Conditions: Heart Failure Iron-deficiency
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3065
Healthy volunteers: no

Brief summary:
The primary objective of this study is to determine the efficacy and safety of iron therapy using intravenous (IV) ferric carboxymaltose (FCM), relative to placebo in the treatment of participants in heart failure with a reduced ejection fraction and with iron deficiency

Detailed description:
This is a double-blind, multicenter, prospective, randomized, placebo-controlled study to assess the effects of IV FCM compared to placebo on the 12-month rate of death, hospitalization for worsening heart failure, and the 6-month change in 6 minute walk test (6MWT) distance for patients in heart failure with iron deficiency.

After an initial screening period of up to 28 days, eligible participants will be stratified by region and randomized in a 1:1 ratio to FCM or placebo for treatment.

Study drug administration will occur on Day 0 and Day 7 (±2) as an undiluted slow IV push, with additional study visits planned at 3 month intervals, and additional dosing administered every 6 months as applicable. In a subset of sites, a sub-study will be conducted to characterize serum phosphate levels over time in participants with heart failure and iron deficiency after dosing with FCM. For all participants, hematology, ferritin, and transferrin saturation (TSAT), with appropriate safety evaluations, to determine additional treatment, will occur at 6 month intervals.

Arms:
arm 1: Ferric Carboxymaltose 2 doses intravenously of 15mg/kg to a maximum individual dose of 750mg 7 days apart and a maximum combined dose of 1500mg - repeated every 6 months as indicated by the results of iron indices. arm 2: Normal saline 15ml - 2 doses 7 days apart repeated every 6 months.

Interventions: intervention 1: Ferric Carboxymaltose intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous Iron intervention 2: Normal Saline Solution

Protocol document:
Prot_SAP_000.pdf: 
This supplement contains the following items: 
1. Original protocol, final protocol, and a summary of changes. 
2. Original statistical analysis plan, final statistical analysis plan, and a summary of 
changes. 
 


Luitpold Pharmaceuticals, Inc.
Protocol No.: 1VIT15043
CONFIDENTIAL 
version: 1.0, 12 January 2017
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LUITPOLD PHARMACEUTICALS, INC.
PROTOCOL
No. 1VIT15043
IND #: 127910
A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy 
and Safety of Injectafer® (Ferric Carboxymaltose) as Treatment for Heart Failure 
with Iron Deficiency 
SPONSOR
Luitpold Pharmaceuticals, Inc.
Clinical Research and Development
800 Adams Avenue
Norristown, PA 19403
610-650-4200


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Luitpold Pharmaceuticals, Inc.
Protocol No.: 1VIT15043
CONFIDENTIAL 
version: 1.0, 12 January 2017
Page 3 of 53
Study Synopsis
Protocol No. 1VIT15043
Title:
A Randomized, Double-Blind, Placebo-Controlled Study to 
Investigate the Efficacy and Safety of Injectafer® (Ferric 
Carboxymaltose) as Treatment for Heart Failure with Iron Deficiency
Study Drug:
Ferric Carboxymaltose (Injectafer®)
Objective:
The primary objective of this study is to determine the efficacy and safety 
of iron therapy using intravenous (IV) ferric carboxymaltose (FCM),
relative to placebo, in the treatment of participants in heart failure with a 
reduced ejection fraction and with iron deficiency.
Design:
This is a double-blind, multicenter, prospective, randomized, placebo-
controlled study to assess the effects of IV FCM compared to placebo on 
the 12-month rate of death, hospitalization for worsening heart failure,
and the 6-month change in 6 minute walk test (6MWT) for patients in 
heart failure with iron deficiency.
After an initial screening period of up to 28 days, eligible participants will 
be stratified by region and randomized in a 1:1 ratio to FCM or placebo 
for treatment. 
Study drug administration will occur on Day 0 and Day 7 (±2) as an 
undiluted slow IV push, with additional study visits planned at 3 month 
intervals, and additional dosing administered every 6 months as
applicable (based on dose regimen below). In a subset of sites, all 
participants will return for recurrent laboratory assessment (chemistry, 
hematology and iron indices) at Day 21 (± 7) after each course of
investigational treatment.  For all participants, hematology, ferritin, and 
transferrin saturation (TSAT), with appropriate safety evaluations, to 
determine additional treatment, will occur at 6 month intervals.
Inclusion Criteria:
1.
Adult (18 years of age) able to provide informed consent.
2.
Stable heart failure (NYHA II-IV) on maximally-tolerated 
background therapy (as determined by the site Principle Investigator) 
for at least 4 weeks with no dose changes in heart failure drugs during 
the last 2 weeks.
3.
Able and willing to perform a 6MWT at the time of randomization. 
4.
Reduced left ventricular ejection fraction. Assessment must be 
performed at least 12 weeks after major cardiac surgical intervention 
including coronary artery bypass graft (CABG), valvular 
repair/replacement, or cardiac resynchronization therapy (CRT) 
device implantation.


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Protocol No.: 1VIT15043
CONFIDENTIAL 
version: 1.0, 12 January 2017
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a.
Left ventricular ejection fraction REWDLQHGGXULQJWKH
screening visit OR either of the following
i.
Historical value of ejection fraction ZLWKLQ
months of screening visit
ii.
Historical value of ejection fraction ZLWKLQ
months of screening visit 
5.
Hemoglobin >9.0 g/dL and <13.5 g/dL (females) or <15.0 g/dL
(males).
6.
Serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT <20%.
7.
Either documented hospitalization for heart failure within 12 months 
of enrollment or screening visit N-terminal-pro-brain natriuretic 
peptide (NT-proBNP) >600 pg/ml (or BNP >200 pg/mL) for patients 
with normal sinus rhythm or NT-proBNP >1000 pg/ml (or BNP >400 
pg/mL) for patients with atrial fibrillation. NOTE: NT-proBNP must 
be used to confirm eligibility for patients taking sacubitril/valsartan.
Exclusion Criteria:   
1.
Current or planned oral iron supplementation. Iron-containing 
multivitamins (<30 mgs /day) are permitted.
2.
Known hypersensitivity reaction to any component of FCM.
3.
History of acquired iron overload, or the recent receipt (within 3 
months) of erythropoietin stimulating agent, IV iron therapy, or blood 
transfusion.
4.
Acute myocardial infarction, acute coronary syndrome, transient 
ischemic attack, or stroke within 3 months of enrollment.
5.
Uncorrected severe aortic stenosis, severe valvular regurgitation, or 
left ventricular outflow obstruction requiring intervention.
6.
Current atrial fibrillation or atrial flutter with a mean ventricular 
response rate >100 per minute (at rest).
7.
Current or planned mechanical circulatory support or heart
transplantation.
8.
Hemodialysis or peritoneal dialysis (current or planned within the 
next 6 months).
9.
Documented liver disease, or active hepatitis (i.e. alanine 
transaminase or aspartate transaminase >3 times the upper limit of 
normal range).
10. Current or recent (within 3 years) malignancy with exception of basal 
cell carcinoma or squamous cell carcinoma of the skin, or cervical 
intraepithelial neoplasia.
11. Known gastrointestinal bleeding. Patients with screening ferritin 
<15ng/ml must have an appropriate evaluation within 3 months of 
screening.
12. Female participant of child-bearing potential who is pregnant, 
lactating, or not willing to use adequate contraceptive precautions 
during the study and for up to 5 days after the last scheduled dose of
study medication. 
13. Inability to return for follow up visits within the necessary windows 


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version: 1.0, 12 January 2017
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Study Drug 
Administration
Initial treatment will occur on Day 0 (date of randomization) and Day 7. 
On Day 0 and Day 7, Group A (FCM) will receive a 750 mg undiluted
blinded dose of IV FCM at the rate of approximately 100 mg (2 
mL)/minute; Group B (placebo) will receive a blinded placebo (15 cc of 
normal saline) IV push at 2 mL/minute. Participants in Group A with 
body weight <50 kg (110 pounds) will have individual FCM doses 
adjusted to 15 mg/kg, not to exceed an individual dose of 750 mg, or a
cumulative dose of 1500 mg per treatment cycle.
All participants will be dosed every 6 months for the duration of the trial.
Participants randomized to the FCM arm will be dosed as indicated based 
on hemoglobin (Hgb) levels (i.e. Hgb <13.5 g/dl [females] or <15.0 g/dl 
[males)]) and iron studies (i.e. serum ferritin <100 ng/mL or 100 to 300 
ng/mL with TSAT <20%). Participants not meeting post- randomization
lab criteria for blood counts and iron studies and all participants
randomized to the placebo arm will be administered IV placebo at each 
visit.
Unblinded site personnel, responsible for preparation and administration 
of the FCM or Placebo, will ensure that the participant and all blinded site 
staff are not able to observe the preparation or administration of study 
treatment.
Patient
Assessments             
Efficacy and Safety Follow-up:  All participants will be followed from the 
time of randomization until completion of the trial.  The last participant
randomized will be followed for 12 months. After treatment on Day 0 
and Day 7, participants will be evaluated at 3 month intervals (in person 
or via telephone), with additional dosing administered every 6 months as 
applicable (based on dose regimen below). In a subset of sites, all 
participants will return for recurrent laboratory assessment (chemistry, 
hematology, and iron indices) at Day 21 (± 7) after each course of 
investigational treatment.  Hematology, ferritin, and transferrin saturation 
(TSAT) laboratory assessments will be performed in all participants, with 
appropriate safety evaluations, to determine if additional treatment will 
occur at 6 month intervals. At the conclusion of the study all participants
will be assessed for the occurrence of any potential endpoint or serious 
adverse events.  Attempts to determine Vital Status, including endpoint 
ascertainment, for participants who are lost to follow-up or withdrawn 
will be made via a search of available public records, and other 
appropriate investigative techniques, including the potential use of third 
party vendors as described in the informed consent form and in 
accordance with applicable regulatory requirements.
Primary
Endpoint:
Hierarchical composite of 1) death, 2) hospitalization for heart failure (as 
defined in section 10.2), or 3) change in 6MWT. (Death and 
hospitalizations  for heart failure will be evaluated at one year, Change in 
6MWT will be evaluated at 6 months) and tested using the nonparametric 
Wilcoxon-type test.


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version: 1.0, 12 January 2017
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Secondary
Endpoints 
1.
Time to first event of the composite of cardiovascular death or heart 
failure hospitalization. The composite endpoint will be composed of 
adjudicated occurrence (as defined in section 10.2) of one of the 
following:
a. Cardiovascular Death
i.
Death due to Heart Failure
ii.
Death due to Acute Myocardial Infarction
iii.
Sudden Cardiac Death
iv.
Death due to Stroke
v.
Death due to other Cardiovascular Causes
b.
Hospitalization for Worsening Heart Failure
2.
Mean change in 6MWT from baseline to 12 months
3.
Time to first event of the composite of cardiovascular death or 
intervention for worsening heart failure (hospitalization or urgent 
heart failure visits)
4.
Time to first event of the composite of cardiovascular death and 
cardiovascular hospitalizations
5.
Time to cardiovascular death
Additional events to be adjudicated for analysis of the secondary endpoints 
include:
a)
Non-cardiovascular death
b) Hospitalization for myocardial infarction
c)
Hospitalization for stroke
d) Other cardiovascular hospitalizations
e)
Urgent heart failure visits
All events are operationally defined in Section 10.2. Events will be confirmed by 
the Clinical Events Classification (CEC) Committee of the Duke Clinical 
Research Institute (DCRI)
Study duration 
per participant:
Screening Phase:  up to 28 days prior to randomization.
Post randomization phase: Variable with a minimum of 365 Days.
Study Sites:
Approximately 200
Participant Number:
Approximately 3014


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Protocol No.: 1VIT15043
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version: 1.0, 12 January 2017
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Figure 1. Study Diagram


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version: 1.0, 12 January 2017
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS .........................................................................................................12 
1.0 INTRODUCTION ....................................................................................................................14 
1.1 HEART FAILURE WITH IRON DEFICIENCY .............................................................................................14 
1.2 TREATMENT OF IRON DEFICIENCY IN HEART FAILURE.........................................................................14 
1.3  INJECTAFER® (FERRIC CARBOXYMALTOSE) ........................................................................................15 
1.3.1 
KEY FEATURES OF FERRIC CARBOXYMALTOSE ...........................................................................15 
1.3.2 
INJECTAFER® VERSUS OTHER PARENTERAL IRON AGENTS ..........................................................15 
1.3.3 
INJECTAFER® HUMAN EXPERIENCE..............................................................................................15 
2.0 TRIAL OBJECTIVE.................................................................................................................16 
2.1 PRIMARY OBJECTIVE ............................................................................................................................16 
2.2 SECONDARY OBJECTIVE .......................................................................................................................16 
3.0 OVERALL STUDY DESIGN AND RATIONALE.................................................................16 
3.1 OVERALL STUDY DESIGN .....................................................................................................................16 
3.2 RATIONALE OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS.....................................................17 
3.3  SCHEDULE OF EVENTS..........................................................................................................................18 
4.0 PARTICIPANT SELECTION ..................................................................................................19 
4.1 NUMBER AND TYPE OF PARTICIPANTS..................................................................................................19 
4.2 SCREENING PHASE................................................................................................................................19 
4.2.1 Inclusion Criteria.........................................................................................................................19 
4.2.2 Exclusion Criteria........................................................................................................................20 
4.3 PARTICIPANT ASSIGNMENT AND RANDOMIZATION PROCESS ...............................................................20 
4.4 WITHDRAWAL FROM STUDY.................................................................................................................21 
4.5 DISCONTINUATION FROM STUDY DRUG ...............................................................................................21 
4.6 PARTICIPANTS DEEMED LOST TO FOLLOW-UP......................................................................................21 
4.7 CONCOMITANT INTERVENTION.............................................................................................................22 
5.0 STUDY DRUG .........................................................................................................................22 
5.1 FORMULATION, PACKAGING AND STORAGE .........................................................................................22 
5.2 DRUG ADMINISTRATION/REGIMEN.......................................................................................................22 
5.3 IV MEDICATION PRECAUTIONS ............................................................................................................23 
5.4 DRUG ACCOUNTABILITY ......................................................................................................................23 
5.5 CONCOMITANT MEDICATION................................................................................................................23 
5.6 BLINDING ALL PARTICIPANTS AND BLINDED STUDY STAFF WILL BE BLINDED TO THE CONTENT OF 
STUDY DRUG FOR THE DURATION OF THE TRIAL. ..................................................................................24 
6.0 STUDY PROCEDURES...........................................................................................................24 
6.1 INFORMED CONSENT ............................................................................................................................24 
6.2 SCREENING PHASE (DAY -28 TO DAY 0)...............................................................................................24 


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6.2.1 Screening  Visit ............................................................................................................................24 
6.3 TREATMENT PHASE (DAY 0 TO DAY 7).................................................................................................25 
6.3.1 Day 0 Visit....................................................................................................................................25 
6.3.2 Day 7 Visit....................................................................................................................................26 
6.4 FOLLOW-UP PHASE ..............................................................................................................................27 
6.4.1   Chemistry Laboratory Collection Subset -Day 21 (± 7).............................................................27 
6.4.2   90 Day Follow-Up .....................................................................................................................27 
6.4.3   6 Month Laboratory Evaluation.................................................................................................27 
6.4.4 ADDITIONAL STUDY DRUG DOSING (EVERY 6 MONTHS) ..................................................................27 
6.4.4.1 
6 Month Dosing Visit #1 (Days 180+7, 360+7, 540+7, 660+7, 840+7, 1,020+7…EOS) 27 
6.4.4.2 
Six Month Dosing Visit #2 (Days 187+7, 367+7, 547+7, 667+7, 847+7, 1,027+7…EOS)
28 
6.5  END OF STUDY VISIT............................................................................................................................29 
6.6 LABORATORY ASSESSMENTS................................................................................................................29 
7.0 ASSESSMENT OF SAFETY ...................................................................................................30 
7.1 ADVERSE EVENTS.................................................................................................................................30 
7.2 REPORTING OF ADVERSE EVENTS.........................................................................................................31 
7.3 SERIOUS ADVERSE EVENTS ..................................................................................................................32 
7.4 REPORTING OF SUSPECTED STUDY ENDPOINT EVENTS THAT MAY REQUIRE ADJUDICATION...............33 
8.0 STATISTIC33 
8.1 STRATIFICATION/RANDOMIZATION ......................................................................................................33 
8.2 ANALYSIS POPULATIONS ......................................................................................................................34 
8.3 DISPOSITION AND BASELINE CHARACTERISTICS...................................................................................34 
8.4 ENDPOINTS AND DEFINITIONS ..............................................................................................................34 
8.4.1 Primary Outcome.........................................................................................................................34 
8.5 SECONDARY OUTCOMES.......................................................................................................................34 
8.6 PRIMARY COMPARISON ........................................................................................................................35 
8.7 SECONDARY COMPARISONS..................................................................................................................36 
8.7.1 Top Secondary Comparison: Time to first event of cardiovascular death or hospitalization of 
heart failure ..........................................................................................................................................36 
8.7.2 Change in 6 Minute Walk Test.....................................................................................................36 
8.7.3 Secondary Outcomes based on time to first event........................................................................36 
8.8 SAMPLE SIZE AND STATISTICAL POWER...............................................................................................37 
8.10 STOPPING RULES AND INTERIM ANALYSIS .........................................................................................39 


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9.0 ADMINISTRATIVE CONSIDERATIONS .............................................................................39 
9.1 RETENTION AND AVAILABILITY OF RECORDS.......................................................................................39 
9.2 INVESTIGATOR RESPONSIBILITIES.........................................................................................................40 
9.3 FINANCIAL DISCLOSURE.......................................................................................................................40 
9.4 ADVERTISEMENT FOR PARTICIPANT RECRUITMENT .............................................................................40 
9.5 DOCUMENTS REQUIRED FOR STUDY INITIATION ..................................................................................41 
9.6 QUALITY CONTROL AND QUALITY ASSURANCE...................................................................................41 
9.6.1 Investigator Selection Criteria.....................................................................................................41 
9.6.2 Clinical Monitoring......................................................................................................................41 
9.6.3 Quality Assurance Audit ..............................................................................................................42 
9.7 ETHICS..................................................................................................................................................42 
9.7.1 Ethical and Legal Issues ..............................................................................................................42 
9.7.2 Institutional Review Board...........................................................................................................42 
9.7.3 Informed Consent.........................................................................................................................43 
9.7.4 Good Clinical Practice ................................................................................................................43 
9.8 DATA HANDLING AND RECORD KEEPING.............................................................................................43 
9.8.1 
Case Report Form ..................................................................................................................43 
9.8.2 Confidentiality..............................................................................................................................43 
9.8.3 Termination of the Study..............................................................................................................44 
9.8.4 Protocol Revisions .......................................................................................................................44 
9.8.5 Protocol Administrative Changes ................................................................................................44 
9.9 PUBLICATION POLICY...........................................................................................................................44 
10.0  GOVERNANCE COMMITTEES..........................................................................................45 
10.1 STEERING COMMITTEE (SC) ..............................................................................................................45 
10.2 ADJUDICATION BY THE CLINICAL ENDPOINT CLASSIFICATION (CEC) COMMITTEE ...........................45 
10.2.1 Death..........................................................................................................................................46 
10.2.1.1 Death Due to Cardiovascular Death ......................................................................................46 
10.2.1.2 Death Due to Heart Failure....................................................................................................46 
10.2.1.3 Death Due to Acute Myocardial Infarction.............................................................................46 
10.2.1.4 Sudden Cardiac Death ............................................................................................................47 
10.2.1.5  Death Due to Stroke...............................................................................................................47 
10.2.1.6 Death Due to Other Cardiovascular Causes ..........................................................................48 


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10.2.1.7 Non-Cardiovascular Death.....................................................................................................48 
10.2.1.8 Undetermined Cause of Death................................................................................................48 
10.2.2 
CARDIOVASCULAR HOSPITALIZATIONS...................................................................................48 
10.2.2.1 
Hospitalization for Heart Failure.....................................................................................48 
10.2.2.2  Hospitalization for Myocardial Infarction.............................................................................49 
10.2.2.3 Hospitalization for Stroke .......................................................................................................50 
10.2.2.4 Other Cardiovascular Hospitalizations ..................................................................................50 
10.2.3 OTHER EVENTS: URGENT HEART FAILURE VISIT............................................................................51 
10.3 DATA AND SAFETY MONITORING BOARD (DSMB)............................................................................51 
INVESTIGATOR’S ACKNOWLEDGEMENT.............................................................................52 


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LIST OF ABBREVIATIONS
6MWT
Six Minute Walk Test
AE
Adverse event
ALT
Alanine Aminotransferase
AST
Aspartate aminotransferase
BNP
Brain Natriuretic Peptide
BP
Blood Pressure
BUN
Blood urea nitrogen
CABG
Coronary Artery Bypass Grafting
cc
cubic centimeter
CEC
Clinical Events Classification
CFR
Code of Federal Regulations
CI
Confidence Interval
CKD
Chronic Kidney Disease
CK-MB                                                 
Creatine Kinase-Myocardial Band
cm
Centimeter
CRF
Case Report Form 
CRT                                                          Cardiac Resynchronization Therapy
CV 
Cardiovascular
DCRI
Duke Clinical Research Institute
dL
Deciliter
DSMB
Data and Safety Monitoring Committee
EC
Ethics Committee 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
e.g.
For example
EOS
End of Study
EU
European Union
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
HF
Heart Failure
Hg
Mercury
Hgb
Hemoglobin
ICD
Implantable Cardioverter-Defibrillator
ICH
International Conference on Harmonisation
i.e.
that is
IND
Investigational New Drug Application
IRB
Institutional Review Board
IV
Intravenous
IRT
Interactive Response Technology
ITT
Intention to Treat
KCCQ
Kansas City Cardiomyopathy Questionnaire
Kg
Kilogram
L
Liter


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LBBB
Left Bundle-Branch Block
LDH
Lactic dehydrogenase
LVEF
Left Ventricular Ejection Fraction
LVOT
Left Ventricular Outflow Tract
MB
Myocardial b Fraction
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
m
Meter
mg 
Milligram
MHRA
Medicines and Healthcare Products Regulatory Agency
MI
Myocardial Infarction
mL
Milliliter
ng
Nanogram
NS
Normal Saline
NT-proBNP
N-Terminal Prohormone of Brain Natriuretic Peptide
NYHA
New York Heart Association
                                                                        
PCI                                                           Percutaneous Coronary Intervention                                                                   
pg 
Picogram
PGA
Patient Global Assessment                                                                                  
PTH
Parathyroid Hormone
RBC
Red blood cell
RDW
Red (cell) distribution width
SAE
Serious Adverse Event
SC
Steering Committee
TIBC
Total Iron Binding Capacity
TSAT
Transferrin Saturation
TVI
Time Velocity Integral
ULN
Upper Limit of the Normal
US
United States
USP
United States Pharmacopeia
UK
United Kingdom
WBC
White Blood Cell
w/v
weight / volume


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1.0 INTRODUCTION
1.1 Heart Failure with Iron Deficiency
Over 5 million people in the United States (US) live with heart failure. Epidemiological studies in 
heart failure suggest a 50% prevalence of either absolute iron deficiency, defined as serum ferritin 
<100 ng/mL, or functional iron deficiency, defined as a ferritin 100 to 300 ng/mL with transferrin 
saturation (TSAT) <20% [van Veldhuisen 2011; Ebner 2013]. The prevalence of iron deficiency 
increases with the severity of heart failure and etiologies include insufficient dietary iron, poor 
iron absorption, gastrointestinal blood loss, chronic disease, and repeated blood sampling for 
ongoing medical evaluation of heart failure and comorbid conditions.
Alteration in iron homeostasis has been identified as an independent risk factor for mortality in 
patients with heart failure [Okonko 2011; Jankowska 2013]. It is hypothesized that reduced 
oxygenation, combined with insufficient iron for appropriate oxygen transportation and storage, 
may have additive untoward effects on oxidative metabolism and cellular immune mechanisms in 
this population. Iron deficiency may also increase the risk of thrombosis and mortality among 
patients in heart failure with iron deficiency [Streja 2008]. 
1.2 Treatment of Iron Deficiency in Heart Failure
Evidence in support of the therapeutic value of intravenous (IV) iron repletion with ferric 
carboxymaltose (FCM) for patients in heart failure with a reduced ejection fraction and iron 
deficiency is provided by 4 European studies: FER-CARS-01, FER-CARS-02 (FAIR-HF), FER-
CARS-03 (EFFICACY-HF), and FER-CARS-05 (CONFIRM-HF). In addition to measures of 
iron repletion and hemoglobin changes, these studies focused on changes from baseline in New 
York Heart Association (NYHA) functional class, Patient Global Assessment (PGA), and the 6-
minute walk test (6MWT).
In the most recent of the studies, CONFIRM HF, a total of 301 participants (150 FCM, 151 
placebo) were treated for up to 52 weeks (longest duration among the 4 studies). The primary 
efficacy analysis confirmed the benefit of FCM relative to placebo for the improvement in 6MWT 
distance at Week 24, with a comparative difference (FCM versus placebo) in the change from 
baseline reported as least squares mean (± standard error) of 33.2 ± 10.52 m (p=0.002). The 
treatment benefit of FCM versus placebo in 6MWT distance was sustained through to Week 52 
(pDQGZDVFRQVLVWHQWDFURVVVXEJURXSV Commensurate with the improvement in 6MWT 
distance, improvements in PGA, NYHA functional class, overall Kansas City Cardiomyopathy 
Questionnaire (KCCQ) score, and fatigue score were seen in FCM-treated participants as
compared to placebo-treated participants. Treatment with FCM versus placebo was also 
associated with a significant reduction in the risk of hospitalization due to worsening heart failure 
(hazard ratio: 0.40; 95% confidence interval [CI]: 0.2 to 0.8; p=0.009) and a significant reduction 
in the risk of first hospitalization due to worsening heart failure or all-cause death (hazard ratio: 
0.53; 95% CI: 0.30 to 0.95; p = 0.03). Similar trends for reduction in hospitalization were 
reported for FCM and iron sucrose [Kapoor 2013].
A meta-analysis of these four trials was conducted to assess the association of FCM exposure with 
morbidity and mortality [Anker 2015]. The analysis included individual participant pooled data 
for 839 participants, 504 of whom with FCM exposure versus 335 with placebo exposure. The 
primary endpoint was defined as the composite outcome of cardiovascular death and 
cardiovascular hospitalization. Participants randomized to FCM had a lower rate of 
cardiovascular death and cardiovascular hospitalization compared to placebo, with a rate ratio of 
0.59 (95% CI: 0.40 to 0.88; p=0.009) in a recurrent events analysis. Additionally, exposure to 


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FCM was associated with reduced cardiovascular death and hospitalization for heart failure, with a 
rate ratio of 0.53 (95% CI: 0.33 to 0.86; p=0.011) and all-cause death and cardiovascular 
hospitalization, with a rate ratio of 0.60 (95% CI: 0.41 to 0.88; p=0.009). 
The four European trials, together with the meta-analysis, suggest that IV iron repletion as 
treatment for patients in reduced left ventricular ejection fraction with iron deficiency is associated 
with improvement in functional health (the 6MWT), patient-reported outcomes, morbidity defined 
as cardiovascular hospitalization, and mortality. Given that FCM is approved by the US Food and 
Drug Administration (FDA) for use in iron-deficiency anemia [US Package Insert], a clinical 
development program is proposed seeking FDA approval for FCM as treatment for patients in 
heart failure with reduced ejection fraction who have iron deficiency.
1.3
Injectafer® (Ferric Carboxymaltose)
1.3.1
Key Features of Ferric Carboxymaltose
Injectafer® (FCM) is a stable Type I polynuclear iron (III)-hydroxide carbohydrate complex 
developed as an IV iron replacement therapy for the treatment of iron deficiency anemia. After IV 
administration, FCM is mainly found in the reticuloendothelial system which includes the liver, 
spleen, and bone marrow.  The iron slowly dissociates from the complex and can be efficiently 
used in the bone marrow for hemoglobin synthesis.  The carbohydrate moiety of FCM is 
metabolized by the glycolytic pathway.  FCM is approved for the treatment of iron deficient 
anemia, and is an investigational product in this study for patients in heart failure with iron 
deficiency.
1.3.2
Injectafer® versus Other Parenteral Iron Agents
There is considerable efficacy and safety experience with the various available parenteral iron 
preparations. However, prior to the approval of non-dextran formulations, the risk of systemic 
adverse reactions restricted IV iron use.  The use of FCM offers significant advantages compared 
to other available IV iron preparations. Due to its structure, Injectafer® is more stable than iron 
gluconate and iron sucrose resulting in a slow delivery of the complexed iron to endogenous iron 
binding sites. In animals, FCM has approximately 1/5th the acute toxicity that has been reported 
for iron sucrose.  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 fewer 
administrations to replenish iron stores, and convenient outpatient use. In the EU, ferumoxytol 
has been withdrawn from use and in the US, it has been given a black box warning.
1.3.3
Injectafer® Human Experience 
The Injectafer® clinical development program demonstrated the effectiveness and safety of 
Injectafer® in the treatment of iron-deficiency anemia.  The drug is approved for the treatment of 
iron deficiency anemia in adult populations who have intolerance to oral iron, have had 
unsatisfactory responses to oral iron, or who have non-dialysis dependent CKD. Clinical data are 
currently available from 20 Phase 2 and 3 studies including 5,799 patients, with iron deficient 
anemia or iron deficiency anemia associated with CKD who received Injectafer®
A clinical pharmacokinetic study (VIT-IV-CL-001) using positron emission tomography 
demonstrated a fast initial elimination of radioactively labeled iron (Fe) 52Fe/59Fe Injectafer (FCM)
from the blood, with rapid transfer to the bone marrow and rapid deposition in the liver and 
spleen.  Eight hours after administration, 5 to 20% of the injected amount of radioactively-labeled 
Fe was still detected in the blood.


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Important details of pre-clinical safety and efficacy and clinical safety and efficacy can be found 
in the Investigator’s Brochure.  Ferric carboxymaltose received approval from the United 
Kingdom (UK) Medicines and Healthcare Products Regulatory Agency (MHRA) on June 15, 
2007 (EU Trade name: Ferinject).  Injectafer® now has marketing authorization in 70 countries,
and is currently marketed in 61 of these countries.  Injectafer® received approval for the treatment 
of iron-deficiency anemia from the US (FDA) on July 25, 2013.
2.0 TRIAL OBJECTIVE
2.1 Primary Objective
To determine the efficacy and safety of iron therapy using intravenous (IV) FCM, relative to 
placebo, in the treatment of patients in heart failure with reduced ejection fraction and with iron 
deficiency.
2.2 Secondary Objective
To evaluate the effect of IV FCM, relative to placebo, on the functional capacity of patients in 
heart failure with reduced ejection fraction and with iron deficiency.
3.0 OVERALL STUDY DESIGN AND RATIONALE
3.1 Overall Study Design 
This is a double-blind, multicenter, prospective, randomized, placebo-controlled study to assess 
the effects of IV FCM compared to placebo on the 12-month rate of death and hospitalization for 
worsening heart failure, and change in 6MWT at 6 month for patients in heart failure with reduced 
ejection fraction and with iron deficiency.
After an initial screening period of up to 28 days, eligible participants will be stratified by region 
and randomized in a 1:1 ratio to FCM or placebo. Study drug administration will occur on Day 0 
and Day 7 as an undiluted slow IV push, with additional study visits (in person or via telephone) 
planned at 3 month intervals, and additional dosing administered every 6 months as applicable
(based on dose regimen below). In a subset of sites, all participants will return for recurrent 
laboratory assessment (chemistry, hematology, and iron indices) at Day 21 (± 7) after each course 
of investigational treatment. For all participants, hematology, ferritin and transferrin saturation 
(TSAT), with appropriate safety evaluations, to determine additional treatment, will occur at 6 
month intervals.
Initial treatment will occur on Day 0 and Day 7. On Day 0 and 7, Group A (FCM) will receive a 
750 mg undiluted, blinded dose of IV FCM at the rate of approximately 100 mg (2 mL)/minute; 
Group B (placebo) will receive a blinded placebo (15 cc of normal saline) IV push at 2 
mL/minute. Participants in Group A with body weight <50 kg (110 pounds) will have individual 
FCM doses adjusted to 15 mg/kg, not to exceed an individual dose of 750 mgs or a cumulative 
dose of 1500 mg per treatment cycle.
All participants randomized will be dosed every 6 months.  Participants randomized to the FCM 
arm will be dosed as indicated based on hemoglobin levels (i.e. Hgb <13.5 g/dl [females] or <15.0
g/dl [males)]) and iron studies (i.e. serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT 
<20%). Participants not meeting pre-specified laboratory criteria for blood counts and iron studies 


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and all participants randomized to the placebo arm will be administered IV placebo infusion at 
each visit.
Unblinded site personnel, responsible for preparation and administration of the FCM or Placebo, 
will ensure that the participant and all blinded site staff are not able to observe the preparation or 
administration of study treatment.
3.2 Rationale of Study Design and Choice of Control Groups 
Since FCM is being studied as a treatment for heart failure patients with a reduced ejection 
fraction and comorbid iron deficiency, it is important to establish its efficacy and safety in terms 
of clinically significant endpoints including cardiovascular morbidity.
This study will assess the efficacy and safety of FCM as a treatment for participants in heart 
failure with reduced ejection fraction and concomitant iron deficiency by comparing the proposed 
regimen to placebo (normal saline). The placebo arm is justified as participants will be maintained 
on the maximally tolerated background therapy for heart failure with a reduced ejection fraction.


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3.3
Schedule of Events
Abbreviations:  EOS = End of Study; FCM = ferric carboxymaltose; IV = intravenous; NT-proBNP = N-terminal 
pro-brain natriuretic peptide; PTH = Parathyroid Hormone;
a
Visits will be repeated every 180 days for the duration of the study
b
Visit should not be performed if it would occur within 30 days of the EOS visit.
c
EOS visit for all participants will be scheduled once the last participant has reached 6 months on study and 
the anticipated number of outcome events (section 8) reaches 840.
d
On study drug dosing days vital signs will be collected predose, immediately postdose, and 30 minutes 
postdose.
e
Height assessed at Day 0 only; weight assessed at Day 0 and prior to each dosing cycle.
f.
Females of childbearing potential
g.
Historical value can be used if performed within 12 months of screening visit (or 24 months if LVEF 
, must be performed at least 12 weeks after major cardiac intervention-including CABG, valvular 
intervention, or cardiac resynchronization therapy device implantation.
h.
Screening laboratory measures may be performed locally all other visits will be analyzed through a central 
laboratory
Screening
Treatment 
Phase
Follow-up Phase
Study Procedures
Select 
Sites 
only
Select 
Sites 
only
Days
-28
to -1
0
7+2
21
+7a,k
90 +14a,b,l 160-178 a,b 180+7 a,b 187 +7 a,b
201
+7a,k
EOSc
Informed consent
X
Inclusion/exclusion criteria
X
Xj
Demographics
X
Targeted medical history
X
Targeted Physical Exam
Xj
X
Vital signs 
Xd
Xd
Xd
Xd
X
Height (cm) & weight (kg)e
Xj
X
Urine pregnancy testf
Xj
X
X
Vitamin D and PTHk
X
Left ventricular ejection fraction
Xg
Randomizationn
X
Hematology laboratoryh
X
X
X
X
X
X
Chemistry laboratoryh
X
X
X
X
X
Iron indicesh
X
X
X
X
X
X
6 Minute Walk Test
Xj
Xm
NT-proBNPh
X
X
X
X
Serious Adverse Event reporting
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
IV FCM/ IV Placebon
X
X
Xi
Xi


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i
All participants randomized will be dosed every 6 months.  Participants randomized to the FCM arm will be 
dosed as indicated based on blood counts (i.e. Hgb <13.5 g/dL [females] or <15.0 g/dL [males)]) and iron 
studies (i.e. serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT <20%). Participants not meeting 
pre-specified laboratory criteria for blood counts and iron studies and all participants randomized to the 
placebo arm will be administered IV placebo infusion at each visit. The second of the 2 dosing visits should 
occur at Day 7+2 after the first dose.
j.
Prior to randomization
k
Only for participants at select sites performing additional chemistry labs on Day 21 (+7) post dosing.
l.
May be performed via telephone or in person.
m.
Performed at Day 180 and Day 360 visits only.
n.
To be performed by unblinded site personnel.  All other procedures must be performed by personnel blinded 
to the treatment assignment
4.0 PARTICIPANT SELECTION
4.1 Number and Type of Participants
The study cohort will comprise approximately 3,014 participants in heart failure with iron 
deficiency who fulfill the inclusion criteria, do not meet any of the exclusion criteria, and who 
have given written informed consent.
4.2 Screening Phase
Once a participant signs the informed consent document and enters the screening phase, a unique 
screening number will be assigned via an interactive response technology (IRT) system.
4.2.1 Inclusion Criteria
1.
Adult (18 years of age) able to provide informed consent
2.
Stable heart failure (NYHA II-IV) on maximally-tolerated 
background therapy (as determined by the site principle investigator) 
for at least 4 weeks with no dose changes in heart failure drugs during 
the last 2 weeks. 
3.
Able and willing to perform a 6MWT at the time of randomization. 
4.
Reduced left ventricular ejection fraction. Assessment must be 
performed at least 12 weeks after major cardiac surgical intervention 
including coronary artery bypass graft (CABG), valvular 
repair/replacement, or cardiac resynchronization therapy (CRT) 
device implantation.
a.
Left ventricular ejection fraction 5% obtained during the 
screening visit OR either of the following
i.
Historical value of ejection fraction ZLWKLQ
months of screening visit
ii.
Historical value of ejection fraction ZLWKLQ
months of screening visit 
5.
Hemoglobin >9.0 g/dl and <13.5 g/dl (females) or <15.0 g/dl (males)
6.
Serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT <20%. 
7.
Either documented hospitalization for heart failure within 12 months 
of enrollment OR screening visit N-terminal-pro-brain natriuretic 
peptide (NT-proBNP) > 600 pg/ml (or BNP > 200 pg/mL) for
patients with normal sinus rhythm or >1000 pg/ml (or BNP > 400 
pg/mL) for patients with normal sinus rhythm or >1000 pg/ml for 
patients with atrial fibrillation. NOTE: NT-proBNP must be used to 
confirm eligibility for patients taking sacubitril/valsartan.


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4.2.2 Exclusion Criteria
1.
Current or planned oral iron supplementation. Iron-containing 
multivitamins (< 30 mgs /day) are permitted.
2.
Known hypersensitivity reaction to any component of FCM.
3.
History of acquired iron overload, or the recent receipt (within 3 
months) of erythropoietin stimulating agent, IV iron therapy, or blood 
transfusion.
4.
Acute myocardial infarction, acute coronary syndrome, transient 
ischemic attack, or stroke within 3 months of enrollment.
5.
Uncorrected severe aortic stenosis, severe valvular regurgitation, or 
left ventricular outflow obstruction requiring intervention.
6.
Current atrial fibrillation or atrial flutter with a mean ventricular 
response rate >100 per minute (at rest).
7.
Current or planned mechanical circulatory support or heart 
transplantation.
8.
Hemodialysis or peritoneal dialysis (current or planned within the 
next 6 months).
9.
Documented liver disease or active hepatitis (i.e. alanine transaminase 
or aspartate transaminase >3 times the upper limit of normal range).
10. Current or recent (within 3 years) malignancy with exception of basal 
cell carcinoma or squamous cell carcinoma of the skin, or cervical 
intraepithelial neoplasia.
11. Known gastrointestinal bleeding.  Patients with screening ferritin <15 
ng/ml must have an appropriate evaluation within 3 months of 
screening.
12. Female participants of child-bearing potential who is pregnant, 
lactating, or not willing to use adequate contraceptive precautions 
during the study and for up to 5 days after the last scheduled dose of 
study medication.
13. Inability to return for follow up visits within the necessary windows 
4.3 Participant Assignment and Randomization Process
Participants who meet all inclusion requirements and no exclusionary criteria will be offered 
enrollment in this study. Enrolled participants will be stratified by region and randomized in a 1:1 
ratio to receive either IV FCM or IV Placebo.
The FCM Group will initially receive 2 blinded doses of FCM at 15 mg/kg to a maximum of 750 
mg per dose for a maximum total dose of 1500 mg. 
The Placebo Group will receive 2 blinded doses of 15 mL of normal saline.
Participants and blinded study staff will remain blinded to the treatment assignment for the 
duration of the study.


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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
At time of withdrawal from the study, procedures for the EOS visit must be immediately 
performed regardless of whether the participant has completed study drug treatment. Information
collected previously as part of the study will be retained unless the patient specifically withdraws 
consent, in writing. The participant should be contacted at the end of the study to assess for the 
occurrence of any potential endpoint events. Additionally, if the participant cannot be contacted,
attempts to determine the Vital Status will be performed via a search of available public records,
third party vendor search, medical record review, additional contacts provided by the patient, and 
other appropriate investigative techniques as described in the informed consent form and in 
accordance with applicable regulatory requirements.
In event of site closure, participants will be asked to agree to follow up at another research site, if 
available, or for follow up by via a patient follow -up group. 
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 endpoint and safety events.
If a participant permanently discontinues investigational product and is unable to attend visits in-
person, he/she will be contacted by telephone, or other methods to assess study outcomes and vital 
status, unless the participant has specifically withdrawn consent for all forms of contact. Every 
effort should be made to educate the participants on the importance of remaining in the study and 
attending scheduled study visits including those required after early discontinuation of 
investigational product. Other participant follow-up options to collect study outcomes and vital 
status should be pursued according to local laws and regulations. If one of these alternate methods 
to collect study outcomes and vital status is acceptable to the participant, then the participant will
be deemed not to have withdrawn consent for follow-up.
4.6 Participants Deemed Lost to Follow-up
Investigators should make every effort to contact participants who are deemed lost to follow-up
and who have not withdrawn consent to follow-up contacts, including medical record review, 
pursuing any alternative contact methods permitted by local regulations. Where permitted, a third
party may be used to locate alternative participant contact information that will be provided to the 
investigator. All attempts to contact participants will be documented in the participant’s source 
notes.
Should a participant fail to attend the clinic for a required study visit, the site should attempt to 
contact the participant and re-schedule the missed visit as soon as possible. The site should also 
counsel the participant on the importance of maintaining the assigned visit schedule. In cases 
where the participant does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the participant. Should 
the participant continue to be unreachable, then and only then, will he/she be considered “Lost to 


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Follow-up.” Nonetheless, efforts to attempt to locate and contact the participant, and to ascertain 
the participant’s vital status will continue until trial completion.
4.7 Concomitant Intervention
Concomitant intervention is defined as follows:
x
Blood transfusion.
x
Use of IV iron outside of protocol.
When concomitant intervention occurs, the date of the intervening event should be recorded in the 
source documents, and the eCase Report Form (eCRF). The participant should continue in the
study as scheduled.
5.0 STUDY DRUG 
5.1 Formulation, Packaging and Storage
All investigational medication to be used in this study [supplied by Luitpold Pharmaceuticals, 
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 -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.  
Placebo (normal saline) will be supplied as 15 ml vials.
All IV study drugs (FCM and Normal Saline) must be kept in a secure place at the investigational 
site, and stored at room temperature (see USP).  The study medication should not be frozen.  Vials 
may not be used for more than 1 dose, or for more than 1 participant. All vials (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 Luitpold Pharmaceuticals, Inc.  
5.2 Drug Administration/Regimen 
The Principal Investigator or designee will supervise administration of the study drug to 
participants.  The participants should remain blinded to the identity of the study drug for the 
duration of the trial.
Group A: 
Group A (FCM) will receive a 750 mg undiluted blinded dose of IV FCM at the 
rate of approximately 100 mg (2 mL)/minute on Day 0 and Day 7; Participants in 
Group A with body weight <50 kg (110 pounds) will have individual FCM doses 
adjusted to 15 mg/kg, not to exceed an individual dose of 750 mg or a cumulative 
dose of 1500 mg per treatment cycle.


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Group B: 
Group B (placebo) will receive a blinded placebo (15 cc of normal saline) IV push 
at 2 mL/minute on Day 0 and Day 7.
All participants will be dosed every 6 months.  At each 6-month interval, 2 doses of study drug 
will be administered as described above for Day 0 and Day 7.  The same randomized treatment 
will be administered if Hgb <13.5 g/dL (females) or <15.0 g/dL (males) and serum ferritin <100 
ng/mL or 100 to 300 ng/mL with TSAT <20%; placebo will be administered to participants in the 
FCM group who do not meet the above criteria. 
Site personnel will ensure the participant and blinded study staff are not able to observe the 
preparation or administration of study treatment injections.
5.3 IV Medication Precautions
When administering FCM or Placebo, the following precautions will be taken:
x
The participant will be evaluated clinically prior to drug administration to assess the 
development of clinically significant conditions.  
x
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.
x
Heart rate and blood pressure will be assessed pre-, immediately post, and 30 minutes
post administration. Participants will be discharged from the site by the Investigator
or his or her designee only if there are no significant signs or symptoms 30 minutes 
after the administration is completed.
x
The participant will be monitored for at least 30 minutes for serious acute reactions as 
hypersensitivity or bioactive (labile) iron reactions to non-dextran IV iron products 
have rarely been reported. The reactions include: hypotension, loss of consciousness, 
bronchospasm with dyspnea, shortness of breath, and seizures.
o
In the event a serious acute reaction is seen, the site must have the capability 
to provide appropriate resuscitation measures.  These may include IV NS, IV 
epinephrine, steroids, and/or antihistamines.
5.4 Drug Accountability
Investigators will keep records of the receipt, administration and return of the study drug (FCM).
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 randomized in the study, or to investigators not listed on the FDA 1572. When the study is 
completed, or if it is prematurely terminated, a final inventory of all clinical supplies must be 
compiled and the remainder of the unused study drug will be returned to Luitpold 
Pharmaceuticals, 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 eCase Report Form (eCRF).


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No prophylactic medications specifically for administration of study drug may be administered 
prior to study drug administration without prior approval from Luitpold Pharmaceuticals, Inc.  
Other standard therapies are permitted. 
5.6 Blinding
All participants and blinded study staff will be blinded to the content of study drug for the 
duration of the trial.
During the period of study drug administration, the blinded personnel will not be with the subject 
or in a location that could result in the blind being inadvertently broken.  However, the Principal 
Investigator or designee will be available in the event of an emergency, and/or the need for 
adverse event assessment. All blinded study personnel will be blinded to the post-treatment iron 
indices and serum phosphorous laboratory results, as the values may break the blind. 
The blinding will be maintained until the study is complete, and the database has been locked. In 
the event of an emergency that would require the investigator to be aware of the treatment 
allocation prior to database lock, the investigator can obtain this information, on a per participant
basis. It is recommended to contact the sponsor’s Medical Monitor or designee prior to 
unblinding. If a participant’s treatment assignment is unblinded, the sponsor must be contacted 
immediately via telephone.
6.0 STUDY PROCEDURES
6.1 Informed Consent
Prior to any study specific procedures, the investigator or his or her designee 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 must voluntarily 
sign an informed consent statement (Required Elements of Informed Consent, 21 CFR 50.25).  
The participant will be given a copy of the signed consent form.
6.2 Screening Phase (Day -28 to Day 0)
6.2.1 Screening Visit 
Each participant who has signed the informed consent and qualifies for inclusion will undergo the 
following clinical evaluations to confirm eligibility for the study (all procedures to be performed 
by blinded study personnel):  
x
Demographic and medical history including NYHA heart failure class and prior heart 
failure hospitalizations
x
Left ventricular ejection fraction (historical values may be used if performed within 
12 months of the screening visit, or 24 months if LVEF ) must be performed at 
least 12 weeks after major cardiac intervention-including CABG, valvular 
intervention, or cardiac resynchronization therapy device implantation
x
Blood samples for hematology, iron indices, and NT-proBNP (local laboratory)
x
Concomitant medications
x
Review inclusion/exclusion criteria 
x
Enter participant in the Interactive Response Technology (IRT) system to obtain 
screening number.


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Participants who do not meet study entry criteria should be entered into the IRT system as a screen 
failure. If all entry criteria can be verified qualified participants may be randomized and proceed to 
the Day 0 visit on the same day as the screening visit.
6.3 Treatment Phase (Day 0 to Day 7)
6.3.1 Day 0 Visit
All eligible participants will be randomized to either Group A or Group B in a 1:1 ratio based on a 
pre-determined randomization schedule via an IRT system.  
The following will be obtained and/or completed before contacting IRT for randomization:
For all participants (all procedures to be performed by blinded study personnel):
x
Verify all inclusion and exclusion criteria 
x
Height and weight
x
Targeted physical exam
x
Blood samples for central lab hematology, chemistries and iron indices for all 
participants; Vitamin D, PTH for participants at sites selected for post dose chemistry 
follow-up visits.
x
Review concomitant medications
x
Urine pregnancy test (women of childbearing potential only)
x
Administer 6MWT per standardized procedure
The IRT system will then be contacted by an Unblinded study team member and all eligible 
participants will be randomized to either Group A or Group B in a 1:1 ratio with stratification by 
region based on a pre-determined randomization schedule. After assignment of the treatment 
group the following will occur: 
Group A:
x
Verify amount of single FCM dose (15mg/kg up to a maximum dose of  750 mg) 
(unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body temperature (blinded 
staff)
x
Administer FCM as a slow IV injection at the rate of approximately 2 mL /minute
taking appropriate measures to ensure the participant and all blinded staff members 
remain blinded to the treatment being administered (unblinded staff)
x
Document start and stop time of FCM administration and the total dose and volume 
administered (unblinded staff)
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after FCM administration (blinded staff)
x
Adverse event / serious adverse event assessment (starting at beginning of FCM 
injection) (blinded staff)
Group B:


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x
Pre-administration, obtain heart rate, blood pressure, and body temperature (blinded 
staff)
x
Administer a 15 mL dose of placebo (normal saline) as a slow IV injection at the rate 
of approximately 2 mL /minute taking appropriate measures to ensure the participant
and all blinded staff members remain blinded to the treatment being administered 
(unblinded staff).
x
Document start and stop time of placebo administration and the total volume 
administered (unblinded staff).
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after placebo administration (blinded staff)
x
Adverse event and serious adverse event assessment (starting at beginning of placebo
injection) (blinded staff)
6.3.2 Day 7 Visit
All participants will return to the clinic for study drug dosing on Day 7(+2).  Prior to the 
administration of the study drug, the participant will be evaluated clinically to assess the 
development of clinically significant conditions that may contraindicate dosing.
Group A participants the following will be performed:
x
Verify amount of single FCM dose (15mg/kg up to a maximum dose of  750 mg) 
(unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body temperature (blinded 
staff)
x
Administer FCM as a slow IV injection at the rate of approximately 2 mL /minute
taking appropriate measures to ensure the participant and all blinded staff members
remain blinded to the treatment being administered (unblinded staff).
x
Document start and stop time of FCM administration and the total dose and volume 
administered (unblinded staff)
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after FCM administration (blinded staff)
x
Adverse event / serious adverse event assessment, including evaluation of potential 
endpoint events (see section 10.2; blinded staff)
x
Review concomitant medications
Group B participants the following will be performed:
x
Pre-administration, obtain heart rate, blood pressure, and body temperature (blinded 
staff)
x
Administer a 15 mL  dose of  placebo (normal saline) as a slow IV injection at the rate 
of approximately 2 mL /minute taking appropriate measures to ensure the participant
and all blinded staff members remain blinded to the treatment being administered 
(unblinded staff).
x
Document start and stop time of  placebo administration and the total volume 
administered (unblinded staff)
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after placebo administration (blinded staff)
x
Adverse event/serious adverse event assessment, including evaluation of potential 


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endpoint events (see section 10.2; blinded staff)Review concomitant medications
(blinded staff)
6.4 Follow-Up Phase
6.4.1 Chemistry Laboratory Collection Subset -Day 21 (± 7)
In a subset of sites approximately 500 participants, will have central lab clinical laboratories
(chemistry, hematology and iron indices) collected following the initial and each subsequent 
course (approximately every 6 months) of study drug treatment (FCM or Placebo).  The
participants will have chemistry laboratories collected 21+7 days post the first treatment for that 
course (i.e. Study Days 21+7, 201+7, 381+7, 561+7, 741+7, 921+7…EOS). (blinded staff)
6.4.2 90 Day Follow-Up 
Following the initial and all subsequent courses of study drug treatments each participant will be 
contacted in person or via telephone 90+14 days post the first treatment for that course (i.e. study 
Days 90+14, 270+14, 450+14, 630+14, 810+14, 990+14…EOS)
During these visits the following will be performed:
x
Adverse event / serious adverse event assessment, including evaluation of potential 
endpoint events (see section 10.2). (blinded staff)
6.4.3   6 Month Laboratory Evaluation
Participants will receive an additional course of study medication every 180 (+7) days.  Within 2
to 20 days prior to these scheduled dosing visits, all participants will return to the clinic to obtain 
central lab hematology, chemistry, and iron indices laboratory tests. (Blood to be collected by 
blinded staff)
6.4.4 Additional Study Drug Dosing (Every 6 Months)
All participants will be dosed every 6 months.  At each 6-month interval, a course of 2 doses of 
study drug will be administered as described above for Day 0 and Day 7 (Section 6.3).  For group 
A, FCM will be administered if Hgb < 13.5 g/dL (females) or <15.0 g/dL (males) and serum 
ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT <20%; placebo (normal saline) will be 
administered to participants in the FCM group who do not meet the above criteria. All group B 
participants will receive placebo (normal saline)
6.4.4.1 6 Month Dosing Visit #1 (Days 180+7, 360+7, 540+7, 660+7, 840+7, 1,020+7…EOS)
On the first of the 2 dosing visits, the following will be performed by blinded study staff for all 
participants:
x
Weight
x
Urine pregnancy test (women of childbearing potential only)
x
Adverse event / serious adverse event assessment, including evaluation of potential 
endpoint events (see section 10.2).
x
Review concomitant medications
x
Administer 6MWT per standardized procedure (at the 6 and 12 month visits).


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For Group A participants the following will be performed:
x
Verify if participant will receive FCM or placebo, based on the following criteria from 
recent labs (within 20 days).  Participants will receive FCM if the Hgb <13.5 g/dL
(females) or <15.0 g/dL (males) and serum ferritin <100 ng/mL or 100 to 300 ng/mL 
with TSAT <20%.  If the participant does not meet these criteria, placebo (normal 
saline) will be administered. (unblinded staff)
x
As appropriate based on criteria above, verify amount of single FCM dose (15mg/kg 
up to a maximum dose of 750 mg) or placebo (15 mL). (unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body temperature. (blinded 
staff)
x
Administer FCM or placebo as a slow IV injection at the rate of approximately 2 mL 
/minute. Appropriate measures must be taken to ensure the participant and all blinded 
staff members remain blinded to the treatment being administered (unblinded staff)
x
Document start and stop time of IV administration, and the total dose and volume 
administered (unblinded staff)
x
Post-administration of FCM, obtain heart rate and blood pressure immediately after 
and 30 minutes after FCM administration (blinded staff)
For Group B participants the following will be performed:
x
Pre-administration, obtain heart rate, blood pressure and body temperature. (blinded 
staff)
x
Administer a 15 mL dose of placebo (normal saline) as a slow IV injection, at the rate 
of approximately 2 mL /minute. Taking appropriate measures to ensure the participant
and all blinded staff members remain blinded to the treatment being administered 
(unblinded staff)
x
Document start and stop time of placebo administration and the total volume 
administered. (unblinded staff)
x
Post-administration of placebo, obtain heart rate and blood pressure immediately after
and 30 minutes after placebo administration(blinded staff)
6.4.4.2 Six Month Dosing Visit #2 (Days 187+7, 367+7, 547+7, 667+7, 847+7, 1,027+7…EOS)
The second of the 2 dosing visits should occur at Day 7 (+2) after the first, with the following 
performed for all participants:
x
Adverse event / serious adverse event assessment, including evaluation of potential 
endpoint events (see section 10.2) (blinded staff), and review of concomitant 
medications (blinded staff).
For Group A participants the following will be performed:
x
Verify amount of single FCM dose (15mg/kg up to a maximum dose of 750 mg) or 
placebo (15 mL). Note: participant should receive the same product (FCM or 
placebo) as received at the first dose of this course of treatment. (unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body temperature. (blinded 
staff)
x
Administer FCM or placebo as a slow IV injection at the rate of approximately 2 mL 
/minute. Taking appropriate measures to ensure the participant and all blinded staff 


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members remain blinded to the treatment being administered (unblinded staff).
x
Document start and stop time of IV administration and the total dose and volume 
administered. (unblinded staff)
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after FCM administration. (blinded staff)
For Group B participants the following will be performed:
x
Pre-administration, obtain heart rate, blood pressure, and body temperature. (blinded 
staff).
x
Administer a 15 mL dose of placebo (normal saline) as a slow IV injection at the rate 
of approximately 2 mL /minute. Taking appropriate measures to ensure the participant
and all blinded staff members remain blinded to the treatment being administered 
(unblinded staff)
x
Document start and stop time of placebo administration and the total volume 
administered. (unblinded staff)
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after placebo administration. (blinded staff).
6.5
End of Study Visit
End of study visits for all participants will be scheduled once the last participant has reached 12
months on study and at least 771 participants have experienced an event of cardiovascular death or 
hospitalization for heart failure. When possible, the participants should return to the clinic and the 
following will be performed by blinded study staff:
x
Targeted physical exam 
x
Vital signs including BP and heart rate
x
Blood samples for central lab hematology, chemistries, iron indices and NT-proBNP.
x
Urine pregnancy test (women of childbearing potential only)
x
Review of concomitant medications
x
Adverse event / serious adverse event assessment, including evaluation of potential 
endpoint events (see section 10.2).
6.6 Laboratory Assessments
Serum samples for laboratory analyses must be obtained at all appropriate visits. Screening 
laboratory values will be analyzed locally. All other visit laboratory samples will be analyzed by a
central clinical laboratory.  All laboratory testing will be provided to the investigator or his/her 
medically qualified designee for review and assessment. Post dose iron indices and serum 
phosphorus results will be provided to the designated unblinded investigator for assessment. The
laboratory assessments will be determined as listed in Section 3.3:
Hematology:
Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, 
differential count, and reticulocyte count
Chemistry: 
Sodium, potassium, chloride, BUN, creatinine, albumin, alkaline 
phosphatase, total bilirubin, GGT, AST, ALT, LDH, calcium, 
phosphorus, glucose, bicarbonate, and magnesium


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Iron indices:
Serum iron, serum ferritin, total iron binding capacity (TIBC), 
and percentage serum transferrin saturation (TSAT)
Other:                            
Vitamin D, Parathyroid Hormone, NT-proBNP
7.0 ASSESSMENT OF SAFETY
7.1 Adverse Events
Any untoward medical event experienced by a participant during the course of this clinical trial, 
whether or not it is related to the investigational product, at any dose, is considered an adverse 
event (AE).
For any laboratory abnormality, the investigator, or his/her medically qualified designee, 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. If the laboratory value is outside the normal range, but not an 
adverse event, the investigator should comment on the findings (i.e. “not clinically significant” or 
“unchanged from baseline”) in the source documentation [laboratory report].
The investigator should use Table 7.1.1 to assign the adverse event severity grade.


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Table 7.1.1 Grading of Adverse Event Severity
Grade
Adjective
Description
1
Mild
Does not interfere with the participant’s usual function
2
Moderate
Interferes to some extent with participant's usual function
3
Severe
Interferes significantly with participant's usual function
4
Life-threatening
Results in a threat to life or in an incapacitating disability
5
Death
Results in Death
Timing: Adverse events and serious adverse events will be reported, as described below in 
Section 7.2, from the time of randomization through the end of study. Adverse events for
participants randomized and who terminate early will be reported for 30 days after the last 
treatment.
Relationship (Causality): The Investigator will be asked to document his/her opinion of the 
relationship of the event to the study drug* as follows:
x
NONE
There is no evidence of any causal relationship.
x
UNLIKELY
There is little evidence to suggest there is a causal relationship.  
There is another reasonable explanation for the event (e.g., the 
participant’s clinical condition, other concomitant treatments).
x
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).
x
PROBABLE
There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely.
*
For the purposes of this trial, “study drug” is defined as:
FCM
OR
Placebo
7.2 Reporting of Adverse Events
For the purposes of this study, any AE that does not meet the protocol definition of a serious AE is 
considered non-serious. Non-serious AEs will not be collected for this trial, except for AEs 
leading to cessation of study medication. Disease progression can be considered as a worsening of 
a patient’s clinical condition attributable to the disease in the patient population for which the 


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study medication is being studied. It may be an increase in the severity of the disease under study,
and/or increases in the symptoms of the disease. The development of the following cardiovascular
disease events will be recorded in the eCRF, however they should be considered as disease 
progression and will not be reported as an AE/SAE during the study unless determined to be 
clinical endpoints. These include the events listed in Section 7.4, “Reporting of Events that May 
Require Adjudication.” 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. 
7.3 Serious Adverse Events
Definition:
An adverse event is classified as SERIOUS if it meets any one of the 
following criteria: 
x
Death
x
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.
x
Hospitalization (initial or prolonged): Required admission to the hospital or 
prolongation of a hospital stay except events which are components of the primary or 
secondary endpoints which will be adjudicated by the CEC Committee as noted above.
x
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.
x
Congenital Anomaly/Birth Defect.
x
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.
Suspected clinical endpoint events that may traditionally meet the definition of an SAE, will not 
be reported by the sites in this trial as an SAE. Those events will therefore not to be reported to 
the sponsor’s Drug Safety Surveillance department.
Certain events of interest that are related to heart failure (serious and non-serious) and selected 
expected (described in the label) serious side effects of the study drug will be listed on the eCRF 
and not be reported by the site as an SAE.
These events will be monitored by the Data Safety Monitoring Board to ensure participant safety.
Additionally suspected clinical events that are reviewed by the CEC but do not meet the criteria of 
an endpoint event will be reviewed by the safety surveillance team for possible unreported SAEs.
Reporting: Any SAE as defined by this protocol, starting with the time of randomization,
that is to be reported (as outlined in the section above) must be reported immediately (by the 
end of the next business day) to Luitpold Pharmaceuticals, Inc. This occurs through entry 
into the eCRF by the local investigator/coordinator and completing the SAE module. In the 


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event that the eCRF module is not available the investigator will contact the Study Safety 
Monitor at   
Luitpold Pharmaceuticals, Inc.  
The local investigator is responsible for reporting SAEs to their local IRB/ Ethics Committee 
based on local reporting guidelines (which may be different than those specified in this protocol).  
The responsible investigator should institute appropriate diagnostic and therapeutic measures and 
keep the participant under observation for as long as is medically indicated.
7.4 Reporting of Suspected Study Endpoint Events that May Require Adjudication
The following events, which are the components of the primary or secondary endpoints will be 
adjudicated by the Clinical Events Classification (CEC) Committee of the Duke Clinical Research 
Institute (DCRI) for both FCM and Placebo and will not require reporting to the sponsor as an 
SAE: 

Cardiovascular Death including:
x
Death due to Heart Failure
x
Death due to Acute Myocardial Infarction
x
Sudden Cardiac Death 
x
Death due to Stroke 
x
Death due to other cardiovascular causes

Hospitalization for heart failure 

Non-Cardiovascular death

Hospitalization for myocardial infarction

Hospitalization for stroke 

Other Cardiovascular hospitalizations

Urgent heart failure visits
Therefore, any event that may possibly constitute one of these endpoints will be evaluated by the 
CEC Committee by a procedure to be described in separate documentation.  A description of the 
CEC Committee and the definitions of the above clinical endpoints may be found in Section 10.2. 
8.0 STATISTIC 
All statistical tests will be two-tailed. Type I error of 0.05 is assumed unless otherwise specified.  
No adjustments for multiple testing will be made.
8.1 Stratification/Randomization 
Participants who meet the inclusion/exclusion criteria will be randomized in a 1:1 ratio on Day 0 
to FCM or Placebo with stratification by region.  


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8.2 Analysis Populations
The Intent-To-Treat (ITT) Population will consist of all participants randomized to a treatment 
group in the study regardless of compliance with the study medication. For all analyzed using the 
ITT population, participants will be analyzed as randomized. This is the primary population of all 
efficacy analyses.
The Per-Protocol Population is a subset of the ITT population excluding participants who 
complied with the randomized treatment for less than 50% of the follow-up. In cases of 
medication error, treatment assignments in the per-protocol analysis will be analyzed according to 
the actual treatment received.
8.3 Disposition and Baseline Characteristics
The number and percent of participants who are randomized, treated with randomized therapy, 
prematurely discontinue, and complete the study will be summarized. The number and percent of 
participants will be summarized for each reason for premature discontinuation.
Categorical baseline characteristics (e.g., sex and race) will be summarized with the number and 
percent of participants in each treatment group with the characteristic.  Quantitative characteristics 
(e.g., age and weight) will be summarized with the mean, median, standard deviation, minimum 
value, and maximum value. Baseline characteristics will be summarized for the safety and ITT 
populations.
8.4 Endpoints and Definitions
8.4.1 Primary Outcome
The primary outcome follows an ordinal scale of clinical severity comprised of 1) death, 2) 
number of hospitalizations for heart failure (as defined in section 10.2) evaluated at one year; or 3) 
change in 6MWT evaluated at 6 months.
8.5 Secondary Outcomes
The following secondary outcomes will be evaluated in the hierarchy listed below.
1.
Time to first event of the composite of cardiovascular death or 
heart failure hospitalization. The composite endpoint will be 
composed of  adjudicated occurrence (as defined in section 
10.2) of one of the following:
a. Cardiovascular Death
i.
Death due to Heart Failure
ii.
Death due to Acute Myocardial Infarction
iii.
Sudden Cardiac Death
iv.
Death due to Stroke
v.
Death due to other Cardiovascular Causes
b.
Hospitalization for Worsening Heart Failure
2.
Mean  change in 6MWT from baseline to 12 months


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3.
Time to first event of the composite of cardiovascular death or 
intervention for worsening heart failure (hospitalization or urgent 
heart failure visits)
4.
Time to first event of the composite of cardiovascular death and 
cardiovascular hospitalizations
5.
Time to cardiovascular death
Additional events to be adjudicated for analysis of the secondary endpoints include:
a)
Non-cardiovascular death
b) Hospitalization for myocardial infarction
c)
Hospitalization for stroke
d) Other cardiovascular hospitalizations
e)
Urgent heart failure visits
An endpoint adjudication committee at DCRI will review all potential events comprising all 
endpoints, and make the final determination whether an endpoint event has occurred for each 
participant (See Section 10.2). 
8.6 Primary Comparison
Each participant from the treatment arm gets ranked/compared with each participant from the 
control arm based on the 12-month experience for Death and Hospitalizations for heart failure and 
6 month results for change in 6MWT to determine treatment response per the following hierarchy: 
1.
Death
If both die, the one who survives longer is better off;
If one dies and one does not, the one that survives is better off;
If neither dies, examine hospitalizations for heart failure.
2.
Hospitalizations for heart failure
The one with fewer hospitalizations is better off;
If neither has been hospitalized for heart failure or the number heart failure 
hospitalizations is equal, compare change in 6MWT.
3.
Change in 6MWT
The one with higher change in 6MWT is better off; 
Statistical Test
The main comparison will be conducted using the Wilcoxon-Mann-Whitney test.  The null 
hypothesis being tested is that a randomly chosen participant in the treatment arm is equally likely 
to be ranked better or worse than a randomly chosen participant in the control group. The two-
sided alternative is that the participant is not equally likely to be ranked better or worse.  In 
addition to performing the test we will estimate the probability that a participant in the treatment 
arm has a better rank than a participant in the control arm and its corresponding confidence 
interval.


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The above comparison of participants in the treatment versus control arms is equivalent to ranking 
all participants according to their experience.  At one end of the ranking are participants with the 
best experience - those alive and not hospitalized for worsening heart failure ordered according to 
their improvement in 6MWT; at the opposite end are those who die ordered according to their 
survival time.  Those participants alive but hospitalized are in the middle, ordered according to 
their number of hospitalizations for worsening heart failure and then by their change in 6MWT.  
The non-parametric Wilcoxon-Mann-Whitney test sums the ranks of those in the treatment arm 
and compares them with the sum of ranks in the control arm.
In all analyses the number of hospitalizations (and the number of days in the hospital in the 
sensitivity analysis described below) will be adjusted for the time on follow-up.  This adjustment 
applies only to individuals who are alive at the end of follow-up (the comparison in those who die 
will be resolved based on time to death) and will be accomplished by dividing the observed 
number by time at risk in years.  For individuals who complete the pre-specified 12 months of 
follow-up, time at risk equals 1.  For all others, it is equal to the fraction of 12 months that the 
person remained in the study. 
8.7 Secondary Comparisons
8.7.1 Top Secondary Comparison: Time to first event of cardiovascular death or 
hospitalization of heart failure
This analysis will compare time to first occurrence of cardiovascular death or hospitalization for 
heart failure.  The Cox proportional hazards model will be employed to conduct this comparison.  
The test will be two-tailed and will be performed at an overall D of 0.05. This analysis will be 
performed by the ITT principle based on randomized treatment assignment and we expect 
adequate power to detect a pre-specified relative risk reduction of 20%.
Sensitivity Analysis
In a sensitivity analysis we will add another layer to the hierarchy described above – in individuals 
who have been hospitalized for heart failure during follow-up, ties in the numbers of 
hospitalizations will be resolved based on the total number of days in the hospital during follow-
up, before proceeding to comparison of differences in the 6MWT.  
8.7.2 Change in 6 Minute Walk Test
Mean change in 6MWT distance from baseline to 12 months will be compared using linear 
regression adjusting for baseline value of 6MWT.
.
8.7.3 Secondary Outcomes based on time to first event
The time to each of the remaining secondary outcomes (Incidence of cardiovascular deaths and 
cardiovascular hospitalizations, Incidence of cardiovascular death or intervention for worsening 
heart failure (hospitalization or urgent heart failure visits) and Incidence of cardiovascular deaths) 
will be compared using the Cox proportional hazards model.


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8.8 Sample Size and Statistical Power
The study design allows for sufficient power for both the primary and top secondary outcomes.
Numerical simulations based on multivariate normal vectors were conducted to estimate power for
the primary treatment comparison based on the following assumptions about events rates 
described in Table 8.8.1.


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Table 8.8.1.   Assumptions About Event Rates for Primary Outcome
Ranked tier at 12-month endpoint (6 month 
for 6 MWT)
Control
Treatment
Death total
Death without hospitalization
Death with hospitalization
8%
4%
4%
6.8%
3.4%
3.4%
Hospitalizations in survivors
1
2
3 or more
6%
3%
1%
4.8%
2.4%
0.8%
Change in 6 Minute Walk Test
Mean = 0
SD = 90
Mean = 18
SD = 90
With 3014 patients (1507 per arm) and 2.5% annual loss to follow-up for clinical outcomes and 
15% of individuals with missing 6MWT at 6 months (unable to perform or lost to follow-up),
projected simulations estimate 90% power at an overall two-sided significance level of  0.01, 
accounting for one interim analysis as described in section 8.10.
For the top secondary composite, an assumed event rate of 0.0128 per month in the control arm 
which represents conservative 75% discounting of the event rate obtained by the FCM meta-
analysis [Anker 2015].  The anticipated hazard ratio was set at 0.80 (20% reduction).  Uniform 
enrollment is assumed over the period of 30 months, with an anticipated minimum follow-up of 12 
months (required minimum of 6 months), anticipated maximum follow-up of 42 months (no 
required maximum), and monthly loss to follow-up of 0.0021 (2.5% annualized).  With these 
assumptions, 1500 per study arm (3000 total) provides 90% power to reject the null hypothesis of 
no difference between treatment arms when tested at an overall two-sided level of significance 
D=0.05, accounting for one interim analysis as described in section 8.10.  This results in a total of 
771 events necessary to achieve the desired power. Thus, the trial has the potential opportunity to
be stopped at a point where the projected number of events reaches 771, but no earlier than the last 
participant reaching 12 months of follow-up.
The primary and top secondary outcome will be tested sequentially, and thus, no multiplicity 
adjustment is necessary.
8.9 Handling of Missing Data
Every effort will be made to limit the number of missing data points.  The trial will be conducted 
in jurisdiction which will allow ascertainment of vital status even in individuals who discontinue 
the study.  Participants who discontinue taking study drug should be encouraged to continue 
participation in the trial so that endpoint data can be collected. Furthermore, consent will be 
obtained to examine hospital records where feasible.  Partnership with transportation companies 


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will be fostered to decrease the burden of travel to clinic visit and increase the likelihood of the 
final study visit taking place.
The prospective plan for the handling of missing data is as follows:
The primary analysis will rely on a multiple imputation model, with Markov chain Monte Carlo 
algorithm based on the totality of observed data.  One exception to this rule will be individuals 
unable to perform the 6MWT test at 6 months will have their value imputed as the worst observed 
change in 6MWT.
Two supporting analyses will be undertaken.  The first one will use multiple imputation for 
clinical outcomes, but will impute the worst observed change in 6MWT to all individuals who do 
not have this measurement, regardless of the reason.
The second series of analyses will perform tipping point assessments to determine the sensitivity 
of the observed result to the missing data.  Given the multi-dimensional nature of outcomes, 
tipping point analyses will be performed separately for each outcome: mortality, hospitalization 
for heart failure and 6MWT.   
8.10 Stopping Rules and Interim Analysis
A Data and Safety Monitoring Committee (DSMB), with statistical support from DCRI will 
review safety data, including a tally of the composite outcome events at least every 6 months (See 
Section 10.3).  The DSMB can recommend stopping the study for safety concern at any point.  In 
addition, one interim analysis is planned to determine if an early stopping for an overwhelming 
efficacy should be recommended or if an increase in sample size is warranted.  This analysis will 
be conducted after 2250 (75%) participants have been enrolled.  Significance level will be set at 
0.0001 for this analysis, resulting in an adjusted significance level for the final analysis of 0.0099 
for the primary endpoint and 0.0499 for the first secondary endpoint, preserving the overall 
significance at 0.01 and 0.05, respectively.  Conditional power will be estimated based on data 
accrued to date and presented to the DSMB.  The DSMB may recommend that the study continues 
as planned, is stopped for overwhelming efficacy or that the sample size or trial duration is 
increased to achieve at least 80% conditional power but not by more than 50% of the original 
sample size or duration.
9.0 ADMINISTRATIVE CONSIDERATIONS
9.1 Retention and Availability of Records
Investigators are required to maintain all study documentation, including a copy of the CRFs, 
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, that includes the signed Informed Consent form and copies 
of all study documentation related to that participant. The investigator must ensure the availability 


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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 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 Luitpold Pharmaceuticals, Inc. All signed financial disclosure forms 
must be submitted to the Sponsor prior to the site enrolling participants into the study.
9.4 Advertisement for Participant Recruitment
All advertisement for participant recruitment must be reviewed and approved by the Sponsor and 
the site's IRB prior to implementation. Advertisement may include but is not limited to:
newspaper, fliers, radio, and television. Any compensation to the participant included in the 
advertisement must be identical to the compensation stated in the IRB-approved informed consent.


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9.5 Documents Required for Study Initiation
Prior to study initiation, the investigator must provide Luitpold Pharmaceuticals Inc. or its 
designee with the following documentation:
x
Curriculum Vitae and medical license for Principal Investigators and co-investigators.
x
Form FDA 1572
x
Financial disclosure form
x
IRB approval of protocol and informed consent
x
Copy of IRB approved informed consent
x
IRB membership list or assurance number
x
Protocol signature page
x
IRB approval of any advertising for participant recruitment [if applicable]
x
Copy of advertising [if applicable]
x
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:
x
Accessible, interested, and available support staff.
x
Availability of adequate facilities to support study requirements.
x
Availability of physician emergency response at all times.
x
Adequate time to conduct study.
x
Adequate training and experience of personnel to conduct study.
x
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.
Luitpold Pharmaceuticals, 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, 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.
Periodic monitoring visits will be made to the site during the clinical study to assure that the 
Investigator obligations are fulfilled, and all applicable regulations and guidelines established by 
the protocol are being followed.
These visits will assure that the facility is still acceptable, the protocol and investigational plan are 
being followed, the IRB/EC has been notified of approved protocol changes as required, complete 


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study records are being maintained, appropriate and timely reports have been made to the sponsor 
or its representative and the IRB/EC, study drug inventory is controlled, and the Investigator is 
carrying out all agreed-upon activities.
In accordance with the FDA Guidance for Industry: Oversight of Clinical Investigations - A Risk-
Based Approach to Monitoring, a combination of on-site and centralized monitoring practices will 
be implemented in order to ensure participant protection, as well as quality and integrity of the 
clinical trial data while promoting efficiency. While the majority of monitoring will be conducted 
centrally, on-site monitoring will be performed based on the findings of previous on-site 
monitoring visits and centralized monitoring. During on-site monitoring, a percentage of the data 
will be compared among the eCRF (i.e. source document review, source document verification) 
and each participant’s source documentation, and data discrepancies will be queried. See the trial 
specific risk based monitoring plan for additional details.
9.6.3 Quality Assurance Audit
For the purpose of data validation, the principal investigators will permit a member of the quality 
assurance unit of Luitpold Pharmaceuticals, Inc. or its designee to inspect the source data and 
compare them with the eCRFs. Pre-study audits, interim audits and post-study audits may be 
performed and may also include review of facilities, equipment, pertinent site documentation, and 
personnel qualifications. Notification of these audits will be sent to 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 Institutional Review 
Board (IRB) before the study is initiated. Documentation of this approval must be provided to the 
Sponsor or designee.  The IRB must comply with current U.S. Regulations (21 CFR 56) for the 
protection of Human Subjects in Research. Investigators are responsible for the following:
x
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.
x
Provide the IRB with any information it requests before or during the study.
x
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.
x
Notify the IRB of all serious adverse events that occur or are reported to you 
by the Sponsor as required by the IRB.


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9.7.3 Informed Consent
Each investigational site must provide the Sponsor (or designee) with a copy of the Informed 
Consent approved by the site's IRB. The Clinical Monitor will assure that each Informed Consent 
meets the requirements of Parts 50.20 and 50.25 of Title 21 of the CFR, which outlines the basic 
elements of informed consent and ICH guidelines prior to its use.
Informed consent must be obtained from each participant prior to enrollment. The informed 
consent will be provided to the participant in their native language. The Informed Consent must 
be signed and dated by each participant before entering the study, and prior to the performance of 
any study-specific procedures. The original signed consent form will be retained in the 
participant's study records, and a copy will be provided to the participant.  Translations of the 
informed consent must be certified by a qualified translator and their use must be documented.
The Informed Consent documents the information the Investigator provides to the participant and 
the participant's agreement to participate.  The Investigator will fully explain the nature of the 
study, along with the purpose, methods, anticipated benefits, potential hazards, and discomfort that 
participation might entail.
9.7.4 Good Clinical Practice
The conduct of the study will conform with the recommendations for clinical studies in humans as 
set out in the most current revision of the “Declaration of Helsinki”, the local 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 on this study.  The participants in this study will 
be identified only by a participant number on these forms.
The eCRF used will be 21 CFR 11 compliant.  The system used for data collection (eCRF) will 
meet all applicable regulatory requirements for recordkeeping and record retention as would be 
provided with a paper system.  Security measures will be utilized to prevent unauthorized access 
to the data and to the computerized system. Changes made to data that are stored on electronic 
media will always require an audit trail, in accordance with 21 CFR 11.10(e).
The eCRFs must be reviewed and verified for accuracy by the Principal Investigator. An
electronic copy of the eCRF will remain at the site at the completion of the study.
9.8.2 Confidentiality
All unpublished information given to the investigator or institution dealing with this study, study
drug or the conduct, financial agreements, or methodologies used in this protocol, as well as 
information obtained during the course of the study, remains confidential and proprietary to the 
Sponsor [“Proprietary Information”]. The Investigator shall not disclose any such Proprietary 
Information to any third party without prior written consent from the sponsor [See also Section 
9.9 Publication Policy]. For purposes of this Section, “Investigator” includes, but is not limited to 
the Principal Investigator and/or his/her agents, designees, sub-investigators or other individuals 


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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 Luitpold Pharmaceuticals, Inc. They will be used for the purposes specified in the protocol. 
Any unused medication will be returned to the sponsor at the conclusion of the study.
No patent application based on the results of this study should be made by the investigator and all 
such rights assigned to Luitpold Pharmaceuticals, Inc., and no assistance should be given to any 
third party to make such an application without the written authorization of Luitpold 
Pharmaceuticals, Inc.
9.8.3 Termination of the Study
The study may be terminated if the DSMB, Sponsor, or Steering Committee discovers conditions 
arising during the course of the study, which indicate that the clinical investigation should be 
halted. The study may be terminated after appropriate consultation and discussion.
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 Luitpold personnel and the investigator and be approved by the 
site's IRB, before the revision may be implemented. The protocol revision will be submitted to the 
FDA.
9.8.5 Protocol Administrative Changes
Clarification or interpretation of the study protocol or changes in the methods of statistical 
analysis may be documented in the form of a numbered memo or other applicable document 
(charter, plan, etc.). Numbered memos do not typically require the investigator’s signature or IRB 
approval.
9.9 Publication Policy
All information resulting from this study is the Proprietary Information of Luitpold 
Pharmaceuticals, 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.
Luitpold Pharmaceuticals, 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 Luitpold Pharmaceuticals, 
Inc.


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The Investigator will provide to the Sponsor any announcement, publication, or presentation of 
data from this study for the Sponsor’s review and comments at least 10 days in advance of such 
disclosure.  Sponsor may, at its sole discretion, require the removal of any proprietary information 
from the disclosure.  The Investigator agrees to provide the Sponsor, at the Sponsor’s discretion, 
with any byline credit in any publication proposed by the Investigator. This is in order to enable 
Luitpold Pharmaceuticals, Inc., to make constructive comments about the manuscript or text and 
to give the opportunity of assessing whether patent protection should be sought by Luitpold on any 
results or ideas connected with the study.
10.0 GOVERNANCE COMMITTEES
10.1  Steering Committee (SC)
The SC will be responsible for oversight of the study. The SC chair will be Dr. Adrian Hernandez
of DCRI. The SC will consist of 4-8 members including the chair, primarily from academic 
institutions, as well as representation of the Sponsor.  The SC will consist of experts in heart 
failure as well as cardiovascular outcomes trials.
The key functions of the SC will be to:
1.
Review and approve the main protocol, amendments, and the Statistical Analysis Plan.
2.
Determine the time to terminate the study based on recommendations from the DSMB and 
other available information.
3.
Review and approve any substudies.
4.
Draft the manuscript describing the main study results and oversee all publications requiring 
trial data
5.
Participate where appropriate in scientific meetings providing updates of study progress.
6.
Oversee trial subcommittees including the Clinical Endpoint Committee and the Data Safety 
Monitoring Board
7.  Assume the role of the publications committee and review, authorize and prioritize proposals 
for publications which require trial or substudy data samples and assign writing groups
10.2 Adjudication by the Clinical Endpoint Classification (CEC) Committee
A Clinical Event Committee (CEC) will be created for this trial to review and adjudicate each 
suspected endpoint event while blinded to treatment in this study. The CEC for this trial will 
consist of cardiologists, neurologists, and physicians with clinical expertise from DCRI or other 
academic institutions. The CEC Chair will lead the development of the definitions of endpoints,
instructions for interpretation, and provide ongoing oversight to the CEC members for this trial to 
ensure that events are adjudicated in consistent fashion over time. The CEC members, as well as 
those overseeing the CEC, will not be investigators in the study, or be otherwise directly 
associated with the sponsor, and will remain blinded to treatment throughout the study and the 
adjudication process. The CEC and the adjudication process will be described in detail in a 
separate CEC charter.
Adjudicated Endpoints


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10.2.1 Death
All deaths will be categorized as Cardiovascular or non-Cardiovascular based on the 
definitions below.  In addition, all deaths will further be sub-typed based on the specific 
cardiovascular categories defined below. Non-cardiovascular deaths will not be further 
adjudicated. 
The cause of death will be determined by the principal condition that caused the death, not the 
immediate mode of death. For example, if a participant is hospitalized and undergoing treatment 
for worsening heart failure dies of ventricular tachycardia, this would be classified as a heart 
failure death. CEC physicians will utilize all available information provided, along with clinical 
expertise in their adjudication of cause of death.
10.2.1.1 Death Due to Cardiovascular Death
Cardiovascular death includes death resulting from an acute MI, sudden cardiac death, death due 
to heart failure, death due to stroke, and death due to other CV causes. 
10.2.1.2 Death Due to Heart Failure
Death due to heart failure refers to a death in association with clinically worsening symptoms 
and/or signs of heart failure regardless of heart failure etiology. Deaths due to heart failure can 
have various etiologies, including single or recurrent myocardial infarctions, ischemic or non-
ischemic cardiomyopathy, hypertension, or valvular disease. 
Deaths that occur during a heart failure hospitalization will generally be attributed to heart failure, 
even if there is another immediate mode of death (e.g, ventricular fibrillation). Deaths that occur 
in hospice or other similar palliative care setting for heart failure will generally be attributed to 
heart failure.
10.2.1.3 Death Due to Acute Myocardial Infarction
Death due to acute MI refers to a death by any CV mechanism (e.g. arrhythmia, sudden death, heart 
failure, stroke, pulmonary embolus, peripheral arterial disease) 

30 days after a MI related to the 
immediate consequences of the MI, such as progressive heart failure or recalcitrant arrhythmia. 
We note that there may be assessable mechanisms of CV death during this time period, but for 
simplicity, if the CV death occurs GD\VRIWKH0,LWZLOOEHFRQVLGHUHGDGHDWKGXHWR0,
Acute MI should be verified to the extent possible by the diagnostic criteria outlined for CV 
hospitalization for acute MI, or by autopsy findings showing recent MI or recent coronary 
thrombosis.
Death resulting from a procedure to treat a MI, percutaneous coronary intervention (PCI), 
coronary artery bypass graft surgery (CABG), or to treat a complication resulting from MI should 
also be considered death due to acute MI.
If death occurs before biochemical confirmation of myocardial necrosis can be obtained,
adjudication should be based on clinical presentation and ECG evidence. Sudden cardiac death, if 
accompanied by symptoms suggestive of myocardial ischemia, new ST elevation, new LBBB, or 
evidence of fresh thrombus by coronary angiography and/or at autopsy should be considered death 
resulting from an acute myocardial infarction, even if death occurs before blood samples or 12-
lead ECG could be obtained, or at a time before the appearance of cardiac biomarkers in the blood. 


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Death resulting from a procedure to treat a myocardial infarction (e.g. PCI, CABG), or to treat a 
complication resulting from MI, should also be considered death due to acute MI. 
10.2.1.4 Sudden Cardiac Death 
Sudden Cardiac Death refers to death that occurs unexpectedly and not following an acute MI, and 
includes the following deaths: 

Death witnessed and occurring without new or worsening symptoms. 

Death witnessed within 60 minutes of the onset of new or worsening cardiac 
symptoms, unless the symptoms suggest acute myocardial infarction.

Death witnessed and attributed to an identified arrhythmia (e.g., captured on an ECG 
recording, witnessed on a monitor, or unwitnessed but found on implantable 
cardioverter-defibrillator (ICD) review) 

Death after unsuccessful resuscitation from cardiac arrest. (e.g., ICD unresponsive 
sudden cardiac death, pulseless electrical activity arrest)

Death after successful resuscitation from cardiac arrest and without identification of a 
specific cardiac or non-cardiac etiology

Unwitnessed death in a participant seen alive and clinically stable KRXUVSULRUto 
being found dead without any evidence supporting a specific non-cardiovascular 
cause of death (information about the participant’s clinical status preceding death 
should be provided, if available)
General Considerations 

Unless additional information suggests an alternate specific cause of 
death (e.g., Death due to Other Cardiovascular Causes), if a participant is
seen alive KRXUVRUDUHDVRQDEOHSHULRGZKHQRWKHUZLVHFOLQLFDOO\
stable) of being found dead OR circumstances suggest sudden death, 
sudden cardiac death should be recorded 
Typical scenarios include:

Participant well the previous day but found dead in bed the next day

Participant found dead at home on the couch with the television on
For participants who were not observed alive within 24 hours of death, 
undetermined cause of death should be recorded (e.g., participant found dead in 
bed, but who had not been seen by family for several days).
“Undetermined cause of death” will be considered as “CV death” for purpose of 
analysis.
10.2.1.5 Death Due to Stroke
Death due to Stroke refers to death after a stroke that is either a direct consequence of the stroke or 
a complication of the stroke.  Acute stroke should be verified to the extent possible by the 
diagnostic criteria outlined for stroke in Section 10.2.2.3 (Hospitalization for Stroke). 


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10.2.1.6 Death Due to Other Cardiovascular Causes 
Death due to Other Cardiovascular Causes refers to a CV death not included in the above 
categories but with a specific, known cause (e.g., pulmonary embolus or peripheral arterial 
disease).
10.2.1.7 Non-Cardiovascular Death
Non-cardiovascular death is defined as any death that is not thought to be CV in nature.  Deaths 
from Non-CV causes will not be further subclassified.
10.2.1.8 Undetermined Cause of Death
Death not attributable to one of the above categories of CV death, or to a non-CV cause. Inability 
to classify the cause of death may be due to lack of information (e.g. the only information is 
“participant died”), or when there is insufficient supporting information or detail to assign the 
cause of death. In general, most deaths should be classified as CV or non-CV, and the use of this 
category of death, therefore, should be discouraged and should apply to few participants..
All deaths adjudicated as “undetermined cause” will be presumed cardiovascular deaths, and as 
such, are part of the cardiovascular mortality endpoint.
10.2.2
Cardiovascular Hospitalizations
The participant’s length-of-stay in hospital extends for at least 24 hours (or a change in calendar 
date, if admission and discharge times are unavailable). 
10.2.2.1 Hospitalization for Heart Failure
A Heart Failure hospitalization is defined as an event that meets ALL of the following criteria: 
1) The participant is admitted to the hospital with a primary diagnosis of heart failure
2) The participant’s length-of-stay in hospital extends for at least 24 hours (or a change 
in calendar date, if admission and discharge times are unavailable). 
3) The participant exhibits documented new or worsening symptoms due to heart failure 
on presentation, including at least ONE of the following:
a.
Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal 
nocturnal dyspnea)
b.
Decreased exercise tolerance
c.
Fatigue
d.
Other symptoms of worsened end-organ perfusion or volume overload (e.g., 
confusion, somnolence, edema, etc.)
4) The participant has objective evidence of new or worsening heart failure, consisting 
of at least TWO physical examination findings OR one physical examination finding 
and at least ONE laboratory criterion), including:
a. Physical examination findings considered to be due to heart failure, including 
new or worsened:
i. Peripheral edema
ii. Increasing abdominal distention or ascites (in the absence of primary 
hepatic disease)
iii. Pulmonary rales, crackles, or crepitations


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iv. Increased jugular venous pressure and/or hepatojugular reflux
v. S3 gallop
vi. Clinically significant or rapid weight gain thought to be related to fluid 
retention (usually more than 3-4 lbs in 3-4 days)
b. Laboratory evidence of new or worsening heart failure, if obtained within 24 
hours of presentation, including:
i. Increased B-type natriuretic peptide (BNP)/ N-terminal pro-BNP (NT-
proBNP) concentrations consistent with decompensation of heart failure 
(such as BNP >500 pg/mL or NT-proBNP >2,000 pg/mL). In patients 
with chronically-elevated natriuretic peptides, a significant (1.25X) 
increase should be noted above baseline 
ii. Radiological evidence of pulmonary congestion
iii. Non-invasive diagnostic evidence of clinically significant elevated 
left- or right-sided ventricular filling pressure or low cardiac output. For 
example, echocardiographic criteria could include: E/e’ >15 or D-
dominant pulmonary venous inflow pattern, plethoric inferior vena cava 
with minimal collapse on inspiration, or decreased left ventricular outflow 
tract (LVOT) minute stroke distance (time velocity integral (TVI)
OR
iv. Invasive diagnostic evidence with right heart catheterization 
showing a pulmonary capillary wedge pressure (pulmonary artery 
occlusion pressure) PP+JFHQWUDOYHQRXVSUHVVXUHPP+JRU
a cardiac index <2.2 L/min/m2
Note: All results from diagnostic tests should be reported, if available, even if they do not 
meet the above criteria, because they provide important information for the adjudication of 
these events. 
5) The participant receives initiation or intensification of treatment specifically for heart 
failure, including at least ONE of the following:
a.
Augmentation in oral diuretic therapy
b.
Intravenous diuretic, or  vasoactive agent (e.g. positive inotrope, vasopressor or 
vasodilator)
c.
Mechanical or surgical intervention, including mechanical
circulatory support (e.g., intra-aortic balloon pump, ventricular assist device, 
extracorporeal membrane oxygenation, total artificial heart)
d. Mechanical fluid removal (e.g., ultrafiltration, Hemofiltration, dialysis)
10.2.2.2 Hospitalization for Myocardial Infarction
Acute MI will be adjudicated when a participant demonstrates at least one of the following 
biochemical indicators of myocardial necrosis:
• CK-MB greater than 2 x ULN or Troponin I or T greater  than 2 x ULN, with a typical pattern of 
rise and fall consistent with MI


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AND at least one of the two following criteria:
• Typical clinical presentation consistent with MI defined as typical cardiac ischemic type 
pain/discomfort or dyspnea felt to be due to ischemia
OR
• Typical ECG changes consisting of any of the following:
• New abnormal Q waves (or new R waves in lead V1-V2) in at least two consecutive leads
• Evolving, ischemic ST segment or T wave changes in at least two consecutive leads
• New LBBB
10.2.2.3 Hospitalization for Stroke
Stroke is defined as an acute episode of focal or global neurologic dysfunction caused by brain, 
spinal cord, or retinal vascular injury a result of hemorrhage or infarction. To be classified as a 
stroke, duration of a focal/global neurological deficit must have a duration >24 hours or imaging 
confirmation clearly documenting a new hemorrhage or infarct. Events may be classified as a 
stroke if symptoms were <24 hours due to either pharmacologic or non-pharmacologic 
interventions or the stroke resulted in death in <24 hours.
 
Classification:
Ischemic Stroke:
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by infarction of central nervous system tissue hemorrhage may be a 
consequence of ischemic stroke.  In this situation, the stroke is an ischemic stroke with 
hemorrhagic transformation and not a hemorrhagic stroke.
Hemorrhagic Stroke
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage.
Undetermined Stroke
Undetermined stroke is defined as an acute episode of focal or global neurological
dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a result of 
hemorrhage or infarction, but with insufficient information to allow categorization as 
ischemic or hemorrhagic stroke.
10.2.2.4 Other Cardiovascular Hospitalizations
Urgent and unscheduled hospitalizations for other cardiovascular causes that do not meet the 
criteria for the specific events listed above will be classified as hospitalization for other 
cardiovascular causes. Examples would include hospitalization for cardiac chest pain that does 
not meet the criteria for MI, hospitalization for arrhythmias, hospitalization for pulmonary 
embolism, etc. These hospitalizations will not be further sub-classified by the CEC.


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10.2.3 Other Events:  Urgent Heart Failure Visit
An urgent heart failure visit is defined as an event that meets all the following:
1) The participant has an urgent, unscheduled office/practice or emergency department 
visit for a primary diagnosis of heart failure, but not meeting the criteria for a heart 
failure hospitalization 
2) Signs and symptoms that constitute a heart failure hospitalization [i.e., 3) symptoms, 
4) physical examination findings/laboratory evidence of new or worsening heart 
failure, as indicated above] must be met 
3) The participant receives initiation or intensification of treatment specifically for heart 
failure, as detailed in the above section with the exception of oral diuretic therapy, 
which will not be sufficient 
10.3 Data and Safety Monitoring Board (DSMB)
The DSMB will be composed of approximately 5 senior academic individuals, including the 
DSMB Chair. The members will have high-level expertise in cardiology, hematology, clinical 
research, and statistics. A senior statistician assigned to the trial from the group performing data 
management services for this trial will oversee the provision of interim data reports for use by the 
DSMB. The data management group for this trial will transfer pre-agreed datasets to the 
statistician preparing data for DSMB. During the Open Session of the DSMB meetings, 
representatives of the SC or Luitpold representatives may present updates on the trial status or the 
safety profile of FCM, but will not be privy to discussions of the data conducted during the Closed 
Sessions and will not vote. Proceedings and minutes of the Closed Session will be held in strict 
confidence and will not be shared outside the DSMB while the trial is ongoing prior to database 
lock.
The DSMB will be responsible for the interests of the study participants, and to this end, will
undertake regular reviews of the safety data. The DSMB will have access to an agreed subset of 
the study data as listed in the DSMB charter (updated as necessary during the trial) throughout the 
study duration. In addition, the DSMB will evaluate interim analyses of the data every at least 
every six months (or on an ad hoc basis if needed) either by face-to-face meeting, or 
teleconference.  The DSMB will determine if it believes the trial should be terminated early 
because clear evidence exists that either of the two groups has a treatment response that is 
substantially better than the other.
If the DSMB finds it necessary to recommend actions regarding interruption of the study, or 
changes to the protocol based on medical rationale that would make it unethical to continue the 
study in its present form, those recommendations will be forwarded to the SC. The details of the 
DSMB's functions and the early stopping rules will be delineated in a separate DSMB charter.


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


Luitpold Pharmaceuticals, Inc.
Protocol No.: 1VIT15043
CONFIDENTIAL 
version: 1.0, 12 January 2017
Page 53 of 53
References
1. Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Ferric carboxymaltose in iron 
deficient heart failure patients: a meta-analysis of individual-patient data from 
randomised clinical trials. Annual Heart Failure Society of America Meeting, 2015; 
Abstract 336.
2. Ebner N, von Haehling S. Iron deficiency in heart failure: a practical guide. Nutrients 
2013;5:3730-9.
3. Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P. Iron 
deficiency and heart failure: Diagnostic dilemma and therapeutic perspectives. Eur 
Heart J 2013;34:816-29.
4. Kapoor M. Schleinitz MD, Gemignani A, Wu, W. Outcomes of patients with chronic 
heart failure and iron deficiency treated with intravenous iron: a meta-analysis. Cardio 
& Hematol Disord – Drug Tar 2013;13:35-44.
5. Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron 
homeostasis in chronic heart failure:  Prevalence, predictors, and relation to anemia, 
exercise capacity, and survival. J Am Coll Cardiol 2011;58:1241-51.
6. Streja E, Kovesdy CP, Greenland S, et al. Erythropoietin, iron depletion, and relative 
thrombocytosis:  a possible explanation for hemoglobin-survival paradox in 
hemodialysis. Amer J Kidn Dis 2008;52:727-36.
7. van Veldhuisen DJ, Anker SD, Ponikowski P, Macdougall IC. Anemia and iron 
deficiency in heart failure: mechanisms and therapeutic approaches. Nat Rev Card 
2011;8(9):485-93.
8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the 
Management of Heart Failure. J Am Coll Cardiol. 2013;62:147-239.


Table of Contents
PROTOCOL No. 1VIT15043: IND #: 127910 A Randomized, Double-Blind, 
Placebo-Controlled Study to Investigate the Efficacy and Safety of Injectafer® 
(Ferric Carboxymaltose) as Treatment for Heart Failure with Iron Deficiency
8
SIGNATURES OF AGREEMENT FOR PROTOCOL
9
Study Synopsis
10
Figure 1. Study Diagram
15
LIST OF ABBREVIATIONS
16
1.0 INTRODUCTION
18
1.1 Heart Failure with Iron Deficiency
18
1.2 Treatment of Iron Deficiency in Heart Failure
18
1.3 Injectafer® (Ferric Carboxymaltose)
19
1.3.1 Key Features of Ferric Carboxymaltose
19
1.3.2 Injectafer® versus Other Parenteral Iron Agents
19
1.3.3 Injectafer® Human Experience
20
2.0 TRIAL OBJECTIVE
20
2.1 Primary Objective
20
2.2 Secondary Objective
20
3.0 OVERALL STUDY DESIGN AND RATIONALE
20
3.1 Overall Study Design
20
3.2 Rationale of Study Design and Choice of Control Groups
21
3.3 Schedule of Events
22
4.0 PARTICIPANT SELECTION
23
4.1 Number and Type of Participants
23
4.2 Screening Phase
23
4.2.1 Inclusion Criteria
23
4.2.2 Exclusion Criteria
24
4.3 Participant Assignment and Randomization Process
25
4.4 Withdrawal from Study
25
4.5 Discontinuation from Study Drug
26
4.6 Participants Deemed Lost to Follow-up
26
4.7 Concomitant Intervention
26
5.0 STUDY DRUG
27
5.1 Formulation, Packaging and Storage
27


5.2 Drug Administration/Regimen
27
5.3 IV Medication Precautions
28
5.4 Drug Accountability
28
5.5 Concomitant Medication
28
5.6 Blinding
29
6.0 STUDY PROCEDURES
29
6.1 Informed Consent
29
6.2 Screening Phase (Day -28 to Day 0)
29
6.2.1 Screening Visit
29
6.3 Treatment Phase (Day 0 to Day 7)
30
6.3.1 Day 0 Visit
30
6.3.2 Day 7 Visit
31
6.4 Follow-Up Phase
32
6.4.1 90 Day Follow-Up
32
6.4.2 6 Month Laboratory Evaluation
33
6.4.3 Additional Study Drug Dosing (Every 6 Months)
33
6.4.3.1 6 Month Dosing Visit #1 (Days 180+7, 360+7, 540+7, 720+7, 900+7,1,
080+7…EOS)
33
6.4.3.2 Six Month Dosing Visit #2 (Days 187+7, 367+7, 547+7, 727+7, 907+7,1,
087+7…EOS)
34
6.5 End of Study Visits
35
6.6 Laboratory Assessments
35
7.0 ASSESSMENT OF SAFETY
36
7.1 Adverse Events
36
Table 7.1.1 Grading of Adverse Event Severity
36
7.2 Reporting of Adverse Events
37
7.3 Serious Adverse Events
38
8.0 STATISTICAL METHODS
40
8.1 Stratification/Randomization
40
8.2 Analysis Populations
40
8.3 Disposition and Baseline Characteristics
40
8.4 Endpoints and Definitions
41
8.4.1 Primary Outcome
41
8.5 Secondary Outcomes
41
8.6 Primary Comparison
42


8.7 Secondary Comparisons
43
8.7.1 Top Secondary Comparison: Time to first event of cardiovascular death 
orhospitalization of heart failure
43
8.7.2 Change in 6 Minute Walk Test
43
8.7.3 Secondary Outcomes based on time to first event
43
8.8 Sample Size and Statistical Power
43
Table 8.8.1. Assumptions About Event Rates for Primary Outcome
44
8.9 Handling of Missing Data
44
8.10 Stopping Rules and Interim Analysis
45
9.0 ADMINISTRATIVE CONSIDERATIONS
45
9.1 Retention and Availability of Records
45
9.2 Investigator Responsibilities
46
9.3 Financial Disclosure
46
9.4 Advertisement for Participant Recruitment
47
9.5 Documents Required for Study Initiation
47
9.6 Quality Control and Quality Assurance
47
9.6.1 Investigator Selection Criteria
47
9.6.2 Clinical Monitoring
48
9.6.3 Quality Assurance Audit
48
9.7 Ethics
48
9.7.1 Ethical and Legal Issues
48
9.7.2 Institutional Review Board
49
9.7.3 Informed Consent
49
9.7.4 Good Clinical Practice
49
9.8 Data Handling and Record Keeping
50
9.8.1 Case Report Form
50
9.8.2 Confidentiality
50
9.8.3 Termination of the Study
50
9.8.4 Protocol Revisions
51
9.8.5 Protocol Administrative Changes
51
9.9 Publication Policy
51
10.0 GOVERNANCE COMMITTEES
51
10.1 Steering Committee (SC)
51
10.2 Adjudication by the Clinical Endpoint Classification (CEC) Committee
52


10.2.1 Death
52
10.2.1.1 Death Due to Cardiovascular Death
53
10.2.1.2 Death Due to Heart Failure
53
10.2.1.3 Death Due to Acute Myocardial Infarction
53
10.2.1.4 Sudden Cardiac Death
53
10.2.1.5 Death Due to Stroke
54
10.2.1.6 Death Due to Other Cardiovascular Causes
54
10.2.1.7 Non-Cardiovascular Death
55
10.2.1.8 Undetermined Cause of Death
55
10.2.2 Cardiovascular Hospitalizations
55
10.2.2.1 Hospitalization for Heart Failure
55
10.2.2.2 Hospitalization for Myocardial Infarction
57
10.2.2.4 Other Cardiovascular Hospitalizations
58
10.2.3 Other Events: Urgent Heart Failure Visit
58
10.3 Data and Safety Monitoring Board (DSMB)
58
11.0 INVESTIGATOR’S ACKNOWLEDGEMENT
60
12.0 REFERENCES
61
13.0 Appendices
62
Appendix 1: Hypophosphatemia Sub-study
63
CONTACT PERSON FOR THE SUB-STUDY
64
TABLE OF CONTENTS
65
LIST OF TABLES
66
LIST OF ABBREVIATIONS
67
1. INTRODUCTION
68
1.1. Pathophysiology
68
1.2. Increased FGF23
69
1.3. Inhibition of Vitamin D Activation
70
1.4. Symptoms and Signs of Hypophosphatemia
70
2. SUB-STUDY OBJECTIVE
71
3. SUB-STUDY RATIONALE AND DESIGN
71
3.1. Sub-Study Rationale
71
3.2. Sub-Study Design
71
3.3. Schedule of Events for Sub-Study
72
Table 1 Schedule of Events for Sub-Study
72


4. PARTICIPANT SELECTION
73
4.1. Number and Type of Participants
73
4.2. Participant Selection
73
4.2.1. Inclusion Criteria
73
4.2.2. Exclusion Criteria
73
4.3. Participant Assignment and Randomization Process
73
4.4. Withdrawal from Study
73
5. CONCOMITANT MEDICATION
73
6. STUDY PROCEDURES
73
6.1. Treatment Phase
73
6.2. Informed Consent
73
6.3. Follow-up Phase
74
6.3.1. Sub-study Specific Visit Days 14 ± 3, 21 ± 3, 35 ± 3, 63 ± 3, 91 ± 3, 119± 3 
(Clinic or Home Visits)
74
6.4. End of Sub-Study
74
6.5. Central Laboratory Assessment
75
7. ASSESSMENT OF SAFETY
75
7.1. Adverse Events
75
7.2. Reporting of Adverse Events
75
8. STATISTICS
76
8.1. Stratification/Randomization
76
8.2. Sample Size Rationale
76
8.3. Analysis Population
76
8.4. Endpoints and Definitions
76
8.4.1. Exploratory Phosphate Homeostasis Endpoints
76
8.5. Safety Analyses
77
8.5.1. Adverse Events
77
8.5.2. Clinical Laboratory Tests
77
9. ETHICS
77
9.1. Informed Consent
77
9.2. Good Clinical Practice
78
10. DATA HANDLING AND RECORD KEEPING
78
10.1. Case Report Form
78
11. REFERENCES
79


Table 2 Hypophosphatemia CTCAE Grade
83
Appendix 2: Protocol Amendment History
84
Overall Rationale for the Amendment (Version 2):
84
Detailed description of Protocol Amendment:
84
Overall Rationale for the Amendment (Version 3):
97
Detailed description of Protocol Amendment (Version 3):
97
Table 1 Hypophosphatemia CTCAE Grade
111
APPENDIX 1: PROTOCOL NO. 1VIT15043 IND# 127910
TABLE OF CONTENTS
114
1. INTRODUCTION
117
1.1. Pathophysiology
117
1.2. Increased FGF23
118
1.3. Inhibition of Vitamin D Activation
118
1.4. Symptoms and Signs of Hypophosphatemia
119
2. SUB-STUDY OBJECTIVE
119
3. SUB-STUDY RATIONALE AND DESIGN
119
3.1. Sub-Study Rationale
119
3.2. Sub-Study Design
120
3.3. Schedule of Events for Sub-Study
121
4. participant SELECTION
122
4.1. Number and Type of Participants
122
4.2. Participant Selection
122
4.2.1. Inclusion Criteria
122
4.2.2. Exclusion Criteria
122
4.3. Participant Assignment and Randomization Process
122
4.4. Withdrawal from Study
122
5. CONCOMITANT MEDICATION
122
6. STUDY PROCEDURES
122
6.1. Treatment Phase
122
6.2. Informed Consent
122
6.3. Follow-up Phase
123
6.3.1. Sub-study Specific Visit Days 14 ± 3, 21 ± 3, 35 ± 3, 63 ± 3, 91 ± 3, 119 ± 
3 (Clinic or Home Visits)
123
6.4. End of Sub-Study
123


6.5. Central Laboratory Assessment
124
7. ASSESSMENT OF SAFETY
124
7.1. Adverse Events
124
7.2. Reporting of Adverse Events
124
8. STATISTICS
125
8.1. Stratification/Randomization
125
8.2. Sample Size Rationale
125
8.3. Analysis Population
125
8.4. Endpoints and Definitions
125
8.4.1. Exploratory Phosphate Homeostasis Endpoints
125
8.5. Safety Analyses
126
8.5.1. Adverse Events
126
8.5.2. Clinical Laboratory Tests
126
9. ETHICS
126
9.1. Informed Consent
126
9.2. Good Clinical Practice
127
10. DATA HANDLING AND RECORD KEEPING
127
10.1. Case Report Form
127
11. REFERENCES
128


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
AMERICAN REGENT, INC.
PROTOCOL
No. 1VIT15043
IND #: 127910
A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy 
and Safety of Injectafer® (Ferric Carboxymaltose) as Treatment for Heart Failure 
with Iron Deficiency  
SPONSOR
American Regent, Inc. 
Clinical Research and Development 
800 Adams Avenue6XLWH
Norristown, PA 19403 
610-650-4200
Protocol Date: 12 January 2017 
Version 2 Final Draft Date: 29 November 2018
Version 3 Final Date: 11 January 2021


American Regent, Inc. 
CONFIDENTIAL
Protocol No.: 1VIT15043
Version 3 Date: Final 11 January 2021
SIGNATURES OF AGREEMENT FOR PROTOCOL


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
3DJHRI
Study Synopsis
Protocol No. 1VIT15043
Title:
Study Drug:
Objective:
Design:
A Randomized, Double-Blind, Placebo-Controlled Study to 
Investigate the Efficacy and Safety of Injectafer® (Ferric 
Carboxymaltose) as Treatment for Heart Failure with Iron 
Deficiency 
Ferric Carboxymaltose (Injectafer®) 
The primary objective of this study is to determine the efficacy and 
safety of iron therapy using intravenous (IV) ferric carboxymaltose 
(FCM), relative to placebo, in the treatment of participants in heart 
failure with a reduced ejection fraction and with iron deficiency. 
This is a double-blind, multicenter, prospective, randomized, 
placebo-controlled study to assess the effects of IV FCM compared 
to placebo on the 12-month rate of death, hospitalization for 
worsening heart failure, and the 6-month change in 6 minute walk 
test  (6MWT) for patients in heart failure with iron deficiency. 
After an initial screening period of up to 28 days, eligible participants 
will be stratified by region and randomized in a 1:1 ratio to FCM or 
placebo for treatment.  
Study drug administration will occur on Day 0 and Day 7 (±2) as an 
undiluted slow IV push, with additional study visits planned at 3
month intervals, and additional dosing administered every 6 months 
as applicable (see Section 3.1).
For all participants, hematology, 
ferritin, and transferrin saturation (TSAT), with appropriate safety 
evaluations, to determine additional treatment, will occur at 6 month 
intervals.  
In a subset of sites, a sub-study will be conducted to characterize 
serum phosphate levels overtime in participants with heart 
failure and iron deficiency after dosing with FCM (see Appendix 1). 
Inclusion Criteria:
1. Adult (≥18 years of age) able to provide signed, written informed
consent.
2. Stable heart failure (NYHA II-IV) on maximally-tolerated
background therapy (as determined by the site Principle
Investigator) for at least 2 weeks prior to randomization.
3. Able and
willing to perform a 6MWT at the time of
randomization.


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
3DJHRI
4. Reduced left ventricular ejection fraction. Assessment must be
performed at least 12 weeks after major cardiac surgical
intervention including coronary artery bypass graft (CABG),
valvular repair/replacement, or cardiac resynchronization therapy
(CRT) device implantation.
a.
Left ventricular ejection fraction ≤40% obtained during
the screening visit OR either of the following
i. Historical value of ejection fraction ≤40% within
24 months of screening visit
ii. Historical value of ejection fraction ≤30% within
36 months of screening visit
5. Hemoglobin >9.0 g/dL and <13.5 g/dL (females) or <15.0 g/dL
(males) within 28 days of randomization.
6. Serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT
<20%. Patients with screening ferritin <15 ng/mL must have
documentation of an appropriate evaluation, as determined by the
Principle Investigator, within 3 months of screening and prior to
randomization.
7. Either documented hospitalization for heart failure within 12
months of enrollment or elevated N-terminal-pro-brain natriuretic
peptide (NT-proBNP) within 90 days of randomization:
a.
For patients in normal sinus rhythm: N-terminal-pro-brain
natriuretic peptide (NT-proBNP) >600 pg/mL (or BNP
>200 pg/mL)
b. For patients in atrial fibrillation: NT-proBNP >1000
pg/mL (or BNP >400 pg/mL
NOTE: NT-proBNP must be used to confirm eligibility for 
patients taking sacubitril/valsartan.
Exclusion Criteria:   
1. Known hypersensitivity reaction to any component of FCM.
2. History of acquired iron overload, or the recent receipt (within
3 months) of erythropoietin stimulating agent, IV iron therapy,
or blood transfusion.
3. Acute myocardial infarction, acute coronary syndrome,
transient ischemic attack, or stroke within 30 days of enrollment.
4. Uncorrected severe aortic stenosis, severe valvular regurgitation
(except mitral regurgitation due to left ventricular dilatation
without planned intervention), or left ventricular outflow
obstruction requiring intervention.
5. Current atrial fibrillation or atrial flutter with a mean ventricular
response rate >100 per minute (at rest).
6. Current or planned mechanical circulatory support or heart
transplantation.
7. Hemodialysis or peritoneal dialysis (current or planned within
the next 6 months).


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
3DJHRI
8. Documented liver disease, or active hepatitis (i.e. alanine
transaminase or aspartate transaminase >3 times the upper limit
of normal range).
9. Current or recent (within 3 years) malignancy with exception of
basal cell carcinoma or squamous cell carcinoma of the skin, or
cervical intraepithelial neoplasia.
10. Active gastrointestinal bleeding.
11. Female participant of child-bearing potential who is pregnant,
lactating, or not willing to use adequate contraceptive
precautions during the study and for up to 5 days after the last
scheduled dose of study medication.
12. Inability to return for follow up visits within the necessary
windows
13. Concurrently in a study with investigational product.
14. Current COVID-19 infection.
Study Drug 
Administration
Initial treatment will occur on Day 0 (date of randomization) and Day 
7. On Day 0 and Day 7, Group A (FCM) will receive a 750 mg
undiluted blinded dose of IV FCM at the rate of approximately 100
mg (2 mL)/minute; Group B (placebo) will receive a blinded placebo
(15 cc of normal saline) IV push at 2 mL/minute. Participants in
Group A with body weight <50 kg (110 pounds) will have individual
FCM doses adjusted to 15 mg/kg, not to exceed an individual dose
of 750 mg, or a cumulative dose of 1500 mg per treatment cycle.
All participants will be dosed every 6 months for the duration of the 
trial.  Participants randomized to the FCM arm will be dosed as 
indicated based on hemoglobin (Hgb) levels (i.e. Hgb <13.5 g/dl 
[females] or <15.0 g/dl [males)]) and iron studies (i.e. serum ferritin 
<100 ng/mL or 100 to 300 ng/mL with TSAT <20%). Participants
not meeting post- randomization lab criteria for blood counts and 
iron studies and all participants randomized to the placebo arm will 
be administered IV placebo at each visit.
Unblinded
site personnel, responsible for preparation and 
administration of the FCM or Placebo, will ensure that the participant
and all blinded site staff are not able to observe the preparation or
administration of study treatment.


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
3DJHRI
Patient
Assessments
Primary
Endpoint:
Efficacy and Safety Follow-up: All participants will be followed 
from the time of randomization until completion of the trial.  The last 
participant randomized will be followed for 12 months.
After 
treatment on Day 0 and Day 7, participants will be evaluated at 3 
month intervals (in person or via telephone), with additional dosing 
administered every 6 months as applicable (see Section 
3.1). Hematology, ferritin, and transferrin saturation (TSAT) 
laboratory assessments will be performed in all participants, with 
appropriate safety evaluations, to determine if additional treatment 
will occur at 6 month intervals.  At the conclusion of the study all 
participants will be assessed for the occurrence of any potential 
endpoint or serious adverse events. 
Attempts to determine 
Vital Status, including endpoint ascertainment, for participants 
who are lost to follow-up or withdrawn will be made via a search of 
available public records, and other appropriate investigative 
techniques, including the potential use of third party vendors as 
described in the informed consent form and in accordance with 
applicable regulatory requirements. 
Hierarchical composite of 1) death, 2) hospitalization for 
heart failure (defined in Section 10.2), or 3) change in 6MWT. 
(Death and hospitalizations for heart failure will be evaluated 
at one year, Change in 6MWT will be evaluated at 6 months) and 
tested using the nonparametric Wilcoxon-type test. 
Secondary
Endpoints 
 Time to first event of the composite of cardiovascular death or
heart failure hospitalization. The composite endpoint will be
composed of adjudicated occurrence (as defined in Section 10.2)
of one of the following:
D Cardiovascular Death
L
Death due to Heart Failure
LL
Death due to Acute Myocardial Infarction
LLL
Sudden Cardiac Death
LY
Death due to Stroke
Y
Death due to other Cardiovascular Causes
E Hospitalization for Worsening Heart Failure
 Mean change in 6MWT  from baseline to 12 months
 Time to first event of the composite of cardiovascular death or
intervention for worsening heart failure (hospitalization or urgent
heart failure visits)
 Time to first event of the composite of cardiovascular death and
cardiovascular hospitalizations


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
3DJHRI
5. Time to cardiovascular death
Additional events to be adjudicated for analysis of the secondary
endpoints include:
a) Non-cardiovascular death
b) Hospitalization for myocardial infarction
c) Hospitalization for stroke
d) Other cardiovascular hospitalizations
e) Urgent heart failure visits
Study duration 
per participant:
All events are operationally defined in Section 10.2. Events will be 
confirmed by the Clinical Events Classification (CEC) Committee of 
the Duke Clinical Research Institute (DCRI) 
Screening Phase:  up to 28 days prior to randomization. 
Post randomization phase: Variable with a minimum of 365 Days. 
Study Sites:
Approximately 300
Participant Number: Approximately 3014


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
3DJHRI
Figure 1. Study Diagram


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
3DJHRI
LIST OF ABBREVIATIONS
6MWT
Six Minute Walk Test
AE
Adverse event
ALT
Alanine Aminotransferase
AST
Aspartate aminotransferase
BNP
Brain Natriuretic Peptide
BP
Blood Pressure
BUN
Blood urea nitrogen
CABG
Coronary Artery Bypass Grafting
cc
cubic centimeter
CEC
Clinical Events Classification
CFR
Code of Federal Regulations
CI
Confidence Interval
CKD
Chronic Kidney Disease
CK-MB
Creatine Kinase-Myocardial Band
cm
Centimeter
CRF
Case Report Form 
CRT
Cardiac Resynchronization Therapy
CV 
Cardiovascular
DCRI
Duke Clinical Research Institute
dL
Deciliter
DSMB
Data and Safety Monitoring Committee
EC
Ethics Committee 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
e.g.
For example
EOS
End of Study
EU
European Union
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
HF
Heart Failure
Hg
Mercury
Hgb
Hemoglobin
ICD
Implantable Cardioverter-Defibrillator
ICH
International Conference on Harmonisation
i.e.
that is
IND
Investigational New Drug Application
IRB
Institutional Review Board
IV
Intravenous


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
3DJHRI
IRT
Interactive Response Technology
ITT
Intention to Treat
KCCQ
Kansas City Cardiomyopathy Questionnaire
Kg
Kilogram
L
Liter
LBBB
Left Bundle-Branch Block
LDH
Lactic dehydrogenase
LVEF
Left Ventricular Ejection Fraction
LVOT
Left Ventricular Outflow Tract
MB
Myocardial b Fraction
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
m
Meter
mg 
Milligram
MHRA Agency
Medicines and Healthcare Products Regulatory
MI
Myocardial Infarction
mL
Milliliter
ng
Nanogram
NS
Normal Saline
NT-proBNP
N-Terminal Prohormone of Brain Natriuretic Peptide
NYHA
New York Heart Association
PCI
Percutaneous Coronary Intervention
pg 
Picogram
PGA
Patient Global Assessment
PTH
Parathyroid Hormone
RBC
Red blood cell
RDW
Red (cell) distribution width
SAE
Serious Adverse Event
SC
Steering Committee
TIBC
Total Iron Binding Capacity
TSAT
Transferrin Saturation
TVI
Time Velocity Integral
ULN
Upper Limit of the Normal
US
United States
USP
United States Pharmacopeia
UK
United Kingdom
WBC
White Blood Cell
w/v
weight / volume


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
1.0 INTRODUCTION 
1.1 Heart Failure with Iron Deficiency 
Over 5 million people in the United States (US) live with heart failure. Epidemiological 
studies in heart failure suggest a 50% prevalence of either absolute iron deficiency, defined 
as serum ferritin <100 ng/mL, or functional iron deficiency, defined as a ferritin 100 to 300 
ng/mL with transferrin saturation (TSAT) <20% [van Veldhuisen 2011; Ebner 2013].  The 
prevalence of iron deficiency increases with the severity of heart failure and etiologies 
include insufficient dietary iron, poor iron absorption, gastrointestinal blood loss, chronic 
disease, and repeated blood sampling for ongoing medical evaluation of heart failure and 
comorbid conditions.
Alteration in iron homeostasis has been identified as an independent risk factor for mortality 
in patients with heart failure [Okonko 2011; Jankowska 2013].
It is hypothesized that
reduced oxygenation, combined with insufficient iron for appropriate oxygen transportation 
and storage, may have additive untoward effects on oxidative metabolism and cellular 
immune mechanisms in this population.
Iron deficiency may also increase the risk of 
thrombosis and mortality among patients in heart failure with iron deficiency [Streja 2008]. 
1.2 Treatment of Iron Deficiency in Heart Failure 
Evidence in support of the therapeutic value of intravenous (IV) iron repletion with ferric 
carboxymaltose (FCM) for patients in heart failure with a reduced ejection fraction and iron 
deficiency is provided by 4 European studies: FER-CARS-01, FER-CARS-02 (FAIR-HF), 
FER-CARS-03 (EFFICACY-HF), and FER-CARS-05 (CONFIRM-HF).
In addition to 
measures of iron repletion and hemoglobin changes, these studies focused on changes from 
baseline in New York Heart Association (NYHA) functional class, Patient Global 
Assessment (PGA), and the 6-minute walk test (6MWT).
In the most recent of the studies, CONFIRM HF, a total of 301 participants (150 FCM, 151 
placebo) were treated for up to 52 weeks (longest duration among the 4 studies).
The 
primary efficacy analysis confirmed the benefit of FCM relative to placebo for the 
improvement in 6MWT distance at Week 24, with a comparative difference (FCM versus 
placebo) in the change from baseline reported as least squares mean (± standard error) of 
33.2 ± 10.52 m (p=0.002).  The treatment benefit of FCM versus placebo in 6MWT distance 
was sustained through to Week 52 (p≤0.001) and was consistent across subgroups.
Commensurate with the improvement in 6MWT distance, improvements in PGA, NYHA 
functional class, overall Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and 
fatigue score were seen in FCM-treated participants as compared to placebo-treated 
participants. Treatment with FCM versus placebo was also associated with a significant 
reduction in the risk of hospitalization due to worsening heart failure (hazard ratio: 0.40; 
95% confidence interval [CI]: 0.2 to 0.8; p=0.009) and a significant reduction in the risk of 
first hospitalization due to worsening heart failure or all-cause death (hazard ratio: 0.53;
95% CI: 0.30 to 0.95; p = 0.03).
Similar trends for reduction in hospitalization were 
reported for FCM and iron sucrose [Kapoor 2013].
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Protocol No.: 1VIT15043 
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A meta-analysis of these four trials was conducted to assess the association of FCM 
exposure with morbidity and mortality [Anker 2015]. The analysis included individual 
participant pooled data for 839 participants, 504 of whom with FCM exposure versus 335 
with placebo exposure. The primary endpoint was defined as the composite outcome of 
cardiovascular death and cardiovascular hospitalization. Participants randomized to FCM 
had a lower rate of cardiovascular death and cardiovascular hospitalization compared to 
placebo, with a rate ratio of 0.59 (95% CI: 0.40 to 0.88; p=0.009) in a recurrent events 
analysis. Additionally, exposure to FCM was associated with reduced cardiovascular death 
and hospitalization for heart failure, with a rate ratio of 0.53 (95% CI: 0.33 to 0.86; p=0.011) 
and all-cause death and cardiovascular hospitalization, with a rate ratio of 0.60 (95% CI: 
0.41 to 0.88; p=0.009). 
The four European trials, together with the meta-analysis, suggest that IV iron repletion as 
treatment for patients in reduced left ventricular ejection fraction with iron deficiency is 
associated with improvement in functional health (the 6MWT), patient-reported outcomes, 
morbidity defined as cardiovascular hospitalization, and mortality. Given that FCM is
approved by the US Food and Drug Administration (FDA) for use in iron-deficiency anemia 
[US Package Insert], a clinical development program is proposed seeking FDA approval for 
FCM as treatment for patients in heart failure with reduced ejection fraction who have iron
deficiency.
1.3
Injectafer® (Ferric Carboxymaltose)
1.3.1
Key Features of Ferric Carboxymaltose 
Injectafer® (FCM) is a stable Type I polynuclear iron (III)-hydroxide carbohydrate 
complex developed as an IV iron replacement therapy for the treatment of iron deficiency 
anemia. After IV administration, FCM is mainly found in the reticuloendothelial system 
which includes the liver, spleen, and bone marrow. The iron slowly dissociates from the 
complex and can be efficiently used in the bone marrow for hemoglobin synthesis. The 
carbohydrate moiety of FCM is metabolized by the glycolytic pathway.  FCM is approved 
for the treatment of iron deficient anemia, and is an investigational product in this study for 
patients in heart failure with iron deficiency. 
1.3.2
Injectafer® versus Other Parenteral Iron Agents 
There is considerable efficacy and safety experience with the various available parenteral 
iron preparations.  However, prior to the approval of non-dextran formulations, the risk of 
systemic adverse reactions restricted IV iron use.
The use of FCM offers significant 
advantages compared to other available IV iron preparations.
Due to its structure, 
Injectafer® is more stable than iron gluconate and iron sucrose resulting in a slow delivery 
of the complexed iron to endogenous iron binding sites.
In animals, FCM has 
approximately 1/5th the acute toxicity that has been reported for iron sucrose.
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 fewer administrations to 
replenish iron stores, and convenient outpatient use.
In the EU, ferumoxytol has been 
withdrawn from use and in the US, it has been given a black box warning. 
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American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
1.3.3
Injectafer® Human Experience 
The Injectafer® clinical development program demonstrated the effectiveness and safety of 
Injectafer® in the treatment of iron-deficiency anemia.
The drug is approved for the
treatment of iron deficiency anemia in adult populations who have intolerance to oral iron, 
have had unsatisfactory responses to oral iron, or who have non-dialysis dependent CKD. 
Clinical data are currently available from 20 Phase 2 and 3 studies including 5,799 patients, 
with iron deficient anemia or iron deficiency anemia associated with CKD who received 
Injectafer®  
A clinical pharmacokinetic study (VIT-IV-CL-001) using positron emission tomography 
demonstrated a fast initial elimination of radioactively labeled iron (Fe) 52Fe/59Fe Injectafer 
(FCM) from the blood, with rapid transfer to the bone marrow and rapid deposition in the 
liver and spleen. Eight hours after administration, 5 to 20% of the injected amount of
radioactively-labeled Fe was still detected in the blood. 
Important details of pre-clinical safety and efficacy and clinical safety and efficacy can be 
found in the Investigator’s Brochure.  Ferric carboxymaltose received approval from the 
United Kingdom (UK) Medicines and Healthcare Products Regulatory Agency (MHRA) 
on June 15, 2007 (EU Trade name: Ferinject).  Injectafer® now has marketing authorization 
in 70 countries, and is currently marketed in 61 of these countries. Injectafer® received 
approval for the treatment of iron-deficiency anemia from the US (FDA) on July 25, 2013.
2.0 TRIAL OBJECTIVE 
2.1 Primary Objective 
To determine the efficacy and safety of iron therapy using intravenous (IV) FCM, relative 
to placebo, in the treatment of patients in heart failure with reduced ejection fraction and 
with iron deficiency. 
2.2 Secondary Objective
To evaluate the effect of IV FCM, relative to placebo, on the functional capacity of patients 
in heart failure with reduced ejection fraction and with iron deficiency. 
3.0 OVERALL STUDY DESIGN AND RATIONALE 
3.1 Overall Study Design  
This is a double-blind, multicenter, prospective, randomized, placebo-controlled study to 
assess the effects of IV FCM compared to placebo on the 12-month rate of death and 
hospitalization for worsening heart failure, and change in 6MWT at 6 month for patients in 
heart failure with reduced ejection fraction and with iron deficiency. 
After an initial screening period of up to 28 days, eligible participants will be stratified by 
region and randomized in a 1:1 ratio to FCM or placebo. Study drug administration will 
occur on Day 0 and Day 7 as an undiluted slow IV push, with additional study visits (in 
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American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
person or via telephone) planned at 3 month intervals, and additional dosing administered 
every 6 months as applicable (based on dose regimen below).
For all participants, 
hematology, ferritin and transferrin saturation (TSAT), with appropriate safety evaluations, 
to determine additional treatment, will occur at 6 month intervals. 
In a subset of sites, a sub-study will be conducted to characterize serum phosphate levels 
overtime in participants in heart failure with iron deficiency after dosing with FCM 
(see Appendix 1). 
Initial treatment will occur on Day 0 and Day 7. On Day 0 and 7, Group A (FCM) will 
receive a 750 mg undiluted, blinded dose of IV FCM at the rate of approximately 100 mg 
(2 mL)/minute; Group B (placebo) will receive a blinded placebo (15 cc of normal saline) 
IV push at 2 mL/minute.  Participants in Group A with body weight <50 kg (110 pounds) 
will have individual FCM doses adjusted to 15 mg/kg, not to exceed an individual dose of 
750 mgs or a cumulative dose of 1500 mg per treatment cycle. Placebo dosing will be 
adjusted for weight based on volume.  
All participants randomized will be dosed every 6 months.  Participants randomized to the 
FCM arm will be dosed as indicated based on hemoglobin levels (i.e. Hgb <13.5 g/dL 
[females] or <15.0 g/dL [males)]) and iron studies (i.e. serum ferritin <100 ng/mL or 100 
to 300 ng/mL with TSAT <20%).  Participants not meeting pre-specified laboratory criteria 
for blood counts and iron studies and all participants randomized to the placebo arm will be 
administered IV placebo infusion at each visit.  
Unblinded site personnel, responsible for preparation and administration of the FCM or
Placebo, will ensure that the participant and all blinded site staff are not able to observe the 
preparation or administration of study treatment. 
3.2 Rationale of Study Design and Choice of Control Groups 
Since FCM is being studied as a treatment for heart failure patients with a reduced ejection 
fraction and comorbid iron deficiency, it is important to establish its efficacy and safety in 
terms of clinically significant endpoints including cardiovascular morbidity. 
This study will assess the efficacy and safety of FCM as a treatment for participants in heart 
failure with reduced ejection fraction and concomitant iron deficiency by comparing the 
proposed regimen to placebo (normal saline).  The placebo arm is justified as participants 
will be maintained on the maximally tolerated background therapy for heart failure with a 
reduced ejection fraction.
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3.3 Schedule of Events
Study Procedures
Screening
Treatment 
Phase
Follow-up Phase
Days
-28 to -1
0
7±2
90
±14a,b, ,l
160-176
a,b
180+7
a,b
187 +7
a,b
EOSc
Informed consent
X
Inclusion/exclusion 
criteria
X
Xj
Demographics
X
Targeted  medical 
history
X
Targeted Physical 
Exam
Xj
X
Vital signs 
Xd
Xd
Xd
Xd
X
Height (cm) & weight 
(kg)
Xej
Xe
Urine or serum 
pregnancy test
Xfj
Xf
Xf
1,25 (OH)2 Vitamin D, 
25 (OH) Vitamin D
and PTHk
Xk
Xk
Left ventricular 
ejection fraction
Xg
Randomization
Xn
Hematology 
laboratory
Xhp
Xh
Xh
Xh
Chemistry laboratory
Xh
Xh
Xh
Iron indices
Xh
Xh
Xh
Xh
6 Minute Walk Test
Xj
Xm
NT-proBNP
Xh
Xh
Xh
Xh
Serious Adverse Event 
and Clinical Endpoint 
Event reporting
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
IV FCM/ IV Placebo
Xn
Xn
Xin
Xin
Abbreviations:  EOS = End of Study; FCM = ferric carboxymaltose; IV = intravenous; NT-
proBNP = N-terminal pro-brain natriuretic peptide; PTH = Parathyroid Hormone;
a
b
c
d
e
Visits will be repeated every 180 days for the duration of the study 
At end of study, the visit should not be performed if it would occur within 30 days of the EOS visit. If 
the participant is prematurely discontinued from the study and completing the EOS visit, the regular 6 or 
12 month visit is needed to obtain the 6MWT.  
EOS visit for all participants will be scheduled once the last participant has reached 12 months on study 
and the anticipated number of outcome events (Section 8) reaches 771.
On study drug dosing days vital signs will be collected predose, immediately postdose, and 30 minutes 
postdose. 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. 
Height assessed at Day 0 only; weight assessed at Day 0 and prior to each dosing cycle. 
f.
Females of childbearing potential
g.
Historical value can be used if performed within 24 months of screening visit (or 36 months if LVEF
≤30%), must be performed at least 12 weeks after major cardiac intervention-including CABG, valvular
intervention, or cardiac resynchronization therapy device implantation.


American Regent, Inc. 
Protocol No.: 1VIT15043 
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Version 3 Date: Final 11 January 2021 
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h.
The method of analysis of screening laboratory values will be by a central clinical laboratory. All visits
will be analyzed through a central laboratory
i
All participants randomized will be dosed every 6 months.  Participants randomized to the FCM arm will
be dosed as indicated based on blood counts (i.e. Hgb <13.5 g/dL [females] or <15.0 g/dL [males)]) and
iron studies (i.e. serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT <20%). Participants not
meeting pre-specified laboratory criteria for blood counts and iron studies and all participants randomized
to the placebo arm will be administered IV placebo infusion at each visit. The second of the 2 dosing
visits should occur at Day 7+2 after the first dose.
j.
Prior to randomization
k
Only for participants at select sites performing additional chemistry labs (1,25 (OH)2 Vitamin D, 25 (OH) 
Vitamin D and PTH) (sub-study).
l.
May be performed via telephone or in person.
m. Performed at Day 180 and Day 360 visits only.
n.
To be performed by unblinded site personnel.  All other procedures must be performed by personnel
blinded to the treatment assignment
p,
Hemoglobin only
4.0 PARTICIPANT SELECTION
4.1 Number and Type of Participants
The study cohort will comprise approximately 3,014 participants in heart failure with iron 
deficiency who fulfill the inclusion criteria, do not meet any of the exclusion criteria, and 
who have given written informed consent.  
4.2 Screening Phase
Once a participant signs the informed consent document and enters the screening phase, a
unique screening number will be assigned via an interactive response technology (IRT) 
system.
4.2.1 Inclusion Criteria 
1. Adult (≥18 years of age) able to provide signed, written informed
consent.
2. Stable heart failure (NYHA II-IV) on maximally-tolerated
background therapy (as determined by the site Principle
Investigator) for at least 2 weeks prior to randomization.
3. Able and willing to perform a 6MWT at the time of
randomization.
4. Reduced left ventricular ejection fraction. Assessment must be
performed at least 12 weeks after major cardiac surgical
intervention including coronary artery bypass graft (CABG),
valvular repair/replacement, or cardiac resynchronization
therapy (CRT) device implantation.
a.
Left ventricular ejection fraction ≤40% obtained during
the screening visit OR either of the following
i. Historical value of ejection fraction ≤40% within
24 months of screening visit


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
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ii. Historical value of ejection fraction ≤30% within
36 months of screening visit
5. Hemoglobin >9.0 g/dL and <13.5 g/dL (females) or <15.0 g/dL
(males) within 28 days of randomization.
6. Serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT
<20%. Patients with screening ferritin <15 ng/mL must have
documentation of an appropriate evaluation, as determined by the
Principle Investigator, within 3 months of screening and prior to
randomization.
7. Either documented hospitalization for heart failure within 12
months of enrollment or
elevated
N-terminal-pro-brain
natriuretic 
peptide 
(NT-proBNP) 
within 
90 
days 
of
randomization:
a.
For patients in normal sinus rhythm:  N-terminal-pro-
brain natriuretic peptide (NT-proBNP) >600 pg/mL (or
BNP >200 pg/mL)
b. For patients in atrial fibrillation: NT-proBNP >1000
pg/mL (or BNP >400 pg/mL
NOTE: NT-proBNP must be used to confirm eligibility for 
patients taking sacubitril/valsartan.
4.2.2 Exclusion Criteria 
1. Known hypersensitivity reaction to any component of FCM.
2. History of acquired iron overload, or the recent receipt (within
3 months) of erythropoietin stimulating agent, IV iron therapy,
or blood transfusion.
3. Acute myocardial infarction, acute coronary syndrome,
transient ischemic attack, or stroke within 30 days ofenrollment.
4. Uncorrected severe aortic stenosis, severe valvular regurgitation
(except mitral regurgitation due to left ventricular dilatation
without planned intervention), or left ventricular outflow
obstruction requiring intervention.
5. Current atrial fibrillation or atrial flutter with a mean ventricular
response rate >100 per minute (at rest).
6. Current or planned mechanical circulatory support or heart
transplantation.
7. Hemodialysis or peritoneal dialysis (current or planned within
the next 6 months).
8. Documented liver disease, or active hepatitis (i.e. alanine
transaminase or aspartate transaminase >3 times the upper limit
of normal range).
9. Current or recent (within 3 years) malignancy with exception of
basal cell carcinoma or squamous cell carcinoma of the skin, or
cervical intraepithelial neoplasia.
10. Active gastrointestinal bleeding.


American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
11. Female participant of child-bearing potential who is pregnant,
lactating, or not willing to use adequate contraceptive
precautions during the study and for up to 5 days after the last
scheduled dose of study medication.
12. Inability to return for follow up visits within the necessary
windows
13. Concurrently in a study with an investigational product.
14. Current COVID-19 infection.
4.3 Participant Assignment and Randomization Process 
Participants who meet all inclusion requirements and no exclusionary criteria will be offered 
enrollment in this study.  Enrolled participants will be stratified by region and randomized 
in a 1:1 ratio to receive either IV FCM or IV Placebo.  
The FCM Group will initially receive 2 blinded doses of FCM at 15 mg/kg to a maximum 
of 750 mg per dose for a maximum total dose of 1500 mg.  
The Placebo Group will receive 2 blinded doses of 15 mL of normal saline. 
Participants and blinded study staff will remain blinded to the treatment assignment for the 
duration of the 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  
At time of withdrawal from the study, procedures for the Termination visit must be 
immediately performed regardless of whether the participant has completed study drug 
treatment.  Information collected previously as part of the study will be retained unless the 
patient specifically withdraws consent, in writing. The participant should be contacted at 
the end of the study to assess for the occurrence of any potential endpoint events.  
Additionally, if the participant cannot be contacted, attempts to determine the Vital Status 
will be performed via a search of available public records, third party vendor search, 
medical record review, additional contacts provided by the patient, and other appropriate 
investigative techniques as described in the informed consent form and in accordance with 
applicable regulatory requirements. 
In event of site closure, participants may be asked to agree to follow up at another research 
site, if available, or for follow up by a patient follow-up group.  
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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 endpoint and safety events. Participants who discontinue study drug 
for reasons unrelated to safety may resume study drug if deemed appropriate by the 
Principal Investigator.  
If a participant permanently discontinues investigational product (drug is considered to be 
permanently discontinued after the second missed dosing cycle with continued follow-up 
in the trial) and is unable to attend visits in-person, he/she will be contacted by telephone,
or other methods to assess study outcomes and vital status, unless the participant has 
specifically withdrawn consent for all forms of contact.  Every effort should be made to 
educate the participants on the importance of remaining in the study and attending 
scheduled study visits including those required after early discontinuation of investigational 
product. Other participant follow-up options to collect study outcomes and vital status 
should be pursued according to local laws and regulations. If one of these alternate methods 
to collect study outcomes and vital status is acceptable to the participant, then the participant
will be deemed not to have withdrawn consent for follow-up.
4.6 Participants Deemed Lost to Follow-up 
Investigators should make every effort to contact participants who are deemed lost to
follow-up and who have not withdrawn consent to follow-up contacts, including medical
record review, pursuing any alternative contact methods permitted by local regulations. 
Where permitted, a third party may be used to locate alternative participant contact 
information that will be provided to the investigator. All attempts to contact participants
will be documented in the participant’s source notes.
Should a participant fail to attend the clinic for a required study visit, the site should attempt
to contact the participant and re-schedule the missed visit as soon as possible. The site 
should also counsel the participant on the importance of maintaining the assigned visit 
schedule. In cases where the participant does not return for the rescheduled visit or cannot 
be reached to reschedule the missed visit, the site should make every effort to regain contact 
with the participant. Should the participant continue to be unreachable, then and only then,
will he/she be considered “Lost to Follow-up.” Nonetheless, efforts to attempt to locate and 
contact the participant, and to ascertain the participant’s vital status will continue until trial 
completion.
4.7 Concomitant Intervention
Concomitant intervention is defined as follows:
x
Blood transfusion.
x
Use of IV iron outside of protocol.


American Regent, Inc. 
Protocol No.: 1VIT15043 
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Version 3 Date: Final 11 January 2021 
When concomitant intervention occurs, the date of the intervening event should be recorded 
in the source documents, and the eCase Report Form (eCRF).
The participant should 
continue in the study as scheduled.
5.0 STUDY DRUG 
5.1 Formulation, Packaging and Storage
All investigational medication to be used in this study [supplied by American Regent, Inc.]
will have been prepared according to Good Manufacturing Practices (GMP).
FCM (trade name, Injectafer®) will be supplied as 15 ml vials, containing 750 mg of iron 
as 5% w/v iron containing a polynuclear iron(III)-hydroxide 4(R)–(poly-(1-->4)-O D -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.  
Placebo (normal saline) will be supplied as 15 ml fill in 20 ml vials.
All IV study drugs (FCM and Normal Saline) must be kept in a secure place at the 
investigational site, and stored at room temperature (see USP).  The study medication 
should not be frozen.  Vials may not be used for more than 1 dose, or for more than 1 
participant.  All vials (used and unused) should be kept by the study staff for reconciliation 
by the monitor unless the site is unable to retain them and documentation (site or institution 
process or procedures, or SOPs, for example) is present.  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.  The participants should remain blinded to the identity of the study drug for 
the duration of the trial.
Group A: 
Group A (FCM) will receive a 750 mg undiluted blinded dose of IV FCM at 
the rate of approximately 100 mg (2 mL)/minute (approximately 7 minutes 
30 seconds) on Day 0 and Day 7, not to exceed an individual dose of 750 mg 
or a cumulative dose of 1500 mg per treatment cycle.
Group B: 
Group B (placebo) will receive a blinded placebo (15 cc of normal saline) 
IV push at 2 mL/minute (approximately 7 minutes 30 seconds) on Day 0 and 
Day 7.
Note: To avoid unblinding on the dose administration worksheet, if a participant is under 
50 kg (110 pounds), the volume of FCM or placebo administered should be calculated based 
on the participant’s weight, e.g. a 45 kg participant will receive a 13.5 mL dose of FCM or 
placebo.
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American Regent, Inc. 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
All participants will be dosed every 6 months.  At each 6-month interval, 2 doses of study 
drug will be administered as described above for Day 0 and Day 7.  The same randomized 
treatment will be administered if Hgb <13.5 g/dL (females) or <15.0 g/dL (males) and serum 
ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT <20%; placebo will be administered 
to participants in the FCM group who do not meet the above criteria. 
Site personnel will ensure the participant and blinded study staff are not able to observe the 
preparation or administration of study treatment injections.
5.3 IV Medication Precautions
When administering FCM or Placebo, the following precautions will be taken:
x
The participant will be evaluated clinically prior to drug administration to assess the
development of clinically significant conditions.
x
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.
x
Heart rate and blood pressure will be assessed pre-, immediately post, and 30 minutes
post administration.  Participants will be discharged from the site by the Investigator or
his or her designee only if there are no significant signs or symptoms 30 minutes after
the administration is completed.
x
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 NS, IV
epinephrine, steroids, and/or antihistamines.
5.4 Drug Accountability 
Investigators will keep records of the receipt, administration and return of the study drug 
(FCM).  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 randomized in the study, or to investigators not listed on the 
FDA 1572.  When the study is completed, or if it is prematurely terminated, a final inventory 
of all clinical supplies must be compiled and the remainder of 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 eCase Report Form (eCRF). 
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American Regent, Inc. 
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CONFIDENTIAL  
Version 3 Date: Final 11 January 2021 
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Note: Oral iron supplementation is permitted prior to screening and during the course of the 
study. 
No prophylactic medications specifically for administration of study drug may be 
administered prior to study drug administration without prior approval from American 
Regent, Inc.  Other standard therapies are permitted.  
5.6 Blinding
All participants and blinded study staff will be blinded to the content of study drug for the 
duration of the trial. 
During the period of study drug administration, the blinded personnel will not be with the 
subject or in a location that could result in the blind being inadvertently broken.  However, 
the Principal Investigator or designee will be available in the event of an emergency, and/or 
the need for adverse event assessment. All blinded study personnel will be blinded to the 
post-treatment iron indices and serum phosphorous laboratory results, as the values may 
break the blind. 
The blinding will be maintained until the study is complete, and the database has been 
locked. In the event of an emergency that would require the investigator to be aware of the 
treatment allocation prior to database lock, the investigator can obtain this information, on 
a per participant basis. It is recommended to contact the sponsor’s Medical Monitor or 
designee prior to unblinding. If a participant’s treatment assignment is unblinded, the 
sponsor must be contacted immediately via telephone.
6.0 STUDY PROCEDURES
6.1 Informed Consent
Prior to any study specific procedures, the investigator or his or her designee 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 must voluntarily sign an informed consent statement (Required Elements of 
Informed Consent, 21 CFR 50.25).  The participant will be given a copy of the signed 
consent form.
6.2 Screening Phase (Day -28 to Day 0)
6.2.1 Screening Visit 
Each participant who has signed the informed consent and qualifies for inclusion will 
undergo the following clinical evaluations to confirm eligibility for the study (all procedures 
to be performed by blinded study personnel):  
x
Demographic and medical history including NYHA heart failure class and prior heart
failure hospitalizations


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x
Left ventricular ejection fraction (historical values may be used if performed within 24
months of the screening visit, or 36 months if LVEF ≤30%) must be performed at least
12 weeks after major cardiac intervention-including CABG, valvular intervention, or
cardiac resynchronization therapy device implantation
x
Blood samples for hematology, iron indices, and NT-proBNP (central laboratory)
x
Concomitant medications
x
Review inclusion/exclusion criteria
x
Enter participant in the Interactive Response Technology (IRT) system to obtain
screening number.
Participants who do not meet study entry criteria should be entered into the IRT system as a screen
failure.
6.3 Treatment Phase (Day 0 to Day 7)
6.3.1 Day 0 Visit
All eligible participants will be randomized to either Group A or Group B in a 1:1 ratio 
based on a pre-determined randomization schedule via an IRT system.  
The following will be obtained and/or completed before contacting IRT for randomization:
For all participants (all procedures to be performed by blinded study personnel):
x
Verify all inclusion and exclusion criteria
x
Height and weight
x
Targeted physical exam
x
Blood samples for central lab hematology, chemistries and iron indices for all
participants; For Hypophosphatemia Sub-Study participants only: 1,25 (OH)2 Vitamin D, 25
(OH) Vitamin D and PTH.
x
Review concomitant medications
x
Urine or serum pregnancy test (women of childbearing potential only)
x
Administer 6MWT per standardized procedure
The IRT system will then be contacted by an Unblinded study team member and all eligible 
participants will be randomized to either Group A or Group B in a 1:1 ratio with 
stratification by region based on a pre-determined randomization schedule.
After 
assignment of the treatment group the following will occur: 
Note: To avoid unblinding on the dose administration worksheet, if a participant is under 
50 kg, the volume of FCM or placebo administered should be calculated based on the 
participant’s weight, e.g. a 45 kg participant will receive a 13.5 mL dose of FCM or placebo.
Note: All IV injection start and stop times should be captured in hh:mm:ss format.
Group A:
x
Verify amount of single FCM dose (15 mg/kg up to a maximum dose of  750 mg)
(unblinded staff)


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x
Pre-administration, obtain heart rate, blood pressure, and body temperature (blinded
staff)
x
Administer FCM as a slow IV injection at the rate of approximately 2 mL /minute taking
appropriate measures to ensure the participant and all blinded staff members remain
blinded to the treatment being administered (unblinded staff).
x
Document start and stop time of FCM administration and the total dose and volume
administered (unblinded staff)
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after FCM administration (blinded staff). 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.
x
Adverse event / serious adverse event assessment (starting at beginning of FCM
injection) (blinded staff)
Group B:
x
Pre-administration, obtain heart rate, blood pressure, and body temperature (blinded
staff)
x
Administer a 15 mL dose of placebo (normal saline) as a slow IV injection at the rate
of approximately 2 mL /minute taking appropriate measures to ensure the participant
and all blinded staff members remain blinded to the treatment being administered
(unblinded staff).
x
Document start and stop time of placebo administration and the total volume
administered (unblinded staff).
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after placebo administration (blinded staff). 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.
x
Adverse event and serious adverse event assessment (starting at beginning of
placebo injection) (blinded staff).
6.3.2 Day 7 Visit
All participants will return to the clinic for study drug dosing on Day 7(+2).  Prior to the 
administration of the study drug, the participant will be evaluated clinically to assess the 
development of clinically significant conditions that may contraindicate dosing. 
Note: To avoid unblinding on the dose administration worksheet, if a participant is under 
50 kg, the volume of FCM or placebo administered should be calculated based on the
participant’s weight, e.g. a 45 kg participant will receive a 13.5 mL dose of FCM or placebo.
Group A participants the following will be performed:
x
Verify amount of single FCM dose (15 mg/kg up to a maximum dose of  750 mg)
(unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body temperature (blinded
staff)


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x
Administer FCM as a slow IV injection at the rate of approximately 2 mL /minute taking
appropriate measures to ensure the participant and all blinded staff members remain
blinded to the treatment being administered (unblinded staff).
x
Document start and stop time of FCM administration and the total dose and volume
administered (unblinded staff).
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after FCM administration (blinded staff). 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.
x
Adverse event / serious adverse event assessment, including evaluation of potential
endpoint events (see Section 10.2; blinded staff)
x
Review concomitant medications
Group B participants the following will be performed:
x
Pre-administration, obtain heart rate, blood pressure, and body temperature (blinded
staff)
x
Administer a 15 mL dose of placebo (normal saline) as a slow IV injection at the rate
of approximately 2 mL /minute taking appropriate measures to ensure the participant
and all blinded staff members remain blinded to the treatment being administered
(unblinded staff).
x
Document start and stop time of placebo administration and the total volume
administered (unblinded staff).
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after placebo administration (blinded staff). 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.
x
Adverse event/serious adverse event assessment, including evaluation of potential
endpoint events (see Section 10.2; blinded staff).
x
Review concomitant medications (blinded staff)
6.4 Follow-Up Phase
6.4.1 90 Day Follow-Up 
Following the initial and all subsequent courses of study drug treatments each participant 
will be contacted in person or via telephone 90+14 days post the first treatment for that 
course (i.e. study Days 90+14, 270+14, 450+14, 630+14, 810+14, 990+14…EOS)
During these visits the following will be performed:
x
Adverse event / serious adverse event assessment, including evaluation of potential
clinical endpoint events (see Section 10.2). (blinded staff)


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6.4.2 6 Month Laboratory Evaluation 
Participants will receive an additional course of study medication every 180 (+7) days.  
Within 4 to 20 days prior to these scheduled dosing visits, all participants will return to the 
clinic to obtain central lab hematology, chemistry, and iron indices laboratory tests. 1,25 
(OH)2 Vitamin D, 25 (OH) Vitamin D and PTH for participants of the hypophosphatemia 
sub-study. (Blood to be collected by blinded staff) 
6.4.3 Additional Study Drug Dosing (Every 6 Months) 
All participants will be dosed every 6 months.  At each 6-month interval, a course of 2 
doses of study drug will be administered as described above for Day 0 and Day 7 (Section 
6.3).  For group A, FCM will be administered if Hgb < 13.5 g/dL (females) or <15.0 g/dL 
(males) and serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT <20%; observe 
carefully that placebo (normal saline) will be administered to participants in the FCM 
group who do not meet the above criteria. All group B participants will receive placebo 
(normal saline). 
6.4.3.1  6 Month Dosing Visit #1 (Days 180+7, 360+7, 540+7, 720+7, 900+7,
1,080+7…EOS)
On the first of the 2 dosing visits, the following will be performed by blinded study staff for 
all participants:
x
Weight
x
Urine or serum pregnancy test (women of childbearing potential only)
x
Adverse event / serious adverse event assessment, including evaluation of potential
endpoint events (see Section 10.2).
x
Review concomitant medications
x
Administer 6MWT per standardized procedure (at the 6 and 12 month visits).
Note: To avoid unblinding on the dose administration worksheet, if a participant is under 
50 kg, the volume of FCM or placebo administered should be calculated based on the 
participant’s weight, e.g. a 45 kg participant will receive a 13.5 mL dose of FCM or placebo.
For Group A participants the following will be performed:
x
Verify if participant will receive FCM or placebo, based on the following criteria from
recent labs (within 20 days).  Participants will receive FCM if the Hgb <13.5 g/dL
(females) or <15.0 g/dL (males) and serum ferritin <100 ng/mL or 100 to 300 ng/mL
with TSAT <20%.  If the participant does not meet these criteria, placebo (normal
saline) will be administered. (unblinded staff)
x
As appropriate based on criteria above, verify amount of single FCM dose (15 mg/kg
up to a maximum dose of 750 mg) or placebo (15 mL). (unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body temperature. (blinded
staff)
x
Administer FCM or placebo as a slow IV injection at the rate of approximately 2 mL
/minute. Appropriate measures must be taken to ensure the participant and all blinded


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staff members remain blinded to the treatment being administered (unblinded staff)
x
Document start and stop time of IV administration, and the total dose and volume
administered (unblinded staff)
x
Post-administration of FCM, obtain heart rate and blood pressure immediately after
and 30 minutes after FCM administration (blinded staff). 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.
For Group B participants the following will be performed:
x
Pre-administration, obtain heart rate, blood pressure and body temperature. (blinded
staff)
x
Administer a 15 mL dose of placebo (normal saline) as a slow IV injection, at the rate
of approximately 2 mL /minute. Taking appropriate measures to ensure the participant
and all blinded staff members remain blinded to the treatment being administered
(unblinded staff)
x
Document start and stop time of placebo administration and the total volume
administered. (unblinded staff)
x
Post-administration of placebo, obtain heart rate and blood pressure immediately
after and 30 minutes after placebo administration (blinded staff). 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.
6.4.3.2 Six Month Dosing Visit #2 (Days 187+7, 367+7, 547+7, 727+7, 907+7,
1,087+7…EOS)
The second of the 2 dosing visits should occur at Day 7 (+2) after the first, with the 
following performed for all participants:
x
Adverse event / serious adverse event assessment, including evaluation of potential
endpoint events (see Section 10.2). (blinded staff), and review of concomitant
medications (blinded staff).
Note: To avoid unblinding on the dose administration worksheet, if a participant is under 
50 kg, the volume of FCM or placebo administered should be calculated based on the 
participant’s weight, e.g. a 45 kg participant will receive a 13.5 mL dose of FCM or placebo.
For Group A participants the following will be performed:
x
Verify amount of single FCM dose (15 mg/kg up to a maximum dose of 750 mg) or
placebo (15 mL). Note: participant should receive the same product (FCM or placebo)
as received at the first dose of this course of treatment. (unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body temperature. (blinded
staff)
x
Administer FCM or placebo as a slow IV injection at the rate of approximately 2 mL


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/minute. Taking appropriate measures to ensure the participant and all blinded staff 
members remain blinded to the treatment being administered (unblinded staff).
x
Document start and stop time of IV administration and the total dose and volume
administered. (unblinded staff)
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after FCM administration. (blinded staff). 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.
For Group B participants the following will be performed:
x
Pre-administration, obtain heart rate, blood pressure, and body temperature (blinded
staff).
x
Administer a 15 mL dose of placebo (normal saline) as a slow IV injection, at the rate
of approximately 2 mL /minute. Taking appropriate measures to ensure the participant
and all blinded staff members remain blinded to the treatment being administered
(unblinded staff)
x
Document start and stop time of placebo administration and the total volume
administered. (unblinded staff).
6.5 (QGRI6WXG\9LVLWV
x
Post-administration, obtain heart rate and blood pressure immediately after and 30
minutes after placebo administration. (blinded staff). 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.
End of study visits for all participants will be scheduled once the last participant has reached 
12 months on study and at least 771 participants have experienced an event of 
cardiovascular death or hospitalization for heart failure. The participants should return to
the clinic and the following will be performed by blinded study staff:
x
Targeted physical exam
x
Vital signs including BP and heart rate
x
Blood samples for central lab hematology, chemistries, iron indices and NT-proBNP.
x
Urine or serum pregnancy test (women of childbearing potential only)
x
Review of concomitant medications
x
Adverse event / serious adverse event assessment, including evaluation of potential
endpoint events (see Section 10.2).
6.6 Laboratory Assessments
Serum samples for laboratory analyses must be obtained at all appropriate visits. The 
method of analysis of screening laboratory values will be by a central clinical
laboratory. All visit laboratory samples will be analyzed by a central clinical
laboratory. All laboratory testing will be provided to the investigator or his/her 


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medically qualified designee for review and assessment. Post dose iron indices and 
serum phosphorus results will be provided to the designated unblinded investigator 
for assessment. The laboratory assessments will be determined as listed in Section 
3.3:
Hematology:
Hgb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, 
platelets, differential count, and reticulocyte count
Chemistry: 
Sodium, potassium, chloride, BUN, creatinine, albumin, 
alkaline phosphatase, total bilirubin, GGT, AST, ALT, 
LDH, calcium, phosphorus, glucose, bicarbonate, and 
magnesium
Iron indices:
Serum iron, serum ferritin, total iron binding capacity 
(TIBC), and percentage serum transferrin saturation (TSAT)
Other: 
1,25 (OH)2 Vitamin D, 25 (OH) Vitamin D and PTH, and
NT-proBNP
7.0 ASSESSMENT OF SAFETY
7.1 Adverse Events
Any untoward medical event experienced by a participant during the course of this clinical 
trial, whether or not it is related to the investigational product, at any dose, is considered an 
adverse event (AE).
For any laboratory abnormality, the investigator, or his/her medically qualified designee,
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. If the laboratory value is outside the normal 
range, but not an adverse event, the investigator should comment on the findings (i.e. “not 
clinically significant” or “unchanged from baseline”) in the source documentation 
[laboratory report].
Table 7.1.1 Grading of Adverse Event Severity
Grade
Adjective
Description
1
Mild
Does not interfere with the participant’s usual 
function
2
Moderate
Interferes to some extent with participant's usual 
function
3
Severe
Interferes significantly with participant's usual 
function
4
Life-threatening
Results in a threat to life or in an incapacitating 
disability
5
Death
Results in Death


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Timing: Adverse events and serious adverse events will be reported, as described below 
in Section 7.2, from the time of randomization through the end of study. Adverse events 
for participants randomized and who terminate early will be reported for 30 days after the 
last treatment. 
Timing: Adverse events and serious adverse events will be reported, as described below 
in Section 7.2, from the time of randomization through the end of study. Adverse events 
for participants randomized and who terminate the study early or permanently 
discontinue study drug (Section 4.5) will be reported for 30 days after the last treatment.  
All reported SAEs should be followed until no longer serious 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: 
x
NONE
There is no evidence of any causal relationship.
x
UNLIKELY
There is little evidence to suggest there is a causal relationship.  There 
is another reasonable explanation for the event (e.g., the participant’s 
clinical condition, other concomitant treatments).
x
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).
x
PROBABLE
There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely.
*
For the purposes of this trial, “study drug” is defined as:
FCM
OR
Placebo 
7.2 Reporting of Adverse Events 
For the purposes of this study, any AE that does not meet the protocol definition of a 
serious AE is considered non-serious.   
All SAEs and only AEs leading to study drug discontinuation will be collected in this 
study.
Non-serious AEs that do not lead to study drug discontinuation (Section 4.5) 
are not being collected in this study. 
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. 
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Disease progression can be considered as a worsening of a patient’s clinical condition 
attributable to the disease in the patient population for which the study medication is being 
studied. It may be an increase in the severity of the disease under study, and/or increases 
in the symptoms of the disease. These also include the events listed in Section 7.4, 
“Reporting of Events that May Require Adjudication.”
The development of the following cardiovascular disease events will be recorded in the 
eCRF, however they should be considered as disease progression and will not be reported 
as an AE/SAE during the study unless determined to be clinical endpoints.  
1. Supraventricular arrhythmia (e.g., atrial fibrillation) requiring urgent/emergent
intervention
2. Ventricular arrhythmia (e.g., ventricular tachycardia or fibrillation) requiring
urgent/emergent intervention including ICD shock
3. Renal failure requiring urgent/emergent intervention (e.g., initiation of dialysis)
These three events will be documented on a dedicated form in the eCRF and they will be 
reported to the DSMB.  An analysis as well as summary data tables of these events will be 
provided in the safety section of the clinical study report which will also include a rationale 
for exclusion of these events from AE or SAE reporting.  Data files containing information 
about the above events will be included in the Regulatory submission in addition to 
hyperlinks or other means to easily direct reviewers to the location of the data.
7.3 Serious Adverse Events
Definition:
An adverse event is classified as SERIOUS if it meets any one of the 
following criteria: 
x
Death
x
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.
x
Hospitalization (initial or prolonged): Required admission to the hospital or
prolongation of a hospital stay except events which are components of the primary
or secondary endpoints which will be adjudicated by the CEC Committee as noted
above.
x
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.
x
Congenital Anomaly/Birth Defect.
x
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.


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Suspected clinical endpoint events that may traditionally meet the definition of an SAE, 
will not be reported by the sites in this trial as an SAE, but will be reported as a suspected 
clinical endpoint. Those events will therefore not be reported to the sponsor’s Drug Safety 
Surveillance department.
Certain events of interest (supraventricular arrhythmia, ventricular arrhythmia, and renal 
failure) that are related to heart failure (serious and non-serious) will be listed on the eCRF 
and not be reported by the site as an SAE.
These events will be monitored by the Data Safety Monitoring Board to ensure participant 
safety.
Additionally suspected clinical events that are reviewed by the CEC but do not meet the 
criteria of an endpoint event will then be reviewed by the safety surveillance team for 
possible unreported SAEs.
Reporting: Any SAE as defined by this protocol, starting with the time of 
randomization, that is to be reported (as outlined in the section above) must be 
reported immediately (by the end of the next business day) to American Regent, Inc.
This occurs through entry into the eCRF by the local investigator/coordinator and 
completing the SAE module. In the event that the eCRF module is not available and 
paper forms have not been provided for use, the investigator will contact the Study 
Safety Monitor at:
American Regent, Inc.
The local investigator is responsible for reporting SAEs to their local IRB/ Ethics 
Committee based on local reporting guidelines (which may be different than those specified 
in this protocol). The responsible investigator should institute appropriate diagnostic and 
therapeutic measures and keep the participant under observation for as long as is medically
indicated.
7.4 Reporting of Suspected Study Endpoint Events that May Require Adjudication
The following events, which are the components of the primary or secondary endpoints will 
be adjudicated by the Clinical Events Classification (CEC) Committee of the Duke Clinical 
Research Institute (DCRI) for both FCM and Placebo and will not require reporting to the 
sponsor as an SAE:
x
Cardiovascular Death including:
x
Death due to Heart Failure
x
Death due to Acute Myocardial Infarction
x
Sudden Cardiac Death


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x
Death due to Stroke
x
Death due to other cardiovascular causes
x
Hospitalization for heart failure
x
Non-Cardiovascular death
x
Hospitalization for myocardial infarction
x
Hospitalization for stroke
x
Other Cardiovascular hospitalizations
x
Urgent heart failure visits
Therefore, any event that may possibly constitute one of these endpoints will be evaluated 
by the CEC Committee by a procedure described in separate documentation.  A description 
of the CEC Committee and the definitions of the above clinical endpoints may be found in 
Section 10.2. 
8.0 STATISTICAL METHODS 
All statistical tests will be two-tailed. Type I error of 0.05 is assumed unless otherwise 
specified. No adjustments for multiple testing will be made. Complete details for the 
summary and statistical analysis of data to be collected will be documented in a Statistical 
Analysis Plan (SAP), which will be finalized prior to unlocking of the study base. The 
important elements of the planned methods are provided below. 
8.1 Stratification/Randomization 
Participants who meet the inclusion/exclusion criteria will be randomized in a 1:1 ratio on
Day 0 to FCM or Placebo with stratification by region.  
8.2 Analysis Populations 
The Intent-To-Treat (ITT) Population will consist of all participants randomized to a 
treatment group in the study regardless of compliance with the study medication. For all 
analyzed using the ITT population, participants will be analyzed as randomized.  This is the 
primary population of all efficacy analyses. 
The Per-Protocol Population is a subset of the ITT population excluding participants who 
complied with the randomized treatment for less than 50% of the follow-up. In cases of 
medication error, treatment assignments in the per-protocol analysis will be analyzed 
according to the actual treatment received. 
8.3 Disposition and Baseline Characteristics 
The number and percent of participants who are randomized, treated with randomized 
therapy, prematurely discontinue, and complete the study will be summarized.  The number 
and percent of participants will be summarized for each reason for premature 
discontinuation.
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Categorical baseline characteristics (e.g., sex and race) will be summarized with the number 
and percent of participants in each treatment group with the characteristic. Quantitative 
characteristics (e.g., age and weight) will be summarized with the mean, median, standard 
deviation, minimum value, and maximum value.
Baseline characteristics will be 
summarized for the safety and ITT populations. 
8.4 Endpoints and Definitions 
8.4.1 Primary Outcome 
The primary outcome follows an ordinal scale of clinical severity comprised of 1) death, 
2) number of hospitalizations for heart failure (as defined in Section 10.2) evaluated at
one year; or 3) change in 6MWT evaluated at 6 months.
8.5 Secondary Outcomes 
The following secondary outcomes will be evaluated in the hierarchy listed below. 
1. Time to first event of the composite of cardiovascular death or
heart failure hospitalization. The composite endpoint will be 
composed of  adjudicated occurrence (as defined in Section 
10.2) of one of the following:
a. Cardiovascular Death
i.
Death due to Heart Failure
ii.
Death due to Acute Myocardial Infarction
iii.
Sudden Cardiac Death
iv.
Death due to Stroke
v.
Death due to other Cardiovascular Causes
b. Hospitalization for Worsening Heart Failure
2. Mean  change in 6MWT from baseline to 12 months
3. Time to first event of the composite of cardiovascular death or
intervention for worsening heart failure (hospitalization or urgent
heart failure visits)
4. Time to first event of the composite of cardiovascular death and
cardiovascular hospitalizations
5. Time to cardiovascular death
Additional events to be adjudicated for analysis of the secondary 
endpoints include:
a) Non-cardiovascular death
b) Hospitalization for myocardial infarction
c) Hospitalization for stroke
d) Other cardiovascular hospitalizations
e) Urgent heart failure visits


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A Clinical Events Classification (CEC) Committee at DCRI will review all potential events 
comprising all endpoints, and make the final determination whether an endpoint event has 
occurred for each participant (See Section 10.2).
8.6 Primary Comparison 
Each participant from the treatment arm gets ranked/compared with each participant from 
the control arm based on the 12-month experience for Death and Hospitalizations for heart 
failure and 6 month results for change in 6MWT to determine treatment response per the 
following hierarchy: 
1. Death
If both die, the one who survives longer is better off;
If one dies and one does not, the one that survives is better off;
If neither dies, examine hospitalizations for heart failure.
2. Hospitalizations for heart failure
The one with fewer hospitalizations is better off;
If neither has been hospitalized for heart failure or the number heart failure
hospitalizations is equal, compare change in 6MWT.
3. Change in 6MWT
The one with higher change in 6MWT is better off;
Statistical Test
The main comparison will be conducted using the Wilcoxon-Mann-Whitney test.  The null 
hypothesis being tested is that a randomly chosen participant in the treatment arm is equally 
likely to be ranked better or worse than a randomly chosen participant in the control group. 
The two-sided alternative is that the participant is not equally likely to be ranked better or 
worse.  In addition to performing the test we will estimate the probability that a participant 
in the treatment arm has a better rank than a participant in the control arm and its 
corresponding confidence interval. 
The above comparison of participants in the treatment versus control arms is equivalent to 
ranking all participants according to their experience.
At one end of the ranking are 
participants with the best experience - those alive and not hospitalized for worsening heart 
failure ordered according to their improvement in 6MWT; at the opposite end are those who 
die ordered according to their survival time.  Those participants alive but hospitalized are 
in the middle, ordered according to their number of hospitalizations for worsening heart 
failure and then by their change in 6MWT.  The non-parametric Wilcoxon-Mann-Whitney 
test sums the ranks of those in the treatment arm and compares them with the sum of ranks 
in the control arm. 
In all analyses the number of hospitalizations (and the number of days in the hospital in the 
sensitivity analysis described below) will be adjusted for the time on follow-up. This
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adjustment applies only to individuals who are alive at the end of follow-up (the 
comparison in those who die will be resolved based on time to death) and will be 
accomplished by dividing the observed number by time at risk in years. For individuals 
who complete the pre-specified 12 months of follow-up, time at risk equals 1. For all 
others, it is equal to the fraction of 12 months that the person remained in the study.
8.7 Secondary Comparisons 
8.7.1 Top Secondary Comparison: Time to first event of cardiovascular death
or hospitalization of heart failure 
This analysis will compare time to first occurrence of cardiovascular death 
or hospitalization for heart failure. 
The Cox proportional hazards model will be 
employed to conduct this comparison.  The test will be two-tailed and will be performed 
at an overall D of 0.05.
This analysis will be performed by the ITT principle based
on randomized treatment assignment and we expect adequate power to detect a pre-
specified relative risk reduction of 20%. 
Sensitivity Analysis
In a sensitivity analysis we will add another layer to the hierarchy described above –
in individuals who have been hospitalized for heart failure during follow-up, ties in 
the numbers of hospitalizations will be resolved based on the total number of days 
in the hospital during follow-up, before proceeding to comparison of differences in the 
6MWT.
8.7.2 Change in 6 Minute Walk Test 
Mean change in 6MWT distance from baseline to 12 months will be compared using
linear regression adjusting for baseline value of 6MWT.
8.7.3 Secondary Outcomes based on time to first event 
The time to each of the remaining secondary outcomes (Incidence of cardiovascular 
deaths and cardiovascular hospitalizations, Incidence of cardiovascular death or 
intervention for worsening heart failure (hospitalization or urgent heart failure visits) 
and Incidence of cardiovascular deaths) will be compared using the Cox proportional 
hazards model. 
8.8 Sample Size and Statistical Power 
The study design allows for sufficient power for both the primary and top
secondary outcomes.
Numerical simulations based on multivariate normal vectors were conducted to 
estimate power for the primary treatment comparison based on the following 
assumptions about events rates described in Table 8.8.1. 
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Table 8.8.1.   Assumptions About Event Rates for Primary Outcome
Ranked tier at 12-month endpoint (6
month for 6 MWT)
Control
Treatment
Death total
Death without hospitalization
Death with hospitalization
8%
4%
4%
6.8%
3.4%
3.4%
Hospitalizations in survivors
1
2
3 or more
6%
3%
1%
4.8%
2.4%
0.8%
Change in 6 Minute Walk Test
Mean = 0
SD = 90
Mean = 18
SD = 90
With 3014 patients (1507 per arm) and 2.5% annual loss to follow-up for clinical 
outcomes and 15% of individuals with missing 6MWT at 6 months (unable to perform 
or lost to follow-up), projected simulations estimate 90% power at an overall two-sided 
significance level of 0.01, accounting for one interim analysis as described in section 
8.10.
For the top secondary composite, an assumed event rate of 0.0128 per month in the 
control arm which represents conservative 75% discounting of the event rate obtained by 
the FCM meta-analysis [Anker 2015]. The anticipated hazard ratio was set at 0.80 (20% 
reduction).
Uniform enrollment is assumed over the period of 30 months, with an 
anticipated minimum follow-up of 12 months (required minimum of 6 months), 
anticipated maximum follow-up of 42 months (no required maximum), and monthly 
loss to follow-up of 0.0021 (2.5% annualized).  With these assumptions, 1500 per study 
arm (3000 total) provides 90% power to reject the null hypothesis of no difference 
between treatment arms when tested at an overall two-sided level of significance D
=0.05, accounting for one interim analysis as described in section 8.10. This results 
in a total of 771 events necessary to achieve the desired power. Thus, the trial has the 
potential opportunity to be stopped at a point where the projected number of events 
reaches 771, but no earlier than the last participant reaching 12 months of follow-up.
The primary and top secondary outcome will be tested sequentially, and thus, no
multiplicity adjustment is necessary.
8.9 Handling of Missing Data 
Every effort will be made to limit the number of missing data points. The trial will be 
conducted in jurisdiction which will allow ascertainment of vital status even in individuals 
who discontinue the study. Participants who discontinue taking study drug should be 
encouraged to continue participation in the trial so that endpoint data can be collected. 
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Furthermore, consent will be obtained to examine hospital records where feasible.  
Partnership with transportation companies will be fostered to decrease the burden of travel 
to clinic visit and increase the likelihood of the final study visit taking place. 
The prospective plan for the handling of missing data is as follows: 
The primary analysis will rely on a multiple imputation model, with Markov chain Monte 
Carlo algorithm based on the totality of observed data.  One exception to this rule will be 
individuals unable to perform the 6MWT test at 6 months will have their value imputed as 
the worst observed change in 6MWT. 
Two supporting analyses will be undertaken.  The first one will use multiple imputation for 
clinical outcomes, but will impute the worst observed change in 6MWT to all individuals 
who do not have this measurement, regardless of the reason. 
The second series of analyses will perform tipping point assessments to determine the 
sensitivity of the observed result to the missing data.  Given the multi-dimensional nature 
of outcomes, tipping point analyses will be performed separately for each outcome: 
mortality, hospitalization for heart failure and 6MWT.    
8.10 Stopping Rules and Interim Analysis 
A Data and Safety Monitoring Committee (DSMB), with statistical support from DCRI will 
review safety data, including a tally of the composite outcome events at least every 6 
months (See Section 10.3). The DSMB can recommend stopping the study for safety 
concern at any point.  In addition, one interim analysis is planned to determine if an early 
stopping for an overwhelming efficacy should be recommended. This analysis will be 
conducted after 2250 (75%) participants have been enrolled.  Significance level will be set 
at 0.0001 for this analysis, resulting in an adjusted significance level for the final analysis 
of 0.0099 for the primary endpoint and 0.0499 for the first secondary endpoint, 
preserving the overall significance at 0.01 and 0.05, respectively.  Conditional power will 
be estimated based on data accrued to date and presented to the DSMB. The DSMB 
may recommend that the study continues as planned, discontinue the study or that 
the trial be continued with recommended changes to the protocol. The Executive 
Steering Committee will determine if an increase in sample size is warranted in order 
that at least 771 participants will experience an event of cardiovascular death or 
hospitalization for heart failure. 
9.0 ADMINISTRATIVE CONSIDERATIONS
9.1 Retention and Availability of Records
Investigators are required to maintain all study documentation, including a copy of the 
CRFs, 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.
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The Investigator must make study data accessible to the monitor, Sponsors, or other 
authorized representatives of the Sponsor and Regulatory Agency (i.e., FDA inspectors.)  A 
case history for each participant must be maintained, that includes the signed Informed 
Consent form and copies of all study documentation related to that participant.  The 
investigator must ensure the availability of source documents including the electronic health 
record, if applicable, from which the information on the eCRF was derived. 
9.2 Investigator Responsibilities
By signing the Form FDA 1572 the Investigator agrees to:
1.
Conduct the study in accordance with the protocol and only make changes after
notifying the Sponsor, except when necessary to protect the safety, rights or
welfare of participants.
2.
Personally conduct or supervise the study (or investigation).
3.
Inform any participants that the drug is being used for investigational purposes.
4.
Ensure that the requirements relating to obtaining informed consent and IRB
review and approval meet Federal guidelines, as stated in 21 CFR, parts 50 and
56.
5.
Report to the Sponsor any adverse events that occur in the course of the study,
in accordance with 21 CFR 312.64.
6.
Have read and understood the Investigator’s Brochure, including potential risks
and side effects of the drug.
7.
Ensure that all associates, colleagues and employees assisting in the conduct of
the study are informed about their obligations in meeting the above
commitments.
8.
Maintain adequate and accurate records, in accordance with 21 CFR 312.62 and
to make those records available for inspection with the Sponsor, their
designated representative, the FDA or any agency authorized by law.
9.
Ensure that an IRB that complies with the requirements of 21 CFR Part 56 will
be responsible for initial and continuing review and approval of the clinical
study.
10. Promptly report to the IRB and the Sponsor all changes in the research activity
and all unanticipated problems involving risks to participants or others
(including amendments and IND safety reports).
11. Not make any changes in the research study without approval, except when
necessary to eliminate hazards to the participant/participants.
12. To comply with all other requirements regarding the obligations of the clinical
investigators and all other pertinent requirements listed in 21 CFR Part 312.
9.3 Financial Disclosure
All principal investigators and co-investigators will be required to complete FDA-required 
financial forms provided by American Regent, Inc. All signed financial disclosure forms 
must be submitted to the Sponsor prior to the site enrolling participants into the study.


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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, television, and the use of social media by a central 
advertising campaign. 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 Luitpold Pharmaceuticals Inc. 
or its designee with the following documentation:
x
Curriculum Vitae and medical license for Principal Investigators and co-
investigators.
x
Form FDA 1572
x
Financial disclosure form
x
IRB approval of protocol and informed consent
x
Copy of IRB approved informed consent
x
IRB membership list or assurance number
x
Protocol signature page
x
IRB approval of any advertising for participant recruitment [if applicable]
x
Copy of advertising [if applicable]
x
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:
x
Accessible, interested, and available support staff.
x
Availability of adequate facilities to support study requirements.
x
Availability of physician emergency response at all times.
x
Adequate time to conduct study.
x
Adequate training and experience of personnel to conduct study.
x
Ability to recruit enough participants to conduct study.
Prior to investigator selection, each site will be evaluated to ensure they meet the criteria 
noted above. 
American Regent, Inc. and/or their designee will insure that no investigator is on FDA’s 
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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, 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.
Periodic monitoring visits will be made to the site during the clinical study to assure that
the Investigator obligations are fulfilled, and all applicable regulations and guidelines 
established by the protocol are being followed. 
These visits will assure that the facility is still acceptable, the protocol and investigational 
plan are being followed, the IRB/EC has been notified of approved protocol changes as 
required, complete study records are being maintained, appropriate and timely reports have 
been made to the sponsor or its representative and the IRB/EC, study drug inventory is 
controlled, and the Investigator is carrying out all agreed-upon activities. 
In accordance with the FDA Guidance for Industry: Oversight of Clinical Investigations - 
A Risk-Based Approach to Monitoring, a combination of on-site and centralized monitoring 
practices will be implemented in order to ensure participant protection, as well as quality 
and integrity of the clinical trial data while promoting efficiency. While the majority of 
monitoring will be conducted centrally, on-site monitoring will be performed based on the 
findings of previous on-site monitoring visits and centralized monitoring. During on-site 
monitoring, a percentage of the data will be compared among the eCRF (i.e. source 
document
review,
source
document
verification)
and
each
participant’s source 
documentation, and data discrepancies will be queried. See the trial specific risk based 
monitoring plan for additional details. 
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 may also include review of facilities, equipment, pertinent site 
documentation, and personnel qualifications. Notification of these audits will be sent to 
investigators in advance.
9.7 Ethics 
9.7.1 Ethical and Legal Issues 
This study will be performed in accordance with the U.S. Code of Federal Regulations on 
Protection of Human Participants (21 CFR 50), IRB regulations (21 CFR 56), the most 
recent revision of the Declaration of Helsinki, all applicable local and state regulations, 21 
CFR Part 312, and applicable ICH guidelines. 
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9.7.2 Institutional Review Board
The Protocol and the Informed Consent must be approved by an appropriate Institutional 
Review Board (IRB) before the study is initiated.  Documentation of this approval must be 
provided to the Sponsor or designee.  The IRB must comply with current U.S. Regulations 
(21 CFR 56) for the protection of Human Subjects in Research. Investigators are responsible 
for the following:
x
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.
x
Provide the IRB with any information it requests before or during the study.
x
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.
x
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
Each investigational site must provide the Sponsor (or designee) with a copy of the 
Informed Consent approved by the site's IRB.  The Clinical Monitor will assure that each 
Informed Consent meets the requirements of Parts 50.20 and 50.25 of Title 21 of the CFR, 
which outlines the basic elements of informed consent and ICH guidelines prior to its use. 
Informed consent must be obtained from each participant prior to enrollment.  The informed 
consent will be provided to the participant in their native language.  The Informed Consent 
must be signed and dated by each participant before entering the study, and prior to the 
performance of any study-specific procedures.  The original signed consent form will be 
retained in the participant's study records, and a copy will be provided to the participant.  
Translations of the informed consent must be certified by a qualified translator and their use 
must be documented.
The Informed Consent documents the information the Investigator provides to the 
participant and the participant's agreement to participate.  The Investigator will fully explain 
the nature of the study, along with the purpose, methods, anticipated benefits, potential 
hazards, and discomfort that participation might entail.
9.7.4 Good Clinical Practice
The conduct of the study will conform with the recommendations for clinical studies in 
humans as set out in the most current revision of the “Declaration of Helsinki”, the local 
legal requirements and the guidelines on “Good Clinical Practice”, [21 CFR Part 312 and 
ICH guidelines].
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9.8 Data Handling and Record Keeping
9.8.1
Case Report Form
The eCRFs will be completed for each participant on this study. The participants in this 
study will be identified only by a participant number and date of birth on these forms.
The eCRF used will be 21 CFR 11 compliant.  The system used for data collection (eCRF) 
will meet all applicable regulatory requirements for recordkeeping and record retention as 
would be provided with a paper system. Security measures will be utilized to prevent 
unauthorized access to the data and to the computerized system.  Changes made to data that 
are stored on electronic media will always require an audit trail, in accordance with 21 CFR 
11.10(e). 
The eCRFs must be reviewed and verified for accuracy by the Principal Investigator. An
electronic copy of the eCRF will remain at the site at the completion of the study. 
9.8.2 Confidentiality
All unpublished information given to the investigator or institution dealing with this study,
study drug or the conduct, financial agreements, or methodologies used in this protocol, as 
well as information obtained during the course of the study, remains confidential and 
proprietary to the Sponsor [“Proprietary Information”].  The Investigator shall not disclose 
any such Proprietary Information to any third party without prior written consent from the 
sponsor [See also Section 9.9 Publication
Policy].
For purposes of this 
Section, “Investigator” includes, but is not limited to the Principal Investigator and/or his/
her agents, designees, sub-investigators or other individuals involved in the running, 
administration, collection or evaluation of participants or data for this study. 
All pharmaceutical formulations supplied for the purpose of the trial shall remain the sole 
property of American Regent, Inc. They will be used 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 DSMB, Sponsor, or Steering Committee discovers 
conditions arising during the course of the study, which indicate that the clinical 
investigation should be halted.  The study may be terminated after appropriate consultation 
and discussion. 
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 
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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 Luitpold personnel and the investigator and 
be approved by the site's IRB, before the revision may be implemented.
The protocol 
revision will be submitted to the FDA. 
9.8.5 Protocol Administrative Changes
Clarification or interpretation of the study protocol or changes in the methods of statistical 
analysis may be documented in the form of a numbered memo or other applicable document 
(charter, plan, etc.).  Numbered memos do not typically require the investigator’s signature 
or IRB approval.
9.9 Publication Policy 
All information resulting from this study is the Proprietary Information of American 
Regent, Inc., as per the Confidentiality Section of this protocol.  The Steering Committee 
will be responsible for the manuscript describing the main study results, and oversee 
publications requiring trial data.  A separate publication charter will govern the process of 
publications. 
American Regent, Inc., and the Steering Committee shall have final and sole control over 
the content of any publication. The Principal Investigator and any sub-investigators may 
make presentations on the study, or may publish results of the study at their site, but only 
after the results of the study have been published, or with the prior approval of American 
Regent, Inc. 
The Investigator will provide to the Sponsor any announcement, publication, or presentation 
of data from this study for the Sponsor’s review and comments at least 10 days in advance 
of such disclosure.
Sponsor may, at its sole discretion, require the removal of any 
proprietary information from the disclosure.
The Investigator agrees to provide the 
Sponsor, at the Sponsor’s discretion, with any byline credit in any publication proposed by 
the Investigator. This is in order to enable American Regent, Inc., to make constructive 
comments about the manuscript or text and to give the opportunity of assessing whether 
patent protection should be sought by Luitpold on any results or ideas connected with the 
study. 
10.0 GOVERNANCE COMMITTEES 
10.1 Steering Committee (SC)
The SC will be responsible for oversight of the study. The SC chair will be Dr. Adrian 
Hernandez of DCRI.  The SC will consist of 6-12 members including the chair, primarily 
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from academic institutions, in addition to representation of the Sponsor.  The SC will consist 
of experts in heart failure as well as cardiovascular outcomes trials.
The key functions of the SC will be to:
1. Review and approve the main protocol, amendments, and the Statistical Analysis Plan.
2. Determine the time to terminate the study based on recommendations from the DSMB
and other available information.
3. Review and approve any substudies.
4. Draft the manuscript describing the main study results and oversee all publications
requiring trial data
5. Participate where appropriate in scientific meetings providing updates of study progress.
6. Oversee trial subcommittees including the Clinical Endpoint Committee and the Data
Safety Monitoring Board
7. Assume the role of the publications committee and review, authorize and prioritize
proposals for publications which require trial or substudy data samples and assign
writing groups
10.2 Adjudication by the Clinical Endpoint Classification (CEC) Committee 
A Clinical Event Committee (CEC) will be created for this trial to review and adjudicate 
each suspected endpoint event while blinded to treatment in this study.  The CEC for this 
trial will consist of cardiologists, neurologists, and physicians with clinical expertise from 
DCRI or other academic institutions. The CEC Chair will lead the development of the 
definitions of endpoints, instructions for interpretation, and provide ongoing oversight to 
the CEC members for this trial to ensure that events are adjudicated in consistent fashion 
over time.
The CEC members, as well as those overseeing the CEC, will not be 
investigators in the study, or be otherwise directly associated with the sponsor, and will 
remain blinded to treatment throughout the study and the adjudication process.  The CEC 
and the adjudication process will be described in detail in a separate CEC charter. 
Adjudicated Endpoints 
10.2.1 Death 
All deaths will be categorized as Cardiovascular or non-Cardiovascular based on the 
definitions below. In addition, all deaths will further be sub-typed based on the specific 
cardiovascular categories defined below. Non-cardiovascular deaths will not be further 
adjudicated.  
The cause of death will be determined by the principal condition that caused the death, not 
the immediate mode of death.  For example, if a participant is hospitalized and undergoing 
treatment for worsening heart failure dies of ventricular tachycardia, this would be classified 
as a heart failure death. CEC physicians will utilize all available information provided, 
along with clinical expertise in their adjudication of cause of death. 
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10.2.1.1 Death Due to Cardiovascular Death 
Cardiovascular death includes death resulting from an acute MI, sudden cardiac death, death 
due to heart failure, death due to stroke, and death due to other CV causes.  
 10.2.1.2 Death Due to Heart Failure 
Death due to heart failure refers to a death in association with clinically worsening 
symptoms and/or signs of heart failure regardless of heart failure etiology.  Deaths due to 
heart failure can have various etiologies, including single or recurrent myocardial 
infarctions, ischemic or non-ischemic cardiomyopathy, hypertension, or valvular disease.  
Deaths that occur during a heart failure hospitalization will generally be attributed to heart 
failure, even if there is another immediate mode of death (e.g, ventricular fibrillation). 
Deaths that occur in hospice or other similar palliative care setting for heart failure will 
generally be attributed to heart failure. 
10.2.1.3 Death Due to Acute Myocardial Infarction 
Death due to acute MI refers to a death by any CV mechanism (e.g. arrhythmia, sudden death, 
heart failure, stroke, pulmonary embolus, peripheral arterial disease) ≤30 days after a MI related 
to the immediate consequences of the MI, such as progressive heart failure or recalcitrant 
arrhythmia. We note that there may be assessable mechanisms of CV death during this 
time period, but for simplicity, if the CV death occurs ≤30 days of the MI, it will be 
considered a death due to MI.
Acute MI should be verified to the extent possible by the diagnostic criteria outlined for CV 
hospitalization for acute MI, or by autopsy findings showing recent MI or recent coronary 
thrombosis. 
Death resulting from a procedure to treat a MI, percutaneous coronary intervention (PCI), 
coronary artery bypass graft surgery (CABG), or to treat a complication resulting from MI 
should also be considered death due to acute MI. 
If death occurs before biochemical confirmation of myocardial necrosis can be obtained, 
adjudication should be based on clinical presentation and ECG evidence. Sudden cardiac 
death, if accompanied by symptoms suggestive of myocardial ischemia, new ST elevation, 
new LBBB, or evidence of fresh thrombus by coronary angiography and/or at autopsy 
should be considered death resulting from an acute myocardial infarction, even if death 
occurs before blood samples or 12-lead ECG could be obtained, or at a time before the 
appearance of cardiac biomarkers in the blood.  Death resulting from a procedure to treat a 
myocardial infarction (e.g. PCI, CABG), or to treat a complication resulting from MI,
should also be considered death due to acute MI.  
10.2.1.4 Sudden Cardiac Death 
Sudden Cardiac Death refers to death that occurs unexpectedly and not following an acute 
MI, and includes the following deaths:
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
Death witnessed and occurring without new or worsening symptoms.

Death witnessed within 60 minutes of the onset of new or worsening cardiac
symptoms, unless the symptoms suggest acute myocardial infarction.

Death witnessed and attributed to an identified arrhythmia (e.g., captured on an
ECG recording, witnessed on a monitor, or unwitnessed but found on
implantable cardioverter-defibrillator (ICD) review)

Death after unsuccessful resuscitation from cardiac arrest. (e.g., ICD
unresponsive sudden cardiac death, pulseless electrical activity arrest)

Death after successful resuscitation from cardiac arrest and without
identification of a specific cardiac or non-cardiac etiology

Unwitnessed death in a participant seen alive and clinically stable ≤ 24 hours
prior to being found dead without any evidence supporting a specific non-
cardiovascular cause of death (information about the participant’s clinical status
preceding death should be provided, if available)
General Considerations 

Unless additional information suggests an alternate specific cause
of death (e.g., Death due to Other Cardiovascular Causes), if a
participant is seen alive ≤24 hours (or a reasonable period when
otherwise clinically stable) of being found dead OR circumstances
suggest sudden death, sudden cardiac death should be recorded
Typical scenarios include:

Participant well the previous day but found dead in bed the next day

Participant found dead at home on the couch with the television on
For participants who were not observed alive within 24 hours of death, 
undetermined cause of death should be recorded (e.g., participant found dead 
in bed, but who had not been seen by family for several days).
“Undetermined cause of death” will be considered as “CV death” for purpose 
of analysis.
10.2.1.5 Death Due to Stroke 
Death due to Stroke refers to death after a stroke that is either a direct consequence of the 
stroke or a complication of the stroke. Acute stroke should be verified to the extent 
possible by the diagnostic criteria outlined for stroke in Section 10.2.2.3 (Hospitalization 
for Stroke). 
10.2.1.6 Death Due to Other Cardiovascular Causes 
Death due to Other Cardiovascular Causes refers to a CV death not included in the above 
categories but with a specific, known cause (e.g., pulmonary embolus, deep vein 
thrombosis, peripheral arterial disease, or aortic aneurysm). 
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10.2.1.7 Non-Cardiovascular Death 
Non-cardiovascular death is defined as any death that is not thought to be CV in nature.  
Deaths from Non-CV causes will not be further subclassified.
10.2.1.8 Undetermined Cause of Death 
Death not attributable to one of the above categories of CV death, or to a non-CV cause. 
Inability to classify the cause of death may be due to lack of information (e.g. the only 
information is “participant died”), or when there is insufficient supporting information or 
detail to assign the cause of death. In general, most deaths should be classified as CV or 
non-CV, and the use of this category of death, therefore, should be discouraged and should 
apply to few participants.
All deaths adjudicated as “undetermined cause” will be presumed cardiovascular deaths,
and as such, are part of the cardiovascular mortality endpoint.
10.2.2
Cardiovascular Hospitalizations
The participant’s length-of-stay in hospital extends for at least 24 hours (or a change in 
calendar date, if admission and discharge times are unavailable). 
10.2.2.1 Hospitalization for Heart Failure 
A Heart Failure hospitalization is defined as an event that meets ALL of the following 
criteria: 
1) The participant is admitted to the hospital with a primary diagnosis of heart
failure
2) The participant’s length-of-stay in hospital extends for at least 24 hours (or a
change in calendar date, if admission and discharge times are unavailable).
3) The participant exhibits documented new or worsening symptoms due to heart
failure on presentation, including at least ONE of the following:
a.
Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal
nocturnal dyspnea)
b. Decreased exercise tolerance
c.
Fatigue
d. Other symptoms of worsened end-organ perfusion or volume overload
(e.g., confusion, somnolence, edema, etc.)
4) The participant
has objective evidence of new or worsening heart failure,
consisting of at least TWO physical examination findings OR one physical
examination finding and at least ONE laboratory criterion), including:
a. Physical examination findings considered to be due to heart failure,
including new or worsened:
i. Peripheral edema


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ii. Increasing abdominal distention or ascites (in the absence of
primary hepatic disease)
iii. Pulmonary rales, crackles, or crepitations
iv. Increased jugular venous pressure and/or hepatojugular reflux
v. S3 gallop
vi. Clinically significant or rapid weight gain thought to be related to
fluid retention (usually more than 3-4 lbs in 3-4 days)
b. Laboratory evidence of new or worsening heart failure, if obtained within
24 hours of presentation, including:
i. Increased B-type natriuretic peptide (BNP)/ N-terminal pro-BNP
(NT-proBNP) concentrations consistent with decompensation of
heart failure (such as BNP >500 pg/mL or NT-proBNP >2,000
pg/mL). In patients with chronically-elevated natriuretic peptides, a
significant (1.25X) increase should be noted above baseline
ii. Radiological evidence of pulmonary congestion
iii. Non-invasive diagnostic evidence of clinically significant
elevated left- or right-sided ventricular filling pressure or low cardiac
output. For example, echocardiographic criteria could include: E/e’
>15 or D-dominant pulmonary venous inflow pattern, plethoric
inferior vena cava with minimal collapse on inspiration, or decreased
left ventricular outflow tract (LVOT) minute stroke distance (time
velocity integral (TVI)
OR
iv. Invasive diagnostic evidence with right heart catheterization
showing a pulmonary capillary wedge pressure (pulmonary artery
occlusion pressure) ≥18 mmHg, central venous pressure ≥12 mmHg,
or a cardiac index <2.2 L/min/m2
Note: All results from diagnostic tests should be reported, if available, even if they do 
not meet the above criteria, because they provide important information for the 
adjudication of these events. 
5) The participant receives initiation or intensification of treatment specifically for
heart failure, including at least ONE of the following:
a.
Augmentation in oral diuretic therapy
b. Intravenous diuretic, or  vasoactive agent (e.g. positive inotrope, vasopressor
or vasodilator)
c.
Mechanical or surgical intervention, including mechanical circulatory
support (e.g., intra-aortic balloon pump,
ventricular assist device,
extracorporeal membrane oxygenation, total artificial heart)


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d. Mechanical fluid removal (e.g., ultrafiltration, Hemofiltration, dialysis)
10.2.2.2 Hospitalization for Myocardial Infarction 
Acute MI will be adjudicated when a participant demonstrates at least one of the 
following biochemical indicators of myocardial necrosis:
• CK-MB greater than 2 x ULN or Troponin I or T greater than 2 x ULN, with a typical
pattern of rise and fall consistent with MI
AND at least one of the two following criteria:
• Typical clinical presentation consistent with MI defined as typical cardiac ischemic type
pain/discomfort or dyspnea felt to be due to ischemia
OR
• Typical ECG changes consisting of any of the following:
• New abnormal Q waves (or new R waves in lead V1-V2) in at least two consecutive
leads
• Evolving, ischemic ST segment or T wave changes in at least two consecutive leads
• New LBBB
10.2.2.3 Hospitalization for Stroke 
Stroke is defined as an acute episode of focal or global neurologic dysfunction caused by 
brain, spinal cord, or retinal vascular injury a result of hemorrhage or infarction. To be 
classified as a stroke, duration of a focal/global neurological deficit must have a duration 
>24 hours or imaging confirmation clearly documenting a new hemorrhage or
infarct. Events may be classified as a stroke if symptoms were <24 hours due to either
pharmacologic or non-pharmacologic interventions or the stroke resulted in death in <24
hours.
Classification:
Ischemic Stroke:
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by infarction of central nervous system tissue hemorrhage may 
be a 
consequence of ischemic stroke.  In this situation, the stroke is an ischemic 
stroke with hemorrhagic transformation and not a hemorrhagic stroke.
Hemorrhagic Stroke
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or 
spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid 
hemorrhage.


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Undetermined Stroke
Undetermined stroke is defined as an acute episode of focal or global neurological
dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a 
result of hemorrhage or infarction, but with insufficient information to allow
categorization as ischemic or hemorrhagic stroke.
10.2.2.4 Other Cardiovascular Hospitalizations 
Urgent and unscheduled hospitalizations for other cardiovascular causes that do not meet 
the criteria for the specific events listed above will be classified as hospitalization for 
other cardiovascular causes. Examples would include, but are not limited to,
hospitalization for cardiac chest pain that does not meet the criteria for MI, hospitalization 
for carotid events, hospitalization for deep vein thrombosis, hospitalization for 
arrhythmias, hospitalization for pulmonary embolism, etc. These hospitalizations will not 
be further sub-classified by the CEC.
10.2.3 Other Events:  Urgent Heart Failure Visit
An urgent heart failure visit is defined as an event that meets all the following:
1) The participant has an urgent, unscheduled office/practice or emergency
department visit for a primary diagnosis of heart failure, but not meeting the
criteria for a heart failure hospitalization
2) Signs and symptoms that constitute a heart failure hospitalization [i.e., 3)
symptoms, 4) physical examination findings/laboratory evidence of new or
worsening heart failure, as indicated above] must be met
3) The participant receives initiation or intensification of treatment specifically
for heart failure, as detailed in the above section with the exception of oral
diuretic therapy, which will not be sufficient
10.3 Data and Safety Monitoring Board (DSMB) 
The DSMB will be composed of approximately 5 senior academic individuals, including 
the DSMB Chair.  The members will have high-level expertise in cardiology, hematology, 
clinical research, and statistics.  A senior statistician assigned to the trial from the group
performing data management services for this trial will oversee the provision of interim 
data reports for use by the DSMB.  The data management group for this trial will transfer 
pre-agreed datasets to the statistician preparing data for DSMB.  During the Open Session 
of the DSMB meetings, representatives of the SC  or Luitpold representatives may present 
updates on the trial status or the safety profile of FCM, but will not be privy to discussions 
of the data conducted during the Closed Sessions and will not vote.  Proceedings and 
minutes of the Closed Session will be held in strict confidence and will not be shared 
outside the DSMB while the trial is ongoing prior to database lock.
The DSMB will be responsible for the interests of the study participants, and to this end, 
will undertake regular reviews of the safety data. The DSMB will have access to an 
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agreed subset of the study data as listed in the DSMB charter (updated as necessary during 
the trial) throughout the study duration. In addition, the DSMB will evaluate interim 
analyses of the data every at least every six months (or on an ad hoc basis if needed) either 
by face-to-face meeting, or teleconference.  The DSMB will determine if it believes the 
trial should be terminated early because clear evidence exists that either of the two groups 
has a treatment response that is substantially better than the other.
If the DSMB finds it necessary to recommend actions regarding interruption of the study,
or changes to the protocol based on medical rationale that would make it unethical to
continue the study in its present form, those recommendations will be forwarded to the
SC. The details of the DSMB's functions and the early stopping rules will be delineated in
a separate DSMB charter.


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11.0 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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12.0 REFERENCES
1. Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Ferric carboxymaltose in iron deficient
heart failure patients: a meta-analysis of individual-patient data from randomised
clinical trials. Annual Heart Failure Society of America Meeting, 2015; Abstract 336.
2. Ebner N, von Haehling S. Iron deficiency in heart failure: a practical guide. Nutrients
2013;5:3730-9.
3. Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P. Iron
deficiency and heart failure: Diagnostic dilemma and therapeutic perspectives. Eur
Heart J 2013;34:816-29.
4. Kapoor M. Schleinitz MD, Gemignani A, Wu, W. Outcomes of patients with chronic
heart failure and iron deficiency treated with intravenous iron: a meta-analysis. Cardio
& Hematol Disord – Drug Tar 2013;13:35-44.
5. Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron
homeostasis in chronic heart failure:  Prevalence, predictors, and relation to anemia,
exercise capacity, and survival. J Am Coll Cardiol 2011;58:1241-51.
6. Streja E, Kovesdy CP, Greenland S, et al. Erythropoietin, iron depletion, and relative
thrombocytosis:  a possible explanation for hemoglobin-survival paradox in
hemodialysis. Amer J Kidn Dis 2008;52:727-36.
7. van Veldhuisen DJ, Anker SD, Ponikowski P, Macdougall IC. Anemia and iron
deficiency in heart failure: mechanisms and therapeutic approaches. Nat Rev Card
2011;8(9):485-93.
8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the
Management of Heart Failure. J Am Coll Cardiol. 2013;62:147-239.
Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron
homeostasis in chronic heart failure:  Prevalence, predictors, and relation to anemia,
exercise capacity, and survival. J Am Coll Cardiol 2011;58:1241-51.
Kapoor M. Schleinitz MD, Gemignani A, Wu, W. Outcomes of patients with chronic
heart failure and iron deficiency treated with intravenous iron: a meta-analysis. Cardio
& Hematol Disord – Drug Tar 2013;13:35-44.
Streja E, Kovesdy CP, Greenland S, et al. Erythropoietin, iron depletion, and relative
thrombocytosis:  a possible explanation for hemoglobin-survival paradox in
hemodialysis. Amer J Kidn Dis 2008;52:727-36.
Ebner N, von Haehling S. Iron deficiency in heart failure: a practical guide. Nutrients
2013;5:3730-9.
Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Ferric carboxymaltose in iron deficient
heart failure patients: a meta-analysis of individual-patient data from randomised
clinical trials. Annual Heart Failure Society of America Meeting, 2015; Abstract 336.
Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P. Iron
deficiency and heart failure: Diagnostic dilemma and therapeutic perspectives. Eur
Heart J 2013;34:816-29.
van Veldhuisen DJ, Anker SD, Ponikowski P, Macdougall IC. Anemia and iron
deficiency in heart failure: mechanisms and therapeutic approaches. Nat Rev Card
2011;8(9):485-93.
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the
Management of Heart Failure. J Am Coll Cardiol. 2013;62:147-239.


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13.0 Appendices
Appendix 1: Hypophosphatemia Sub-study


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APPENDIX 1
AMERICAN REGENT, INCORPORATED
PROTOCOL NO. 1VIT15043
IND# 127910
A SUB-STUDY TO CHARACTERIZE SERUM PHOSPHORUS LEVELS OVER TIME
WITH INTRAVENOUS FERRIC CARBOXYMALTOSE (FCM) VS. PLACEBO AS 
TREATMENT FOR HEART FAILURE WITH IRON DEFICIENCY
SPONSOR:
American Regent, Inc.
Clinical Research and Development
800 Adams Avenue, Suite 200
Norristown, PA 19403
(610) 650-4200


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CONTACT PERSON FOR THE SUB-STUDY
For study-related questions, please contact:


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TABLE OF CONTENTS   
PAGE
LIST OF ABBREVIATIONS ............................................................................................. 5 
1.
INTRODUCTION ..................................................................................................... 6 
1.1. 
Pathophysiology ........................................................................................... 6 
1.2. 
Increased FGF23.......................................................................................... 7 
1.3. 
Inhibition of Vitamin D Activation .................................................................. 8 
1.4. 
Symptoms and Signs of Hypophosphatemia ................................................ 8 
2.
SUB-STUDY OBJECTIVE........................................................................................ 9 
3.
SUB-STUDY RATIONALE AND DESIGN ................................................................ 9 
3.1. 
Sub-Study Rationale..................................................................................... 9 
3.2. 
Sub-Study Design......................................................................................... 9 
3.3. 
Schedule of Events for Sub-Study.............................................................. 10 
4.
PARTICIPANT SELECTION .................................................................................. 11 
4.1. 
Number and Type of Participants ............................................................... 11 
4.2. 
Participant Selection................................................................................... 11 
4.2.1. 
Inclusion Criteria.......................................................................... 11 
4.2.2. 
Exclusion Criteria......................................................................... 11 
4.3. 
Participant Assignment and Randomization Process.................................. 11 
4.4. 
Withdrawal from Study................................................................................ 11 
5.
CONCOMITANT MEDICATION ............................................................................. 11 
6.
STUDY PROCEDURES......................................................................................... 11 
6.1. 
Treatment Phase........................................................................................ 11 
6.2. 
Informed Consent....................................................................................... 11 
6.3. 
Follow-up Phase......................................................................................... 12 
6.3.1. 
Sub-study Specific Visit Days 14 ± 3, 21 ± 3, 35 ± 3, 63 ± 3, 91 ± 
3, 119 ± 3 (Clinic or Home Visits) ................................................ 12 
6.4. 
End of Sub-Study ....................................................................................... 12 
6.5. 
Central Laboratory Assessment.................................................................. 13 
7.
ASSESSMENT OF SAFETY.................................................................................. 13 
7.1. 
Adverse Events .......................................................................................... 13 
7.2. 
Reporting of Adverse Events ...................................................................... 13 
8.
STATISTICS .......................................................................................................... 14 
8.1. 
Stratification/Randomization ....................................................................... 14 
8.2. 
Sample Size Rationale ............................................................................... 14 
8.3. 
Analysis Population .................................................................................... 14 
8.4. 
Endpoints and Definitions........................................................................... 14 
8.4.1. 
Exploratory Phosphate Homeostasis Endpoints .......................... 14 
8.5. 
Safety Analyses.......................................................................................... 15 


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8.5.1. 
Adverse Events ........................................................................... 15 
8.5.2. 
Clinical Laboratory Tests ............................................................. 15 
9.
ETHICS.................................................................................................................. 15
9.1. 
Informed Consent....................................................................................... 15 
9.2. 
Good Clinical Practice ................................................................................ 16 
10. DATA HANDLING AND RECORD KEEPING......................................................... 16 
10.1. 
Case Report Form...................................................................................... 16 
11. REFERENCES ...................................................................................................... 17 
LIST OF TABLES
PAGE
Table 1. 
Schedule of Events for Sub-Study ......................................................... 10 
Table 2. 
Hypophosphatemia CTCAE Grade ........................................................ 21 


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LIST OF ABBREVIATIONS
ALT
Alanine Aminotransferase
AST
Aspartate aminotransferase
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CRF
Case Report Form 
CTCAE
Common Terminology Criteria for Adverse Event
dL
Deciliter
e.g.
for example
FCM
Ferric Carboxymaltose
Fe
Iron
FGF-23
Fibroblast growth factor 23
g
Gram
GGT
Gamma-glutamyl transferase
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDA
Iron Deficiency Anemia
i.e.
that is
IV
Intravenous
Kg
Kilogram
L
Liter
LDH
Lactic dehydrogenase
MedDRA
Medical dictionary for regulatory activities
mg
Milligram
mL
Milliliter
N
Number
NCI
National Cancer Institute
PCS
Potentially clinically significant
SAP
Statistical Analysis Plan
SOC
System organ class
U.S.
United States
vs.
Versus
w/v
weight / volume


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1. INTRODUCTION
Ferric Carboxymaltose (FCM) is a parenteral form of iron that can be used to treat iron 
deficiency (IDA) when oral iron is either ineffective or contraindicated [Lyseng-Williamson,
2009].  Several randomized controlled trials demonstrated the efficacy and safety of 
intravenous (IV) FCM for treating iron deficiency associated with chronic kidney disease, 
inflammatory bowel disease, heavy uterine bleeding, and during the postpartum period
[Barish, 2012; Breymann, 2008; Evstatiev, 2011; Kulnigg, 2008; Qunibi, 2011; Seid, 2008;
Van Wyck , 2007; Van Wyck, 2009;Charytan, 2012].
In these populations, several 
patients who received FCM developed transient and asymptomatic reductions in serum 
phosphate that typically appeared within 2 to 4 weeks of treatment and resolved 
spontaneously within 6 to 12 weeks [Van Wyck, 2009].
1.1. Pathophysiology
Phosphate is the most abundant intracellular anion and is essential for membrane 
structure, energy storage, and transport in all cells.  Approximately 85% of the body's 
phosphorus is in bone as hydroxyapatite, while most of the remainder (15%) is present in 
soft tissue.  Only 0.1 % of phosphorus is present in extracellular fluid and it is this fraction 
that is measured with a serum phosphorus level [Moe, 2008]. Phosphorus homeostasis 
is complex and is regulated by several hormones.  Hypophosphatemia can occur in the 
presence of low, normal, or high total body phosphate.  In the latter two instances, a shift 
from the extracellular pool into the intracellular compartment is a major contributory factor.
Parathyroid hormone causes phosphate to be released from bone and inhibits renal 
reabsorption of phosphate, resulting in phosphaturia.  Vitamin D aids in the intestinal 
absorption of phosphate.  Thyroid hormone and growth hormone act to increase renal 
reabsorption of phosphate.  Finally, a new class of phosphate-regulating factors, the so-
called phosphatonins, including fibroblast growth factor 23 (FGF23), have been shown to 
be important in phosphate-wasting diseases, such as oncogenic osteomalacia, X-linked 
and 
autosomal 
dominant 
hypophosphatemic 
rickets, 
autosomal 
recessive 
hypophosphatemia, and tumoral calcinosis [Shaikh, 2008].  Additionally, FGF23 is up-
regulated 
in 
patients 
with 
early-stage 
chronic 
kidney 
disease
to 
prevent 
hyperphosphatemia [Takeda, 2011].  A link between IV iron application and increase in 
FGF23 has been proposed [Takeda, 2011; Schouten, 2009a].
Serum phosphorus concentration is determined by several factors.  Dietary phosphorus 
intake, stage of growth and time of day contribute to the variability of fasting serum 
phosphorus concentrations.  Optimal cellular function is dependent on maintenance of a 
normal serum phosphorus concentration.  The most important determinant of serum 
phosphorus concentration is regulation of phosphorus reabsorption by the kidney.  The 
majority of this reabsorption (80%) occurs in the proximal tubule and is mediated by an 
isoform of the Na-phosphate-cotransporter.  Parathyroid hormone, via a variety of 
intracellular signaling cascades leads to Na-phosphate-IIa internalization and down-
regulation, and is the main regulator of renal phosphate reabsorption.


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Hypophosphatemia is observed in approximately 2% of hospitalized patients, and can be 
related to decreased intestinal absorption of phosphorus, re-distribution of phosphorus 
from the extracellular to the intracellular compartment, increased loss of phosphorus 
through the kidneys, or any combination of these processes.  The most common 
manifestation of hypophosphatemia in hospitalized patients is secondary to re-distribution 
of 
phosphorus 
as 
a 
result 
of 
respiratory 
alkalosis 
[Amanzadeh, 
2006].
Hypophosphatemia has been implicated as a cause of rhabdomyolysis, respiratory 
failure, hemolysis and left ventricular dysfunction.  With the exception of ventilated 
patients, there is little evidence that moderate hypophosphatemia has significant clinical 
consequences in humans, and aggressive IV phosphate replacement is unnecessary.
The data on the incidence of hypophosphatemia (defined as <0.64 mmol/L) in outpatients 
is sparse, but has been reported as 0.9% [Betro, 1972].
1.2. Increased FGF23
Studies have shown that IV FCM, iron polymaltose and saccharated ferric oxide increase 
the levels of FGF23 post-infusion [Takeda, 2001; Schouten, 2009b; Wolf, 2013].  This 
hormone, besides the parathyroid hormone, is key for serum phosphate regulation. The 
phosphatonin FGF23 has been shown to decrease serum phosphate levels by reducing 
the number of Na-phosphate-cotransporters in the proximal tubule and by inhibiting the 
production of the active form of Vitamin D [Razzaque, 2007].  FGF23 is predominantly
expressed in bone osteocytes [Liu, 2006].  Increased concentrations of circulating FGF23 
are central to the pathogenesis of several hypophosphatemic diseases including 
autosomal-dominant, -recessive, and X-linked hypophosphatemic rickets, tumor-induced 
osteomalacia and selected cases of McCune-Albright syndrome [Imel, 2005; Yamamoto,
2005].
A study tested the association of IDA with cFGF23 (the C-terminal form of the protein) 
and iFGF23 (only the intact and hence active form) levels in 55 women with a history of 
heavy uterine bleeding, and assessed the longitudinal biochemical response over 35 days 
to equivalent doses of randomly assigned, IV elemental iron in the form of FCM or iron 
dextran [Wolf, 2013].  The IDA was associated with markedly elevated cFGF23 (807.8± 
123.9 RU/mL) but normal iFGF23 (28.5± I. I pg/mL) levels at baseline.  Within 24 hours 
of iron administration, cFGF23 levels decreased by approximately 80% in both groups.  
In contrast, iFGF23 transiently increased in the FCM group alone, and was followed by a
transient, asymptomatic reduction in serum phosphate <2.0 mg P/dL in 10 women in the 
FCM group compared to none in the iron dextran group.  Reduced serum phosphate was 
accompanied by increased urinary fractional excretion of phosphate, decreased calcitriol
levels and increased parathyroid hormone levels.  These finding suggest the IDA
increases cFGF23 levels, and that certain iron preparations temporarily increase iFGF23 
levels.  It may therefore be concluded that IV iron lowers cFGF23 in humans by reducing
FGF23 transcription as it does in mice, whereas carbohydrate moieties in certain iron 
preparations may simultaneously inhibit FGF23 degradation in osteocytes leading to 
transient increases in iFGF23 and reduced serum phosphate.  Overall, it seems plausible 


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that an increase in iFGF23 with all the downstream effects may be induced by application 
of IV iron.
1.3. Inhibition of Vitamin D Activation
It has been described that IV iron might have an inhibitory effect on renal 25-(OH)-Vitamin 
D Iα-hydroxylase expression [Sato, 1997].  This in turn reduces the availability of 1,25-
(OH)2-Vitamin D3, which leads to decreased absorption of phosphate from the gut and to 
decreased reabsorption of filtered phosphate in the proximal tubules of the kidney [Sato,
1997].  However, this mechanism was proposed before FGF23 was found to be a direct 
inhibitor of Iα-hydroxylase expression and it can be assumed that the effect of IV iron on 
Iα-hydroxylase expression is triggered via an increase in FGF23 concentration (as 
mentioned above), which leads to decreased production and increased degradation of 
25-(OH)-Vitamin D Iα-hydroxylase [Shimada, 2011; Shimada, 2004a; Shimada, 2004b].
1.4. Symptoms and Signs of Hypophosphatemia
Although an FGF23-mediated decrease in serum phosphate after a single infusion of iron 
is usually transient, the risk of developing clinical symptoms and the actual clinical 
presentation is determined by the severity of hypophosphatemia and the time to recovery.  
Management of hypophosphatemia is within the judgment and discretion of the 
investigator.
Patients with hypophosphatemia typically report bone pain, general weakness, and 
asthenia [Okada, 1982;Schouten, 2009b; Mani, 2010; Shiraki, 1986; Sato, 1998; Suzuki,
1998; Konjiki, 1994; Shimizu, 2009; Yamamoto, 2013; Moore, 2013; Blazevic, 2014;
Fierz, 2014; Vandemergel, 2014; Barea Mendoza, 2014; Poursac, 2015; Sangros Sahun,
2016].  In severe cases, proximal myopathy that also affects the diaphragm and 
rhabdomyolysis have been reported.  The latter can also affect the heart or cause 
cardiomyopathy or cardiac arrhythmias [Bacchetta, 2012].  Rare manifestations include 
hemolysis, encephalopathy, seizures [Haglin, 2016].  The type of clinical manifestation 
expression is also dependent on the age at onset and the duration of hypophosphatemia.  
Young patients with long-standing hypophosphatemia typically present with growth 
retardation, delayed dentation and rickets [Elder, 2014].  In adults with hypophosphatemia 
persisting for several months, long-term complications such as osteomalacia can occur 
(Fig.2) [Gonciulea, 2017].  Presentation of osteomalacia can include bone pain, fractures, 
and pseudofractures, which may be difficult to diagnose on conventional X-ray.
Radiological findings are a coarse trabecular structure, and a loss of secondary 
trabeculae [Phan, 2016].  Low trauma fractures affecting the ribs or scapular “stress-“
fractures of the lumbar spine, pelvic structures, and long bones such as femur, tibia, or 
metatarsal are also common complications of osteomalacia.  More sensitive diagnostic 
tests to identify looser zones, known as 'pseudofractures,' include computed tomography, 
magnetic resonance imaging, and bone scintigraphy.  Bone biopsy showing increased 
ratio of osteoid to bone surface and reduced tetracycline labeling remains the gold 
standard for diagnosis, but is rarely performed due to its invasiveness.  Although there is 


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no specific laboratory test for osteomalacia, mildly elevated total and bone-specific 
alkaline phosphatase in plasma have been repeatedly reported in the context of iron-
induced hypophosphatemia [Phan, 2016].
2. SUB-STUDY OBJECTIVE
The objective of this sub-study is to characterize serum phosphorus levels over time in 
participants with heart failure with iron deficiency after dosing with FCM versus placebo.
3. SUB-STUDY RATIONALE AND DESIGN
3.1. Sub-Study Rationale
In two randomized clinical studies conducted with FCM (1VIT09030 and 1VIT09031), 
hypophosphatemia was an adverse drug reaction (treatment emergent adverse event 
assessed as related by the Investigator) that occurred in 2.1% (37/1775) of the study 
participants.  Transient decreases in laboratory blood phosphorus levels (< 2 mg/dL) were 
observed in 27% (440/1638) of participants.  Mean decreases from baseline in 
phosphorus occurred by Day 7, were highest at Day 14 and were returning toward 
baseline at Day 35 (1VIT09031) or Day 56 (1VIT09030).  The objective of this sub-study 
is to characterize serum phosphorus levels over time in participants with heart failure with 
iron deficiency after dosing with FCM versus placebo.
3.2. Sub-Study Design
Participation in the sub-study is optional.  Although all investigational sites are
encouraged to participate, each study site’s participation will be determined based on the 
feasibility of the site to participate.  If a site decides to participate, all subsequent 
participants at the sites will be invited to enroll in the sub-study until enrollment of 110 
study participants is achieved. Sites and participants have the option to perform sub-
study visits either at the clinic or at a home visit.
A total of approximately 110 participants will be enrolled and the sample size has been 
determined based on the feasibility of enrollment.
Sub-study duration will be up to 6
months for each participant.  With this number of participants to be enrolled in the sub-
study and the current knowledge on the course of hypophosphatemia with FCM, the 
evaluation after the initial dosing regimen only was determined to be sufficient to 
characterize the course of hypophosphatemia in participants with congestive heart failure. 
A separate informed consent form (ICF) for the sub-study will be signed by participants.  
Each participant in the sub-study will have additional blood samples collected at either 
clinic visits or at home visits on Days 14 ± 3, 21 ± 3, 35 ± 3, 63 ± 3, 91 ± 3, and 119± 3).
These samples are in addition to the baseline (Day 0) and 6 month (Day 160-176) blood 
samples collected at the  clinic visits for the main study.


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CONFIDENTIAL  
3.3. Schedule of Events for Sub-Study 
Table 1Schedule of Events for Sub-Study 
Screening
Treatment 
Phase
Follow-up Phase
Visit
Week of main-study
-28 to -1
Day
0
Day
7±2
1
Day 
14±3*
2
Day 
21±3*
3
Day 
35±3*
5
Day 
63±3*
9
Day 90±14†
13
Day 
91±3*
13
Day 
119±3*
17
Day 160-176, Day 
180, Day 187, EOS
Participant follows the 
main study schedule of 
events
Participant 
follows the 
main study 
Participant follows 
the main study 
schedule of events
Check that informed consent 
was signed at screening or at 
Day 0
X
Inclusion/ Exclusion criteria
X
Complete study activities as 
outlined in the main study 
Section 3.3 
X
X
X
Serum Chemistry (see Section 
6.5)
X
X
X
X
X
X
1,25 (OH)2 Vitamin D‡
X
X
X
X
X
X
25 (OH) Vitamin D‡
X
X
X
X
X
X
Parathyroid Hormone‡
X
X
X
X
X
X
* In Clinic or Home visit
† Phone call or clinic visit
‡ Reminder that laboratory testing for 1,25 (OH)2 Vitamin D, 1,25 (OH)2 Vitamin D, and Parathyroid Hormone levels are also done outside the
hypophosphatemia substudy at Day 0 and Day 160-176


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4. PARTICIPANT SELECTION
4.1. Number and Type of Participants
Approximately 110 participants newly enrolled in the main 1VIT15043 study, who fulfill 
the inclusion criteria, do not meet any of the exclusion criteria and who have given written 
informed consent will be included.
4.2. Participant Selection
4.2.1. Inclusion Criteria
1. Demonstrate the ability to understand the requirements of the sub-study, willingness
to abide by sub-study participation, and to return for the required assessments.
4.2.2. Exclusion Criteria
1. History 
of 
primary 
hypophosphatemic 
disorder 
(for 
example 
X-linked
hypophosphatemia)
2. Baseline serum phosphate <2.5 mg/dL
3. Untreated primary hyperparathyroidism.
4.3. Participant Assignment and Randomization Process
Please follow guidance as detailed in the main body of the protocol.
4.4. Withdrawal from Study
Please follow guidance as detailed in the main body of the protocol.
5. CONCOMITANT MEDICATION
Please follow guidance as detailed in the main body of the protocol.
6. STUDY PROCEDURES
6.1. Treatment Phase
For Day 0 and Day 7 visits, follow guidance as detailed in the main body of the protocol.
6.2. Informed Consent
Check that the participant signed an informed consent form for the hypophosphatemia 
study at screening or at Day 0.


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Prior to any study specific procedures, the investigator or his or her designee must 
explain to each participant the nature of the study, study purpose, procedures to be 
performed, expected duration, and the benefits and risks of study participation.  After 
this explanation the participant must voluntarily sign an informed consent statement 
(Required Elements of Informed Consent, 21 CFR 50.25).  The participant will be 
given a copy of the signed consent form.
6.3. Follow-up Phase
Clinic visits will be performed by study personnel.
Home visits will be performed by a contracted third party person qualified to collect 
blood or site personnel.
Once a home visit or clinic visit choice has been made, that patient must continue with 
that venue for the those visits for the duration of their sub-study participation.
After completing the 6-month sub-study, the participant returns to follow the main study 
protocol.
6.3.1. Sub-study Specific Visit Days 14 ± 3, 21 ± 3, 35 ± 3, 63 ± 3, 91 ± 3, 119
± 3 (Clinic or Home Visits)
x
Laboratory samples will be collected

Serum for:
x
Chemistry (see Section 6.5 for details)
x
1,25 (OH)2 Vitamin D
x
25 (OH) Vitamin D

Plasma for:
x
Parathyroid Hormone
Note that Visit Day 90±14 days (Phone call or Study visit) is a procedure in the main 
protocol to collect adverse event / serious adverse event assessment, including 
evaluation of potential endpoint events (blinded staff).
Study Visit Day 91±3 days will be an in-clinic visit (if the patient has chosen in-clinic visits) 
or a home visit (if the patient has chosen home visits) which will be performed by a
qualified person to collect laboratory samples.
6.4. End of Sub-Study
Sub-study visits only occur within the first 180 days. No other sub-study dosing or blood 
collections will occur after that time.


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6.5. Central Laboratory Assessment
Serum and plasma samples for laboratory analyses will be obtained at 1) Day 0 of the 
main study; 2) Days 14, 21, 35, 63, 91, and 119 at additional clinic visits or scheduled as 
home visits; 3) Day 160-178 of the main study. All serum and plasma laboratory testing 
shall be provided to the study personnel for review and assessment.  
The laboratory 
assessments will be determined as follows: 
Chemistry: 
Sodium, 
potassium, 
chloride, 
BUN, 
creatinine, 
albumin, 
alkaline 
phosphatase, total bilirubin, GGT, AST, ALT, LDH, calcium, phosphate, 
glucose, bicarbonate and magnesium
Other:
1,25 dihydroxy Vitamin D; 25 hydroxy Vitamin D
Plasma:
Parathyroid Hormone
7. ASSESSMENT OF SAFETY
7.1. Adverse Events
7.2. Reporting of Adverse Events
Please follow guidance for reporting of adverse events as detailed in the main body of the 
1VIT15043 study protocol.  For qualifying adverse events of hypophosphatemia, the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE
Version 5.0) should be followed.
The serum phosphorus level normally ranges from 2.5-4.5 mg/dL or 0.80-1.45 mmol/L in 
adults. The reporting of hypophosphatemia, per the 2009 NCI CTCAE Version 4.0, is:
x
Grade 1:  mild (<LLN-2.5 mg/dL; <LLN-0.8 mmol/L),
x
Grade 2:  moderate (<2.5-2.0 mg/dL; <0.8-0.6 mmol/L),
x
Grade 3:  severe (<2.0-1.0 mg/dL; <0.6-0.3 mmol/L),
x
Grade 4:  potentially life threatening (<1.0 mg/dL; <0.3mmol/L; life-threatening
consequences),
x
Grade 5:  death. (NCI 2009 [NIH, 2009]).
The updated 2017 NCI CTCAE Version 5.0 includes the revised categorization and 
reporting of hypophosphatemia to the following:  
x
Grade 1: laboratory finding only and intervention not indicated;
x
Grade 2: oral replacement therapy indicated;
x
Grade 3: severe or medically significant but not immediately life-threatening -
hospitalization or prolongation of existing hospitalization indicated;
x
Grade 4:  life-threatening consequences;
x
Grade 5:  death. (NCI 2017 [NIH, 2017]).


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For this substudy, the analyses of changes in serum phosphate will be captured by 
laboratory changes, per NCI CTCAE version 4.0, and/ or safety reporting by any 
interventions determined and reported by the study investigator, per NCI CTCAE 
version 5.0.  Please refer to Table 2: Hypophophosphatemia CTCAE Grade. 
8. STATISTICS
Given the exploratory nature of this sub-study, the focus of the analyses will be on 
estimation rather than hypothesis testing. Continuous variables will be summarized in
terms of the number of observations, mean, standard deviation, median, minimum, and 
maximum.
Other descriptive statistics (e.g., quartiles, coefficient of variation) may be 
reported when appropriate. Categorical variables will be summarized using frequency 
counts and percentages. Two-sided 95% confidence intervals will be presented, when 
appropriate. 
Complete details of the analysis for this sub-study will be outlined in a Statistical Analysis 
Plan (SAP). This SAP will be completed prior to database lock.
8.1. Stratification/Randomization
Please follow guidance as detailed in the main body of the protocol. 
8.2. Sample Size Rationale 
No formal sample size calculations were made.  Sample size for this sub-study was based 
on feasibility and practicality. The target sample size will be a total of approximately 110 
participants, i.e., 55 participants per treatment group.
8.3. Analysis Population 
The sub-study population will be defined as all participants in the Intent-to-Treat 
population who provided informed consent to participate in this sub-study. 
Disposition, demographics, and baseline characteristics will be summarized for the sub-
study population.  Outcome measurements will be analyzed based on the available data 
from this population. 
8.4. Endpoints and Definitions
8.4.1. Exploratory Phosphate Homeostasis Endpoints 
The exploratory endpoints will be changes in laboratory values following study drug 
administration for: 
1. Serum Phosphorous


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2. 1, 25 dihydroxy Vitamin D (1,25[OH]2D)
3. 25 hydroxy Vitamin D (25[OH]D)
4. Plasma intact Parathyroid hormone
In addition to routine blood chemistry endpoints, the above laboratory studies will be 
summarized.
Details of the analysis of these exploratory endpoints will be described in the SAP.
8.5. Safety Analyses
8.5.1. Adverse Events
Adverse events will analyzed for the sub-study population as detailed in the main body of 
the 1VIT15043 study protocol.  
8.5.2. Clinical Laboratory Tests
Clinical laboratory data will be summarized by scheduled visit using descriptive statistics.
The actual values as well as the change from baseline will be summarized.  Unscheduled 
visits will be excluded from these by-visit summaries.  Maximum changes relative to 
baseline will be over all visits (both scheduled and unscheduled).
The time course for changes in serum phosphate will be evaluated and compared to that 
of other laboratory parameters.
Where applicable, the number and percent of participants with laboratory values outside 
pre-determined ranges will be summarized by scheduled visit. Unscheduled visits will be 
excluded from these by-visit summaries. The number and percent of participants with the 
laboratory values outside pre-determined ranges at any time during the sub-study will be 
summarized; and these summaries will be over all visits (both scheduled and 
unscheduled). 
The proportion of participants with serum phosphate level <2.5 mg/dL (<0.8 mmol/L), per 
NCI CTCAE version 4, will be summarized by treatment group.  Point estimates will be 
reported with exact two-sided 95% confidence intervals.
Full details will be described in the SAP.
9. ETHICS
9.1. Informed Consent
Informed consent must be obtained from each participant prior to sub-study participation.  
The informed consent will be provided to the participant in their native language.  The 
consent form must be signed by the participant.  Each investigational site must provide 
the Sponsor (or designee) with a copy of the Informed Consent approved by that site's 


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Institutional Review Board.  The original signed consent 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 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 International Conference on Harmonisation (ICH) guidelines.  Translations of the 
informed consent must be certified by a qualified translator and their use must be 
documented.
The Informed Consent documents the information that the Investigator provides to the 
participant as well as the participant's agreement to participate.  The Investigator will fully 
explain the nature of the study, along with the aims, methods, anticipated benefits, 
potential hazards and discomfort that participation might entail.  The Informed Consent 
must be signed and dated by each participant before entering the study and prior to the 
performance of any study specific procedures.
9.2. Good Clinical Practice
The conduct of the study will conform with the recommendations for clinical studies in 
man as set out in the 2000 Edinburgh, Scotland Revision of the “Declaration of Helsinki”, 
the local legal requirements and the guidelines on “Good Clinical Practice”, [21 CFR Part 
312 and ICH guidelines.
10. DATA HANDLING AND RECORD KEEPING
10.1. Case Report Form
The eCRFs will be completed for each participant on this study.  The participants in this 
study will be identified only by a participant number and date of birth on these forms.
The eCRF used will be 21 CFR 11 compliant.  The system used for data collection (eCRF) 
will meet all applicable regulatory requirements for recordkeeping and record retention as 
would be provided with a paper system.  Security measures will be utilized to prevent 
unauthorized access to the data and to the computerized system.  Changes made to data 
that are stored on electronic media will always require an audit trail, in accordance with 
21 CFR 11.10(e).
The eCRFs must be reviewed and verified for accuracy by the Principal Investigator.  An 
electronic copy of the eCRF will remain at the site at the completion of the study.


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Hypophosphatemia: an evidence-based approach to 
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S.[hypophosphatemia, a poorly known adverse reaction of intravenous use of iron].  
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Blazevic A, Hunze J, Boots JM. Severe hypophosphataemia after intravenous iron 
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Barish CF, Koch T, Butcher A, Morris D, Bregman DB.  Safety and efficacy of 
intravenous ferric carboxymaltose (750 mg) in the treatment of iron deficiency 
anemia: two randomized, controlled trials. Anemia. 2012:172104.
Betro MG, Pain RW. 
Hypophosphatemia and hyperphosphatemia in hospitalized 
patients. BMJ.  1972;1:273-276. 
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ferric carboxymaltose versus standard medical care in the treatment of iron deficiency 
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multi-centre study.  Nephrol Dial Transplant.  Epub.  2012 Dec 5.  DOl:10.  1093/ ndt/
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Elder CJ. Bishop NJ. Rickets. Lancet 2014; 383:1665-1676 
Evstatiev R, Marteau P, Iqbal T, Khalif IL, Stein J, Bokemeyer B, Chopey IV, Gutzwiller
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Riopel L, Gasche C. 
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Gonciulea AR, Jan De Beur SM. Fibroblast growth factor 23-medicated bone disease.  
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Konjiki O, Fukaya S, Kanou H, et al. 
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Vandemergel X, Vandergheynst F. 
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Yamamoto T, Imanishi Y, Kinoshita E, Nakagomi Y, Shimizu N, Miyauchi A, et al.  The 
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UOEH 2013; 35:25-31. 


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Table 2 Hypophosphatemia CTCAE Grade 
Hypophosphatemia:  A disorder characterized by laboratory test results that indicate a low concentration of phosphates in the blood.
CTCAE Grade:
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Grade refers to the 
severity of the AE.
The CTCAE displays 
Grades 1 through 5 
with unique clinical 
descriptions of 
severity for each AE 
based on this general 
guideline.*
Mild; asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated.
Moderate; minimal, 
local or noninvasive 
intervention indicated; 
limiting age-
appropriate 
instrumental ADL.
Severe or medically 
significant but not 
immediately life-threatening; 
hospitalization or 
prolongation of 
hospitalization indicated; 
disabling; limiting self-care 
ADL.
Life-threatening 
consequences; urgent 
intervention 
indicated.
Death
related to 
AE.
From CTCAE v4.0
Metabolism and 
Nutrition Disorders -
Hypophosphatemia:  
May 28, 2009: Page 
45
<LLN - 2.5 mg/dL; 
<LLN - 0.8 mmol/L
<2.5 - 2.0 mg/dL; 
<0.8 - 0.6 mmol/L
<2.0 - 1.0 mg/dL; 
<0.6 - 0.3 mmol/L
<1.0 mg/dL; 
<0.3 mmol/L;
Life-threatening 
consequences
Death
From CTCAE v5.0
Metabolism and 
Nutrition Disorders -
Hypophosphatemia: 
November 27, 2017: 
Page 94
Laboratory finding only 
and intervention not 
indicated 
Oral replacement 
therapy indicated 
Severe or medically 
significant but not 
immediately life-threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated 
Life-threatening 
consequences 
Death 
*A semi-colon indicates ‘or’ within the description of the grade.


American Regent, Inc. 
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Version 3 Date: Final 11 January 2021 
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Appendix 2: Protocol Amendment History
Overall Rationale for the Amendment (Version 2): 
Affected 
Sections 
Summary of Revisions Made
Rationale
Appendix 1
Added a sub-study protocol to 
evaluate hypophosphatemia.
To characterize serum phosphorus levels 
over time in participants with heart failure 
and iron deficiency after dosing with 
FCM.
Study
synopsis and 
4.2.1
Inclusion
Criteria
Changes were made to inclusion 
criteria 2, 4, 5, 6, and 7. Details are 
provided below.
To specify certain time frames and values 
for inclusion and to further clarify certain 
inclusion criteria
Study
synopsis and 
4.2.2
Exclusion
Criteria
Changes were made to exclusion 
criteria 3, 10, and 13. Details are 
provided below.
To specify certain time frames for, and to 
further clarify, certain exclusion criteria
8.10
Stopping
Rules and
Interim
Analysis
The DSMB may recommend that 
the study continues as planned, 
discontinue the study or that the 
trial be continued with 
recommended changes to the 
protocol. The Executive Steering 
Committee will determine if an 
increase in sample size is 
warranted in order that to least 771 
participants will experience an 
event of cardiovascular death or 
hospitalization for heart failure.
To clarify the roles of the DSMB and 
Steering Committee.
Detailed description of Protocol Amendment:
The deleted text (strikethrough) and the changed text (bold italics) is provided below.
Affected Sections
Detailed Changes
Signature page 


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Protocol No.: 1VIT15043 
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Version 3 Date: Final 11 January 2021 
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American Regent, Inc.
Study synopsis: Design
Study drug administration will occur on Day 0 and Day 7 (±2) as an 
undiluted slow IV push, with additional study visits planned at 3 
month intervals, and additional dosing administered every 6 months 
as applicable (see Section 3.1based on dose regimen below). In a 
subset of sites, all participants will return for recurrent laboratory 
assessment (chemistry, hematology and iron indices) at Day 21 
(± 7) after each course of investigational treatment.  For all 
participants, hematology, ferritin, and transferrin saturation (TSAT), 
with appropriate safety evaluations, to determine additional 
treatment, will occur at 6 month intervals.  
In a subset of sites, a sub-study will be conducted to 
characterize serum phosphate levels overtime in participants 
with heart failure and iron deficiency after dosing with FCM
(see Appendix 1).
Study synopsis:
Inclusion Criteria 
and 4.2.1 Inclusion 
Criteria
2. Stable heart failure (NYHA II-IV) on maximally-tolerated
background therapy (as determined by the site Principle
Investigator) for at least 4 weeks with no dose changes in heart
failure drugs during the last 2 weeks 2 weeks prior to
randomization.
4. Reduced left ventricular ejection fraction. Assessment must be
performed at least 12 weeks after major cardiac surgical intervention
including coronary artery bypass graft (CABG), valvular
repair/replacement, or cardiac resynchronization therapy (CRT)
device implantation.
a Left ventricular ejection fraction ≤35 40% obtained during the 
screening visit OR either of the following
i  Historical value of ejection fraction ≤35 40%% within 12 24
months of screening visit
ii  Historical value of ejection fraction ≤25 30% % within 24
36 months of screening visit 
5. Hemoglobin >9.0 g/dL and <13.5 g/dL (females) or <15.0 g/dL
(males) within 28 days of randomization.
6. Serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT
<20%. Patients with screening ferritin <15 ng/ml must have
documentation of an appropriate evaluation, as determined by the
Principle Investigator, within 3 months of screening and prior to
randomization.


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7. Either documented hospitalization for heart failure within 12
months of enrollment or screening visit elevated N-terminal-pro-
brain natriuretic peptide (NT-proBNP) within 90 days of
randomization:
a For patients in normal sinus rhythm: N-terminal-pro-brain 
natriuretic peptide (NT-proBNP) >600 pg/ml (or BNP >200 
pg/mL) for
b For patients with normal sinus rhythm or in atrial fibrillation:
NT-proBNP >1000 pg/ml (or BNP >400 pg/mL) for patients with 
atrial fibrillation.
Study synopsis:
Exclusion Criteria and 
4.2.2 Exclusion 
Criteria
1,  Current or planned oral iron supplementation. Iron-containing 
multivitamins (<30 mgs /day) are permitted. 
4, 3. Acute myocardial infarction, acute coronary syndrome, 
transient ischemic attack, or stroke within 3 months 30 days of 
enrollment.
11, 10.
Known Active gastrointestinal bleeding. Patients with 
screening ferritin <15ng/ml must have an appropriate evaluation 
within 3 months of screening.
13. Concurrently in a study with investigational product.
Study synopsis: 
Patient Assessments
Efficacy and Safety Follow-up: All participants will be followed 
from the time of randomization until completion of the trial.  The 
last participant randomized will be followed for 12 months.  After 
treatment on Day 0 and Day 7, participants will be evaluated at 3 
month intervals (in person or via telephone), with additional dosing 
administered every 6 months as applicable (see Section 3.1 based on 
dose regimen below)…..
Study synopsis:
Study Sites: 
Approximately 200 225
3.1 Overall 
Study Design
After an initial screening period of up to 28 days, eligible 
participants will be stratified by region and randomized in a 1:1 ratio 
to FCM or placebo.  Study drug administration will occur on Day 0 
and Day 7 as an undiluted slow IV push, with additional study visits 
(in person or via telephone) planned at 3 month intervals, and 
additional dosing administered every 6 months as applicable (based 
on dose regimen below).  In a subset of sites, all participants will 
return for recurrent laboratory assessment (chemistry, hematology, 
and iron indices) at Day 21 (± 7) after each course of investigational 
treatment. For all participants, hematology, ferritin and transferrin 
saturation (TSAT), with appropriate safety evaluations, to determine 
additional treatment, will occur at 6 month intervals
In a subset of sites, a sub-study will be conducted to characterize 
serum phosphate levels overtime in participants with heart failure 
and iron deficiency after dosing with FCM (see Appendix 1).
Initial treatment will occur on Day 0 and Day 7.  On Day 0 and 7, 
Group A (FCM) will receive a 750 mg undiluted, blinded dose of IV 
FCM at the rate of approximately 100 mg (2 mL)/minute; Group B 
(placebo) will receive a blinded placebo (15 cc of normal saline) IV 
push at 2 mL/minute.  Participants in Group A with body weight <50 
kg (110 pounds) will have individual FCM doses adjusted to 15 


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Version 3 Date: Final 11 January 2021 
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mg/kg, not to exceed an individual dose of 750 mgs or a cumulative 
dose of 1500 mg per treatment cycle. Placebo dosing will be 
adjusted for weight based on volume.
3.3 Schedule of Events
See changes below
Study Procedures
Screening
Treatment 
Phase
Follow-up Phase
Days
-28 to -1
0
7±2
90
±14a,b,k,
l
160-
176
178 
a,b
180+7
a,b
187
+7 a,b
EOSc
Informed consent
X
Inclusion/exclusion 
criteria
X
Xj
Demographics
X
Targeted  medical 
history
X
Targeted Physical Exam
Xj
X
Vital signs 
Xd
Xd
Xd
Xd
X
Height (cm) & weight 
(kg)e
Xj
X
Urine or serum
pregnancy testf
Xj
X
X
Vitamin D, 1,25 (OH)2
Vitamin D, 25 (OH) 
Vitamin D and PTHk
X
X
Left ventricular ejection 
fraction
Xg
Randomizationn
X
Hematology laboratoryh
Xp
X
X
X
Chemistry laboratoryh
X
X
X
Iron indicesh
X
X
X
X
6 Minute Walk Test
Xj
Xm
NT-proBNPh
X
X
X
X
X
Serious Adverse Event 
and Clinical Endpoint 
Event reporting
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
IV FCM/ IV Placebon
X
X
Xi
Xi
Abbreviations:  EOS = End of Study; FCM = ferric carboxymaltose; IV = intravenous; NT-
proBNP = N-terminal pro-brain natriuretic peptide; PTH = Parathyroid Hormone; 
a
Visits will be repeated every 180 days for the duration of the study
b
At end of study, the visitVisit should not be performed if it would occur within 30 days of 
the EOS visit. If the participant is prematurely discontinued from the study and 
completing the EOS visit, the regular 6 or 12 month visit is needed to obtain the 6MWT.
c
EOS visit for all participants will be scheduled once the last participant has reached 6 12
months on study and the anticipated number of outcome events (section 8) reaches 840
771.
d
On study drug dosing days vital signs will be collected predose, immediately postdose, and 
30 minutes postdose. Participants will be discharged from the site by the Investigator or 


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his or her designee only if there are no significant signs or symptoms 30 minutes after the 
administration is completed.
e
Height assessed at Day 0 only; weight assessed at Day 0 and prior to each dosing cycle.
f.
Females of childbearing potential
g.
Historical value can be used if performed within 12 24 months of screening visit (or 24 36
months if LVEF ≤25 30%), must be performed at least 12 weeks after major cardiac
intervention-including CABG, valvular intervention, or cardiac resynchronization therapy
device implantation.
h.
The method of analysis of screening laboratory values will be by a central clinical
laboratory. These laboratory values may also be analyzed locally. Screening laboratory
measures may be performed locally all All other visits will be analyzed through a central
laboratory
i
All participants randomized will be dosed every 6 months.  Participants randomized to the 
FCM arm will be dosed as indicated based on blood counts (i.e. Hgb <13.5 g/dL [females] 
or <15.0 g/dL [males)]) and iron studies (i.e. serum ferritin <100 ng/mL or 100 to 300 
ng/mL with TSAT <20%). Participants not meeting pre-specified laboratory criteria for 
blood counts and iron studies and all participants randomized to the placebo arm will be 
administered IV placebo infusion at each visit. The second of the 2 dosing visits should 
occur at Day 7+2 after the first dose.
j.
Prior to randomization
k
Only for participants at select sites performing additional chemistry labs (1,25 (OH)2 Vitamin
D, 25 (OH) Vitamin D and PTH) on Day 21  (+7) post dosing (sub-study).
l.
May be performed via telephone or in person.
m. Performed at Day 180 and Day 360 visits only.
n.
To be performed by unblinded site personnel.  All other procedures must be performed by
personnel blinded to the treatment assignment
p,
Hemoglobin only
4.4 Withdrawal 
from Study
At time of withdrawal from the study, procedures for the
Termination EOS visit must be immediately performed regardless 
of whether the participant has completed study drug treatment…..
In event of site closure, participants will may be asked to agree to 
follow up at another research site, if available, or for follow up by 
via a patient follow-up group
5.2 Drug 
Administration/
Regimen
Group A: 
Group A (FCM) will receive a 750 mg 
undiluted blinded dose of IV FCM at the rate of 
approximately 100 mg (2 mL)/minute on Day 0 
and Day 7; Participants in Group A with body 
weight <50 kg (110 pounds) will have 
individual FCM doses adjusted to 15 mg/kg, not
to exceed an individual dose of 750 mg or a 
cumulative dose of 1500 mg per treatment 
cycle.
Group B: 
Group B (placebo) will receive a blinded 
placebo (15 cc of normal saline) IV push at 2 
mL/minute on Day 0 and Day 7.


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Note: To avoid unblinding on the dose administration 
worksheet, if a participant is under 50 kg (110 pounds), the 
volume of FCM or placebo administered should be 
calculated based on the participant’s weight, e.g. a 45 kg 
participant will receive a 13.5 mL dose of FCM or placebo.
6.2.1 Screening Visit
Each participant who has signed the informed consent and qualifies 
for inclusion will undergo the following clinical evaluations to 
confirm eligibility for the study (all procedures to be performed by 
blinded study personnel):  
x
Demographic and medical history including NYHA heart failure
class and prior heart failure hospitalizations
x
Left ventricular ejection fraction (historical values may be used
if performed within 12 24 months of the screening visit, or 24 36
months if LVEF ≤25 30%) must be performed at least 12 weeks
after major cardiac intervention-including CABG, valvular
intervention, or cardiac resynchronization therapy device
implantation
x
Blood samples for hematology, iron indices, and NT-proBNP
(local central laboratory)
6.3.1 Day 0 Visit 
For all participants (all procedures to be performed by blinded study 
personnel):
x
Verify all inclusion and exclusion criteria
x
Height and weight
x
Targeted physical exam
x
Blood samples for central lab hematology, chemistries and iron
indices for all participants; Vitamin D, PTH 1,25 (OH)2 Vitamin
D, 25 (OH) Vitamin D and PTH for participants of the
hypophosphatemia sub-study at sites selected for post dose
chemistry follow-up visits.
x
Review concomitant medications
x
Urine or serum pregnancy test (women of childbearing potential
only)
Note: To avoid unblinding on the dose administration worksheet, 
if a participant is under 50 kg, the volume of FCM or placebo 
administered should be calculated based on the participant’s 
weight, e.g. a 45 kg participant will receive a 13.5 mL dose of FCM 
or placebo. 
Group A:
x
Verify amount of single FCM dose (15mg/kg up to a maximum
dose of  750 mg) (unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body
temperature (blinded staff)
x
Administer FCM as a slow IV injection at the rate of
approximately 2 mL /minute taking appropriate measures to
ensure the participant and all blinded staff members remain


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blinded to the treatment being administered (unblinded staff)
x
Document start and stop time of FCM administration and the
total dose and volume administered (unblinded staff)
x
Post-administration, obtain heart rate and blood pressure
immediately after and 30 minutes after FCM administration
(blinded staff). 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.
Group B: 
x
Pre-administration, obtain heart rate, blood pressure, and body
temperature (blinded staff)
x
Administer a 15 mL dose of  placebo (normal saline) as a slow
IV injection at the rate of approximately 2 mL /minute taking
appropriate measures to ensure the participant and all blinded
staff members remain blinded to the treatment being
administered (unblinded staff).
x
Document start and stop time of placebo administration and
the total volume administered (unblinded staff).
x
Post-administration, obtain heart rate and blood pressure
immediately after and 30 minutes after placebo
administration (blinded staff). 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.
6.3.2 Day 7 Visit 
All participants will return to the clinic for study drug dosing on Day 
7(+2).  Prior to the administration of the study drug, the participant 
will be evaluated clinically to assess the development of clinically 
significant conditions that may contraindicate dosing. 
Note: To avoid unblinding on the dose administration worksheet, 
if a participant is under 50 kg, the volume of FCM or placebo 
administered should be calculated based on the participant’s 
weight, e.g. a 45 kg participant will receive a 13.5 mL dose of FCM 
or placebo.
Group A participants the following will be performed:
x
Verify amount of single FCM dose (15mg/kg up to a maximum
dose of  750 mg) (unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body
temperature (blinded staff)
x
Administer FCM as a slow IV injection at the rate of
approximately 2 mL /minute taking appropriate measures to
ensure the participant and all blinded staff members remain
blinded to the treatment being administered (unblinded staff)
x
Document start and stop time of FCM administration and the
total dose and volume administered (unblinded staff)
x
Post-administration, obtain heart rate and blood pressure


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immediately after and 30 minutes after FCM administration 
(blinded staff). 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.
Group B participants the following will be performed:
x
Pre-administration, obtain heart rate, blood pressure, and body
temperature (blinded staff)
x
Administer a 15 mL dose of  placebo (normal saline) as a slow
IV injection at the rate of approximately 2 mL /minute taking
appropriate measures to ensure the participant and all blinded
staff members remain blinded to the treatment being
administered (unblinded staff).
x
Document start and stop time of placebo administration and
the total volume administered (unblinded staff).
x
Post-administration, obtain heart rate and blood pressure
immediately after and 30 minutes after placebo
administration (blinded staff). 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.
6.4.1   Chemistry 
Laboratory Collection
Subset -Day 21 (± 7)
In a subset of sites approximately 500 participants, will have central 
lab clinical laboratories (chemistry, hematology and iron indices) 
collected following the initial and each subsequent course 
(approximately every 6 months) of study drug treatment (FCM or 
Placebo).  The participants will have chemistry laboratories 
collected 21+7 days post the first treatment for that course (i.e. 
Study Days  21+7, 201+7, 381+7, 561+7, 741+7, 921+7…EOS). 
(blinded staff)
6.4.3 6.4.2   6 Month 
Laboratory Evaluation
Participants will receive an additional course of study medication 
every 180 (+7) days.  Within 2 4 to 20 days prior to these scheduled 
dosing visits, all participants will return to the clinic to obtain central 
lab hematology, chemistry, and iron indices laboratory tests. 1,25 
(OH)2 Vitamin D, 25 (OH) Vitamin D and PTH for participants of the 
hypophosphatemia sub-study. (Blood to be collected by blinded staff)
6.4.4 6.4.3
Additional Study Drug
Dosing
(Every 6 Months) 
All participants will be dosed every 6 months.  At each 6-month 
interval, a course of 2 doses of study drug will be administered as 
described above for Day 0 and Day 7 (Section 6.3).  For group A, 
FCM will be administered if Hgb < 13.5 g/dL (females) or <15.0 
g/dL (males) and serum ferritin <100 ng/mL or 100 to 300 ng/mL 
with TSAT <20%; observe carefully that placebo (normal saline) 
will be administered to participants in the FCM group who do not 
meet the above criteria. All group B participants will receive placebo 
(normal saline).
6.4.4.1 6.4.3.1
6 Month Dosing Visit #1 (Days 180+7, 360+7, 540+7, 660 720+7, 
840 900+7, 1,020 1,080+7…EOS)


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x
Weight
x
Urine or serum pregnancy test (women of childbearing
potential only)
Note: To avoid unblinding on the dose administration worksheet, 
if a participant is under 50 kg, the volume of FCM or placebo 
administered should be calculated based on the participant’s 
weight, e.g. a 45 kg participant will receive a 13.5 mL dose of FCM 
or placebo.
For Group A participants the following will be performed:
x
Administer FCM or placebo as a slow IV injection at the rate of
approximately 2 mL /minute. Appropriate measures must be
taken to ensure the participant and all blinded staff members
remain blinded to the treatment being administered (unblinded
staff)
x
Document start and stop time of IV administration, and the
total dose and volume administered (unblinded staff)
x
Post-administration of FCM, obtain heart rate and blood
pressure immediately after and 30 minutes after FCM
administration (blinded staff). 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.
For Group B participants the following will be performed:
x
Pre-administration, obtain heart rate, blood pressure and body
temperature. (blinded staff)
x
Administer a 15 mL dose of placebo (normal saline) as a slow
IV injection, at the rate of approximately 2 mL /minute. Taking
appropriate measures to ensure the participant and all blinded
staff members remain blinded to the treatment being
administered (unblinded staff)
x
Document start and stop time of placebo administration and
the total volume administered. (unblinded staff)
x
Post-administration of placebo, obtain heart rate and blood
pressure immediately after and 30 minutes after placebo
administration (blinded staff). 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.
6.4.4.2 6.4.3.2
Six Month Dosing Visit #2 (Days 187+7, 367+7, 547+7, 667 727+7,
847 907+7, 1,027 1,087+7…EOS)
Note: To avoid unblinding on the dose administration worksheet, 
if a participant is under 50 kg, the volume of FCM or placebo 
administered should be calculated based on the participant’s 
weight, e.g. a 45 kg participant will receive a 13.5 mL dose of FCM 
or placebo.


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Protocol No.: 1VIT15043 
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Version 3 Date: Final 11 January 2021 
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For Group A participants the following will be performed:
x
Verify amount of single FCM dose (15mg/kg up to a maximum
dose of 750 mg) or placebo (15 mL).  Note: participant should
receive the same product (FCM or placebo) as received at the
first dose of this course of treatment. (unblinded staff)
x
Pre-administration, obtain heart rate, blood pressure, and body
temperature. (blinded staff)
x
Administer FCM or placebo as a slow IV injection at the rate of
approximately 2 mL /minute. Taking appropriate measures to
ensure the participant and all blinded staff members remain
blinded to the treatment being administered (unblinded staff).
x
Document start and stop time of IV administration, and the
total dose and volume administered (unblinded staff)
x
Post-administration of FCM, obtain heart rate and blood
pressure immediately after and 30 minutes after FCM
administration (blinded staff). 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.
For Group B participants the following will be performed:
x
Pre-administration, obtain heart rate, blood pressure and body
temperature. (blinded staff)
x
Administer a 15 mL dose of placebo (normal saline) as a slow
IV injection, at the rate of approximately 2 mL /minute. Taking
appropriate measures to ensure the participant and all blinded
staff members remain blinded to the treatment being
administered (unblinded staff)
x
Document start and stop time of placebo administration and
the total volume administered. (unblinded staff).
x
Post-administration, obtain heart rate and blood pressure
immediately after and 30 minutes after placebo
administration (blinded staff). 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.
6.5  End of Study Visit
End of study visits for all participants will be scheduled once the last 
participant has reached 12 months on study and at least 771 
participants have experienced an event of cardiovascular death or 
hospitalization for heart failure.  When possible, the The participants 
should return to the clinic and the following will be performed by 
blinded study staff:
x
Targeted physical exam
x
Vital signs including BP and heart rate
x
Blood samples for central lab hematology, chemistries, iron
indices and NT-proBNP.
x
Urine or serum pregnancy test (women of childbearing potential


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only)
6.6
Laboratory
Assessments
Serum samples for laboratory analyses must be obtained at all 
appropriate visits. The method of analysis of screening Screening 
laboratory values will be analyzed by a central clinical laboratory. 
These laboratory values may also be analyzed locally. All other 
visit laboratory samples will be analyzed by a central clinical 
laboratory.  All laboratory testing will be provided to the 
investigator or his/her medically qualified designee for review and 
assessment.  Post dose iron indices and serum phosphorus results 
will be provided to the designated unblinded investigator for 
assessment. The laboratory assessments will be determined as 
listed in Section 3.3: 
Other: 
Vitamin D, Parathyroid Hormone, 1,25 (OH)2 Vitamin D, 25 
(OH) Vitamin D, PTH, and NT-proBNP
7.2 Reporting 
of Adverse
Events
For the purposes of this study, any AE that does not meet the 
protocol definition of a serious AE is considered non-serious.  Non-
serious AEs will not be collected for this trial, except for AEs 
leading to cessation of study medication. 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.
Disease progression can be considered as a worsening of a patient’s 
clinical condition attributable to the disease in the patient population 
for which the study medication is being studied. It may be an 
increase in the severity of the disease under study, and/or increases 
in the symptoms of the disease. These also include the events listed 
in Section 7.4, “Reporting of Events that May Require 
Adjudication.”
The development of the following cardiovascular disease events will 
be recorded in the eCRF, however they should be considered as 
disease progression and will not be reported as an AE/SAE during 
the study unless determined to be clinical endpoints.
1.
Supraventricular arrhythmia (e.g., atrial fibrillation)
requiring urgent/emergent intervention
2.
Ventricular arrhythmia (e.g., ventricular tachycardia or
fibrillation) requiring urgent/emergent intervention
including ICD shock
3.
Renal failure requiring urgent/emergent intervention (e.g.,
initiation of dialysis)
These also include the events listed in Section 7.4, “Reporting of 
Events that May Require Adjudication.”  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.


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These three events will be documented on a dedicated form in the 
eCRF and they will be reported to the DSMB.  An analysis as well 
as summary data tables of these events will be provided in the 
safety section of the clinical study report which will also include a 
rationale for exclusion of these events from AE or SAE reporting.  
Data files containing information about the above events will be 
included in the Regulatory submission in addition to hyperlinks or 
other means to easily direct reviewers to the location of the data.
7.3 Serious 
Adverse Events
Suspected clinical endpoint events that may traditionally meet the 
definition of an SAE, will not be reported by the sites in this trial as
an SAE, but will be reported as a suspected clinical endpoint.
Those events will therefore not to be reported to the sponsor’s Drug 
Safety Surveillance department.
Certain events of interest (supraventricular arrhythmia, ventricular 
arrhythmia, and renal failure) that are related to heart failure 
(serious and non-serious) and selected expected (described in the 
label) serious side effects of the study drug will be listed on the 
eCRF and not be reported by the site as an SAE.
These events will be monitored by the Data Safety Monitoring 
Board to ensure participant safety.
Additionally suspected clinical events that are reviewed by the CEC 
but do not meet the criteria of an endpoint event will then be
reviewed by the safety surveillance team for possible unreported 
SAEs.
Reporting: Any SAE as defined by this protocol, starting with the 
time of randomization, that is to be reported (as outlined in the 
section above) must be reported immediately (by the end of the next 
business day) to American Regent, Inc. This occurs through entry 
into the eCRF by the local investigator/coordinator and completing 
the SAE module.  In the event that the eCRF module is not available 
and paper forms have not been provided for use, the investigator 
will contact the Study Safety Monitor at
7.4 Reporting of
Suspected Study 
Endpoint Events
that May Require
Adjudication
Therefore, any event that may possibly constitute one of these 
endpoints will be evaluated by the CEC Committee by a procedure 
to be described in separate documentation.  A description of the 
CEC Committee and the definitions of the above clinical 
endpoints may be found in Section 10.2. 
8.5
Secondary
Outcomes
An A Clinical Events Classification (CEC) endpoint adjudication 
committee Committee at DCRI will review all potential events 
comprising all endpoints, and make the final determination
whether an endpoint event has occurred for each participant (See 
Section 10.2).
8.10 Stopping Rules
and Interim Analysis
A Data and Safety Monitoring Committee (DSMB), with statistical 
support from DCRI will review safety data, including a tally of the
composite outcome events at least every 6 months (See Section 
10.3).  The DSMB can recommend stopping the study for safety
concern at any point.  In addition, one interim analysis is planned 
to


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determine if an early stopping for an overwhelming efficacy should 
be recommended or if an increase in sample size is warranted.  This 
analysis will be conducted after 2250 (75%) participants have been 
enrolled.  Significance level will be set at 0.0001 for this analysis, 
resulting in an adjusted significance level for the final analysis of 
0.0099 for the primary endpoint and 0.0499 for the first secondary 
endpoint, preserving the overall significance at 0.01 and 0.05, 
respectively.  Conditional power will be estimated based on data 
accrued to date and presented to the DSMB.  The DSMB may 
recommend that the study continues as planned, is stopped for 
overwhelming efficacy or that the sample size or trial duration is 
increased to achieve at least 80% conditional power but not by more 
than 50% of the original sample size or duration discontinue the 
study or that the trial be continued with recommended changes to 
the protocol. The Executive Steering Committee will determine if 
an increase in sample size is warranted in order that at least 771 
participants will experience an event of cardiovascular death or 
hospitalization for heart failure.
9.8.1 Case Report Form
The eCRFs will be completed for each participant on this 
study.  The participants in this study will be identified only by 
a participant number and date of birth on these forms.
10.1  Steering 
Committee (SC)
The SC will be responsible for oversight of the study.  The SC chair 
will be Dr. Adrian Hernandez of DCRI.  The SC will consist of 4-8
6-12 members including the chair, primarily from academic
institutions, as well as in addition to representation of the Sponsor.
The SC will consist of experts in heart failure as well as
cardiovascular outcomes trials.
10.2.1.6 Death Due 
to Other 
Cardiovascular
Causes
Death due to Other Cardiovascular Causes refers to a CV death not 
included in the above categories but with a specific, known cause 
(e.g., pulmonary embolus, deep vein thrombosis, or peripheral 
arterial disease, or aortic aneurysm).
10.2.2.4 Other
Cardiovascular
Hospitalizations
Urgent and unscheduled hospitalizations for other cardiovascular 
causes that do not meet the criteria for the specific events listed 
above will be classified as hospitalization for other cardiovascular 
causes.  Examples would include, but are not limited to,
hospitalization for cardiac chest pain that does not meet the criteria 
for MI, hospitalization for carotid events, hospitalization for deep 
vein thrombosis, hospitalization for arrhythmias, hospitalization for 
pulmonary embolism, etc.  These hospitalizations will not be further 
sub-classified by the CEC.
13.0 Appendices
Appendix 1: Protocol for hypophosphatemia study was added
Appendix 2: Added protocol amendment history


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Overall Rationale for the Amendment (Version 3): 
Affected Sections 
Summary of Revisions Made
Rationale
Study synopsis
and 4.2.2 
Exclusion Criteria 
Changes were made to 
exclusion criteria 4 to include 
participants with mitral 
regurgitation due to left 
ventricular dilatation without 
planned intervention
This exclusion criteria was leading to 
exclusion of eligible participant’s into 
the study
Study Synopsis
and 4.2.2
Exclusion Criteria 
Added exclusion criteria 14
To not allow participants with current 
COVID-19 infection into the study.
4.5
Discontinuation
from Study Drug
Added the following sentence: 
Participants who discontinue 
study drug for reasons unrelated 
to safety may resume study 
drug if deemed appropriate by 
the Principal Investigator.
To provide guidance to the sites.
4.5
Discontinuation
from Study Drug
Added a definition for a 
participant permanently 
discontinued from the study.
To provide guidance to the sites.
Appendix 1,
Section 3.2 
Added that sites and 
participants have the option to 
perform sub-study visits either 
at the clinic or at a home visit.
To provide the sites and participants 
flexibility in deciding how sub-study 
visits will be conducted.
Appendix 1,
Section 7.2: 
Reporting of
Adverse
Events and
Table 2 
The changes in serum 
phosphate will be captured by 
laboratory changes, per NCI 
CTCAE version 4, and any 
interventions per the study 
investigator, per NCI CTCAE 
version 5.
Inclusion of the most CTCAE version 
for the investigator’s awareness.
Appendix 1,
Guidance for 
Managing
Hypophosphatemia
This section has been removed
Management of hypophosphatemia is 
within the judgment and discretion of 
the investigator.
Detailed description of Protocol Amendment (Version 3):
The deleted text (strikethrough) and the changed text (bold italics) is provided below.
Affected Sections
Detailed Changes
Signature page 


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Study Synopsis: 
Inclusion Criteria and 
4.2.1 Inclusion Criteria 
1. Adult (≥18 years of age) able to provide signed, written informed
consent.
Study Synopsis: 
Exclusion Criteria and 
4.2.2 Exclusion Criteria 
4. Uncorrected severe aortic stenosis, severe valvular regurgitation
(except mitral regurgitation due to left ventricular dilatation
without planned intervention), or left ventricular outflow
obstruction requiring intervention.
Study Synopsis: 
Exclusion Criteria and 
4.2.2 Exclusion Criteria 
14. Current COVID-19 infection.
Study Synopsis:
Study Sites: 
Approximately 225 300
3.3 Schedule of Events:
See changes below
Study Procedures
Screening
Treatment 
Phase
Follow-up Phase
Days
-28 to -1
0
7±2
90
±14a,b, ,l
160-176
a,b
180+7
a,b
187 +7
a,b
EOSc
Informed consent
X
Inclusion/exclusion 
criteria
X
Xj
Demographics
X
Targeted  medical 
history
X
Targeted Physical 
Exam
Xj
X
Vital signs 
Xd
Xd
Xd
Xd
X
Height (cm) & weight 
(kg) e
Xej
Xe
Urine or serum 
pregnancy testf
Xfj
Xf
Xf
1,25 (OH)2 Vitamin D, 
25 (OH) Vitamin D
and PTHk
Xk
Xk
Left ventricular 
ejection fraction
Xg
Randomizationn
Xn
Hematology 
laboratoryh
Xhp
Xh
Xh
Xh
Chemistry laboratoryh
Xh
Xh
Xh
Iron indicesh
Xh
Xh
Xh
Xh
6 Minute Walk Test
Xj
Xm
NT-proBNPh
Xh
Xh
Xh
Xh
Serious Adverse Event 
and Clinical Endpoint 
Event reporting
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
IV FCM/ IV Placebon
Xn
Xn
Xin
Xin
h. The method of analysis of screening laboratory values will be by a central clinical laboratory. These
laboratory values may also be analyzed locally. All other visits will be analyzed through a central
laboratory


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4.4 Withdrawal 
from Study
In event of site closure, participants may be asked to agree to follow 
up at another research site, if available, or for follow up by via a
patient follow-up group
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 
endpoint and safety events. Participants who discontinue study 
drug for reasons unrelated to safety may resume study drug if 
deemed appropriate by the Principal Investigator.
If a participant permanently discontinues investigational product
(drug is considered to be permanently discontinued after the 
second missed dosing cycle with continued follow-up in the trial)
investigational product and is unable to attend visits in-person, 
he/she will be contacted by telephone, or other methods to assess 
study outcomes and vital status, unless the participant has 
specifically withdrawn consent for all forms of contact…..
5.1 Formulation, 
Packaging and Storage 
Placebo (normal saline) will be supplied as 15 ml fill in 20 ml
vials.
All IV study drugs (FCM and Normal Saline) must be kept in a 
secure place at the investigational site, and stored at room 
temperature (see USP).  The study medication should not be frozen.  
Vials may not be used for more than 1 dose, or for more than 1 
participant.  All vials (used and unused) should be kept by the study 
staff for reconciliation by the monitor unless the site is unable to 
retain them and documentation (site or institution process or 
procedures, or SOPs, for example) is present.  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
Group A: 
Group A (FCM) will receive a 750 mg 
undiluted blinded dose of IV FCM at the rate of 
approximately 100 mg (2 mL)/minute 
(approximately 7 minutes 30 seconds) on Day 
0 and Day 7, not to exceed an individual dose 
of 750 mg or a cumulative dose of 1500 mg per 
treatment cycle.
Group B: 
Group B (placebo) will receive a blinded 
placebo (15 cc of normal saline) IV push at 2 
mL/minute (approximately 7 minutes 30 
seconds) on Day 0 and Day 7.
5.5
Concomitant 0HGLFDWLRQ
All Concomitant medications will be recorded in the eCase 
Report Form (eCRF). 


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Note: Oral iron supplementation is permitted prior to screening 
and during the course of the study. 
6.2.1 Screening Visit
x
Enter participant in the Interactive Response Technology
(IRT) system to obtain screening number.
x
Participants who do not meet study entry criteria
should be entered into the IRT system as a screen
failure. If all entry criteria can be verified qualified
participants may be randomized and proceed to the
Day 0 visit on the same day as the screening visit. 
6.3.1 Day 0 Visit 
For all participants (all procedures to be performed by blinded study 
personnel):
x
Blood samples for central lab hematology, chemistries and iron
indices for all participants; For Hypophosphatemia Sub-Study
participants only: 1,25 (OH)2 Vitamin D, 25 (OH) Vitamin D and
PTH for participants of the hypophosphatemia sub-study.
Note: To avoid unblinding on the dose administration worksheet, if a 
participant is under 50 kg, the volume of FCM or placebo 
administered should be calculated based on the participant’s weight, 
e.g. a 45 kg participant will receive a 13.5 mL dose of FCM or
placebo.
Note: All IV injection start and stop times are to be captured in 
hh:mm:ss format.
6.6
Laboratory
Assessments
Serum samples for laboratory analyses must be obtained at all 
appropriate visits. The method of analysis of screening 
laboratory values will be by a central clinical laboratory. These 
laboratory values may also be analyzed locally. All other visit 
laboratory samples will be analyzed by a central clinical 
laboratory. All laboratory testing will be provided to the 
investigator or his/her medically qualified designee for review 
and assessment. Post dose iron indices and serum phosphorus 
results will be provided to the designated unblinded 
investigator for assessment. The laboratory assessments will 
be determined as listed in Section 3.3: 
7.1 Adverse Events
Timing: Adverse events and serious adverse events will be
reported, as described below in Section 7.2, from the time of 
randomization through the end of study. Adverse events for 
participants randomized and who terminate the study early or
permanently discontinue study drug (Section 4.5) will be reported 
for 30 days after the last treatment.  All reported SAEs should be 
followed until no longer serious or return to baseline grade.


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7.2 Reporting 
of Adverse
Events
For the purposes of this study, any AE that does not meet 
the protocol definition of a serious AE is considered non-
serious.   
All SAEs and only AEs leading to study discontinuation will 
be collected in this study.  Non-serious AEs that do not lead to 
study drug discontinuation are not being collected in this 
study.” 
Non-serious AEs will not be collected for this trial, except for 
AEs leading to cessation of study medication. 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.
8. Statistical Methods
All statistical tests will be two-tailed. Type I error of 0.05 is 
assumed unless otherwise specified.  No adjustments for 
multiple testing will be made. Complete details for the 
summary and statistical analysis of data to be collected will 
be documented in a Statistical Analysis Plan (SAP), which 
will be finalized prior to unlocking of the study base.  The 
important elements of the planned methods are provided 
below.
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, and the use of 
social media by the central ad campaign.  Any compensation to 
the participant included in the advertisement must be identical 
to the compensation stated in the IRB-approved informed 
consent.
Appendix 1, Cover Page
Sponsor
American Regent, Inc.
Clinical Research and Development
800 Adams Avenue, Suite 200 100
Norristown, PA 19403
Appendix 1, Contact
Person for the Sub-study 


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Appendix 1, List 
of Abbreviations
ICF
Informed Consent Form
Appendix 1, Section 
1.1, Pathophysiology 
The serum phosphorus level normally ranges from 0.80-1.45
mmol/L or approximately 2.5-4.5 mg/dL in adults.  
Hypophosphatemia is defined per the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Event (CTCAE) 
as mild (0.6-<0.8 mmol/L or 2.0-<2.5 mg/dL), moderate (0.3-<0.6
mmol/L or 1.0-<2.0 mg/dL), or severe (<0.3 mmol/L or <1.0 mg/dL) 
(NCI 2009 NIH, 2009].  Symptoms usually occur when serum 
phosphorus level decrease below 0.32 mmol/l [Prinsloo, 2016].
Phosphorus homeostasis is complex and is regulated by several 
hormones.  A decrease in the level of serum phosphorus 
(hypophosphatemia) should be distinguished from a decrease in total 
body content of phosphate (phosphate deficiency).
Hypophosphatemia can occur in the presence of low, normal, or 
high total body phosphate.  In the latter two 2 instances, a shift from 
the extracellular pool into the intracellular compartment is a major 
contributory factor.
Phosphorus homeostasis is complex and is regulated by several 
hormones. Parathyroid hormone causes phosphate to be released 
from bone and inhibits renal reabsorption of phosphate, resulting in 
phosphaturia….
Appendix 1, Section 
1.2, Increased FGF23 
These finding suggest the IDA increases cFGF23 cFHF23 levels, 
and that certain iron preparations temporarily increase iFGF23 
levels.  
Appendix 1, Section 
1.4, Symptoms and 
Signs of 
Hypophosphatemia
Although an FGF23-mediated decrease in serum phosphate after a 
single infusion of iron is usually transient, the risk of developing 
clinical symptoms and the actual clinical presentation is determined 
by the severity of hypophosphatemia and the time to recovery.  The 
Common Terminology Criteria for Adverse Events has graded the 
severity of hypophosphatemia as mild.  (<LLN-2.5 mg/dl; <LLN-0.8
mmol/1), moderate (<2.5-2.0 mg/dl; <0.8-0.6 mmol/1), severe (<2.0-
1.0 mg/dl; <0.6-0.3 mmol/1), or potentially life threatening (< 1.0 
mg/dl; <0.3 mmol/1; life-threatening consequences) [Zoller, 2017].
Management of hypophosphatemia is within the judgment and 
discretion of the investigator.
Appendix 1, Section 
2, Sub-Study 
Objectives
The objective of this sub-study is to characterize serum phosphorus 
levels over time in participants with heart failure with and iron 
deficiency after dosing with FCM versus placebo
Appendix 1, Section 
3.1, Sub-Study 
Rationale
In two randomized clinical studies conducted with FCM 
(1VIT09030 and 1VIT09031), hypophosphatemia was an adverse 
drug reaction (treatment emergent adverse event assessed as related 
by the Investigator) that occurred in 2.1% (37/1775) of the study
participants.  Transient decreases in laboratory blood phosphorus 


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levels (< 2 mg/dL) were observed in 27% (440/1638) of participants.
Mean decreases from baseline in phosphorus occurred by Day 7, 
were highest at Day 14 and were returning toward baseline at Day 
35 (1VIT09031) or Day day 56 (1VIT09030). The objective of this 
sub-study is to characterize serum phosphorus levels over time in 
participants with heart failure with and iron deficiency after dosing 
with FCM versus placebo.
Appendix 1, Section 
3.2, Sub-Study Design
Participation in the sub-study is optional.  Although all 
investigational sites are encouraged to participate, each study site’s 
participation will be determined based on the feasibility of the site to 
participate.  If Once a site decides to participate, all subsequent 
participants at the sites will be invited to enroll in the sub-study until 
enrollment of 110 study participants is achieved. Sites and 
participants have the option to perform sub-study visits either at 
the clinic or at a home visit.
A total of approximately 110 participants will be enrolled and in the 
sub-study the The sample size has been determined chosen based on 
the feasibility of enrollment in the sub-study.  Sub-study duration 
will be up to 6 months for each participant.  With this number of 
participants to be enrolled in the sub-study and the current 
knowledge on the course of hypophosphatemia with FCM, the 
evaluation after the initial dosing regimen only was determined to be 
sufficient to characterize the course of hypophosphatemia in 
participants with congestive heart failure.  A separate informed 
consent form (ICF) for the sub-study will be signed by participants.  
Each participant in the sub-study will have additional blood samples 
collected at either the clinic visits or at a home visits on Days 14 ±
3, 21 ± 3, 35 ± 3, 63 ± 3, 91 ± 3, and 119± 3). These samples are in 
addition to the baseline (Day 0) and 6 month (Day 160-176) blood 
samples collected at the  clinic visits for the main study.


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Appendix 1, Section 
3.3 Schedule of Events
for Sub-Study 
See changes below
Table 1Schedule of Events for Sub-Study
Screening
Treatment 
Phase
Follow-up Phase
Visit
Week of main-study
-28 to -1
Day
0
Day
7± 2
1
Day 
14±3
2*
2
Day 
21±3*
3
Day 
35±3*
5
Day 
63±3*
9
Day 90±14†
13
Day 
91±3*
13
Day 
119±3*
17
Day 160-176, Day 
180, Day 187, EOS
* In Clinic or Home visit
† Phone call or clinic visit
‡ Reminder that laboratory testing for 1,25 (OH)2 Vitamin D, 1,25 (OH)2 Vitamin D, and Parathyroid Hormone levels are also done outside the
hypophosphatemia sub-study at Day 0 and Day 160-176


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Appendix 1, Section 
4.1, Number and Type 
of Participants 
Approximately 110 participants newly enrolled in the main 
1VIT15043 study, who fulfill the inclusion criteria, do not meet 
any of the exclusion criteria and who have given written informed 
consent will be included.
Appendix 1, Section 
4.2.1, Inclusion Criteria 
1. Demonstrate the ability to understand the requirements of the
sub-study, willingness to abide by sub-study participation
restrictions, and to return for the required assessments
Appendix 1, Section 
4.2.2, Exclusion Criteria 
2. Baseline serum phosphate Hypophosphatemia <2.5 mg/dL
Appendix 1, Section 
6.2, Informed Consent 
Prior to any study specific procedures, the investigator or his or 
her designee must explain to each participant the nature of the 
study, study its purpose, procedures to be performed, expected 
duration, and the benefits and risks of study participation….
Appendix 1, Section 
6.3, Follow-up Phase 
Clinic visits will be performed by study personnel.
Home visits will be performed by a contracted third party 
person qualified to collect blood or sitepersonnel.
Once a home visit or clinic visit choice has been made, that 
patient must continue with that venue for those visits for the 
duration of their sub-study participation.
After completing the 6-month sub-study sub-cohort follow-up
phase, the participant returns to follow the main study protocol.  
Home visits will be performed by a contracted third party person 
qualified to collect blood. They will not be performed by study 
personnel.
Appendix 1, Section 
6.3.1, Sub-Study Specific
Visit Days 14  ± 3, 21 ± 3,
35 ± 3, 63 ± 3, 91 ± 3, 119
± 3 (Clinic or Home
Visits)
Study Visit Day 91±3 days may will be an in-clinic visit (if the 
patient has chosen in-clinic visits) or is a home visit (if the 
patient has chosen home visits) which will be performed by a
licensed qualified person to collect laboratory samples.


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Appendix 1, Section 
6.5 Central Laboratory
Assessment
Serum and plasma Plasma samples for laboratory analyses will 
be obtained at 1) Day 0 of the main study; 2) Days 14, 21, 35, 63, 
91, and 119 at additional clinic visits or scheduled as home 
visits; 3) At Day 160-178 of the main study.  All serum and
plasma laboratory testing shall will be provided to the unblinded
study personnel for review and assessment.  Investigators may 
refer to Appendix 1 for guidance in managing 
hypophosphatemia. The laboratory assessments will be 
determined as follows: 
Appendix 1, Section 
7.2 Reporting of
Adverse Events 
Please follow guidance for reporting of adverse events as
detailed in the main body of the 1VIT15043 study protocol. For 
qualifying adverse events of hypophosphatemia, the National 
Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Event (CTCAE Version 5.0) should be followed.
The serum phosphorus level normally ranges from 2.5-4.5
mg/dL or 0.80-1.45 mmol/L in adults. The reporting of 
hypophosphatemia, per the 2009 NCI CTCAE Version 4.0, is:
x
Grade 1:  mild (<LLN-2.5 mg/dL; <LLN-0.8
mmol/L),
x
Grade 2:  moderate (<2.5-2.0 mg/dL; <0.8-0.6
mmol/L),
x
Grade 3:  severe (<2.0-1.0 mg/dL; <0.6-0.3 mmol/L),
x
Grade 4:  potentially life threatening (< 1.0 mg/dL;
<0.3 mmol/L; life-threatening consequences),
x
Grade 5:  death. (NCI 2009 [NIH, 2009]).
The updated 2017 NCI CTCAE Version 5.0 includes the 
revised categorization and reporting of hypophosphatemia to 
the following:


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x
Grade 1: laboratory finding only and intervention not
indicated;
x
Grade 2: oral replacement therapy indicated;
x
Grade 3: severe or medically significant but not
immediately life-threatening - hospitalization or
prolongation of existing hospitalization indicated;
x
Grade 4:  life-threatening consequences;
x
Grade 5:  death. (NCI 2017 [NIH, 2017]).
For this substudy, the analyses of changes in serum phosphate 
will be captured by laboratory changes, per NCI CTCAE 
version 4, and/or safety reporting by any interventions 
determined and reported by the study investigator, per NCI 
CTCAE version 5.0.  Please refer to Table 2: 
Hypophophosphatemia CTCAE Grade..
Appendix 1, Section 
8.3, Analysis Population 
The Hypophosphatemia sub sub-study population will be defined 
as all participants in the Intent-to-Treat population who provided 
informed consent to participate in this sub-study.
Disposition, demographics, and baseline characteristics will be 
summarized for the Hypophosphatemia sub sub -study 
population.  Outcome measurements will be analyzed based on 
the available data from this population.
Appendix 1, Section 
8.4.1, Exploratory 
Phosphate Homeostasis
Endpoints
The exploratory endpoints will be changes in laboratory values
serum phosphate following study drug IV iron administration for:
1. Serum Phosphorous
2. 1, 25 dihydroxy Vitamin D (1,25[OH]2D)
3. 25 hydroxy Vitamin D (25[OH]D)


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4. Plasma intact Parathyroid hormone
In addition to routine blood chemistry endpoints, the above
following laboratory studies blood markers of phosphate will be 
summarized.
x
Incidence of hypophosphatemia defined as a serum
phosphate level <2.0 mg/dL (<0.6 mmol/L)
x
Serum phosphate levels at each visit and the changes
from baseline
x
1, 25 dihydroxy Vitamin D (1,25 [OH]2D)
x
25 hydroxy Vitamin D (25OH-D)
x
Plasma intact Parathyroid hormone
Details of the analysis of these exploratory endpoints will 
be described in the SAP.
Appendix 1, Section 
8.5.1, Adverse Events
Adverse events will analyzed for the sub-study population as 
detailed in the main body of the 1VIT1503 study protocol.
Please follow guidance as detailed in the main body of the study 
protocol.
Appendix 1, Section 
8.5.2, Clinical Laboratory
Tests
The proportion of participants with incident hypophosphatemia 
(defined as serum phosphate level <2.5 2.0 mg/dL) (<0.8 
mmol/L), per NCI CTCAE version 4, will be summarized by 
treatment group.  Point estimates will be reported with exact two-
sided 95% confidence intervals.  
Appendix 1, Section 
9.1, Informed Consent 
The Informed Consent documents the information that the 
Investigator provides to the participant as well as and the 
participant's agreement to participate.  The Investigator will fully 
explain the nature of the study, along with the aims, methods, 
anticipated benefits, potential hazards and discomfort that 


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participation might entail.  The Informed Consent must be signed 
and dated by each participant before entering the study and prior 
to the performance of any study specific procedures.
Appendix 1, Section 
11, References 
National Institutes of Health (NIH), National Cancer Institute.  
US Department of Health and Human Services.  Common 
Terminology Criteria For Adverse Events (CTCAE) Version 
4.0.  Published 2009 May 28 (v4.03: 2010 June 14).  Available 
from: http://evs.nci.nih.gov/ftp 1/CTCAE/CTCAE _ 4.03_2010-
06-14 Quick Reference_5x7.pdf.
National Institutes of Health (NIH), National Cancer Institute. 
US Department of Health and Human Services.  Common 
Terminology Criteria For Adverse Events (CTCAE) Version 
5.0. Published 2017 November 27.  Available from: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/
Prinsloo P.  Guideline for the treatment of hypophosphataemia in 
adults by Nottingham University Hospitals, published in March 
2016.
Zoller H, Schaefer B, Glodny B.  Iron-induced 
hypophosphatemia: an emerging complication.  Curr Opin 
Nephrol Hypertens.  2017;26:266-275.
Appendix 1, Guidance for 
Managing 
Hypophosphatemia
Appendix 1 
Guidance for Managing Hypophosphatemia 
x
If serum phosphate is lower than the lower limit of
normal (LLN) but > 1 g/dL and asymptomatic, it is 
acceptable to simply monitor the serum phosphate level 
x
If phosphorus is lower than LLN but > 1 g/dL and
accompanied by symptoms associated with 
hypophosphatemia (e.g., palpitations, dizziness, or 
muscle weakness) whether or not they are clearly due to 
hypophosphatemia, the patient may be treated by either 
the investigator if he/she feels comfortable or in an 


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3DJHRI
emergency department if he/she does not feel 
comfortable treating. Treatment options include dietary 
sources of phosphate (e.g., dairy products) or oral 
phosphate supplements 
x
If patient serum phosphate is < 1 g/dL without
symptoms, oral phosphate repletion is acceptable at 
discretion of treating physician. 
x
If patient has phosphate < 1 g/dL and is symptomatic
(which may include palpitations, dizziness or muscle 
weakness, etc.) whether or not they are clearly due to 
hypophosphatemia, the patient should be evaluated and 
treated in an emergency department.  
Table 2.Hypophosphatemia 
CTCAE Grade
See below 


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Table 1 
Hypophosphatemia CTCAE Grade
Hypophosphatemia:  A disorder characterized by laboratory test results that indicate a low concentration of phosphates in the blood.
CTCAE Grade:
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Grade refers to the 
severity of the AE.
The CTCAE displays 
Grades 1 through 5 
with unique clinical 
descriptions 
of 
severity for each AE 
based on this general 
guideline.*
Mild; asymptomatic or 
mild symptoms; clinical 
or 
diagnostic 
observations 
only; 
intervention 
not 
indicated.
Moderate; 
minimal, 
local or noninvasive 
intervention indicated; 
limiting 
age-
appropriate 
instrumental ADL.
Severe 
or 
medically 
significant 
but 
not 
immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization 
indicated; 
disabling; limiting self-care 
ADL.
Life-threatening 
consequences; 
urgent 
intervention 
indicated.
Death 
related 
to 
AE.
From CTCAE v4.0
Metabolism 
and 
Nutrition Disorders -
Hypophosphatemia:  
May 28, 2009: Page 45
<LLN - 2.5 mg/dL; 
<LLN - 0.8 mmol/L
<2.5 - 2.0 mg/dL; 
<0.8 - 0.6 mmol/L
<2.0 - 1.0 mg/dL; 
<0.6 - 0.3 mmol/L
<1.0 mg/dL; 
<0.3 mmol/L;
Life-threatening 
consequences
Death
From CTCAE v5.0
Metabolism 
and 
Nutrition Disorders -
Hypophosphatemia: 
November 27, 2017: 
Page 94
Laboratory 
finding 
only and intervention 
not indicated 
Oral 
replacement 
therapy indicated 
Severe 
or 
medically 
significant 
but 
not 
immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization indicated 
Life-threatening 
consequences 
Death 
*A semi-colon indicates ‘or’ within the description of the grade.


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APPENDIX 1 
 
 
AMERICAN REGENT, INCORPORATED 
 
 
 
PROTOCOL NO.  1VIT15043 
 
IND# 127910 
 
 
A SUB-STUDY TO CHARACTERIZE SERUM PHOSPHORUS LEVELS OVER TIME 
WITH INTRAVENOUS FERRIC CARBOXYMALTOSE (FCM) VS.  PLACEBO AS 
TREATMENT FOR HEART FAILURE WITH IRON DEFICIENCY 
 
 
SPONSOR: 
American Regent, Inc. 
Clinical Research and Development 
800 Adams Avenue, Suite 200 
Norristown, PA 19403 
 
 
 


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CONTACT PERSON FOR THE SUB-STUDY 
For study-related questions, please contact: 
  
 
 
 
 
 
 


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TABLE OF CONTENTS    
PAGE 
LIST OF ABBREVIATIONS ............................................................................................. 5 
1. 
INTRODUCTION ..................................................................................................... 6 
1.1. 
Pathophysiology ........................................................................................... 6 
1.2. 
Increased FGF23 .......................................................................................... 7 
1.3. 
Inhibition of Vitamin D Activation .................................................................. 7 
1.4. 
Symptoms and Signs of Hypophosphatemia ................................................ 8 
2. 
SUB-STUDY OBJECTIVE ........................................................................................ 8 
3. 
SUB-STUDY RATIONALE AND DESIGN ................................................................ 8 
3.1. 
Sub-Study Rationale ..................................................................................... 8 
3.2. 
Sub-Study Design ......................................................................................... 9 
3.3. 
Schedule of Events for Sub-Study .............................................................. 10 
4. 
PARTICIPANT SELECTION .................................................................................. 11 
4.1. 
Number and Type of Participants ............................................................... 11 
4.2. 
Participant Selection ................................................................................... 11 
4.2.1. 
Inclusion Criteria .......................................................................... 11 
4.2.2. 
Exclusion Criteria ......................................................................... 11 
4.3. 
Participant Assignment and Randomization Process .................................. 11 
4.4. 
Withdrawal from Study................................................................................ 11 
5. 
CONCOMITANT MEDICATION ............................................................................. 11 
6. 
STUDY PROCEDURES ......................................................................................... 11 
6.1. 
Treatment Phase ........................................................................................ 11 
6.2. 
Informed Consent ....................................................................................... 11 
6.3. 
Follow-up Phase ......................................................................................... 12 
6.3.1. 
Sub-study Specific Visit Days 14 ± 3, 21 ± 3, 35 ± 3, 63 ± 3, 91 ± 3, 119 
± 3 (Clinic or Home Visits) ............................................................. 12 
6.4. 
End of Sub-Study ....................................................................................... 12 
6.5. 
Central Laboratory Assessment .................................................................. 13 
7. 
ASSESSMENT OF SAFETY .................................................................................. 13 
7.1. 
Adverse Events .......................................................................................... 13 
7.2. 
Reporting of Adverse Events ...................................................................... 13 
8. 
STATISTICS .......................................................................................................... 14 
8.1. 
Stratification/Randomization ....................................................................... 14 
8.2. 
Sample Size Rationale ............................................................................... 14 
8.3. 
Analysis Population .................................................................................... 14 
8.4. 
Endpoints and Definitions ........................................................................... 14 
8.4.1. 
Exploratory Phosphate Homeostasis Endpoints .......................... 14 
8.5. 
Safety Analyses .......................................................................................... 15 
8.5.1. 
Adverse Events ........................................................................... 15 
8.5.2. 
Clinical Laboratory Tests ............................................................. 15 


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9. 
ETHICS .................................................................................................................. 15 
9.1. 
Informed Consent ....................................................................................... 15 
9.2. 
Good Clinical Practice ................................................................................ 16 
10. DATA HANDLING AND RECORD KEEPING ......................................................... 16 
10.1. 
Case Report Form ...................................................................................... 16 
11. REFERENCES ...................................................................................................... 17 
 
LIST OF TABLES 
PAGE 
Table 1. 
Schedule of Events for Sub-Study ......................................................... 10 
Table 2. 
Hypophosphatemia CTCAE Grade ........................................................ 21 
 


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LIST OF ABBREVIATIONS 
ALT 
 
 
 
 
Alanine Aminotransferase 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form  
CTCAE 
Common Terminology Criteria for Adverse Event 
dL 
Deciliter 
e.g. 
for example 
FCM 
Ferric Carboxymaltose 
Fe 
Iron 
FGF-23 
Fibroblast growth factor 23 
g 
Gram 
GGT 
Gamma-glutamyl transferase 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDA 
Iron Deficiency Anemia 
i.e. 
that is 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
LDH 
Lactic dehydrogenase 
MedDRA 
Medical dictionary for regulatory activities 
mg  
Milligram 
mL 
Milliliter 
N 
Number 
NCI 
National Cancer Institute 
PCS 
Potentially clinically significant  
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
U.S. 
United States 
vs. 
Versus 
w/v 
weight / volume 


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1. 
INTRODUCTION 
Ferric Carboxymaltose (FCM) is a parenteral form of iron that can be used to treat iron 
deficiency (IDA) when oral iron is either ineffective or contraindicated [Lyseng-Williamson, 
2009].  Several randomized controlled trials demonstrated the efficacy and safety of intravenous 
(IV) FCM for treating iron deficiency associated with chronic kidney disease, inflammatory 
bowel disease, heavy uterine bleeding, and during the postpartum period [Barish, 2012; 
Breymann, 2008; Evstatiev, 2011; Kulnigg, 2008; Qunibi, 2011; Seid, 2008; Van Wyck , 2007; 
Van Wyck, 2009;Charytan, 2012].  In these populations, several patients who received FCM 
developed transient and asymptomatic reductions in serum phosphate that typically appeared 
within 2 to 4 weeks of treatment and resolved spontaneously within 6 to 12 weeks [Van Wyck, 
2009]. 
1.1. 
Pathophysiology 
Phosphate is the most abundant intracellular anion and is essential for membrane structure, 
energy storage, and transport in all cells.  Approximately 85% of the body's phosphorus is in 
bone as hydroxyapatite, while most of the remainder (15%) is present in soft tissue.  Only 0.1 % 
of phosphorus is present in extracellular fluid and it is this fraction that is measured with a serum 
phosphorus level [Moe, 2008].  Phosphorus homeostasis is complex and is regulated by several 
hormones.  Hypophosphatemia can occur in the presence of low, normal, or high total body 
phosphate.  In the latter two instances, a shift from the extracellular pool into the intracellular 
compartment is a major contributory factor.  Parathyroid hormone causes phosphate to be 
released from bone and inhibits renal reabsorption of phosphate, resulting in phosphaturia.  
Vitamin D aids in the intestinal absorption of phosphate.  Thyroid hormone and growth hormone 
act to increase renal reabsorption of phosphate.  Finally, a new class of phosphate-regulating 
factors, the so-called phosphatonins, including fibroblast growth factor 23 (FGF23), have been 
shown to be important in phosphate-wasting diseases, such as oncogenic osteomalacia, X-linked 
and autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemia, and 
tumoral calcinosis [Shaikh, 2008].  Additionally, FGF23 is up-regulated in patients with early-
stage chronic kidney disease to prevent hyperphosphatemia [Takeda, 2011].  A link between IV 
iron application and increase in FGF23 has been proposed [Takeda, 2011; Schouten, 2009a]. 
Serum phosphorus concentration is determined by several factors.  Dietary phosphorus intake, 
stage of growth and time of day contribute to the variability of fasting serum phosphorus 
concentrations.  Optimal cellular function is dependent on maintenance of a normal serum 
phosphorus concentration.  The most important determinant of serum phosphorus concentration 
is regulation of phosphorus reabsorption by the kidney.  The majority of this reabsorption (80%) 
occurs in the proximal tubule and is mediated by an isoform of the Na-phosphate-cotransporter.  
Parathyroid hormone, via a variety of intracellular signaling cascades leads to Na-phosphate-IIa 
internalization and down-regulation, and is the main regulator of renal phosphate reabsorption. 
Hypophosphatemia is observed in approximately 2% of hospitalized patients, and can be related 
to decreased intestinal absorption of phosphorus, re-distribution of phosphorus from the 
extracellular to the intracellular compartment, increased loss of phosphorus through the kidneys, 
or any combination of these processes.  The most common manifestation of hypophosphatemia 
in hospitalized patients is secondary to re-distribution of phosphorus as a result of respiratory 


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alkalosis [Amanzadeh, 2006].  Hypophosphatemia has been implicated as a cause of 
rhabdomyolysis, respiratory failure, hemolysis and left ventricular dysfunction.  With the 
exception of ventilated patients, there is little evidence that moderate hypophosphatemia has 
significant clinical consequences in humans, and aggressive IV phosphate replacement is 
unnecessary. 
The data on the incidence of hypophosphatemia (defined as <0.64 mmol/L) in outpatients is 
sparse, but has been reported as 0.9% [Betro, 1972]. 
1.2. 
Increased FGF23 
Studies have shown that IV FCM, iron polymaltose and saccharated ferric oxide increase the 
levels of FGF23 post-infusion [Takeda, 2001; Schouten, 2009b; Wolf, 2013].  This hormone, 
besides the parathyroid hormone, is key for serum phosphate regulation.  The phosphatonin 
FGF23 has been shown to decrease serum phosphate levels by reducing the number of Na-
phosphate-cotransporters in the proximal tubule and by inhibiting the production of the active 
form of Vitamin D [Razzaque, 2007].  FGF23 is predominantly expressed in bone osteocytes 
[Liu, 2006].  Increased concentrations of circulating FGF23 are central to the pathogenesis of 
several hypophosphatemic diseases including autosomal-dominant, -recessive, and X-linked 
hypophosphatemic rickets, tumor-induced osteomalacia and selected cases of McCune-Albright 
syndrome [Imel, 2005; Yamamoto, 2005]. 
A study tested the association of IDA with cFGF23 (the C-terminal form of the protein) and 
iFGF23 (only the intact and hence active form) levels in 55 women with a history of heavy 
uterine bleeding, and assessed the longitudinal biochemical response over 35 days to equivalent 
doses of randomly assigned, IV elemental iron in the form of FCM or iron dextran [Wolf, 2013].  
The IDA was associated with markedly elevated cFGF23 (807.8± 123.9 RU/mL) but normal 
iFGF23 (28.5± I. I pg/mL) levels at baseline.  Within 24 hours of iron administration, cFGF23 
levels decreased by approximately 80% in both groups.  In contrast, iFGF23 transiently 
increased in the FCM group alone, and was followed by a transient, asymptomatic reduction in 
serum phosphate <2.0 mg P/dL in 10 women in the FCM group compared to none in the iron 
dextran group.  Reduced serum phosphate was accompanied by increased urinary fractional 
excretion of phosphate, decreased calcitriol levels and increased parathyroid hormone levels.  
These finding suggest the IDA increases cFGF23 levels, and that certain iron preparations 
temporarily increase iFGF23 levels.  It may therefore be concluded that IV iron lowers cFGF23 
in humans by reducing FGF23 transcription as it does in mice, whereas carbohydrate moieties in 
certain iron preparations may simultaneously inhibit FGF23 degradation in osteocytes leading to 
transient increases in iFGF23 and reduced serum phosphate.  Overall, it seems plausible that an 
increase in iFGF23 with all the downstream effects may be induced by application of IV iron. 
1.3. 
Inhibition of Vitamin D Activation 
It has been described that IV iron might have an inhibitory effect on renal 25-(OH)-Vitamin D 
,Į-hydroxylase expression [Sato, 1997].  This in turn reduces the availability of 1,25-(OH)2-
Vitamin D3, which leads to decreased absorption of phosphate from the gut and to decreased 
reabsorption of filtered phosphate in the proximal tubules of the kidney [Sato, 1997].  However, 
WKLVPHFKDQLVPZDVSURSRVHGEHIRUH)*)ZDVIRXQGWREHDGLUHFWLQKLELWRURI,Į-hydroxylase 
expression and it can be assumHGWKDWWKHHIIHFWRI,9LURQRQ,Į-hydroxylase expression is 


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triggered via an increase in FGF23 concentration (as mentioned above), which leads to decreased 
production and increased degradation of 25-(OH)-9LWDPLQ',Į-hydroxylase [Shimada, 2011; 
Shimada, 2004a; Shimada, 2004b]. 
1.4. 
Symptoms and Signs of Hypophosphatemia 
Although an FGF23-mediated decrease in serum phosphate after a single infusion of iron is 
usually transient, the risk of developing clinical symptoms and the actual clinical presentation is 
determined by the severity of hypophosphatemia and the time to recovery.  Management of 
hypophosphatemia is within the judgment and discretion of the investigator. 
Patients with hypophosphatemia typically report bone pain, general weakness, and asthenia 
[Okada, 1982;Schouten, 2009b; Mani, 2010; Shiraki, 1986; Sato, 1998; Suzuki, 1998; Konjiki, 
1994; Shimizu, 2009; Yamamoto, 2013; Moore, 2013; Blazevic, 2014; Fierz, 2014; 
Vandemergel, 2014; Barea Mendoza, 2014; Poursac, 2015; Sangros Sahun, 2016].  In severe 
cases, proximal myopathy that also affects the diaphragm and rhabdomyolysis have been 
reported.  The latter can also affect the heart or cause cardiomyopathy or cardiac arrhythmias 
[Bacchetta, 2012].  Rare manifestations include hemolysis, encephalopathy, seizures [Haglin, 
2016].  The type of clinical manifestation expression is also dependent on the age at onset and 
the duration of hypophosphatemia.  Young patients with long-standing hypophosphatemia 
typically present with growth retardation, delayed dentation and rickets [Elder, 2014].  In adults 
with hypophosphatemia persisting for several months, long-term complications such as 
osteomalacia can occur (Fig.2) [Gonciulea, 2017].  Presentation of osteomalacia can include 
bone pain, fractures, and pseudofractures, which may be difficult to diagnose on conventional X-
ray.   
Radiological findings are a coarse trabecular structure, and a loss of secondary trabeculae [Phan, 
2016].  Low trauma fractures affecting the ribs or scapular “stress-“ fractures of the lumbar 
spine, pelvic structures, and long bones such as femur, tibia, or metatarsal are also common 
complications of osteomalacia.  More sensitive diagnostic tests to identify looser zones, known 
as 'pseudofractures,' include computed tomography, magnetic resonance imaging, and bone 
scintigraphy.  Bone biopsy showing increased ratio of osteoid to bone surface and reduced 
tetracycline labeling remains the gold standard for diagnosis, but is rarely performed due to its 
invasiveness.  Although there is no specific laboratory test for osteomalacia, mildly elevated total 
and bone-specific alkaline phosphatase in plasma have been repeatedly reported in the context of 
iron-induced hypophosphatemia [Phan, 2016]. 
2. 
SUB-STUDY OBJECTIVE 
The objective of this sub-study is to characterize serum phosphorus levels over time in 
participants with heart failure with iron deficiency after dosing with FCM versus placebo. 
3. 
SUB-STUDY RATIONALE AND DESIGN 
3.1. 
Sub-Study Rationale 
In two randomized clinical studies conducted with FCM (1VIT09030 and 1VIT09031), 
hypophosphatemia was an adverse drug reaction (treatment emergent adverse event assessed as 


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related by the Investigator) that occurred in 2.1% (37/1775) of the study participants.  Transient 
decreases in laboratory blood phosphorus levels (< 2 mg/dL) were observed in 27% (440/1638) 
of participants.  Mean decreases from baseline in phosphorus occurred by Day 7, were highest at 
Day 14 and were returning toward baseline at Day 35 (1VIT09031) or Day 56 (1VIT09030).  
The objective of this sub-study is to characterize serum phosphorus levels over time in 
participants with heart failure with iron deficiency after dosing with FCM versus placebo. 
3.2. 
Sub-Study Design 
Participation in the sub-study is optional.  Although all investigational sites are encouraged to 
participate, each study site’s participation will be determined based on the feasibility of the site 
to participate.  If a site decides to participate, all subsequent participants at the sites will be 
invited to enroll in the sub-study until enrollment of 110 study participants is achieved.  Sites and 
participants have the option to perform sub-study visits either at the clinic or at a home visit. 
A total of approximately 110 participants will be enrolled and the sample size has been 
determined based on the feasibility of enrollment.  Sub-study duration will be up to 6 months for 
each participant.  With this number of participants to be enrolled in the sub-study and the current 
knowledge on the course of hypophosphatemia with FCM, the evaluation after the initial dosing 
regimen only was determined to be sufficient to characterize the course of hypophosphatemia in 
participants with congestive heart failure.  A separate informed consent form (ICF) for the sub-
study will be signed by participants.  Each participant in the sub-study will have additional blood 
samples collected at either clinic visits or at home visits on Days 14 ± 3, 21 ± 3, 35 ± 3, 63 ± 3, 
91 ± 3, and 119± 3).  These samples are in addition to the baseline (Day 0) and 6 month (Day 
160-176) blood samples collected at the  clinic visits for the main study. 


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3.3. 
Schedule of Events for Sub-Study 
Table 1. 
Schedule of Events for Sub-Study 
 
Screening 
Treatment  
Phase 
Follow-up Phase 
Visit 
 
Week of main-study 
-28 to -1 
Day 
0 
Day 
7±2 
1 
Day 
14±3* 
2 
Day 
21±3* 
3 
Day 
35±3* 
5 
Day 
63±3* 
9 
Day 90±14† 
13 
Day 
91±3* 
13 
Day 
119±3* 
17 
Day 160-176, Day 
180, Day 187, EOS 
 
 
Participant follows the 
main study schedule of 
events 
 
 
 
 
Participant 
follows the 
main study  
 
 
Participant follows 
the main study 
schedule of events 
Check that informed consent 
was signed at screening or at 
Day 0 
 
X 
 
 
 
 
 
 
 
Inclusion/ Exclusion criteria 
 
X 
 
 
 
 
 
 
 
Complete study activities as 
outlined in the main study 
Section 3.3 
X 
 
 
 
 
X 
 
 
X 
Serum Chemistry (see Section 
6.5) 
 
X 
X 
X 
X 
 
X 
X 
 
1,25 (OH)2 Vitamin D‡ 
 
X 
X 
X 
X 
 
X 
X 
 
25 (OH) Vitamin D‡ 
 
X 
X 
X 
X 
 
X 
X 
 
Parathyroid Hormone‡ 
 
X 
X 
X 
X 
 
X 
X 
 
* In Clinic or Home visit 
† Phone call or clinic visit 
‡ Reminder that laboratory testing for 1,25 (OH)2 Vitamin D, 1,25 (OH)2 Vitamin D, and Parathyroid Hormone levels are also done outside the 
hypophosphatemia substudy at Day 0 and Day 160-176 
 


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4. 
PARTICIPANT SELECTION 
4.1. 
Number and Type of Participants 
Approximately 110 participants newly enrolled in the main 1VIT15043 study, who fulfill the 
inclusion criteria, do not meet any of the exclusion criteria and who have given written informed 
consent will be included. 
4.2. 
Participant Selection 
4.2.1. 
Inclusion Criteria 
1. Demonstrate the ability to understand the requirements of the sub-study, willingness to abide 
by sub-study participation, and to return for the required assessments. 
4.2.2. 
Exclusion Criteria 
1. History of primary hypophosphatemic disorder (for example X-linked hypophosphatemia) 
2. Baseline serum phosphate  <2.5 mg/dL 
3. Untreated primary hyperparathyroidism. 
4.3. 
Participant Assignment and Randomization Process 
Please follow guidance as detailed in the main body of the protocol. 
4.4. 
Withdrawal from Study 
Please follow guidance as detailed in the main body of the protocol. 
5. 
CONCOMITANT MEDICATION 
Please follow guidance as detailed in the main body of the protocol. 
6. 
STUDY PROCEDURES 
6.1. 
Treatment Phase 
For Day 0 and Day 7 visits, follow guidance as detailed in the main body of the protocol. 
6.2. 
Informed Consent 
Check that the participant signed an informed consent form for the hypophosphatemia study at 
screening or at Day 0. 


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Prior to any study specific procedures, the investigator or his or her designee must explain to 
each participant the nature of the study, study purpose, procedures to be performed, 
expected duration, and the benefits and risks of study participation.  After this explanation 
the participant must voluntarily sign an informed consent statement (Required Elements of 
Informed Consent, 21 CFR 50.25).  The participant will be given a copy of the signed 
consent form. 
6.3. 
Follow-up Phase 
Clinic visits will be performed by study personnel.  
Home visits will be performed by a contracted third party person qualified to collect blood 
or site personnel. 
Once a home visit or clinic visit choice has been made, that patient must continue with that 
venue for the those visits for the duration of their sub-study participation. 
After completing the 6-month sub-study, the participant returns to follow the main study 
protocol. 
6.3.1. 
Sub-study Specific Visit Days 14 ± 3, 21 ± 3, 35 ± 3, 63 ± 3, 91 ± 3, 119 ± 3 
(Clinic or Home Visits) 
x 
Laboratory samples will be collected 
 Serum for: 
x 
Chemistry (see Section 6.5 for details) 
x 
1,25 (OH)2 Vitamin D 
x 
25 (OH) Vitamin D 
 Plasma for: 
x 
Parathyroid Hormone 
Note that Visit Day 90±14 days (Phone call or Study visit) is a procedure in the main protocol to 
collect adverse event / serious adverse event assessment, including evaluation of potential 
endpoint events (blinded staff). 
Study Visit Day 91±3 days will be an in-clinic visit (if the patient has chosen in-clinic visits) or a 
home visit (if the patient has chosen home visits) which will be performed by a qualified person 
to collect laboratory samples. 
6.4. 
End of Sub-Study 
Sub-study visits only occur within the first 180 days.  No other sub-study dosing or blood 
collections will occur after that time. 


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6.5. 
Central Laboratory Assessment 
Serum and plasma samples for laboratory analyses will be obtained at 1) Day 0 of the main 
study; 2)  Days 14, 21, 35, 63, 91, and 119 at additional clinic visits or scheduled as home visits; 
3)  Day 160-178 of the main study.  All serum and plasma laboratory testing shall be provided to 
the study personnel for review and assessment.    The laboratory assessments will be determined 
as follows:  
Chemistry:  
Sodium, potassium, chloride, BUN, creatinine, albumin, alkaline phosphatase, 
total bilirubin, GGT, AST, ALT, LDH, calcium, phosphate, glucose, bicarbonate 
and magnesium 
Other: 
1,25 dihydroxy Vitamin D; 25 hydroxy Vitamin D 
Plasma: 
Parathyroid Hormone 
7. 
ASSESSMENT OF SAFETY 
7.1. 
Adverse Events 
7.2. 
Reporting of Adverse Events 
Please follow guidance for reporting of adverse events as detailed in the main body of the 
1VIT15043 study protocol.  For qualifying adverse events of hypophosphatemia, the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE Version 5.0) 
should be followed.  
The serum phosphorus level normally ranges from 2.5-4.5 mg/dL or 0.80-1.45 mmol/L in adults.  
The reporting of hypophosphatemia, per the 2009 NCI CTCAE Version 4.0, is: 
x Grade 1:  mild (<LLN-2.5 mg/dL; <LLN-0.8 mmol/L), 
x Grade 2:  moderate (<2.5-2.0 mg/dL; <0.8-0.6 mmol/L), 
x Grade 3:  severe (<2.0-1.0 mg/dL; <0.6-0.3 mmol/L), 
x Grade 4:  potentially life threatening (<1.0 mg/dL; <0.3mmol/L; life-threatening 
consequences),  
x Grade 5:  death. (NCI 2009 [NIH, 2009]).   
 
The updated 2017 NCI CTCAE Version 5.0 includes the revised categorization and reporting of 
hypophosphatemia to the following:   
x Grade 1: laboratory finding only and intervention not indicated;  
x Grade 2: oral replacement therapy indicated;  
x Grade 3: severe or medically significant but not immediately life-threatening - hospitalization 
or prolongation of existing hospitalization indicated;  
x Grade 4:  life-threatening consequences;  
x Grade 5:  death. (NCI 2017 [NIH, 2017]). 
 


American Regent, Inc. 
 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
 
Version 3 Date: Final 11 January 2021 
 
14 
 
For this substudy, the analyses of changes in serum phosphate will be captured by laboratory 
changes, per NCI CTCAE version 4.0, and/ or safety reporting by any interventions determined 
and reported by the study investigator, per NCI CTCAE version 5.0.  Please refer to Table 2: 
Hypophophosphatemia CTCAE Grade. 
8. 
STATISTICS 
Given the exploratory nature of this sub-study, the focus of the analyses will be on estimation 
rather than hypothesis testing.  Continuous variables will be summarized in terms of the number 
of observations, mean, standard deviation, median, minimum, and maximum.  Other descriptive 
statistics (e.g., quartiles, coefficient of variation) may be reported when appropriate.  Categorical 
variables will be summarized using frequency counts and percentages.  Two-sided 95% 
confidence intervals will be presented, when appropriate. 
Complete details of the analysis for this sub-study will be outlined in a Statistical Analysis Plan 
(SAP).  This SAP will be completed prior to database lock. 
8.1. 
Stratification/Randomization 
Please follow guidance as detailed in the main body of the protocol. 
8.2. 
Sample Size Rationale 
No formal sample size calculations were made.  Sample size for this sub-study was based on 
feasibility and practicality.  The target sample size will be a total of approximately 110 
participants, i.e., 55 participants per treatment group. 
8.3. 
Analysis Population 
The sub-study population will be defined as all participants in the Intent-to-Treat population who 
provided informed consent to participate in this sub-study. 
Disposition, demographics, and baseline characteristics will be summarized for the sub-study 
population.  Outcome measurements will be analyzed based on the available data from this 
population. 
8.4. 
Endpoints and Definitions 
8.4.1. 
Exploratory Phosphate Homeostasis Endpoints 
The exploratory endpoints will be changes in laboratory values following study drug 
administration for: 
1. Serum Phosphorous 
2. 1, 25 dihydroxy Vitamin D (1,25[OH]2D)  
3. 25 hydroxy Vitamin D (25[OH]D) 
4. Plasma intact Parathyroid hormone 
 


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In addition to routine blood chemistry endpoints, the above laboratory studies will be 
summarized. 
Details of the analysis of these exploratory endpoints will be described in the SAP. 
8.5. 
Safety Analyses 
8.5.1. 
Adverse Events 
Adverse events will analyzed for the sub-study population as detailed in the main body of the 
1VIT15043 study protocol.     
8.5.2. 
Clinical Laboratory Tests 
Clinical laboratory data will be summarized by scheduled visit using descriptive statistics.  The 
actual values as well as the change from baseline will be summarized.  Unscheduled visits will 
be excluded from these by-visit summaries.  Maximum changes relative to baseline will be over 
all visits (both scheduled and unscheduled). 
The time course for changes in serum phosphate will be evaluated and compared to that of other 
laboratory parameters. 
Where applicable, the number and percent of participants with laboratory values outside pre-
determined ranges will be summarized by scheduled visit.  Unscheduled visits will be excluded 
from these by-visit summaries.  The number and percent of participants with the laboratory 
values outside pre-determined ranges at any time during the sub-study will be summarized; and 
these summaries will be over all visits (both scheduled and unscheduled).  
The proportion of participants with serum phosphate level <2.5 mg/dL (<0.8 mmol/L), per NCI 
CTCAE version 4, will be summarized by treatment group.  Point estimates will be reported with 
exact two-sided 95% confidence intervals.   
Full details will be described in the SAP. 
9. 
ETHICS 
9.1. 
Informed Consent 
Informed consent must be obtained from each participant prior to sub-study participation.  The 
informed consent will be provided to the participant in their native language.  The consent form 
must be signed by the participant.  Each investigational site must provide the Sponsor (or 
designee) with a copy of the Informed Consent approved by that site's Institutional Review 
Board.  The original signed consent 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 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 International Conference on Harmonisation (ICH) 
guidelines.  Translations of the informed consent must be certified by a qualified translator and 
their use must be documented. 


American Regent, Inc. 
 
Protocol No.: 1VIT15043 
CONFIDENTIAL  
 
Version 3 Date: Final 11 January 2021 
 
16 
 
The Informed Consent documents the information that the Investigator provides to the 
participant as well as the participant's agreement to participate.  The Investigator will fully 
explain the nature of the study, along with the aims, methods, anticipated benefits, potential 
hazards and discomfort that participation might entail.  The Informed Consent must be signed 
and dated by each participant before entering the study and prior to the performance of any study 
specific procedures. 
9.2. 
Good Clinical Practice 
The conduct of the study will conform with the recommendations for clinical studies in man as 
set out in the 2000 Edinburgh, Scotland Revision of the “Declaration of Helsinki”, the local legal 
requirements and the guidelines on “Good Clinical Practice”, [21 CFR Part 312 and ICH 
guidelines. 
10. 
DATA HANDLING AND RECORD KEEPING 
10.1. 
Case Report Form 
The eCRFs will be completed for each participant on this study.  The participants in this study 
will be identified only by a participant number and date of birth on these forms. 
The eCRF used will be 21 CFR 11 compliant.  The system used for data collection (eCRF) will 
meet all applicable regulatory requirements for recordkeeping and record retention as would be 
provided with a paper system.  Security measures will be utilized to prevent unauthorized access 
to the data and to the computerized system.  Changes made to data that are stored on electronic 
media will always require an audit trail, in accordance with 21 CFR 11.10(e). 
The eCRFs must be reviewed and verified for accuracy by the Principal Investigator.  An 
electronic copy of the eCRF will remain at the site at the completion of the study. 


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CONFIDENTIAL  
 
Version 3 Date: Final 11 January 2021 
 
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11. 
REFERENCES 
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consequences and management.  Nat Clin Pract Nephrol.  2006 Mar;2(3): 136-48. 
Bacchetta J.  Salusky IB.  Evaluation of hypophosphatemia: lessons from patients with genetic 
disorders.  AM J Kidney Dis 2012;59:152-159. 
Barea Mendoza JA, Gredilla Zubiria I, Gonzalez Olmedo J, Mateo Alvarez 
S.[hypophosphatemia, a poorly known adverse reaction of intravenous use of iron].  Med Clin 
2014; 143:284-285. 
Blazevic A, Hunze J, Boots JM.  Severe hypophosphataemia after intravenous iron 
administration.  Netherlands J Med 2014; 72:49-53. 
Barish CF, Koch T, Butcher A, Morris D, Bregman DB.  Safety and efficacy of intravenous 
ferric carboxymaltose (750 mg) in the treatment of iron deficiency anemia: two randomized, 
controlled trials.  Anemia.  2012:172104. 
Betro MG, Pain RW.  Hypophosphatemia and hyperphosphatemia in hospitalized patients.  BMJ.  
1972;1:273-276. 
Breymann C, Gliga F, Bejenariu C, Strizhova N.  Comparative efficacy and safety of intravenous 
ferric carboxymaltose in the treatment of postpartum iron deficiency anemia.  Int J Gynaecol 
Obstet.  2008;101 :67-73. 
Charytan C, Bernardo MV, Koch TA, Butcher A, Morris D, Bregman DB.  Intravenous ferric 
carboxymaltose versus standard medical care in the treatment of iron deficiency anemia in 
patients with chronic kidney disease: a randomised, active-controlled, multi-centre study.  
Nephrol Dial Transplant.  Epub.  2012 Dec 5.  DOl:10.  1093/ ndt/gfs528. 
Elder CJ.  Bishop NJ.  Rickets.  Lancet 2014; 383:1665-1676 
Evstatiev R, Marteau P, Iqbal T, Khalif IL, Stein J, Bokemeyer B, Chopey IV, Gutzwiller FS,  
Riopel L, Gasche C.  FERGlcor, a randomized controlled trial on ferric carboxymaltose for iron 
deficiency anemia in inflammatory bowel disease.  Gastroenterology.  2011;141:846-53. 
Fierz YC, Kenmeni R, Gonthier A, et al.  Severe and prolonged hyphosphatemia after 
intravenous iron administration in a malnourished patient.  Eur J Clin Nutr 2014; 68:531-533. 
Gonciulea AR, Jan De Beur SM.  Fibroblast growth factor 23-medicated bone disease.  
Endocrinol Metab Clin North Am 2017; 46:19-39. 
Haglin L.  Using phosphate supplementation to reverse hypophosphatemia and phosphate 
depletion in neurological disease and disturbance.  Nutr Neurosci 2016; 19:213-223 
Imel EA, Econs MJ.  Fibroblast growth factor 23: roles in health and disease.  J Am Soc 
Nephrol.  2005;16:2565-75. 
Konjiki O, Fukaya S, Kanou H, et al.  [a case of hypophosphatemia induced by intravenous 
administration of saccharated iron oxide].  Nihon Ronan lgakkai Zasshi 1994; 31:805-810. 
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inflammatory bowel disease: the ferric carboxymaltose (FERINJECD randomized controlled 
trial.Am J Gastroenterol.  2008;103:1182-92. 
Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD.  Pathogenic role of Fgf23 in Hyp mice.  
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Lyseng-Williamson KA, Keating GM.  Ferric carboxymaltose: a review of its use in iron-
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Mani LY, Nseir G, Venetz JP, Pascual M.  Severe hypophosphatemia after intravenous 
administration of iron carboxymaltose in a stable renal transplant recipient.  Transplantation 
2010; 90:804 - 805. 
Moe SM.  Disorders involving calcium, phosphorus, and magnesium.  Prim Care Clin Office 
Pract.  2008;35:215-37. 
Moore KL, Kildahl-Andersen O, Kildahl·Andersen R, Tjonnfjord GE.  Uncommon adverse 
effect of a common medication.  Tidsskr Nor Laegeforen 2013; 133:165. 
National Institutes of Health (NIH), National Cancer Institute.  US Department of Health and 
Human Services.  Common Terminology Criteria For Adverse Events (CTCAE) Version 4.0.  
Published 2009 May 28 (v4.03: 2010 June 14).  Available from: http://evs.nci.nih.gov/ftp 
1/CTCAE/CTCAE _ 4.03_2010-06-14 Quick Reference_5x7.pdf. 
National Institutes of Health (NIH), National Cancer Institute. US Department of Health and 
Human Services.  Common Terminology Criteria For Adverse Events (CTCAE) Version 5.0. 
Published 2017 November 27.  Available from: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/ 
Okada M, Imamura K, Fuchigami T, et al.  [2 cases of nonspecific multiple ulcers of the small 
intestine associated with osteomalacia caused by long· term intravenous administration of 
saccharated ferric oxide].  Nihon Naika Gakkai zasshi 1982; 71:1566-1572. 
Phan CM, Guglielmi G.  Metabolic bone disease in patients with malabsorption.  Semin 
Musculoskelet Radiol 2016; 20:369-375 
Poursac N.  [Hypophosphatémie et fgf23 élevé, Rhumatos] 2015; 12:61-64. 
Qunibi WY, Martinez C, Smith M, Benjamin J, Mangione A, Roger SD.  A randomized 
controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron 
deficiency anaemia of non-dialysis-dependent chronic kidney disease patients.  Nephrol Dial 
Transplant.  2011;26:1599-607. 
Razzaque MS, Lanske B.  The emerging role of the fibroblast growth factor-23- klotho axis in 
renal regulation of phosphate homeostasis.  J Endocrinol.  2007;194: 1-10. 
Sangros Sahun MJ, Goni Girones E, Camarero Salazar A, et al.  Symptomatic 
hypophosphataemic osteomalacia secondary to the treatment with iron carboxymaltose detected 
in bone scineigraphy.  Rev Esp Med Nucl Imagen Mol 2016; 35:391-393. 
Sato K, Nohtomi K, Demura H, et al.  Saccharated ferric oxide (sfo) induced osteomalacia: In 
vitro  inhibition by sfo of bone formation and 1,25-dihydroxy·vitamin d production in renal 
tubules.  Bone 1997; 21:57-64. 


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Sato K, Shiraki M.  Saccharated ferric oxide-induced osteomalacia in japan: iron-induced 
osteopathy due to nephropathy.  Endocr J 1998; 45:431-439. 
Schaefer B, Glodny, Zoller H.  Loosing blood and bone.  Gastroenterology2017;152: [Epub 
ahead of print] 
Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG.  FGF23 elevation and 
hypophosphatemia after intravenous iron polymaltose: a prospective study.  J Clin Endocrinol 
Metab.  2009b Jul;94(7):2332-7.  Epub 2009 Apr 14. 
Schouten BJ, Doogue MP, Soule SG, Hunt PJ.  Iron polymaltose·induced fgf23 elevation 
complicated by hypophosphataemic osteomalacia.  Ann Clin Biochem 2009a; 46 (Pt 2):167-169. 
Seid MH, Derman RJ, Baker JB, Banach W, Goldberg C, Rogers R.  Ferric carboxymaltose 
injection in the treatment of postpartum iron deficiency anemia: a randomized controlled clinical 
trial.  Am J Obstet Gynecol.  2008;199:435-7. 
Shaikh A, Berndt T, Kumar R.  Regulation of phosphate homeostasis by the phosphatonins and 
other novel mediators.  Pediatr Nephrol.  2008;23:1203-10.  Epub 2008 Feb 21. 
Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al.  Cloning and 
characterization of FGF23 as a causative factor of tumor-induced osteomalacia.  Proc Natl Acad 
Sci.  2001 May 22;98(11):6500-5. 
Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al.  Targeted 
ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and 
vitamin D metabolism.  J Clin Invest.  2004a Feb;l 13(4):561-8. 
Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al.  FGF-23 is a potent 
regulator of vitamin D metabolism and phosphate homeostasis.  J Bone Miner Res.  
2004b;19(3):429-35.  Epub 2003 Dec 29. 
Shimizu Y, Tada Y, Yamauchi M, et al.  Hypophosphatemia induced by intravenous 
administration of saccharated ferric oxide.  Bone 2009;45:814-816. 
Shiraki M.  [metabolic bone diseases: osteomalacia due to fe oral poisoning].  Nihon Rinsho 
1986; 44:2493-2498. 
Suzuki A, Ohoike H, Matsuoka Y, lrimajiri S.  Iatrogenic osteomalacia caused by intravenous 
administration of saccharated ferric oxide.  Am J Hematol 1993;43:75-76. 
Takeda Y, Komaba H, Goto S, Fujii H, Umezu M, Hasegawa H, et al.  Effect of intravenous 
saccharated ferric oxide on serum FGF23 and mineral metabolism in hemodialysis patients.  Am 
J Nephrol.  2011 ;33:421-6.  Epub 2011 Apr 19. 
Vandemergel X, Vandergheynst F.  Potentially life-threatening phosphate diabetes induced by 
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Van Wyck DB, Martens MG, Seid MH, Baker JB, Mangione A.  Intravenous ferric 
carboxymaltose compared with oral iron in the treatment of postpartum anemia: a randomized 
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Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT.  Large-dose 
intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: 
a randomized, controlled trial.  Transfusion.  2009;49:2719-28. 
Wolf M, Koch TA, Bregman DB.  Effects of iron deficiency anemia and its treatment on 
fibroblast growth factor 23 and phosphate homeostasis in women.  J Bone Miner Res.  2013 
Aug;28(8): 1793-803.  Epub 2013 Mar 16. 
Yamamoto T, Imanishi Y, Kinoshita E, Nakagomi Y, Shimizu N, Miyauchi A, et al.  The role of 
fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D 
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Yamamoto S, Okada Y, Mori H, et al.  Iatrogenic osteomalacia: report of two cases.  J UOEH 
2013; 35:25-31. 


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Table 2. 
Hypophosphatemia CTCAE Grade 
Hypophosphatemia:  A disorder characterized by laboratory test results that indicate a low concentration of phosphates in the blood. 
CTCAE Grade: 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  
Grade refers to the 
severity of the AE.  
The CTCAE displays 
Grades 1 through 5 
with unique clinical 
descriptions of 
severity for each AE 
based on this general 
guideline.* 
Mild; asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated. 
Moderate; minimal, 
local or noninvasive 
intervention indicated;  
limiting age-
appropriate 
instrumental ADL. 
Severe or medically 
significant but not 
immediately life-threatening; 
hospitalization or 
prolongation of 
hospitalization indicated; 
disabling; limiting self-care 
ADL. 
Life-threatening 
consequences; urgent 
intervention 
indicated. 
Death 
related to 
AE. 
From CTCAE v4.0 
Metabolism and 
Nutrition Disorders - 
Hypophosphatemia:  
May 28, 2009: Page 
45 
<LLN - 2.5 mg/dL;  
<LLN - 0.8 mmol/L 
<2.5 - 2.0 mg/dL;  
<0.8 - 0.6 mmol/L 
<2.0 - 1.0 mg/dL;  
<0.6 - 0.3 mmol/L 
<1.0 mg/dL;  
<0.3 mmol/L; 
Life-threatening 
consequences 
Death 
From CTCAE v5.0 
Metabolism and 
Nutrition Disorders - 
Hypophosphatemia: 
November 27, 2017: 
Page 94 
Laboratory finding only 
and intervention not 
indicated  
Oral replacement 
therapy indicated  
Severe or medically 
significant but not 
immediately life-threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated  
Life-threatening 
consequences  
Death  
*A semi-colon indicates ‘or’ within the description of the grade. 


Protocol/Version No.: 1VIT15043/3 
Statistical Analysis Plan Version: 1.0 September 2021 
 
Page 1 of 27 
 
 
 
 
Statistical Analysis Plan  
for  
Heart Failure with Iron Deficiency (HEART-FID). 
 
Version: 1.0 
Date: 21 September 2021  
 
 
Clinical Study Protocol/Amendment No: 1VIT15043/3 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO 
INVESTIGATE THE EFFICACY AND SAFETY OF INJECTAFER® (FERRIC 
CARBOXYMALTOSE) AS TREATMENT FOR HEART FAILURE WITH IRON 
DEFICIENCY. 
 
 
 
 
 
Prepared by: CT Statistics Group  
 
Prepared For: American Regent, Inc. 
[Duke Clinical Research Institute] 
[Sponsor] 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations.  
 
 


Protocol/Version No.: 1VIT15043/3
Statistical Analysis Plan Version: 1.0 September 2021
Page 2 of 27
Statistical Analyses Plan Amendment x
The original Statistical Analysis Plan was finalized and issued on 21/Sep/2021. Major changes 
and clarifications of planned analyses in SAP Vx.0 since the original SAP are listed below
Version
Date
Author(s)
Brief Summary of Changes
V1.0
21/Sep2021
Final version after American Regent’s final 
comments on 14/Sep/2021. Signed.


Protocol/Version No.: 1VIT15043/3 
Statistical Analysis Plan Version: 1.0 September 2021 
 
Page 3 of 27 
 
TABLE of CONTENTS  
Statistical Analyses Plan Amendment x .......................................................................... 2 
1 
INTRODUCTION ....................................................................................................... 7 
1.1 
Study Objectives ................................................................................................ 7 
1.1.1 
Primary Objective ....................................................................................... 7 
1.1.2 
Secondary Objective ................................................................................... 7 
1.2 
Study Design ...................................................................................................... 7 
1.3 
Randomization and Blinding ............................................................................. 8 
1.4 
Sample Size and Power ...................................................................................... 8 
1.5 
Schedule of Major Assessments ........................................................................ 9 
1.6 
Summary of Relevant Amendments to the Protocol ......................................... 9 
2 
ANALYSIS SETS ........................................................................................................ 9 
2.1 
Intent-to-treat (ITT) Population ......................................................................... 9 
2.2 
Safety Population ............................................................................................. 10 
2.3 
Per-protocol (PP) Population ........................................................................... 10 
2.4 
Hypophosphatemia Sub-study (HS) Population .............................................. 10 
3 
BACKGROUND CHARACTERISTICS .............................................................10 
3.1 
Disposition of Participants ............................................................................... 10 
3.2 
Demographic and Baseline Characteristics ..................................................... 10 
3.3 
Medical History ............................................................................................... 10 
4 
METHODS OF ANALYSIS ....................................................................................11 
4.1 
General Principles ............................................................................................ 11 
4.2 
Multiple comparisons ...................................................................................... 12 
4.3 
Visit Windows for Analysis ............................................................................. 12 
4.4 
Right Censoring ............................................................................................... 12 
4.5 
Handling of Missing Data ................................................................................ 12 
4.5.1 
Outcome Data/Dates ................................................................................. 12 
4.5.2 
Other Missing Data ................................................................................... 13 
4.6 
Assessment of Model Assumption .................................................................. 13 
5 
OUTCOMES ...............................................................................................................13 
5.1 
Primary Outcome ............................................................................................. 13 
5.2 
Top Secondary Outcome ................................................................................. 14 
5.3 
Analyses of the Primary and the Top Secondary Outcome ............................. 14 
5.3.1 
Nonparametric Test of FCM vs. Placebo for Primary Composite ........... 14 
5.3.2 
FCM vs. Placebo for Top Secondary Outcome ........................................ 16 
5.4 
Subgroup Analyses for Top Secondary Outcome ............................................ 16 
5.5 
Secondary Outcomes ....................................................................................... 16 
5.6 
Hypophosphatemia Sub-study Analyses ......................................................... 17 
5.7 
Exploratory Analyses ....................................................................................... 17 
6 
SAFETY ANALYSIS ................................................................................................18 
6.1 
Adverse Events (AEs) ...................................................................................... 18 
6.2 
Laboratory Data ............................................................................................... 19 
6.3 
Previous and Concomitant Medications and Interventions ............................. 19 
6.4 
Vitals and Physical Assessments ..................................................................... 19 
6.5 
Drug Exposure ................................................................................................. 20 
6.6 
Events of Special Interest related to HF that did not lead to Hospitalization .. 20 
6.7 
Hospitalizations not part of Primary and Secondary Outcomes ...................... 20 


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6.8 
COVID-19 Related .......................................................................................... 20 
6.9 
Other Safety Assessments ................................................................................ 20 
7 
DATA SAFETY MONITORING BOARD AND INTERIM ANALYSES ..21 
7.1 
Interim Analyses .............................................................................................. 21 
8 
DATABASE SOURCES ...........................................................................................21 
9 
REFERENCES ...........................................................................................................21 
10 APPENDICES ............................................................................................................22 
10.1 
Appendix 1: Summary of Amendments to the Protocol relevant to the SAP 
are here. Details can be found within the CSP. .......................................................... 23 
10.2 
Appendix 2: Simulations for power estimation for the primary endpoint were 
conducted at the time of writing the original version of the CSP. The below detailed 
information was used at the time. ............................................................................... 24 
10.3 
Appendix 3: Ranking Algorithm (primary efficacy endpoint)..................... 27 
 
 
 


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Page 5 of 27 
 
LIST OF ABBREVIATIONS  
 
6MWT              
6 Minute Walk Test                      
ADaM 
Analysis Data Model 
AE 
Adverse Experience 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BNP 
Brain Natriuretic Peptide 
BUN 
Blood Urea Nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CEC 
Clinical Events Committee 
CKD 
Chronic Kidney Disease 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CTMS 
Clinical Trial Management System 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DCRI 
Duke Clinical Research Institute 
DSMB  
Data and Safety Monitoring Board 
EDC 
Electronic Data Capture 
FCM 
Ferric Carboxymaltose 
GGT 
Gamma-Glutamyl Transferase 
Hb 
Haemoglobin 
Hct 
Haematocrit 
HF 
Heart Failure 
HLT 
High Level Term 
HR  
Hazard Ratio 
HS 
Hypophosphatemia Sub-study  
ICH 
International Council for Harmonisation 
ITT 
Intent-To-Treat 
IV 
Intravenous 
IXRS 
Interactive Web Response Systems 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI  
Myocardial Infarction 
NYHA 
New York Heart Association 
PP 
Per Protocol 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RDW 
Red Cell Distribution Width 


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SDTM 
Study Data Tabulation Model 
SAE   
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SMQ 
Standardised MedDRA Queries 
SOC 
System Organ Class 
TESAE 
Treatment Emergent Serious Adverse 
Experiences 
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
WBC 
White Blood Cell 
 
 
 
 
 
 
 


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1 
INTRODUCTION 
HEART-FID is a double-blind, multicenter, prospective, randomized, placebo-controlled study 
to assess the effects of intravenous (IV) ferric carboxymaltose (FCM) compared to placebo on the 
hierarchical, composite endpoint of 12-month rate of death and hospitalization for worsening 
heart failure and change in 6 minute walk test (6MWT) at 6 months for participants in heart failure 
with reduced ejection fraction and with iron deficiency. The reader of this Statistical Analysis 
Plan (SAP) is also encouraged to read the corresponding protocol (1VIT15043, version 3.0, 11 
January 2021) which provides detail on the conduct of the study, the operational aspects of clinical 
assessments, and the timings of individual participant assessments. 
This SAP contains definitions of analysis populations, and details on the statistical methods for 
the analyses and summaries of study data that are to be performed, to help support the completion 
of the final Clinical Study Report (CSR) for study 1VIT15043. Details regarding analysis of the 
hypophosphatemia sub-study can be found in a supplemental SAP. Information on important 
definitions and reporting conventions and table shells to support the SAP will be in a supplemental 
Appendix. 
Specifications of supporting tables, figures, and data listings are contained in a separate document.   
Outcomes that are confirmed by clinical events classification (CEC) adjudication, the process for 
which is governed by specific charters referenced in the protocol, will be referred to as 
“confirmed” events in the SAP. The term outcome is used throughout this document as 
synonymous with the term endpoint used in the clinical trial protocol. The following events are 
confirmed by the CEC in HEART-FID: Death (Cardiovascular [CV] and Non-Cardiovascular), 
Cardiovascular Hospitalizations (Heart Failure, Acute Myocardial Infarction [MI], Stroke, and 
Other cardiovascular hospitalizations), and Urgent Heart Failure Visit. CEC data take precedence 
over investigator data when both are available and investigator response is different from the CEC 
adjudicated response.   
1.1 
Study Objectives  
1.1.1 
Primary Objective 
To determine the efficacy and safety of iron therapy using intravenous (IV) FCM, relative to 
placebo, in the treatment of participants in heart failure with reduced ejection fraction and with 
iron deficiency. 
1.1.2 
Secondary Objective 
To evaluate the effect of IV FCM, relative to placebo, on the functional capacity of participants 
in heart failure with reduced ejection fraction and with iron deficiency. 
1.2 
Study Design 
This is a double-blind, multicenter, prospective, randomized, placebo-controlled study to assess 
the effects of IV FCM compared to placebo on the 12-month rate of death, hospitalization for 
worsening heart failure, and change in 6MWT from baseline at 6 months for participants with 
heart failure, reduced ejection fraction, and with iron deficiency. 
After an initial screening period of up to 28 days, eligible participants will be stratified by 
region and randomized in a 1:1 ratio to FCM or placebo. Study drug administration will occur 
on Day 0 and Day 7 as an undiluted slow IV push, with additional study visits (in person or via 
telephone) planned at 3 month intervals, and additional dosing administered every 6 months as 
applicable (based on dose regimen below).  
For all participants, laboratory tests for haematology, ferritin, and transferrin saturation (TSAT) 
with appropriate safety evaluations, to determine additional treatment, will occur at 6 month 
intervals.  


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In a subset of sites, a sub-study will be conducted to characterize serum phosphate levels over 
time in participants in heart failure with reduced ejection fraction with iron deficiency after 
dosing with FCM. There will be additional visits for these participants during the first 6 months 
(Clinical Study Protocol [CSP] Appendix 1, Section 3.3)  
 
Initial treatment will occur on Day 0 and Day 7. On Day 0 and 7, Group A (FCM) will receive a 
750 mg undiluted, blinded dose of IV FCM at the rate of approximately 100 mg (2 mL)/minute 
(approximately 7 minutes 30 seconds); Group B (placebo) will receive a blinded placebo (15 cc 
of normal saline) IV push at 2 mL/minute (approximately 7 minutes 30 seconds). Participants in 
Group A with body weight <50 kg (110 pounds) will have individual FCM doses adjusted to 15 
mg/kg, not to exceed an individual dose of 750 mgs or a cumulative dose of 1500 mg per 
treatment cycle. Placebo dosing will be adjusted for weight based on volume. 
 
All participants randomized will be dosed every 6 months. Participants randomized to the FCM 
arm will be dosed as indicated based on haemoglobin levels (i.e. Hb <13.5 g/dl [females] or 
<15.0 g/dl [males)]) and iron studies (i.e. serum ferritin <100 ng/mL or 100 to 300 ng/mL with 
TSAT <20%). Participants not meeting pre-specified laboratory criteria for blood counts and 
iron studies and all participants randomized to the placebo arm will be administered IV placebo 
infusion at each visit.  
Unblinded site personnel, responsible for preparation and administration of the FCM or Placebo, 
will ensure that the participant and all blinded site staff are not able to observe the preparation or 
administration of study treatment.  
1.3 
Randomization and Blinding 
The randomization scheme was generated by a statistician at DCRI who is firewalled to the 
operational team, using Statistical Analysis System (SAS) with region as the only stratification 
field. Blocking was used in the scheme with random block sizes (3 different levels). This 
scheme was implemented into the Interactive Web Response Systems (IXRS) by the vendor 
Almac. The vendor maintains randomized treatment assignments as well as unblinded kit 
dispensation information. The operational team for this trial is to remain blinded until data base 
lock, at which time the unblinded treatment codes received from Almac will be combined with 
blinded data.  
In the event of the need to break an individual participant blind, the site can call Almac for this 
information. The operational team gets informed if such unblinding occurs; however, they do 
not know the true treatment assignment. 
The 3 regions are defined within the randomization scheme as follows (Details can be found in 
the SAP Appendix for Definitions and Reporting Conventions): 
x 
North America 
x 
Asia Pacific 
x 
Europe 
1.4 
Sample Size and Power  
The study design allows for sufficient power for both the primary and top secondary outcomes.  
Numerical simulations based on multivariate normal vectors (Appendix 2) were conducted to 
estimate power for the primary treatment comparison based on the following assumptions about 
events rates described in Table 1.4.1 
 
 
 
 


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Table 1.4.1. Assumptions about Event Rates for Primary Outcome 
Ranked tier at 12-month endpoint 
(6 month for 6 MWT)  
Control  
Treatment  
Death total  
Death without hospitalization  
Death with hospitalization  
8%  
4%  
4%  
6.8%  
3.4%  
3.4%  
Hospitalizations in survivors  
1 
2 
3 or more  
 
6%  
3%  
1%  
 
4.8%  
2.4%  
0.8%  
Change in 6 Minute Walk Test  
Mean = 0  
SD = 90  
Mean = 18  
SD = 90  
 
With 3014 participants (1507 per arm) and 2.5% annual loss to follow-up for clinical outcomes 
and 15% of individuals with missing 6MWT at 6 months (unable to perform or lost to follow-
up), projected simulations estimate 90% power at an overall two-sided significance level of 
0.01, accounting for one interim analysis as described in Section 7.1.  
 
For the top secondary composite, there is an assumed event rate of 0.0128 per month in the 
control arm which represents conservative 75% discounting of the event rate obtained by the 
FCM meta-analysis [Anker 2015]. The anticipated hazard ratio (HR) was set at 0.80 (20% 
reduction). Uniform enrollment was assumed over the period of 30 months, with an anticipated 
minimum follow-up of 12 months (required minimum of 6 months), anticipated maximum 
follow-up of 42 months (no required maximum), and monthly loss to follow-up of 0.0021 (2.5% 
annualized). With these assumptions, 1500 per study arm (3000 total) provides 90% power to 
reject the null hypothesis of no difference between treatment arms when tested at an overall 
two-sided level of significance α=0.05, accounting for one interim analysis as described in 
Section 8.10. This results in a total of 771 participants with events (in case of multiple events 
experienced by a participant, only their first one will be counted towards the 771) necessary to 
achieve the desired power. Thus, the trial has the potential opportunity to be stopped at a point 
where the projected number of participants reaches 771 events, but no earlier than the last 
participant reaching 12 months of follow-up.  
The primary and top secondary outcome will be tested sequentially, and thus, no multiplicity 
adjustment is necessary.  
1.5 
Schedule of Major Assessments 
Following randomization, outcomes and serious adverse event data are collected at 90 days and 
at every 6 monthly visit as detailed in schedule of events (Section 3.3 of the CSP)  
1.6 
Summary of Relevant Amendments to the Protocol 
Please refer to Appendix 1 for this information. The version the participant was enrolled under 
will be available in the database. 
 
2 
 ANALYSIS SETS 
2.1 
Intent-to-treat (ITT) Population  
The ITT population consists of all participants randomized to a treatment group in the study 
regardless of their compliance with the study medication. The participants are analysed in the 


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treatment group to which they were randomized. This is the primary population of all efficacy 
analyses. 
Any participant who gets a treatment assigned via the IXRS will be considered to have been 
randomized. 
2.2 
Safety Population 
The Safety population will consist of all ITT participants who received at least 1 dose of study 
medication identified by the presence of injection start date. When summarizing data using this 
population, participants are analyzed in the As Treated group. If a participant receives any FCM 
study drug, then the participant will be counted as treated in the FCM arm, regardless of the 
amount of medication received; otherwise the participant will be counted as treated in the 
placebo arm. 
The Safety population will be used for assessing Safety. 
2.3 
 Per-protocol (PP) Population  
The Per-Protocol Population is a subset of the ITT population excluding participants who 
complied with the randomized treatment for less than 50% of the 1 year follow-up. In cases of 
medication error, treatment assignments in the per-protocol analysis will be analyzed according 
to the actual treatment received as the first study drug dose.  
2.4 
Hypophosphatemia Sub-study (HS) Population  
The Hypophosphatemia Sub-study (HS) population will consist of all ITT participants who 
enrolled in the sub-study identified by the presence of injection start date. When summarizing 
data using this population, participants will be analyzed according to the actual treatment 
received as the first dose. 
The HS population will be used for assessing Safety. 
Please see the HS SAP for further details. 
3 
BACKGROUND CHARACTERISTICS 
3.1 
Disposition of Participants 
Disposition data will be summarized for all randomized participants. The summary by treatment 
will include 
x 
Inclusion in the three study populations 
x 
Participants completing study alive 
x 
Lost to follow up 
x 
Withdrawn consent for follow up 
x 
Reason study drug permanently discontinued  
3.2 
Demographic and Baseline Characteristics  
The demographic, baseline clinical and anthropometric characteristics collected in the study will 
be tabulated and summarised as descriptive statistics by treatment for both ITT and Safety 
populations.  
3.3 
Medical History  
Participant medical history will be summarized within both ITT and Safety populations. 
x 
Duration of heart failure calculated as (year of randomization – year of onset) +1 and 
etiology of heart failure at baseline will be summarized by treatment. 
All other medical history data collected in the study will be summarized by treatment group. 
 


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4 
METHODS OF ANALYSIS 
4.1 
General Principles 
In addition to specific analyses and presentations that are detailed in the following sections, 
results will be summarised using descriptive statistics, including the number of participants, 
mean, standard deviation, median, and range as appropriate. For categorical variables, counts 
and percentage per treatment group will be presented. 
 
Summaries of continuous characteristics will be based on non-missing observations. Percentage 
for categorical variables will be calculated based on number of participants with non-missing 
values for the variable.  
 
Unless otherwise stated, timings of efficacy endpoints will be relative to the date of 
randomization. Specifically, for all time-to event analyses (defined as [event date – 
randomization date] +1 where event occurs and as [appropriate censoring date based on analytic 
population – randomization date] +1 where event does not occur), the treatment groups will be 
analysed using a Cox proportional hazards model that includes treatment as an explanatory 
factor and region as stratification factors unless specified otherwise. The Efron method will be 
used for handling ties. P-value and confidence intervals for the HR will be based on the Wald 
statistic. Any analyses using events that are confirmed by the CEC will use the CEC adjudicated 
responses and related dates. Analyses of Cardiovascular (CV) death, will include deaths with 
cause of death confirmed as unknown.  
In addition, the summary tables of these analyses will include the number of participants with 
event and the cumulative incidence (1 – the “survival” or event-free proportion) over time per 
treatment group presented annually through the last time point where 90 % of the events have 
occurred. Cumulative incidence function of participants with events will also be calculated and 
plotted through maximum follow up available in the study, with number of participants at risk 
indicated below the plot at specific times.  
The timing of safety data will be relative to the study drug start date. Specifically, any time to 
safety event durations will be defined as [event date – study drug start date] +1 where event 
occurs and as [appropriate censoring date based on analytic population – study drug start date] 
+1 where event does not occur). 
Baseline is defined as response/value collected closest to randomization date and prior to study 
drug start. 
Date of last follow-up for the participant will be driven off of the date of their final study 
disposition. This can be different from date of mortality status for lost to follow-up or 
withdrawn consent participants. 
The median and total person-years of follow-up for the whole study will also be reported. 
  
All analyses included in this SAP will be performed using SAS v9.4 or higher. They will be 
based on Clinical Data Interchange Standards Consortium (CDISC) standard data (Analysis 
Data Model (ADaM) and/or Study Data Tabulation Model (SDTM)). The summaries will be 
presented as either tables or, where appropriate, as figures. International Council for 
Harmonisation (ICH) required listings will also be produced. 
 
x 
“n” will be displayed as a whole number 
x 
The Mean, SD, Median, Q1, and Q3 will be displayed with 1 more decimal place than 
the source data precision.  
x 
The Min and Max will be displayed with the same number of decimal places as the 
source data. Any other presentation of raw data will be also be displayed with the same 
decimal places as the source data. 
 
x 
All tests and confidence intervals are 2-sided unless specified otherwise. 


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x 
All p-values will be displayed with three decimal places. 
 
x 
All by visit summaries and analyses will use analyses visits. Analysis visits will be 
derived from the date of assessment (or visit date if assessment date is not collected or 
is missing) relative to randomization date. Visit windows will be contiguous (Details 
will be included in the SAP Appendix for Definitions and Reporting Conventions) 
 
4.2 
Multiple comparisons   
We will complete multiplicity adjustment as noted in the CSP Section 8.8. The primary and top 
secondary outcomes will be tested sequentially, and thus, no multiplicity adjustment is 
necessary 
 
4.3 
Visit Windows for Analysis 
Visit windows for presentation of results will be derived from date of the assessment (or visit date 
if assessment date was not collected or is missing). Visit windows will be contiguous and are 
based on assessment-specific scheduled visits.  The specific windows for the study are included 
in the Appendix for definitions. 
4.4 
Right Censoring 
In this study we expect missing outcome data to be infrequent and every effort will be made to 
collect all information regarding the primary outcomes prior to study termination, even in those 
who have discontinued the study treatment.  
 
In primary and secondary analyses in the ITT population, the observation time for participants 
who have not had an event in the analysis of a specific outcome will be right censored at the date 
of last contact where all elements of the outcome could be assessed. Same algorithm will be 
followed for inclusion of events in the analyses. 
Note that for the analysis of the components of the primary composite outcome, participant 
exposure will be censored at the date of the occurrence of the component outcome of interest.    
 
Note that for outcomes not including CV death, all deaths are censoring events.  
 
Participants that withdraw consent for follow-up or are lost to follow-up at the end of study will 
be censored at the last contact where all elements of the outcome could be assessed.  
 
In safety time-to-event analyses in the Safety population, participants who have not had the event 
in question will be censored following same rules as detailed for the ITT population. 
4.5 
Handling of Missing Data 
4.5.1 
Outcome Data/Dates 
The primary analysis will rely on a multiple imputation model, with Markov chain Monte Carlo 
algorithm based on the totality of observed data. One exception to this rule will be that 
individuals unable to perform the 6MWT test at 6 months will have their value imputed as the 
worst observed change in 6MWT.  
 
The SAS PROC MI procedure will be used for multiple imputations, with 20 imputations on each 
variable. To ensure consistency in the imputed data for future possible validations, a seed number 
will be fixed to 1000 for every study variable. Imputed data set(s) will include an index variable 
to identify the number of imputed data. The results across the imputed datasets will be combined 
using Rubin’s rule (Rubin 1987) to obtain one set of results for a given variable. Basic statistics 


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on the original data (incomplete data) and the data following imputation for each of the relevant 
study variable will be provided in the Clinical Study Report (CSR). 
 
For secondary efficacy endpoints, missing data relating to the indicator for the confirmed 
composite CV outcome and/or its components will not be imputed. Any partial or completely 
missing date for a confirmed composite CV outcome at the time of database lock will be 
imputed as follows: 
x 
If the day is missing, 15th of the month, or the randomization date (if participant 
randomized after 15th of the same month and same year) will be used, making sure the 
imputed date is not post end of study date; 
x 
If the month is missing, June, or the randomization month (if participant randomized 
after June and year of the event is same as randomization year) will be used, making 
sure the imputed date is not post end of study date; 
x 
If the complete date is missing, the midpoint between randomization and the date of last 
known event-free visit will be used. 
 
4.5.2 
Other Missing Data 
Any other partial date of relevance (for example, date of last study contact at the time of 
database lock will be imputed as follows: 
x 
If the day is missing, 15th of the month, or the randomization date (if participant 
randomized after 15th of the same month and same year) will be used, making sure the 
imputed date is not post end of study date. 
x 
If the month is missing, June, or the randomization month (if participant randomized 
after June and year of the event is same as randomization year) will be used, making 
sure the imputed date is not post end of study date. 
 
We do not plan to impute any missing baseline data. 
4.6 
 Assessment of Model Assumption 
The validity of the proportional hazards assumption made in the secondary analysis will be 
examined using standard graphical methods such as Log (-log) plots; if the assumption holds the 
curves should be approximately parallel to each other.  
 
An additional analytical method that includes treatment*log (time) as a factor in the model and 
tests the interaction factor at the 0.05 significance level may be employed; non-significance 
(p>0.05) of this factor would suggest proportionality.   
 
If there is evidence of non-proportionality its cause will be investigated by exploring hazard ratios 
within few pre-specified clinically meaningful time landmarks such as every six months.  
5 
OUTCOMES 
Please refer to Section 10.2 of the CSP for information on which endpoints are adjudicated. 
 
5.1 
 Primary Outcome 
The primary outcome follows an ordinal scale of clinical severity comprised of 1) confirmed 
death, 2) number of confirmed hospitalizations for heart failure evaluated at one year; or 3) 
change in 6MWT from baseline evaluated at 6 months.  
 
Each participant from the treatment arm gets ranked/compared with each participant from the 
control arm based on the 12-month experience for Death and Hospitalizations for heart failure 


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and 6 month results for change in 6MWT to determine treatment response per the following 
hierarchy:  
 
1. Death  
 
If both die, the one who survives longer is better off;  
If one dies and one does not, the one that survives is better off;  
If neither dies, examine hospitalizations for heart failure.  
 
2. Hospitalizations for heart failure  
 
The one with fewer hospitalizations is better off;  
If neither has been hospitalized for heart failure or the number heart failure 
hospitalizations is equal, compare change in 6MWT.  
 
3. Change in 6MWT  
The one with higher change in 6MWT is better off;  
5.2 
Top Secondary Outcome     
The top secondary outcome is defined as the time from randomization to the onset of first 
confirmed event in the composite CV outcome of CV-related death (any deaths confirmed as 
unknown are included in CV deaths) or hospitalization for heart failure.   
In the unlikely event that two confirmed outcomes occur on the same day, the following hierarchy 
will be used to ascribe the primary component of the composite: 
x 
CV-related death 
x 
Hospitalization for heart failure 
5.3 
Analyses of the Primary and the Top Secondary Outcome     
The analytic approaches for the primary and top secondary outcome are detailed in below 
sections. 
5.3.1 
Nonparametric Test of FCM vs. Placebo for Primary Composite 
The null hypothesis being tested is that a randomly chosen participant in the treatment arm is 
equally likely to be ranked better or worse than a randomly chosen participant in the control group. 
The two-sided alternative is that the participant is not equally likely to be ranked better or worse.  
 
In addition to performing the test, we will estimate the probability that a participant in the 
treatment arm has a better rank than a participant in the control arm and its corresponding 
confidence interval. 
 
The main comparison will be conducted using the Wilcoxon-Mann-Whitney test in ITT 
population relying on multiple imputation model as summarized in Section 4.5.1.  
 
The above comparison of participants in the treatment versus control arms is equivalent to 
ranking all participants according to their experience. At one end of the ranking are participants 
with the best experience - those alive and not hospitalized for worsening heart failure ordered 
according to their improvement in 6MWT; at the opposite end are those who die ordered 
according to their survival time. Those participants alive but hospitalized are in the middle, 
ordered according to their number of hospitalizations for worsening heart failure and then by 
their change in 6MWT. The non-parametric Wilcoxon-Mann-Whitney test sums the ranks of 
those in the treatment arm and compares them with the sum of ranks in the control arm 
(Finklestein 1999). 
 


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In all analyses, the number of hospitalizations (and the number of days in the hospital in the 
sensitivity analysis described in Section 5.3.1.1) will be adjusted for the time in follow-up. This 
adjustment applies only to individuals who are alive at the end of follow-up (the comparison in 
those who die will be resolved based on time to death) and will be accomplished by dividing the 
observed number by time at risk in years. For individuals who complete the pre-specified 12 
months of follow-up, time at risk equals 1. For all others, it is equal to the fraction of 12 months 
that the person remained in the study.  
 
5.3.1.1 
Sensitivity Analysis (Additional Layer to Hierarchy) for Nonparametric Test of 
FCM vs. Placebo for Primary Composite 
In a sensitivity analysis we will add another layer to the hierarchy described above – in individuals 
who have been hospitalized for heart failure during follow-up, ties in the numbers of 
hospitalizations will be resolved based on the total number of days in the hospital during follow-
up, before proceeding to comparison of differences in the 6MWT. This will be conducted in the 
ITT population only. 
 
5.3.1.2 
Sensitivity Analysis for Potential Covid-19 Impact for Nonparametric Test of 
FCM vs. Placebo for Primary Composite 
In case there are 5% or more of randomized participants with missing 6 month 6MWT due to 
COVID-19 who also did not have a qualifying clinical event (death or heart failure hospitalization 
through 1 year), then we will assess the sensitivity of primary results to the missing data by 
conducting a tipping point analyses on the primary analyses method in ITT population. 
The tipping point analysis will assume progressively biased tie breaking. Hence, starting with all 
missing 6MWT values favouring the placebo to break the tie and checking if this does not change 
inference from the primary analyses. However, if it does change the inference then we will 
continue going down the scale to find the tipping point. 
 
5.3.1.3 
Key Supportive Analysis for Nonparametric Test of FCM vs. Placebo for 
Primary Composite 
As the key supportive analysis, the null hypothesis for the primary composite end point, that a 
randomly chosen participant in the treatment arm is equally likely to be ranked better or worse 
than a randomly chosen participant in the control group, will be tested using the same approach 
as in the primary analysis based on PP population.  
 
In case of a difference in inference between the primary analysis and the key supportive analyses, 
further exploratory analyses will be conducted to understand the reason for a possible difference. 
 
5.3.1.4 
Supportive Analysis (Impute to Worst Observed Change) for Nonparametric 
Test of FCM vs. Placebo for Primary Composite 
We will use multiple imputation for clinical outcomes in the primary composite, but will impute 
the worst observed change in 6MWT to all individuals who do not have this measurement, 
regardless of the reason. This will be conducted in the ITT population only. 
 
5.3.1.5 
Supportive Analysis (Tipping Point) for Nonparametric Test of FCM vs. Placebo 
for Primary Composite 
We will perform tipping point assessments to determine the sensitivity of the observed result to 
the missing data. Given the multi-dimensional nature of outcomes, tipping point analyses will be 
performed separately for each outcome: mortality, hospitalization for heart failure, and 6MWT. 
This will be conducted in the ITT population only. 
 
5.3.1.6 
Supportive Analysis (Total burden of HF impact) for Nonparametric Test of 
FCM vs. Placebo for Primary Composite 
To further understand the burden of the disease, we will analyse a combined endpoint of CV death 
and frequency of intervention for worsening heart failure (hospitalization or urgent heart failure 


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visits), through the duration of the study. The analytic methods will follow that for the primary 
analyses. The analysis will be conducted in the ITT population only. 
 
5.3.2 
FCM vs. Placebo for Top Secondary Outcome 
This analysis will compare time from randomization to the first occurrence of CV death or 
hospitalization for heart failure. The Cox proportional hazards model will be employed to conduct 
this comparison. The cox model will be adjusted for baseline covariates decided prior to database 
lock. The test will be two-tailed and will be performed at an overall α of 0.05. This analysis will 
be performed by the ITT principle based on randomized treatment assignment and we expect 
adequate power to detect a pre-specified relative risk reduction of 20%.  
 
5.3.2.1 
Supportive Analysis for FCM vs. Placebo for Top Secondary Outcome  
As supportive analysis, time from randomization to the first occurrence of CV death or 
hospitalization for heart failure will be analysed in PP using the same approach as for the primary 
analysis based on the ITT population.  
5.4 
Subgroup Analyses for Top Secondary Outcome 
Subgroup analyses will be performed for the top secondary outcome in the ITT population in 
order to explore whether treatment effects on the risk of developing CV events are consistent 
across subgroups. Subgroup analyses will be performed using the same analysis models as for the 
top secondary endpoints, with the addition of the subgroup factor and its interaction with 
treatment. The same subgroup analyses will also be repeated in the PP population. 
 
The subgroups will be divided by categories for continuous variables. The subgroup analyses 
will be summarized via a forest plot and interaction p-values will be reported. 
Pre-specified subgroups are detailed below.  
 
Key Subgroups of Interest include split by:  
Age, BNP, NYHA, heart failure etiology, ejection fraction, glomerular filtration rate, sex, ferritin, 
TSAT, CKD, diabetes mellitus, haemoglobin, BMI, enrolling country, race, atrial fibrillation, 
hospitalization for HF within past 12 months 
5.5 
Secondary Outcomes 
All other secondary outcomes are listed and defined below. These secondary outcomes will be 
tested in the order listed below and are considered as supportive in the assessment of the effect 
size attributable to FCM and will be analysed in ITT only and without a multiplicity adjustment.   
 
(1) Mean change in 6MWT distance from baseline to 12 months will be compared using linear  
regression adjusting for baseline value of 6MWT distance.   
 
(2) Time to CV deaths or intervention for worsening heart failure (hospitalization or urgent 
heart failure visits) defined as time from randomization to the earliest of confirmed CV death 
or confirmed intervention for worsening heart failure will be compared using the Cox 
proportional hazards model. 
 
(3) Time to CV deaths or CV hospitalizations defined as time from randomization to the earliest 
of confirmed CV death or confirmed CV hospitalization will be compared using the Cox 
proportional hazards model.  
 
(4) Time to CV deaths defined as time from randomization to confirmed CV death (deaths 
confirmed as “Unknown” type will be included in the CV death counts) will be compared 
using the Cox proportional hazards model. 


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(5) Time to non-cardiovascular deaths defined as time from randomization to confirmed non-
CV death will be compared using the Cox proportional hazards model. 
 
(6) Time to first confirmed hospitalization for myocardial infarction (MI) defined as time from 
randomization to the earliest confirmed hospitalization for MI will be compared using the 
Cox proportional hazards model. 
 
(7) Time to first confirmed hospitalization for stroke defined as time from randomization to the 
earliest confirmed hospitalization for stroke will be compared using the Cox proportional 
hazards model. 
 
(8) Time to first confirmed hospitalization for other CV event defined as time from 
randomization to the earliest confirmed hospitalization for other CV event will be compared 
using the Cox proportional hazards model. 
 
(9) Time to first confirmed urgent heart failure visit defined as time from randomization to the 
earliest confirmed urgent heart failure visit will be compared using the Cox proportional 
hazards model. 
 
All time to event secondary outcomes will be analysed using the same approach as in the top 
secondary outcome analysis based on the ITT population. To assess change from baseline, a 
baseline measurement and the 12-month measurement both are required. 
5.6 
Hypophosphatemia Sub-study Analyses 
 
A separate appendix to this SAP will detail analyses to be conducted in the Hypophosphatemia 
safety sub-study participants. 
5.7 
Exploratory Analyses 
The below endpoints will be explored to further help interpret the primary analyses.  
 
(1) Time to all cause death at one year defined as time from randomization to all cause death 
within 1 year (non-events censored at 1 year) will be compared using the Cox proportional 
hazards model. 
 
(2) Number of heart failure hospitalizations at one year will be analysed using negative binomial 
regression analysis.  
 
(3) Combination of all cause death and number of heart failure hospitalizations at one year will 
be analysed using the same method as used for the primary efficacy endpoint. 
 
(4) Mean change in the 6MWT distance from baseline to six months will be compared using 
linear regression adjusting for baseline value of 6MWT distance.   
 
(5) Time to all cause death through the duration of the study defined as time from 
randomization to all cause death (non-events censored at last known alive date) will be 
compared using the Cox proportional hazards model. 
 
(6) Combination of CV death and total number of heart failure hospitalizations through the 
duration of the study will be analysed using the same method as used for the primary efficacy 
endpoint. 
 


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(7) Combination of CV death and total number of urgent heart failure events through the 
duration of the study will be analysed using the same method as used for the primary efficacy 
endpoint. 
6 
SAFETY ANALYSIS 
There are no a priori hypotheses to be tested for safety. Safety will be assessed within the Safety 
population. Analyses visit-based Box and Whisker plots will be produced for continuous safety 
variables by randomized treatment where applicable. Shift tables for vital signs will be created 
for dosing days. Supplementary analyses will only be performed where these summaries suggest 
that there may be clinically significant differences.  
 
For continuous safety parameters, at least one post-randomization measurement is required for 
inclusion in the analysis. To assess change from baseline, a baseline measurement is also required. 
 
6.1 
Adverse Events (AEs) 
The original term used by investigators to identify non-serious AEs leading to discontinuation of 
study drug, or the SAEs, will be coded to the Preferred Term level using the Medical Dictionary 
for Regulatory Activities (MedDRA). 
 
The treatment emergent serious adverse experiences (TESAE) are defined as those SAEs that 
have a start date on or after the date of first study medication administration. Events that have 
been determined as primary or secondary outcomes in the study are not regarded as SAEs for the 
safety analysis. Any adverse experience (AE) that does not meet the definition of SAE is 
considered non-serious. Non-serious AEs will not be collected for this trial except for AEs leading 
to cessation of study medication administration.   
 
Summary of the following AEs will be provided by treatment group and by System Organ Class 
(SOC), Preferred Term (PT). These summaries will also be presented overall and by the 
subgroups of age, sex, race, and body mass index (BMI): 
x 
All AEs (serious or non-serious resulting in discontinuation of study drug) 
x 
All SAEs 
x 
All TEAEs 
x 
All TESAEs 
x 
TEAEs (serious or non-serious) that result in discontinuation of study drug  
x 
TESAEs considered related (possibly, probably or definitely) to study drug 
x 
TESAEs with a fatal outcome. 
We will also summarize severity, relatedness, seriousness criteria, and outcome at participant 
level for All TEAEs, the TEAEs categorized as below, all TESAEs, and All non-serious 
TEAEs.  
 
TEAEs of Hypophosphatemia by SOC and PT  
-MedDRA PT Blood phosphorus decrease 
-MedDRA PT Blood phosphorus abnormal 
-MedDRA PT Hypophosphatemia 
-MedDRA PT Hypophosphatemic rickets 
-MedDRA PT Rickets familial hypophosphatemic 
 
TEAEs of Hypersensitivity/anaphylactoid reactions by SOC and PT 
- MedDRA SMQ Anaphylactic reaction 
- MedDRA SMQ Angioedema 
- MedDRA PT of Hypersensitivity 
 


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TEAEs of Injection/infusion site reactions by SOC and PT  
-MedDRA HLT Infusion site reactions 
-MedDRA HLT Injection site reactions 
-MedDRA HLT Administration site reactions NEC 
-MedDRA PT Infusion related reaction 
 
TEAEs of Medication error by SOC and PT  
- MedDRA SMQ Medication errors 
 
  
TEAEs of Hemosiderosis by SOC and PT  
-MedDRA PT Hemosiderosis 
-MedDRA PT Hematochromatosis 
-MedDRA PT Iron overload 
-MedDRA PT Hepatic siderosis 
-MedDRA PT Cardiac siderosis 
-MedDRA PT Pulmonary hemosiderosis 
-MedDRA PT Superficial siderosis of central nervous system 
6.2 
Laboratory Data 
x 
Descriptive statistics will be provided for central laboratory measurements as identified 
below at baseline and each scheduled (or reported) time point, and for changes from 
baseline by treatment. Grades based on most recent Common Terminology Criteria for 
Adverse Events (CTCAE) will be identified algorithmically for Haematology and 
Chemistry central laboratory data and will be summarized by visit using bar-chart and 
percentages. Shift tables will be provided for the max or min changes relative to 
baselines. 
a. Hematology: Hb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, 
differential count, and reticulocyte count  
b. Chemistry: Sodium, potassium, chloride, BUN, creatinine, albumin, alkaline 
phosphatase, total bilirubin, GGT, AST, ALT, LDH, calcium, phosphorus, 
glucose, bicarbonate, and magnesium 
c. Iron indices: Serum iron, serum ferritin, total iron binding capacity (TIBC), 
and percentage serum transferrin saturation (TSAT)  
d. Other: 1,25 (OH)2 Vitamin D, 25 (OH) Vitamin D, Parathyroid Hormone, NT-
proBNP 
6.3 
Previous and Concomitant Medications and Interventions 
Concomitant medications and interventions to be summarized for ITT and Safety. 
Baseline and post-baseline determination will be made programatically in reference to 
randomization date and assessment date(s). 
x 
Concomitant medications of interest at baseline will be summarized by treatment. 
x 
Post baseline concomitant medications of interest will be summarized by treatment and 
nominal visit. 
x 
Post baseline concomitant intervention will be summarized by treatment and nominal 
visit. 
6.4 
Vitals and Physical Assessments 
x 
Descriptive statistics will be provided for vital sign and targeted physical exam 
measures: systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, 
body weight, and BMI at baseline and at each scheduled time point and for change 
from baseline by treatment.  
x 
Shift tables for SBP and DBP will be provided for the dosing days 


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6.5 
Drug Exposure  
The following types of treatment durations will be calculated for FCM and placebo arm.  
x 
Total treatment duration (including days off study drug) = Number of days between the 
first and last injection (last injection date – first injection date) +1 
x 
Treatment duration (excluding days off study drug) = Number of days of taking study 
drug as calculated above, minus the total duration of study drug interruption (each 
duration of dose interruption is calculated as: (injection restart date – temporary 
injection stop date) +1.  
Temporary injection stop date is the first visit date at which an injection is not given. 
An injection restart date is when the injection is given following a temporary stop date. 
x 
Total observation duration = Number of days in the study (date of final study 
disposition –date of randomization) +1. 
 
We will also summarize the total number of infusions received and cumulative dose by 
treatment for the participants.   
 
Kaplan Meier estimates of time to permanent study drug discontinuation will be 
summarized by treatment. 
 
Frequency rates of participants, whose treatment was switched due to improved iron 
indices or whose drug dosage was decreased through the study will be provided by 
treatment. 
 
              Summaries of duration of treatment, study drug interruption, and drug compliance will  
              be provided by treatment through the overall study period in Safety Population. 
6.6 
Events of Special Interest related to HF that did not lead to Hospitalization 
x 
All events of interest related to HF that did not lead to hospitalization collected in the 
study will be summarized by treatment. Specifically, the events are: supraventricular 
arrhythmia, ventricular arrhythmia, and renal failure, all requiring urgent/emergent 
intervention. 
6.7 
Hospitalizations not part of Primary and Secondary Outcomes 
x 
All hospitalizations collected in the study that do not comprise primary or secondary 
outcomes (non-CV hospitalizations) will be summarized by treatment.  
6.8 
COVID-19 Related 
Any deviations from the protocol related to COVID-19 will be summarized by treatment and a 
listing will be generated. Listings of all participants recorded as impacted by COVID-19 
(related to visit completion, early study or treatment discontinuation, inability to complete 
6MWT, and any reported adverse events of COVID-19) will also be provided, as appropriate. 
6.9 
Other Safety Assessments 
All adverse events of special interest (ventricular tachycardia, supraventricular tachycardia, and 
renal failure, all requiring urgent/emergent intervention) will be summarized at participant level 
by treatment. 
If participant or participant's partner becomes pregnant while on the study, the information will 
be included in the narratives and no separate table will be provided. 


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7 
DATA SAFETY MONITORING BOARD AND INTERIM ANALYSES 
7.1 
Interim Analyses  
 
A Data and Safety Monitoring Board (DSMB) Committee will review safety data, including a 
tally of the composite outcome events at least every 6 months. The DSMB can recommend 
stopping the study for safety concern at any point. In addition, one interim analysis is planned to 
determine if an early stopping for an overwhelming efficacy should be recommended or if an 
increase in sample size is warranted. The details as identified in Section 8.10 of the protocol are 
that this analysis will be conducted after 2250 (75%) participants have been randomized. 
Significance level will be set at 0.0001 for this analysis, resulting in an adjusted significance level 
for the final analysis of 0.0099 for the primary endpoint and 0.0499 for the first secondary 
endpoint, preserving the overall significance at 0.01 and 0.05, respectively. Conditional power 
will be estimated based on data accrued to date and presented to the DSMB.  
The DSMB may recommend that the study continues as planned, discontinue the study, or that 
the trial be continued with recommended changes to the protocol.  
The Executive Steering Committee will determine if an increase in sample size is warranted in 
order that at least 771 participants will experience an event of CV death or hospitalization for 
heart failure. 
8 
DATABASE SOURCES 
The HEART-FID clinical database will be housed in RAVE Electronic Data Capture (EDC) 
hosted by Duke Clinical Research Institute (DCRI). In addition, DCRI and KCR will obtain 
protocol deviation from CTMS, the central laboratory data from Covance, and the CEC data from 
the DCRI CEC group. DCRI will obtain unblinded randomization data collected in the Interactive 
Web Response System (IXRS) from Almac after the database is locked at the end of the trial. 
 
9 
REFERENCES 
1. 
Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Ferric carboxymaltose in iron 
deficient heart failure patients: a meta-analysis of individual-patient data from 
randomised clinical trials. Annual Heart Failure Society of America Meeting, 2015; 
Abstract 336.  
2. 
Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in 
clinical trials. Stat Med. 1999; 18:1341-1354.  
3. 
Anker SD, Schroeder S, Atar D, et al. Erratum to "Traditional and new composite 
endpoints in heart failure clinical trials: facilitating comprehensive efficacy 
assessments and improving trial efficiency" [Eur J Heart Fail 2016;18:482-489]. 
European Journal of Heart Failure. 2016 Jun;18(6):727. DOI: 10.1002/ejhf.591 
4. 
Gheorghiade M, Vaduganathan M, Fonarow GC, et al. Rehospitalization for heart 
failure: problems and perspectives. J Am Coll Cardiol. 2013 Jan 29;61(4):391-403. 
doi: 10.1016/j.jacc.2012.09.038. Epub 2012 Dec 5. 
5. 
Zannad F, Garcia AA, Anker SD, et al. Clinical outcome endpoints in heart failure 
trials: a European Society of Cardiology Heart Failure Association consensus 
document. Eur J Heart Fail. 2013 Oct;15(10):1082-94. doi: 10.1093/eurjhf/hft095. 
Epub 2013 Jun 19. 
6. 
Forman DE, Fleg JL, Kitzman DW, et al. 6-min walk test provides prognostic utility 
comparable to cardiopulmonary exercise testing in ambulatory outpatients with 
systolic heart failure. J Am Coll Cardiol. 2012 Dec 25;60(25):2653-61. doi: 
10.1016/j.jacc.2012.08.1010. Epub 2012 Nov 21 
7. 
Rubin DB. Multiple imputation for nonresponse in surveys. 1987; John Wiley, New 
York 
 
 


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Page 22 of 27 
 
10 APPENDICES 
Additional Appendices will be produced separately and finalised following finalisation of SAP 
but before database lock. 
 
 


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Page 23 of 27 
 
10.1 Appendix 1: Summary of Amendments to the Protocol relevant to the SAP are here. 
Details can be found within the CSP. 
Protocol Version 2 and 3:  
Affected Sections 
Summary of Revisions 
Appendix 1 
Added a sub-study protocol to 
evaluate hypophosphatemia. 
8.10 Stopping Rules and Interim Analysis 
The DSMB may recommend that 
the study continues as planned, 
discontinue the study or that the 
trial be continued with 
recommended changes to the 
protocol. The Executive Steering 
Committee will determine if an 
increase in sample size is 
warranted in order that at least 771 
participants will experience an 
event of cardiovascular death or 
hospitalization for heart failure. 
4.5 Discontinuation from Study Drug 
Added a definition for a 
participant permanently 
discontinued from the study. 
 
 
 


Protocol/Version No.: 1VIT15043/3 
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Page 24 of 27 
 
10.2 Appendix 2: Simulations for power estimation for the primary endpoint were 
conducted at the time of writing the original version of the CSP. The below detailed 
information was used at the time. 
Clinical Rationale: The proposed composite endpoint is intended to capture the clinical effects 
of the proposed treatment of participants in heart failure with reduced ejection fraction with iron 
deficiency with or without anemia. From a participant’s and clinician’s perspective, the essential 
elements are aimed towards improving the health and well-being of participants with disease as 
complex as heart failure with reduced ejection fraction.  By targeting the experience of 
participants with heart failure as measured by survival, burden of heart failure hospitalizations, 
and functional status the proposed composite end-point reflects the key characteristics of a 
robust composite endpoint (Anker 2016). The rationale for including the burden of 
hospitalizations is based on the well-recognized problem that recurrent hospitalizations for 
worsening heart failure are a common occurrence in participants, and they impose a substantial 
clinical burden on participants and their families as indicative of worsening of their condition 
(Gheorghiade 2013 ). Despite the importance of repeat events, they are often ignored in the 
majority of clinical trials in favour of ‘time to first event’ analyses (Zannad 2013).  In addition, 
heart failure is characterized as a disorder with significant functional impairment in physical 
activities. One of the most robust assessments of functional impairment that may be feasible on 
a large scale is the 6MWT (Forman 2012 ). This standardized assessment has been used to 
define functional status and stratify risk for participants in heart failure as well as other 
conditions such as pulmonary hypertension. The use of this hierarchical, composite endpoint 
will enable us to provide a more robust and clinically-meaningful classification of participants 
with heart failure with iron deficiency into those who have improved, remained unchanged, or 
have deteriorated based on survival, burden of hospitalizations with heart failure, and functional 
status as measured by the 6MWT distance. 
Methods: 
Each participant from the treatment arm gets compared with each participant from the control 
arm based on the 12-month experience to determine treatment response per the following 
hierarchy:  
 
1. CV death 
If both die, the one who survives longer is better off; 
If one dies, the one that survives is better off; 
If neither dies, examine hospitalizations. 
 
2. Hospitalization for worsening heart failure  
The one with fewer hospitalizations is better off; 
If number hospitalized equal (both not hospitalized, both with 1 hospitalization etc.), 
compare 6MWT; 
 
3. Change in 6MWT 
The one with higher change in 6MWT is better off;  
 
Statistical Test 
The main comparison will be conducted using the Wilcoxon-Mann-Whitney test. The 
comparison of individuals in the treatment versus control arms is equivalent to ranking all 
individuals according to their experience. At one end of the ranking are individuals with the best 
experience - those alive and not hospitalized for worsening heart failure ordered according to 
their improvement in 6MWT; at the opposite end are those who die ordered according to their 
survival time. Those alive but hospitalized are in the middle, ordered according to their number 


Protocol/Version No.: 1VIT15043/3 
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Page 25 of 27 
 
of hospitalizations for worsening heart failure and then by their change in 6MWT.  The non-
parametric Wilcoxon-Mann-Whitney test sums the ranks of those in the treatment arm and 
compares them with the sum of ranks in the control arm. 


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Page 26 of 27 
 
Table 10.2.1   Assumptions for Sample Size Calculations 
 
Ranked tier at 12-month endpoint 
Control 
Treatment 
Death total 
Death without hospitalization 
Death with hospitalization 
8% 
4% 
4% 
6.8% 
3.4% 
3.4% 
Hospitalizations in survivors 
1 
2 
3 or more 
 
6% 
3% 
1% 
 
4.8% 
2.4% 
0.8% 
Change in 6MWT  
Mean = 0 
SD = 90 
Mean = 18 
SD = 90 
Empirical Power: 0.9500 (N=2930, α=0.0025) 
Clinically-Meaningful Difference: 0.068/0.08 = 0.85 
 
Conclusion 
With 3000 participants (1500 per arm) and 2.5% annual loss to follow up, our simulations 
estimate ≥90% power at various two-sided significance levels between 0.0025 and 0.01. 
 
 


Protocol/Version No.: 1VIT15043/3 
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Page 27 of 27 
 
 
10.3 Appendix 3: Ranking Algorithm (primary efficacy endpoint) 
 
Scenario Participant: 
i/j 
All-cause 
Mortality 
(1 year) 
Survival 
Times (from 
baseline) 
Cardiovascular-
related 
hospitalization 
(1 year) 
6 month 
change in 
6MWT 
Score 
1 
i 
Dead 
Low 
not in 
consideration 
not in 
consideration 
-1 
 
j 
Dead 
High 
not in 
consideration 
not in 
consideration 
+1 
2 
i 
Dead 
not in 
consideration 
not in 
consideration 
not in 
consideration 
-1 
j 
Alive 
not in 
consideration 
not in 
consideration 
not in 
consideration 
+1 
3 
i 
Alive 
not in 
consideration 
High 
not in 
consideration 
-1 
 
j 
Alive 
not in 
consideration 
Low 
not in 
consideration 
+1 
4 
i 
Alive 
not in 
consideration 
Tied 
Low 
-1 
 
j 
Alive 
not in 
consideration 
Tied 
High 
+1 
 
 
 
 
 
 
 
 


Protocol/Version No.: 1VIT15043/3 
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Page 1 of 31 
 
 
 
 
Statistical Analysis Plan  
for  
Heart Failure with Iron Deficiency (HEART-FID). 
 
Version: 1.3 
Date: 6 March 2023  
 
 
 
Clinical Study Protocol/Amendment No: 1VIT15043/3 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO 
INVESTIGATE THE EFFICACY AND SAFETY OF INJECTAFER® (FERRIC 
CARBOXYMALTOSE) AS TREATMENT FOR HEART FAILURE WITH IRON 
DEFICIENCY. 
 
 
 
 
 
Prepared by: CT Statistics Group  
 
Prepared For: American Regent, Inc. 
[Duke Clinical Research Institute] 
[Sponsor] 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations.  
 
 


Protocol/Version No.: 1VIT15043/3
Statistical Analysis Plan Version: 1.3 6 March 2023
Page 2 of 31
Statistical Analyses Plan Amendment x
The original Statistical Analysis Plan was finalized and issued on 21/Sep/2021. Major changes 
and clarifications of planned analyses in SAP V1.2 since the original SAP are listed below. All 
changes to the SAP have been instituted prior to unblinding of the HEART-FID study
Version
Date
Author(s)
Brief Summary of Changes
V1.0
21/Sep2021
Final version after American Regent’s final 
comments on 14/Sep/2021. Signed.
V1.1
03/Oct2022
x
Added baseline covariates to be used for 
model adjustment in section 4.1
x
Updated references across the SAP to 
analysis visits to nominal/scheduled 
visit
x
Added sub-group categories
x
Added sensitivity tipping point analysis 
for key secondary
x
Added win-ratio analyses for 
hierarchical primary endpoint
x
Added clarity for tipping point analyses 
for hierarchical primary endpoint
x
Removed the inaccurately placed 
Finkelstein reference
V1.2
31/Jan2023
x
Section 1.4: edit on alpha usage based 
on FDA feedback
x
Section 4.1: added clarifications about 
handling of missing data on covariates. 
Secondly added empirical curves to 
address FDA feedback.
x
Section 4.3: edit for clarity
x
Section 4.4.1: Couple of updates to add 
clarity about baseline 6MWT and 
address FDA feedback.
x
Section 4.4.2: removed the last line 
based on edits in section 4.1 and 4.4.1
x
Section 5.3.1: Added a new sensitivity 
analyses in 5.3.1.5 to address FDA 
feedback. Downstream section 
numbering updated based on this.
x
Section 5.3.2: updated alpha for top 
secondary to 0.04 based on FDA 
feedback.
x
Section 5.4: updated the cut-off points 
to 2 of the sub-groups based on FDA 
feedback.
x
Section 5.7: clarification regarding ITT 
population added. Exploratory 
endpoints 8-13 added based on FDA 
feedback on the SAP V1.1. 
x
Section 6.2: Minor clarifications added
V1.3
6/Mar2023
x
Updated the language towards the end 
of section 1.4 which describes the alpha 


Protocol/Version No.: 1VIT15043/3 
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Page 3 of 31 
 
 
 
to be used for primary and top  
secondary analyses 
x 
Clarified that the alpha mentioned in 
section 7.1 is from the protocol and will 
not be used for the final analyses.  
 


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TABLE of CONTENTS  
Statistical Analyses Plan Amendment x .......................................................................... 2 
1 
INTRODUCTION ....................................................................................................... 8 
1.1 
Study Objectives ................................................................................................ 8 
1.1.1 
Primary Objective ....................................................................................... 8 
1.1.2 
Secondary Objective ................................................................................... 8 
1.2 
Study Design ...................................................................................................... 8 
1.3 
Randomization and Blinding ............................................................................. 9 
1.4 
Sample Size and Power ...................................................................................... 9 
1.5 
Schedule of Major Assessments ...................................................................... 10 
1.6 
Summary of Relevant Amendments to the Protocol ....................................... 10 
2 
ANALYSIS SETS ......................................................................................................11 
2.1 
Intent-to-treat (ITT) Population ....................................................................... 11 
2.2 
Safety Population ............................................................................................. 11 
2.3 
Per-protocol (PP) Population ........................................................................... 11 
2.4 
Hypophosphatemia Sub-study (HS) Population .............................................. 11 
3 
BACKGROUND CHARACTERISTICS .............................................................11 
3.1 
Disposition of Participants ............................................................................... 11 
3.2 
Demographic and Baseline Characteristics ..................................................... 11 
3.3 
Medical History ............................................................................................... 11 
4 
METHODS OF ANALYSIS ....................................................................................12 
4.1 
General Principles ............................................................................................ 12 
4.2 
Multiple comparisons ...................................................................................... 13 
4.3 
Right Censoring ............................................................................................... 13 
4.4 
Handling of Missing Data ................................................................................ 13 
4.4.1 
Outcome Data/Dates ................................................................................. 13 
4.4.2 
Other Missing Data ................................................................................... 14 
4.5 
Assessment of Model Assumption .................................................................. 14 
5 
OUTCOMES ...............................................................................................................15 
5.1 
Primary Outcome ............................................................................................. 15 
5.2 
Top Secondary Outcome ................................................................................. 15 
5.3 
Analyses of the Primary and the Top Secondary Outcome ............................. 15 
5.3.1 
Nonparametric Test of FCM vs. Placebo for Primary Composite ........... 16 
5.3.2 
FCM vs. Placebo for Top Secondary Outcome ........................................ 18 
5.4 
Subgroup Analyses for Top Secondary Outcome ............................................ 19 
5.5 
Secondary Outcomes ....................................................................................... 19 
5.6 
Hypophosphatemia Sub-study Analyses ......................................................... 20 
5.7 
Exploratory Analyses ....................................................................................... 20 
6 
SAFETY ANALYSIS ................................................................................................21 
6.1 
Adverse Events (AEs) ...................................................................................... 21 
6.2 
Laboratory Data ............................................................................................... 23 
6.3 
Previous and Concomitant Medications and Interventions ............................. 23 
6.4 
Vitals and Physical Assessments ..................................................................... 23 
6.5 
Drug Exposure ................................................................................................. 24 
6.6 
Events of Special Interest related to HF that did not lead to Hospitalization .. 24 
6.7 
Hospitalizations not part of Primary and Secondary Outcomes ...................... 24 
6.8 
COVID-19 Related .......................................................................................... 24 


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6.9 
Other Safety Assessments ................................................................................ 24 
7 
DATA SAFETY MONITORING BOARD AND INTERIM ANALYSES ..25 
7.1 
Interim Analyses .............................................................................................. 25 
8 
DATABASE SOURCES ...........................................................................................25 
9 
REFERENCES ...........................................................................................................25 
10 APPENDICES ............................................................................................................26 
10.1 
Appendix 1: Summary of Amendments to the Protocol relevant to the SAP 
are here. Details can be found within the CSP. .......................................................... 27 
10.2 
Appendix 2: Simulations for power estimation for the primary endpoint were 
conducted at the time of writing the original version of the CSP. The below detailed 
information was used at the time. ............................................................................... 28 
10.3 
Appendix 3: Ranking Algorithm (primary efficacy endpoint)..................... 31 
 
 
 


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LIST OF ABBREVIATIONS  
 
6MWT              
6 Minute Walk Test                      
ADaM 
Analysis Data Model 
AE 
Adverse Experience 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BNP 
Brain Natriuretic Peptide 
BUN 
Blood Urea Nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CEC 
Clinical Events Committee 
CKD 
Chronic Kidney Disease 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CTMS 
Clinical Trial Management System 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DCRI 
Duke Clinical Research Institute 
DSMB  
Data and Safety Monitoring Board 
EDC 
Electronic Data Capture 
FCM 
Ferric Carboxymaltose 
GGT 
Gamma-Glutamyl Transferase 
Hb 
Haemoglobin 
Hct 
Haematocrit 
HF 
Heart Failure 
HLT 
High Level Term 
HR  
Hazard Ratio 
HS 
Hypophosphatemia Sub-study  
ICH 
International Council for Harmonisation 
ITT 
Intent-To-Treat 
IV 
Intravenous 
IXRS 
Interactive Web Response Systems 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI  
Myocardial Infarction 
NYHA 
New York Heart Association 
PP 
Per Protocol 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RDW 
Red Cell Distribution Width 


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Page 7 of 31 
 
SDTM 
Study Data Tabulation Model 
SAE   
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SMQ 
Standardised MedDRA Queries 
SOC 
System Organ Class 
TESAE 
Treatment Emergent Serious Adverse 
Experiences 
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
WBC 
White Blood Cell 
 
 
 
 
 
 
 


Protocol/Version No.: 1VIT15043/3 
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Page 8 of 31 
 
1 
INTRODUCTION 
HEART-FID is a double-blind, multicenter, prospective, randomized, placebo-controlled study 
to assess the effects of intravenous (IV) ferric carboxymaltose (FCM) compared to placebo on the 
hierarchical, composite endpoint of 12-month rate of death and hospitalization for worsening 
heart failure (HF) and change in 6 minute walk test (6MWT) at 6 months for participants in HF 
with reduced ejection fraction and with iron deficiency. The reader of this Statistical Analysis 
Plan (SAP) is also encouraged to read the corresponding protocol (1VIT15043, version 3.0, 11 
January 2021) which provides detail on the conduct of the study, the operational aspects of clinical 
assessments, and the timings of individual participant assessments. 
This SAP contains definitions of analysis populations, and details on the statistical methods for 
the analyses and summaries of study data that are to be performed, to help support the completion 
of the final Clinical Study Report (CSR) for study 1VIT15043. Details regarding analysis of the 
hypophosphatemia sub-study can be found in a supplemental SAP. Information on important 
definitions and reporting conventions and table shells to support the SAP will be in a supplemental 
Appendix. 
Specifications of supporting tables, figures, and data listings are contained in a separate document.   
Outcomes that are confirmed by clinical events classification (CEC) adjudication, the process for 
which is governed by specific charters referenced in the protocol, will be referred to as 
“confirmed” events in the SAP. The term outcome is used throughout this document as 
synonymous with the term endpoint used in the clinical trial protocol. The following events are 
confirmed by the CEC in HEART-FID: Death (Cardiovascular [CV] and Non-Cardiovascular), 
Cardiovascular Hospitalizations (Heart Failure, Acute Myocardial Infarction [MI], Stroke, and 
Other cardiovascular hospitalizations), and Urgent Heart Failure Visit. CEC data take precedence 
over investigator data when both are available and investigator response is different from the CEC 
adjudicated response.   
1.1 
Study Objectives  
1.1.1 
Primary Objective 
To determine the efficacy and safety of iron therapy using intravenous (IV) FCM, relative to 
placebo, in the treatment of participants in heart failure with reduced ejection fraction and with 
iron deficiency. 
1.1.2 
Secondary Objective 
To evaluate the effect of IV FCM, relative to placebo, on the functional capacity of participants 
in heart failure with reduced ejection fraction and with iron deficiency. 
1.2 
Study Design 
This is a double-blind, multicenter, prospective, randomized, placebo-controlled study to assess 
the effects of IV FCM compared to placebo on the 12-month rate of death, hospitalization for 
worsening heart failure, and change in 6MWT from baseline at 6 months for participants with 
heart failure, reduced ejection fraction, and with iron deficiency. 
After an initial screening period of up to 28 days, eligible participants will be stratified by 
region and randomized in a 1:1 ratio to FCM or placebo. Study drug administration will occur 
on Day 0 and Day 7 as an undiluted slow IV push, with additional study visits (in person or via 
telephone) planned at 3 month intervals, and additional dosing administered every 6 months as 
applicable (based on dose regimen below).  
For all participants, laboratory tests for haematology, ferritin, and transferrin saturation (TSAT) 
with appropriate safety evaluations, to determine additional treatment, will occur at 6 month 
intervals.  


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In a subset of sites, a sub-study will be conducted to characterize serum phosphate levels over 
time in participants in heart failure with reduced ejection fraction with iron deficiency after 
dosing with FCM. There will be additional visits for these participants during the first 6 months 
(Clinical Study Protocol [CSP] Appendix 1, Section 3.3)  
 
Initial treatment will occur on Day 0 and Day 7. On Day 0 and 7, Group A (FCM) will receive a 
750 mg undiluted, blinded dose of IV FCM at the rate of approximately 100 mg (2 mL)/minute 
(approximately 7 minutes 30 seconds); Group B (placebo) will receive a blinded placebo (15 cc 
of normal saline) IV push at 2 mL/minute (approximately 7 minutes 30 seconds). Participants in 
Group A with body weight <50 kg (110 pounds) will have individual FCM doses adjusted to 15 
mg/kg, not to exceed an individual dose of 750 mgs or a cumulative dose of 1500 mg per 
treatment cycle. Placebo dosing will be adjusted for weight based on volume. 
 
All participants randomized will be dosed every 6 months. Participants randomized to the FCM 
arm will be dosed as indicated based on haemoglobin levels (i.e. Hb <13.5 g/dl [females] or 
<15.0 g/dl [males)]) and iron studies (i.e. serum ferritin <100 ng/mL or 100 to 300 ng/mL with 
TSAT <20%). Participants not meeting pre-specified laboratory criteria for blood counts and 
iron studies and all participants randomized to the placebo arm will be administered IV placebo 
infusion at each visit.  
Unblinded site personnel, responsible for preparation and administration of the FCM or Placebo, 
will ensure that the participant and all blinded site staff are not able to observe the preparation or 
administration of study treatment.  
1.3 
Randomization and Blinding 
The randomization scheme was generated by a statistician at DCRI who is firewalled to the 
operational team, using Statistical Analysis System (SAS v9.4) with region as the only 
stratification field. Blocking was used in the scheme with random block sizes (3 different 
levels). This scheme was implemented into the Interactive Web Response Systems (IXRS) by 
the vendor Almac. The vendor maintains randomized treatment assignments as well as 
unblinded kit dispensation information. The operational team for this trial is to remain blinded 
until data base lock, at which time the unblinded treatment codes received from Almac will be 
combined with blinded data.  
In the event of the need to break an individual participant blind, the site can call Almac for this 
information. The operational team gets informed if such unblinding occurs; however, they do 
not know the true treatment assignment. 
The 3 regions are defined within the randomization scheme as follows (Details can be found in 
the SAP Appendix for Definitions and Reporting Conventions): 
x 
North America 
x 
Asia Pacific 
x 
Europe 
1.4 
Sample Size and Power  
The study design allows for sufficient power for both the primary and top secondary outcomes.  
Numerical simulations based on multivariate normal vectors (Appendix 2) were conducted to 
estimate power for the primary treatment comparison based on the following assumptions about 
events rates described in Table 1.4.1 
 
 
 
 


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Table 1.4.1. Assumptions about Event Rates for Primary Outcome 
Ranked tier at 12-month endpoint 
(6 month for 6 MWT)  
Control  
Treatment  
Death total  
Death without hospitalization  
Death with hospitalization  
8%  
4%  
4%  
6.8%  
3.4%  
3.4%  
Hospitalizations in survivors  
1 
2 
3 or more  
 
6%  
3%  
1%  
 
4.8%  
2.4%  
0.8%  
Change in 6 Minute Walk Test  
Mean = 0  
SD = 90  
Mean = 18  
SD = 90  
 
With 3014 participants (1507 per arm) and 2.5% annual loss to follow-up for clinical outcomes 
and 15% of individuals with missing 6MWT at 6 months (unable to perform or lost to follow-
up), projected simulations estimate 90% power at an overall two-sided significance level of 
0.01, accounting for one interim analysis as described in Section 7.1.  
 
For the top secondary composite, there is an assumed event rate of 0.0128 per month in the 
control arm which represents conservative 75% discounting of the event rate obtained by the 
FCM meta-analysis [Anker 2015]. The anticipated hazard ratio (HR) was set at 0.80 (20% 
reduction). Uniform enrollment was assumed over the period of 30 months, with an anticipated 
minimum follow-up of 12 months (required minimum of 6 months), anticipated maximum 
follow-up of 42 months (no required maximum), and monthly loss to follow-up of 0.0021 (2.5% 
annualized). With these assumptions, 1500 per study arm (3000 total) provides 90% power to 
reject the null hypothesis of no difference between treatment arms when tested at an overall 
two-sided level of significance α=0.05, accounting for one interim analysis as described in 
Section 8.10 of the CSP. This results in a total of 771 participants with events (in case of 
multiple events experienced by a participant, only their first one will be counted towards the 
771) necessary to achieve the desired power. Thus, the trial has the potential opportunity to be 
stopped at a point where the projected number of participants reaches 771 events, but no earlier 
than the last participant reaching 12 months of follow-up.  
 
In order to maintain an overall alpha of 0.01 and account for interim analysis we will use a two-
sided alpha of 0.0099 for the final analysis of the primary endpoint. 
 
At the request of the FDA, the overall alpha for the top secondary endpoint was changed from 
0.05 to 0.04.  In order to maintain an overall alpha of 0.04 and account for interim analysis we 
will use a two-sided alpha of 0.0399 for the final analysis of the top secondary endpoint.  
1.5 
Schedule of Major Assessments 
Following randomization, outcomes and serious adverse event data are collected at 90 days and 
at every 6 monthly visit as detailed in schedule of events (Section 3.3 of the CSP)  
1.6 
Summary of Relevant Amendments to the Protocol 
Please refer to Appendix 1 for this information. The version the participant was enrolled under 
will be available in the database. 
 


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2 
 ANALYSIS SETS 
2.1 
Intent-to-treat (ITT) Population  
The ITT population consists of all participants randomized to a treatment group in the study 
regardless of their compliance with the study medication. The participants are analysed in the 
treatment group to which they were randomized. This is the primary population of all efficacy 
analyses. 
Any participant who gets a treatment assigned via the IXRS will be considered to have been 
randomized. 
2.2 
Safety Population 
The Safety population will consist of all ITT participants who received at least 1 dose of study 
medication identified by the presence of injection start date.季When summarizing data using this 
population, participants are analyzed in the As Treated group. If a participant receives any FCM 
study drug, then the participant will be counted as treated in the FCM arm, regardless of the 
amount of medication received; otherwise the participant will be counted as treated in the 
placebo arm. 
The Safety population will be used for assessing Safety. 
2.3 
 Per-protocol (PP) Population  
The Per-Protocol Population is a subset of the ITT population excluding participants who 
complied with the randomized treatment for less than 50% of the dosing prior to 1 year follow-
up. In cases of medication error, treatment assignments in the per-protocol analysis will be 
analyzed according to the actual treatment received as the first study drug dose.  
2.4 
Hypophosphatemia Sub-study (HS) Population  
The Hypophosphatemia Sub-study (HS) population will consist of all ITT participants who 
enrolled in the sub-study identified by the presence of injection start date.季When summarizing 
data using this population, participants will be analyzed according to the actual treatment 
received as the first dose. 
The HS population will be used for assessing Safety. 
Please see the HS SAP for further details. 
3 
BACKGROUND CHARACTERISTICS 
3.1 
Disposition of Participants 
Disposition data will be summarized for all randomized participants. The summary by treatment 
will include 
x 
Inclusion in the four study populations 
x 
Participants completing study alive 
x 
Lost to follow up 
x 
Withdrawn consent for follow up 
x 
Reason study drug permanently discontinued  
3.2 
Demographic and Baseline Characteristics  
The demographic, baseline clinical and anthropometric characteristics collected in the study will 
be tabulated and summarised as descriptive statistics by treatment for both ITT and Safety 
populations.  
3.3 
Medical History  
Participant medical history will be summarized within both ITT and Safety populations. 


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x 
Duration of HF calculated as (year of randomization – year of onset) +1 and etiology of 
HF at baseline will be summarized by treatment. 
All other medical history data collected in the study will be summarized by treatment group. 
 
4 
METHODS OF ANALYSIS 
4.1 
General Principles 
In addition to specific analyses and presentations that are detailed in the following sections, 
results will be summarised using descriptive statistics, including the number of participants, 
mean, standard deviation, median, and range as appropriate. For categorical variables, counts 
and percentage per treatment group will be presented. 
 
Summaries of continuous characteristics will be based on non-missing observations. Percentage 
for categorical variables will be calculated based on number of participants with non-missing 
values for the variable.  
 
Unless otherwise stated, timings of efficacy endpoints will be relative to the date of 
randomization. Specifically, for all time-to event analyses (defined as [event date – 
randomization date] +1 where event occurs and as [appropriate censoring date based on analytic 
population – randomization date] +1 where event does not occur), the treatment groups will be 
analysed using a Cox proportional hazards model that includes treatment as an explanatory 
factor, region as stratification factors along with pre-specified baseline covariates: age, sex, 
ejection fraction, NYHA class, heart failure etiology (Ischemic vs. non-ischemic (unknown 
etiology considered as non-ischemic)), NT-proBNP, haemoglobin, ferritin, TSAT, eGFR and 
BMI, unless specified otherwise. If any of the pre-specified baseline covariates have >5 
participants with missing data, they will not be used in the analyses to maintain the ITT 
population for the model. If the baseline covariate is missing data on <= 5 participants, we will 
impute the missing value with overall mode if categorical covariate and the overall mean if 
continuous variable. The Efron method will be used for handling ties. P-value and confidence 
intervals for the HR will be based on the Wald statistic. Any analyses using events that are 
confirmed by the CEC will use the CEC adjudicated responses and related dates. Analyses of 
Cardiovascular (CV) death, will include deaths with cause of death confirmed as unknown.  
In addition, the summary tables of these analyses will include the number of participants with 
event and the cumulative incidence (1 – the “survival” or event-free proportion) over time per 
treatment group presented annually through the last time point where 90% of the overall events 
have occurred. Cumulative incidence function and Kaplan-Meier estimates of participants with 
events will also be calculated and plotted through maximum follow up available in the study, 
with number of participants at risk indicated below the plot at specific times.  
We will present empirical cumulative distribution function curves by treatment of change in 
6MWT distance at 6 and 12 months. 
For all the hierarchical composite endpoints, in addition to primary analytic method, we will 
present win-ratio along with its confidence interval. 
The timing of safety data will be relative to the study drug start date. Specifically, any time to 
safety event durations will be defined as [event date – study drug start date] +1 where event 
occurs and as [appropriate censoring date based on analytic population – study drug start date] 
+1 where event does not occur). 
Baseline is defined as response/value collected closest to randomization and on or prior to study 
drug start. If both date and time are available we will use the value prior to the first study drug 
start date time. However, if only dates are available, we will use the values on or prior to first 
study drug start date as the baseline. Any measures (for example central labs) without a value in 
this window will have a missing baseline value.  
End of study date for the participant will be driven off of the date of their final study 
disposition. Date of last contact for the participant will be driven off of their last visit 


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performed, these dates can be different from the date last known alive collected on end of study 
form  for withdrawn consent participants. 
The median and total person-years of follow-up for the whole study will also be reported. 
  
All analyses included in this SAP will be performed using SAS v9.4 or higher. They will be 
based on Clinical Data Interchange Standards Consortium (CDISC) standard data (Analysis 
Data Model (ADaM) and/or Study Data Tabulation Model (SDTM)). The summaries will be 
presented as either tables or, where appropriate, as figures. International Council for 
Harmonisation (ICH) required listings will also be produced. 
 
x 
“n” will be displayed as a whole number 
x 
The Mean, SD, Median, Q1, and Q3 will be displayed with 1 more decimal place than 
the source data precision.  
x 
The Min and Max will be displayed with the same number of decimal places as the 
source data. Any other presentation of raw data will be also be displayed with the same 
decimal places as the source data. 
 
x 
All tests and confidence intervals are 2-sided unless specified otherwise. 
 
x 
All p-values will be displayed with three decimal places. 
 
x 
All by visit summaries and analyses will use scheduled/nominal.  
 
4.2 
Multiple comparisons   
We will complete multiplicity adjustment as noted in the CSP Section 8.8. The primary and top 
secondary outcomes will be tested sequentially, and thus, no multiplicity adjustment is 
necessary 
 
4.3 
Right Censoring 
In this study we expect missing outcome data to be infrequent and every effort will be made to 
collect all information regarding the primary outcomes prior to study termination, even in those 
who have discontinued the study treatment.  
 
For all analyses covered by this SAP, the observation time for participants who have not had an 
event in the analysis of a specific outcome will be right censored at the date of last contact where 
any elements of the outcome could be assessed unless otherwise specified. Same algorithm will 
be followed for inclusion of events in the analyses. 
Note that for the analysis of the components of the primary composite outcome, participant 
exposure will be censored at the date of the occurrence of the component outcome of interest.    
 
Note that for outcomes not including CV death, all deaths are censoring events.  
 
 In safety time-to-event analyses in the Safety population, participants who have not had the 
event in question will be censored following same rules as detailed for the ITT population. 
4.4 
Handling of Missing Data 
4.4.1 
Outcome Data/Dates 
The primary analysis will rely on a multiple imputation model, with Markov chain Monte Carlo 
algorithm based on the totality of observed data. One exception to this rule will be that 


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individuals unable to perform the 6MWT test at 6 months i.e. those who did not perform a 
6MWT or died prior to 180 days will have their value imputed as the worst possible 6MWT 
distance which is 0 meters. Any missing death dates will be imputed using date imputation rules 
in this section. A baseline 6MWT distance is needed to be able to calculate change from 
baseline 6MWT, hence, any missing baseline 6MWT distance will be imputed as overall mean 
to allow full ITT population to be included in primary analyses. 
 
The SAS PROC MI procedure will be used for multiple imputations on the 6 month 6MWT 
distance, with 20 imputations. To ensure consistency in the imputed data for future possible 
validations, a seed number will be fixed to 1000. Baseline 6MWT, treatment and region will be 
included as covariates in the imputation model. We will include all observed data in the 
imputation model with the exception of participants unable to perform 6MWT at 6 months who 
will have their 6MWT distance included as 0 meters before performing multiple imputation. 
Imputed data set(s) will include an index variable to identify the number of imputed data. The 
results across the imputed datasets will be combined using Rubin’s rule (Rubin 1987) to obtain 
one set of results for the primary analysis. These same missing data handling rules will be used 
for the Win-Ratio analyses. Basic statistics on the overall original data (incomplete data) and the 
data following imputation will be provided in the Clinical Study Report (CSR). 
 
For secondary efficacy endpoints, missing data relating to the indicator for the confirmed 
composite CV outcome and/or its components will not be imputed. Any partial or completely 
missing date for a confirmed composite CV outcome at the time of database lock will be 
imputed as follows: 
x 
If the day is missing, 15th of the month, or the randomization date (if participant 
randomized after 15th of the same month and same year) will be used, making sure the 
imputed date is not post date last known alive on end of study form; 
x 
If the month is missing, June, or the randomization month (if participant randomized 
after June and year of the event is same as randomization year) will be used, making 
sure the imputed date is not post date last known alive on end of study form; 
x 
If the complete date is missing, the midpoint between randomization and the date of last 
known event-free visit will be used with the exception of death date. 
x 
If the death date is completely missing, it will be imputed to be the date after last 
contact date. 
 
4.4.2 
Other Missing Data 
Any other partial date of relevance (for example, date of last study contact at the time of 
database lock will be imputed as follows: 
x 
If the day is missing, 15th of the month, or the randomization date (if participant 
randomized after 15th of the same month and same year) will be used, making sure the 
imputed date is not post end of study date. 
x 
If the month is missing, June, or the randomization month (if participant randomized 
after June and year of the event is same as randomization year) will be used, making 
sure the imputed date is not post date last known alive on end of study form. 
 
4.5 
Assessment of Model Assumption 
The validity of the proportional hazards assumption made in the secondary analysis will be 
examined using standard graphical methods such as Log (-log) plots; if the assumption holds the 
curves should be approximately parallel to each other.  
 
An additional analytical method that includes treatment*log (time) as a factor in the model and 
tests the interaction factor at the 0.05 significance level may be employed; non-significance 
(p>0.05) of this factor would suggest proportionality.   


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If there is evidence of non-proportionality its cause will be investigated by exploring hazard ratios 
within few pre-specified clinically meaningful time landmarks such as every six months.  
5 
OUTCOMES 
Please refer to Section 10.2 of the CSP for information on which endpoints are adjudicated. 
 
5.1 
 Primary Outcome 
The primary outcome follows an ordinal scale of clinical severity comprised of 1) confirmed 
death at one year, 2) number of confirmed hospitalizations for heart failure evaluated at one 
year; or 3) change in 6MWT from baseline evaluated at 6 months.  
 
We will rank all participants from the lowest to the highest based on their 12-month experience, 
regardless of their treatment assignment.  
 
Each participant from the treatment arm gets ranked/compared with each participant from the 
control arm based on the 12-month experience for Death and Hospitalizations for heart failure 
and 6 month results for change in 6MWT to determine treatment response per the following 
hierarchy:  
 
1. Death  
 
If both die, the one who survives longer is better off;  
If one dies and one does not, the one that survives is better off;  
If neither dies, examine hospitalizations for heart failure.  
 
2. Hospitalizations for heart failure  
 
The one with fewer hospitalizations is better off 
If neither has been hospitalized for heart failure or the number heart failure 
hospitalizations is equal, compare change in 6MWT.  
 
3. Change in 6MWT  
The one with higher change in 6MWT is better off;  
Any ties that cannot be resolved by change in 6MWT remain as ties. 
5.2 
Top Secondary Outcome     
The top secondary outcome is defined as the time from randomization to the onset of first 
confirmed event in the composite CV outcome of CV-related death (any deaths confirmed as 
unknown are included in CV deaths) or hospitalization for heart failure.   
In the unlikely event that two confirmed outcomes occur on the same day, the following hierarchy 
will be used to ascribe the primary component of the composite: 
x 
CV-related death 
x 
Hospitalization for heart failure 
5.3 
Analyses of the Primary and the Top Secondary Outcome     
The analytic approaches for the primary and top secondary outcome are detailed in below 
sections. 
 


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5.3.1 
Nonparametric Test of FCM vs. Placebo for Primary Composite 
The null hypothesis being tested is that a randomly chosen participant in the treatment arm is 
equally likely to be ranked better or worse than a randomly chosen participant in the control group. 
The two-sided alternative is that the participant is not equally likely to be ranked better or worse.  
 
In addition to performing the test, we will estimate the probability that a participant in the 
treatment arm has a better rank than a participant in the control arm and its corresponding 
confidence interval. 
 
The main comparison will be conducted using the Wilcoxon-Mann-Whitney test in ITT 
population relying on multiple imputation model as summarized in Section 4.4.1.  
 
The above comparison of participants in the treatment versus control arms is equivalent to 
ranking all participants according to their experience. At one end of the ranking are participants 
with the best experience - those alive and not hospitalized for worsening heart failure ordered 
according to their improvement in 6MWT; at the opposite end are those who die ordered 
according to their survival time. Those participants alive but hospitalized are in the middle, 
ordered according to their number of hospitalizations for worsening heart failure and then by 
their change in 6MWT. The non-parametric Wilcoxon-Mann-Whitney test sums the ranks of 
those in the treatment arm and compares them with the sum of ranks in the control arm. 
 
Win-Ratio and its confidence intervals will be calculated to aid in interpretation of the results for 
primary efficacy analysis. The unmatched pair win ratio will be calculated by adding all wins 
from treatment group and dividing it by all wins from placebo group. The confidence interval will 
be calculated using the supplementary material for the reference (Pocock 2012). 
 
In all analyses, the number of hospitalizations (and the number of days in the hospital in the 
sensitivity analysis described in Section 5.3.1.1) will be adjusted for the time in follow-up. This 
will be accomplished by dividing the observed number by time at risk in years. For individuals 
who complete the pre-specified 12 months of follow-up, time at risk equals 1. For all others, it is 
equal to the fraction of 12 months that the person remained in the study.  
 
5.3.1.1 
Sensitivity Analysis (Additional Layer to Hierarchy) for Nonparametric Test of 
FCM vs. Placebo for Primary Composite 
In a sensitivity analysis we will add another layer to the hierarchy described above – in individuals 
who have been hospitalized for heart failure during follow-up, ties in the numbers of 
hospitalizations will be resolved based on the total number of days in the hospital during follow-
up, before proceeding to comparison of differences in the 6MWT using the primary analytic 
method. This will be conducted in the ITT population only. 
 
5.3.1.2 
Sensitivity Analysis for Potential Covid-19 Impact for Nonparametric Test of 
FCM vs. Placebo for Primary Composite 
In case there are 5% or more of randomized participants with missing 6 month 6MWT due to 
COVID-19 (those with visits not performed or visit type modified due to Covid-19) who also did 
not have a qualifying clinical event (death or heart failure hospitalization through 1 year), then 
we will assess the sensitivity of primary results to the missing 6MWT data by conducting a tipping 
point analyses on the primary analyses method in ITT population. 
The tipping point analysis will assume progressively biased tie breaking for 6MWT distance 
missing due to COVID-19 varying from worst distance favouring the placebo to the best distance. 
Hence, starting with all missing 6MWT values favouring the placebo to break the tie and checking 
if this does not change inference from the primary analyses. However, if it does change the 
inference then we will continue going down the scale to find the tipping point. The 6MWT 
distance at 6 months missing for non-COVID-19 reasons will be imputed as for primary analysis. 
 


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5.3.1.3 
Sensitivity Analysis for Russia Ukraine War Impact (censor the data after 
invasion) for Nonparametric Test of FCM vs. Placebo for Primary Composite 
We plan to conduct two different sensitivity analyses to assess the impact of the Russia-Ukraine 
war. In the first of these two analyses we will censor the data from Russia and Ukraine for the 
hierarchical primary composite endpoint with a date after invasion (24 February, 2022), before 
proceeding to comparison of the endpoint using the primary analytic method. This will be 
conducted in the ITT population only. 
  
5.3.1.4 
Sensitivity Analysis for Russia Ukraine War Impact (exclude participants from 
these two countries) for Nonparametric Test of FCM vs. Placebo for Primary 
Composite 
As a second sensitivity method to assess the impact of the war on the hierarchical primary 
composite, we will exclude participants from Russia and Ukraine for comparison of the endpoint 
using the primary analytic method. This will be conducted in the ITT population only. 
 
5.3.1.5 
Sensitivity Analysis to account for Clinically Meaningful Difference in Change 
from Baseline in 6MWT for Nonparametric Test of FCM vs. Placebo for 
Primary Composite 
In this sensitivity analysis of hierarchical primary composite, we will use the win-ratio method 
with the additional condition of requiring a change from baseline in 6MWT for the participant to 
be 10 and 20 meters respectively to be considered clinically meaningful (Khan 2022). Hence, if 
two participants are tied based on their data on death time and number of HF hospitalizations 
within 1 year, further tie-breaking will require 10 meters and 20 meters difference in 6MWD 
change when they are compared for win-ratio analysis.  Only the win-ratio and its 95% confidence 
interval will be computed. This analysis will be conducted in the ITT population only. 
 
5.3.1.6 
Key Supportive Analysis for Nonparametric Test of FCM vs. Placebo for 
Primary Composite 
As the key supportive analysis, the null hypothesis for the primary composite end point, that a 
randomly chosen participant in the treatment arm is equally likely to be ranked better or worse 
than a randomly chosen participant in the control group, will be tested using the same approach 
as in the primary analysis based on PP population.  
 
In case of a difference in inference between the primary analysis and the key supportive analyses, 
further exploratory analyses will be conducted to understand the reason for a possible difference. 
 
5.3.1.7 
Supportive Analysis (Impute to Worst Possible 6MWT Distance at 6 Months) for 
Nonparametric Test of FCM vs. Placebo for Primary Composite 
As supportive analysis, we will impute the worst possible 6MWT distance at 6 months as the 
component for primary hierarchical composite for all individuals who do not have this 
measurement, regardless of the reason. We will use the primary analytic method here and the 
analysis will be conducted in the ITT population only. 
 
5.3.1.8 
Supportive Analysis (Tipping Point) for Nonparametric Test of FCM vs. Placebo 
for Primary Composite 
We will perform tipping point assessments to determine the sensitivity of the primary efficacy 
result to the missing 6 month 6MWT distance data. The tipping point analysis will assume 
progressively biased tie breaking. Hence, starting with all missing 6MWT values favouring the 
placebo to break the tie and checking if this does not change inference from the primary analyses. 
However, if it does change the inference then we will continue going down the scale to find the 
tipping point.  This will be conducted in the ITT population only. 
 


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5.3.1.9 
Supportive Analysis (Total burden of HF impact) for Nonparametric Test of 
FCM vs. Placebo for Primary Composite 
To further understand the burden of the disease, we will analyse a combined endpoint of CV death 
and frequency of intervention for worsening heart failure (hospitalization or urgent heart failure 
visits), through the duration of the study. The analytic methods will follow that for the primary 
analyses. The analysis will be conducted in the ITT population only. 
 
5.3.2 
FCM vs. Placebo for Top Secondary Outcome 
This analysis will compare time from randomization to the first occurrence of CV death or 
hospitalization for heart failure. The Cox proportional hazards model will be employed to conduct 
this comparison. The Cox model will include treatment, region as a stratification variable and will 
be adjusted for pre-decided baseline covariates as noted in section 4.1. The test will be two-tailed 
and will be performed at an overall α of 0.04. This analysis will be performed by the ITT principle 
based on randomized treatment assignment and we expect adequate power to detect a pre-
specified relative risk reduction of 20%.  
 
5.3.2.1 
Supportive Analysis for FCM vs. Placebo for Top Secondary Outcome  
As supportive analysis, time from randomization to the first occurrence of CV death or 
hospitalization for heart failure will be analysed in PP using the same approach as for the primary 
analysis based on the ITT population.  
 
5.3.2.2 
Sensitivity Analysis (Tipping Point) for FCM vs. Placebo for Top Secondary 
Outcome 
 
In case there are 5% or more participants who prematurely discontinue from the study follow-up 
without having an event of death or hospitalization for heart failure, and the hazard ratio obtained 
from the top secondary outcome analysis is between 0.85 and 1.15 inclusive, we will perform 
tipping point assessments to determine the sensitivity of the result obtained from the top 
secondary analysis to the missing data caused by participants’ early discontinuation. Events will 
be imputed during their missed follow-up time (i.e., time from early discontinuation to trial 
termination visit) under various scenarios for the hazard rates for the non-completers in each 
treatment arm. For each scenario, 20 imputations will be performed and the results will be 
combined across the 20 datasets that have both the actual events and imputed events using Rubin’s 
rule (Rubin, 1987). Hazard ratio (95% CI) and p-value will be calculated for each scenario.  The 
goal of this analysis is to find the scenarios where the top secondary outcome results conclusion 
could be changed.  This analysis will be conducted in the ITT population only. 
 
5.3.2.3 
Sensitivity Analysis for Russia Ukraine War Impact (censor the data after 
invasion) for FCM vs. Placebo for Top Secondary Outcome 
As one of the two sensitivity analyses to assess the impact of the Russia-Ukraine war on the top 
secondary outcome, we will censor the data from Russia and Ukraine for the time from 
randomization to the first occurrence of CV death or hospitalization for heart failure outcome 
with a date after invasion (24 February, 2022). The analytic method will the same as used for top 
secondary analysis. This will be conducted in the ITT population only. 
  
5.3.2.4 
Sensitivity Analysis for Russia Ukraine War Impact (exclude participants from 
these two countries) for FCM vs. Placebo for Top Secondary Outcome 
As the second sensitivity method to assess the impact of the war on the top secondary outcome, 
we will exclude participants from Russia and Ukraine for comparison of the time from 
randomization to the first occurrence of CV death or hospitalization for heart failure outcome 
using the primary analytic method. This will be conducted in the ITT population only. 


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5.4 
Subgroup Analyses for Top Secondary Outcome 
Subgroup analyses will be performed for the top secondary outcome in the ITT population in 
order to explore whether treatment effects on the risk of developing CV events are consistent 
across subgroups. Subgroup analyses will be performed using the same analysis models as for the 
top secondary endpoints, with the addition of the subgroup factor and its interaction with 
treatment. The same subgroup analyses will also be repeated in the PP population. 
 
The subgroups will be divided by categories for continuous variables. The subgroup analyses 
will be summarized via a forest plot and interaction p-values will be reported. We would look 
further into the subgroup if any interaction p-values are smaller than 0.15. 
Pre-specified subgroups are detailed below.  
 
Key Subgroups of Interest include split by:  
Age (<65 vs >=65 years old),  
NT-proBNP (<median vs >=median pg/mL),  
NYHA class (I and II vs III and IV),  
Heart failure etiology (Ischemic, Non-ischemic, Unknown),  
Ejection fraction (<= median vs. > median),  
Estimated glomerular filtration rate (<60 vs 60+ ml/min/1.73m2),  
Sex (Male/Female),  
Ferritin-TSAT (<100 ferritin vs ferritin >=100-300 with TSAT<20%),  
Chronic renal insufficiency (Yes/No),  
Diabetes mellitus (Yes/No),  
Iron deficiency anaemia (female and haemoglobin <12 g/dL or male and haemoglobin <13.5 
g/dL, vs higher haemoglobin value for either sex),  
BMI (<25, >=25 to <30, and >=30),  
Region (North America, Europe (includes Russia and Georgia), Asia Pacific),  
Race (White, Black, Other(American indian or Alaska native, Asian, multiple, native Hawaiian 
or other pacific islander, other)),  
Atrial fibrillation (Yes/No),  
Hospitalization for HF within past 12 months (Yes/No) 
 
5.5 
Secondary Outcomes 
All other secondary outcomes are listed and defined below. These secondary outcomes will be 
tested in the order listed below and are considered as supportive in the assessment of the effect 
size attributable to FCM and will be analysed in ITT only and without a multiplicity adjustment.   
 
(1) Mean change in 6MWT distance from baseline to 12 months will be compared using linear  
regression adjusting for baseline value of 6MWT distance and region. We will not adjust for 
other baseline covariates.   
 
(2) Time to CV deaths or intervention for worsening heart failure (hospitalization or urgent 
heart failure visits) defined as time from randomization to the earliest of confirmed CV death 
or confirmed intervention for worsening heart failure will be compared using the Cox 
proportional hazards model. 
 
(3) Time to CV deaths or CV hospitalizations defined as time from randomization to the earliest 
of confirmed CV death or confirmed CV hospitalization will be compared using the Cox 
proportional hazards model.  
 
(4) Time to CV deaths defined as time from randomization to confirmed CV death (deaths 
confirmed as “Unknown” type will be included in the CV death counts) will be compared 
using the Cox proportional hazards model. 


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(5) Time to non-cardiovascular deaths defined as time from randomization to confirmed non-
CV death will be compared using the Cox proportional hazards model. 
 
(6) Time to first confirmed hospitalization for myocardial infarction (MI) defined as time from 
randomization to the earliest confirmed hospitalization for MI will be compared using the 
Cox proportional hazards model. 
 
(7) Time to first confirmed hospitalization for stroke defined as time from randomization to the 
earliest confirmed hospitalization for stroke will be compared using the Cox proportional 
hazards model. 
 
(8) Time to first confirmed hospitalization for other CV event defined as time from 
randomization to the earliest confirmed hospitalization for other CV event will be compared 
using the Cox proportional hazards model. 
 
(9) Time to first confirmed urgent heart failure visit defined as time from randomization to the 
earliest confirmed urgent heart failure visit will be compared using the Cox proportional 
hazards model. 
 
All time to event secondary outcomes will be analysed using the same approach as in the top 
secondary outcome analysis based on the ITT population. To assess change from baseline, a 
baseline measurement and the 12-month measurement both are required. 
5.6 
Hypophosphatemia Sub-study Analyses 
 
A separate appendix to this SAP will detail analyses to be conducted in the Hypophosphatemia 
safety sub-study participants. 
5.7 
Exploratory Analyses 
The below endpoints will be explored to further help interpret the primary analyses. All analyses 
will be conducted in ITT population only. 
 
(1) Time to all cause death at one year defined as time from randomization to all cause death 
within 1 year (non-events censored at 1 year) will be compared using the Cox proportional 
hazards model. 
 
(2) Number of heart failure hospitalizations at one year will be analysed using negative binomial 
regression analysis.  
 
(3) Combination of all cause death and number of heart failure hospitalizations at one year will 
be analysed using the same method as used for the primary efficacy endpoint. 
 
(4) Mean change in the 6MWT distance from baseline to six months will be compared using 
linear regression adjusting for baseline value of 6MWT distance and region. To assess 
change from baseline, a baseline measurement and the 6-month measurement both are 
required 
 
(5) Time to all cause death through the duration of the study defined as time from 
randomization to all cause death (non-events censored at last known alive date) will be 
compared using the Cox proportional hazards model. 
 


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(6) Combination of CV death and total number of heart failure hospitalizations through the 
duration of the study will be analysed using the same method as used for the primary efficacy 
endpoint. 
 
(7) Combination of CV death and total number of urgent heart failure visits through the duration 
of the study will be analysed using the same method as used for the primary efficacy 
endpoint. 
 
(8) Combination of investigator-reported events of cardiovascular death and number of heart 
failure hospitalizations at 1 year and change in 6-minute walk distance (6MWD) at 6 months 
using the same method as for the primary efficacy endpoint. 
 
(9) Time to first investigator-reported cardiovascular death or hospitalization for heart failure 
will be compared using the Cox proportional hazards model. 
 
(10) Days alive and out of hospital (any cause) at 1 year as reported by investigator will be 
summarized overall and by region. It will be compared using a modified Poisson approach. 
 
(11) Mean change in the 6MWT distance from baseline to 12 months will be compared using 
linear regression adjusting for baseline value of 6MWT distance and region in the subset of 
population with NYHA class of III/IV at baseline. To assess change from baseline, a 
baseline measurement and the 12-month measurement both are required 
 
(12) Mean change in the 6MWT distance from baseline to 6 months will be compared using 
linear regression adjusting for baseline value of 6MWT distance and region in the subset of 
population with NYHA class of III/IV at baseline. To assess change from baseline, a 
baseline measurement and the 6-month measurement both are required 
 
(13) Responder analyses for change in 6MWT distance from baseline to 6 months, where a 
change of 10 and 20 meters respectively is considered as a responder will be tested using 
chi-square test. 
 
6 
SAFETY ANALYSIS 
There are no a priori hypotheses to be tested for safety. Safety will be assessed within the Safety 
population unless specified otherwise. Nominal visit-based Box and Whisker plots will be 
produced for continuous safety variables by randomized treatment where applicable. Shift tables 
for vital signs will be created for dosing days. Supplementary analyses will only be performed 
where these summaries suggest that there may be clinically significant differences.  
 
For continuous safety parameters, at least one post-randomization measurement is required for 
inclusion in the analysis. To assess change from baseline, a baseline measurement is also required. 
 
6.1 
Adverse Events (AEs) 
In the HEART-FID trial, any adverse experience (AE) that does not meet the definition of SAE 
is considered non-serious. Non-serious AEs will not be collected for this trial except for AEs 
leading to cessation of study medication administration.  The original term used by investigators 
to identify non-serious AEs leading to discontinuation of study drug, or the SAEs, will be coded 
to the Preferred Term level using the Medical Dictionary for Regulatory Activities (MedDRA). 
 
Treatment emergent adverse experiences (TEAE) are defined as those serious or non-serious 
adverse events that have a start date that is on or after the date of first study medication 
administration and on or before 30 days from the date of permanent drug discontinuation. 


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Similarly, treatment emergent serious adverse experiences (TESAE) are defined as those SAEs 
that have a start date on or after the date of first study medication administration and on or before 
30 days from the date of permanent drug discontinuation. Events that have been determined as 
primary or secondary outcomes in the study are not regarded as SAEs for the safety analysis.  
 
Summary of the following AEs will be provided by treatment group and by System Organ Class 
(SOC), Preferred Term (PT). These summaries will also be presented overall and by the 
subgroups of age, sex, race, and body mass index (BMI): 
x 
All AEs (serious or non-serious resulting in discontinuation of study drug) 
x 
All SAEs 
x 
All TEAEs 
x 
All TESAEs 
x 
TEAEs (serious or non-serious) that result in discontinuation of study drug  
x 
TESAEs considered related (possibly, probably or definitely) to study drug 
x 
TESAEs with a fatal outcome. 
We will also summarize severity, relatedness, seriousness criteria, and outcome at participant 
level for All TEAEs, the TEAEs categorized as below, all TESAEs, and All non-serious 
TEAEs.  
 
TEAEs of Hypophosphatemia by SOC and PT  
-MedDRA PT Blood phosphorus decreased 
-MedDRA PT Blood phosphorus abnormal 
-MedDRA PT Hypophosphataemia 
-MedDRA LLT Hypophosphatemic rickets (or Hypophosphataemic rickets) 
-MedDRA LLT Rickets familial hypophosphatemic (or Rickets familial 
hypophosphataemic) 
-MedDRA PT Hypophosphatemia osteomalacia  
 
TEAEs of Hypersensitivity/anaphylactoid reactions by SOC and PT 
- MedDRA SMQ Anaphylactic reaction (narrow scope) 
- MedDRA SMQ Angioedema (narrow scope) 
- MedDRA PT of Hypersensitivity 
- MedDRA PT of Type II hypersensitivity 
- MedDRA PT of Serum sickness 
- MedDRA PT of Serum sickness-like reaction 
- MedDRA PT of Administration site vasculitis 
- MedDRA PT of Type IV hypersensitivity reaction 
- MedDRA PT of Stevens-Johnson syndrome 
- MedDRA PT of Toxic epidermal necrolysis 
- MedDRA Lower Level Term of Type III hypersensitivity reaction 
- MedDRA Lower Level Term of Hemolytic anemia drug-induced 
- MedDRA Lower Level Term of Haemolytic anaemia drug-induced 
- MedDRA Lower Level Term of Immune hemolytic anemia drug-induced 
- MedDRA Lower Level Term of Immune haemolytic anaemia drug-induced 
- MedDRA Lower Level Term of Drug fever 
 
TEAEs of Injection/infusion site reactions by SOC and PT  
-MedDRA HLT Infusion site reactions 
-MedDRA HLT Injection site reactions 
-MedDRA HLT Administration site reactions NEC 
-MedDRA PT Infusion related reaction 
-MedDRA SOC of Skin and subcutaneous disorders with a PT of Skin      
discolourations 
 
TEAEs of Medication error by SOC and PT  


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- MedDRA SMQ Medication errors (narrow scope) 
 
  
TEAEs of Hemosiderosis by SOC and PT  
-MedDRA PT Haemosiderosis 
-MedDRA PT Haemotochromatosis 
-MedDRA PT Iron overload 
-MedDRA PT Hepatic siderosis 
-MedDRA LLT Pulmonary siderosis 
-MedDRA PT Pulmonary haemosiderosis 
-MedDRA PT Superficial siderosis of central nervous system 
 
 
We will also summarize any non-serious TEAEs occurring in 5 or more percent of participants 
in any treatment arm. Non-serious AEs as collected for this trial are defined at the beginning of 
the section. 
6.2 
Laboratory Data 
x 
Descriptive statistics at baseline and at each scheduled (or reported) visit through 1 
year along with the lowest observed value and the highest observed value will be 
provided for central laboratory measurements as identified below, and for changes 
from baseline by treatment. Shift tables will be provided for the max or min changes 
relative to baselines. Grades based on Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 or higher will be identified algorithmically where 
possible and as applicable for Haematology and Chemistry central laboratory data and 
they will be summarized by scheduled visit through 1 year using bar-chart and 
percentages. Any subjects with missing baseline values will not be included in change 
from baseline or shift tables 
a. Hematology: Hb, Hct, RBC, WBC, MCV, MCH, MCHC, RDW, platelets, 
differential count, and reticulocyte count  
b. Chemistry: Sodium, potassium, chloride, BUN, creatinine, eGFR (calculated 
using CKD-EPI formula), albumin, alkaline phosphatase, total bilirubin, GGT, 
AST, ALT, LDH, calcium, phosphorus, glucose, bicarbonate, serum glucose, 
albumin and magnesium 
c. Iron indices: Serum iron, serum ferritin, total iron binding capacity (TIBC), 
percentage serum transferrin saturation (TSAT), and  Unsaturated Iron Binding 
capacity  
d. Other: 1,25 (OH)2 Vitamin D, 25 (OH) Vitamin D, Parathyroid Hormone as 
collected in sub-study participants, NT-proBNP 
Additionally, Hb and iron indices laboratory data will be summarized in ITT population too. 
6.3 
Previous and Concomitant Medications and Interventions 
Concomitant medications and interventions to be summarized for ITT and Safety. 
Baseline and post-baseline determination will be made programatically in reference to 
randomization date and assessment date(s). 
x 
Concomitant medications of interest at baseline will be summarized by treatment. 
x 
Post baseline concomitant medications of interest will be summarized by treatment. 
x 
Post baseline concomitant intervention will be summarized by treatment. 
6.4 
Vitals and Physical Assessments 
x 
Descriptive statistics and change from baseline by treatment at each scheduled visit 
will be provided through 1 year along with the worst observed value and the best 
observed value  targeted physical exam results and vital signs (pre-dose, post-dose and 


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30 min post-dose) and: systolic blood pressure (SBP), diastolic blood pressure (DBP), 
heart rate, and BMI.  
x 
Shift tables for Heart rate, SBP and DBP will be provided for the dosing days through 1 
year. Baseline for these shift tables will be the pre-dosing value at the respective visit. 
6.5 
Drug Exposure  
The following types of treatment durations will be calculated for FCM and placebo arm.  
x 
Total treatment duration (including days off study drug) = Months between the first 
and last injection (last injection date – first injection date +1)/30.4375 
x 
Total observation duration = Number of months in the study (date of final study 
disposition –date of randomization +1)/30.4375. 
 
We will also summarize the total number of infusions received and cumulative dose by 
treatment for the participants.   
 
Kaplan Meier estimates of time to permanent study drug discontinuation will be 
summarized by treatment. 
 
Frequency rates of participants, who reach the improved iron indices threshold 
hemoglobin levels (i.e. participants whose dosing labs are outside the following levels: 
Hgb <13.5 g/dL(females) or <15.0 g/dL (males) and serum ferritin <100 ng/mL or 100 
to 300 ng/mL with TSAT <20% prior to any dosing visit will be presented by 
treatment. We will also summarize any participants whose treatment was switched due 
to improved iron indices through the study for FCM arm. 
 
              Summaries of duration of treatment, study drug interruption, and drug compliance will  
              be provided by treatment through the overall study period in Safety Population. 
6.6 
Events of Special Interest related to HF that did not lead to Hospitalization 
x 
All events of interest related to HF that did not lead to hospitalization collected in the 
study will be summarized by treatment. Specifically, the events are: supraventricular 
arrhythmia, ventricular arrhythmia, and renal failure, all requiring urgent/emergent 
intervention. 
6.7 
Hospitalizations not part of Primary and Secondary Outcomes 
x 
All hospitalizations collected in the study that do not comprise primary or secondary 
outcomes (non-CV hospitalizations) will be summarized by treatment.  
6.8 
COVID-19 Related 
Any deviations from the protocol related to COVID-19 will be summarized by treatment and a 
listing will be generated. Listings of all participants recorded as impacted by COVID-19 
(related to visit completion, early study or treatment discontinuation, and any reported adverse 
events of COVID-19 as defined by MedDRA SMQ COVID-19 narrow scope) will also be 
provided, as appropriate. 
6.9 
Other Safety Assessments 
All adverse events of special interest (ventricular tachycardia, supraventricular tachycardia, and 
renal failure, all requiring urgent/emergent intervention) will be summarized at participant level 
by treatment. 
If participant or participant's partner becomes pregnant while on the study, the information will 
be included in the narratives and no separate table will be provided. 


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7 
DATA SAFETY MONITORING BOARD AND INTERIM ANALYSES 
7.1 
Interim Analyses  
The below text regarding interim analyses is as is written in the CSP 1VIT15043, version 3.0, 
11 January 2021. The overall alpha levels to be used for primary and top secondary analyses are 
described in section 1.4.  
A Data and Safety Monitoring Board (DSMB) Committee will review safety data, including a 
tally of the composite outcome events at least every 6 months. The DSMB can recommend 
stopping the study for safety concern at any point. In addition, one interim analysis is planned to 
determine if an early stopping for an overwhelming efficacy should be recommended or if an 
increase in sample size is warranted. The details as identified in Section 8.10 of the protocol are 
that this analysis will be conducted after 2250 (75%) participants have been randomized. 
Significance level will be set at 0.0001 for this analysis, resulting in an adjusted significance level 
for the final analysis of 0.0099 for the primary endpoint and 0.0499 for the first secondary 
endpoint, preserving the overall significance at 0.01 and 0.05, respectively. Conditional power 
will be estimated based on data accrued to date and presented to the DSMB.  
The DSMB may recommend that the study continues as planned, discontinue the study, or that 
the trial be continued with recommended changes to the protocol.  
The Executive Steering Committee will determine if an increase in sample size is warranted in 
order that at least 771 participants will experience an event of CV death or hospitalization for 
heart failure. 
8 
DATABASE SOURCES 
The HEART-FID clinical database will be housed in RAVE Electronic Data Capture (EDC) 
hosted by Duke Clinical Research Institute (DCRI). In addition, DCRI and KCR will obtain 
protocol deviation from CTMS, the central laboratory data from Labcorp, and the CEC data from 
the DCRI CEC group. DCRI will obtain unblinded randomization data collected in the Interactive 
Web Response System (IXRS) from Almac after the database is locked at the end of the trial. 
9 
REFERENCES 
1. 
Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Ferric carboxymaltose in iron 
deficient heart failure patients: a meta-analysis of individual-patient data from 
randomised clinical trials. Annual Heart Failure Society of America Meeting, 2015; 
Abstract 336.  
2. 
Pocock, Stuart J et al. “The win ratio: a new approach to the analysis of composite 
endpoints in clinical trials based on clinical priorities.” European heart journal vol. 
33,2 (2012): 176-82. doi:10.1093/eurheartj/ehr352  
3. 
Anker SD, Schroeder S, Atar D, et al. Erratum to "Traditional and new composite 
endpoints in heart failure clinical trials: facilitating comprehensive efficacy 
assessments and improving trial efficiency" [Eur J Heart Fail 2016;18:482-489]. 
European Journal of Heart Failure. 2016 Jun;18(6):727. DOI: 10.1002/ejhf.591 
4. 
Gheorghiade M, Vaduganathan M, Fonarow GC, et al. Rehospitalization for heart 
failure: problems and perspectives. J Am Coll Cardiol. 2013 Jan 29;61(4):391-403. 
doi: 10.1016/j.jacc.2012.09.038. Epub 2012 Dec 5. 
5. 
Zannad F, Garcia AA, Anker SD, et al. Clinical outcome endpoints in heart failure 
trials: a European Society of Cardiology Heart Failure Association consensus 
document. Eur J Heart Fail. 2013 Oct;15(10):1082-94. doi: 10.1093/eurjhf/hft095. 
Epub 2013 Jun 19. 
6. 
Forman DE, Fleg JL, Kitzman DW, et al. 6-min walk test provides prognostic utility 
comparable to cardiopulmonary exercise testing in ambulatory outpatients with 
systolic heart failure. J Am Coll Cardiol. 2012 Dec 25;60(25):2653-61. doi: 
10.1016/j.jacc.2012.08.1010. Epub 2012 Nov 21 


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7. 
Rubin DB. Multiple imputation for nonresponse in surveys. 1987; John Wiley, New 
York 
8. 
Khan, Muhammad Shahzeb, et al. "Minimal Clinically Important Differences in 6-
Minute Walk Test in Patients With HFrEF and Iron Deficiency." Journal of Cardiac 
Failure (2022). 
10 APPENDICES 
Additional Appendices may be produced separately and finalised following finalisation of SAP 
but before database lock. 
 
 


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10.1 Appendix 1: Summary of Amendments to the Protocol relevant to the SAP are here. 
Details can be found within the CSP. 
Protocol Version 2 and 3:  
Affected Sections 
Summary of Revisions 
Appendix 1 
Added a sub-study protocol to 
evaluate hypophosphatemia. 
8.10 Stopping Rules and Interim Analysis 
The DSMB may recommend that 
the study continues as planned, 
discontinue the study or that the 
trial be continued with 
recommended changes to the 
protocol. The Executive Steering 
Committee will determine if an 
increase in sample size is 
warranted in order that at least 771 
participants will experience an 
event of cardiovascular death or 
hospitalization for heart failure. 
4.5 Discontinuation from Study Drug 
Added a definition for a 
participant permanently 
discontinued from the study. 
 
 
 


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10.2 Appendix 2: Simulations for power estimation for the primary endpoint were 
conducted at the time of writing the original version of the CSP. The below detailed 
information was used at the time. 
Clinical Rationale: The proposed composite endpoint is intended to capture the clinical effects 
of the proposed treatment of participants in heart failure with reduced ejection fraction with iron 
deficiency with or without anemia. From a participant’s and clinician’s perspective, the essential 
elements are aimed towards improving the health and well-being of participants with disease as 
complex as heart failure with reduced ejection fraction.  By targeting the experience of 
participants with heart failure as measured by survival, burden of heart failure hospitalizations, 
and functional status the proposed composite end-point reflects the key characteristics of a 
robust composite endpoint (Anker 2016). The rationale for including the burden of 
hospitalizations is based on the well-recognized problem that recurrent hospitalizations for 
worsening heart failure are a common occurrence in participants, and they impose a substantial 
clinical burden on participants and their families as indicative of worsening of their condition 
(Gheorghiade 2013 ). Despite the importance of repeat events, they are often ignored in the 
majority of clinical trials in favour of ‘time to first event’ analyses (Zannad 2013).  In addition, 
heart failure is characterized as a disorder with significant functional impairment in physical 
activities. One of the most robust assessments of functional impairment that may be feasible on 
a large scale is the 6MWT (Forman 2012 ). This standardized assessment has been used to 
define functional status and stratify risk for participants in heart failure as well as other 
conditions such as pulmonary hypertension. The use of this hierarchical, composite endpoint 
will enable us to provide a more robust and clinically-meaningful classification of participants 
with heart failure with iron deficiency into those who have improved, remained unchanged, or 
have deteriorated based on survival, burden of hospitalizations with heart failure, and functional 
status as measured by the 6MWT distance. 
Methods: 
Each participant from the treatment arm gets compared with each participant from the control 
arm based on the 12-month experience to determine treatment response per the following 
hierarchy:  
 
1. CV death 
If both die, the one who survives longer is better off; 
If one dies, the one that survives is better off; 
If neither dies, examine hospitalizations. 
 
2. Hospitalization for worsening heart failure  
The one with fewer hospitalizations is better off; 
If number hospitalized equal (both not hospitalized, both with 1 hospitalization etc.), 
compare 6MWT; 
 
3. Change in 6MWT 
The one with higher change in 6MWT is better off;  
 
Statistical Test 
The main comparison will be conducted using the Wilcoxon-Mann-Whitney test. The 
comparison of individuals in the treatment versus control arms is equivalent to ranking all 
individuals according to their experience. At one end of the ranking are individuals with the best 
experience - those alive and not hospitalized for worsening heart failure ordered according to 
their improvement in 6MWT; at the opposite end are those who die ordered according to their 
survival time. Those alive but hospitalized are in the middle, ordered according to their number 


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of hospitalizations for worsening heart failure and then by their change in 6MWT.  The non-
parametric Wilcoxon-Mann-Whitney test sums the ranks of those in the treatment arm and 
compares them with the sum of ranks in the control arm. 


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Table 10.2.1   Assumptions for Sample Size Calculations 
 
Ranked tier at 12-month endpoint 
Control 
Treatment 
Death total 
Death without hospitalization 
Death with hospitalization 
8% 
4% 
4% 
6.8% 
3.4% 
3.4% 
Hospitalizations in survivors 
1 
2 
3 or more 
 
6% 
3% 
1% 
 
4.8% 
2.4% 
0.8% 
Change in 6MWT  
Mean = 0 
SD = 90 
Mean = 18 
SD = 90 
Empirical Power: 0.9500 (N=2930, α=0.0025) 
Clinically-Meaningful Difference: 0.068/0.08 = 0.85 
 
Conclusion 
With 3000 participants (1500 per arm) and 2.5% annual loss to follow up, our simulations 
estimate ≥90% power at various two-sided significance levels between 0.0025 and 0.01. 
 
 


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10.3 Appendix 3: Ranking Algorithm (primary efficacy endpoint) 
 
Scenario Participant: 
i/j 
All-cause 
Mortality 
(1 year) 
Survival 
Times (from 
baseline) 
Heart Failure 
hospitalization 
(1 year) 
6 month 
change in 
6MWT 
Score 
1 
i 
Dead 
Low 
not in 
consideration 
not in 
consideration 
-1 
 
j 
Dead 
High 
not in 
consideration 
not in 
consideration 
+1 
2 
i 
Dead 
not in 
consideration 
not in 
consideration 
not in 
consideration 
-1 
j 
Alive 
not in 
consideration 
not in 
consideration 
not in 
consideration 
+1 
3 
i 
Alive 
not in 
consideration 
High 
not in 
consideration 
-1 
 
j 
Alive 
not in 
consideration 
Low 
not in 
consideration 
+1 
4 
i 
Alive 
not in 
consideration 
Tied 
Low 
-1 
 
j 
Alive 
not in 
consideration 
Tied 
High 
+1