRT 
 Medical history, including documented history of an inadequate response after at 
least 8 weeks of prior oral iron therapy use 
 Hematology, chemistries and iron indices  
 Serum pregnancy test for female participants of child bearing potential (negative 
results must be obtained prior to randomizing the participant for study drug 
dosing). 
 Height and weight 
 Vitals signs (including sitting heart rate and blood pressure)  


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 Concomitant medications assessment 
 ESA and IBD therapy stability (if applicable)  
** Participants who do not meet the entry criteria should be entered into the IRT system as 
a screen failure.  A participant may be re-screened, only one time, once it is believed that 
they would qualify for study entry.  The participant will need to re-sign a new consent form 
and all screening procedures in section 6.2 will need to be repeated. 
6.3 Treatment Phase (Day 0 to Day 35) 
6.3.1 Day 0 Visit 
The following will be obtained and/or completed before contacting IRT for randomization: 
For all participants: 
 Verify all inclusion and exclusion criteria (See section 4.2.1 and 4.2.2) 
 Physical exam 
 Review concomitant medications (to include ESA and IBD stability, if 
applicable). 
A participant who develops a bacterial infection during the screening phase should be 
discontinued and treated appropriately.  These participants may be re-screened, one time, 
once the enrolling physician deems the participant would qualify for study entry.  The 
participant will need to re-sign a new consent / assent form and all screening procedures in 
section 6.2 will need to be repeated. 
After verifying the eligibility of the participant, the IRT system will then be contacted by a 
study team member.  Randomization will be stratified by hemoglobin (<10, ≥10 g/dL) and 
age (1 to <12 and ≥12 to 17 years), and randomized in a 1:1 ratio to either Group A (FCM 
at 15 mg/kg to a maximum single dose of 750 mg on Days 0 and 7 for a maximum total 
dose of 1500 mg) or Group B (Ferrous sulfate, dose and regimen dependent upon age and 
weight, twice daily for 28 days. 
After a randomization number has been obtained, the first dose of oral ferrous sulfate will 
be administered in the clinic according to the following: infants and children (1 to <4 years 
of age) will receive ferrous sulfate drops; children (≥4 to <12 years of age) will receive 
ferrous sulfate elixir or ferrous sulfate tablets; and adolescents (≥12 to 17 years of age) will 
receive ferrous sulfate tablets. 
A sufficient quantity of doses for a 7-day period will be dispensed to the parent or guardian 
of the participant. The parent or guardian of the participant will be responsible for the 
administration of two daily doses of oral ferrous sulfate to the participant. 
After assignment of the treatment group, the following will occur:  
All participant’s (prior to study drug administration/dispensing, if applicable) on Day 0: 
 Blood samples for central lab hematology, chemistries, and iron indices (Group 


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A participants will have an additional blood sample for PK prior to dosing) 
 Vital signs: temperature, sitting heart rate and blood pressure 
 Weight 
Group A: 
 Blood samples for PK immediately (within 5 minutes) post-dose and 60 
minutes post dose. 
 Verify amount of single FCM dose (15mg/kg up to a maximum single dose of 
750 mg).  
 Administer FCM as a slow IV injection at the rate of approximately 2 mL 
/minute or in no more than 250 mL of normal saline and infused over 15 
minutes.  
 Document start and stop time of FCM administration and the total dose 
administered and if diluted.  
 Post-administration evaluation to include measurement of sitting heart rate and 
blood pressure immediately (within 5 minutes) after and 30 minutes after FCM 
administration.  
 Adverse event / serious adverse event assessment (starting at beginning of 
FCM injection).  
Group B:  
 Oral ferrous sulfate dispensing: 
o The first dose of ferrous sulfate will be administered before the end of 
the Day 0 visit. 
o Parents or guardians of participants will be responsible for the 
administration of twice daily dosing of oral ferrous sulfate. Participants 
that experience adverse events may continue with a dose-reduced 
regimen [3 mg/kg twice daily] of oral ferrous sulfate after a consult 
with the investigator. (See Section 6.3.5 for oral iron dose reduction) 
o Parents or guardians of participants will be dispensed oral iron on Days 
0, 7, and 14.  Used dispensing packs/blisters/syringes will be returned 
and are to include both the empty containers and any unused 
medication.   
o A record of compliance will be maintained for each participant and 
reviewed at each study visit. (See Section 6.3.2 for compliance 
assessment).  
o If the participant took less than the amount of oral iron expected, 
document the reason(s) for missed doses and counsel the 
participant/parents/guardians about the importance of taking the study 
drug as prescribed. 
 Adverse event assessment (starting once the participant takes the first in-clinic 
dose). 


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6.3.2 Day 7 and Day 14 Visit 
All participants will return to the clinic on Day 7 and 14.  Prior to the administration of the 
study drug (if applicable), the participant will be evaluated clinically to assess for the 
development of clinically significant conditions that may contraindicate dosing. 
 Vital signs (including sitting heart rate and blood pressure)  
 Blood samples for central lab hematology, chemistries and iron indices (Group A 
participants will have an additional blood sample for PK prior to dosing). 
 Concomitant medications assessment 
 Adverse events assessment 
 ESA and IBD stability (if applicable) 
 
For Group A participants the following will be performed on Day 7 only: 
 Blood samples for PK immediately (within 5 minutes) post-dose and 60 minutes 
post dose. 
 Verify amount of single FCM dose (15mg/kg up to a maximum dose of 750 mg).  
 Pre-administration evaluation to include measurement of heart rate, blood 
pressure, and body temperature.  
 Administer FCM as a slow IV injection at the rate of approximately 2 mL /minute 
or in no more than 250 mL of normal saline and infused over 15 minutes. 
 Document start and stop time of FCM administration and the total dose 
administered and if diluted. 
 Post-administration, obtain sitting heart rate and blood pressure immediately 
(within 5 minutes) after and 30 minutes after FCM administration. 
 
For Group B participants the following will be performed:  
 Oral iron dispensing (Day 7 and Day 14). 
 Compliance will be assessed according to the following: 
For ferrous sulfate tablets: 
o Used blister packs will be returned and are to include both the empty 
containers and any unused medication.   
o The blister packs will be examined to assess compliance (the number taken 
divided by the number of pills expected to be taken). A record of compliance 
will be maintained for each participant and reviewed.   
o If the participant took less than the number of tablets expected, document the 
reason(s) for missed doses and counsel the participant/parent/guardian about 
the importance of taking the study drug as prescribed. 
 
For ferrous sulfate drops and elixir: 
o Used oral syringes will be returned which will include any unused medication.   


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o The oral syringes will be examined to assess compliance (the volume 
remaining in the oral syringes divided by the expected amount to be taken). A 
record of compliance will be maintained for each participant and reviewed. 
o If the participant took less than the volume expected, document the reason(s) 
for missed doses and counsel the participant/parent/guardian about the 
importance of taking the study drug as prescribed. 
6.3.3 Day 28 
 Vitals signs  
 Hematology, chemistries and iron indices  
 Concomitant medications assessment 
 ESA and IBD stability (if applicable) 
 Adverse events assessment 
 For Group B participants, oral iron compliance assessment 
6.3.4 Day 35 (End of Study / Early Termination) 
 Physical exam  
 Vitals signs  
 Hematology, chemistries, and iron indices  
 Serum pregnancy test for female participants of child bearing potential 
 Concomitant medications assessment 
 ESA and IBD stability (if applicable) 
 Adverse events assessment 
 Log into IRT and enter participant as complete 
The participant has completed the study after the Day 35 visit is complete.  If for any reason 
the participant does not complete the study the Day 35 procedures should be completed 
prior to the participant exiting from the trial.   
6.3.5 Oral Iron Dose Reduction during the Treatment Phase 
Participants who experience adverse events possibly or probably due to the oral iron during 
the treatment phase will have their dose of ferrous sulfate reduced from 6 mg/kg to 3 mg/kg 
while maintaining the same frequency of twice per day. If the participant is receiving tablets, 
the dose will be reduced from one tablet taken twice daily to one tablet per day. 
6.3.6 Pharmacokinetic Sampling 
Blood samples will be collected for PK assessment pre-dose, immediately (within 5 
minutes) post-dose, and 60 minutes post-dose for participants receiving FCM on Days 0 
and 7. Blood samples should be taken at approximately the same time of day (within 1 hour) 
on Day 7 as Day 0. 
The pharmacokinetic parameters to be analyzed in this study are as follows: the maximum 
serum concentration (Cmax) and the time at which Cmax occurs (Tmax), the area under the 


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serum concentration-time curve from time zero to the last sampling time 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). 
The secondary parameters were 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). 
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 3.4.  
Hematology: 
Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, 
platelets, differential count, reticulocyte count, and 
reticulocyte hemoglobin content (CHr) 
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 participant during the course of this clinical 
trial, whether or not it is related to the investigational product, at any dose, is considered an 
adverse event (AE).  
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. 


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For the purposes of this study, non-serious anemia (Hgb 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 5 or higher 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 
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 AE will be reported from the initial treatment with *Study Drug 
through the completion of the study Day 35. Adverse events will be captured 28 days post 
the last dose of study drug for participants who receive study drug and terminate early from 
the trial. This can be completed via a phone call. All ongoing AE’s related to study drug 
(FCM or ferrous sulfate) should be followed until they are no longer related, have taken a 
confounding medication or return to baseline grade 
Relationship (Causality): The Investigator will be asked to document his/her opinion of 
the relationship of the event to the study drug* as follows: 
 NONE  
There is no evidence of any causal relationship. 


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 UNLIKELY There is little evidence to suggest there is a causal relationship. 
There is another reasonable explanation for the event (e.g., the 
participant’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 participant’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: 
    
FCM 
 
OR 
 
Ferrous Sulfate 
7.2 Reporting of Adverse Events 
Adverse experiences will be elicited by nonspecific questions such as “Have you noticed 
any problems?”  Participants will be encouraged to report adverse events at their onset.   
Any adverse experience spontaneously reported by, elicited from the participant, 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 participant was at substantial risk of dying at the time of the 
adverse event or it is suspected that the use or continued use of the product would 
result in the participant's death. 
 Hospitalization (initial or prolonged): Required admission to the hospital or 
prolongation of a hospital stay. 


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 Disability: Resulted in a significant, persistent, or permanent change, impairment, 
damage or disruption in the participant’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 participant or may require intervention to 
prevent one of the other outcomes listed above. 
A distinction should be drawn between SAE and severe AE.  A SAE is a major experience 
of its type.  A SAE 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 day of initial treatment with *study drug 
through the completion of the study Day 35.  Serious adverse events will be captured 28 
days post the last dose of study drug for participants who are randomized and terminate 
early from the trial. This can be completed via a phone call. Hospitalization resulting from 
a historical condition (present prior to initial treatment with study drug or prescheduled 
prior to treatment with study drug) that has not increased in severity or led to prolongation 
of hospital stay should not be considered a SAE. All reported SAE 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 American Regent, Inc. by telephone, email and/or fax of the 
written SAE report form to the contacts listed below: 
American Regent, Inc. 
Tel: 800-734-9236 
Email: pv@americanregent.com 
The local investigator is responsible for reporting SAEs to their local IRB/ Ethics 
Committee based on local reporting guidelines (which may be different than those specified 
in this protocol). The responsible investigator should institute appropriate diagnostic and 
therapeutic measures and keep the participant under observation for as long as is medically 
indicated. 
8.0 STATISTICS 
All hypothesis tests and confidence intervals will be two-sided.  No correction for multiple 
testing will be applied amongst the secondary endpoints.  Except where otherwise noted, 
the statistical model on which inference is based will include terms for randomization strata.   


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Continuous variables will be summarized in terms of the number of observations, mean, 
standard deviation, median, Q1, Q3, minimum and maximum. Other descriptive statistics 
(e.g., coefficient of variation) may be reported when appropriate. Categorical variables will 
be summarized using frequency counts and percentages.   
Generally, data will be summarized by nominal visit.  However, data from both unscheduled 
and scheduled will be used for determination of last observed value, and in worst- or best-
case changes and/or shifts from baseline. Assessment windows will not be defined for the 
purpose of classifying measurements obtained outside scheduled assessment times. 
A complete description of the statistical analyses and methods will be available in a 
Statistical Analysis Plan (SAP), which will be finalized before the database is locked. 
8.1 Stratification/Randomization 
Participants who meet the inclusion/exclusion criteria will be randomized on Day 0 to FCM 
or oral iron in a 1:1 ratio. The randomization will be stratified by hemoglobin (<10, ≥10 
g/dL) and age (1 to <12 and ≥12 to 17 years).  
8.2 Analysis Populations 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will comprise all randomized participants. Participants 
will be evaluated according to the treatment to which they were randomized. Any 
participant who receives a treatment randomization number will be considered to have been 
randomized. 
Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) population will comprise all participated in the ITT 
population who receive at least one dose of study drug, have a baseline hemoglobin 
measurement, and at least one corresponding post-baseline measurement.  Participants will 
be evaluated according to the treatment to which they were randomized.  The primary 
population for the assessing efficacy will be the mITT population. 
Safety Population 
The safety population will consist of all participants in the ITT population who received at 
least one dose of study drug.  Participants will be evaluated according to treatment received.  
This population will be used for assessing safety. 
Pharmacokinetics Population 
The Pharmacokinetics (PK) population will consist of all participants in the Safety 
population with at least one measurable concentration of FCM. 


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8.3 Disposition and Baseline Characteristics 
The number of participants in each investigative site will be summarized.  The number of 
participants who are screened, randomized, treated, prematurely discontinue, and complete 
the study will be summarized.    
The clinical team will identify deviations and the deviations will be identified in the 
database.  Participants with clinically important protocol deviations will be summarized. 
Demographics and baseline characteristics will be summarized using descriptive statistics 
or frequency counts. 
8.4 Endpoints and Definitions 
8.4.1 Primary Endpoint 
The primary endpoint is the change in hemoglobin from baseline to day 35.  The change in 
hemoglobin from baseline to day 35 will be analyzed using parametric analysis of 
covariance (ANCOVA).  The model will include terms for the randomization strata 
(hemoglobin and age categories), baseline hemoglobin, as well as treatment group. Baseline 
hemoglobin will be defined as the last hemoglobin obtained before randomization. 
The primary endpoint will be analyzed for the mITT population. 
Subgroup analyses 
The change in hemoglobin from baseline to day 35 will be summarized separately for the 
following subgroups: 
 Cause of IDA: IBD, not IBD     
 CKD, not CKD 
 Baseline hemoglobin : <10,  ≥10 g/dL   
 Age:  1 to <12,  ≥12 to 17 years 
Estimates of treatment effect together with 95% confidence intervals will be displayed 
graphically. 
Subgroup analyses will be conducted for the mITT population. 
8.4.2 Secondary Endpoints 
Secondary efficacy endpoints include: 
 Change in ferritin from baseline to Day 35 
 Change in TSAT from baseline to Day 35  
 Changes from baseline to in hemoglobin, ferritin, TSAT, and reticulocyte 
hemoglobin content. 
 Pharmacokinetic assessments, including Cmax, Tmax, AUC0-time last measured concentration, 
AUC0-infinity, T1/2, MRT, Cl, VD, VDc, VDss, and VDarea. These assessments will be 


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based on a population pharmacokinetic analysis using data from this study and 
1VIT13036. 
Continuous efficacy endpoints will be analyzed using ANCOVA as described for the 
primary endpoint. Binary efficacy variables will be analyzed using stratified Cochran-
Mantel-Haenszel chi-square tests. 
All secondary efficacy endpoints will be analyzed for the mITT population. 
Details of analyses for these endpoints will be outlined in the SAP.   
Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints 
The PK  parameters will be calculated by standard non-compartmental analysis according 
to current working practices and using WinNonlin®. All calculations of non-
compartmental parameters will be based on actual sampling times. The actual sampling 
times and doses will be used for the analysis.  The PK parameters will be calculated with 
and without adjustment for baseline. All derived PK parameters will be listed. The 
following summary statistics will be calculated: n, mean, standard deviation [SD], 
coefficient of variation (CV) , median, minimum, and maximum, along with geometric 
mean, geometric mean SD, geometric percent coefficient of variation [%CV], and 95% 
CIs around the geometric mean. For Tmax, only n, median, minimum and maximum will be 
presented.  
In addition, nonlinear mixed effects modelling will be used derive population PK parameters and/or 
models. The influence of various covariates (e.g., age, weight, sex, race) on the variability will be 
examined. Further details will be provided in the SAP. 
The relationship between FCM exposure and clinical outcome may be explored graphically. If 
appropriate, a relationship may be established between FCM exposure and effect or any special 
interest adverse events. Further details will be provided in the SAP. 
8.4.3 Missing Data 
A participant who withdraws from the study for any reason will be included in the analyses 
regardless of time on study. Methods for handling withdrawals and missing data will be 
specific to each endpoint to be analyzed. Details will be provided in the SAP. 
8.5 Analyses of Safety 
8.5.1 Study Drug Exposure 
For FCM, the number of infusions and total administered amount of iron will be 
summarized descriptively. For oral iron, the total amount of iron will be summarized 
descriptively. 
8.5.2 Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  


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The number and percent of participants who report TEAE will be summarized for each 
treatment group. A TEAE is an event with onset date on or after the study drug start date.  
Adverse event summaries will exclude preferred terms that describe asymptomatic serum 
ferritin, TSAT, and reticulocyte values (or changes). This approach is justified by the 
reporting of these values in efficacy summaries and is consistent with the protocol-defined 
reporting standards for hemoglobin/hematocrit and low iron indices.  For the purposes of 
this study, non-serious anemia (hemoglobin or hematocrit 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. 
The adverse event profile will be characterized with severity (as graded by  the National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]) and 
relationship (unrelated and related) to study drug. Related adverse events will be events that 
are possibly or probably related to treatment in the investigator’s judgment.  
Participants 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 participant 
reports multiple preferred terms for a SOC, the subject will be counted only once for that 
SOC.   
The number and percent of participants who report treatment-emergent serious adverse 
events will be similarly summarized for each treatment group. The number and percent of 
participants who report treatment-emergent adverse events resulting in discontinuation of 
study drug will be similarly summarized for each treatment group. 
8.5.3 Adverse Events of Special Interest 
Adverse events (AEs) of special interest include hypersensitivity, hypersensitivity-like 
reactions, and cardiovascular events. Hypersensitivity and hypersensitivity-like reactions 
will be identified using standardized MedDRA queries. Cardiovascular events will be 
identified using the SOCs for cardiac disorders and vascular disorders. 
The overviews and summaries that are provided for all TEAEs will also be provided for the 
AEs of special interest. In addition, the time to onset and time to recovery will be 
summarized. 
8.5.4 Clinical Laboratory Findings 
Clinical laboratory variables will be presented in two ways.  First, the mean change from 
baseline to each scheduled visit will be summarized. Second, the number and percent of 
participants with treatment-emergent PCS laboratory values will be tabulated. Treatment-
emergent PCS laboratory tests are those in which the baseline value is normal and post-
baseline value is abnormal (i.e., meets Grade III or Grade IV toxicity criteria from the NCI-
CTC Version 5 or higher).  Baseline will be defined as the last value obtained before 
randomization. 


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No formal statistical tests will be performed.   
8.5.5 Vital Signs 
For the FCM group, the change in vital signs (including sitting heart rate and blood pressure) 
from pre-infusion to each post-infusion time point will be summarized descriptively on each 
dosing day. 
8.6 Sample Size Rationale 
A total of 60 participants (30 per treatment group) are required to detect an expected 
difference in hemoglobin of 1.0 g/dL (common standard deviation = 1.16 g/dL) at two-sided 
alpha=0.05 with 90% power.  Assuming 20% attrition of subjects not meeting the definition 
of mITT, approximately 72 participants will be randomized. 
9.0 ADMINISTRATIVE CONSIDERATIONS 
9.1 Retention and Availability of Records 
Investigators are required to maintain all study documentation, including a copy of the 
eCRFs, Informed Consent documents, and adequate records for the receipt and disposition 
of study medications, for a period of two years following a supplemental application for the 
drug for the indication being investigated, or until two years after the drug investigational 
program is discontinued. 
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 participant must be maintained, and this should include the signed 
Informed Consent form and copies of all study documentation related to that participant.  
The investigator must ensure the availability of source documents including the electronic 
health record, if applicable, 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 participants. 
2. 
Personally conduct or supervise the study (or investigation). 
3. 
Inform any participants 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’s Brochure, including 
potential risks and side effects of the drug. 


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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 participants 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 participant/participants. 
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 American Regent, Inc. All signed financial disclosure forms 
must be submitted to the Sponsor prior to the site enrolling participants into the study. 
9.4 Advertisement for Participant Recruitment 
All advertisement for participant recruitment must be reviewed and approved by the 
Sponsor and the site's IRB prior to implementation.  Advertisement may include but is not 
limited to: newspaper, fliers, radio, and television.  Any compensation to the participant 
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 American Regent, Inc. or its 
designee with the following documentation: 
 Curriculum Vitae and medical licenses for Principal Investigators and co-
investigators. 
 Form FDA 1572 
 Financial disclosure form(s) 
 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 participant recruitment [if applicable] 
 Copy of advertising [if applicable] 


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 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 available support staff. 
 Availability of adequate facilities to support study 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 participants to conduct study. 
Prior to investigator selection, each site will be evaluated to ensure they meet the criteria 
noted above. 
American Regent, Inc. and/or their designee 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 Good Clinical Practices (GCPs), 21CFR Part 
312. As part of a concerted effort to follow the study in a detailed and orderly manner, and 
in accordance with established principles of GCP and applicable regulations, a Monitor will 
visit the site according to the monitoring plan and will maintain telephone and written 
communication throughout the duration of the study. 
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 American Regent, Inc. or its designee to inspect the source data 
and compare them with the eCRFs. Pre-study audits, interim audits, and post-study audits 
may be performed and these may include a review of facilities, equipment, pertinent site 
documentation, and personnel qualifications. Notification of these audits will be sent to 
investigators in advance. 
9.7 Ethics 
9.7.1 Ethical and Legal Issues  
This study will be performed in accordance with the U.S. Code of Federal Regulations on 
Protection of Human Participants (21 CFR 50), IRB regulations (21 CFR 56), the most 
recent revision of the Declaration of Helsinki, all applicable local and state regulations, 21 
CFR Part 312, and applicable ICH guidelines. 


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9.7.2 Institutional Review Board 
The Protocol and the Informed Consent must be approved by an appropriate Institutional 
Review Board (IRB) before the study is initiated.  Documentation of this approval must be 
provided to the Sponsor or designee. The IRB must comply with current U.S. Regulations 
(21 CFR 56) for the protection of Human Subjects in Research. Investigators are responsible 
for the following: 
 Obtain IRB approval of the protocol, Informed Consent, and any 
advertisements to recruit participants; 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 of all serious adverse events that occur or are reported to 
you by the Sponsor as required by the IRB. 
9.7.3 Informed Consent 
Informed consent / Assent (when appropriate) must be obtained from each participant prior 
to study participation. The informed consent / assent will be provided to the participant in 
their native language. The consent/assent form must be signed by the participant and/or the 
participants 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 
participant's study records, and a copy will be provided to the participant. 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 that the Investigator provides to 
the participant and the participants 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 participant 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 with the recommendations for clinical studies in 
humans as set out in the most current revision of the “Declaration of Helsinki”, the local 


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legal requirements and the guidelines on “Good Clinical Practice”, [21 CFR Part 312 and 
ICH guidelines]. 
9.8 Data Handling and Record Keeping 
9.8.1 Case Report Form 
The eCRFs will be completed for each participant in this study.  The participants in this 
study will be identified only by a participant number on these forms. 
The eCRF used will be 21 CFR 11 compliant. The system used for data collection (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). 
The eCRFs must be reviewed and verified for accuracy by the Principal Investigator. An 
electronic copy of the eCRF will remain at the site at the completion of the study. 
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 also 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 participants or data for this study. 
All pharmaceutical formulations supplied for the purpose of the trial shall remain the sole 
property of American Regent, Inc.  They will be used exclusively 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 American Regent, Inc., and no assistance should be given to 
any third party to make such an application without the written authorization of American 
Regent, Inc. 
9.8.3 Termination of the Study 
The study may be terminated if the Data Safety Monitoring Board (DSMB), Sponsor, or 
Steering Committee 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. 


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Conditions that may warrant study termination include, but are not limited to, the discovery 
of a significant, unexpected and unacceptable risk to the participants, failure of the 
investigator to enroll participants 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 participant safety or 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 American Regent 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. 
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 a numbered memo or other applicable document 
(charter, plan, etc.).  Numbered memos do not typically require the investigator’s signature 
or IRB approval. 
9.9 Publication Policy 
All information resulting from this study is the Proprietary Information of American Regent 
Inc., as per the Confidentiality Section of this protocol.  The Steering Committee will be 
responsible for the manuscript describing the main study results, and oversee publications 
requiring trial data.  A separate publication charter will govern the process of publications. 
American Regent, Inc., and the Steering 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 American 
Regent, 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 American Regent, Inc., to make constructive 
comments about the manuscript or text and to give the opportunity of assessing whether 
patent protection should be sought by American Regenton any results or ideas connected 
with the study. 
10.0  GOVERNANCE COMMITTEES 
10.1  Data and Safety Monitoring Board (DSMB) 
The DSMB will be composed of at least four senior academic individuals, including the 
DSMB Chair. The members will have high-level expertise in pediatric IDA and/or statistics. 


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Protocol No.: 1VIT17044 
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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 American Regent 
representatives may present updates on the trial status or the safety profile of FCM, 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 participants 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. 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 312 and all applicable local, 
state, and federal regulations and International Conference on 
Harmonisation guidelines. 
 
 
_______________________________________________________________ 
Investigator’s signature 
 
__________________ 
Date 
 
___________________________________________ 
Investigator’s Name (Please print) 
 


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Protocol No.: 1VIT17044 
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References 
1. WHO 
Micronutrient 
deficiencies. 
Iron 
deficiency 
anemia. 
http://www.who.int/nutrition/topics/ida/en/  
2. Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn's disease. 
Aliment Pharmacol Ther. 2006; 24: 1507-1523 
3. 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 
4. 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 
5. Wharton BA. Iron deficiency in children: detection and prevention. Br J Haematol. 
1999; 106: 270-280 
6. Kazal LA, Jr. Prevention of iron deficiency in infants and toddlers. Am Fam Physician 
2002; 66: 1217-1224 
7. 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 
8. 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 
9. 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 
10.  Powers JM, Buchanan GR. Diagnosis and management of iron deficiency anemia. 
Hematol Oncol Clin North Am. 2014;28(4):729-45. 
11. Powers JM, McCavit TL, Buchanan GR. Management of iron deficiency anemia: a 
survey of pediatric hematology/oncology specialists. Pediatr Blood Cancer. 
2015;62(5):842-6. 
12. Powers JM, Shamoun M, McCavit TL, Adix L, Buchanan GR. Intravenous ferric 
carboxymaltose in children with iron deficiency anemia who respond poorly to oral 
iron. J Pediatr. 2017;180:212-16. 
13. Recommendations to prevent and control iron deficiency in the United States: centers 
for disease control and prevention. MMWR Recomm Rep. 1998;47:1-29. 
14. Data on File  
15. Ferrous Sulfate Drops PI. 
16. Data on File. 
17. Fishbane S.  Safety in iron management.  Am J Kidney Dis 2003;41(5Suppl):18-26. 
18. Safety and Efficacy of Ferric Carboxymaltose In Pediatric Inflammatory Bowel 
Disease Poster: Alexander Favreau, Annette Langseder, Ruth Irizarry, Stephanie 
Schuckalo, Michelle Neier, Joel Rosh. Inflammatory Bowel Diseases: February 2017 
doi: 10.1097/01.MIB.0000512714.16903.dc 
19. Van Wyck D, Anderson J, Johnson K. Labile iron in parenteral iron formulations: a 
quantitative and comparative study. 2004;19(3):561-565.


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APPENDIX 1: AMENDMENT CHANGES 
AMENDMENT 1 CHANGES 
 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
HEADER 
Right upper corner of the heading was changed to reflect the current protocol version 
number and date of version. 
To reflect the updated 
version of the protocol. 
Original Wording: 
Luitpold Pharmaceuticals, Inc.                 Protocol No.: 1VIT17044 
CONFIDENTIAL                                      version: 1.0, 06 March 2017 
 
New Wording:  
Luitpold Pharmaceuticals, Inc.                  Protocol No.: 1VIT17044 
CONFIDENTIAL                                     Amendment I Date: 14 September 2017 
TITLE PAGE 
Protocol Date was changed. 
Original Wording: 
Protocol Date: 20 April 2017 
New Wording:  
Protocol Date: 20 April 2017 
Amendment I Protocol Date: 14 September 2017 
To reflect the date of 
the current protocol 
version. 


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SIGNATURES OF 
AGREEMENT FOR 
PROTOCOL 
 
Removal of: Sumita Chowdhury, MD, MPH, FACC, MBA 
                      Prema Krishnarao, MD 
 
Addition of: Susan Oskins, RN, BSN, Pharmacovigilance Manager 
                      Nicole Blackman, PhD 
 
To reflect current 
reviewers. 
STUDY SYNOPSIS: DESIGN 
 
 
 
STUDY SYNOPSIS: DESIGN 
& 
3.1 OVERALL STUDY 
DESIGN 
 
 
 
 
 
 
 
The study design has been modified to eliminate the prospective 14 day oral 
iron run-in phase and randomization based on response to the run-in phase and 
replaced with participants requiring a documented history of an insufficient 
response to oral iron therapy over a longer time period (8 weeks) as suggested.  
 
A reduced regimen for Cohort B was modified from the proposed one dose per 
day to a dose reduction to 3 mg/kg for participants that experience adverse 
events.  
 
Cohort B age groups cutoffs were modified to 1 to <4 years of age and ≥4 to 
<12 years of age for those receiving ferrous sulfate drops and elixir, 
respectively. 
 
Sparse PK sampling on Day 0 and Day 7 for FCM only participants. 
 
Original Wording: 
This is a Phase III, multicenter, randomized, active-controlled study that compares 
the efficacy and safety of FCM to oral iron in pediatric participants with IDA who 
have had an inadequate response after a 14-day oral iron run-in period.   
Participants who satisfy the inclusion requirements and no exclusionary criteria will 
be eligible to participate in this study. All appropriate participants will enter a 14-
day oral iron run-in period. The oral ferrous sulfate formulation received will be 
based on the participant’s age, such that: infants and toddlers (1 to <5 years of age) 
will receive ferrous sulfate drops, children (≥5 to <12 years of age) will receive 
ferrous sulfate elixir, and adolescents (≥12 to 17 years of age) will receive ferrous 
sulfate tablets. 
The dose reduction is 
still within the 
recommended range of 
3-6 mg/kg for iron 
supplementation and 
will mitigate expected 
tolerance and/or 
adherence issues. 
The cutoffs reflect the 
age group specified in 
the oral iron drops 
supplement label and 
traditional age range for 
infants (1 to 3 years 
old). 
Sparse PK sampling 
included to facilitate 
exposure-response 
analysis 


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STUDY SYNOPSIS: DESIGN 
& 
3.1 OVERALL STUDY 
DESIGN 
 
 
 
 
 
 
 
Participants who have an adequate response to oral iron (as defined by an 
increase in hemoglobin (Hgb) of ≥1 g/dL in 14 days) will be defined as oral iron 
treatment responders and will not be randomized.   
Participants who have an unsatisfactory response to oral iron (as defined by an 
increase in Hgb of <1 g/dL from baseline despite ≥ 67% compliance based on 
tablet/drops/elixir count) will be defined as non-responders to oral iron 
treatment.  Non-responders who continue to meet inclusion criteria (including 
Hgb <12 g/dL) and no exclusion criteria will be stratified by baseline Hgb (<10, 
≥10 g/dL) and age (1 to <12 and ≥12 to 17 years).  Randomization will occur in a 
1:1 ratio to either Group A, participants receiving FCM (oral iron product from the 
run in phase will be discontinued), or Group B, participants continuing to receive 
oral iron (oral solution drops, elixir or oral tablets) up to Day 14.  
Participants who had a Hgb value increase <1 g/dL from baseline in the run-in 
period BUT less than 67% compliance will not be randomized. 
Participants who experience other symptoms due to the oral iron during the run-in 
phase will have their twice-daily dose regimen of ferrous sulfate reduced to one 
dose per day. Participants that demonstrate a ≥1 g/dL increase in Hgb in 
response to once daily oral iron therapy during the run-in phase, or those that 
experience ongoing adverse clinical symptoms after a reduction to once daily 
oral iron therapy will not be randomized.  Participants receiving once-daily oral 
iron that do not experience a ≥1 g/dL increase in Hgb after the 14 day run-in 
phase (despite ≥67% compliance with the reduced dose schedule) will be 
stratified by Hgb and age, and then randomized in the same 1:1 ratio to either 
Group A, participants receiving FCM (oral iron product from the run-in phase 
will be discontinued), or Group B, participants continuing to receive oral iron 
(Reduced regimen [one dose per day] oral solution drops, elixir or oral tablets) 
up to Day 14. 
The response to oral iron will be calculated by subtracting the point-of-care Hgb 
value determined at the initial screening visit (Day -15) from the point-of-care 
determinations made on Day 0. 


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STUDY SYNOPSIS: DESIGN 
& 
3.1 OVERALL STUDY 
DESIGN 
 
Participants who have a >2 g/dL decrease in Hgb from the initial screening visit 
(Day -15) after compared to the point-of-care sample at Day 0 will not be 
randomized.  These participants will be discontinued in the interactive response 
technology (IRT) system and referred to their primary health care provider for 
further management. 
Once randomized, all participants will return for efficacy and safety evaluations, 
including adverse events and laboratory assessments, on Days 7, 14, 28, and 35. 
New Wording:  
This is a Phase III, multicenter, randomized, active-controlled study that compares 
the efficacy and safety of FCM to oral iron in pediatric participants with IDA and a 
documented history of an inadequate response to oral iron therapy in at least 8 
weeks (56 days) prior to randomization.   
Participants who satisfy the inclusion requirements and no exclusionary criteria will 
be eligible to participate in this study and enter into a screening phase to confirm 
eligibility. Randomization will occur via the IRT system in a 1:1 ratio to either Group 
A, participants receiving FCM, or Group B, participants receiving oral iron (oral 
solution drops, elixir or oral tablets). Randomization will be stratified by baseline 
Hgb (<10, ≥10 g/dL) and age (1 to <12 and ≥12 to 17 years).   
The oral ferrous sulfate formulation received will be based on the participant’s age, 
such that: infants and children (1 to <4 years of age) will receive ferrous sulfate 
drops, children (≥4 to <12 years of age) will receive ferrous sulfate elixir, and 
adolescents (≥12 to 17 years of age) will receive ferrous sulfate tablets. Participants 
who experience adverse clinical symptoms due to the oral iron during the treatment 
phase may have their weight-based dose of ferrous sulfate reduced from 6 mg/kg to 
3 mg/kg. If the participant is receiving tablets, the dose will be reduced from one 
tablet taken twice daily to one tablet per day. 
Once randomized, all participants will return for efficacy and safety evaluations, 
including adverse events and laboratory assessments, on Days 7, 14, 28, and 35. 


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Administrative Change 1 Date: Final 26 September 2019 
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Additional pharmacokinetic sampling and analysis will be performed for 
participants receiving FCM on Days 0 and 7. 
STUDY SYNOPSIS: 
INCLUSION CRITERIA 
& SECTION 4.2.1 OF 
PARTIPANT SELECTION 
 
 
 
 
 
 
STUDY SYNOPSIS: 
INCLUSION CRITERIA & 
SECTION 4.2.1 OF 
PARTIPANT SELECTION 
Additional diagnostic parameters were included to support the diagnosis of iron 
deficiency anemia and the unsatisfactory response was changed from prospective to 
retrospective. No point of care testing will be performed. 
Original Wording: 
2. Screening Transferrin Saturation (TSAT) <20%. 
4. Randomization Hgb 12 g/dL (based on the average point of care Hgb performed 
on Screening and Day 0). 
5. Participants must demonstrate an unsatisfactory response to oral iron after the 14 
days prior to randomization. 
New Wording:  
3. Screening ferritin ≤300 ng/mL and Transferrin Saturation (TSAT) <30%. 
4. Participants must have a documented history of an inadequate response to any oral 
iron therapy for at least 8 weeks (56 days) prior to randomization. 
Because ferritin is an 
acute-phase reactant, 
ferritin may be normal 
or increased in iron-
deficient participants 
with other medical 
problems. This cutoff 
would not exclude 
participants with 
comorbidities. The 
increased TSAT in 
combination with the 
ferritin measurement 
should adequately 
identify participants 
with iron deficiency 
anemia. 
 
STUDY SYNOPSIS: 
EXCLUSION CRITERIA 
& SECTION 4.2.2 OF 
PARTICIPANT 
SELECTION 
 
The following exclusion criterion was removed from the original protocol: 
       8. Development of a bacterial infection in the run-in phase. 
12. Cyclophosphamide therapy 
In addition, the following exclusion criteria were modified as follows: 
Original Wording: 
5. Screening ferritin level > 300 ng/mL 
Run-in phase removed. 
The use of 
cyclophosphamide 
therapy may be an 
independent cause of 
drug-associated anemia. 
As there are other such 
potential concomitant 
medication exposures 
associated with drug-
associated anemia, 


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11. Anemia due to reasons other than iron deficiency (i.e. hemoglobinopathy). 
Participants treated for vitamin B12 or folic acid deficiency are permitted. 
New Wording:  
10. Anemia due to reasons other than iron deficiency (e.g., hemoglobinopathy and 
vitamin B12 or folic acid deficiency).  
 
 
 
 
Luitpold has removed 
this exclusion criterion. 
 
Participants with 
vitamin B12 or folic 
acid deficiency may be 
receiving hematinic 
supplementation that 
may confound outcome 
measures and will thus 
be excluded. 
 
STUDY SYNOPSIS: 
OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following changes below have been made to the various sections of the study 
synopsis.  
 Additionally, Figure 1 of the Study Diagram has been modified to reflect 
the proposed change in study design. 
Study Drug Administration: 
Original Wording: 
Group B (Oral ferrous sulfate) will receive or continue to receive an age-dependent 
formulation of oral ferrous sulfate daily for 14 days as follows: participants <12 years 
of age will receive 3 mg (elemental iron)/kg/day divided into 2 daily doses of an oral 
drop or elixir and participants ≥12 will receive 2 daily doses of oral tablets. Infants 
and toddlers (ages 1 to <5 years) will receive oral ferrous sulfate drops, while children 
(ages ≥5 to <12 years) will receive oral ferrous sulfate elixir. Adolescents (ages ≥12 
to 17 years) will receive an oral ferrous sulfate tablet (65 mg of elemental 
iron/tablet/dose) twice a day (BID). The maximum daily dose for participants <12 
The change in 
reticulocyte 
hemoglobin content 
will be analyzed at all 
time points instead of 
specifically Day 35 
only.  
 
 
 
 
 
 


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STUDY SYNOPSIS: 
OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
years of age is 130 mg of elemental iron. The maximum daily dose for participants 
≥12 years of age is 130 mg of elemental iron. 
New Wording:  
Group B (Oral ferrous sulfate) will receive an age-dependent formulation of oral 
ferrous sulfate daily for 28 days as follows: participants <12 years of age will receive 
6 mg (elemental iron)/kg/day divided into 2 daily doses of an oral liquid 
formulation, either drops or elixir, and participants ≥12 will receive 2 daily doses 
of oral tablets. Infants and children (ages 1 to <4 years) will receive oral ferrous 
sulfate drops, while children (ages ≥4 to <12 years) will receive oral ferrous sulfate 
elixir. Adolescents (ages ≥12 to 17 years) will receive an oral ferrous sulfate tablet 
(65 mg of elemental iron/tablet/dose) twice a day (BID). The maximum daily dose 
for all participants is 130 mg of elemental iron. 
 
Patient Assessments: 
Original Wording: 
All participants who provide informed consent / assent will enter a 14-day run-in 
phase.  Participants will be required to return on day 7 to assess adverse events 
and their degree of compliance with oral iron therapy.  Participants completing 
the run-in phase and are non-responders (see design section above), continue to 
meet the inclusion criteria, and do not meet exclusion criteria, will be 
randomized. Starting on Day 0, the time of study drug dosing, through Day 35, all 
randomized participants will be subject to safety assessments including vital signs 
(including sitting heart rate and blood pressure), laboratory samples include 
hematology, chemistries and iron indices, and adverse event queries. 
New Wording:  
All participants who provide informed consent/assent, meet inclusion criteria, and 
do not meet exclusion criteria will be randomized. Starting on Day 0 (the time of 
 
 
 
 
 
 
 
 
To modify for 
consistency with the 
updated study design. 
 
 
 
 
 
 
 
 


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STUDY SYNOPSIS: 
OTHER 
 
study drug dosing) through Day 35, all randomized participants will be subject to 
safety assessments including vital signs (including sitting heart rate and blood 
pressure), laboratory samples include hematology, chemistries and iron indices, and 
adverse event queries. Participants receiving oral iron treatment will be assessed 
for degree of compliance. 
Secondary Endpoints: 
Original Wording: 
Change in reticulocyte hemoglobin from baseline to day 35 
Changes from baseline to individual time points will be summarized descriptively for 
hemoglobin, ferritin, TSAT, and reticulocyte hemoglobin. 
 
New Wording:  
Changes from baseline in  hemoglobin, ferritin, TSAT, and reticulocyte hemoglobin 
content throughout the study. 
Pharmacokinetic assessments, including Cmax, Tmax, AUC0-time last measured 
concentration, AUC0-infinity, T1/2, MRT, Cl, VD, VDc, VDss, and VDarea. 
 
Study Duration per Participant: 
Original Wording: 
Approximately 8 weeks 
New Wording:  
Approximately 6 weeks 
Study Sites: 
 
 
 
 
 
 
 
 
To modify for 
consistency with the 
updated study design. 
 
 
 
 
 
 
 
 


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Original Wording: 
Approximately 12 to 15 
New Wording:  
Approximately 20 
Participant Number:  
Original Wording: 
Approximately 56 randomized (N=28 FCM / N=28 Oral Iron) 
New Wording:  
Approximately 72 randomized (N=36 FCM / N=36 Oral Iron) 
 
 
 
 
 
A total of 60 
participants (30 per 
treatment group) are 
required to detect an 
expected difference in 
Hgb of 1.0 g/dL 
(common standard 
deviation = 1.16 g/dL) 
at two-sided alpha = 
0.05 with 90% power.  
Assuming 20% attrition 
of subjects not meeting 
the definition of 
modified intention to 
treat (mITT), 
approximately 72 
participants will be 
randomized. 
 
1.0 INTRODUCTION 
The following subsections were modified as follows: 
1.2.2 Ferric Carboxymaltose versus Other Parenteral Iron Agents 
These statements are 
based on information 
contained within the 
following article: Van 


American Regent, Inc. 
 
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A reference (#19) was added to the following text: 
“Iron sucrose and iron gluconate preparations carry a significant risk of inducing a 
bioactive iron reaction when delivered at higher doses. These reactions are 
characterized by hypotension (without allergic signs) accompanied by pain in the 
chest, abdomen, flank and/or nausea, vomiting, and diarrhea.”  
 
Wyck D, Anderson J, 
Johnson K. Labile iron 
in parenteral iron 
formulations: a 
quantitative and 
comparative study. 
2004;19(3):561-565. 
2.0 TRIAL OBJECTIVE 
The following subsections were modified as follows: 
2.1 Primary Objective 
Original Wording: 
The primary objective of this study is to demonstrate the efficacy and safety of an 
investigational IV ferric carboxymaltose, (FCM) compared to oral iron in pediatric 
participants who have IDA and have been shown to have an unsatisfactory 
response to oral iron. 
New Wording:  
The primary objective of this study is to demonstrate the efficacy and safety of an 
investigational IV ferric carboxymaltose, (FCM) compared to oral iron in pediatric 
participants who have IDA. 
To modify for 
consistency with 
changes in study 
design. 


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3.0 OVERALL STUDY 
DESIGN AND 
RATIONALE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following subsections were modified as follows: 
3.2 Rationale of Study Design and Choice of Control Groups 
 
In addition to the following text, Tables 1 “Mean Change from Screening in 
Hemoglobin, Ferritin, and TSAT (Safety Population)” and 2 “Overview of 
Treatment-Emergent Adverse Events (Safety Population)” were added. 
Original Wording: 
While the recommended total daily dose of oral elemental iron for the treatment of 
IDA in pediatric patients ranges between 3-6 mg/kg/day divided into one to three 
doses, a total daily dose of 3 mg/kg/day divided into 2 doses (maximum daily dose 
of 130 mg of elemental iron) was selected for all ages because evidence suggests 
that low-dose oral iron therapy may be as effective as higher doses.11 
Additionally, the simplified regimen may minimize adverse effects associated with 
high-dose oral iron therapy and thus improve medication adherence.13 
New Wording:  
Per the recommended total daily dose of oral elemental iron for the treatment of IDA 
in pediatric patients ranges between 3-6 mg/kg/day divided into one to three doses, a 
total daily dose of 6 mg/kg/day divided into 2 doses (maximum daily dose of 130 mg 
of elemental iron) was selected for all ages based on the most common practice of 
pediatric hematology physicians in the United States.11 Additionally, the 
simplified regimen may minimize adverse effects associated with high-dose oral iron 
therapy and thus improve medication adherence.13  
With respect to FCM, doses of 15 mg/kg with a maximum of 750 mg per dose have 
been selected based off evidence generated from Luitpold’s Phase II dose-finding 
PK/PD study in which cohorts received single, weight-based doses of FCM at either 
7.5 mg/kg or 15 mg/kg.16 Results from this study demonstrate that the higher weight-
based dose is both efficacious and safe (summarized below in Tables 1 and 2). The 
mean increase from baseline to Day 35 was larger for participants in Cohort 2 
receiving 15 mg/kg (2.8±1.15 g/dL) than those in Cohort 1 receiving 7.5 mg/kg 
(1.9±1.38 g/dL). The mean increase in ferritin and TSAT at Day 35 was 
While the referenced 
article indicated that no 
data support iron 
dosing of 6 mg/kg/day 
in children, this was the 
preference of 
physicians who 
responded in the survey 
and has been modified 
per FDA 
recommendation. 
Preliminary PK, PD, 
and safety data from the 
dose-finding Phase 2 
trial, 1VIT13036, has 
been provided to 
further justify the 
selected dose for FCM. 


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3.0 OVERALL STUDY 
DESIGN AND 
RATIONALE  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
35.1±98.22 ng/mL and 9.9±11.54% for Cohort 1 (N=16) and 52.4±31.7 ng/mL 
and 13.5±6.88% for Cohort 2 (N=18), respectively. Similar percentages of 
participants in Cohort 1 (56.3%) and Cohort 2 (63.2%) reported at least 1 
treatment-emergent adverse event. At least 1 drug-related treatment-emergent 
adverse event was reported by 3 of 16 participants in Cohort 1 and 6 of 19 
participants in Cohort 2. Specifically, the only treatment-emergent AE 
considered related to study drug that was experienced by >1 participant was 
urticaria (3 participants in Cohort 2). Other treatment-emergent AEs 
considered related to study drug and experienced by 1 participant each included 
infusion site pruritus, thirst, and hot flush in Cohort 1 and abdominal pain 
upper, 
gastroduodenitis, 
hyperthermia, 
injection 
site 
pain, 
alanine 
aminotransferase increased, headache, pruritus, rash, and hypertension in 
Cohort 2.  Two participants in Cohort 1 experienced a serious adverse event. 
Further justification for the 15 mg/kg dose is provided by internal modeling data, 
which demonstrated comparable total serum iron clearance profiles between pediatric 
and adult populations. Lastly, a retrospective cohort study of 72 pediatric patients 
with IDA refractory to oral iron treatment ranging in age from 9 months to 18 years 
treated with 15 mg/kg of FCM (maximum single dose of 750 mg; median dose 750 
mg) supports this dosing.12   
 
Section “3.3 Rationale for Oral Run-in” has been modified as follows to 
“3.3 Rationale for Sparse PK Sampling”: 
 
Original Wording: 
3.3 Rationale for Oral Run-in 
Oral iron represents a cost-effective option for patients with IDA who do not need 
rapid repletion of iron stores and who are able to tolerate it. The proposed study 
enables all participants to complete a 14-day trial of oral iron therapy. Those 
participants who achieve a Hgb increase of ≥1 g/dL in the oral iron run-in period will 
not be randomized. The 14-day run-in criteria were selected based on a review of 
adult Phase III studies of IDA among participants with heavy uterine bleeding, 
inflammatory bowel disease, or postpartum anemia. It was observed that participants 
who achieved a <1 g/dL increase in 14 days were less likely to achieve satisfactory 


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3.0 OVERALL STUDY 
DESIGN AND 
RATIONALE  
 
 
 
 
 
 
 
 
 
 
responses to oral iron at the end of the respective studies than those who achieved a 
≥1 g/dL increase in 14 days.14 Participants who do not have an adequate response to 
oral iron therapy and are at least 67% compliant, will be randomized to IV FCM or 
an additional two weeks of oral iron therapy. This design permits an efficacy and 
safety comparison of switching to FCM versus continuing oral iron in a clinical 
scenario that reflects real life use of parenteral therapy. Participants who have a >2 
g/dL Hgb decrease, do not tolerate oral iron, or those deemed by their physicians not 
appropriate for continued participation in the study will be discontinued and referred 
to their primary care or GI providers for appropriate evaluation and management. 
New Wording: 
3.3 Rationale for Sparse PK Sampling 
Population-based PK/PD modelling describing the time course of total serum iron 
(TSI) concentrations and the relationship between TSI and changes of hemoglobin 
following a single dose of intravenous FCM in pediatric subjects with iron deficiency 
anemia (IDA) has been performed using intensively sampled data from Study 
1VIT13036.16  It is proposed to supplement this initial modelling with additional 
sparsely sampled PK data from this study. Based on the anticipated visit duration on 
the 2 FCM administration days in this study, the following sparse PK sampling 
scheme is proposed: pre-dose, immediately post-infusion and 60 minutes post-dose 
on Days 0 and 7, on which subjects will receive 15 mg/kg (up to a maximum dose of 
750 mg). This pragmatic approach, which minimizes the number of blood draws 
compared to a full PK profile, is expected to facilitate exposure-response analysis for 
the proposed FCM regimen. 
Section 3.4 Schedule of Events 
The following organizational changes were made to the original table: 
 
Column 3, “Scr 2 (Day -8 or -7)”, was removed.  
 
Row 11, “Hemoglobin Point of Care Testing”, was removed. 
 
Column 2, “Scr 1 (Day -15)”, was changed to “Screening (-7 +1)”. 
 
Row 17, “Pharmacokinetic Sampling”, was added. 


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3.0 OVERALL STUDY 
DESIGN AND 
RATIONALE  
 
The following assessments were added for the following Visit Days: 
 
Oral Iron Dosing, Oral Iron Dispensing were removed from “Screening (-7 
+ 1)”. 
 
Oral Iron Dosing was added to “Day 28”. 
 
Oral Iron Dispensing was added to “Day 14”. 
 
Oral Iron Compliance Assessment was added to “Day 28” (Assessment at 
Day 0 removed). 
 
The following footnote was added to Row 12, “Hematology, Chemistry and Iron 
Indices”: 
 
 
1 For a full description of central laboratory assessments, refer to Protocol 
Section 6.4. 
 
The following footnote was added to Row 17, “Pharmacokinetic Sampling”: 
 
 
2 Blood samples for pharmacokinetic analysis will be collected pre-dose, 
immediately post-dose, and 60 minutes post-dose for participants receiving 
FCM. For a full description of the pharmacokinetic parameters, refer to 
Protocol section 6.3.6. 
 
4.0 PARTICIPANT 
SELECTION 
 
 
 
4.0 PARTICIPANT 
SELECTION 
The following subsections were modified as follows: 
 
Subsection 4.7 “Unsatisfactory and Adequate response to the 14 day Oral 
Iron Run-in Defined” was removed. 
 
4.1 Number and Type of Participants 
Original Wording: 
To modify for 
consistency with the 
updated study design. 
 


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4.0 PARTICIPANT 
SELECTION 
 
Approximately 56 participants who have given written informed consent / assent with 
a diagnosis of IDA who fulfill the inclusion criteria, do not meet any of the exclusion 
criteria, and completed the 14-day run-in phase as a non-responder will be 
randomized to receive either FCM or Oral Iron. 
New Wording: 
Approximately 72 participants who have given written informed consent/assent with 
a diagnosis of IDA who fulfill the inclusion criteria and do not meet any of the 
exclusion criteria will be randomized to receive either FCM or Oral Iron.  
4.3 Participant Assignment and Randomization Process 
Original Wording: 
Participants who have an unsatisfactory response to oral iron, as defined by Hgb value 
increases <1 g/dL from baseline despite ≥67% compliance based on 
tablet/drops/elixir count, will be defined as non-responders. Participants who 
continue to meet the inclusion criteria (including Hgb <12 g/dL) and no exclusion 
criteria will be entered into the IRT system, stratified by baseline Hgb (<10, ≥10 
g/dL) and age (1 to <12 and ≥12 to 17 years). Randomization will occur in a 1:1 ratio 
to either Group A, FCM (oral iron product from the run-in phase will be discontinued) 
or Group B, continuation of Oral Iron (oral solution drops/elixir or oral tablets) up to 
day 14. 
Participants who had an Hgb value increase <1 g/dL from baseline in the run-in 
period BUT had less than 67% compliance will not be randomized. Participants who 
have a >2 g/dL decrease in Hgb from the initial screening visit (Day -15) after 
calculating the point-of-care samples at Day 0 should not be randomized. These 
participants should be discontinued in the IRT system and assessed and evaluated 
appropriately by their treating physician. 
New Wording: 


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Participants who satisfy the inclusion requirements and no exclusionary criteria will 
be eligible to participate in this study and entered into the IRT system. Randomization 
will occur in a 1:1 ratio to either Group A, participants receiving FCM, or Group B, 
participants receiving oral iron (oral solution drops, elixir or oral tablets). 
Randomization will be stratified by baseline Hgb (<10, ≥10 g/dL) and age (1 to <12 
and ≥12 to 17 years).   
The oral ferrous sulfate formulation received will be based on the participant’s age, 
such that: infants and children (1 to <4 years of age) will receive ferrous sulfate 
drops, children (≥4 to <12 years of age) will receive ferrous sulfate elixir, and 
adolescents (≥12 to 17 years of age) will receive ferrous sulfate tablets. Participants 
who experience adverse clinical symptoms due to the oral iron during the treatment 
phase may have their weight-based dose of ferrous sulfate reduced from 6 mg/kg to 
3 mg/kg. If the participant is receiving tablets, the dose will be reduced from one 
tablet taken twice daily to one tablet per day. 
5.0 STUDY DRUG 
 
 
 
 
 
 
 
The following subsections were modified as follows: 
5.2 Drug Administration/Regimen 
Original Wording: 
Group B:  
Group B (Ferrous sulfate) will continue to receive oral iron 
through the Day 14 visit. 
 
New Wording: 
Group B:  
Group B (Ferrous sulfate) will receive an age-dependent 
formulation of oral ferrous sulfate daily for 28 days as follows: 
participants <12 years of age will receive 6 mg (elemental 
iron)/kg/day divided into 2 daily doses of an oral liquid 
formulation, either drops or elixir, and participants ≥12 will 
receive 2 daily doses of oral tablets. Infants and children (ages 1 
to <4 years) will receive oral ferrous sulfate drops, while children 
(ages ≥4 to <12 years) will receive oral ferrous sulfate elixir. 
To modify for 
consistency with the 
updated study design. 
 


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Adolescents (ages ≥12 to 17 years) will receive an oral ferrous 
sulfate tablet (65 mg of elemental iron/tablet/dose) twice a day 
(BID). The maximum daily dose for all participants is 130 mg of 
elemental iron. 
 
5.5 Concomitant Medication 
Original Wording: 
If receiving treatment for IBD, therapy must be stable for at least 90 days prior to 
consent and remain stable through the remaining of the study. 
New Wording: 
If receiving treatment for IBD, therapy must be stable for at least 8 weeks prior 
to consent and remain stable through the remaining of the study. 
To modify for 
consistency with the 
updated inclusion 
criteria. 
6.0 STUDY PROCEDURES 
 
 
 
 
 
 
The following subsections were modified as follows: 
 
Section 6.2.2, “Screening Visit 2 (Day -8 ± 1)”, was removed. 
 
Section 6.2.3, “Oral iron Dose Reduction in the 14 Day Run-in”, was 
removed and replaced with Section 6.3.5, “Oral Iron Dose Reduction 
during the Treatment Phase”. 
 
Section 6.3.6, “Pharmacokinetic Sampling”, was added. 
 
 
6.2.1 Screening Visit 1  
Original Wording (only affected areas appear below): 
6.2.1 Screening Visit 1 (Day -15) 
• Hgb by point-of-care testing 
• ** If the point-of-care testing Hgb is >11.0 g/dL all study procedures should 
be stopped and the participant entered into the IRT as a screen failure. 
 


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After a screening number has been obtained and the POC Hgb ≤11 g/dL is 
confirmed, the first dose of oral ferrous sulfate will be administered according 
to the following: infants and toddlers (1 to <5 years of age) will receive ferrous 
sulfate drops; children (≥5 to <12 years of age) will receive ferrous sulfate elixir; 
and adolescents (≥12 to 17 years of age) will receive ferrous sulfate tablets. 
A sufficient quantity of doses for a 7 day period will be dispensed to the parent 
or guardian of the participant. The parent or guardian of the participant will be 
responsible for the administration of two daily doses of oral ferrous sulfate to 
the participant. 
New Wording: 
6.2.1 Screening Visit 1 (Day -7 ± 1) 
Each participant who qualifies for inclusion will undergo the following clinical 
evaluations to confirm their eligibility for the study: 
 
Obtain screening number from IRT 
 
Medical history, including documented history of an inadequate response 
after at least 8 weeks of prior oral iron therapy use 
 
Hematology, chemistries and iron indices  
 
Serum pregnancy test for female participants of child bearing potential 
(negative results must be obtained prior to randomizing the participant for 
study drug dosing). 
 
Height and weight 
 
Vitals signs (including sitting heart rate and blood pressure)  
 
Concomitant medications assessment 
 
ESA and IBD therapy stability (if applicable)  
** Participants who do not meet the entry criteria should be entered into the IRT 
system as a screen failure.  A participant may be re-screened, only one time, once it 
is believed that they would qualify for study entry.  The participant will need to re-


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6.0 STUDY PROCEDURES 
 
 
 
 
 
 
sign a new consent form and all screening procedures in section 6.2 will need to be 
repeated. 
6.3.1 Day 0 Visit 
Original Wording: 
The following will be obtained and/or completed before contacting IRT for 
randomization: 
For all participants: 
 Verify all inclusion and exclusion criteria 
 Blood samples for central lab hematology, chemistries, and 
iron indices 
 Weight 
A participant who develops a bacterial infection during the run-in phase should be 
discontinued and treated appropriately. These participants may be re-screened, one 
time, once the enrolling physician deems the participant would qualify for study 
entry. The participant will need to re-sign a new consent / assent form and all 
screening procedures in section 6.2 will need to be repeated. After verifying the 
eligibility of the participant, the IRT system will then be contacted by a study team 
member. Participants will be stratified by Hgb (<10, ≥10 g/dL) and age (1 to <12 
and ≥12 to 17 years), and randomization in a 1:1 ratio to either Group A (FCM at 15 
mg/kg to a maximum single dose of 750 mg on Days 0 and 7 for a maximum total 
dose of 1500 mg) or Group B (Ferrous sulfate will continue to receive oral iron 
through the Day 14 visit). After assignment of the treatment group the following will 
occur: 
Group A: 
 
Pre-administration evaluation to include measurement of heart 
rate, blood pressure, and body temperature on Day 0.  


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6.0 STUDY PROCEDURES 
 
 
 
 
 
 
 
Group B: 
• Oral ferrous sulfate dispensing: 
 
Pre-administration evaluation to include measurement of heart 
rate, blood pressure, and body temperature on Day 0.  
o Parents or guardians of participants will be responsible for the 
administration of twice daily dosing of oral ferrous sulfate. Participants that 
experience adverse events during the run-in will continue the reduced 
regimen [one dose per day] of oral ferrous sulfate. 
o A record of compliance will be maintained for each participant and 
reviewed at each study visit. (see section 6.2.2 for compliance assessment). 
 
• Adverse event assessment (starting once the participant takes the first in-clinic 
dose). 
New Wording: 
A participant who develops a bacterial infection during the screening phase should 
be discontinued and treated appropriately.  These participants may be re-screened, 
one time, once the enrolling physician deems the participant would qualify for study 
entry.  The participant will need to re-sign a new consent / assent form and all 
screening procedures in section 6.2 will need to be repeated. 
After verifying the eligibility of the participant, the IRT system will then be contacted 
by a study team member.  Randomization will be stratified by Hgb (<10, ≥10 g/dL) 
and age (1 to <12 and ≥12 to 17 years), and randomized in a 1:1 ratio to either Group 
A (FCM at 15 mg/kg to a maximum single dose of 750 mg on Days 0 and 7 for a 
maximum total dose of 1500 mg) or Group B (Ferrous sulfate, dose and regimen 
dependent upon age and weight, twice daily for 28 days).   
After a randomization number has been obtained, the first dose of oral ferrous 
sulfate will be administered in the clinic according to the following: infants and 


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6.0 STUDY PROCEDURES 
 
 
 
 
 
 
children (1 to <4 years of age) will receive ferrous sulfate drops; children (≥4 to 
<12 years of age) will receive ferrous sulfate elixir; and adolescents (≥12 to 17 
years of age) will receive ferrous sulfate tablets. 
A sufficient quantity of doses for a 7 day period will be dispensed to the parent 
or guardian of the participant. The parent or guardian of the participant will be 
responsible for the administration of two daily doses of oral ferrous sulfate to 
the participant. 
After assignment of the treatment group the following will occur:  
All participant’s (prior to study drug administration/dispensing, if applicable) 
on Day 0: 
 
Blood samples for central lab hematology, chemistries, and iron 
indices (Group A participants will have an additional blood sample 
for PK prior to dosing) 
 
Vital signs: temperature, sitting heart rate and blood pressure 
 
Weight 
Group A: 
 Blood samples for PK immediately post-dose and 60 minutes post-dose. 
 
Group B:  
 Oral ferrous sulfate dispensing: 
o Parents or guardians of participants will be responsible for the 
administration of twice daily dosing of oral ferrous sulfate. Participants 
that experience adverse events may continue with a dose-reduced 
regimen [3 mg/kg twice daily] of oral ferrous sulfate after a consult 
with the investigator. (See section 6.3.5 for oral iron dose reduction) 


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6.0 STUDY PROCEDURES 
 
 
 
 
 
 
o Parents or guardians of participants will be dispensed oral iron on Days 
0, 7, and 14.  Used dispensing packs/blisters/syringes will be returned 
and are to include both the empty containers and any unused medication.  
o A record of compliance will be maintained for each participant and 
reviewed at each study visit. (See section 6.3.2 for compliance 
assessment).  
 
6.3.2 Day 7 and Day 14 Visit 
Original Wording: 
For Group A participants the following will be performed on Day 7 only: 
 Pre-administration evaluation to include measurement of heart 
rate, blood pressure, and body temperature.  
 
For Group B participants the following will be performed: 
•  Oral iron dispensing (Day 7 only). 
• Oral iron compliance assessment (see section 6.2.2 for compliance 
assessment). 
 
New Wording: 
All participants will return to the clinic on Day 7 and 14.  Prior to the administration 
of the study drug (if applicable), the participant will be evaluated clinically to assess 
for the development of clinically significant conditions that may contraindicate 
dosing. 
 
Blood samples for central lab hematology, chemistries and iron indices 
(Group A participants will have an additional blood sample for PK 
prior to dosing). 
 


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6.0 STUDY PROCEDURES 
 
 
 
 
 
 
For Group A participants the following will be performed on Day 7 only: 
 
Blood samples for PK immediately post-dose and 60 minutes post dose. 
 Pre-administration evaluation to include body temperature.  
 
For Group B participants the following will be performed:  
 
Oral iron dispensing (Day 7 and Day 14). 
Compliance will be assessed according to the following: 
For ferrous sulfate tablets: 
o Used blister packs will be returned and are to include both the 
empty containers and any unused medication.   
o The blister packs will be examined to assess compliance (the 
number taken divided by the number of pills expected to be taken). 
A record of compliance will be maintained for each participant 
and reviewed.   
o If the participant took less than the number of tablets expected, 
document the reason(s) for dose reduction and counsel the 
participant about the importance of taking the study drug as 
prescribed. 
 
For ferrous sulfate drops and elixir: 
o Used oral syringes will be returned which will include any unused 
medication.   
o The oral syringes will be examined to assess compliance (the 
volume remaining in the oral syringes divided by the expected 
amount to be taken). A record of compliance will be maintained 
for each participant and reviewed. 
o If the participant took less than the volume expected, document 
the reason(s) for dose reduction and counsel the participant about 
the importance of taking the study drug as prescribed. 


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6.0 STUDY PROCEDURES 
6.3.5 Oral Iron Dose Reduction during the Treatment Phase 
New Wording: 
Participants who experience AE possibly or probably due to the oral iron during the 
treatment phase will have their dose of ferrous sulfate reduced from 6 mg/kg to 3 
mg/kg while maintaining the same frequency of twice per day. If the participant is 
receiving tablets, the dose will be reduced from one tablet taken twice daily to one 
tablet per day. 
6.3.6 Pharmacokinetic Sampling 
New Wording: 
Blood samples will be collected for PK assessment pre-dose, immediately post-dose, 
and 60 minutes post-dose for participants receiving FCM on Days 0 and 7. Blood 
samples should be taken at approximately the same time of day on Day 7 as Day 0. 
 The pharmacokinetic parameters to be analyzed in this study are as follows: the 
maximum serum concentration (Cmax) and the time at which Cmax occurs (Tmax), the 
area under the serum concentration-time curve from time zero to the last sampling 
time 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). 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). 
6.4 Central Laboratory Assessments 
Original Wording: 


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Hematology: 
Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, 
platelets, differential count, reticulocyte count, and 
reticulocyte hemoglobin (ret-he %) 
 
New Wording: 
Hematology: 
Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, 
platelets, differential count, reticulocyte count, and 
reticulocyte hemoglobin content (CHr) 
 
8.0 STATISTICS 
 
8.0 STATISTICS 
 
 
 
 
 
 
The following subsections were modified as follows: 
 Section 8.5.3, “Clinical Laboratory Findings”, was changed to Section 
8.5.4. 
 Section 8.5.4, “Vital Signs”, was changed to Section 8.5.5. 
 
New Wording: 
All hypothesis tests and confidence intervals will be two-sided.  No correction 
for multiple testing will be applied amongst the secondary endpoints.  Except 
where otherwise noted, the statistical model on which inference is based will 
include terms for randomization strata.   
Continuous variables will be summarized in terms of the number of 
observations, mean, standard deviation, median, Q1, Q3, minimum and 
maximum. Other descriptive statistics (e.g., coefficient of variation) may be 
reported when appropriate. Categorical variables will be summarized using 
frequency counts and percentages.   
Generally, data will be summarized by nominal visit.  However, data from both 
unscheduled and scheduled will be used for determination of last observed 
value, and in worst- or best-case changes and/or shifts from baseline. Assessment 
To modify for 
consistency with the 
updated study design. 
 


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8.0 STATISTICS 
 
 
 
 
 
 
windows will not be defined for the purpose of classifying measurements 
obtained outside scheduled assessment times. 
A complete description of the statistical analyses and methods will be available 
in a Statistical Analysis Plan (SAP), which will be finalized before the database 
is locked. 
8.2 Analysis Populations 
Original Wording: 
The Oral Iron Run-In Population will include all participants who receive oral 
iron during the oral iron run-in period. 
All participants who receive at least 1 dose of randomized study drug will be 
included in the Safety Population. If a participant receives the wrong study 
drug, the participant will be analyzed under the study drug that was received. 
All safety analyses will be performed with the Safety Population. 
All participants in the Safety Population who have a hemoglobin measurement 
at baseline and at least 1 hemoglobin measurement after receiving study drug 
will be included in the Efficacy Population. If a participant receives the wrong 
study drug, the participant will be analyzed under the randomized study drug. 
All efficacy analyses will be performed with the Efficacy Population. 
New Wording: 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will comprise all randomized participants. 
Participants will be evaluated according to the treatment to which they were 
randomized. Any participant who receives a treatment randomization number 
will be considered to have been randomized. 
Modified Intent-to-Treat Population 


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8.0 STATISTICS 
 
 
 
 
 
 
The modified Intent-to-Treat (mITT) population will comprise all participated 
in the ITT population who receive at least one dose of study drug, have a baseline 
Hgb measurement, and at least one corresponding post-baseline measurement.  
Participants will be evaluated according to the treatment to which they were 
randomized.  The primary population for the assessing efficacy will be the mITT 
population. 
Safety Population 
The Safety population will consist of all participants in the ITT population who 
received at least one dose of study drug.  Participants will be evaluated according 
to treatment received.  This population will be used for assessing safety. 
Pharmacokinetics Population 
The Pharmacokinetics (PK) population will consist of all participants in the 
Safety population with at least one measurable concentration of FCM. 
8.3 Disposition and Baseline Characteristics 
Original Wording: 
For the oral iron run-in period, the number and percentage of participants who 
are treated with oral iron, discontinue oral iron, respond to oral iron, and enter 
the randomized portion of the study will be summarized. 
For the randomized portion of the study, the number and percentage of 
participants who are randomized, treated, prematurely discontinue, and complete the 
study will be summarized by treatment group.   
Participants with clinically important protocol deviations will be identified by 
treatment group and type of deviation.  The clinical team will identify deviations 
and the deviations will be identified in the database.   


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8.0 STATISTICS 
 
 
 
 
 
 
The number of participants will be summarized for each investigative site.  
Baseline characteristics (e.g., sex, race, and age) will be summarized descriptively 
by treatment group and overall. 
New Wording: 
The number of participants in each investigative site will be summarized.  The 
number of participants who are screened, randomized, treated, prematurely 
discontinue, and complete the study will be summarized.    
The clinical team will identify deviations and the deviations will be identified in the 
database. Participants with clinically important protocol deviations will be 
summarized. 
Demographics and baseline characteristics will be summarized using descriptive 
statistics or frequency counts. 
8.4.1 Primary Endpoint 
Original Wording: 
The change in hemoglobin from baseline to day 35 will be assessed with an analysis 
of covariance (ANCOVA) model with baseline stratification factors (Hgb and age 
categories), treatment, and a covariate of baseline hemoglobin. Baseline 
hemoglobin will be defined as the last hemoglobin obtained before randomization. 
New Wording: 
Primary analysis 
The primary endpoint is the change in hemoglobin from baseline to day 35.  The 
change in hemoglobin from baseline to day 35 will be analyzed using parametric 
analysis of covariance (ANCOVA).  The model will include terms for the 
randomization strata (Hgb and age categories),  baseline Hgb, as well as treatment 


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8.0 STATISTICS 
 
 
 
 
 
 
group. Baseline hemoglobin will be defined as the last hemoglobin obtained before 
randomization. 
The primary endpoint will be analyzed for the mITT population. 
Subgroup analyses 
The change in hemoglobin from baseline to day 35 will be summarized 
separately for the following subgroups: 
 
Cause of IDA:  inflammatory bowel disease (IBD), not IBD     
 
Baseline hemoglobin: <10,  ≥10 g/dL   
 
Age:  1 to <12,  ≥12 to 17 years 
Estimates of treatment effect together with 95% confidence intervals will be 
displayed graphically. 
Subgroup analyses will be conducted for the mITT population. 
8.4.2 Secondary Endpoint 
Original Wording: 
The change in ferritin, TSAT, and reticulocyte hemoglobin content from baseline to 
day 35 will be assessed with an ANCOVA model with baseline stratification factors 
(Hgb and age categories), treatment, and a covariate of baseline value.  
Baseline will be defined as the last value obtained before randomization. 
Change from baseline to individual time points will be summarized descriptively for 
Hgb, ferritin, TSAT, and reticulocyte hemoglobin content. 
New Wording: 


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8.0 STATISTICS 
 
 
 
 
 
 
 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
 Change in ferritin from baseline to Day 35 
 Change in TSAT from baseline to Day 35  
 Changes from baseline in hemoglobin, ferritin, TSAT, and 
reticulocyte hemoglobin content throughout the study. 
 Pharmacokinetic assessments, including Cmax, Tmax, AUC0-time last 
measured concentration, AUC0-infinity, T1/2, MRT, Cl, VD, VDc, VDss, and 
VDarea. 
 
Continuous efficacy endpoints will be analyzed using ANCOVA as described for the 
primary endpoint.  Binary efficacy variables will be analyzed using stratified 
Cochran-Mantel-Haenszel chi-square tests.. 
All secondary endpoints will be analyzed for the mITT population. 
Details of analyses for these endpoints will be outlined in the SAP.   
Pharmacokinetics and Pharmacodynamics (PK/PD) Endpoints 
The pharmacokinetic parameters will be calculated by standard non-
compartmental analysis according to current working practices and using 
WinNonlin®. All calculations of non-compartmental parameters will be based 
on actual sampling times. The actual sampling times and doses will be used for 
the analysis.  The PK parameters will be calculated with and without adjustment 
for baseline. All derived PK parameters will be listed. The following summary 
statistics will be calculated: n, mean, standard deviation [SD], coefficient of 
variation (CV) , median, minimum, and maximum, along with geometric mean, 
geometric mean SD, geometric percent coefficient of variation [%CV], and 95% 


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8.0 STATISTICS 
 
 
 
 
 
 
 
Cis around the geometric mean. For Tmax, only n, median, minimum and 
maximum will be presented.  
In addition, nonlinear mixed effects modelling will be used derive population 
PK parameters and/or models. The influence of various covariates (e.g., age, 
weight, sex, race) on the variability will be examined.  Further details will be 
provided in the SAP. 
The relationship between FCM exposure and clinical outcome may be explored 
graphically. If appropriate, a relationship may be established between FCM 
exposure and effect or any special interest adverse events. Further details will 
be provided in the SAP. 
8.4.3 Missing Data 
Original Wording: 
The effect of missing data on the primary efficacy endpoint may be examined with 
sensitivity analyses to be described in the Statistical Analysis Plan. 
New Wording: 
A participant who withdraws from the study for any reason will be included in the 
analyses regardless of time on study.  Methods for handling withdrawals and missing 
data will be specific to each endpoint to be analyzed.  Details will be provided in the 
SAP. 
8.5.2 Adverse Events 
Original Wording: 
Oral Iron Run-In Period 
The number and percent of participants who report treatment-emergent 
adverse events will be summarized. A treatment-emergent adverse event is an 
event that begins after receipt of oral iron. The Medical Dictionary for Regulatory 


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8.0 STATISTICS 
 
Activities [MedDRA] Terminology will be used to classify all adverse events with 
respect to system organ class (SOC) and preferred term. 
Randomized Period 
The number and percent of participants who report treatment-emergent adverse 
events will be summarized for each treatment group. A treatment-emergent adverse 
event is an event that begins after receipt of randomized treatment. The Medical 
Dictionary for Regulatory Activities [MedDRA] Terminology will be used to 
classify all adverse events with respect to system organ class (SOC) and 
preferred term. 
New Wording: 
Adverse events will be coded by system organ class (SOC) and preferred term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
The number and percent of participants who report treatment-emergent adverse 
events will be summarized for each treatment group. A treatment-emergent adverse 
event is an event with onset date on or after the study drug start date..  
8.5.3 Adverse Events of Special Interest 
Adverse events of special interest (AESI) include hypersensitivity, hypersensitivity-
like reactions, and cardiovascular events. Hypersensitivity and hypersensitivity-like 
reactions will be identified using standardized MedDRA queries. Cardiovascular 
events will be identified using the SOCs for cardiac disorders and vascular disorders.  
The overviews and summaries that are provided for all TEAEs will also be provided 
for the AESIs. In addition, the time to onset and time to recovery will be summarized. 
 
8.6 Sample Size Rationale 


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Original Wording: 
Enrollment is planned for approximately 56 randomized participants (28 per 
treatment group). Based on Study 1VIT09031, a mean difference in change from 
baseline for hemoglobin of 1.0 g/dL between FCM and oral iron and a pooled 
standard deviation of 1.0 g/dL, 23 participants/group will achieve 90% power for 
the primary endpoint. Up to 56 participants/group will be randomized in order to 
account for premature discontinuations. 
New Wording: 
A total of 60 participants (30 per treatment group) are required to detect an expected 
difference in Hgb of 1.0 g/dL (common standard deviation = 1.16 g/dL) at two-sided 
alpha=0.05 with 90% power.  Assuming 20% attrition of subjects not meeting the 
definition of mITT, approximately 72 participants will be randomized. 
REFERENCES 
The following reference was added:  
19. Van Wyck D, Anderson J, Johnson K. Labile iron in parenteral iron 
formulations: a quantitative and comparative study. 2004;19(3):561-565. 
To support the claim 
that other parenteral 
iron preparations carry 
a significant risk of 
inducing a bioactive 
iron reaction when 
delivered at higher 
doses. 
 
 


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AMENDMENT 2 CHANGES 
 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
HEADER 
The heading was changed to reflect the change in company name and the 
current protocol version number and date of version. 
To reflect the updated 
version of the 
protocol. 
Original Wording: 
Luitpold Pharmaceuticals, Inc.       Protocol No.: 1VIT17044 
CONFIDENTIAL                       Amendment 1 Date: 14 September 2017 
New Wording:  
American Regent, Inc.              Protocol No.: 1VIT17044 
CONFIDENTIAL                       Amendment 2 Date: 13 March 2019 
Many sections throughout the protocol 
Luitpold Pharmaceuticals, Inc. was changed to American Regent, Inc. 
To reflect the current 
name of the company 
TITLE PAGE and STUDY SYNOPSIS: 
TITLE 
Title was changed. 
Original Wording: 
A Multicenter, Randomized, Active-Controlled Study to Investigate the 
Efficacy and Safety of Intravenous Ferric Carboxymaltose in Pediatric 
Patients with Iron Deficiency Anemia  
New Wording:  
A Multicenter, Multinational, Randomized, Active-Controlled Study to 
Investigate the Efficacy and Safety of Intravenous Ferric Carboxymaltose 
in Pediatric Patients with Iron Deficiency Anemia  
To reflect that it is a 
global study 


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TITLE PAGE and STUDY SYNOPSIS 
Protocol Date was changed. 
Original Wording: 
Protocol Date: 20 April 2017 
Amendment I Protocol Date: 14 September 2017 
New Wording:  
Protocol Date: 20 April 2017 
Amendment 1 Protocol Date: 14 September 2017 
Amendment 2 Protocol Date: 13 March 2019 
To reflect the date of 
the current protocol 
version. 
SIGNATURES OF AGREEMENT FOR 
PROTOCOL 
 
Removal of: Linda M. Mundy, MD, PhD, FACP 
Susan Oskins, RN, BSN, Pharmacovigilance Manager 
Nicole Blackman, PhD, Statistician 
Addition of: Geoffrey Mukwaya, MD, Head, Clinical R&D 
Mark Falone, MD, Medical Director, Clinical R&D 
Anthony DiGuglielmo, DPM, Head of Pharmacovigilance 
Nicole Blackman, PhD, Head of Quantitative Sciences 
To reflect current 
reviewers. 
Many sections throughout the protocol 
Luitpold Pharmaceuticals, Inc. was changed to American Regent, Inc. 
To reflect the current 
name of the company 
STUDY SYNOPSIS: DESIGN and 3.1 
OVERALL STUDY DESIGN 
 
Original Wording: 
This is a Phase III, multicenter, randomized, active-controlled study that 
compares the efficacy and safety of FCM to oral iron in pediatric 
participants with IDA and a documented history of an inadequate response 
to oral iron therapy at least 8 weeks (56 days) prior to randomization. 
The oral ferrous sulfate formulation received will be based on the 
participant’s age, such that infants and children (1 to <4 years of age) will 
receive ferrous sulfate drops, children (≥4 to <12 years of age) will receive 
ferrous sulfate elixir, and adolescents (≥12 to 17 years of age) will receive 
ferrous sulfate tablets. Participants who experience adverse clinical 
symptoms due to the oral iron during the treatment phase may have a 
weight-based dose of ferrous sulfate reduced from 6 mg/kg to 3 mg/kg. If 
To allow children (≥4 
to <12 years of age) 
the option to receive 
either ferrous sulfate 
elixir or ferrous 
sulfate tablets. 
 


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the participant is receiving tablets, the dose will be reduced from one 
tablet taken twice daily to one tablet per day.  
New Wording:  
This is a Phase III, multicenter, multinational, randomized, active-
controlled study that compares the efficacy and safety of FCM to oral iron 
in pediatric participants with IDA and a documented history of an 
inadequate response to oral iron therapy at least 8 weeks (56 days) prior to 
randomization. 
The oral ferrous sulfate formulation received will be based on the 
participant’s age, such that infants and children (1 to <4 years of age) will 
receive ferrous sulfate drops, children (≥4 to <12 years of age) will have 
the option to receive ferrous sulfate elixir or ferrous sulfate tablets, and 
adolescents (≥12 to 17 years of age) will receive ferrous sulfate tablets. 
Participants who experience adverse clinical symptoms due to the oral iron 
during the treatment phase may have a weight-based dose of ferrous sulfate 
reduced from 6 mg/kg to 3 mg/kg. If the participant is receiving tablets, the 
dose will be reduced from one tablet taken twice daily to one tablet per 
day.  
STUDY SYNOPSIS: INCLUSION 
CRITERIA 
and 
4.2.1 INCLUSION CRITERIA  
Original Wording: 
4.  Documented history of an inadequate response to any oral iron therapy 
for at least 8 weeks (56 days) prior to randomization. 
New Wording:  
4.  Documented history of an inadequate response to any oral iron therapy 
for at least 8 weeks (56 days) prior to screening. 
Section 4.1 states no 
oral iron from time of 
consent so the 
sentence was changed 
screening instead of 
randomization. 
STUDY SYNOPSIS: EXCLUSION 
CRITERIA 
and 
4.2.2 EXCLUSION CRITERIA  
Original Wording: 
2.  Previous randomization and treatment in this study or any other clinical 
study of FCM or VIT-45. 
4.  Chronic kidney disease participants on hemodialysis. 
FDA requested that 
children with chronic 
kidney disease on 
hemodialysis be 


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New Wording:  
2.  Previous randomization and treatment in this study or any other clinical 
study of FCM. 
4.  Chronic kidney disease participants on hemodialysis. 
allowed to participate 
in the study 
STUDY SYNOPSIS: STUDY DRUG 
ADMINISTRATION 
and 
5.2 DRUG 
ADMINISTRATION/REGIMEN  
 
Original Wording: 
Group A (FCM) will receive 2 doses (Day 0 and Day 7) of FCM at 15 
mg/kg to a maximum of single dose of 750 mg (whichever is smaller) up to 
a maximum total dose of 1500 mg. FCM will be administered as either an 
undiluted IV push at a rate of 100 mg (2 mL)/minute OR in no more than 
250 mL of normal saline and infused over 15 minutes. 
Group B:  
Group B (Ferrous sulfate) will receive an age-dependent 
formulation of oral ferrous sulfate daily for 28 days as follows: participants 
<12 years of age will receive 6 mg (elemental iron)/kg/day divided into 2 
daily doses of an oral liquid formulation, either drops or elixir, and 
participants ≥12 will receive 2 daily doses of oral tablets. Infants and 
children (ages 1 to <4 years) will receive oral ferrous sulfate drops, while 
children (ages ≥4 to <12 years) will receive oral ferrous sulfate elixir. 
Adolescents (ages ≥12 to 17 years) will receive an oral ferrous sulfate 
tablet (65 mg of elemental iron/tablet/dose) twice a day (BID). The 
maximum daily dose for all participants is 130 mg of elemental iron 
New Wording:  
Group A (FCM) will receive 2 doses (Day 0 and Day 7) of FCM at 15 
mg/kg to a maximum of single dose of 750 mg (whichever is smaller) up to 
a maximum total dose of 1500 mg. FCM will be administered as either an 
undiluted IV push at a rate of 100 mg (2 mL)/minute OR in no more than 
250 mL of normal saline and infused over 15 minutes. 
Group B:  
Group B (Oral Ferrous sulfate) will receive an age-
dependent formulation of oral ferrous sulfate daily for 28 days as follows: 
participants <12 years of age will receive 6 mg (elemental iron)/kg/day 
To allow children (≥4 
to <12 years of age) 
the option to receive 
either ferrous sulfate 
elixir or ferrous 
sulfate tablets. 
 


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divided into 2 daily doses of an oral liquid formulation, either drops or 
elixir, and participants ≥12 will receive 2 daily doses of oral tablets. 
Infants and children (ages 1 to <4 years) will receive oral ferrous sulfate 
drops, while children (ages ≥4 to <12 years) will have the option receive 
oral ferrous sulfate elixir or oral ferrous sulfate tablets. Adolescents 
(ages ≥12 to 17 years) will receive an oral ferrous sulfate tablet (65 mg of 
elemental iron/tablet/dose) twice a day (BID). The maximum daily dose 
for all participants is 130 mg of elemental iron. 
STUDY SYNOPSIS: STUDYSITES 
Original Wording: 
Approximately 20 
New Wording:  
Approximately 30 
To reflect anticipated 
number of sites 
STUDY SYNOPSIS, FIGURE 1 
Original Wording: 
Ferrous Sulfate Oral Solution (Drops: <4y.o.; Elixer ≥4 y.o.) 
New Wording: 
Ferrous Sulfate Oral Solution (Drops: <4y.o.; Elixer or Oral Tablets ≥4 
y.o.) 
 
3.3 RATIONALE FOR SPARSE 
PHARMACOKINETIC SAMPLING 
Original Wording: 
Population-based PK/PD modelling describing the time course of total 
serum iron (TSI) concentrations and the relationship between TSI and 
changes of hemoglobin following a single dose of intravenous FCM in 
pediatric subjects with IDA has been performed using intensively sampled 
data from Study 1VIT13036.16  It is proposed to supplement this initial 
modelling with additional sparsely sampled PK data from this study. Based 
on the anticipated visit duration on the 2 FCM administration days in this 
study, the following sparse PK sampling scheme is proposed: pre-dose, 
immediately post-infusion and 60 minutes post-dose on Days 0 and 7, on 
which subjects will receive 15 mg/kg (up to a maximum dose of 750 mg). 
This pragmatic approach, which minimizes the number of blood draws 
To provide a 
timeframe for what 
immediately means. 


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compared to a full PK profile, is expected to facilitate exposure-response 
analysis for the proposed FCM regimen. 
New Wording:  
Population-based PK/PD modelling describing the time course of total 
serum iron (TSI) concentrations and the relationship between TSI and 
changes of hemoglobin following a single dose of intravenous FCM in 
pediatric subjects with IDA has been performed using intensively sampled 
data from Study 1VIT13036.16  It is proposed to supplement this initial 
modelling with additional sparsely sampled PK data from this study. 
Based on the anticipated visit duration on the 2 FCM administration days 
in this study, the following sparse PK sampling scheme is proposed: pre-
dose, immediately (within 5 minutes) post-infusion and 60 minutes post-
dose on Days 0 and 7, on which subjects will receive 15 mg/kg (up to a 
maximum dose of 750 mg). This pragmatic approach, which minimizes 
the number of blood draws compared to a full PK profile, is expected to 
facilitate exposure-response analysis for the proposed FCM regimen. 
 
3.4 SCHEDULE OF EVENTS 
Footnote #2 
Original Wording: 
Blood samples for pharmacokinetic analysis will be collected pre-dose, 
immediately post-dose, and 60 minutes post-dose for participants receiving 
FCM. For a full description of the pharmacokinetic parameters, refer to 
Protocol section 6.3.6. 
New Wording: 
Blood samples for pharmacokinetic analysis will be collected pre-dose, 
immediately (within 5 minutes) post-dose, and 60 minutes post-dose for 
participants receiving FCM. For a full description of the pharmacokinetic 
parameters, refer to Protocol section 6.3.6. 
 
To provide a 
timeframe for what 
immediately means. 


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4.3 PARTICIPANT ASSIGNMENT AND 
RANDOMIZATION PROCESS 
Original Wording: 
The oral ferrous sulfate formulation received will be based on the 
participant’s age, such that: infants and children (1 to <4 years of age) will 
receive ferrous sulfate drops, children (≥4 to <12 years of age) will receive 
ferrous sulfate elixir, and adolescents (≥12 to 17 years of age) will receive 
ferrous sulfate tablets. 
New Wording:  
The oral ferrous sulfate formulation received will be based on the 
participant’s age, such that: infants and children (1 to <4 years of age) will 
receive ferrous sulfate drops, children (≥4 to <12 years of age) will 
receive ferrous sulfate elixir or ferrous sulfate tablets, and adolescents 
(≥12 to 17 years of age) will receive ferrous sulfate tablets. 
 
To allow children (≥4 
to <12 years of age) 
the option to receive 
either ferrous sulfate 
elixir or ferrous 
sulfate tablets. 
 
5.3 MEDICATION PRECAUTION 
Original Wording: 
When administering FCM, the following precautions will be taken: 
 
Heart rate and blood pressure will be assessed pre-, immediately post, 
and 30 minutes post administration.  Participants will be discharged 
from the site by the Investigator or his or her designee only if there are 
no significant signs or symptoms 30 minutes after the administration 
is completed. 
New Wording:  
When administering FCM, the following precautions will be taken: 
 
Heart rate and blood pressure will be assessed pre-, immediately 
(within 5 minutes) post, and 30 minutes post administration.  
Participants will be discharged from the site by the Investigator or his 
or her designee only if there are no significant signs or symptoms 30 
minutes after the administration is completed. 
To provide a 
timeframe for what 
immediately means. 
5.5 CONCOMITANT MEDICATION 
Original Wording: 
For clarification. 


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If receiving treatment for IBD, therapy must be stable for at least 8 weeks 
prior to consent and remain stable through the remaining of the study. 
New Wording:  
If receiving treatment for IBD, therapy must be stable for at least 8 weeks 
prior to consent and remain stable through the duration of the study. 
 
6.1 INFORMED CONSENT 
Original Wording: 
Prior to any study specific procedures, the investigator must explain to each 
participant 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 participant (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 US government. The 
participant’s legal guardian will be given a copy of the signed consent form. 
New Wording:  
Prior to any study specific procedures, the investigator must explain to each 
participant 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 participant (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 US government. 
Subjects who are too young to sign an ICF, but mature enough to 
understand the study, will provide informed assent per local law.  The 
subject must be able to understand that he or she can withdraw from 
the trial at any time and for any reason.  The participant’s legal guardian 
will be given a copy of the signed consent form. 
To provide additional 
guidance about 
informed assent 


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6.3.1 DAY 0 VISIT 
Original Wording: 
After a randomization number has been obtained, the first dose of oral 
ferrous sulfate will be administered in the clinic according to the 
following: infants and children (1 to <4 years of age) will receive ferrous 
sulfate drops; children (≥4 to <12 years of age) will receive ferrous sulfate 
elixir; and adolescents (≥12 to 17 years of age) will receive ferrous sulfate 
tablets. 
Group A: 
 
Blood samples for PK immediately post-dose and 60 minutes post 
dose. 
 
Post-administration, obtain sitting heart rate and blood pressure 
immediately after and 30 minutes after FCM administration. 
Group B  
 
Oral ferrous sulfate dispensing: 
o If the participant took less than the amount of oral iron 
expected, document the reason(s) for dose reduction and 
counsel the participant/parents/guardians about the 
importance of taking the study drug as prescribed. 
New Wording:  
After a randomization number has been obtained, the first dose of oral 
ferrous sulfate will be administered in the clinic according to the 
following: infants and children (1 to <4 years of age) will receive ferrous 
sulfate drops; children (≥4 to <12 years of age) will receive ferrous sulfate 
elixir or ferrous sulfate tablets; and adolescents (≥12 to 17 years of age) 
will receive ferrous sulfate tablets. 
Group A: 
 
Blood samples for PK immediately (within 5 minutes) post-dose and 
60 minutes post dose. 
To allow children (≥4 
to <12 years of age) 
the option to receive 
either ferrous sulfate 
elixir or ferrous 
sulfate tablets. 
To provide a 
timeframe for what 
immediately means. 
To correct a typo: 
missed doses instead 
of dose reduction. 


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 
Post-administration, obtain sitting heart rate and blood pressure 
immediately (within 5 minutes) after and 30 minutes after FCM 
administration. 
Group B  
 
Oral ferrous sulfate dispensing: 
o If the participant took less than the amount of oral iron 
expected, document the reason(s) for missed doses and 
counsel the participant/parents/guardians about the 
importance of taking the study drug as prescribed. 
 
For ferrous sulfate drops and elixir: 
o If the participant took less than the volume expected, document 
the reason(s) for missed doses and counsel the 
participant/parent/guardian about the importance of taking the 
study drug as prescribed. 
 
 
6.3.2 DAY 7 AND DAT 14 VISIT 
Original Wording: 
Group A: 
 
Blood samples for PK immediately post-dose and 60 minutes post 
dose. 
 
Post-administration, obtain sitting heart rate and blood pressure 
immediately after and 30 minutes after FCM administration. 
Group B  
 
Oral ferrous sulfate dispensing: 
o If the participant took less than the number of tablets expected, 
document the reason(s) for dose reduction and counsel the 
To provide a 
timeframe for what 
immediately means. 
To correct a typo: 
missed doses instead 
of dose reduction. 


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participant/parent/guardian about the importance of taking the 
study drug as prescribed. 
 
For ferrous sulfate drops and elixir: 
o If the participant took less than the volume expected, document 
the reason(s) for dose reduction and counsel the 
participant/parent/guardian about the importance of taking the 
study drug as prescribed. 
 
New Wording:  
Group A: 
 
Blood samples for PK immediately (within 5 minutes) post-dose and 
60 minutes post dose. 
 
Post-administration, obtain sitting heart rate and blood pressure 
immediately (within 5 minutes) after and 30 minutes after FCM 
administration. 
Group B 
 
 Oral ferrous sulfate dispensing: 
o If the participant took less than the number of tablets expected, 
document the reason(s) for missed doses and counsel the 
participant/parent/guardian about the importance of taking the 
study drug as prescribed. 
 
For ferrous sulfate drops and elixir: 
o If the participant took less than the volume expected, document 
the reason(s) for missed doses and counsel the 
participant/parent/guardian about the importance of taking the 
study drug as prescribed. 
6.3.6 PHARMACOKINETIC 
SAMPLING 
Original Wording: 
Blood samples will be collected for PK assessment pre-dose, immediately 
post-dose, and 60 minutes post-dose for participants receiving FCM on Days 
To clarify the time for 
blood sampling. 


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0 and 7. Blood samples should be taken at approximately the same time of 
day on Day 7 as Day 0. 
New Wording:  
Blood samples will be collected for PK assessment pre-dose, immediately 
(within 5 minutes) post-dose, and 60 minutes post-dose for participants 
receiving FCM on Days 0 and 7. Blood samples should be taken at 
approximately the same time of day (within 1 hour) on Day 7 as Day 0. 
7.1 ADVERSE EVENTS 
Original Wording: 
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. 
New Wording:  
To quantify the severity of adverse events, the National Cancer Institute 
(NCI)-Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5 or higher should be used to grade all events.  These criteria are 
provided in the procedure manual. 
To make sure the 
latest version of the 
NCI CTCAE is used 
7.3 SERIOUS ADVERSE EVENTS 
Original Wording: 
Email: pv@luitpold.com 
New Wording:  
Email: pv@americanregent.com 
To reflect the change 
in the e-mail for 
Pharmacovigilance 
8.4.1 PRIMARY ENDPOINTS 
Subgroup analyses 
Original Wording: 
The change in hemoglobin from baseline to day 35 will be 
summarized separately for the following subgroups: 
 Cause of IDA: IBD, not IBD     
 Baseline hemoglobin : <10,  ≥10 g/dL   
Since children with 
chronic kidney 
disease on 
hemodialysis are 
allowed to participate 
in the study, they 


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 Age:  1 to <12,  ≥12 to 17 years 
New Wording: 
The change in hemoglobin from baseline to day 35 will be 
summarized separately for the following subgroups: 
 Cause of IDA: IBD, not IBD     
 CKD, not CKD 
 Baseline hemoglobin : <10,  ≥10 g/dL   
 Age:  1 to <12,  ≥12 to 17 years 
were included in the 
subgroup analyses 
8.4.2 SECONDARY ENDPOINTS 
Original Wording: 
Secondary efficacy endpoints include: 
 Change in ferritin from baseline to Day 35 
 Change in TSAT from baseline to Day 35  
 Changes from baseline to in hemoglobin, ferritin, TSAT, and 
reticulocyte hemoglobin content. 
 Pharmacokinetic assessments, including Cmax, Tmax, AUC0-
time last measured concentration, AUC0-infinity, T1/2, MRT, Cl, VD, VDc, 
VDss, and VDarea.  
New Wording: 
Secondary efficacy endpoints include: 
 Change in ferritin from baseline to Day 35 
 Change in TSAT from baseline to Day 35  
 Changes from baseline to in hemoglobin, ferritin, TSAT, and 
reticulocyte hemoglobin content. 
 Pharmacokinetic assessments, including Cmax, Tmax, AUC0-
time last measured concentration, AUC0-infinity, T1/2, MRT, Cl, VD, VDc, 
To clarify 
pharmacokinetic 
assessment 


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VDss, and VDarea. These assessments will be based on a 
population pharmacokinetic analysis using data from this 
study and 1VIT13036. 
8.5.4 CLINICAL LABORATORY 
FINDINGS 
Original Wording: 
Clinical laboratory variables will be presented in two ways.  First, the mean 
change from baseline to each scheduled visit will be summarized. Second, 
the number and percent of participants with treatment-emergent PCS 
laboratory values will be tabulated. Treatment-emergent PCS laboratory 
tests are those in which the baseline value is normal and post-baseline value 
is abnormal (i.e., meets Grade III or Grade IV toxicity criteria from the NCI-
CTC).  Baseline will be defined as the last value obtained before 
randomization. 
New Wording:  
Clinical laboratory variables will be presented in two ways.  First, the 
mean change from baseline to each scheduled visit will be summarized. 
Second, the number and percent of participants with treatment-emergent 
PCS laboratory values will be tabulated. Treatment-emergent PCS 
laboratory tests are those in which the baseline value is normal and post-
baseline value is abnormal (i.e., meets Grade III or Grade IV toxicity 
criteria from the NCI-CTC Version 5 or higher).  Baseline will be defined 
as the last value obtained before randomization. 
To update the version 
of NCI-CTC to be 
used. 
 


American Regent, Inc. 
 
Protocol No.: 1VIT17044 
CONFIDENTIAL  
 
Administrative Change 1 Date: Final 26 September 2019 
Page 92 of 93 
ADMINISTRATIVE CHANGE 1 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
HEADER 
The heading was changed to reflect the current protocol version number 
and date of version. 
To reflect the updated 
version of the 
protocol. 
Original Wording: 
American Regent, Inc.                Protocol No.: 1VIT17044 
CONFIDENTIAL            
Amendment 2 Date: 13 March 2019 
New Wording:  
American Regent, Inc.              Protocol No.: 1VIT17044 
CONFIDENTIAL                       Administrative Change 1 Date: 26 
September 2019 
TITLE PAGE 
Protocol Date was changed. 
Original Wording: 
Protocol Date: 20 April 2017 
Amendment I Protocol Date: 14 September 2017 
Amendment 2 Protocol Date: 13 March 2019 
New Wording:  
Protocol Date: 20 April 2017 
Amendment 1 Protocol Date: 14 September 2017 
Amendment 2 Protocol Date: 13 March 2019 
Administrative Change 1 Date: 26 September 2019 
To reflect the date of 
the current protocol 
version. 
SIGNATURES OF AGREEMENT FOR 
PROTOCOL 
 
Removal of: Anthony DiGuglielmo, DPM, Medical, Director, Head 
of Pharmacovigilance 
 Marsha Simon, Director of Regulatory Affairs 
 Nicole Blackman, PhD, Head of Quantitative Sciences 
An Administrative 
Change does not need 
all functions to 
approve. 


American Regent, Inc. 
 
Protocol No.: 1VIT17044 
CONFIDENTIAL  
 
Administrative Change 1 Date: Final 26 September 2019 
Page 93 of 93 
 
Section 4.2.1 INCLUSION CRITERIA 
 
Original Wording: 
4. Documented history of an inadequate response to any oral iron therapy 
for at least 8 weeks (56 days) prior to screening.  
New Wording:  
4. Documented history of an inadequate response to any oral iron therapy 
for at least 8 weeks (56 days) prior to randomization. 
To revert back to the 
inclusion criteria # 4 
sentence in the 
original protocol and 
Amendment 1. 
 
 

SAP_001.pdf: 
NCT03523117 
1VIT17044   Multicenter Randomized 
Active-controlled Study to Investigate 
Efficacy & Safety of IV FCM in 
Pediatric Patients With IDA 
State Plan dated 26SEP2019


Table of Contents
1VIT17044-STATISTICAL
STATISTICAL ANALYSIS PLAN
4
TABLE OF CONTENTS
6
LIST OF ABBREVIATIONS AND DEFINITIONS
8
1. INTRODUCTION
10
1.1 STUDY OBJECTIVES
10
1.1.1 Primary Objective(s)
10
1.2 STUDY ENDPOINTS
10
1.2.1 Primary Efficacy Endpoint
10
1.2.2 Secondary Efficacy Endpoint(s)
10
1.2.3 Safety Endpoints
10
1.3 SUMMARY OF THE STUDY DESIGN
11
1.3.1 General Study Design and Plan
11
Table 1 Schedule of Events
12
1.3.2 Stratification/Randomization
13
1.3.3 Blinding
13
1.3.4 Sample Size and Statistical Power Considerations
13
2. STATISTICAL METHODS
13
2.1 GENERAL CONSIDERATIONS
13
2.1.1 Reporting Precision
13
2.2 DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS)
14
2.2.1 Intent-to-Treat Population
14
2.2.2 Modified Intent-to-Treat Population
14
2.2.3 Safety Population
14
2.3 DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
15
2.3.1 Baseline Definition
15
2.3.2 Study Day
15
2.3.3 Time Windows for Analysis
15
2.3.4 Handling of Missing Data
15
2.4 POOLING OF CENTERS
16
2.5 ANALYSIS SOFTWARE
16


3. STUDY SUBJECTS
16
3.1 DISPOSITION OF SUBJECTS
16
3.2 PROTOCOL DEVIATIONS
17
3.3 CONCOMITANT INTERVENTION
17
4. DEMOGRAPHY AND BASELINE CHARACTERISTICS
17
4.1 DEMOGRAPHY AND BASELINE CHARACTERISTICS
17
4.2 MEDICAL HISTORY
18
5. STUDY DRUG
18
5.1 TREATMENT COMPLIANCE
18
5.2 PRIOR AND CONCOMITANT MEDICATION
18
6. EFFICACY ANALYSES
19
6.1 PRIMARY EFFICACY ANALYSIS
19
6.1.1 Change in hemoglobin from baseline to Day 35
19
6.1.2 Examination of Subgroups
20
6.2 SECONDARY EFFICACY ANALYSES
20
6.2.1 Change in ferritin from baseline to Day 35
20
6.2.2 Change in TSAT from baseline to Day 35
21
6.2.3 Change in hemoglobin from baseline to each visit
21
6.2.4 Change in ferritin from baseline to each visit
22
6.2.5 Change in TSAT from baseline to each visit
22
6.2.6 Change in Reticulocyte Hemoglobin Content from baseline to each visit
22
7. SAFETY ANALYSES
22
7.1 EXTENT OF EXPOSURE
23
7.2 ADVERSE EVENTS
23
7.2.1 Adverse Events of Special Interest
24
7.2.2 Deaths, Serious and Other Significant Adverse Events
25
7.3 CLINICAL LABORATORY PARAMETERS
25
7.4 VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS
26
7.4.1 Vital Signs
26
7.4.2 Physical Examination
26
8. INTERIM ANALYSES AND DATA AND SAFETY MONITORING BOARD 
(DSMB)
26
8.1 INTERIM ANALYSES
26
DATA AND SAFETY MONITORING BOARD (DSMB)
27


9. SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES
27
10. APPENDICES
29
APPENDIX 1.1 ADVERSE EVENT SCALE
29
APPENDIX 1.2 PEDIATRIC VITAL SIGNS REFERENCE CHART
31


Sponsor: American Regent, Inc. 
 
Protocol No: 1VIT17044 Administrative Change 1 (26 SEP 2019) 
Statistical Analysis Plan
 
 
Version: 2.0 (15-July-2020)  
Confidential 
Page 1 of 28 
 
 
 
Statistical Analysis Plan 
 
Protocol No.: 1VIT17044 
 
 
A Multicenter, Multinational, Randomized, Active-Controlled Study 
to Investigate the Efficacy and Safety of Intravenous Ferric 
Carboxymaltose in Pediatric Patients with Iron Deficiency Anemia 
 
 
 
 
Sponsor: 
 
American Regent, Inc. 
 
Version: 
 
Version 2.0 
 
Issue Date: 
15 July 2020 
 
 
 
 
 




Sponsor: American Regent, Inc. 
 
Protocol No: 1VIT17044 Administrative Change 1 (26 SEP 2019) 
Statistical Analysis Plan
 
 
Version: 2.0 (15-July-2020)  
Confidential 
Page 3 of 28 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION 
7 
1.1 
STUDY OBJECTIVES 
7 
1.1.1 Primary Objective(s) 
7 
1.2 
STUDY ENDPOINTS 
7 
1.2.1 Primary Efficacy Endpoint 
7 
1.2.2 Secondary Efficacy Endpoint(s) 
7 
1.2.3 Safety Endpoints 
7 
1.3 
SUMMARY OF THE STUDY DESIGN 
8 
1.3.1 General Study Design and Plan 
8 
1.3.2 Stratification/Randomization 
10 
1.3.3 Blinding 
10 
1.3.4 Sample Size and Statistical Power Considerations 
10 
2. 
STATISTICAL METHODS 
10 
2.1 
GENERAL CONSIDERATIONS 
10 
2.1.1 Reporting Precision 
10 
2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) 
11 
2.2.1 Intent-to-Treat Population 
11 
2.2.2 Modified Intent-to-Treat Population 
11 
2.2.3 Safety Population 
11 
2.3 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
12 
2.3.1 Baseline Definition 
12 
2.3.2 Study Day 
12 
2.3.3 Time Windows for Analysis 
12 
2.3.4 Handling of Missing Data 
12 
2.4 
POOLING OF CENTERS 
13 
2.5 
ANALYSIS SOFTWARE 
13 
3. 
STUDY SUBJECTS 
13 
3.1 
DISPOSITION OF SUBJECTS 
13 
3.2 
PROTOCOL DEVIATIONS 
14 
3.3 
CONCOMITANT INTERVENTION 
14 
4. 
DEMOGRAPHY AND BASELINE CHARACTERISTICS 
14 
4.1 
DEMOGRAPHY AND BASELINE CHARACTERISTICS 
14 
4.2 
MEDICAL HISTORY 
15 
5. 
STUDY DRUG 
15 
5.1 
TREATMENT COMPLIANCE 
15 
5.2 
PRIOR AND CONCOMITANT MEDICATION 
15 
6. 
EFFICACY ANALYSES 
16 
6.1 
PRIMARY EFFICACY ANALYSIS 
16 


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Page 4 of 28 
 
6.1.1 Change in hemoglobin from baseline to Day 35 
16 
6.1.2 Examination of Subgroups 
17 
6.2 
SECONDARY EFFICACY ANALYSES 
17 
6.2.1 Change in ferritin from baseline to Day 35 
17 
6.2.2 Change in TSAT from baseline to Day 35 
18 
6.2.3 Change in hemoglobin from baseline to each visit 
18 
6.2.4 Change in ferritin from baseline to each visit 
19 
6.2.5 Change in TSAT from baseline to each visit 
19 
6.2.6 Change in Reticulocyte Hemoglobin Content from baseline 
to each visit 
19 
7. 
SAFETY ANALYSES 
19 
7.1 
EXTENT OF EXPOSURE 
20 
7.2 
ADVERSE EVENTS 
20 
7.2.1 Adverse Events of Special Interest 
21 
7.2.2 Deaths, Serious and Other Significant Adverse Events 
22 
7.3 
CLINICAL LABORATORY PARAMETERS 
22 
7.4 
VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS 
23 
7.4.1 Vital Signs 
23 
7.4.2 Physical Examination 
23 
8. 
INTERIM ANALYSES AND DATA AND SAFETY MONITORING 
BOARD (DSMB) 
23 
8.1 
INTERIM ANALYSES 
23 
8.2 
DATA AND SAFETY MONITORING BOARD (DSMB) 
24 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED 
ANALYSES 
24 
10. APPENDICES 
26 
APPENDIX 1.1 ADVERSE EVENT SCALE 
26 
APPENDIX 1.2 PEDIATRIC VITAL SIGNS REFERENCE CHART 
28 
 


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Confidential 
Page 5 of 28 
 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
AST 
Aspartate Aminotransferase Test 
ALT 
Alanine Transaminase Test 
ATC 
Anatomical Therapeutic Chemical 
ANCOVA 
Analysis of Covariance 
AUC0−infinity 
Extrapolated Area Under the Serum 
Concentration- time Curve from Time Zero to 
Infinity 
AUC0−time last measured concentration 
Area Under the Serum Concentration-time 
Curve from Time Zero to the Last Sampling 
Time with a Quantifiable Concentration             
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
eCRF 
Electronic Case Report Form 
Cmax                                                     
Maximum Serum Concentration 
CHr                        
Reticulocyte Hemoglobin Content 
Cl   
Apparent Serum Clearance 
CI 
Confidence Interval  
DSMB   
Data and Safety Monitoring Board 
ESA 
Erythropoietin Stimulating Agent 
FCM 
Ferric Carboxymaltose 
GGT 
Gamma-Glutamyl Transferase 
Hct 
Hematocrit Test 
Hgb 
Hemoglobin 
IDA 
Iron-deficiency Anemia 
IBD 
Inflammatory Bowel Disease 
IRT   
Interactive Response Technology 
IV 
 
Intravenous 
LDH    
Lactate Dehydrogenase 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
mg 
Milligrams 
PCS 
Potentially Clinically Significant 
PE 
Physical Examination 
PT 
Preferred Term 
RBC 
Red Blood Cells 
RDW 
Red Cell Distribution Width 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SD 
Standard Deviation  


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Tmax                                                     
Time at Which Cmax Occurs 
T1/2      
Half-life 
TEAE 
Treament Emergent Adverse Event  
TIBC 
Total Iron Binding Capcacity 
TSAT 
% Transferrin Saturation 
VD                                                         
Apparent Volume of Distribution 
VDc                                                        
Apparent Volume of Distribution Includes the 
Initial Volume of Distribution Following the 
Injection 
VDss        
Volume of Distribution at the Steady State 
VDarea                                                   
Volume of Distribution at the Final 
Elimination 
WBC      
White Blood Cells 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Protocol 1VIT17044 (Administrative 
Change 1 Protocol Date: 26 SEP 2019). This SAP pertains to clinical safety and efficacy analysis 
and should be read in conjunction with the study protocol and electronic case report forms 
(eCRFs). Pharmacokinetic analyses are out of scope for this SAP. 
1.1 
STUDY OBJECTIVES 
1.1.1 
Primary Objective(s) 
The primary objective of this study is to demonstrate the efficacy and safety of intravenous (IV) 
ferric carboxymaltose (FCM), compared to oral iron, in pediatric participants who have iron 
deficiency anemia (IDA). 
1.2 
STUDY ENDPOINTS 
1.2.1 
Primary Efficacy Endpoint 
Change in hemoglobin from baseline to Day 35. 
 
1.2.2 
Secondary Efficacy Endpoint(s) 
 Change in ferritin from baseline to Day 35  
 Change in transferrin saturation (TSAT) from baseline to Day 35  
 Changes from baseline in hemoglobin, ferritin, TSAT, and reticulocyte hemoglobin 
content (CHr) throughout the study.  
 Pharmacokinetic assessments, including Cmax, Tmax, T1/2, MRT, Cl, VD,  VDc, VDss, 
VDarea, AUC0−infinity and AUC0−time last measured concentration. These assessments will be 
based on a population pharmacokinetic analysis using data from this study and the 
1VIT13036 study.  
The analysis of PK assessments is not addressed in this SAP.  
 
1.2.3 
 Safety Endpoints 
Safety endpoints include: 
 Extent of exposure 
 Adverse events 
 Laboratory assessments 
 Vital signs  
 
 
 


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1.3 
SUMMARY OF THE STUDY DESIGN  
1.3.1 
General Study Design and Plan 
This is a Phase III, multicenter, multinational, randomized, active-controlled study that compares 
the efficacy and safety of FCM to oral iron in pediatric participants with IDA and a documented 
history of an inadequate response to oral iron therapy at least 8 weeks (56 days) prior to 
screening.  
 
FCM injection is a stable, non-dextran, Type I polynuclear iron (III) -hydroxide carbohydrate 
complex developed as an intravenous (IV) iron replacement therapy for the treatment of IDA. 
The duration of this study is approximately 6 weeks and the number of sites is approximately 30. 
Participants who satisfy the inclusion requirements and no exclusion criteria will be eligible to 
participate in this study and enter into a screening phase to confirm eligibility. All eligible 
participants will be randomized in a 1:1 ratio to receive either FCM at 15 mg/kg to a maximum 
single dose of 750 mg on Days 0 and 7 for a maximum total dose of 1500 mg in Group A or oral 
iron (oral solution drops, elixir or oral tablets) twice daily for 28 days in Group B. 
Randomization will be stratified by baseline hemoglobin (<10, ≥10 g/dL) and age (1 to <12 and 
≥12 to 17 years). The oral ferrous sulfate formulation received will be based on the participant’s 
age, such that infants and children (1 to <4 years of age) will receive ferrous sulfate drops, 
children (≥4 to <12 years of age) will have the option to receive ferrous sulfate elixir or ferrous 
sulfate tablets, and adolescents (≥12 to 17 years of age) will receive ferrous sulfate tablets. If the 
participants experience adverse clinical symptoms due to the oral iron during the treatment 
phase, the weight-based dose of ferrous sulfate will be reduced from 6 mg/kg to 3 mg/kg. As for 
the participants who receive tablets, the dose will be reduced from one tablet taken twice daily to 
one tablet per day.  
 
Once randomized, all participants will return for efficacy and safety evaluations, including 
adverse events and laboratory assessments, on Days 7, 14, 28, and 35. Additional 
pharmacokinetic sampling and analyses will be performed for participants receiving FCM on 
Days 0 and 7. 
 
 


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The Schedule of Events is presented by Table 1.  
Table 1 Schedule of Events 
Visit Day 
Screening 
(Day -7 + 1) 
Day 0 
Day 7 
Day 14 
Day 28 
 
DAY 35 
Informed Consent / 
Assent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Exam 
 
X 
 
 
 
X 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
IRT 
X 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
Temperature 
 
X 
X 
 
 
 
Hematology, 
Chemistry and Iron 
Indices1  
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test 
X 
 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
IBD Treatment / ESA 
Stability (if applicable) 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
Injectafer® Dosing 
 
X 
X 
 
 
 
Pharmacokinetic 
Sampling2  
 
X 
X 
 
 
 
Oral Iron Dosing 
 
X 
X 
X 
X 
 
Oral Iron Dispensing 
 
X 
X 
X 
 
 
Oral Iron Compliance 
Assessment 
 
 
X 
X 
X 
 
For
 1
 a full description of central laboratory assessments, refer to Protocol Section 6.4. 
Blood
 2
 samples for pharmacokinetic analysis will be collected pre-dose, immediately (within 5 minutes)  post-dose, and 60 
minutes post-dose for participants receiving FCM. For a full description of the pharmacokinetic parameters, refer to Protocol 
section 6.3.6. 
 
 
 


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1.3.2 
Stratification/Randomization 
On Day 0, participants who meet the inclusion/exclusion criteria will be randomized via IRT 
system in a 1:1 ratio to receive either FCM in Group A or oral iron (oral solution drops, elixir or 
oral tablets) in Group B. Randomization will be stratified by baseline hemoglobin (<10, ≥10 
g/dL) and age (1 to <12 and ≥12 to 17 years).    
 
1.3.3 
Blinding 
The randomization schedule is generated by an independent randomization statistician. Although 
the study is open-label, other than designated randomization personnel, the study statisticians and 
the ARI statistician are blinded to study drug assignment prior to database lock.  
 
1.3.4 
Sample Size and Statistical Power Considerations 
A total of 60 participants (30 per treatment group) are required to detect an expected difference 
in hemoglobin of 1.0 g/dL (common standard deviation = 1.16 g/dL) at two-sided alpha=0.05 
with 90% power.  Assuming attrition of subjects not being evaluable for efficacy analysis, 
approximately 72 participants will be randomized. 
 
2. 
STATISTICAL METHODS 
2.1 
GENERAL CONSIDERATIONS 
Analysis datasets will be produced according to CDISC standards. All study-collected data will 
be summarized in tables or graphs. Listing will be produced when appropriate and all ICH-
required listings will be produced.   
 
Continuous variables will be summarized by number of observations (n), mean, standard 
deviation (SD), median, quartiles (Q1 and Q3), minimum (min), and maximum (max) values. 
Other descriptive statistics (e.g., coefficient of variation) may be reported when appropriate. 
Analysis of categorical variables will include frequency counts and percentages. Unknown and 
missing data may be presented as a separate category and the denominator will include unknown 
or missing values as appropriate.  
 
If applicable, hypothesis testing will be carried out at the two-sided α=0.05 level unless 
otherwise specified; 2-sided 95% confidence intervals (CIs) will be presented, where specified. 
2.1.1 
Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
 
Statistics 
Degree of Precision 


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Mean, Geometric mean, Median, 
Quartiles, Confidence limit boundaries 
One decimal place more than the raw data. 
Standard deviation, Standard error 
Two decimal places more than the raw data. 
Minimum, Maximum 
The same as the raw data. 
p-value 
Rounded to 4 decimal places and therefore 
presented as 0. xxxx; p-values smaller than 
0.0001 as ‘<0.0001’; p-values greater than 0.9999 
as ‘>0.9999’. 
Percentage 
One decimal place. A percentage of 100% will be 
reported as 100%. Percentages of zero will be 
reported as 0. 
 
For weight and height, one decimal place will be used for summary statistics. Fractional numeric 
values will be presented with a zero to the left of the decimal point (for example, 0.12 – 0.30). 
 
2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) 
2.2.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will comprise all randomized participants. Participants will 
be evaluated according to the treatment to which they were randomized. Any participant who 
receives a treatment randomization number will be considered to have been randomized. Unless 
otherwise stated, disposition and baseline data will be summarized in ITT population. The 
primary population for assessing efficacy will be the ITT population.  
 
2.2.2 
Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) population will comprise all participants in the ITT 
population who receive at least one dose of study drug, have a baseline hemoglobin 
measurement, and at least one corresponding post-baseline measurement.  Participants will be 
evaluated according to the treatment to which they were randomized.  The mITT population may 
be used for post hoc sensitivity analyses. 
 
2.2.3 
Safety Population 
The safety population will consist of all participants in the ITT population who received at least 
one dose of study drug. Participants will be evaluated according to treatment received.  This 
population will be used for assessing safety. 
 


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2.3 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
2.3.1 
Baseline Definition  
For evaluations collected at multiple time points, the baseline will be defined as the last value 
obtained before randomization.   
  
2.3.2 
Study Day  
Study Day will be calculated relative to the day of first dose (defined as Day 1). 
 
If the assessment (or event) date falls on or after the date of first dose then 
Study Day = Assessment Date – Date of First Dose + 1 
 
If assessment date falls before the date of first dose then 
Study Day = Assessment Date – Date of First Dose 
 
In the case of adverse events or concomitant medications where the assessment date is partially 
or completely missing, Study Day and any corresponding durations will follow the conventions 
given in Section 2.3.4. 
 
2.3.3 
Time Windows for Analysis 
Assessment windows will not be defined for the purpose of classifying measurements obtained 
outside scheduled assessment times for safety and efficacy analyses. The summary by visit will 
be based on the observations at scheduled visits only. Shift tables will be based on the 
observations at all visits including both scheduled and unscheduled visits. 
 
2.3.4 
Handling of Missing Data 
A participant who withdraws from the study for any reason will be included in the analyses 
regardless of time on study. Methods for handling withdrawals and missing data will be specific 
to each endpoint to be analyzed. Missing data will not be imputed for descriptive statistical 
summaries in safety or efficacy. 
 
For statistical inferential (models) analyses, missing data will be imputed using last observation 
carried forward (LOCF) method for hemoglobin and other efficacy endpoints. e.g. for primary 
endpoint, hemoglobin, when Day 35 data is missing (subject has discontinued before Day 35, or 
measurement not taken at Day 35 though subject was not discontinued), Day 28 result will be 
carried forward. If the post-baseline value of the first scheduled visit is missing, the worst value 
obtained from the same time point of all subjects in ITT population will be used for both 
treatment groups. The worst value is defined as the lowest value for hemoglobin, ferritin, TSAT 
and reticulocyte hemoglobin content.  
 
Supportive analyses will assess the impact of missing values on inferences based on primary 
efficacy endpoints and missing data will be handled by using missing at random (MAR) in 


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mixed effect model repeat measurement (MMRM) model. The observed case will also be applied 
for primary analysis.  
 
Dates missing the day or both day and month of the year will adhere to the following 
conventions to classify TEAE and to classify prior/concomitant medications. 
 
 A medication with a completely missing start date will be considered a prior medication. 
A medication with a completely missing stop date will be considered a concomitant 
medication. 
 
 If complete AE onset date is missing and AE end date is on or after the first dose date 
then it will be counted as a treatment emergent AE (TEAE) for the study. If complete AE 
onset date is missing and AE end date is before the first dose date then it will be counted 
as a not treatment emergent AE (TEAE) for the study. 
 
 If an AE or a medication has a partial missing start or stop date, the following rules will 
be used for imputation:  
 
o If year is present but month and day are missing, impute start date as January 1 of that 
year or first dose date if the year is the same as the year of first dose date and impute 
stop date as December 31 of that year.  
 
o If year and day are present but month is missing, impute start month as January or the 
month of the first dose date if the year and day is the same as the year and day of first 
dose date and impute stop month as December. 
 
o If year and month are present but day is missing, impute start date as first day of that 
month or first dose date if the year and month are the same as the year and month of 
first dose date and impute stop date as last day of that month. 
2.4 
POOLING OF CENTERS 
The study centers are not planned to be used as a stratification factor nor a covariate in the 
statistical modeling and testing, therefore it is not necessary to pool small centers together.   
2.5 
ANALYSIS SOFTWARE 
All summaries and statistical analyses will be generated using SAS® version 9.4 or higher. 
 
3. 
STUDY SUBJECTS 
3.1 
DISPOSITION OF SUBJECTS 
Disposition will be summarized by treatment group and overall for all enrolled subjects and also 
summarized in each investigative site.  
 
The disposition will include the following: 


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 Participants who are randomized (= ITT population) 
 Participants who are in Safety Population  
 Participants who complete the study 
 Participants who discontinue the study 
 
The number and percent of subjects will be summarized for each reason for premature 
discontinuation based on the ITT population.  
 
A listing of dispositions will be provided for all randomized subjects. In addition, a listing of 
randomization will also be provided. 
 
3.2 
PROTOCOL DEVIATIONS 
The clinical team will identify deviations and the deviations will be identified in the database 
prior to database lock. The number and percent of participants with clinically important protocol 
deviations will be summarized for each type of deviation by treatment group and overall based 
on the ITT population. 
 
A listing of inclusion/exclusion criteria violations and a listing of all protocol deviations will be 
provided. 
 
3.3 
CONCOMITANT INTERVENTION 
Concomitant intervention is defined as follows:  
 Blood transfusion.  
 Use of IV or oral iron outside of protocol. 
 Increase in erythropoietin for any reason (Day 0 thru Day 35). 
 Change in IBD treatment   
 
The interventions mentioned above are non-study interventions. When concomitant intervention 
occurs, the date of the intervening event should be recorded in the source documents, and the 
electronic Case Report Form (eCRF).  The participant should continue in the study as scheduled. 
The number (percentage) of subjects who have concomitant intervention will be summarized by 
treatment group and overall for ITT population.  
 
4. 
DEMOGRAPHY AND BASELINE CHARACTERISTICS 
4.1 
DEMOGRAPHY AND BASELINE CHARACTERISTICS 
Demography data such as sex, age, age group (1 to <12 and ≥12 to 17 years), race, ethnicity, 
body height, body weight, BMI and BMI group (underweight ≤18.5, 18.5 < normal weight≤ 
24.9, 25 < overweight ≤ 29.9, obesity = BMI of 30 or greater) will be summarized with 
descriptive statistics or frequency counts by treatment group and overall for all patients in ITT 
and Safety populations..  
 


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The following disease-specific baseline characteristics will also be summarized with descriptive 
statistics or frequency counts by treatment and overall for ITT and Safety populations,  
 Cause of IDA  
 Baseline hemoglobin and the categories (baseline hemoglobin <10 g/dL, baseline 
hemoglobin≥10 g/dL).  
 Status of IV iron intolerance 
 Status of oral iron tolerance response  
 Status of drug allergy/intolerance (other than iron) 
 
A subject data listing of demographics and baseline characteristics will be provided.  
 
4.2 
MEDICAL HISTORY 
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) 
Terminology. Events will be coded to System Organ Class (SOC) and preferred term (PT) using 
MedDRA Version 22.0 or higher. The number and percent of subjects with clinically significant 
medical history at screening will be summarized by SOC and PT by treatment group and overall 
for the ITT and Safety Populations. Documented history of an inadequate response after at least 
8 weeks of prior oral iron therapy use will be included in medical history. 
 
5. 
STUDY DRUG  
5.1 
TREATMENT COMPLIANCE  
As for each subject, the individual compliance rate will be summarized by descriptive statistics 
for ITT population.  
FCM Compliance = (total dose of iron administered/target dose) ×100 
 
Oral iron compliance = (total dose of iron taken/total dose prescribed) ×100 
 
5.2 
PRIOR AND CONCOMITANT MEDICATION  
Prior medications are defined as medications that started prior to the first dose of study drug. 
Concomitant medications are defined as medications (other than the study drug) taken on or after 
the first dose of the study drug during the entire study. Medications started before the first dose 
of study drug and continuing at the time of the first dose of study drug are considered both prior 
medication and concomitant medication. As for the medications that stopped with end date prior 
to study drug start date will be considered as prior medications. Partial dates for 
prior/concomitant medication will be classified based on rules in Section 2.3.4.  
 
All investigator terms for medications recorded on the CRF will be coded using the World 
Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) drug dictionary 
(WHODrug, March 2019 B3). Summaries of prior and concomitant medications will be provided 
by level 3 ATC classification and preferred term using frequency and percentages by treatment 


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group and overall for safety population. If ATC level 3 is not applicable, then the level 2 ATC 
will be used.  
 
6. 
EFFICACY ANALYSES 
All efficacy analyses will be based on the ITT Population. Missing data will be imputed per 
Section 2.3.4 for statistical inference analysis (no imputation for descriptive statistical 
summaries).  
 
6.1 
PRIMARY EFFICACY ANALYSIS 
6.1.1 
Change in hemoglobin from baseline to Day 35 
The actual value of hemoglobin on baseline, Day 35, and change from baseline to Day 35 will be 
summarized via descriptive statistics by treatment group.  
 
Treatment group difference for change in hemoglobin will be assessed with the analysis of 
covariance (ANCOVA), with treatment and randomization strata (hemoglobin and age 
categories) as fixed factors and baseline value of hemoglobin as a covariate. Baseline 
hemoglobin will be defined as the last hemoglobin obtained before randomization. Missing value 
will be imputed using LOCF as specified in Section 2.3.4. P-values to test treatment effect will 
be determined. Point estimates, associated 95% confidence interval and p-values will be 
reported. 
 
Supportive analysis  
To assess the robustness of this primary efficacy analysis, supportive analyses will be performed 
using the MMRM model described in the following for this primary endpoint: 
 
MMRM Analysis of Change in hemoglobin from baseline to Day 35: 
A mixed model repeated measures (MMRM) model will be conducted to provide an analysis 
under the assumption that data are missing at random (MAR). The MMRM model will include 
changes in hemoglobin from baseline to each post-baseline visit as the dependent variables; and 
treatment group, visit and treatment group by visit interaction as fixed effects; and subjects 
within treatment group as random effects; and baseline hemoglobin (<10, ≥10 g/dL) and age (1 
to <12 and ≥12 to 17 years) as covariate. An unstructured covariance matrix will be used to 
allow for unequal variances between visits.  If the model does not converge with unstructured 
variance – covariance matrix, then the Toeplitz, first-order autoregressive, compound symmetric, 
variance components structures will be tried and the covariance structure will be decided based 
on model convergence status and the AKaike information criterion. The Kenward-Roger 
approximation will be used to calculate the denominator of degrees of freedom for the fixed 
effect. If the interaction term is not significant, it will be dropped from the model. No imputation 
of missing data other than that inherent in the MMRM model will be performed.  P-values to test 
treatment effect on Day 35 will be reported. Point estimates and associated 95% confidence 
interval will be reported. 


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6.1.2 
Examination of Subgroups 
The following subgroups using LOCF will be examined for the primary efficacy endpoint (i.e., 
change in hemoglobin from baseline to Day 35): 
 
 Baseline hemoglobin (<10, ≥10 g/dL)  
 Age (1 to <12, ≥12 to 17 years) 
 
The actual value of hemoglobin on baseline, Day 35, and change from baseline to Day 35 will be 
summarized via descriptive statistics by treatment group and subgroups. 
 
Treatment group difference for change in hemoglobin by subgroup will be assessed with the 
analysis of covariance (ANCOVA), with treatment and randomization strata (hemoglobin and 
age categories) as fixed factors and baseline value of hemoglobin as a covariate. Missing value 
will be imputed using LOCF as specified in Section 2.3.4. Point estimates and associated 95% 
confidence interval will be reported.  
 
6.2 
SECONDARY EFFICACY ANALYSES 
6.2.1 
Change in ferritin from baseline to Day 35 
The actual value of ferritin on baseline, Day 35, and change from baseline to Day 35 will be 
summarized via descriptive statistics by treatment group.  
 
Treatment group difference for change in ferritin will be assessed with the analysis of covariance 
(ANCOVA), with treatment and randomization strata (hemoglobin and age categories) as fixed 
factors and baseline value of ferritin as a covariate. Missing value will be imputed using LOCF 
as specified in Section 2.3.4. P-values to test treatment effect will be determined. Point estimates, 
associated 95% confidence interval and p-values will be reported.  
 
Supportive analysis  
To assess the robustness of this secondary efficacy analysis, supportive analyses will be 
performed using the following approach.  
 
MMRM Analysis of Change in ferritin from baseline to Day 35: 
A mixed model repeated measures (MMRM) model will be conducted to provide an analysis 
under the assumption that data are missing at random (MAR). The MMRM model will include 
changes in ferritin from baseline to each post-baseline visit as the dependent variables; and 
treatment group, visit and treatment group by visit interaction as fixed effects; and subjects 
within treatment group as random effects; and baseline ferritin and randomization strata 
(hemoglobin and age categories) as covariate. An unstructured covariance matrix will be used to 
allow for unequal variances between visits.  If the model does not converge with unstructured 
variance – covariance matrix, then the Toeplitz, first-order autoregressive, compound symmetric, 


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variance components structures will be tried and the covariance structure will be decided based 
on model convergence status and the AKaike information criterion. The Kenward-Roger 
approximation will be used to calculate the denominator of degrees of freedom for the fixed 
effect. If the interaction term is not significant, it will be dropped from the model. No imputation 
of missing data other than that inherent in the MMRM model will be performed.  P-values to test 
treatment effect on Day 35 will be reported. Point estimates and associated 95% confidence 
interval will be reported. 
 
6.2.2 
Change in TSAT from baseline to Day 35 
The actual value of TSAT on baseline, Day 35, and change from baseline to Day 35 will be 
summarized via descriptive statistics by treatment group.  
 
Treatment group difference for change in TSAT will be assessed with the analysis of covariance 
(ANCOVA), with treatment and randomization strata (hemoglobin and age categories) as fixed 
factors and baseline value of TSAT as a covariate. Missing value will be imputed using LOCF as 
specified in Section 2.3.4. P-values to test treatment effect will be determined. Point estimates, 
associated 95% confidence interval and p-values will be reported.  
 
To assess the robustness of this secondary efficacy analysis, supportive analyses will be 
performed using the following approach: 
 
MMRM Analysis of Change in TSAT from baseline to Day 35: 
A mixed model repeated measures (MMRM) model will be conducted to provide an analysis 
under the assumption that data are missing at random (MAR). The MMRM model will include 
changes in TSAT from baseline to each post-baseline visit as the dependent variables; and 
treatment group, visit and treatment group by visit interaction as fixed effects; and subjects 
within treatment group as random effects; and baseline TSAT and randomization strata 
(hemoglobin and age categories) as covariate. An unstructured covariance matrix will be used to 
allow for unequal variances between visits.  If the model does not converge with unstructured 
variance – covariance matrix, then the Toeplitz, first-order autoregressive, compound symmetric, 
variance components structures will be tried and the covariance structure will be decided based 
on model convergence status and the AKaike information criterion. The Kenward-Roger 
approximation will be used to calculate the denominator of degrees of freedom for the fixed 
effect. If the interaction term is not significant, it will be dropped from the model. No imputation 
of missing data other than that inherent in the MMRM model will be performed. P-values to test 
treatment effect on Day 35 will be reported. Point estimates and associated 95% confidence 
interval will be reported. 
 
6.2.3 
Change in hemoglobin from baseline to each visit 
The actual value of hemoglobin on baseline, each post-baseline visit, and change from baseline 
to each post-baseline visit will be summarized via descriptive statistics by treatment group.  
 


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6.2.4 
Change in ferritin from baseline to each visit 
The actual value of ferritin on baseline, each post-baseline visit, and change from baseline to 
each post-baseline visit will be summarized via descriptive statistics by treatment group.  
 
6.2.5 
Change in TSAT from baseline to each visit 
The actual value of TSAT on baseline, each post-baseline visit, and change from baseline to each 
post-baseline visit will be summarized via descriptive statistics by treatment group.  
 
6.2.6 
Change in Reticulocyte Hemoglobin Content from baseline to each visit 
The actual value of reticulocyte hemoglobin content (CHr) on baseline, each post-baseline visit, 
and change from baseline to each post-baseline visit will be summarized via descriptive statistics 
by treatment group.  
 
Supportive analysis  
To assess the robustness of this secondary efficacy analysis, supportive analyses will be 
performed using the following approach: 
 
MMRM Analysis of Change in CHr from baseline to Day 35: 
A mixed model repeated measures (MMRM) model will be conducted to provide an analysis 
under the assumption that data are missing at random (MAR). The MMRM model will include 
changes in CHr from baseline to each post-baseline visit as the dependent variables; and 
treatment group, visit and treatment group by visit interaction as fixed effects; and subjects 
within treatment group as random effects; and baseline CHr and randomization strata 
(hemoglobin and age categories) as covariate. An unstructured covariance matrix will be used to 
allow for unequal variances between visits.  If the model does not converge with unstructured 
variance – covariance matrix, then the Toeplitz, first-order autoregressive, compound symmetric, 
variance components structures will be tried and the covariance structure will be decided based 
on model convergence status and the AKaike information criterion. The Kenward-Roger 
approximation will be used to calculate the denominator of degrees of freedom for the fixed 
effect. If the interaction term is not significant, it will be dropped from the model. No imputation 
of missing data other than that inherent in the MMRM model will be performed.  P-values to test 
treatment effect on Day 35 will be reported. Point estimates, and associated 95% confidence 
interval will be reported. 
 
7. 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety Population. Safety assessments include: 
 
 Extent of exposure 
 Adverse events 
 Laboratory assessments (hematology, iron indices, chemistry, and other) 


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 Vital signs  
 
Baseline of clinical laboratory findings will be defined as the last value obtained before 
randomization.  
7.1 
EXTENT OF EXPOSURE 
For each type of IV administration of FCM, total dose of iron administered (mg), total calculated 
FCM dose to be given (mg), the number of infusions will be summarized descriptively. For oral 
iron, the total dose of iron taken (mg), daily dose of iron (mg) will be summarized descriptively.  
The study drug exposure will be presented in subject data listings.  
7.2 
ADVERSE EVENTS 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. The verbatim 
term will be included in the AE listings. Adverse event summaries will exclude preferred terms 
that describe asymptomatic serum ferritin, TSAT, and reticulocyte values (or changes). This 
approach is justified by the reporting of these values in efficacy summaries and is consistent with 
the protocol-defined reporting standards for hemoglobin/hematocrit and low iron indices. For the 
purposes of this study, non-serious anemia (hemoglobin or hematocrit 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. 
 
A treatment-emergent adverse event (TEAE) is defined as an event with onset date on or after 
the study drug start date. Partial date TEAE classification rules refer to Section 2.3.4. Only 
TEAEs will be included in summary tables by treatment group.  
 
The incidence of TEAEs will be summarized as the number (percentage) of subjects with TEAEs 
within SOC and PT by treatment group.  Subjects who report the same PT on multiple occasions 
will be counted once for the PT: under the highest severity (severe > moderate > mild) CTCAE 
when summarized by severity and under the closest relationship (probably related > possibly 
related > unlikely related > none) to study drug when summarized by relationship. If a subject 
reports multiple PT for a SOC, the subject will be counted only once for that SOC. Events with 
unknown severity or relationship will be counted as unknown.  
 
TEAEs will be summarized as below.  
 An overview table, including number of subjects with  
o TEAEs 
o serious TEAEs  
o study drug related TEAEs 
o study drug related Serious TEAEs 


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o TEAEs by severity  
o TEAEs leading to study drug discontinuation or withdrawal from study 
o TEAEs leading to death 
 TEAE by SOC  
 TEAE by PT 
 TEAE by SOC and PT 
 TEAE by SOC, PT, and Severity(CTCAE) 
 Study drug related TEAEs by SOC, PT 
 Serious TEAEs by SOC and PT 
 Study drug related serious TEAEs by SOC and PT 
 TEAEs leading to study drug discontinuation or withdrawal from study by SOC and PT 
 TEAEs leading to death by SOP and PT 
Unless otherwise stated, all TEAE tables will be sorted by SOC and PT in decreasing frequency 
of the number and percentage of subjects in the treatment group.  
    
7.2.1 
Adverse Events of Special Interest  
Adverse events of special interest include hypophosphatemia, hypersensitivity/anaphylactoid 
reactions, injection/infusdion site reactions, and cardiovascular events. The search strategy will 
be identified as follows: 
 
 TEAEs of hypophosphatemia: 
o MedDRA PT Blood phosphorus decrease 
o MedDRA PT Blood phosphorus abnormal 
o MedDRA PT Hypophosphataemia 
o MedDRA PT Hypophosphataemic rickets 
o MedDRA PT Rickets familial hypophosphataemic 
 
 TEAEs indicative of hypersensitivity/anaphylactoid reactions: 
o SMQ Anaphylactic reaction 
o SMQ Angioedema 
o PT Hypersensitivity 
 
 TEAEs of injection/infusion site reactions: 
o MedDRA HLT Infusion site reactions 
o MedDRA HLT Injection site reactions 
o MedDRA HLT Administration site reactions NEC 
o MedDRA PT Infusion related reaction 
 


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 Cardiovascular TEAEs: 
o Cardiovascular disorders SOC 
o Vascular disorders SOC 
 
The AEs of special interest will be summarized as below:   
 Treatment-emergent AESI by SOC and PT 
 Serious treatment-emergent AESI by SOC, PT 
 Serious or severe treatment-emergent AESI by SOC and PT 
 
7.2.2 
Deaths, Serious and Other Significant Adverse Events  
The AEs, serious AEs, AE leading to study discontinuation of study drug or withdrawal from 
study, and subjects who died during the study will be listed.  
 
7.3 
CLINICAL LABORATORY PARAMETERS 
Laboratory assessments include hematology, clinical chemistry, and iron indices: 
 Hematology: Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, differential 
count, reticulocyte count and reticulocyte hemoglobin content (CHr) 
 
 Clinical 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 
 
All laboratory parameters will be presented in conventional units. The actual value and mean 
change from baseline to each scheduled visit will be summarized using descriptive statistics by 
treatment for each laboratory test group above. All abnormal laboratory values will be presented 
in listings. 
 
Time course table for serum phosphate will be constructed for FCM subjects in safety 
population. Descriptive statistics of days to first value of specified CTC grade and days to return 
to normal will be summarized. Only the subjects that were under FCM treatment and had a 
normal serum phosphate baseline value will be included in this table.  
 
The number and percent of subjects with treatment-emergent potentially clinically significant 
(PCS) laboratory values after baseline will be summarized by visit and by treatment. The 
denominator is all subjects with normal baseline and at least one post baseline assessment in the 


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safety population and the numerator is the number of subjects with PCS (i.e., meets Grade 3 or 
Grade 4 AE scale defined in Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events, Version 2.1 from March 2017 (Division of AIDS, National 
Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of 
Health and Human Services)) at any post-baseline visit. 
 
Shift from baseline AE grade to maximum post-baseline AE grade, and shift from baseline to the 
last visit in terms of AE grade will be summarized by treatment, separately.  
 
The AE grade for Chemistries and Hematology are defined in Appendix 1.1. BUN, hematocrit, 
bands and iron indices do not have adverse event scales available and are not evaluated 
separately as possible AEs. 
 
7.4 
VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS  
7.4.1 
Vital Signs 
Vital signs will be collected including sitting body temperature, blood pressure (BP) and heart 
rate. On study drug dosing days BP and heart rate will be collected pre-dosing, immediately 
(within 5 minutes) post, and 30 minutes post dosing, and body temperature will be collected on 
each dosing day. For the FCM group, the actual value and the change in vital signs (including 
sitting heart rate and blood pressure) from pre-infusion to each post-infusion time point will be 
summarized descriptively on each dosing day. Markedly abnormal values should be determined 
by PALS Guidelines, 2015 in Appendix 1.2. Children >15 years of age will use the criteria for 
15 years old children. 
 
  
7.4.2 
Physical Examination 
Physical examination (PE) results were collected at Day 0 and Day 35 including six body 
systems, i.e. skin, cardiovascular, pulmonary/respiration, abdominal, central nervous system and 
musculoskeletal/extremities. Each component of the baseline physical examination will be 
recorded as normal or abnormal. Each component of the post baseline physical examinations will 
be recorded as No Change from Previous PE or Change from Previous PE. The number and 
percent of subjects who have normal, abnormal and significant changes at each visit will be 
summarized in table.   
 
8. 
INTERIM ANALYSES AND DATA AND SAFETY MONITORING BOARD 
(DSMB) 
8.1 
INTERIM ANALYSES 
The study will have a Data Safety Monitoring Board (DSMB) whose primary remit is safety. No 
formal interim analyses of efficacy are planned for this study.  
 


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8.2 
DATA AND SAFETY MONITORING BOARD (DSMB)  
The DSMB will be composed of at least four senior academic individuals, including the DSMB 
Chair. The members will have high-level expertise in pediatric IDA 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 American Regent representatives may 
present updates on the trial status or the safety profile of FCM, 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 participants 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. 
The DSMB will determine if it believes the trial should be terminated early because clear 
evidence of a significant safety concern exists.  
 
If the DSMB finds it necessary to recommend actions regarding interruption of the study or 
changes to the protocol based on medical rationale that would make it unethical to continue the 
study in its present form, those recommendations will be forwarded to the Study Chair and 
Sponsor. The details of the DSMB's functions and the early stopping rules will be delineated in a 
separate DSMB charter. 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
Compared with the study protocol (26SEP2019 Administrative Change 1), below items are the 
major changes made in this SAP: 
 
 
1. The efficacy analyses will be conducted for the ITT population instead of the mITT population 
to be more in keeping with accepted practice. The mITT population will still be defined and will 
be used for post-hoc sensitivity analyses. 
 
2. In protocol, the sentence of “Changes from baseline in hemoglobin, ferritin, TSAT, and 
reticulocyte hemoglobin content throughout the study” in section 8.4.2 is not consistent with the 
sentence in study synopsis. In this SAP, we just keep this endpoint in consistency with 
descriptions in synopsis. 
 
3. To assess the robustness of primary and secondary efficacy analysis, supportive analyses will 
be performed using MMRM model. 
 
4. The scale defined in Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 2.1 from March 2017 (Division of AIDS, National Institute of 


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Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and 
Human Services) will be used to identify abnormal clinical laboratory values instead of toxicity 
criteria from the National Cancer Institute Common Terminology Criteria version 5 for Adverse 
Events specified in the protocol. 
 
5. The subgroups Cause of IDA: IBD, not IBD and CKD, not CKD are not included in this SAP 
because of insufficient sample size for meaningful estimates. 
 
 


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10. 
APPENDICES 
APPENDIX 1.1 ADVERSE EVENT SCALE 
CHEMISTRIES Adverse Event Scale 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Albumin, Low (g/dL; 
g/L) 
3.0 to < LLN  
30 to < LLN 
≥ 2.0 to < 3.0  
≥ 20 to < 30 
< 2.0  
< 20 
NA 
Alkaline 
Phosphatase, High 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN ≥ 10.0 x ULN 
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN ≥ 10.0 x ULN 
AST or SGOT, High 
Report only one 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN ≥ 10.0 x ULN 
Calcium, High 
(mg/dL; mmol/L)  
≥ 7 days of age 
10.6 to < 11.5  
2.65 to < 2.88 
11.5 to < 12.5  
2.88 to < 3.13 
12.5 to < 13.5  
3.13 to < 3.38 
≥ 13.5  
≥ 3.38 
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8 to < 8.4  
1.95 to < 2.10 
7.0 to < 7.8  
1.75 to < 1.95 
6.1 to < 7.0  
1.53 to < 1.75 
< 6.1  
< 1.53 
Creatinine, High 
Report only one 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase to 1.3 to 
< 1.5 x participant’s 
baseline 
> 1.8 to < 3.5 x ULN 
OR Increase to 1.5 to 
< 2.0 x participant’s 
baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
participant’s baseline 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0  
5.6 to < 6.0 
6.0 to < 6.5  
6.0 to < 6.5 
6.5 to < 7.0  
6.5 to < 7.0 
≥ 7.0  
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4  
3.0 to < 3.4 
2.5 to < 3.0  
2.5 to < 3.0 
2.0 to < 2.5  
2.0 to < 2.5 
< 2.0  
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150  
146 to < 150 
150 to < 154  
150 to < 154 
154 to < 160  
154 to < 160 
≥ 160  
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135  
130 to < 135 
125 to < 130  
125 to < 130 
121 to < 125  
121 to < 125 
≤ 120  
≤ 120 
 
ULN and LLN required for the chemistries AE Scale 
(based on the high and low range from Covance Central Laboratory Services Manual, American Regent, Inc) 
Sex 
Age 
Alkaline 
Phosphatase 
LLN (U/L) 
ALT ULN 
(U/L) 
AST ULN 
(U/L) 
Age 
Creatinine 
ULN (mg/dL) 
Age 
Albumin 
LLN 
(g/dL) 
Female 
1-4 yr 
<108 
>34 
>56 
1-4 yr 
>0.4 
2 m–4 yr <2.8 
 
4-7 yr 
<96 
>34 
>48 
4-7 yr 
>0.5 
4-16 yr 
<2.9 
 
7-10 yr 
<69 
>34 
>40 
7-10 yr 
>0.6 
16-18 yr <3.3 
 
10-15 yr 
<51 
>34 
>40 
10-13 yr 
>0.7 
18 yr 
<3.3 
 
15-18 yr 
<31 
>34 
>40 
13-16 yr 
>0.8 
 
18 yr 
<31 
>34 
>34 
16-18 yr 
>0.9 
 
 
 
18 yr 
>1.1 
Male 
1-4 yr 
<104 
>34 
>69 
1-4 yr 
>0.4 
2 m–4 yr <2.8 


Sponsor: American Regent, Inc. 
 
Protocol No: 1VIT17044 Administrative Change 1 (26 SEP 2019) 
Statistical Analysis Plan
 
 
Version: 2.0 (15-July-2020)  
Confidential 
Page 27 of 28 
 
 
4-7 yr 
<93 
>34 
>59 
4-7 yr 
>0.5 
4-16 yr 
<2.9 
 
7-10 yr 
<86 
>34 
>40 
7-10 yr 
>0.6 
16-18 yr <3.3 
 
10-15 yr 
<95 
>43 
>40 
10-13 yr 
>0.7 
18 yr 
<3.3 
 
15-18 yr 
<50 
>43 
>40 
13-16 yr 
>0.9 
 
18 yr 
<31 
>43 
>36 
16-18 yr 
>1.1 
 
 
 
18 yr 
>1.2 
 
HEMATOLOGY Adverse Event Scale 
PARAMETER 
GRADE 1 MILD GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 1.000 x 
109 
600 to 799 
0.600 x 109 to 0.799 
x 109 
400 to 599 
0.400 x 109 to 0.599 x 
109 
< 400  
< 0.400 x 109 
Hemoglobin, Low 
(g/dL; mmol/L) 
≥ 13 years of age 
(male only) 
10.0 to 10.9  
6.19 to 6.76 
9.0 to < 10.0  
5.57 to < 6.19 
7.0 to < 9.0  
4.34 to < 5.57 
< 7.0  
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4  
5.88 to 6.48 
8.5 to < 9.5  
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age to < 
13 years of age  
(male and female) 
9.5 to 10.4  
5.88 to 6.48 
8.5 to < 9.5  
5.25 to < 5.88 
6.5 to < 8.5  
4.03 to < 5.25 
< 6.5  
< 4.03 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000 to < 125,000 
100.000 x 109 to < 
125.000 x 109 
50,000 to < 100,000 
50.000 x 109 to < 
100.000 x 109 
25,000 to < 50,000 
25.000 x 109 to < 
50.000 x 109 
< 25,000  
< 25.000 x 109 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 2.499 x 
109 
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109 
1,000 to 1,499 
1.000 x 109 to 1.499 x 
109 
< 1,000 
< 1.000 x 109 
 
 
 


Sponsor: American Regent, Inc. 
 
Protocol No: 1VIT17044 Administrative Change 1 (26 SEP 2019) 
Statistical Analysis Plan
 
 
Version: 2.0 (15-July-2020)  
Confidential 
Page 28 of 28 
 
APPENDIX 1.2 PEDIATRIC VITAL SIGNS REFERENCE CHART 
Heart Rate 
Normal Heart Rate by Age (beats/minute) 
Reference: PALS Guidelines, 2015 
Age 
Awake Rate 
Sleeping Rate 
Neonate (<28 d) 
100-205 
90-160 
Infant (1 mo-1 y) 
100-190 
90-160 
Toddler (1-2 y) 
98-140 
80-120 
Preschool (3-5 y) 
80-120 
65-100 
School-age (6-11 y) 
75-118 
58-90 
Adolescent (12-15 y) 
60-100 
50-90 
 
 
Temperature 
Normal Temperature Range by Method 
Reference: CPS Position Statement on Temperature Measurement in Pediatrics, 2015 
Method 
Normal Range (oC) 
Rectal 
36.6-38 
Ear 
35.8-38 
Oral 
35.5-37.5 
Axillary 
36.5-37.5 
 
Blood Pressure 
Normal Blood Pressure by Age (mm Hg) 
Reference: PALS Guidelines, 2015 
Age 
Systolic Pressure 
Diastolic Pressure 
Systolic Hypotension 
Birth (12 h, <1000 g) 
39-59 
16-36 
<40-50 
Birth (12 h, 3 kg) 
60-76 
31-45 
<50 
Neonate (96 h) 
67-84 
35-53 
<60 
Infant (1-12 mo) 
72-104 
37-56 
<70 
Toddler (1-2 y) 
86-106 
42-63 
<70 + (age in years x 2) 
Preschooler (3-5 y) 
89-112 
46-72 
<70 + (age in years x 2) 
School-age (6-9 y) 
97-115 
57-76 
<70 + (age in years x 2) 
Preadolescent (10-11 y) 
102-120 
61-80 
<90 
Adolescent (12-15 y) 
110-131 
64-83 
<90