Clinical trial NCT04269707
Conditions: Iron Deficiency Anemia
Sponsor: American Regent, Inc.
Start date: 2019-11-19; Completion date: 2021-01-29
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Evaluating the Efficacy and Safety of Intravenous Ferric Carboxymaltose in Pediatric Patients with Iron Deficiency Anemia and an Unsatisfactory Response to Oral Iron under Study Protocol 1VIT17044

Detailed description:
This is a single arm, open-label, multi-center, multi-national, non-randomized study that will evaluate the efficacy and safety of a one course treatment with FCM in participants who had an unsatisfactory response to oral iron in study 1VIT17044.

Subjects will have an End of Study (EOS) Visit (Day 35) from the 1VIT17044 study to qualify for entry. Subjects will then be screened, meet all inclusion criteria, no exclusion criteria and have a baseline evaluation. Based on the successful completion of the baseline evaluations, subjects will be enrolled and will receive the first dose of FCM (Day 0). The second FCM dose will occur 7 days from the first dose. Subjects will return to the clinic 14 and 28 days post their first dose for laboratory and safety assessments, and at 35 days post the first dose, participants will return to the clinic for final safety and efficacy assessments. Once all assessments are complete the participant will exit the study.

An unsatisfactory response to oral iron (i.e., an increase in hemoglobin (Hgb) of \<1 g/dL from baseline) will be defined as non-responders to oral iron treatment. Non-responders who continue to meet all inclusion criteria (including Hgb \<11 g/dL) and none of the exclusion criteria will receive 1 course of FCM.

Arms: arm 1: The primary objective in this study is to allow participants who were randomized to receive oral iron in the 1VIT17044 trial and who had an unsatisfactory response to oral iron or those that required a concomitant intervention, (defined as, blood transfusion, use of IV or oral iron outside of protocol, increase in erythropoietin for any reason \[Day 0 thru Day 35 of study protocol 1VIT17044\], change in IBD treatment) to receive one course of FCM. This course of FCM will consist of two doses of FCM at 15 mg/kg (maximum single dose of 750 mg), separated by seven days.
Interventions: intervention 1: Ferric carboxymaltose
Intervention descriptions: intervention 1: IV iron

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
1VIT18045 Efficacy and Safety of Intravenous Ferric 
Carboxymaltose in Pediatric Patients With Iron Deficiency 
Anemia and Unsatisfactory Response Oral Iron Under Study 
Protocol 1VIT17044   NCT04269707 
 
 
 
03DEC2019 
 


Table of Contents
1VIT18045-INITIAL PROTOCOL AND AMENDMENTS
7
SIGNATURES OF AGREEMENT FOR PROTOCOL
8
Study Synopsis
9
Figure 1 Study diagram
12
TABLE OF CONTENTS
13
LIST OF TABLES
16
LIST OF FIGURES
16
LIST OF ABBREVIATIONS
17
1. INTRODUCTION
19
1.1. Treatment of Iron Deficiency Anemia
19
1.2. Ferric Carboxymaltose
20
1.2.1. Key features of Ferric Carboxymaltose
20
1.2.2. Ferric Carboxymaltose versus Other Parenteral Iron Agents
20
2. TRIAL OBJECTIVE
21
2.1. Primary Objective
21
3. OVERALL STUDY DESIGN AND RATIONALE
21
3.1. Overall Study Design
21
3.2. Rationale of Study Design
22
3.3. Schedule of Events
23
Table 1 Schedule of Activities
23
4. PARTICIPANT SELECTION
24
4.1. Number and Type of Participants
24
4.2. Screening Phase
24
4.2.1. Inclusion Criteria
24
4.2.2. Exclusion Criteria
24
4.3. Participant Assignment Process
25
4.4. Withdrawal from Study
25
4.5. Discontinuation from Study Drug
25
5. STUDY DRUG
25
5.1. Formulation, Packaging and Storage
25
5.2. Drug Administration/Regimen
25
5.3. IV Medication Precautions
26


5.4. Drug Accountability
26
5.5. Concomitant Medication
26
6. STUDY PROCEDURES
27
6.1. Informed Consent
27
6.2. Screening Phase
27
6.2.1. Screening Visit 1 (Day -7 to -1)
27
6.3. Treatment Phase (Day 0 to Day 35)
28
6.3.1. Enrollment: Visit 1 Day 0
28
6.3.2. Visit 2 Day 7 ± 1 day
29
6.3.3. Visit 3 Day 14 ± 1 day
29
6.3.4. Visit 4 Day 28 ± 1 day
29
6.3.5. Visit 5 Day 35 ± 1 day (End of Study)
29
6.4. Central Laboratory Assessments
30
7. ASSESSMENT OF SAFETY
30
7.1. Adverse Events
30
Table 2 Grading of Adverse Event Severity
31
7.2. Reporting of Adverse Events
32
7.3. Serious Adverse Events
32
8. STATISTICS
33
8.1. Stratification/Randomization
34
8.2. Analysis Populations
34
8.3. Disposition and Baseline Characteristics
34
8.4. Endpoints and Definitions
34
8.4.1. Primary Endpoint
34
8.4.2. Secondary Endpoints
34
8.4.3. Missing Data
35
8.5. Analyses of Safety
35
8.5.1. Study Drug Exposure
35
8.5.2. Adverse Events
35
8.5.3. Adverse Events of Special Interest
36
8.5.4. Clinical Laboratory Findings
36
8.5.5. Vital Signs
36
summarized descriptively on each dosing day.
36
9. ADMINISTRATIVE CONSIDERATIONS
36


9.1. Retention and Availability of Records
36
9.2. Investigator Responsibilities
37
9.3. Financial Disclosure
37
9.4. Advertisement for Participant Recruitment
38
9.5. Documents Required for Study Initiation
38
9.6. Quality Control and Quality Assurance
38
9.6.1. Investigator Selection Criteria
38
9.6.2. Clinical Monitoring
39
9.6.3. Quality Assurance Audit
39
9.7. Ethics
39
9.7.1. Ethical and Legal Issues
39
9.7.2. Institutional Review Board
39
9.7.3. Informed Consent
40
9.7.4. Good Clinical Practice
40
9.8. Data Handling and Record Keeping
40
9.8.1. Case Report Form
40
9.8.2. Confidentiality
41
9.8.3. Termination of the Study
41
9.8.4. Protocol Revisions
41
9.8.5. Protocol Administrative Changes
42
9.9. Publication Policy
42
10. INVESTIGATOR’S ACKNOWLEDGEMENT
43
11. REFERENCES
44
12. APPENDIX 1: AMENDMENT/ADMINISTRATIVE CHANGES
45
12.1. ADMINISTRATIVE CHANGE 1
45
1VIT18045 Final Protocol Version 1.0 with signatures (26APR2019)
46
SIGNATURES OF AGREEMENT FOR PROTOCOL
47
Study Synopsis
48
Figure 1 Study diagram
51
TABLE OF CONTENTS
52
LIST OF TABLES
54
LIST OF FIGURES
54
LIST OF ABBREVIATIONS
55
1. INTRODUCTION
57


1.1. Treatment of Iron Deficiency Anemia
57
1.2. Ferric Carboxymaltose
58
1.2.1. Key features of Ferric Carboxymaltose
58
1.2.2. Ferric Carboxymaltose versus Other Parenteral Iron Agents
58
2. TRIAL OBJECTIVE
59
2.1. Primary Objective
59
3. OVERALL STUDY DESIGN AND RATIONALE
59
3.1.  Overall Study Design
59
3.2. Rationale of Study Design
60
3.3. Schedule of Events
61
Table 1 Schedule of Activities
61
4. PARTICIPANT SELECTION
62
4.1. Number and Type of Participants
62
4.2. Screening Phase
62
4.2.1. Inclusion Criteria
62
4.2.2. Exclusion Criteria
62
4.3. Participant Assignment Process
63
4.4. Withdrawal from Study
63
4.5. Discontinuation from Study Drug
63
5. STUDY DRUG
63
5.1. Formulation, Packaging and Storage
63
5.2. Drug Administration/Regimen
63
5.3. IV Medication Precautions
64
5.4. Drug Accountability
64
5.5. Concomitant Medication
64
6. STUDY PROCEDURES
65
6.1. Informed Consent
65
6.2. Screening Phase
65
6.2.1. Screening Visit 1 (Day -7 to -1)
65
6.3. Treatment Phase (Day 0 to Day 35)
66
6.3.1. Enrollment: Visit 1 Day 0
66
6.3.2. Visit 2 Day 7 ± 1 day
67
6.3.3. Visit 3 Day 14 ± 1 day
67
6.3.4. Visit 4 Day 28 ± 1 day
67


6.3.5. Visit 5 Day 35 ± 1 day (End of Study)
67
6.4. Central Laboratory Assessments
68
7. ASSESSMENT OF SAFETY
68
7.1. Adverse Events
68
7.2. Reporting of Adverse Events
70
7.3. Serious Adverse Events
70
8. STATISTICS
71
8.1. Stratification/Randomization
72
8.2. Analysis Populations
72
8.3. Disposition and Baseline Characteristics
72
8.4. Endpoints and Definitions
72
8.4.1. Primary Endpoint
72
8.4.2. Secondary Endpoints
72
8.4.3. Missing Data
73
8.5. Analyses of Safety
73
8.5.1. Study Drug Exposure
73
8.5.2. Adverse Events
73
8.5.3. Adverse Events of Special Interest
74
8.5.4. Clinical Laboratory Findings
74
8.5.5. Vital Signs
74
8.5.6. Sample Size Rationale
74
9. ADMINISTRATIVE CONSIDERATIONS
74
9.1. Retention and Availability of Records
74
9.2. Investigator Responsibilities
75
9.3. Financial Disclosure
75
9.4. Advertisement for Participant Recruitment
76
9.5. Documents Required for Study Initiation
76
9.6. Quality Control and Quality Assurance
76
9.6.1. Investigator Selection Criteria
76
9.6.2. Clinical Monitoring
77
9.6.3. Quality Assurance Audit
77
9.7. Ethics
77
9.7.1. Ethical and Legal Issues
77
9.7.2. Institutional Review Board
77


9.7.3. Informed Consent
78
9.7.4. Good Clinical Practice
78
9.8. Data Handling and Record Keeping
78
9.8.1. Case Report Form
78
9.8.2. Confidentiality
79
9.8.3. Termination of the Study
79
9.8.4. Protocol Revisions
79
9.8.5. Protocol Administrative Changes
80
9.9. Publication Policy
80
10. INVESTIGATOR’S ACKNOWLEDGEMENT
81
11. REFERENCES
82


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
Page 1 of 40 
AMERICAN REGENT, INC. 
PROTOCOL 
 
No. 1VIT18045 
 
IND #: 63,243 
 
Evaluating the Efficacy and Safety of Intravenous Ferric Carboxymaltose in 
Pediatric Patients with Iron Deficiency Anemia and an Unsatisfactory Response to 
Oral Iron under Study Protocol 1VIT17044 
 
SPONSOR 
American Regent, Inc. 
Clinical Research and Development 
800 Adams Avenue 
Norristown, PA 19403 
631-772-3500  
 
 
Protocol Date: Final 26 April 2019 
Administrative Change 1 Date: Final 03 December 2019 


CONFIDENTIAL 
American Regent, Inc. 
Protocol No.: I VITI 8045 
Administrative Change I Date: Final 03 December 2019 
SIGNATURES OF AGREEMENT FOR PROTOCOL 
D3 
ZOJ 
Geoffrey Mu 
aya MD, M.Sc., FAAP, FRCPC 
Date 
Head, Clinical Research and Development 
American Regent, Inc. 
·k Falone, MD 
edical Director, 
inical Research and Development 
American Regent, 
Page 2 of 40 
Date 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
 
Page 3 of 40 
Study Synopsis 
Protocol No. 1VIT18045 
Title: 
Evaluating the Efficacy and Safety of Intravenous Ferric 
Carboxymaltose in Pediatric Patients with Iron Deficiency 
Anemia and an Unsatisfactory Response to Oral Iron under 
Study Protocol 1VIT17044 
Study Drug: 
Injectafer® (Ferric Carboxymaltose [FCM]) 
Objectives: 
 
The primary objective of this study is to evaluate the 
efficacy and safety of intravenous (IV) ferric 
carboxymaltose (FCM) in pediatric participants who 
have iron deficiency anemia (IDA). 
Nature of Study: 
Phase III 
Design: 
This is a single arm, open-label, multi-center, multi-national, 
non-randomized study that will evaluate the efficacy and 
safety of a one course treatment with FCM in participants 
who had an unsatisfactory response to oral iron in study 
1VIT17044. 
Subjects will have an End of Study (EOS) Visit (Day 35) 
from the 1VIT17044 study to qualify for entry.  Subjects will 
then be screened, meet all inclusion criteria, no exclusion 
criteria and have a baseline evaluation.  Based on the 
successful completion of the baseline evaluations, subjects 
will be enrolled and will receive the first dose of FCM (Day 
0). The second FCM dose will occur 7 days from the first 
dose.  Subjects will return to the clinic 14 and 28 days post 
their first dose for laboratory and safety assessments, and at 
35 days post the first dose, participants will return to the 
clinic for final safety and efficacy assessments.  Once all 
assessments are complete the participant will exit the study. 
An unsatisfactory response to oral iron (i.e., an increase in 
hemoglobin (Hgb) of <1 g/dL from baseline) will be defined 
as non-responders to oral iron treatment.  Non-responders 
who continue to meet all inclusion criteria (including Hgb 
<11 g/dL) and none of the exclusion criteria will receive 1 
course of FCM.  
Inclusion Criteria: 
1. Unsatisfactory response to oral iron or those that required 
a concomitant intervention, (defined as, blood 
transfusion, use of IV or oral iron outside of protocol, 
increase in erythropoietin for any reason [Day 0 thru Day 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
 
Page 4 of 40 
35 of study protocol 1VIT17044], change in 
Inflammatory Bowel Disease [IBD] treatment). 
2. Hgb <11 g/dL 
3. Ferritin ≤300 ng/mL and Transferrin Saturation (TSAT) 
<30% 
Exclusion Criteria: 
1. Known history of hypersensitivity reaction to any 
component of FCM. 
2. History of acquired iron overload, hemochromatosis, or 
other iron accumulation disorders. 
3. History of significant diseases of the liver, hematopoietic 
system, cardiovascular system, psychiatric disorder, or 
other conditions which, in the opinion of the investigator, 
may place a subject at added risk for participation in the 
study. 
4. Any existing non-viral infection.  
5. Known history of positive hepatitis B surface antigen 
(HBsAg) or hepatitis C viral antibody (HCV) with 
evidence of active hepatitis. 
6. Known history of positive human immunodeficiency 
virus (HIV-1/HIV-2) antibodies (anti-HIV). 
7. Anemia due to reasons other than iron deficiency (e.g., 
hemoglobinopathy and vitamin B12 or folic acid 
deficiency) that has not been corrected.  
8. Administration and / or use of an investigational product 
(drug or device) within 30 days of screening. 
9. Alcohol or drug abuse within the past six months. 
10. Female participant who is pregnant or lactating, or 
sexually active females who are of childbearing potential 
not willing to use an acceptable form of contraceptive 
precautions during the study. 
11. Unable to comply with study procedures and assessments. 
Study Drug 
Administration 
Participants 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 
Endpoints: 
Primary Endpoint: 
 
Change in Hgb from baseline to Day 35 
 
Secondary Endpoints: 
 
Change in ferritin from baseline to Day 35 
 
Change in TSAT from baseline to Day 35  


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
 
Page 5 of 40 
 
Changes from baseline in Hgb, ferritin, TSAT, and 
reticulocyte hemoglobin content (CHr) throughout the 
study 
Participant 
Duration: 
35 Days 
Study Sites: 
Approximately 25 sites 
Participant Number: 
Maximum of approximately 36 participants 
 
 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
 
Page 6 of 40 
Figure 1 
Study diagram 
 
 
E
Day 0
Day 14 ± 1 
day
Day 28 ± 1 
day
FCM
Day 7 ± 1 
day
15 mg/kg/dose x 2 doses 
(maximum single dose of 750 mg)
X 
X
Participants meeting 
inclusion criteria and no 
exclusion criteria and are 
confirmed to have had 
an inadequate response 
to oral iron 
Day 35 ± 1 
day (EOS)
Visit In Clinic
X
X
X
Final Visit In Clinic
Screening *
Day -7 to -1
Enrollment
Visit In Clinic
* Note that there will be a 7 ± 1 day waiting period between 1VIT17044 end of study and extension screening
._____ _ 
_____,I 
.____I-------' 
DD D DD 
> 
.____I------' 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
Page 7 of 40 
TABLE OF CONTENTS 
PAGE 
STUDY SYNOPSIS ........................................................................................................ 3 
LIST OF ABBREVIATIONS ........................................................................................... 11 
1. 
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. 
TRIAL OBJECTIVE ................................................................................................ 15 
2.1. 
Primary Objective ....................................................................................... 15 
3. 
OVERALL STUDY DESIGN AND RATIONALE ..................................................... 15 
3.1. 
3.1 Overall Study Design ............................................................................ 15 
3.2. 
Rationale of Study Design .......................................................................... 16 
3.3. 
Schedule of Events ..................................................................................... 17 
4. 
PARTICIPANT SELECTION .................................................................................. 18 
4.1. 
Number and Type of Participants ............................................................... 18 
4.2. 
Screening Phase ........................................................................................ 18 
4.2.1. 
Inclusion Criteria .......................................................................... 18 
4.2.2. 
Exclusion Criteria ......................................................................... 18 
4.3. 
Participant Assignment Process ................................................................. 19 
4.4. 
Withdrawal from Study................................................................................ 19 
4.5. 
Discontinuation from Study Drug ................................................................ 19 
5. 
STUDY DRUG ....................................................................................................... 19 
5.1. 
Formulation, Packaging and Storage .......................................................... 19 
5.2. 
Drug Administration/Regimen ..................................................................... 19 
5.3. 
IV Medication Precautions .......................................................................... 20 
5.4. 
Drug Accountability ..................................................................................... 20 
5.5. 
Concomitant Medication ............................................................................. 20 
6. 
STUDY PROCEDURES ......................................................................................... 21 
6.1. 
Informed Consent ....................................................................................... 21 
6.2. 
Screening Phase ........................................................................................ 21 
6.2.1. 
Screening Visit 1 (Day -7 to -1) .................................................... 21 
6.3. 
Treatment Phase (Day 0 to Day 35) ........................................................... 22 
6.3.1. 
Enrollment: Visit 1 Day 0 ............................................................. 22 
6.3.2. 
Visit 2 Day 7 ± 1 day .................................................................... 23 
6.3.3. 
Visit 3 Day 14 ± 1 day .................................................................. 23 
6.3.4. 
Visit 4 Day 28 ± 1 day .................................................................. 23 
6.3.5. 
Visit 5 Day 35 ± 1 day (End of Study) .......................................... 23 
6.4. 
Central Laboratory Assessments ................................................................ 24 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
Page 8 of 40 
7. 
ASSESSMENT OF SAFETY .................................................................................. 24 
7.1. 
Adverse Events .......................................................................................... 24 
7.2. 
Reporting of Adverse Events ...................................................................... 26 
7.3. 
Serious Adverse Events ............................................................................. 26 
8. 
STATISTICS .......................................................................................................... 27 
8.1. 
Stratification/Randomization ....................................................................... 28 
8.2. 
Analysis Populations .................................................................................. 28 
8.3. 
Disposition and Baseline Characteristics .................................................... 28 
8.4. 
Endpoints and Definitions ........................................................................... 28 
8.4.1. 
Primary Endpoint ......................................................................... 28 
8.4.2. 
Secondary Endpoints .................................................................. 28 
8.4.3. 
Missing Data ................................................................................ 29 
8.5. 
Analyses of Safety ...................................................................................... 29 
8.5.1. 
Study Drug Exposure .................................................................. 29 
8.5.2. 
Adverse Events ........................................................................... 29 
8.5.3. 
Adverse Events of Special Interest .............................................. 30 
8.5.4. 
Clinical Laboratory Findings ........................................................ 30 
8.5.5. 
Vital Signs ................................................................................... 30 
8.5.6. 
Sample Size Rationale ................................................................ 30 
9. 
ADMINISTRATIVE CONSIDERATIONS ................................................................ 30 
9.1. 
Retention and Availability of Records ......................................................... 30 
9.2. 
Investigator Responsibilities ....................................................................... 31 
9.3. 
Financial Disclosure ................................................................................... 31 
9.4. 
Advertisement for Participant Recruitment .................................................. 32 
9.5. 
Documents Required for Study Initiation ..................................................... 32 
9.6. 
Quality Control and Quality Assurance ....................................................... 32 
9.6.1. 
Investigator Selection Criteria ...................................................... 32 
9.6.2. 
Clinical Monitoring ....................................................................... 33 
9.6.3. 
Quality Assurance Audit .............................................................. 33 
9.7. 
Ethics ......................................................................................................... 33 
9.7.1. 
Ethical and Legal Issues .............................................................. 33 
9.7.2. 
Institutional Review Board ........................................................... 33 
9.7.3. 
Informed Consent ........................................................................ 34 
9.7.4. 
Good Clinical Practice ................................................................. 34 
9.8. 
Data Handling and Record Keeping............................................................ 34 
9.8.1. 
Case Report Form ....................................................................... 34 
9.8.2. 
Confidentiality .............................................................................. 35 
9.8.3. 
Termination of the Study .............................................................. 35 
9.8.4. 
Protocol Revisions ....................................................................... 35 
9.8.5. 
Protocol Administrative Changes ................................................. 36 
9.9. 
Publication Policy ....................................................................................... 36 
10. INVESTIGATOR’S ACKNOWLEDGEMENT .......................................................... 37 
11. REFERENCES ...................................................................................................... 38 
12. APPENDIX 1: AMENDMENT/ADMINISTRATIVE CHANGES ................................ 39 
12.1. 
ADMINISTRATIVE CHANGE 1 .................................................................. 39 


CONFIDENTIAL 
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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
Page 9 of 40 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
Page 10 of 40 
LIST OF TABLES 
PAGE 
Table 1 
Schedule of Activities ............................................................................. 17 
Table 2 
Grading of Adverse Event Severity ........................................................ 25 
LIST OF FIGURES 
PAGE 
Figure 1 
Study diagram .......................................................................................... 6 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
Page 11 of 40 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
Anti-HIV 
Antibodies to Human Immunodeficiency Virus 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CFR  
Code of Federal Regulations 
CHr 
Reticulocyte Hemoglobin Content 
CTCAE 
Common Terminology Criteria for Adverse Events 
dL 
Deciliter 
eCRF 
Electronic Case Report Form 
e.g. 
For Example 
EOS. 
End of Study 
FCM 
Ferric Carboxymaltose 
FDA 
Food and Drug Administration 
Fe 
Iron 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GMP 
Good Manufacturing Practice 
Hct 
Hematocrit 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Viral Antibody 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
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 
IRT 
Interactive Response Technology 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
LDH 
Lactic Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
m 
Meter 
mg  
Milligram 
mL 
Milliliter 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
Page 12 of 40 
NCI 
National Cancer Institute 
ng 
Nanogram 
PCS 
Potentially Clinically Significant 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RDW 
Red (cell) Distribution Width 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
US 
United States 
WBC 
White Blood Cell 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
Page 13 of 40 
1. 
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) [Looker, 1997]. 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 [Kulnigg, 2006]. Anemia may also decrease 
survival rates in adults and children with chronic renal impairment where it is a 
commonly encountered problem [Foley, 1996; Staples, 2010]. 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 [Kulnigg, 2006]. 
Non-hematologic consequences of iron deficiency in children include poor weight gain, 
anorexia, irritability, decreased attention span, exercise intolerance, and decreased 
physical activity [Wharton, 1999]. 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 
[Kazal, 2002]. 
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 [Kulnigg, 2006]. 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 [Powers, 2014]. 
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 [Michaud, 2002; Pinsk, 2008; Surico, 2002]. 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 [Michaud, 2002]. 
Ferric Carboxymaltose has been characterized as an iron complex (Type 1) with a 
molecular mass of about 150,000 Daltons. The solution is a dark brown color with a near 


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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
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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 completed 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-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 
Hgb, ferritin, and TSAT [Favreau, 2017]. 
The proposed study will provide safety and efficacy data on the use of FCM in pediatric 
patients (aged between 1 and 18 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 
Ferric Carboxymaltose 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 Hgb 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 [Staples, 2010]. 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% [Michaud, 2002].  Over the last 
20 years, 30 deaths have been attributed to the use of IV iron dextran [Fishbane, 2003].  
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 iron dextran is associated with a higher rate of life threatening adverse 
events and anaphylactic reactions in comparison to low molecular weight iron dextran, 
the US Food and Drug Administration (FDA) was unable to find a clear difference after 
an examination of post-marketing data, clinical trial data, death certificates, and 
emergency room diagnoses [Pinsk, 2008].  Iron dextran is limited to second line therapy 
for treatment of iron deficiency.   


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Administrative Change 1 Date: Final 03 December 2019 
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More recently approved IV 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 [Van Wyck, 
2004].  
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.  
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. 
TRIAL OBJECTIVE 
2.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy and safety of IV FCM in 
pediatric participants who have IDA. 
3. 
OVERALL STUDY DESIGN AND RATIONALE 
3.1. 
Overall Study Design  
This is a single arm, open-label, multi-center, multi-national, non-randomized study that 
will evaluate the efficacy and safety of a one course treatment with FCM in participants 
who had an unsatisfactory response to oral iron in study 1VIT17044. 
Subjects will have an EOS Visit (Day 35) from the 1VIT17044 study to qualify for entry.  
Subjects will then be screened, meet all inclusion criteria, no exclusion criteria and have a 
baseline evaluation.  Based on the successful completion of the baseline evaluations, 
subjects will be enrolled and will receive the first dose of FCM (Day 0). The second 
FCM dose should occur 7 days from the first dose.  Subjects will return to the clinic 14 
and 28 days post their first dose for laboratory and safety assessments, and at 35 days 
post the first dose, participants will return to the clinic for final safety and efficacy 
assessments.  Once all assessments are complete the participant will exit the study. 
An unsatisfactory response to oral iron (i.e., an increase in Hgb of <1 g/dL from 
baseline) will be defined as non-responders to oral iron treatment.  Non-responders who 
continue to meet all inclusion criteria (including Hgb <11 g/dL) and none of the 
exclusion criteria will receive 1 course of FCM. 


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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
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3.2. 
Rationale of Study Design 
The primary objective in this study is to allow participants who were randomized to 
receive oral iron in the 1VIT17044 trial and who had an unsatisfactory response to oral 
iron or those that required a concomitant intervention, (defined as, blood transfusion, use 
of IV or oral iron outside of protocol, increase in erythropoietin for any reason [Day 0 
thru Day 35 of study protocol 1VIT17044], change in IBD treatment) to receive one 
course of FCM.  This course of FCM will consist of two doses of FCM at 15 mg/kg 
(maximum single dose of 750 mg), separated by seven days. 
This study is a rollover for study 1VIT17044 which is an open label, multi-center, multi-
national, randomized, active-control parallel group study that will evaluate the efficacy 
and safety of FCM in pediatric participants, ages 1 to 18 years with iron deficiency 
anemia. 


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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
 
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3.3. 
Schedule of Events 
Table 1 
Schedule of Activities 
Procedures 
Screening1 
Day -7 to -1  
Enrollment 
Visit 1, Day 0 
Study Visit 2 
Day 7 ± 1 day 
Study Visit 3 
Day 14 ± 1 day 
Study Visit 4 
Day 28 ± 1 day 
Study Visit 5 
Day 35 ± 1 day 
Informed Consent / Assent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Exam 
 
X 
 
 
 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Interactive Response 
Technology (IRT) 
X 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
Temperature 
 
X 
X 
 
 
 
Blood sampling for 
Hematology, Chemistry and 
Iron Indices (5.5 mL) 1 
X 
X 
X 
X 
X 
X 
Blood sampling for Serum 
Pregnancy Test (1.5 mL), if 
applicable 
X 
 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Adverse Event Assessments 
 
X 
X 
X 
X 
X 
FCM Dosing 
 
X 
X 
 
 
 
1.  Note that there will be a 7 ± 1 day waiting period between 1VIT17044 end of study and extension screening 
2.  For a full description of central laboratory assessments, refer to Protocol Section 6.4. 
 


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4. 
PARTICIPANT SELECTION 
4.1. 
Number and Type of Participants 
A maximum of approximately 36 participants from study 1VIT17044 who had an 
unsatisfactory response to oral iron. 
4.2. 
Screening Phase 
A subject who enters the screening phase will be assigned, via the IRT system, a unique 
screening number.  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). 
4.2.1. 
Inclusion Criteria  
1. Unsatisfactory response to oral iron or those that required a concomitant intervention, 
(defined as, blood transfusion, use of IV or oral iron outside of protocol, increase in 
erythropoietin for any reason [Day 0 thru Day 35 of study protocol 1VIT17044], 
change in IBD treatment).  
2. Hgb <11 g/dL 
3. Ferritin ≤300 ng/mL and TSAT <30% 
4.2.2. 
Exclusion Criteria 
1. Known history of hypersensitivity reaction to any component of FCM. 
2. History of acquired iron overload, hemochromatosis, or other iron accumulation 
disorders. 
3. History of significant diseases of the liver, hematopoietic system, cardiovascular 
system, psychiatric disorder, or other conditions which, in the opinion of the 
investigator, may place a subject at added risk for participation in the study. 
4. Any existing non-viral infection.  
5. Known history of positive HBsAg or HCV with evidence of active hepatitis. 
6. Known history of positive HIV-1/HIV-2 antibodies (anti-HIV). 
7. Anemia due to reasons other than iron deficiency (e.g., hemoglobinopathy and 
vitamin B12 or folic acid deficiency) that has not been corrected.  
8. Administration and / or use of an investigational product (drug or device) within 30 
days of screening. 
9. Alcohol or drug abuse within the past six months. 
10. Female participant who is pregnant or lactating, or sexually active females who are of 
childbearing potential not willing to use an acceptable form of contraceptive 
precautions during the study. 
11. Unable to comply with study procedures and assessments. 


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4.3. 
Participant Assignment Process 
Participants who satisfy the inclusion requirements and no exclusionary criteria will be 
eligible to participate in this study. This is an open label study. 
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. 
5. 
STUDY DRUG  
5.1. 
Formulation, Packaging and Storage 
The 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.   
FCM must be kept in a secure place at the investigational site, and stored at room 
temperature (see United States Pharmacopeia).  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 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. All subjects will be dosed with FCM based on the Hgb, TSAT and ferritin 
values from the last scheduled visit in the 1VIT17044 study.  
Participants 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 


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Administrative Change 1 Date: Final 03 December 2019 
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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. 
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 post (within 5 
minutes), 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. 
 
In the event a serious acute reaction is seen, the site must have the capability to 
provide appropriate resuscitation measures. These may include IV normal 
saline, 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).  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.   


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6. 
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 -18 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 informed consent form, 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 to -1) 
Note that there will be a 7 ± 1 day waiting period between 1VIT17044 end of study 
and extension screening. 
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 
 
Hematology, chemistries and iron indices. For a full description of central laboratory 
assessments, refer to Protocol Section 6.4.  
 
Serum pregnancy test for female participants of child bearing potential (negative 
results must be obtained prior to study drug dosing). 
 
Height and weight 
 
Vitals signs (sitting heart rate and blood pressure)  
 
Concomitant medications assessment 
Participants who do not meet the entry criteria should be entered into the IRT system as a 
screen failure.   


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6.3. 
Treatment Phase (Day 0 to Day 35) 
6.3.1. 
Enrollment: Visit 1 Day 0 
The following will be obtained and/or completed before contacting IRT for a subject 
number: 
For all participants: 
 
Verify all inclusion and exclusion criteria (see Sections 4.2.1 and 4.2.2) 
 
Physical exam 
 
Review concomitant medications. 
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.  After assignment of the subject number, 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 (prior to 
study drug administration) 
 
Vital signs: temperature, sitting heart rate and blood pressure 
 
Weight 
 
Verify amount of single FCM dose (15 mg/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 (SAE) assessment (starting at beginning of 
FCM injection).  


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6.3.2. 
Visit 2 Day 7 ± 1 day 
All participants will return to the clinic on Day 7.  Prior to the administration of the study 
drug, the participant will be evaluated clinically to assess for the development of 
clinically significant conditions that may contraindicate dosing. 
 
Vital signs (temperature, sitting heart rate and blood pressure)  
 
Blood samples for central lab hematology, chemistries and iron indices (prior to 
study drug administration). 
 
Concomitant medications assessment 
 
Verify amount of single FCM dose (15 mg/kg up to a maximum 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 / SAE assessment (starting at beginning of FCM injection).  
6.3.3. 
Visit 3 Day 14 ± 1 day 
All participants will return to the clinic on Day 14.  The participant will be evaluated 
clinically to assess for the development of clinically significant conditions. 
 
Vital signs (sitting heart rate and blood pressure)  
 
Blood samples for central lab hematology, chemistries and iron indices 
 
Concomitant medications assessment 
 
Adverse events assessment 
6.3.4. 
Visit 4 Day 28 ± 1 day 
 
Vitals signs (sitting heart rate and blood pressure) 
 
Hematology, chemistries and iron indices  
 
Concomitant medications assessment 
 
Adverse events assessment 
6.3.5. 
Visit 5 Day 35 ± 1 day (End of Study) 
 
Physical exam  


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 
Vitals signs (sitting heart rate and blood pressure) 
 
Blood samples for central lab hematology, chemistries and iron indices 
 
Serum pregnancy test for female participants of child bearing potential 
 
Concomitant medications assessment 
 
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.   
6.4. 
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 3.3.  
Hematology: 
Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, 
differential count, reticulocyte count, and 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 TSAT 
Other: 
Serum pregnancy test  
7. 
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 electronic case 
report form (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 


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report]. All laboratory values at the EOS/Day 35 that have been deemed clinical 
significant by the Investigator should be followed until they are back into normal range. 
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 NCI-CTCAE criterion does not exist, the investigator should use Table 2 to assign 
the adverse event grade. 
Table 2 
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 FCM 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 FCM should be 
followed until they are no longer related, have taken a confounding medication or return 
to baseline grade. 
Relationship (Causality): The Investigator will be asked to document his/her opinion of 
the relationship of the event to the study drug* as follows: 
 NONE 
There is no evidence of any causal relationship 
 UNLIKELY 
There is little evidence to suggest there is a causal 
relationship. There is another reasonable explanation for the 


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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 purpose of this trial, study drug is defined as FCM. 
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. 
 
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. 


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 
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 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: 
Safety Monitor 
American Regent, Inc. 
Phone: (800) 734-9236 
Fax: (610) 650-0170 
Email: pv@americanregent.com 
The local investigator is responsible for reporting SAEs to their local Institutional Review 
Board (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. 
STATISTICS 
Continuous variables will be summarized in terms of the number of observations, mean, 
standard deviation (SD), 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 


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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
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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 
This is a non-randomized, single arm study. 
8.2. 
Analysis Populations 
Safety Population 
The safety population will consist of all participants who received at least one dose of 
study drug.   
8.3. 
Disposition and Baseline Characteristics 
The number of participants in each investigative site will be summarized.  The number of 
participants who are screened, 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 Hgb from baseline to day 35.  Descriptive statistics 
will be provided for the baseline Hgb, the day 35 Hgb, and the within-participant change 
from baseline.  The change in Hgb from baseline to day 35 will be analyzed using paired 
t-tests. 
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 in Hgb, ferritin, TSAT, and CHr throughout the study 
Details of analyses for these endpoints will be outlined in the SAP. 


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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
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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. Missing data will not be imputed for 
descriptive statistical summaries in safety or efficacy. Details will be provided in the 
SAP. 
8.5. 
Analyses of Safety 
8.5.1. 
Study Drug Exposure 
The number of infusions and total administered 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. 
The number and percent of participants who report treatment emergent AE (TEAE) will 
be summarized. 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 Hgb/hematocrit (Hct) and low iron indices.  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. 
The adverse event profile will be characterized with severity (as graded by the 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. 


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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
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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 potentially clinically significant (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-CTCAE Version 5 or higher).  Baseline will be 
defined as the last value obtained before receiving study drug. 
No formal statistical tests will be performed.   
8.5.5. 
Vital Signs 
The change in vital signs (sitting heart rate and blood pressure) from pre-infusion to each 
post-infusion time point will be summarized descriptively on each dosing day. 
8.5.6. 
Sample Size Rationale 
There were no sample size estimations for this study.  The current study is a rollover for 
study 1VIT17044. There will be a maximum of approximately 36 participants from study 
1VIT17044 who had an unsatisfactory response to oral iron or required an intervention. 
9. 
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 


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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
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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. 
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 Investigational New Drug Application (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. 


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Administrative Change 1 Date: Final 03 December 2019 
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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] 
 
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. 


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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. 
9.7.2. 
Institutional Review Board 
The Protocol and the Informed Consent must be approved by an appropriate 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. 


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Administrative Change 1 Date: Final 03 December 2019 
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 
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 to the recommendations for clinical studies in 
humans as set out in the most current revision of the “Declaration of Helsinki”, the local 
legal requirements and the guidelines on “Good Clinical Practice”, [21 CFR Part 312 and 
ICH guidelines]. 
9.8. 
Data Handling and Record Keeping 
9.8.1. 
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). 


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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 Sponsor discovers conditions arising during the 
course of the study, which indicate that the clinical investigation should be halted.  The 
study may be terminated after appropriate consultation and discussion. 
Conditions that may warrant study termination include, but are not limited to, the 
discovery of a significant, unexpected and unacceptable risk to the 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, Inc. 
personnel and the investigator and be approved by the site's IRB, before the revision may 
be implemented.  The protocol revision will be submitted to the FDA. 


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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
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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 Regent, Inc. on any 
results or ideas connected with the study. 


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Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
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10. 
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.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
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11. 
REFERENCES 
Favreau A, Langseder A, Irizarry R, Schuckalo S, Neier M, Rosh J. Safety and Efficacy 
of Ferric Carboxymaltose In Pediatric Inflammatory Bowel Disease. Poster: 
Inflammatory Bowel Diseases: February 2017 doi: 
10.1097/01.MIB.0000512714.16903.dc 
Fishbane S.  Safety in iron management.  Am J Kidney Dis 2003;41(5Suppl):18-26. 
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. 
Kazal LA, Jr. Prevention of iron deficiency in infants and toddlers. Am Fam Physician 
2002; 66: 1217-1224. 
Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn's disease. Aliment 
Pharmacol Ther. 2006; 24: 1507-1523. 
Looker, A.C.; Dallman, P.R.; Carroll, M.D.; Gunter, E.W.; Johnson, C.L. Prevalence of 
iron deficiency in the United States. JAMA. 1997; 277: 973–976. 
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. 
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 
Powers JM, Buchanan GR. Diagnosis and management of iron deficiency anemia. 
Hematol Oncol Clin North Am. 2014; 28(4): 729-45. 
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. 
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 
Van Wyck D, Anderson J, Johnson K. Labile iron in parenteral iron formulations: a 
quantitative and comparative study. Nephrol Dial Transplant. 2004; 19(3): 561-565. 
Wharton BA. Iron deficiency in children: detection and prevention. Br J Haematol. 1999; 
106: 270-280. 


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Administrative Change 1 Date: Final 03 December 2019 
 
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12. 
APPENDIX 1: AMENDMENT/ADMINISTRATIVE CHANGES 
12.1. 
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.: 1VIT18045 
CONFIDENTIAL            
Final version: 1.0 26 April 2019 
New Wording:  
American Regent, Inc.              Protocol No.: 1VIT18045 
CONFIDENTIAL                       Administrative Change 1 Date: 
Final 03 December 2019 
TITLE PAGE 
Protocol Date was changed. 
Original Wording: 
Protocol Date: 26 April 2019 
New Wording:  
Protocol Date: 26 April 2019 
Administrative Change 1 Date: Final 03 December 2019 
To reflect the date 
of the current 
protocol version. 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Final version: 1.0 26 April 2019 
Page 1 of 37 
AMERICAN REGENT, INC. 
PROTOCOL 
 
No. 1VIT18045 
 
IND #: 63,243 
 
Evaluating the Efficacy and Safety of Intravenous Ferric Carboxymaltose in 
Pediatric Patients with Iron Deficiency Anemia and an Unsatisfactory Response to 
Oral Iron under Study Protocol 1VIT17044 
 
SPONSOR 
American Regent, Inc. 
Clinical Research and Development 
800 Adams Avenue 
Norristown, PA 19403 
631-772-3500  
 
 
Protocol Date: Final 26 April 2019 


CONFIDENTIAL 
American Regent, Inc. 
Protocol No.: I VITI 8045 
Final version: 1.0 26 April 2019 
SIGNATURES OF AGREEMENT FOR PROTOCOL 
't::R-- c~~~~~~~~'<AA-14(-4- ({~ a~~ 
Head, Clinical Research and Development 
American Regent, Inc. 
M rk Falone, 
Medical Director Clinical Research and Development 
American Regent, Inc. 
Medical Director, Head of Pharmacovigilance 
American Regent, Inc. 
Marsha Simon 
Director of Regulatory Affairs 
American Regent, Inc. 
Nicole Blackman, PhD 
Head of Quantitative Sciences 
American Regent, Inc. 
Page 2 of 37 
Date 
Date 
Date 
Date 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
 
Final version: 1.0 26 April 2019 
 
Page 3 of 37 
Study Synopsis 
Protocol No. 1VIT18045 
Title: 
Evaluating the Efficacy and Safety of Intravenous Ferric 
Carboxymaltose in Pediatric Patients with Iron Deficiency 
Anemia and an Unsatisfactory Response to Oral Iron under 
Study Protocol 1VIT17044 
Study Drug: 
Injectafer® (Ferric Carboxymaltose [FCM]) 
Objectives: 
 
The primary objective of this study is to evaluate the 
efficacy and safety of intravenous (IV) ferric 
carboxymaltose (FCM) in pediatric participants who 
have iron deficiency anemia (IDA). 
Nature of Study: 
Phase III 
Design: 
This is a single arm, open-label, multi-center, multi-national, 
non-randomized study that will evaluate the efficacy and 
safety of a one course treatment with FCM in participants 
who had an unsatisfactory response to oral iron in study 
1VIT17044. 
Subjects will have an End of Study (EOS) Visit (Day 35) 
from the 1VIT17044 study to qualify for entry.  Subjects will 
then be screened, meet all inclusion criteria, no exclusion 
criteria and have a baseline evaluation.  Based on the 
successful completion of the baseline evaluations, subjects 
will be enrolled and will receive the first dose of FCM (Day 
0). The second FCM dose will occur 7 days from the first 
dose.  Subjects will return to the clinic 14 and 28 days post 
their first dose for laboratory and safety assessments, and at 
35 days post the first dose, participants will return to the 
clinic for final safety and efficacy assessments.  Once all 
assessments are complete the participant will exit the study. 
An unsatisfactory response to oral iron (i.e., an increase in 
hemoglobin (Hgb) of <1 g/dL from baseline) will be defined 
as non-responders to oral iron treatment.  Non-responders 
who continue to meet all inclusion criteria (including Hgb 
<11 g/dL) and none of the exclusion criteria will receive 1 
course of FCM.  
Inclusion Criteria: 
1. Unsatisfactory response to oral iron or those that required 
a concomitant intervention, (defined as, blood 
transfusion, use of IV or oral iron outside of protocol, 
increase in erythropoietin for any reason [Day 0 thru Day 


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American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
 
Final version: 1.0 26 April 2019 
 
Page 4 of 37 
35 of study protocol 1VIT17044], change in 
Inflammatory Bowel Disease [IBD] treatment). 
2. Hgb <11 g/dL 
3. Ferritin ≤300 ng/dL and Transferrin Saturation (TSAT) 
<30% 
Exclusion Criteria: 
1. Known history of hypersensitivity reaction to any 
component of FCM. 
2. History of acquired iron overload, hemochromatosis, or 
other iron accumulation disorders. 
3. History of significant diseases of the liver, hematopoietic 
system, cardiovascular system, psychiatric disorder, or 
other conditions which, in the opinion of the investigator, 
may place a subject at added risk for participation in the 
study. 
4. Any existing non-viral infection.  
5. Known history of positive hepatitis B surface antigen 
(HBsAg) or hepatitis C viral antibody (HCV) with 
evidence of active hepatitis. 
6. Known history of positive human immunodeficiency 
virus (HIV-1/HIV-2) antibodies (anti-HIV). 
7. Anemia due to reasons other than iron deficiency (e.g., 
hemoglobinopathy and vitamin B12 or folic acid 
deficiency) that has not been corrected.  
8. Administration and / or use of an investigational product 
(drug or device) within 30 days of screening. 
9. Alcohol or drug abuse within the past six months. 
10. Female participant who is pregnant or lactating, or 
sexually active females who are of childbearing potential 
not willing to use an acceptable form of contraceptive 
precautions during the study. 
11. Unable to comply with study procedures and assessments. 
Study Drug 
Administration 
Participants 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 
Endpoints: 
Primary Endpoint: 
 
Change in Hgb from baseline to Day 35 
 
Secondary Endpoints: 
 
Change in ferritin from baseline to Day 35 
 
Change in TSAT from baseline to Day 35  


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 
Changes from baseline in Hgb, ferritin, TSAT, and 
reticulocyte hemoglobin content (CHr) throughout the 
study 
Participant 
Duration: 
35 Days 
Study Sites: 
Approximately 25 sites 
Participant Number: 
Maximum of approximately 36 participants 
 
 


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Protocol No.: 1VIT18045 
 
 
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Page 6 of 37 
Figure 1 
Study diagram 
 
 
E
Day 0
Day 14 ± 1 
day
Day 28 ± 1 
day
FCM
Day 7 ± 1 
day
15 mg/kg/dose x 2 doses 
(maximum single dose of 750 mg)
X 
X
Participants meeting 
inclusion criteria and no 
exclusion criteria and are 
confirmed to have had 
an inadequate response 
to oral iron 
Day 35 ± 1 
day (EOS)
Visit In Clinic
X
X
X
Final Visit In Clinic
Screening *
Day -7 to -1
Enrollment
Visit In Clinic
* Note that there will be a 7 ± 1 day waiting period between 1VIT17044 end of study and extension screening
._____ _ 
_____,I 
.____I-------' 
DD D DD 
> 
.____I------' 


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Protocol No.: 1VIT18045 
 
Final version: 1.0 26 April 2019 
Page 7 of 37 
TABLE OF CONTENTS 
PAGE 
STUDY SYNOPSIS ........................................................................................................ 3 
LIST OF ABBREVIATIONS ........................................................................................... 10 
1. 
INTRODUCTION ................................................................................................... 12 
1.1. 
Treatment of Iron Deficiency Anemia .......................................................... 12 
1.2. 
Ferric Carboxymaltose................................................................................ 13 
1.2.1. 
Key features of Ferric Carboxymaltose ........................................ 13 
1.2.2. 
Ferric Carboxymaltose versus Other Parenteral Iron 
Agents ......................................................................................... 13 
2. 
TRIAL OBJECTIVE ................................................................................................ 14 
2.1. 
Primary Objective ....................................................................................... 14 
3. 
OVERALL STUDY DESIGN AND RATIONALE ..................................................... 14 
3.1. 
3.1 Overall Study Design ............................................................................ 14 
3.2. 
Rationale of Study Design .......................................................................... 15 
3.3. 
Schedule of Events ..................................................................................... 16 
4. 
PARTICIPANT SELECTION .................................................................................. 17 
4.1. 
Number and Type of Participants ............................................................... 17 
4.2. 
Screening Phase ........................................................................................ 17 
4.2.1. 
Inclusion Criteria .......................................................................... 17 
4.2.2. 
Exclusion Criteria ......................................................................... 17 
4.3. 
Participant Assignment Process ................................................................. 18 
4.4. 
Withdrawal from Study................................................................................ 18 
4.5. 
Discontinuation from Study Drug ................................................................ 18 
5. 
STUDY DRUG ....................................................................................................... 18 
5.1. 
Formulation, Packaging and Storage .......................................................... 18 
5.2. 
Drug Administration/Regimen ..................................................................... 18 
5.3. 
IV Medication Precautions .......................................................................... 19 
5.4. 
Drug Accountability ..................................................................................... 19 
5.5. 
Concomitant Medication ............................................................................. 19 
6. 
STUDY PROCEDURES ......................................................................................... 20 
6.1. 
Informed Consent ....................................................................................... 20 
6.2. 
Screening Phase ........................................................................................ 20 
6.2.1. 
Screening Visit 1 (Day -7 to -1) .................................................... 20 
6.3. 
Treatment Phase (Day 0 to Day 35) ........................................................... 21 
6.3.1. 
Enrollment: Visit 1 Day 0 ............................................................. 21 
6.3.2. 
Visit 2 Day 7 ± 1 day .................................................................... 22 
6.3.3. 
Visit 3 Day 14 ± 1 day .................................................................. 22 
6.3.4. 
Visit 4 Day 28 ± 1 day .................................................................. 22 
6.3.5. 
Visit 5 Day 35 ± 1 day (End of Study) .......................................... 22 
6.4. 
Central Laboratory Assessments ................................................................ 23 


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7. 
ASSESSMENT OF SAFETY .................................................................................. 23 
7.1. 
Adverse Events .......................................................................................... 23 
7.2. 
Reporting of Adverse Events ...................................................................... 25 
7.3. 
Serious Adverse Events ............................................................................. 25 
8. 
STATISTICS .......................................................................................................... 26 
8.1. 
Stratification/Randomization ....................................................................... 27 
8.2. 
Analysis Populations .................................................................................. 27 
8.3. 
Disposition and Baseline Characteristics .................................................... 27 
8.4. 
Endpoints and Definitions ........................................................................... 27 
8.4.1. 
Primary Endpoint ......................................................................... 27 
8.4.2. 
Secondary Endpoints .................................................................. 27 
8.4.3. 
Missing Data ................................................................................ 28 
8.5. 
Analyses of Safety ...................................................................................... 28 
8.5.1. 
Study Drug Exposure .................................................................. 28 
8.5.2. 
Adverse Events ........................................................................... 28 
8.5.3. 
Adverse Events of Special Interest .............................................. 29 
8.5.4. 
Clinical Laboratory Findings ........................................................ 29 
8.5.5. 
Vital Signs ................................................................................... 29 
8.5.6. 
Sample Size Rationale ................................................................ 29 
9. 
ADMINISTRATIVE CONSIDERATIONS ................................................................ 29 
9.1. 
Retention and Availability of Records ......................................................... 29 
9.2. 
Investigator Responsibilities ....................................................................... 30 
9.3. 
Financial Disclosure ................................................................................... 30 
9.4. 
Advertisement for Participant Recruitment .................................................. 31 
9.5. 
Documents Required for Study Initiation ..................................................... 31 
9.6. 
Quality Control and Quality Assurance ....................................................... 31 
9.6.1. 
Investigator Selection Criteria ...................................................... 31 
9.6.2. 
Clinical Monitoring ....................................................................... 32 
9.6.3. 
Quality Assurance Audit .............................................................. 32 
9.7. 
Ethics ......................................................................................................... 32 
9.7.1. 
Ethical and Legal Issues .............................................................. 32 
9.7.2. 
Institutional Review Board ........................................................... 32 
9.7.3. 
Informed Consent ........................................................................ 33 
9.7.4. 
Good Clinical Practice ................................................................. 33 
9.8. 
Data Handling and Record Keeping............................................................ 33 
9.8.1. 
Case Report Form ....................................................................... 33 
9.8.2. 
Confidentiality .............................................................................. 34 
9.8.3. 
Termination of the Study .............................................................. 34 
9.8.4. 
Protocol Revisions ....................................................................... 34 
9.8.5. 
Protocol Administrative Changes ................................................. 35 
9.9. 
Publication Policy ....................................................................................... 35 
10. INVESTIGATOR’S ACKNOWLEDGEMENT .......................................................... 36 
11. REFERENCES ...................................................................................................... 37 


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LIST OF TABLES 
PAGE 
Table 1 
Schedule of Activities ............................................................................. 16 
Table 2 
Grading of Adverse Event Severity ........................................................ 24 
LIST OF FIGURES 
PAGE 
Figure 1 
Study diagram .......................................................................................... 6 


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Protocol No.: 1VIT18045 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
Anti-HIV 
Antibodies to Human Immunodeficiency Virus 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CFR  
Code of Federal Regulations 
CHr 
Reticulocyte Hemoglobin Content 
CTCAE 
Common Terminology Criteria for Adverse Events 
dL 
Deciliter 
eCRF 
Electronic Case Report Form 
e.g. 
For Example 
EOS. 
End of Study 
FCM 
Ferric Carboxymaltose 
FDA 
Food and Drug Administration 
Fe 
Iron 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GMP 
Good Manufacturing Practice 
Hct 
Hematocrit 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Viral Antibody 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
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 
IRT 
Interactive Response Technology 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
LDH 
Lactic Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
m 
Meter 
mg  
Milligram 
mL 
Milliliter 


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NCI 
National Cancer Institute 
ng 
Nanogram 
PCS 
Potentially Clinically Significant 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RDW 
Red (cell) Distribution Width 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
US 
United States 
WBC 
White Blood Cell 


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1. 
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) [Looker, 1997]. 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 [Kulnigg, 2006]. Anemia may also decrease 
survival rates in adults and children with chronic renal impairment where it is a 
commonly encountered problem [Foley, 1996; Staples, 2010]. 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 [Kulnigg, 2006]. 
Non-hematologic consequences of iron deficiency in children include poor weight gain, 
anorexia, irritability, decreased attention span, exercise intolerance, and decreased 
physical activity [Wharton, 1999]. 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 
[Kazal, 2002]. 
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 [Kulnigg, 2006]. 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 [Powers, 2014]. 
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 [Michaud, 2002; Pinsk, 2008; Surico, 2002]. 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 [Michaud, 2002]. 
Ferric Carboxymaltose has been characterized as an iron complex (Type 1) with a 
molecular mass of about 150,000 Daltons. The solution is a dark brown color with a near 


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Protocol No.: 1VIT18045 
 
Final version: 1.0 26 April 2019 
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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 completed 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-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 
Hgb, ferritin, and TSAT [Favreau, 2017]. 
The proposed study will provide safety and efficacy data on the use of FCM in pediatric 
patients (aged between 1 and 18 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 
Ferric Carboxymaltose 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 Hgb 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 [Staples, 2010]. 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% [Michaud, 2002].  Over the last 
20 years, 30 deaths have been attributed to the use of IV iron dextran [Fishbane, 2003].  
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 iron dextran is associated with a higher rate of life threatening adverse 
events and anaphylactic reactions in comparison to low molecular weight iron dextran, 
the US Food and Drug Administration (FDA) was unable to find a clear difference after 
an examination of post-marketing data, clinical trial data, death certificates, and 
emergency room diagnoses [Pinsk, 2008].  Iron dextran is limited to second line therapy 
for treatment of iron deficiency.   


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Final version: 1.0 26 April 2019 
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More recently approved IV 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 [Van Wyck, 
2004].  
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.  
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.
TRIAL OBJECTIVE
2.1. 
Primary Objective
The primary objective of this study is to evaluate the efficacy and safety of IV FCM in 
pediatric participants who have IDA. 
3.
3.1. 
OVERALL STUDY DESIGN AND RATIONALE 
Overall Study Design
This is a single arm, open-label, multi-center, multi-national, non-randomized study that 
will evaluate the efficacy and safety of a one course treatment with FCM in participants 
who had an unsatisfactory response to oral iron in study 1VIT17044. 
Subjects will have an EOS Visit (Day 35) from the 1VIT17044 study to qualify for entry.  
Subjects will then be screened, meet all inclusion criteria, no exclusion criteria and have a 
baseline evaluation.  Based on the successful completion of the baseline evaluations, 
subjects will be enrolled and will receive the first dose of FCM (Day 0). The second 
FCM dose should occur 7 days from the first dose.  Subjects will return to the clinic 14 
and 28 days post their first dose for laboratory and safety assessments, and at 35 days 
post the first dose, participants will return to the clinic for final safety and efficacy 
assessments.  Once all assessments are complete the participant will exit the study. 
An unsatisfactory response to oral iron (i.e., an increase in Hgb of <1 g/dL from 
baseline) will be defined as non-responders to oral iron treatment.  Non-responders who 
continue to meet all inclusion criteria (including Hgb <11 g/dL) and none of the 
exclusion criteria will receive 1 course of FCM. 


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Protocol No.: 1VIT18045 
 
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3.2. 
Rationale of Study Design 
The primary objective in this study is to allow participants who were randomized to 
receive oral iron in the 1VIT17044 trial and who had an unsatisfactory response to oral 
iron or those that required a concomitant intervention, (defined as, blood transfusion, use 
of IV or oral iron outside of protocol, increase in erythropoietin for any reason [Day 0 
thru Day 35 of study protocol 1VIT17044], change in IBD treatment) to receive one 
course of FCM.  This course of FCM will consist of two doses of FCM at 15 mg/kg 
(maximum single dose of 750 mg), separated by seven days. 
This study is a rollover for study 1VIT17044 which is an open label, multi-center, multi-
national, randomized, active-control parallel group study that will evaluate the efficacy 
and safety of FCM in pediatric participants, ages 1 to 18 years with iron deficiency 
anemia. 


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Protocol No.: 1VIT18045 
 
 
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3.3. 
Schedule of Events 
Table 1 
Schedule of Activities 
Procedures 
Screening1 
Day -7 to -1  
Enrollment 
Visit 1, Day 0 
Study Visit 2 
Day 7 ± 1 day 
Study Visit 3 
Day 14 ± 1 day 
Study Visit 4 
Day 28 ± 1 day 
Study Visit 5 
Day 35 ± 1 day 
Informed Consent / Assent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Exam 
 
X 
 
 
 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Interactive Response 
Technology (IRT) 
X 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
Temperature 
 
X 
X 
 
 
 
Blood sampling for 
Hematology, Chemistry and 
Iron Indices (5.5 mL) 1 
X 
X 
X 
X 
X 
X 
Blood sampling for Serum 
Pregnancy Test (1.5 mL), if 
applicable 
X 
 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Adverse Event Assessments 
 
X 
X 
X 
X 
X 
FCM Dosing 
 
X 
X 
 
 
 
1.  Note that there will be a 7 ± 1 day waiting period between 1VIT17044 end of study and extension screening 
2.  For a full description of central laboratory assessments, refer to Protocol Section 6.4. 
 


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Protocol No.: 1VIT18045 
 
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4. 
PARTICIPANT SELECTION 
4.1. 
Number and Type of Participants 
A maximum of approximately 36 participants from study 1VIT17044 who had an 
unsatisfactory response to oral iron. 
4.2. 
Screening Phase 
A subject who enters the screening phase will be assigned, via the IRT system, a unique 
screening number.  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). 
4.2.1. 
Inclusion Criteria  
1. Unsatisfactory response to oral iron or those that required a concomitant intervention, 
(defined as, blood transfusion, use of IV or oral iron outside of protocol, increase in 
erythropoietin for any reason [Day 0 thru Day 35 of study protocol 1VIT17044], 
change in IBD treatment).  
2. Hgb <11 g/dL 
3. Ferritin ≤300 ng/dL and TSAT <30% 
4.2.2. 
Exclusion Criteria 
1. Known history of hypersensitivity reaction to any component of FCM. 
2. History of acquired iron overload, hemochromatosis, or other iron accumulation 
disorders. 
3. History of significant diseases of the liver, hematopoietic system, cardiovascular 
system, psychiatric disorder, or other conditions which, in the opinion of the 
investigator, may place a subject at added risk for participation in the study. 
4. Any existing non-viral infection.  
5. Known history of positive HBsAg or HCV with evidence of active hepatitis. 
6. Known history of positive HIV-1/HIV-2 antibodies (anti-HIV). 
7. Anemia due to reasons other than iron deficiency (e.g., hemoglobinopathy and 
vitamin B12 or folic acid deficiency) that has not been corrected.  
8. Administration and / or use of an investigational product (drug or device) within 30 
days of screening. 
9. Alcohol or drug abuse within the past six months. 
10. Female participant who is pregnant or lactating, or sexually active females who are of 
childbearing potential not willing to use an acceptable form of contraceptive 
precautions during the study. 
11. Unable to comply with study procedures and assessments. 


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4.3. 
Participant Assignment Process 
Participants who satisfy the inclusion requirements and no exclusionary criteria will be 
eligible to participate in this study. This is an open label study. 
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. 
5. 
STUDY DRUG  
5.1. 
Formulation, Packaging and Storage 
The 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.   
FCM must be kept in a secure place at the investigational site, and stored at room 
temperature (see United States Pharmacopeia).  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 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. All subjects will be dosed with FCM based on the Hgb, TSAT and ferritin 
values from the last scheduled visit in the 1VIT17044 study.  
Participants 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 


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Protocol No.: 1VIT18045 
 
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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. 
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 post (within 5 
minutes), 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. 
 
In the event a serious acute reaction is seen, the site must have the capability to 
provide appropriate resuscitation measures. These may include IV normal 
saline, 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).  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.   


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6. 
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 -18 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 informed consent form, 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 to -1) 
Note that there will be a 7 ± 1 day waiting period between 1VIT17044 end of study 
and extension screening. 
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 
 
Hematology, chemistries and iron indices. For a full description of central laboratory 
assessments, refer to Protocol Section 6.4.  
 
Serum pregnancy test for female participants of child bearing potential (negative 
results must be obtained prior to study drug dosing). 
 
Height and weight 
 
Vitals signs (sitting heart rate and blood pressure)  
 
Concomitant medications assessment 
Participants who do not meet the entry criteria should be entered into the IRT system as a 
screen failure.   


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6.3. 
Treatment Phase (Day 0 to Day 35) 
6.3.1. 
Enrollment: Visit 1 Day 0 
The following will be obtained and/or completed before contacting IRT for a subject 
number: 
For all participants: 
 
Verify all inclusion and exclusion criteria (see Sections 4.2.1 and 4.2.2) 
 
Physical exam 
 
Review concomitant medications. 
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.  After assignment of the subject number, 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 (prior to 
study drug administration) 
 
Vital signs: temperature, sitting heart rate and blood pressure 
 
Weight 
 
Verify amount of single FCM dose (15 mg/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 (SAE) assessment (starting at beginning of 
FCM injection).  


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6.3.2. 
Visit 2 Day 7 ± 1 day 
All participants will return to the clinic on Day 7.  Prior to the administration of the study 
drug, the participant will be evaluated clinically to assess for the development of 
clinically significant conditions that may contraindicate dosing. 
 
Vital signs (temperature, sitting heart rate and blood pressure)  
 
Blood samples for central lab hematology, chemistries and iron indices (prior to 
study drug administration). 
 
Concomitant medications assessment 
 
Verify amount of single FCM dose (15 mg/kg up to a maximum 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 / SAE assessment (starting at beginning of FCM injection).  
6.3.3. 
Visit 3 Day 14 ± 1 day 
All participants will return to the clinic on Day 14.  The participant will be evaluated 
clinically to assess for the development of clinically significant conditions. 
 
Vital signs (sitting heart rate and blood pressure)  
 
Blood samples for central lab hematology, chemistries and iron indices 
 
Concomitant medications assessment 
 
Adverse events assessment 
6.3.4. 
Visit 4 Day 28 ± 1 day 
 
Vitals signs (sitting heart rate and blood pressure) 
 
Hematology, chemistries and iron indices  
 
Concomitant medications assessment 
 
Adverse events assessment 
6.3.5. 
Visit 5 Day 35 ± 1 day (End of Study) 
 
Physical exam  


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 
Vitals signs (sitting heart rate and blood pressure) 
 
Blood samples for central lab hematology, chemistries and iron indices 
 
Serum pregnancy test for female participants of child bearing potential 
 
Concomitant medications assessment 
 
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.   
6.4. 
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 3.3.  
Hematology: 
Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, 
differential count, reticulocyte count, and 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 TSAT 
Other: 
Serum pregnancy test  
7. 
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 electronic case 
report form (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 


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report]. All laboratory values at the EOS/Day 35 that have been deemed clinical 
significant by the Investigator should be followed until they are back into normal range. 
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 NCI-CTCAE criterion does not exist, the investigator should use Table 2 to assign 
the adverse event grade. 
Table 2 
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 FCM 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 FCM should be 
followed until they are no longer related, have taken a confounding medication or return 
to baseline grade. 
Relationship (Causality): The Investigator will be asked to document his/her opinion of 
the relationship of the event to the study drug* as follows: 
 NONE 
There is no evidence of any causal relationship 
 UNLIKELY 
There is little evidence to suggest there is a causal 
relationship. There is another reasonable explanation for the 


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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 purpose of this trial, study drug is defined as FCM. 
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. 
 
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. 


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 
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 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: 
Safety Monitor 
American Regent, Inc. 
Phone: (800) 734-9236 
Fax: (610) 650-0170 
Email: pv@americanregent.com 
The local investigator is responsible for reporting SAEs to their local Institutional Review 
Board (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. 
STATISTICS 
Continuous variables will be summarized in terms of the number of observations, mean, 
standard deviation (SD), 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 


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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 
This is a non-randomized, single arm study. 
8.2. 
Analysis Populations 
Safety Population 
The safety population will consist of all participants who received at least one dose of 
study drug.   
8.3. 
Disposition and Baseline Characteristics 
The number of participants in each investigative site will be summarized.  The number of 
participants who are screened, 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 Hgb from baseline to day 35.  Descriptive statistics 
will be provided for the baseline Hgb, the day 35 Hgb, and the within-participant change 
from baseline.  The change in Hgb from baseline to day 35 will be analyzed using paired 
t-tests. 
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 in Hgb, ferritin, TSAT, and CHr throughout the study 
Details of analyses for these endpoints will be outlined in the SAP. 


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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. Missing data will not be imputed for 
descriptive statistical summaries in safety or efficacy. Details will be provided in the 
SAP. 
8.5. 
Analyses of Safety 
8.5.1. 
Study Drug Exposure 
The number of infusions and total administered 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. 
The number and percent of participants who report treatment emergent AE (TEAE) will 
be summarized. 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 Hgb/hematocrit (Hct) and low iron indices.  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. 
The adverse event profile will be characterized with severity (as graded by the 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. 


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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 potentially clinically significant (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-CTCAE Version 5 or higher).  Baseline will be 
defined as the last value obtained before receiving study drug. 
No formal statistical tests will be performed.   
8.5.5. 
Vital Signs 
The change in vital signs (sitting heart rate and blood pressure) from pre-infusion to each 
post-infusion time point will be summarized descriptively on each dosing day. 
8.5.6. 
Sample Size Rationale 
There were no sample size estimations for this study.  The current study is a rollover for 
study 1VIT17044. There will be a maximum of approximately 36 participants from study 
1VIT17044 who had an unsatisfactory response to oral iron or required an intervention. 
9. 
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 


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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. 
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 Investigational New Drug Application (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. 


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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] 
 
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. 


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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. 
9.7.2. 
Institutional Review Board 
The Protocol and the Informed Consent must be approved by an appropriate 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. 


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 
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 to the recommendations for clinical studies in 
humans as set out in the most current revision of the “Declaration of Helsinki”, the local 
legal requirements and the guidelines on “Good Clinical Practice”, [21 CFR Part 312 and 
ICH guidelines]. 
9.8. 
Data Handling and Record Keeping 
9.8.1. 
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). 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Final version: 1.0 26 April 2019 
Page 34 of 37 
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 Sponsor discovers conditions arising during the 
course of the study, which indicate that the clinical investigation should be halted.  The 
study may be terminated after appropriate consultation and discussion. 
Conditions that may warrant study termination include, but are not limited to, the 
discovery of a significant, unexpected and unacceptable risk to the 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, Inc. 
personnel and the investigator and be approved by the site's IRB, before the revision may 
be implemented.  The protocol revision will be submitted to the FDA. 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Final version: 1.0 26 April 2019 
Page 35 of 37 
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 Regent, Inc. on any 
results or ideas connected with the study. 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Final version: 1.0 26 April 2019 
Page 36 of 37 
10. 
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) 
 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Final version: 1.0 26 April 2019 
Page 37 of 37 
11. 
REFERENCES 
Favreau A, Langseder A, Irizarry R, Schuckalo S, Neier M, Rosh J. Safety and Efficacy 
of Ferric Carboxymaltose In Pediatric Inflammatory Bowel Disease. Poster: 
Inflammatory Bowel Diseases: February 2017 doi: 
10.1097/01.MIB.0000512714.16903.dc 
Fishbane S.  Safety in iron management.  Am J Kidney Dis 2003;41(5Suppl):18-26. 
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. 
Kazal LA, Jr. Prevention of iron deficiency in infants and toddlers. Am Fam Physician 
2002; 66: 1217-1224. 
Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn's disease. Aliment 
Pharmacol Ther. 2006; 24: 1507-1523. 
Looker, A.C.; Dallman, P.R.; Carroll, M.D.; Gunter, E.W.; Johnson, C.L. Prevalence of 
iron deficiency in the United States. JAMA. 1997; 277: 973–976. 
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. 
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 
Powers JM, Buchanan GR. Diagnosis and management of iron deficiency anemia. 
Hematol Oncol Clin North Am. 2014; 28(4): 729-45. 
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. 
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 
Van Wyck D, Anderson J, Johnson K. Labile iron in parenteral iron formulations: a 
quantitative and comparative study. Nephrol Dial Transplant. 2004; 19(3): 561-565. 
Wharton BA. Iron deficiency in children: detection and prevention. Br J Haematol. 1999; 
106: 270-280. 


CONFIDENTIAL 
American Regent, Inc. 
 
Protocol No.: 1VIT18045 
 
Administrative Change 1 Date: Final 03 December 2019 
 
Page 40 of 40 
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. 
Synopsis and Section 4.2.1 
INCLUSION CRITERIA 
 
Original Wording: 
3. Ferritin ≤300 ng/dL and Transferrin Saturation (TSAT) <30%. 
New Wording:  
3. Ferritin ≤300 ng/mL and Transferrin Saturation (TSAT) <30%.. 
To correct a typo to 
inclusion criteria # 
3. 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
1VIT18045 Efficacy and Safety of Intravenous Ferric 
Carboxymaltose in Pediatric Patients With Iron Deficiency 
Anemia and Unsatisfactory Response Oral Iron Under Study 
Protocol 1VIT17044   NCT04269707 
 
 
 
03DEC2019 
 


Table of Contents
IVIT18045-STATISTICAL
3
STATISTICAL ANALYSIS PLAN APPROVAL
4
TABLE OF CONTENTS
5
LIST OF ABBREVIATIONS AND DEFINITIONS
7
1. INTRODUCTION
9
1.1 STUDY OBJECTIVES
9
1.1.1 Primary Objective
9
1.2 STUDY ENDPOINTS
9
1.2.1 Primary Efficacy Endpoint
9
1.2.2 Secondary Efficacy Endpoints
9
1.2.3 Safety Endpoints
9
1.3 SUMMARY OF THE STUDY DESIGN
10
1.3.1 General Study Design and Plan
10
Table 1: Schedule of Activities
11
1.3.2 Stratification/Randomization
12
1.3.3 Sample Size and Statistical Power Considerations
12
2. STATISTICAL METHODS
12
2.1 GENERAL CONSIDERATIONS
12
2.1.1 Reporting Precision
12
2.2 DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS)
13
2.2.1 Safety Population
13
2.3 DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
13
2.3.1 Baseline Definition
13
2.3.2 Study Day
13
2.3.3 Time Windows for Analysis
13
2.3.4 Handling of Missing Data
14
2.4 POOLING OF CENTERS
15
2.5 ANALYSIS SOFTWARE
15
3. STUDY SUBJECTS
15
3.1 DISPOSITION OF SUBJECTS
15
3.2 PROTOCOL DEVIATIONS
15


4. DEMOGRAPHY AND BASELINE CHARACTERISTICS
15
4.1 DEMOGRAPHY AND BASELINE CHARACTERISTICS
15
4.2 MEDICAL HISTORY
15
4.3 PRIOR AND CONCOMITANT MEDICATION
16
5. STUDY DRUG
16
5.1 TREATMENT COMPLIANCE
16
5.2 EXTENT OF EXPOSURE
16
6. EFFICACY ANALYSES
16
6.1 PRIMARY EFFICACY ANALYSIS
16
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
17
6.2.3 Change in Hgb, ferritin, TSAT and Reticulocyte Hemoglobin Content from 
baseline throughout the Study
17
7. SAFETY ANALYSES
17
7.1 ADVERSE EVENTS
17
7.1.1 Adverse Events of Special Interest
19
7.2 CLINICAL LABORATORY PARAMETERS
19
7.3 VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS
20
7.3.1 Vital Signs
20
7.3.2 Physical Examination
21
8. INTERIM ANALYSES AND DATA AND SAFETY MONITORING BOARD 
(DSMB)
21
8.1 INTERIM ANALYSES
21
8.2 DATA AND SAFETY MONITORING BOARD (DSMB)
21
9. SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES
21
10. APPENDICES
22
APPENDIX 1.1 ADVERSE EVENT SCALE
22
APPENDIX 1.2 PEDIATRIC VITAL SIGNS REFERENCE CHART
24


Sponsor: American Regent, Inc. 
Protocol No: 1VIT18045 Administrative Change 1 (03 DEC 2019) 
Statistical Analysis Plan 
Version: 1.0 (12 August 2020) 
Confidential 
Page 1  of 22 
Statistical Analysis Plan 
 
Protocol No.: 1VIT18045 
 
Evaluating the Efficacy and Safety of Intravenous Ferric 
Carboxymaltose in Pediatric Patients with Iron Deficiency Anemia 
and an Unsatisfactory Response to Oral Iron under Study Protocol 
1VIT17044 
Sponsor: 
American Regent, Inc. 
Version: 
Version 1.0 
Issue Date: 
12 August 2020 


Sponsor: American Regent, Inc. 
Protocol No: 1VIT18045 Administrative Change 1 (03 DEC 2019) 
Statistical Analysis Plan 
Version: 1.0 (12 August 2020) 
Confidential 
Page 2  of 22 
_______________ 
STATISTICAL ANALYSIS PLAN APPROVAL 
Author: 
 
Sisi Gu 
 
 
Digitally signed by Sisi Gu 
DN: cn=Sisi Gu, o, ou, email=sisi.gu@klserv.com, c=US 
Date: 2020.08.13 13D
:52a:t3e8:-04'00' 
/ 
/ 
Senior Biostatistician, Biostatistics, FMD K&L Inc. 
Reviewed and approved by: 
Li Liang 
Principal Biostatistician, Biostatistics, FMD K&L Inc. 
Sponsor Review: 
 
Date: 
/ 
/ 
 
 
Mark Falone, MD 
Medical Director, Clinical Research and Development 
American Regent, Inc. 
 
Date:  
/  
/  
 
 
Nicole Blackman, PhD 
Executive Director, Head of Quantitative Sciences 
American Regent, Inc. 
Date:  
/  
/  
 
Li Liang 
Digitally signed by Li Liang 
DN: cn=Li Liang, o, ou, 
email=li.liang@klserv.com, c=US 
Date: 2020.08.12 22:47:51 -04'00' 


Sponsor: American Regent, Inc. 
Protocol No: 1VIT18045 Administrative Change 1 (03 DEC 2019) 
Statistical Analysis Plan 
Version: 1.0 (12 August 2020) 
Confidential 
Page 3  of 22 
TABLE OF CONTENTS 
1. 
INTRODUCTION 
7 
1.1 
STUDY OBJECTIVES 
7 
1.1.1 Primary Objective 
7 
1.2 
STUDY ENDPOINTS 
7 
1.2.1 Primary Efficacy Endpoint 
7 
1.2.2 Secondary Efficacy Endpoints 
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 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 Safety Population 
11 
2.3 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
11 
2.3.1 Baseline Definition 
11 
2.3.2 Study Day 
11 
2.3.3 Time Windows for Analysis 
11 
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 
13 
4. 
DEMOGRAPHY AND BASELINE CHARACTERISTICS 
13 
4.1 
DEMOGRAPHY AND BASELINE CHARACTERISTICS 
13 
4.2 
MEDICAL HISTORY 
13 
4.3 
PRIOR AND CONCOMITANT MEDICATION 
14 
5. 
STUDY DRUG 
14 
5.1 
TREATMENT COMPLIANCE 
14 
5.2 
EXTENT OF EXPOSURE 
14 
6. 
EFFICACY ANALYSES 
14 
6.1 
PRIMARY EFFICACY ANALYSIS 
14 
6.1.1 Change in Hgb from baseline to Day 35 
14 
6.2 
SECONDARY EFFICACY ANALYSES 
15 
6.2.1 Change in ferritin from baseline to Day 35 
15 


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Page 4  of 22 
6.2.2 Change in TSAT from baseline to Day 35 
15 
6.2.3 
Change in Hgb, ferritin, TSAT and Reticulocyte Hemoglobin 
Content from baseline throughout the Study 
15 
7. 
SAFETY ANALYSES 
15 
7.1 
ADVERSE EVENTS 
15 
7.1.1 Adverse Events of Special Interest 
17 
7.2 
CLINICAL LABORATORY PARAMETERS 
17 
7.3 
VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS 
18 
7.3.1 Vital Signs 
18 
7.3.2 Physical Examination 
19 
8. 
INTERIM ANALYSES AND DATA AND SAFETY MONITORING 
BOARD (DSMB) 
19 
8.1 
INTERIM ANALYSES 
19 
8.2 
DATA AND SAFETY MONITORING BOARD (DSMB) 
19 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED 
ANALYSES 
19 
10. APPENDICES 
20 
APPENDIX 1.1 ADVERSE EVENT SCALE 
20 
APPENDIX 1.2 PEDIATRIC VITAL SIGNS REFERENCE CHART 
22 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CHr 
Reticulocyte Hemoglobin Content 
CTCAE 
Common Terminology Criteria for Adverse Events 
dL 
Deciliter 
eCRF 
Electronic Case Report Form 
e.g. 
For Example 
EOS 
End of Study 
FCM 
Ferric Carboxymaltose 
FDA 
Food and Drug Administration 
Fe 
Iron 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
Hct 
Hematocrit 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Viral Antibody 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
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 
IRT 
Interactive Response Technology 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
m 
Meter 
mg 
Milligrams 
mL 
Milliliter 
NCI 
National Cancer Institute 
ng 
Nanogram 
PCS 
Potentially Clinically Significant 
PE 
Physical Examination 


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PT 
Preferred Term 
RBC 
Red Blood Cells 
RDW 
Red Cell Distribution Width 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treament Emergent Adverse Event 
TIBC 
Total Iron Binding Capcacity 
TSAT 
Transferrin Saturation 
US 
United States 
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 1VIT18045 (Administrative 
Change 1 Date: 03 December 2019). This SAP should be read in conjunction with the 
corresponding clinical study protocol and electronic case report forms (eCRFs). 
1.1 
STUDY OBJECTIVES 
1.1.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy and safety of intravenous (IV) 
Ferric Carboxymaltose (FCM) in pediatric participants who have iron deficiency anemia (IDA). 
1.2 
STUDY ENDPOINTS 
1.2.1 
Primary Efficacy Endpoint 
The primary endpoint is the change in hemoglobin (Hgb) from baseline to Day 35. 
1.2.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
 Change in ferritin from baseline to Day 35 
 Change in transferrin saturation (TSAT) from baseline to Day 35 
 Changes from baseline in Hgb, ferritin, TSAT, and reticulocyte hemoglobin content 
(CHr) throughout the study. 
1.2.3 
Safety Endpoints 
Safety endpoints include: 
 Extent of exposure 
 Adverse events 
 Laboratory assessments 
 Vital signs 
 Physical examinations 


Sponsor: American Regent, Inc. 
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1.3 
SUMMARY OF THE STUDY DESIGN 
1.3.1 
General Study Design and Plan 
This is a single arm, open-label, multi-center, multi-national, non-randomized study that will 
evaluate the efficacy and safety of a one course treatment with FCM in participants who had an 
unsatisfactory response to oral iron in study 1VIT17044. 
Subjects will have an EOS Visit (Day 35) from the 1VIT17044 study to qualify for entry. 
Subjects will then be screened, meet all inclusion criteria, no exclusion criteria and have a 
baseline evaluation. Based on the successful completion of the baseline evaluations, subjects will 
be enrolled and will receive the first dose of FCM (Day 0). The second FCM dose should occur 7 
days from the first dose. Subjects will return to the clinic 14 and 28 days post their first dose for 
laboratory and safety assessments, and at 35 days post the first dose, participants will return to 
the clinic for final safety and efficacy assessments. Once all assessments are complete the 
participant will exit the study. 
An unsatisfactory response to oral iron (i.e., an increase in Hgb of <1 g/dL from baseline) will 
be defined as non-responders to oral iron treatment. Non-responders who continue to meet all 
inclusion criteria (including Hgb <11 g/dL) and none of the exclusion criteria will receive 1 
course of FCM. 


Version: 1.0 (12 August 2020) 
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Page 9 of 22 
Sponsor: American Regent, Inc. 
Protocol No:  1VIT18045 Administrative Change 1 (03 DEC 2019) 
Statistical Analysis Plan 
 
Table 1: Schedule of Activities 
Procedures 
Screening1 
Day -7 to -1 
Enrollment 
Visit 1, Day 0 
Study Visit 2 
Day 7 ± 1 day 
Study Visit 3 
Day 14 ± 1 day 
Study Visit 4 
Day 28 ± 1 day 
Study Visit 5 
Day 35 ± 1 day 
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 
Blood sampling for 
Hematology, Chemistry and 
Iron Indices (5.5 mL) 1 
X 
X 
X 
X 
X 
X 
Blood sampling for Serum 
Pregnancy Test (1.5 mL), if 
applicable 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
FCM Dosing 
X 
X 
1. Note that there will be a 7 ± 1 day waiting period between 1VIT17044 end of study and extension screening 
2. For a full description of central laboratory assessments, refer to Protocol Section 6.4. 


Sponsor: American Regent, Inc. 
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Version: 1.0 (12 August 2020) 
Confidential 
Page 10  of 22 
 
 
 
1.3.2 
Stratification/Randomization 
This is a non-randomized, single arm study. 
 
1.3.3 
Sample Size and Statistical Power Considerations 
There were no sample size estimations for this study. The current study is a rollover for study 
1VIT17044. There will be a maximum of approximately 36 participants from study 1VIT17044 
who had an unsatisfactory response to oral iron or required an intervention. 
 
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 in terms of the 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. 
 
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. 
 
2.1.1 
Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
 
Statistics 
Degree of Precision 
Mean, Geometric mean, Median, 
Quartiles, Confidence limit boundaries 
One decimal place more than the raw data. 
Standard deviation, Standard error 
Two decimal places more than the raw data. 
Minimum, Maximum 
The same as the raw data. 
p-value 
Rounded to 4 decimal places and therefore 
presented as 0. xxxx; p-values smaller than 


Sponsor: American Regent, Inc. 
Protocol No: 1VIT18045 Administrative Change 1 (03 DEC 2019) 
Statistical Analysis Plan 
Version: 1.0 (12 August 2020) 
Confidential 
Page 11  of 22 
 
 
 
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 
Safety Population 
The safety population will consist of all participants who received at least one dose of study drug 
(IV FCM). 
 
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 the first dose of study drug. 
 
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 
No assessment windows will be defined for the purpose of classifying measurement obtained 
outside scheduled assessment times. The summary by visit will be based on the observations at 
scheduled visits only. 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. 


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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 (paired t-tests) 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 or 
last unscheduled result will be carried forward. If there is no post-baseline value observed, the 
worst value obtained from Day 35 of all subjects in the safety population will be used. The worst 
value is defined as the lowest value for hemoglobin, ferritin, TSAT and reticulocyte hemoglobin 
content. 
 
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 not be counted as 
a 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 is the same as the year 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. 


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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 for all screened subjects and the number of subjects in Safety 
Population will be summarized in each investigative site. 
 
The disposition will include the following: 
 Participants who are screened 
 Participants who are included 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. 
 
3.2 
PROTOCOL DEVIATIONS 
The clinical team will identify deviations and the deviations will be identified in the database. 
The number and percent of participants with clinically important protocol deviations will be 
summarized for each type of deviation based on the safety 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 18 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 for all patients in the safety populations. 
 
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 for the safety populations. 


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4.3 
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 for the safety 
population. If ATC level 3 is not applicable, then the level 2 ATC will be used. 
 
5. 
STUDY DRUG 
5.1 
TREATMENT COMPLIANCE 
As for each subject, the individual compliance rate will be summarized by descriptive statistics 
for the safety population. 
 
FCM Compliance = (total dose of iron administered/target dose) ×100 
 
5.2 
EXTENT OF EXPOSURE 
 
The total calculated FCM dose to be given (mg), the total dose of elemental iron administered 
(mg), the number of infusions and treatment duration (days) will be summarized descriptively. 
 
6. 
EFFICACY ANALYSES 
All primary and secondary efficacy analyses will be based on the safety population unless 
otherwise specified. Missing data will be imputed per Section 2.3.4 for primary and secondary 
efficacy endpoints (no imputation for descriptive statistical summaries). P-values to determine 
the mean difference between baseline and Day 35 will be reported. The mean difference and 
corresponding 95% confidence interval will be tabulated where appropriate. 
 
6.1 
PRIMARY EFFICACY ANALYSIS 
6.1.1 
Change in Hgb from baseline to Day 35 
The primary efficacy endpoint is the change in Hgb from baseline to day 35. The actual value of 
Hgb on baseline, Day 35, and change from baseline to Day 35 will be summarized via 
descriptive statistics. 


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The change in Hgb from baseline to Day 35 will be assessed using paired t-tests (two-sided test, 
α=0.05). Baseline Hgb will be defined as the last Hgb obtained before the first dose. Missing 
value will be imputed using LOCF as specified in Section 2.3.4. 
 
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. 
 
The change in ferritin from baseline to day 35 will be assessed using paired t-tests (two-sided 
test, α=0.05). Baseline ferritin will be defined as the last ferritin obtained before the first dose. 
Missing value will be imputed using LOCF as specified in Section 2.3.4. 
 
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. 
 
The change in TSAT from baseline to day 35 will be assessed using paired t-tests (two-sided test, 
α=0.05). Baseline TSAT will be defined as the last TSAT obtained before the first dose. Missing 
value will be imputed using LOCF as specified in Section 2.3.4. 
 
6.2.3 
Change in Hgb, ferritin, TSAT and Reticulocyte Hemoglobin Content from 
baseline throughout the Study 
The actual value of Hgb, ferritin, TSAT and reticulocyte hemoglobin content (CHr) on baseline, 
each post-baseline visit (Day 7, 14, 28 and 35), and change from baseline to each post-baseline 
visit will be summarized via descriptive statistics. 
 
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) 
 Vital signs 
 
Baseline of clinical laboratory findings will be defined as the last value obtained before the first 
dose of study drug. 
 
7.1 
ADVERSE EVENTS 
 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. Adverse event 


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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. 
 
The incidence of TEAEs will be summarized as the number (percentage) of subjects with TEAEs 
within SOC and PT. 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 
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 


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 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. 
 
7.1.1 
Adverse Events of Special Interest 
 
Adverse events of special interest include hypophosphatemia, hypersensitivity/anaphylactoid 
reactions, injection/infusion 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 
 
 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 
CLINICAL LABORATORY PARAMETERS 
Laboratory assessments include hematology, clinical chemistry, and iron indices: 
 
 Hematology: Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, differential 


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count, reticulocyte count and 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 for 
each laboratory test group above. 
 
Time course table for serum phosphate will be constructed for 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 with 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. The denominator is all 
subjects with normal baseline and at least one post baseline assessment in the safety population 
and the numerator is the number of subjects with PCS (i.e., meets Grade 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, 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. 
 
7.3 
VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS 
7.3.1 
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. 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 


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Guidelines, 2015 in Appendix 1.2. Children >15 years of age will use the criteria for 15 years old 
children. 
 
7.3.2 
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 Baseline PE or Change from Baseline 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 
 
No formal interim analysis is planned for this study. 
 
8.2 
DATA AND SAFETY MONITORING BOARD (DSMB) 
 
No Data Safety Monitoring Board for this study. 
 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
 
Compared with the study protocol (03 December 2019 Administrative Change 1), below items 
are the major changes made in this SAP: 
 
1. The LOCF imputation method was proposed for paired t-test for primary and secondary 
efficacy endpoints in SAP. 
 
2. 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 
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. 


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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 


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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) 
10.0 to 10.9 
9.0 to < 10.0 
7.0 to < 9.0 
< 7.0 
≥ 13 years of age 
6.19 to 6.76 
5.57 to < 6.19 
4.34 to < 5.57 
< 4.34 
(male only) 
≥ 13 years of age 
9.5 to 10.4 
8.5 to < 9.5 
6.5 to < 8.5 
< 6.5 
(female only) 
5.88 to 6.48 
5.25 to < 5.88 
4.03 to < 5.25 
< 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 


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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 
 
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 
 
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