A Randomised, Double-Blind Placebo Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient Patients Admitted for Acute Heart Failure (Affirm-AHF)
Phase: PHASE4
Conditions: Iron Deficiency, Heart Failure
Sponsor: Vifor (International) Inc.

 
 
This trial will be conducted in compliance with this protocol, ICH GCP and applicable regulatory requirements. 
The information contained in this document is proprietary to Vifor Pharma and is not to be copied, disclosed or otherwise distributed 
by an outside authority to any person or persons without the prior written permission of Vifor Pharma. 
 
 
A Randomised, Double-blind Placebo Controlled Trial 
Comparing the Effect of Intravenous Ferric Carboxymaltose 
on Hospitalisations and Mortality in Iron Deficient Patients 
Admitted for Acute Heart Failure (AFFIRM-AHF) 
 
Clinical Protocol Number: 
FER-CARS-06  
 
 
Date: 
1 April 2020 
 
 
Version/Amendment Number: 
Version 3.1 
 
 
Prior Version/Amendments 
Version 3.0, 16 March 2018 
 
Version 2.1, 5 January 2018 (SG only) 
Version 2.1, 19 December 2017 (ES only) 
Version 2.0, 25 April 2017 
Version 1.2, 31 January 2017 (NL only) 
Version 1.2, 19 January 2017 (UK only) 
Version 1.1, 1 August 2016 
Version 1.0, 29 June 2016 
 
 
EudraCT Number: 
2016-001467-36 
 
 
Co-ordinating Investigator: 
 
Department of Heart Disease 
Medical University 
Cardiology Department 
Centre for Heart Disease 
Clinical Military Hospital 
Weigla 5, 50-891 Wroclaw 
Poland 
 
 
Sponsor Contact: 
 
 
 
Sponsor Address:  
Vifor (International) Inc. 
Rechenstrasse 37 
St. Gallen CH-9001 
Switzerland 
 

 
 
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SIGNATURE PAGE 
Declaration of Sponsor 
Title: A Randomised, Double-Blind Placebo Controlled Trial Comparing the Effect of 
Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient 
Patients Admitted for Acute Heart Failure (AFFIRM-AHF) 
Version/Amendment Number/Date: Version 3.1, 1 April 2020. 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, and the International Council for Harmonisation 
Guidelines on Good Clinical Practice. 
 
 
 
 
Clinical Representative 
Vifor Pharma  
 
Date (day month year) 
 
 
 
 
Sponsor Statistician 
Vifor Pharma 
 
 
Date (day month year) 
 
 
 
 
Regulatory Representative 
Vifor Pharma 
 
Date (day month year) 
 
 
 
 
Sponsor Medical Expert 
Vifor Pharma 
 
Date (day month year) 
 

 
 
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SIGNATURE PAGE 
Declaration of Co-ordinating Investigator 
Title: A Randomised, Double-Blind Placebo Controlled Trial Comparing the Effect of 
Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient 
Patients Admitted for Acute Heart Failure (AFFIRM-AHF) 
Version/Amendment Number/Date: Version 3.1, 1 April 2020. 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, and the International Council for Harmonisation 
Guidelines on Good Clinical Practice. 
 
 
 
Signature of Co-ordinating Investigator 
 
Date (day month year) 
 
 
 
Name, Title, Address and Telephone 
Number of Co-ordinating Investigator 
 
 
 

 
 
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SIGNATURE PAGE 
Declaration of National Co-ordinating Investigator 
Title: A Randomised, Double-Blind Placebo Controlled Trial Comparing the Effect of 
Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient 
Patients Admitted for Acute Heart Failure (AFFIRM-AHF) 
Version/Amendment Number/Date: Version 3.1, 1 April 2020 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, and the International Council for Harmonisation 
Guidelines on Good Clinical Practice. 
 
 
 
Signature of National Co-ordinating 
Investigator 
 
Date (day month year) 
 
 
 
Name, Title, Address and Telephone 
Number of National Co-ordinating 
Investigator 
 
 
 

 
 
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INVESTIGATOR AGREEMENT AND SIGNATURE PAGE 
I have read the attached protocol entitled A Randomised, Double-Blind Placebo 
Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on 
Hospitalisations and Mortality in Iron Deficient Patients Admitted for Acute Heart 
Failure (AFFIRM-AHF), Version 3.1, 1 April 2020, and agree to abide by all provisions 
set forth therein. 
I agree to comply with the current International Council for Harmonisation Guidelines on 
Good Clinical Practice and applicable regulations and guidelines. 
I agree to ensure that financial disclosure statements will be completed by: 
• me (including, if applicable, my spouse (or legal partner) and dependent children) 
• my Sub-Investigators 
before the start of the study and to report any changes that affect my financial disclosure 
status for up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Vifor Pharma. 
Signature by the Investigator on this Protocol Signature Page documents review, 
agreement and approval of the requirements contained within this protocol. 
 
 
 
Signature of Principal Investigator 
 
Date (day month year) 
 
 
 
Name, Title, Address and Telephone 
Number of Principal Investigator 
 
 

 
 
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SYNOPSIS 
Protocol Number FER-CARS-06 
Title: 
A randomised, double-blind placebo controlled trial comparing the effect of 
intravenous ferric carboxymaltose on hospitalisations and mortality in iron deficient 
patients admitted for acute heart failure (AFFIRM-AHF) 
Short Title: 
Assessment oF Ferric carboxymaltose to Improve moRbidity and Mortality in 
iron-deficient patients hospitalised for Acute Heart Failure (AFFIRM-AHF) 
Study Product(s): 
Ferric carboxymaltose (FCM) or placebo 
Indication: 
Acute heart failure with iron deficiency (ID) 
Phase: 
Phase 4, therapeutic use 
Sponsor: 
Vifor Pharma 
Study Code: 
FER-CARS-06 
Co-ordinating 
Investigator:  
Prof Piotr Ponikowski, MD 
Objectives: 
Primary Objective(s) 
• 
To evaluate, relative to placebo, the effect of intravenous (IV) FCM on repeated 
heart failure (HF) hospitalisations and cardiovascular (CV) death. 
Secondary Objective(s) 
• 
To evaluate, relative to placebo, the effect of IV FCM on: 
• 
HF hospitalisations, CV hospitalisations, CV mortality and all-cause mortality. 
• 
Quality of life and New York Heart Association Classification (NYHA). 
• 
Tolerability and safety. 
Design: 
Multicentre, 
randomised, 
double-blind 
prospective, 
parallel-group, 
placebo-controlled, trial with a fixed follow-up of 52 weeks per subject after 
randomisation. 
Treatment: 
• 
Active treatment arm: IV FCM 
• 
Control treatment arm: IV NaCl 0.9% 
Eligible subjects will be randomised (1:1) to either FCM or placebo using a validated 
centralised procedure (Interactive Web-based Randomisation System (IWRS)). FCM 
will be supplied in 10 mL vials – one 10 mL vial contains 500 mg iron. Study 
treatment will be administered as an undiluted bolus injection. The study treatment 
dose (mL) to be administered will be determined by the subject’s body weight and 
haemoglobin (Hb) value based on the dosing scheme per below – see Table 1 

 
 
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Treatment 
(Cont’d): 
Table 1 
Study Treatment Dosing Regimen 
Treatment 
Visit 
Total mL FCM or Saline 
Weight <70 kg 
Weight ≥70 kg 
Any Weight 
8 g/dL(1) 
≤ Hb 
<10 g/dL 
10 g/dL 
≤ Hb 
≤14 g/dL 
8 g/dL(1) 
≤ Hb 
<10 g/dL 
10 g/dL 
≤ Hb 
≤14 g/dL 
14 g/dL  
< Hb 
≤15 g/dL 
Visit 2 
(Week 0) 
2x10 mL 
1x10 mL 
Visit 3(2) 
(Week 6) 
1x10 mL  
No dose 
2x10 mL 
1x10 mL 
No dose 
Visit 4, Visit 5 
(Week 12, 
Week 24) 
1x10 mL  
(only if ID persists) 
1 Following section in italics is applicable for The Netherlands, Spain and Singapore only (NL, ES and 
SG only)  The lower threshold of Hb values for subject eligibility prior to enrolment into the study is 
set to 10 g/dL. Subjects enrolled in the study in NL, ES and SG only with Hb levels that are falling 
below the threshold of 10 g/dL during the study will need to be withdrawn from further study treatment 
dosing. 
2 Dosing at Week 6 (Visit 3) will be based on the iron need upon screening Hb and weight values and 
only be done in subjects for whom Hb at Week 6 (Visit 3) ≤15 g/dL. 
Notes: FCM=Ferric carboxymaltose; Hb=Haemoglobin; ID=Iron deficiency. 
The study treatment doses administered at Visits 2 and 3 are considered as the 
“repletion phase” and any subsequent administrations (if ID persists) will be 
considered as the “maintenance phase”. The first dose of study treatment will be 
administered for all randomised subjects at Visit 2 while the subject is still 
hospitalised for the Index hospitalisation. It is recommended that the first dose of 
study treatment is administered on the same day as randomisation. To accommodate 
local hospital practice, the first dose of study treatment may be administered either 
on the same day or the day before the planned discharge day. Note that a planned 
overnight stay following study treatment administration does NOT fulfil the criteria 
of a serious adverse event (SAE) unless there is a medical reason for doing this. The 
subsequent administrations of study treatment will be done as part of the outpatient 
clinic visits at Week 6 (Visit 3), and at Weeks 12 (Visit 4) and 24 (Visit 5). Dosing at 
Week 6 (Visit 3) will be based on the iron need upon screening Hb and weight values 
to replete iron as described in Table 1 and only be done in subjects for whom Hb at 
Week 6 (Visit 3) ≤15 g/dL. Maintenance dosing at Weeks 12 (Visit 4) and 24 
(Visit 5) is only for subjects in whom ID persists and for whom Hb ≥8 g/dL* and 
≤15 g/dL at those visits. ID is defined as serum ferritin <100 ng/mL, or 100 ng/mL 
≤ serum ferritin ≤299 ng/mL if transferrin saturation (TSAT) <20%. The serum 
pregnancy test must also be negative for the respective visit for females of 
childbearing potential. Subjects will be requested to return to the outpatient clinic for 
the administration of study treatment maximally 7 days after the date when the blood 
sample was drawn. 
Study treatment will be prepared by an unblinded study personnel using black 
syringes and once prepared, study treatment should be administered immediately 
thereafter using a curtain (or similar) to maintain subject blinding. Each subject 
should be observed for adverse effects for at least 30 minutes following each 
injection of study treatment. The unblinded study personnel may be involved in 
performing screening activities. Following randomisation the unblinded study 
personnel will not be operationally involved in the study for the subject concerned 
other than the preparation and administration of study treatment and assessment and 
interpretation of post-randomisation laboratory test results. 
* Following section in italics is applicable for The Netherlands, Spain and Singapore 

 
 
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only (NL, ES and SG only): 
The lower threshold of Hb values is set to 10 g/dL. 
Inclusion Criteria: 
1. Currently hospitalised for an episode of acute heart failure (AHF) where AHF 
was the primary reason for hospitalisation. All of the following (i.e., items 
a to d) must apply: 
a. 
Upon admission for the AHF episode, persistent dyspnoea at rest in a 
recumbent sitting position (30-45°) or with minimal exertion 
b. Upon or during the AHF admission, at least 2 of the following clinical 
findings were present: 
i. 
Congestion on chest X-ray 
ii. Rales on chest auscultation 
iii. Oedema ≥1+ on a 0-3+ scale, indicating indentation of skin with mild 
digital pressure that requires 10 or more seconds to resolve in any 
dependent area including extremities or sacral region 
iv. Elevated jugular venous pressure (≥8 cm H2O) 
c. 
Natriuretic peptide levels, measured ≤72 hours of the AHF admission must 
have been: 
i. 
Brain natriuretic peptide (BNP) ≥400 pg/mL or N-terminal-pro-brain 
natriuretic peptide (NT-proBNP) ≥1,600 pg/mL or  
ii. BNP ≥600 pg/mL or NT-proBNP ≥2,400 pg/mL for subjects presenting 
with atrial fibrillation when the blood sample was taken 
iii. For subjects treated with an angiotensin receptor neprilysin inhibitor 
(ARNI) in the previous 4 weeks prior to randomisation only 
NT-proBNP values should be considered 
d. AHF episode treated with minimally 40 mg of IV furosemide (or equivalent 
IV loop diuretic defined as 20 mg of torasemide or 1 mg of bumetanide) 
2. Subject is iron deficient defined as serum ferritin <100 ng/mL or 100 ng/mL 
≤ serum ferritin ≤299 ng/mL if TSAT <20%. 
3. Left ventricular ejection fraction <50% (assessed and documented within 
12 months prior to randomisation). 
4. Male or female aged ≥18 years old. 
5. Subject (or legally acceptable representative)* has provided the appropriate 
written informed consent. Subject must provide written informed consent before 
any study-specific procedures are performed. 
* Following section in italics is applicable for The Netherlands only (NL only): 
The option that legally accepted representatives of subjects can sign the written 
informed consent is not valid for sites in The Netherlands. 

 
 
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Exclusion Criteria 
1. Dyspnoea due to non-cardiac causes such as acute or chronic respiratory 
disorders or infections (i.e., severe chronic obstructive pulmonary disease, acute 
bronchitis, pneumonia, primary pulmonary hypertension). 
2. Temperature >38°C (oral or equivalent), active infective endocarditis, sepsis, 
systemic inflammatory response syndrome, or any other active infection 
requiring anti-microbial treatment at any time during an Index hospitalisation. 
(Note that it does NOT include short-term prophylactic administration of 
antibiotics or short-term temperature elevation at admission which is no longer 
present at the time point of discharge/randomisation). 
3. Documented restricted amyloid myocardiopathy, or acute myocarditis or 
hypertrophic obstructive, restrictive, or constrictive cardiomyopathy. (Note that 
it does NOT include restrictive mitral filling patterns seen on Doppler 
echocardiographic assessments of diastolic function). 
4. Clinical evidence of acute coronary syndrome, transient ischemic attack or 
stroke, within the last 30 days prior randomisation. 
5. Severe valvular or left ventricular outflow obstruction disease needing 
intervention. 
6. Coronary-artery bypass graft, cardiac resynchronisation therapy device 
implantation, percutaneous intervention (e.g., cardiac, cerebrovascular, aortic, 
diagnostic catheters are allowed) or major surgery that led to significant blood 
loss, including thoracic and cardiac surgery, within the last 3 months prior to 
randomisation. 
7. Subject has a body weight <35 kg at randomisation. 
8. Subject at an immediate need of transfusion or with a Hb <8 g/dL* or with a 
Hb >15 g/dL. 
9. Subjects on treatment for Vitamin B12 and/or serum folate deficiency. Note: Use 
of Vitamin B12 and folic acid as supplement therapy (not for deficiency 
treatment) is permitted. 
10. Subject with a known anaemia not attributed to ID (e.g., other microcytic 
anaemia) or with an evidence of iron overload (e.g., haemochromatosis) or 
disturbances in the utilisation of iron. 
11. Subject has known hypersensitivity to any of the study products to be 
administered or known serious hypersensitivity to other parenteral iron products. 
12. Subject with known severe allergies including drug allergies, history of severe 
asthma, eczema or other atopic allergy and in subjects with immune or 
inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid 
arthritis). 
13. History of erythropoietin stimulating agent, IV iron therapy, and/or blood 
transfusion in previous 3 months prior to randomisation. 
14. Oral iron therapy at doses >100 mg/day in previous 4 weeks prior to 
randomisation. Note: Ongoing use of multivitamins containing iron <75 mg/day 
are permitted. 
15. Currently receiving systemic chemotherapy and/or radiotherapy. 
16. Renal dialysis (previous, current or planned within the next 6 months). 
17. Subject has known active malignancy of any organ system, i.e., clinical evidence 

 
 
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of current malignancy or not in stable remission for at least 3 years since 
completion of last treatment with exception of non-invasive basal cell 
carcinoma, squamous cell carcinoma of the skin or cervical intra-epithelial 
neoplasia. 
18. Terminal illness other than HF with expected survival <12 months. 
19. Chronic liver disease (including active hepatitis) and/or alanine transaminase or 
aspartate transaminase above 3 times the upper limit of the normal range. 
20. Subjects with known hepatitis B surface antigen positivity and/or hepatitis C 
virus ribonucleic acid positivity. 
21. Subject previously randomised into this study. Note: Subjects may be rescreened 
but when rescreened, all tests must fall inside the maximum specified screening 
windows for each criterion. 
22. Subject is currently enrolled in or has completed any other investigational device 
or drug study <30 days prior to screening, or is receiving other investigational 
agent(s). 
23. Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast 
feeding. 
24. If of childbearing potential, subject is not using adequate contraceptive 
precautions. Subject must agree to use adequate contraception during the study 
and for 1 month after the last dose of study treatment. A highly effective method 
of birth control must be used. 
25. Subject has a history of drug or alcohol abuse within 2 years prior to screening. 
26. Subject has a significant medical condition(s), anticipated need for major 
surgery during the study, or any other kind of disorder that may be associated 
with increased risk to the subject, or may interfere with study assessments, 
outcomes, or the ability to provide written informed consent or comply with 
study procedures, in the Investigator’s opinion. 
* Following section in italics is applicable for The Netherlands, Spain and Singapore 
only (NL, ES and SG only): 
The lower threshold of Hb values is set to 10 g/dL. 
Primary and 
Secondary 
Endpoints: 
Primary Endpoint 
• 
The composite of recurrent HF hospitalisations and CV death up to 52 weeks 
after randomisation. 
Secondary Endpoints 
The secondary endpoints will evaluate, relative to placebo, the effect of IV FCM. 
Hochberg’s procedure will be used to control the overall Type I error for the 
evaluation of the secondary endpoints. The secondary endpoints are the following: 
• 
The composite of recurrent CV hospitalisations and CV death up to 52 weeks 
after randomisation. 
• 
HF hospitalisations up to 52 weeks after randomisation (analysed as recurrent 
event).  
• 
CV mortality analysed as time to first event at 52 weeks after randomisation. 

 
 
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• 
The composite of HF hospitalisations or CV death analysed as time to first event 
at 52 weeks after randomisation.  
• 
Days lost due to HF hospitalisations or CV death at 52 weeks after 
randomisation. 
Complete details concerning the analyses and statistical tests to be performed will be 
detailed in the SAP – the latter will be finalised prior to unblinding of the trial 
database. 
Other Endpoints 
The other endpoints will evaluate, relative to placebo, the effect of IV FCM on: 
• 
The composite of recurrent HF hospitalisations and CV death up to 30 days after 
randomisation. 
• 
The composite of recurrent CV hospitalisations and CV death up to 30 days after 
randomisation. 
• 
The composite of HF hospitalisations or CV death analysed as time to first event 
at 30 days after randomisation. 
• 
The composite of CV hospitalisations or CV death analysed as time to first event 
at 30 days after randomisation.  
• 
HF hospitalisations up to 30 days after randomisation (analysed as recurrent 
event). 
• 
HF hospitalisations up to 30 days and 52 weeks after randomisation (analysed as 
time to first event). 
• 
CV hospitalisations up to 30 days and 52 weeks after randomisation (analysed as 
recurrent event and time to first event). 
• 
The composite of CV hospitalisations or CV death analysed as time to first event 
at 30 days and 52 weeks after randomisation.  
• 
CV mortality analysed as time to first event at 30 days after randomisation. 
• 
All-cause mortality analysed as time to first event at 30 days and 52 weeks after 
randomisation. 
• 
Proportion of patients with an event (HF hospitalisations, CV hospitalisations, 
CV mortality; composite and individual categories). 
• 
Change from baseline in NYHA functional class as assessed at 6, 12, 24 and 
52 weeks after randomisation. 
• 
Change from baseline in the Kansas City Cardiomyopathy Questionnaire-12 up 
to 52 weeks after randomisation. 
• 
Change from baseline in the European quality of life – 5 dimensions 
questionnaire up to 52 weeks after randomisation. 
• 
Days lost due to HF hospitalisations or CV death at 30 days after randomisation.  
Safety Endpoints: 
• 
Summary of adverse events (AEs): by system organ class and preferred term 
(Medical Dictionary for Regulatory Activities (MedDRA) coded term), by 
severity and relation to study product. 

 
 
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• 
Summary of SAEs by study treatment group presented by system organ class 
and preferred terms (MedDRA coded term). 
• 
Summary of clinical laboratory panels and cardiac biomarkers (absolute and 
change from baseline). 
Procedures: 
See Table 2 for full details of protocol required procedures and applicable visits (and 
timings). 
Screening Visit 
The AHF hospitalisation will be considered as the Index hospitalisation. 
Screening visit – performed in-hospital: 
• 
Subjects who have been hospitalised for an AHF episode will be screened to 
determine potential eligibility to participate in the AFFIRM-AHF trial. 
• 
The Investigator will obtain written informed consent from potentially eligible 
subjects before any trial-related procedure is performed. 
• 
As of the date of informed consent for each subject, the sites will document in 
the electronic case report form all AEs and changes/additions made to 
concomitant medications. SAEs will be reported as they occur but no later than 
24 hours after the Investigator’s awareness of the event. 
• 
A blood test will be drawn, which will be analysed locally, to determine if the 
subject is iron deficient and for whom Hb ≥8 g/dL* and ≤15 g/dL. The assays to 
be performed are: serum ferritin, TSAT and Hb. In addition, serum phosphorus 
levels analysed locally from the same blood draw will be documented in the 
eCRF. 
• 
During the same blood draw, a serum pregnancy test will be taken for females of 
childbearing potential.  
Baseline Visit, Randomisation and Administration of the First Dose of Study 
Treatment 
• 
The baseline visit will be performed in hospital (for the Index hospitalisation) 
upon receipt of the screening visit blood test results. 
• 
Upon receipt and review of the screening visit blood test results, the baseline 
visit will be performed for subjects in whom ID is confirmed and for whom the 
baseline Hb ≥8 g/dL* and ≤15 g/dL. In addition, for females of childbearing 
potential, the serum pregnancy test must be negative. The Investigator will 
perform/complete the baseline procedures/assessments as shown in Table 2. 
• 
In a subset of subjects samples for determination of blood biomarkers will be 
retained. 
• 
Upon completion of the baseline visit procedures/assessments and after the IV 
drugs prescribed to treat the AHF episode have been stopped for ≥12 hours, 
eligible subjects will be randomised using a validated centralised procedure 
(IWRS) to either FCM or placebo. The first dose of study treatment must be 
administered on the same day as randomisation. To accommodate local hospital 
practice, the first dose of study treatment may be administered either on the 
same day or the day before the planned discharge day. Note that a planned 
overnight stay following study treatment administration does NOT fulfil the 
criteria of an SAE unless there is a medical reason for doing this. 

 
 
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• 
Study treatment will be prepared and administered by unblinded study personnel 
who will otherwise not be involved in any study assessments for the subject 
concerned other than assessment and interpretation of post-randomisation 
laboratory test results. 
• 
The dose of study treatment to be administered will be determined following the 
instructions in Table 1. 
Each subject should be observed for adverse effects for at least 30 minutes following 
each injection of study treatment. Thereafter, the subject may be discharged from 
hospital, at the discretion of the Investigator. 
Post-randomisation Visit 
• 
Subjects will return to the outpatient clinic at 6, 12, 24 and 52 weeks after 
randomisation. 
Note: due to the COVID-19 pandemic situation the Investigator can perform the 
52 week visit (Visit 6) via remote methods (such as phone calls, video calls, etc.) to 
ensure collecting at a minimum subject’s health status, AEs and concomitant 
medications. 
• 
During 
the 
outpatient 
visits, 
the 
Investigator 
will 
perform 
the 
procedures/assessments as shown in Table 2 for the respective visit. 
• 
At Weeks 6 (Visit 3), 12 (Visit 4), 24 (Visit 5) and 52 (Visit 6) a blood test 
which will be analysed locally will be performed. The assays to be performed 
are: serum ferritin, TSAT and Hb. In addition, serum phosphorus levels analysed 
locally from the same blood draw will be documented in the eCRF. 
• 
During the same blood draw (except at Week 52 (Visit 6)), a serum pregnancy 
test will be taken for females of childbearing potential.  
• 
Blood test for biomarkers at Week 6 (Visit 3), Week 24 (Visit 5) and Week 52 
(Visit 6) in a subset of subjects. 
• 
At Week 6 (Visit 3) the repletion dose of study treatment will be administered 
based on the iron need as assessed at the baseline visit (Table 1). Dosing will 
only be done in subjects for whom Hb at Week 6 (Visit 3) ≤15 g/dL and for 
whom the serum pregnancy test is negative in females of childbearing potential. 
• 
If ID persists and Hb ≥8 g/dL* and ≤15 g/dL at Week 12 (Visit 4) and Week 24 
(Visit 5) and for whom the serum pregnancy test is negative in females of 
childbearing potential, the dose of study treatment to be administered will be 
determined as shown in Table 1. 
• 
Subjects for whom an administration of study treatment is necessary during an 
outpatient clinic visit will be requested to return to the outpatient clinic for the 
administration of study treatment maximally 7 days after the date when the 
blood sample was performed. 
• 
Study treatment will be prepared and administered by unblinded study personnel 
as described in the ‘Treatment’ section. 
• 
If ID persists at Week 52 (Visit 6), the Investigator will treat the ID according to 
local routine/standard practice. 
• 
Subjects will be contacted by telephone at Weeks 2, 4 and 36 after 
randomisation – see Table 2. 

 
 
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* Following section in italics is applicable for The Netherlands, Spain and Singapore 
only (NL, ES and SG only): 
The lower threshold of Hb values is set to 10 g/dL. 
Study Committees and Trial Oversight 
A Steering Committee (SC), a Data Safety Monitoring Board (DSMB) and a Clinical 
Endpoint Committee (CEC) will be established for this trial. 
The SC will ensure the scientific integrity of the trial in addition to overseeing the 
operational conduct. The DSMB will be constituted to oversee the safety of study 
participants and the CEC will adjudicate all events suggestive of the study outcomes 
using predefined criteria detailed in the adjudication charter. 
Sample Size: 
A total of 1,100 subjects is planned to be randomised (i.e., 550 per treatment group). 
Using the negative binomial statistical approach, the study would require 
1,000 subjects in total (500 per study group) for a power of 80% and a 2-sided alpha 
of 0.05 to demonstrate a statistically significant rate ratio of 0.75 (i.e., 25% reduction 
in the composite of recurrent HF hospitalisations and CV death, between the FCM 
and placebo groups) assuming a recurrent event rate of 0.7 events/year for HF 
hospitalisations and CV death in the placebo group. The mean follow-up time is 
estimated to 11 month accounting for a death rate of 12%. Taking into account loss 
to follow-up, an overall sample size of 1,100 subjects (550 per treatment group) is 
planned. 
Statistical 
Methods: 
No interim analysis is planned. 
Analysing Recurrent Heart Failure Hospitalisations and Cardiovascular Death 
The crude rate of HF hospitalisations and CV deaths per 100 patient-years of 
follow-up will be calculated by dividing the total number of HF hospitalisations and 
CV deaths by the total follow-up duration of all subjects in each group. The rate ratio 
(95% confidence interval and p-value) between treatment groups for the composite 
of recurrent HF hospitalisations and CV death will be estimated for the full analysis 
set (FAS) using the negative binomial model. A sensitivity analysis will be 
performed on the per-protocol set. 
All secondary and other endpoints will be analysed on the FAS and all statistical 
tests will be performed at a 5% level. 
Concerning the safety data, the total number of events and number (%) of subjects 
with event will be presented by MedDRA system organ class and preferred term by 
treatment group. 
Further details will be specified in the Statistical Analysis Plan. 
 

 
 
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Figure 1 
Flow Chart 
 
1 Study treatment to be administered only if ID persists. 
2 Performed in hospital during the AHF admission (Index hospitalisation). 
3 Discharge after administration of study treatment at the discretion of the Investigator. 
4 Telephone contact. 
5 Outpatient clinic visit. 
6 The repletion dose of study treatment will be administered based on the iron need as assessed at the baseline visit. 
Notes: AHF=Acute heart failure; FCM=Ferric carboxymaltose; ID=Iron deficiency; PL=Placebo; V=Visit; W=Week. 
 

 
 
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Table 2 
Schedule of Events 
FLOW CHART 
In-hospital 
 AHF 
Discharge 
Outpatient Clinic Visits/Telephone Contact 
V1 
Screening(1) 
V2 
Baseline and 
Randomisation 
Tel. Call 
1 
Tel. Call 
2 
V3 
V4 
V5 
Tel. Call 3 
V6(16) 
Early 
Termination 
 
Day  
0(2) 
W2(3) 
±3 days 
W4(3) 
±3 days 
W6(3) 
±5 days 
W12(3) 
±5 days 
W24(3) 
±10 days 
W36(3) 
±10 days 
W52(3) 
±10 days 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
(Review of) eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
  
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
 
 
 
 
 
 
X 
X 
Body weight 
 
X 
 
 
X 
X 
X 
 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
Vital signs (Seated blood pressure, pulse 
rate and rhythm ) 
 
X 
 
 
X 
X 
X 
 
X 
X 
12-lead Electrocardiogram 
 
X 
 
 
 
 
 
 
X 
X 
Serum Ferritin, TSAT, Hb, Phosphorus 
X 
 
 
 
X 
X 
X 
 
X 
X 
Serum pregnancy test 
X(4) 
 
 
 
X(4) 
X(4) 
X(4) 
 
 
 
Adverse events 
X(5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Prior)/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KCCQ-12 (completion) 
 
X(6) 
X(6) 
X(6) 
X(6) 
X(6) 
X(6) 
X(6) 
X(6,7) 
X(6) 
KCCQ-12 – provisions for completion at 
home 
 
X(7) 
 
 
 
 
X(7) 
 
X(6,7) 
 
EQ-5D 
 
X(6) 
 
 
X(6) 
 
X(6) 
 
X(6,7) 
X(6) 
HF signs and symptoms, NYHA class 
 
X 
 
 
X 
X 
X 
 
X 
X 

 
 
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FLOW CHART 
In-hospital 
 AHF 
Discharge 
Outpatient Clinic Visits/Telephone Contact 
V1 
Screening(1) 
V2 
Baseline and 
Randomisation 
Tel. Call 
1 
Tel. Call 
2 
V3 
V4 
V5 
Tel. Call 3 
V6(16) 
Early 
Termination 
 
Day  
0(2) 
W2(3) 
±3 days 
W4(3) 
±3 days 
W6(3) 
±5 days 
W12(3) 
±5 days 
W24(3) 
±10 days 
W36(3) 
±10 days 
W52(3) 
±10 days 
 
Randomisation 
 
X(8) 
 
 
 
 
 
 
 
 
Administer study treatment(9) 
 
X(10) 
 
 
X(11) 
X(12) 
X(12) 
 
(13) 
(13) 
Check occurrence of events suggestive of 
study endpoints 
 
X(14) 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker blood sample(15) 
 
X 
 
 
X 
 
X 
 
X 
X 
Dispense subject identification card 
 
X 
 
 
 
 
 
 
 
 
1 
Subject screening can start at the discretion of the Investigator during the Index hospitalisation. 
2 
Baseline visit to be performed only if subject has ID – i.e., serum ferritin <100 ng/mL or 100 ng/mL ≤ serum ferritin ≤299 ng/mL if TSAT <20% and Hb ≥8* g/dL and ≤15 g/dL. The screening visit serum 
pregnancy test must also be negative in females of childbearing potential. (* Following section in italics is applicable for The Netherlands, Spain and Singapore only (NL ES and SG only): The lower 
threshold of Hb values is set to 10 g/dL). 
3 
Telephone calls/visit scheduling relative to randomisation date. 
4 
Only in females of childbearing potential. 
5 
As of the signing of informed consent. 
6 
KCCQ-12 and EQ-5D questionnaires to be completed before any trial related procedure performed for the visit concerned. For the telephone contacts, subjects will complete the self-administered KCCQ-12 
questionnaire at home on the same day as the telephone contact. 
7 
Provisions to remind the subject that the KCCQ-12 questionnaire must be completed at home for the Telephone Calls 1 and 2 at Weeks 2 and 4 respectively and for Telephone Call 3 at Week 36 (and for 
Visit 6/Week 52). 
8 
Upon completion of the baseline visit procedures/assessments and after the IV drugs prescribed to treat the AHF episode have been stopped for ≥12 hours, eligible subjects will be randomised. Note: The 
biomarker blood sample should be drawn just prior to the administration of the first dose of study treatment. 
9 
Study treatment will be prepared and administered by an unblinded study personnel using black syringes and once prepared, study treatment should be administered immediately thereafter using a curtain (or 
similar) to maintain subject blinding. Each subject should be observed for adverse effects for at least 30 minutes following each injection of study treatment. 
10 The first dose of study treatment must be administered on the same day as randomisation. To accommodate local hospital practice, the first dose of study treatment may be administered either on the same day 
or the day before the planned discharge day. Note that a planned overnight stay following study treatment administration does NOT fulfil the criteria of a serious adverse event unless there is a medical reason 
for doing this. 
11 Repletion dose of study treatment to be administered based on the iron need as assessed at the baseline visit (Table 1). Dosing only in subjects for whom Hb at Week 6 (Visit 3) ≤15 g/dL. The serum 
pregnancy test must also be negative in females of childbearing potential. Subjects must return to the outpatient clinic for the administration of study treatment within maximally 7 days after the date when the 
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12 Study treatment must only be administered if ID persists (i.e., serum ferritin <100 ng/mL or 100 ≤ serum ferritin ≤299 ng/mL if TSAT <20%) and Hb ≥8 g/dL* and ≤15 g/dL. The serum pregnancy test must 
also be negative in females of childbearing potential. Subjects must return to the outpatient clinic for the administration of study treatment within maximally 7 days after the date when the blood sample was 
drawn at the respective visit. (* Following section in italics is applicable for The Netherlands, Spain and Singapore only (NL, ES and SG only): The lower threshold of Hb values is set to 10 g/dL. 
13 If ID persists, subject to be treated for ID according to local routine/standard practice. 
14 As of the start of the administration of study treatment. 
15 Biomarker blood sample to be taken in a subset of subjects of approximately 60% of randomised subjects. The first blood sample to be taken prior to the administration of study treatment. 
16  Note: due to the COVID-19 pandemic situation the Investigator can perform the 52 week visit Visit 6 via remote methods (such as phone calls, video calls, etc.) to ensure at a minimum collecting subject’s 
health status, adverse events and concomitant medications. 
 

 
 
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TABLE OF CONTENTS 
Page 
SIGNATURE PAGE ..........................................................................................................2 
INVESTIGATOR AGREEMENT AND SIGNATURE PAGE .....................................5 
SYNOPSIS ..........................................................................................................................6 
TABLE OF CONTENTS ................................................................................................19 
LIST OF TABLES ...........................................................................................................24 
LIST OF FIGURES .........................................................................................................25 
LIST OF APPENDICES .................................................................................................26 
LIST OF ABBREVIATIONS .........................................................................................27 
1. 
INTRODUCTION AND BACKGROUND ............................................................29 
1.1 
Background of the Disease and Treatment Options ..............................................29 
1.2 
Summary of Nonclinical and Clinical Data ...........................................................31 
2. 
RATIONALE ...........................................................................................................33 
3. 
STUDY OBJECTIVES ............................................................................................35 
3.1 
Primary Objective ..................................................................................................35 
3.2 
Secondary Objectives.............................................................................................35 
4. 
INVESTIGATIONAL PLAN .................................................................................36 
4.1 
Overall Study Design .............................................................................................36 
4.1.1 
Screening Visit ....................................................................................................36 
4.1.2 
Baseline Visit, Randomisation and Administration of the First Dose of 
Study Treatment ..................................................................................................37 
4.1.3 
Post-Randomisation Visits ..................................................................................37 
4.2 
Duration of Subject Participation and Study .........................................................39 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................40 
5.1 
Number of Subjects................................................................................................40 
5.2 
Inclusion Criteria ...................................................................................................40 
5.3 
Exclusion Criteria ..................................................................................................41 
5.4 
Withdrawal of Subjects ..........................................................................................43 
5.4.1 
Withdrawal of Subjects from Study Drug ..........................................................43 
5.4.2 
Withdrawal of Subjects from Follow-up ............................................................44 
5.5 
Rescreening of Subjects .........................................................................................45 
5.5.1 
Subject Rescreening During the Same Index Hospitalisation ............................45 
5.5.2 
Subject Rescreening ............................................................................................45 
6. 
RANDOMISATION, BLINDING AND UNBLINDING PROCEDURES .........46 
6.1 
Randomisation .......................................................................................................46 
6.2 
Blinding..................................................................................................................46 

 
 
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6.3 
Unblinding .............................................................................................................47 
7. 
STUDY TREATMENTS .........................................................................................48 
7.1 
Dosage Forms/Formulation ...................................................................................48 
7.1.1 
Formulation of Ferric Carboxymaltose...............................................................48 
7.1.2 
Formulation of Normal Saline ............................................................................48 
7.2 
Study Treatment Dosage and Administration ........................................................48 
7.2.1 
Treatment Arms ..................................................................................................48 
7.2.2 
Dosing and Administration Guidelines...............................................................49 
7.2.2.1 
Preparation of Study Treatment .......................................................................49 
7.2.2.2 
Administration of Ferric Carboxymaltose and Placebo ...................................49 
7.3 
Package and Labelling ...........................................................................................50 
7.4 
Study Treatment Allocation ...................................................................................50 
7.5 
Site Supply, Storage, Accountability .....................................................................50 
7.5.1 
Site Supply ..........................................................................................................50 
7.5.2 
Storage ................................................................................................................51 
7.5.3 
Accountability .....................................................................................................51 
7.6 
Study Treatment Dose Modification ......................................................................51 
7.6.1 
Procedures for Overdose .....................................................................................51 
7.7 
Prohibited Therapy and Concomitant Treatment ...................................................51 
7.7.1 
Basic Regimen ....................................................................................................52 
7.7.2 
Concomitant Treatment Restrictions ..................................................................52 
7.7.3 
Treatment in the Case of an Emergency .............................................................52 
8. 
RISKS/PRECAUTIONS .........................................................................................54 
8.1 
IV Iron Risks ..........................................................................................................54 
8.2 
Ferric Carboxymaltose ...........................................................................................54 
8.3 
Sodium Chloride (NaCl 0.9%) ...............................................................................54 
9. 
STUDY PROCEDURES .........................................................................................55 
9.1 
Description of Study Assessments .........................................................................55 
9.2 
Schedule of Assessments .......................................................................................55 
9.2.1 
Screening Procedures ..........................................................................................55 
9.2.1.1 
Screening Visit .................................................................................................55 
9.2.1.2 
Baseline Visit, Randomisation and Administration of the First Dose of 
Study Treatment ...............................................................................................56 
9.2.2 
Post-randomisation Visits ...................................................................................57 
9.2.2.1 
Outpatient Clinic Visits....................................................................................57 
9.2.2.2 
Refusal of Subjects to Come to the Outpatient Clinic Visits ...........................58 
9.2.2.3 
Telephone Contact ...........................................................................................59 
9.2.2.4 
Extra Visits.......................................................................................................59 
9.2.2.5 
Premature Termination of Follow-up ..............................................................59 
9.2.3 
Clinical and Laboratory Assessments .................................................................59 
9.2.3.1 
Medical History ...............................................................................................59 
9.2.3.2 
General Physical Examination .........................................................................59 
9.2.3.3 
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9.2.3.4 
Vital Signs ........................................................................................................60 
9.2.3.5 
Symptoms and Signs of Heart Failure .............................................................60 
9.2.3.6 
New York Heart Association Functional Classification ..................................60 
9.2.3.7 
12-lead Electrocardiogram ...............................................................................61 
9.2.3.8 
Documentation of Concomitant Treatments ....................................................61 
9.2.3.9 
Final Review of the Inclusion/Exclusion Criteria ............................................61 
9.2.3.10 
Health-related Quality of Life ..........................................................................62 
9.2.3.11 
Laboratory Tests Mandated by the Study Protocol..........................................62 
9.2.3.12 
Randomisation .................................................................................................63 
9.2.3.13 
Administration of Study Treatment .................................................................63 
9.2.3.14 
Reporting of Events Suggestive of the Study Outcomes .................................63 
9.2.4 
Treatment Procedures .........................................................................................63 
9.2.5 
Data Which Must be Available in Source Data ..................................................64 
9.2.5.1 
Laboratory Test Results ...................................................................................64 
9.2.5.2 
Symptoms and Clinical Findings Relating to Heart Failure ............................64 
9.2.6 
End of Treatment Procedures .............................................................................64 
9.2.7 
End of Study (or Early Discontinuation) Procedures .........................................64 
10. EVALUATION, RECORDING AND REPORTING OF AES, SAES AND 
SPECIAL SITUATIONS .........................................................................................65 
10.1 
Definitions..............................................................................................................65 
10.1.1 
Reference Safety Information .............................................................................65 
10.1.2 
Adverse Event .....................................................................................................65 
10.1.3 
Adverse Drug Reaction .......................................................................................65 
10.1.4 
Unexpected Adverse Event/Adverse Drug Reaction ..........................................65 
10.1.5 
Serious Adverse Event ........................................................................................65 
10.1.6 
Suspected Unexpected Serious Adverse Reaction..............................................66 
10.1.7 
Special Situations ................................................................................................67 
10.2 
AE Descriptors .......................................................................................................67 
10.2.1 
Intensity/Severity Categorisation ........................................................................67 
10.2.2 
Causal Relationship Categorisation ....................................................................68 
10.2.3 
Outcome Categorisation .....................................................................................69 
10.2.4 
Pre-existing Medical Conditions ........................................................................69 
10.2.5 
Worsening of the Disease Under Study ..............................................................69 
10.2.6 
Clinical Laboratory Evaluations .........................................................................69 
10.2.7 
Abnormal Vital Signs .........................................................................................70 
10.2.8 
Special Situations ................................................................................................71 
10.3 
Reporting Procedure for AEs, SAEs and Pregnancy .............................................71 
10.3.1 
Adverse Events ...................................................................................................71 
10.3.2 
Serious Adverse Events ......................................................................................72 
10.3.2.1 
Elective Surgery/Routine Examination............................................................75 
10.3.3 
Pregnancy............................................................................................................75 
11. STUDY COMMITTEES .........................................................................................78 
11.1 
DSMB/DMC Procedures .......................................................................................78 

 
 
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11.2 
Steering Committee ...............................................................................................78 
11.3 
Clinical Endpoint Committee ................................................................................79 
12. STATISTICAL ANALYSIS ...................................................................................80 
12.1 
Statistical Methods .................................................................................................80 
12.2 
Sample Size and Power Calculations .....................................................................80 
12.3 
Analysis Sets ..........................................................................................................81 
12.3.1 
Full Analysis Set .................................................................................................81 
12.3.2 
Per-protocol Set ..................................................................................................81 
12.3.3 
Safety Set ............................................................................................................81 
12.4 
Background and Demographic Characteristics ......................................................81 
12.5 
Study Treatment .....................................................................................................81 
12.6 
Concomitant Therapy.............................................................................................81 
12.7 
Efficacy Evaluations ..............................................................................................81 
12.7.1 
Primary................................................................................................................81 
12.7.2 
Secondary and Other Endpoints .........................................................................82 
12.8 
Safety Evaluations .................................................................................................84 
12.9 
Interim Analyses ....................................................................................................84 
12.10 Other Evaluations...................................................................................................85 
12.10.1 Exploratory Analyses ..........................................................................................85 
12.10.2 Biomarker Blood Samples ..................................................................................85 
12.10.3 Quality of Life ....................................................................................................85 
12.10.4 Pooling of AFFIRM-AHF, FAIR-HF2 and FAIR-HFpEF studies .....................85 
13. STUDY ETHICAL CONSIDERATIONS .............................................................87 
13.1 
Ethical Conduct of the Study .................................................................................87 
13.2 
Informed Consent...................................................................................................87 
13.3 
Institutional Review Board or EC/IEC ..................................................................87 
14. QUALITY CONTROL AND QUALITY ASSURANCE .....................................88 
15. ADMINISTRATIVE PROCEDURES ...................................................................89 
15.1 
Sponsor’s Responsibilities .....................................................................................89 
15.1.1 
Study Supplies ....................................................................................................89 
15.1.2 
Insurance .............................................................................................................89 
15.1.3 
Investigator Training...........................................................................................89 
15.1.4 
Study Monitoring ................................................................................................89 
15.1.5 
Medical Monitoring ............................................................................................90 
15.2 
Investigator’s Responsibilities ...............................................................................90 
15.2.1 
Reporting and Recording of Data .......................................................................90 
15.2.2 
Source Documentation ........................................................................................90 
15.2.3 
Records Retention ...............................................................................................91 
15.2.4 
Site Documentation.............................................................................................91 
16. PROCEDURE 
FOR 
MODIFICATION 
OF 
PROTOCOL 
OR 
PREMATURE TERMINATION OF THE STUDY .............................................92 
16.1 
Protocol Waivers, Deviations and Violations ........................................................92 

 
 
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16.2 
Protocol Amendments ............................................................................................92 
16.3 
Study Termination .................................................................................................92 
17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ................94 
18. REFERENCES .........................................................................................................95 
 

 
 
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LIST OF TABLES 
Page 
Table 1 
Study Treatment Dosing Regimen ...............................................................7 
Table 2 
Schedule of Events .....................................................................................16 
Table 3 
New York Heart Association Classification ..............................................61 
 

 
 
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LIST OF FIGURES 
Page 
Figure 1 
Flow Chart .................................................................................................15 
 

 
 
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LIST OF APPENDICES 
Page 
Appendix 1 
Serious Adverse Event Form (Sample)......................................................99 
Appendix 2 
Report on Exposure to Medicines During Pregnancy (Sample) ..............105 
Appendix 3 
Guidelines for Administering Informed Consent ....................................107 
 

 
 
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LIST OF ABBREVIATIONS 
AHF 
Acute heart failure 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ARNI 
Angiotensin receptor neprilysin inhibitor 
BNP 
Brain natriuretic peptide 
CHF 
Chronic heart failure 
CI 
Confidence interval 
CEC 
Clinical Endpoint Committee 
CRO 
Contract Research Organisation 
CV 
Cardiovascular 
DMC 
Data Monitoring Committee 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EQ-5D 
European quality of life – 5 dimensions 
ES 
Spain 
FAS 
Full analysis set 
FCM 
Ferric carboxymaltose 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
Hb 
Haemoglobin 
HF 
Heart failure 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Iron deficiency 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 

 
 
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IWRS 
Interactive web-based randomisation system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NL 
The Netherlands 
NT-proBNP 
N-terminal-pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
OR 
Odds ratio 
PP 
Per-protocol set 
PT 
Preferred term 
QoL 
Quality of life 
RCT 
Randomised controlled trial 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SG 
Singapore 
SOC 
System organ class 
TSAT 
Transferrin saturation 
UK 
United Kingdom 
VAS 
Visual analogue scale 
WMA 
World Medical Association 
w/v 
Weight per volume 

 
 
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1. INTRODUCTION AND BACKGROUND 
Two major clinical trials (FAIR-HF and CONFIRM-HF) have demonstrated that the 
treatment with intravenous (IV) ferric carboxymaltose (FCM) improves functional 
capacity, exercise tolerance, symptoms and quality of life (QoL) in stable iron deficient 
subjects with heart failure (HF) [1,2]. Additionally, in the secondary analysis of the 
CONFIRM-HF trial, the treatment with IV FCM was associated with a significant 60% 
reduction of the risk of hospitalisations for worsening HF during the 12 month follow-up. 
Moreover, the recent meta-analysis of 5 trials with IV iron therapy in patients with stable 
HF (including 509 subjects receiving IV iron therapy in comparison with 342 subjects 
receiving placebo) has shown that IV iron therapy can reduce the risk of the combined 
endpoint of all-cause death or/and cardiovascular (CV) hospitalisation (odds ratio (OR) 
0.44, 95% confidence interval (CI) 0.30-0.64, P < 0.0001), and the combined endpoint of 
CV death or hospitalisation for worsening HF (OR 0.39, 95% CI 0.24-0.63, P=0.0001) [3]. 
Acute heart failure (AHF) constitutes a clinically and economically challenging problem. 
The prognosis of these patients remains poor, and so far, major clinical trials have failed 
to improve outcomes in these patients. The current treatment of AHF remained virtually 
unchanged in recent decades. iron deficiency (ID) is frequent among patients with HF and 
predicts poor outcome [4]. Although, there are premises that correction of ID in AHF 
patients could improve clinical outcomes, it has not been investigated to date. 
We aim to investigate the effect of IV FCM, relative to placebo on recurrent HF 
hospitalisations and CV death up to 52 weeks after randomisation in iron deficient 
subjects hospitalised for AHF. 
1.1 
Background of the Disease and Treatment Options 
Based on rough estimates, at least 10 million people suffer from HF in European 
countries [5]. The incidence of HF approaches 10 per 1,000 population after age 65, and 
approximately 80% of patients hospitalised with HF are more than 65 years old [6]. HF 
results in poor life expectancy, impaired QoL, repeated hospitalisations and is a 
considerable economic burden, accounting for 1–2% of health care expenditure in 
European countries [4]. Despite advances in its treatment, the prognosis of HF remains 
poor. The Euro Heart Survey showed that the in-hospital mortality of patients admitted 
for de novo AHF was 8.1%, and 5.8% for patients admitted for worsening HF [7]. About 
50% of patients with HF will die within 4 years of the initial diagnosis, and for patients 
with severe chronic heart failure (CHF), approximately 50% will die within 1 year [5]. 
AHF has become the leading cause for hospital admissions among patients over 65 years, 
with unacceptably poor outcomes [8]. Despite initial stabilisation and symptomatic relief, 
sustained improvement in signs and symptoms of HF is difficult to maintain. In-hospital 
worsening of HF requiring intensification of therapy occurs in 15-20% of patients and 
in-hospital mortality ranges from 4-10% [7]. Post-discharge outcomes are even more 

 
 
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alarming; more than half of all patients will be either readmitted to the hospital or die 
within the first 6 months after hospital discharge [9]. 
The prevalence of ID is high in patients with HF as described above, most importantly 
both in anaemic and non-anaemic subjects. Moreover, the clear beneficial effects of IV 
FCM supplementation have been observed in both anaemic and non-anaemic patients 
with HF, suggesting that optimal iron status is crucial for the proper functioning of both 
haematopoietic and non-haematopoietic tissues. It should be emphasised that in spite of 
the critical evident role of iron for erythropoiesis, there is accumulating evidence showing 
that iron is needed for optimal energy metabolism of all cells [4]. Iron is essential for the 
transport and storage of oxygen, oxidative metabolism in the skeletal and heart muscle 
and the synthesis and degradation of lipids, carbohydrates, DNA, RNA [10,11]. Iron 
deficiency leads to mitochondrial dysfunction, and therefore unfavourable effects of 
depleted iron are seen predominantly in tissues of high energy demand, such as skeletal or 
heart muscles [4]. 
There is growing scientific literature describing the prevalence of ID in CHF, and 
individual manuscripts report that up to 50% of CHF patients may suffer from ID 
[12,13,14]. Patients with HF are also at risk of iron loss secondary to gastritis or 
ulceration caused by concomitant pharmacotherapy, and from proteinuria arising from 
chronic renal disease [15,16]. This decrease in iron intake respectively stores may lead to 
absolute ID. 
In subjects with CHF, ID has been defined as serum ferritin less than 100 ng/mL 
(absolute ID) or serum ferritin less than 300 ng/mL with transferrin saturation (TSAT) 
less than 20% (functional ID) [17]. Taking into consideration the biological role of iron, it 
may be hypothesised that ID is a key reason for the greatly reduced exercise capacity, 
fatigue and breathlessness observed in these subjects. Anker et al. [18] suggested that 
therapeutic options to improve functional capacity are very limited and, as such, targeting 
abnormalities impeding oxygen transportation and/or utilisation may confer functional 
benefits. These hypotheses were confirmed in the FAIR-HF study with demonstrated 
improvements in symptomatic, functional and exercise capacity of subjects treated with 
FCM [1]. Several other smaller studies had shown similar benefits with the treatment of 
subjects using IV iron [19-22]. Beyond the improvements observed in the randomised 
controlled trials (RCTs) alluded to, initial evidence (in small sample sizes) suggests that 
iron repletion in iron deficient subjects with anaemia may also have additional benefits 
and improve the left ventricular dysfunction, decrease N-terminal-pro-brain natriuretic 
peptide (NT-proBNP) levels and inflammatory status, as measured by C-reactive protein 
[21]. 
The origin of ID in patients with HF remains unknown. Patients with HF (particularly 
during circulatory decompensation) have high circulating levels of pro-inflammatory 
cytokines, and the inflammation has been postulated by several experts as the key 
pathomechanism triggering the development of functional ID due to the increased liver 
production of hepcidin in patients with HF, similarly as in chronic kidney disease and 

 
 
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other chronic inflammatory disorders [23-27]. Although theoretically anticipated, until 
now it has not been demonstrated that ID occurring in the course of HF is linked with 
inflammation. On the contrary, patients with stable systolic HF developing ID have very 
low circulating hepcidin (without increased interleukin 6), suggesting severely depleted 
iron stores [28]. Also, patients with coronary artery disease undergoing coronary artery 
bypass graft surgery with depleted iron stores in bone marrow demonstrate low serum 
levels of hepcidin [29]. Finally, it has been shown that 46% of patients admitted due to 
AHF have extremely low circulating hepcidin level (<14.5 ng/mL), and those with low 
hepcidin accompanied by high circulating soluble transferrin receptor have very high 
12-month all-cause mortality [4]. Provided evidence suggests that patients with HF (either 
when in stable or decompensated conditions) have extremely low hepcidin, which 
suggests the presence of profound absolute ID not related with inflammation. Such severe 
ID can be effectively supplemented only intravenously [3,5]. 
1.2 
Summary of Nonclinical and Clinical Data 
Geisser et al. [30] have characterised FCM as a robust and strong type iron complex 
(Type I) with a molecular mass of about 150,000 Daltons. The solution is a dark brown 
colour with a near neutral pH and a physiological osmolarity. As the product does not 
contain dextran it has been demonstrated to not cross react with dextran antibodies hence 
avoiding dextran-induced anaphylactic reactions. After IV administration, FCM is mainly 
found in the reticuloendothelial system of the liver, in the spleen and in the bone marrow. 
Since the iron is predominantly deposited in the reticuloendothelial system, and not in the 
parenchyma, iron induced radical forming lipid peroxidation, which takes place in the 
parenchyma only, is not triggered by FCM. Results from nonclinical histotoxicological 
investigations confirm that FCM does not cause any necroses in the liver, and no changes 
of toxicological importance were detected in kidney, adrenal, lung and spleen tissue 
following FCM administration. Except for the spleen, only a small amount of iron is 
found in the organs, which is due to high iron complex stability. 
A clinical pharmacokinetics study [31,32] using positron emission tomography 
demonstrated a fast initial elimination of radioactively labelled iron 52Fe/59Fe FCM from 
the blood, along with rapid transfer to the bone marrow and rapid deposition in the liver 
and spleen. At 8 hours after administration, 5-20% of the injected amount was still in the 
blood. The projected calculated half-life of terminal elimination was about 16 hours, in 
comparison to 3 to 4 days for iron dextran and 6 hours for iron sucrose. A further Phase 2 
study in subjects with ID anaemia demonstrated a monoexponential elimination pattern 
with a half-life of terminal elimination in the range 10 to 18 hours. There was negligible 
renal elimination. In this and another registration study, total serum iron returned to the 
normal range within 3 and 7 days allowing for a weekly dosing schedule. In general, 
clinical safety and efficacy studies have been conducted in numerous settings that are 
representative of underlying diseases that may lead to ID i.e., diseases with increased 
inflammatory status that impairs iron absorption as well as diseases with large losses of 
iron that cannot be compensated via dietary iron. 

 
 
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Since the developmental international birth date, more than 7,000 subjects are known to 
have been exposed to FCM with at least one dose in more than 35 completed prospective, 
interventional clinical studies. Across various clinical studies, replenishment of iron 
stores has been consistently observed. Markers of ID have included both TSAT and 
serum ferritin. In subjects with more severe or prolonged ID that has led to anaemia, 
correction of ID using FCM has consistently resulted in medically significant increases in 
haemoglobin (Hb) values (correction of anaemia). This improvement was usually seen 
within 2 weeks. In addition to the correction of laboratory parameters, iron replacement 
therapy has demonstrated significant improvements in subject QoL and functional status. 
Ferric carboxymaltose was well tolerated by study participants. In the completed clinical 
studies, up until the 1 January 2015, approximately 50% of the subjects experienced at 
least 1 treatment-emergent adverse event (AE), and events considered related to treatment 
occurred in just over 17% of subjects who received FCM. The most commonly reported 
adverse drug reactions (ADRs) in the FCM group were nausea, injection/infusion site 
reactions, hypophosphataemia, headache, flushing, dizziness, and hypertension. 
In relation to laboratory parameters recorded in clinical studies, no consistent pattern of 
clinically meaningful changes requiring intervention have been observed. However, mild 
and transient changes of liver enzymes, such as aspartate aminotransferase and alanine 
aminotransferase, gamma-glutamyl transferase and alkaline phosphatase, have been 
reported in some studies. A transient decrease in blood phosphorus levels was frequently 
observed. The nadir occurred approximately 2 weeks after dosing and resolved without 
treatment in most subjects within the follow-up period of up to 12 weeks. Severe 
hypophosphataemia (i.e., <0.3 mmol/L) was observed in very few cases, and was of short 
duration. 
No formal interaction studies have been performed. Except for the reduced uptake of oral 
iron administered in parallel with parenteral iron, no interactions with other medications 
are known. 
The first marketing authorisation for FCM was received in July 2007, and as of 
1 January 2015, FCM has received marketing authorisation in a total of 63 countries 
worldwide. The total exposure of patients since the introduction of FCM into the market 
up to December 2014 corresponded to more than 2,000,000 patient-years. The total 
number of spontaneous and solicited adverse drug experience cases reported is considered 
small with respect to the overall drug exposure. Post-marketing reports up to 
December 2014 confirm the known AE profile and the positive benefit/risk ratio of FCM. 
Please see the Investigator’s Brochure for further details. 

 
 
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2. RATIONALE 
Currently there are 8 studies of varying sizes performed using IV iron in stable HF 
subjects, and 2 of these studies using IV FCM conducted as placebo-controlled, 
double-blinded studies [1,2]. These two RCTs have provided evidence, that relative to 
placebo, the correction of ID with IV FCM improves clinical functional capacity, 
symptoms, clinical findings related to HF and QoL. In addition, IV FCM was well 
tolerated. 
To date, no data exists concerning the impact of IV FCM on recurrent HF hospitalisations 
and CV death in a HF population with ID who have recently stabilised after an AHF 
episode. The intervention is planned in subjects with diagnosed ID at the time of 
randomisation and left ventricular ejection fraction (LVEF) <50% demonstrated at any 
time within 12 months prior to randomisation. In this trial, it is planned to administer the 
first IV dose of FCM/placebo just prior to discharge for the AHF episode. Subjects will 
be followed for 52 weeks and study treatment will be administered at Week 6 based on 
the iron need as assessed at the baseline visit, and at Weeks 12 and 24 if ID persists at 
these time points. Recent observational data from Jankowska et al. [33] in subjects with 
systolic CHF, suggested that ID constitutes a strong independent predictor of 
unfavourable outcome proposing that iron supplementation may be considered as a 
therapeutic approach in CHF subjects to improve outcome. In this observational study, a 
distinct difference in survival curves in favour of non-iron deficient subjects was 
observed within the first 6-12 months. After 12 months the difference between iron 
deficient and non-iron deficient subjects remained stable. 
Study Design Rationale 
This is a randomised, double-blind, placebo-controlled trial. The 52 weeks observation 
period following randomisation is considered appropriate to investigate the primary 
endpoint of recurrent HF hospitalisations and CV death. To evaluate the effect of IV 
FCM in iron deficient subjects with AHF, subjects will be enrolled during a hospital stay 
(Index hospitalisation) after the acute care treatment of the index event has been stabilised. 
All subjects will continue to receive their established standard therapy for HF and 
medical emergencies will be treated according to local routine. Placebo-treatment will be 
used for blinding reasons of IV FCM treatment, and as such does not bear any additional 
risk to the subject. Given that there is no proven effective intervention for the condition 
under investigation in the AFFIRM-AHF trial, the use of a placebo arm is considered 
ethically justified. 
For this trial, the same treatment algorithm was selected to be used as that implemented in 
an RCT with IV FCM in stable CHF subjects [2]. First treatment will be administered in 
the hospital prior to discharge. Over the 52 weeks following randomisation, the collected 
endpoints will focus on important events for this subject population (hospitalisations, 
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A Data and Safety Monitoring Board (DSMB)/Data Monitoring Committee (DMC) will 
be constituted to protect the safety of study participants and a Clinical Endpoint 
Committee (CEC) will be established to ensure robust assessment of all events suggestive 
of the primary study endpoint. 

 
 
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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to evaluate, relative to placebo, the effect of IV FCM on 
repeated HF hospitalisations and CV death. 
3.2 
Secondary Objectives 
The secondary objectives are to evaluate, relative to placebo, the effect of IV FCM on: 
• HF hospitalisations, CV hospitalisations, CV mortality and all-cause mortality 
• Quality of life and New York Heart Association (NYHA) Classification 
• Tolerability and safety 

 
 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
The AFFIRM-AHF trial is multicentre, randomised, double-blind, prospective, 
parallel-group, placebo-controlled, trial with a fixed follow-up of 52 weeks after 
randomisation per subject. The Schedule of Events is shown in Table 2 and Figure 1. 
4.1.1 
Screening Visit 
The AHF hospitalisation will be considered as the Index hospitalisation. The screening 
visit will be performed in-hospital. The screening visit process can be summarised as 
follows: 
• Subjects who have been hospitalised for an AHF episode will be screened to 
determine potential eligibility to participate in the AFFIRM-AHF trial. 
• The Investigator will obtain written informed consent from potentially eligible 
subjects before any trial-related procedure is performed. 
• As of the date of informed consent for each subject, the sites will document in the 
electronic case report form (eCRF) all AEs and changes/additions made to 
concomitant medications. SAEs will be reported as they occur but no later than 
24 hours after the Investigator’s awareness of the event. 
• In potentially eligible subjects, a blood test will be drawn, which will be analysed 
locally, to determine if the subject is iron deficient and if the Hb ≥8 g/dL* and 
≤15 g/dL. Iron deficiency is defined as serum ferritin <100 ng/mL, or 
100 ng/mL ≤ serum ferritin ≤299 ng/mL if TSAT <20%. The assays to be performed 
are: serum ferritin, TSAT and Hb. In addition, serum phosphorus levels analysed 
locally from the same blood draw will be documented in the eCRF. 
• During the same blood draw, a serum pregnancy test will be taken for females of 
childbearing potential. 
*Following section in italics is applicable for The Netherlands, Spain and Singapore only 
(NL, ES and SG only): 
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4.1.2 
Baseline Visit, Randomisation and Administration of the First Dose of 
Study Treatment 
The baseline visit process/procedures can be summarised as follows: 
• Upon receipt of the screening visit blood test results, the baseline visit will be 
performed for subjects in whom ID is confirmed and for whom the baseline 
Hb ≥8 g/dL* and ≤15 g/dL. In addition, for females of childbearing potential, the 
serum pregnancy test must be negative. The Investigator will perform/complete the 
baseline procedures/assessments as shown in Table 2. 
*Following section in italics is applicable for The Netherlands, Spain and Singapore 
only (NL, ES and SG only): 
The lower threshold of Hb values is set to 10 g/dL. 
• In a subset of subjects samples for determination of blood biomarkers will be retained. 
• Upon completion of the baseline visit procedures/assessments and after the IV drugs 
prescribed to treat the AHF episode have been stopped for ≥12 hours, eligible subjects 
will be randomised using a validated centralised procedure (interactive web-based 
randomisation system (IWRS)) to either FCM or placebo. Study treatment must be 
administered on the same day as randomisation. To accommodate local hospital 
practice, the first dose of study treatment may be administered either on the same day 
or the day before the planned discharge day. Note that a planned overnight stay 
following study treatment administration does NOT fulfil the criteria of an SAE 
unless there is a medical reason for doing this. 
• Study treatment will be prepared and administered by unblinded study personnel who 
will otherwise not be involved in any study assessments for the subject concerned 
other than assessment and interpretation of post-randomisation laboratory test results. 
• The dose of study treatment to be administered will be done following the instructions 
in Table 1. Each subject should be observed for adverse effects for at least 30 minutes 
following each injection of study treatment. Thereafter, the subject may be discharged 
from hospital, at the discretion of the Investigator. 
4.1.3 
Post-Randomisation Visits 
The post-randomisation subject contacts can be summarised as follows: 
• Subjects will return to the outpatient clinic at 6, 12, 24 and 52 weeks after 
randomisation.  
Note: due to the COVID-19 pandemic situation the Investigator can perform the 52 week 
visit (Visit 6) via remote methods (such as phone calls, video calls, etc.) to ensure 
collecting at a minimum subject’s health status, AEs and concomitant medications. 

 
 
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• During the outpatient visits, the Investigator will perform the procedures/assessments 
as shown in Table 2 for each respective visit. 
• At Weeks 6 (Visit 3), 12 (Visit 4), 24 (Visit 5) and 52 (Visit 6) a blood test, which 
will be analysed locally, will be drawn. The assays to be performed are: serum ferritin, 
TSAT and Hb. If ID persists and Hb ≥8* g/dL and ≤15 g/dL at Weeks 12 (Visit 4) and 
24 (Visit 5), the dose of study treatment to be administered will be determined as 
shown in Table 1. In addition, serum phosphorus levels analysed locally from the 
same blood draw will be documented in the eCRF. 
*Following section in italics is applicable for The Netherlands, Spain and Singapore 
only (NL, ES and SG only): 
The lower threshold of Hb values is set to 10 g/dL. 
• During the same blood draw (except at Week 52 (Visit 6)), a serum pregnancy test 
will be taken for females of childbearing potential. 
• At Week 6 (Visit 3) the repletion dose of study treatment will be administered based 
on the iron need as assessed at the baseline visit (Table 1) and only in subjects for 
whom Hb at Week 6 (Visit 3) ≤15 g/dL. For females of childbearing potential, the 
serum pregnancy test must be negative. 
• Subjects for whom an administration of study treatment is necessary during an 
outpatient clinic visit, will be requested to return to the outpatient clinic for the 
administration of study treatment maximally 7 days after the date when the blood 
sample was performed for the respective outpatient clinic visit. For females of 
childbearing potential, the serum pregnancy test must be negative. 
• In a subset of subjects samples for determination of blood biomarkers will be retained 
at Weeks 6 (Visit 3), 24 (Visit 5) and 52 (Visit 6). 
• Study treatment will be prepared and administered by unblinded study personnel who 
will otherwise not be involved in any study assessments for the subject concerned 
other than assessment and interpretation of post-randomisation laboratory test results. 
• The dose of study treatment to be administered will be determined following the 
instructions in Table 1. Each subject should be observed for adverse effects for at 
least 30 minutes following each injection of study treatment. Thereafter, the subject 
may leave the outpatient clinic at the discretion of the Investigator. 

 
 
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• The site will contact the subject by telephone at Week 2 (Telephone Call 1), Week 4 
(Telephone Call 2), and Week 36 (Telephone Call 3), after randomisation to enquire 
about the subject’s health status and enquire if the subjects experienced a deterioration 
of their condition or if they were hospitalised since the last visit contact and/or if there 
were changes made to their concomitant treatments. The latter will be reported in the 
eCRF. The subjects will be requested to complete the Kansas City Cardiomyopathy 
Questionnaire (KCCQ)-12 questionnaire at home on the same day as the Week 2, 
Week 4 and Week 36 telephone call. The subjects will be instructed to return the 
completed questionnaires at the following out-patient clinic Visit. Adverse events will 
also be reported in the eCRF. If the subject reports a hospitalisation, the Investigator 
must report the SAE as per the protocol requirements (see Section 10). 
• If ID persists at Week 52 (Visit 6), the Investigator will treat the ID according to local 
routine/standard practice. 
The FCM and placebo solutions differ in appearance. Hence, unblinded study personnel 
not otherwise involved in any study assessments (other than assessment and interpretation 
of post-randomisation laboratory test results) will be responsible for preparing and 
administering the study treatment injections in black syringes and using a curtain (or 
similar) to maintain subject blinding. The unblinded study personnel will ensure that the 
subject is not able to observe the preparation and administration of the study treatment 
injections. The unblinded physician will review the laboratory test results at the 
respective follow-up visits to determine if ID persists and hence the need to administer 
study treatment (or not). 
4.2 
Duration of Subject Participation and Study 
The duration of subject participation is 52 weeks (i.e., 12 months) as of randomisation. 
The end of study is defined as the Last Subject Last Visit. 

 
 
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5. SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 
Number of Subjects 
In total, 1,100 subjects will be randomised from approximately 100 sites. For a detailed 
justification of the sample size please refer to Section 12.2. 
5.2 
Inclusion Criteria 
Investigators must maintain a screening log of all potential study candidates that includes 
limited information about the potential candidate, date, and outcome of the screening 
process (e.g., enrolled into study, reason for ineligibility, or refused to participate). The 
following inclusion criteria must be met for each subject: 
1. Currently hospitalised for an episode of AHF where AHF was the primary reason for 
hospitalisation. All of the following (i.e., items a to d) must apply: 
a. Upon admission for the AHF episode, persistent dyspnoea at rest in a recumbent 
sitting position (30-45°) or with minimal exertion 
b. Upon or during the AHF admission, at least two (2) of the following clinical 
findings were present: 
i. Congestion on chest x-ray 
ii. Rales on chest auscultation 
iii. Oedema ≥1+ on a 0-3+ scale, indicating indentation of skin with mild digital 
pressure that requires 10 or more seconds to resolve in any dependent area 
including extremities or sacral region 
iv. Elevated jugular venous pressure (≥8 cm H2O) 
c. Natriuretic peptide levels, measured ≤72 hours of the AHF admission must have 
been: 
i. Brain natriuretic peptide (BNP) ≥400 pg/mL or NT-proBNP ≥1,600 pg/mL or  
ii. BNP ≥600 pg/mL or NT-proBNP ≥2,400 pg/mL for subjects presenting with 
atrial fibrillation when the blood sample was taken 
iii. For subjects treated with an angiotensin receptor neprilysin inhibitor (ARNI) 
in the previous 4 weeks prior to randomisation only NT-proBNP values should 
be considered 
d. AHF episode treated with minimally 40 mg of IV furosemide (or equivalent IV 
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2. Subject is iron deficient defined as serum ferritin <100 ng/mL or 100 ng/mL ≤ serum 
ferritin ≤299 ng/mL if TSAT <20%. 
3. Left ventricular ejection fraction <50% (assessed and documented within 12 months 
prior to randomisation) 
4. Male or female aged ≥18 years old. 
5. Subject (or legally acceptable representative)* has provided the appropriate written 
informed consent. Subject must provide written informed consent before any 
study-specific procedures are performed. 
*Following section in italics is applicable for The Netherlands only (NL only): 
The option that legally accepted representatives of subjects can sign the written informed 
consent is not valid for sites in The Netherlands. 
5.3 
Exclusion Criteria 
The following exclusion criteria must NOT be present for each subject: 
1. Dyspnoea due to non-cardiac causes such as acute or chronic respiratory disorders or 
infections (i.e., severe chronic obstructive pulmonary disease, acute bronchitis, 
pneumonia, primary pulmonary hypertension). 
2. Temperature >38°C (oral or equivalent), active infective endocarditis, sepsis, systemic 
inflammatory response syndrome, or any other active infection requiring 
anti-microbial treatment at any time during an Index hospitalisation. (Note that it does 
NOT include short-term prophylactic administration of antibiotics or short-term 
temperature elevation at admission which is no longer present at the time point of 
discharge/randomisation). 
3. Documented restricted amyloid myocardiopathy, or acute myocarditis or hypertrophic 
obstructive, restrictive, or constrictive cardiomyopathy. (Note that it does NOT 
include restrictive mitral filling patterns seen on Doppler echocardiographic 
assessments of diastolic function). 
4. Clinical evidence of acute coronary syndrome, transient ischemic attack or stroke, 
within the last 30 days prior randomisation. 
5. Severe valvular or left ventricular outflow obstruction disease needing intervention. 
6. Coronary-artery bypass graft, cardiac resynchronisation therapy device implantation, 
percutaneous intervention (e.g., cardiac, cerebrovascular, aortic; diagnostic catheters 
are allowed) or major surgery that led to significant blood loss, including thoracic and 
cardiac surgery, within the last 3 months prior to randomisation. 

 
 
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7. Subject has a body weight <35 kg at randomisation. 
8. Subject at an immediate need of transfusion or with a Hb <8 g/dL* or with a 
Hb >15 g/dL. 
9. Subjects on treatment for Vitamin B12 and/or serum folate deficiency. Note: Use of 
Vitamin B12 and folic acid as supplement therapy (not for deficiency treatment) is 
permitted. 
10. Subject with a known anaemia not attributed to ID (e.g., other microcytic anaemia) or 
with an evidence of iron overload (e.g., haemochromatosis) or disturbances in the 
utilisation of iron. 
11. Subject has known hypersensitivity to any of the study products to be administered or 
known serious hypersensitivity to other parenteral iron products. 
12. Subject with known severe allergies including drug allergies, history of severe asthma, 
eczema or other atopic allergy and in subjects with immune or inflammatory 
conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis). 
13. History of erythropoietin stimulating agent, IV iron therapy, and/or blood transfusion 
in previous 3 months prior to randomisation. 
14. Oral iron therapy at doses >100 mg/day in previous 4 weeks prior to randomisation. 
Note: Ongoing use of multivitamins containing iron <75 mg/day are permitted. 
15. Currently receiving systemic chemotherapy and/or radiotherapy. 
16. Renal dialysis (previous, current or planned within the next 6 months). 
17. Subject has known active malignancy of any organ system, i.e., clinical evidence of 
current malignancy or not in stable remission for at least 3 years since completion of 
last treatment with exception of non-invasive basal cell carcinoma, squamous cell 
carcinoma of the skin or cervical intra-epithelial neoplasia. 
18. Terminal illness other than HF with expected survival <12 months. 
19. Chronic liver disease (including active hepatitis) and/or alanine transaminase or 
aspartate transaminase above 3 times the upper limit of the normal range. 
20. Subjects with known hepatitis B surface antigen positivity and/or hepatitis C virus 
ribonucleic acid positivity. 
21. Subject previously randomised into this study. Note: Subjects may be rescreened but 
when rescreened, all tests must fall inside the maximum specified screening windows 
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22. Subject is currently enrolled in or has completed any other investigational device or 
drug study <30 days prior to screening, or is receiving other investigational agent(s). 
23. Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast 
feeding. 
24. If of childbearing potential, subject is not using adequate contraceptive precautions. 
Subject must agree to use adequate contraception during the study and for 1 month 
after the last dose of study treatment. A highly effective method of birth control must 
be used. 
25. Subject has a history of drug or alcohol abuse within 2 years prior to screening. 
26. Subject has a significant medical condition(s), anticipated need for major surgery 
during the study, or any other kind of disorder that may be associated with increased 
risk to the subject, or may interfere with study assessments, outcomes, or the ability to 
provide written informed consent or comply with study procedures, in the 
Investigator’s opinion. 
*Following section in italics is applicable for The Netherlands, Spain and Singapore only 
(NL, ES and SG only): 
The lower threshold of Hb values is set to 10 g/dL. 
5.4 
Withdrawal of Subjects 
5.4.1 
Withdrawal of Subjects from Study Drug 
Study drug must be stopped if the subject experiences any kind of hypersensitivity 
reaction related to the study drug during administration. The subject concerned will 
remain under follow-up and the subsequent visits should be performed in accordance with 
the protocol schedule. Whether the subject should receive additional doses of study 
treatment will be discussed with the Medical Monitor and will be decided on a case by 
case basis. If study drug is stopped prematurely for any one subject, the subject concerned 
will not be replaced. 
Subjects may be withdrawn from the study drug if in the opinion of the Medical Monitor 
or the Investigator there would be a risk to the subject’s safety if they received any further 
dose of study drug.  
Following section in italics is applicable for The Netherlands, Spain and Singapore only 
(NL, ES and SG only): 
Subjects enrolled in the study with Hb levels that are falling below the threshold of 
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If study treatment is stopped prematurely for a subject, follow-up for the subject 
concerned should continue in accordance with the protocol schedule. The discontinuation 
of study treatment is mandatory in circumstances that therapies or treatments listed in 
Section 7.7.2 as restricted need to be applied to the subjects for general health reasons. 
Discontinuation of study treatment is also mandatory in the case a subject enrolled into 
the study is getting pregnant (see Section 10.3.3 for reporting instructions). 
The reason for study-drug discontinuation and the date must be recorded on the 
appropriate page of the eCRF. The follow-up of these subjects should continue in 
accordance with the protocol schedule. 
5.4.2 
Withdrawal of Subjects from Follow-up 
Subjects may voluntarily withdraw their participation from the trial at any time without 
having to provide a reason or a subject may be withdrawn from follow-up at the 
Investigator’s discretion if it is in the subject’s best interest. The reason(s), including the 
primary reason for withdrawal from follow-up, if provided by the subject, will be 
recorded in the eCRF. Although a subject is not obliged to give her/his reason(s) for 
discontinuing trial participation prematurely, the Investigator should make a reasonable 
effort to ascertain the reason(s), while fully respecting the subject's rights. If the subject 
does not wish to provide a reason, the source documents and the eCRF should document 
the reason for discontinuation as “withdrawal by subject”. Whenever possible, the 
Investigator should request the subject to return for a clinic assessment at the time of or 
soon after discontinuation from follow-up. The Investigator is required to make every 
effort possible to follow the subject concerned for survival and hospitalisation after 
discontinuation of follow-up on the condition that the subject has not withdrawn consent 
to do so. 
If subjects refuse to return to the outpatient clinic for the scheduled visits, all reasonable 
efforts should be made to contact the subject by telephone at the time point of the 
scheduled visits. In such situations and unless the subject withdraws informed consent for 
further participation in the trial, all randomised subjects who withdraw from follow-up 
visits prematurely will continue to be followed for the occurrence events suggestive of the 
study outcomes. 
It is vital to obtain follow-up data on any subject withdrawn because of an AE. In any 
case, every effort must be made to undertake protocol-specified safety follow-up 
procedures. If a subject is discontinued due to an AE, the event should be followed by the 
Investigator through contact with the subject until resolution or stabilisation has occurred. 
All AEs should be followed until resolution, stabilisation or the subject is lost to 
follow-up and cannot be contacted. 
Reasons for discontinuations will be documented in the eCRFs. Subjects who discontinue 
prematurely will not be replaced. 

 
 
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5.5 
Rescreening of Subjects 
A subject can only be randomised once in the AFFIRM-AHF trial. If a randomised 
subject withdraws consent for further follow-up, the subject concerned cannot be 
rescreened. However, a subject who fails to meet the protocol selection criteria and who 
was not randomised during the initial Index hospitalisation may be reconsidered for 
participation during any subsequent hospitalisation for AHF. 
5.5.1 
Subject Rescreening During the Same Index Hospitalisation 
If during the initial Index hospitalisation, the blood test results and/or ejection fraction 
measurement are outside the criteria defined in the study protocol, the diagnostic tests 
may be repeated once during the same Index hospitalisation. If the second blood test 
results and/or second ejection fraction measurement are still outside the limits set by the 
study protocol, the subject will not be eligible to participate. 
5.5.2 
Subject Rescreening 
Subjects determined as being ineligible during the initial Index hospitalisation may be 
rescreened for participation at a subsequent hospitalisation(s) for worsening HF. The 
subject(s) concerned will be considered as a de-novo screening and the subsequent 
hospitalisation for worsening HF will be considered as the Index hospitalisation. The 
subject must sign a new informed consent form (ICF) and will be allocated a new subject 
identification number. The screening and baseline visits must be performed in accordance 
with Table 2 and with Section 5.5.1. 

 
 
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6. RANDOMISATION, BLINDING AND UNBLINDING 
PROCEDURES 
6.1 
Randomisation 
All subjects enrolled must be identifiable throughout the study. The Investigator will 
maintain a list of subject numbers and subject names to enable records to be found at a 
later date. 
Numbered study treatment packs will contain either FCM solution or placebo 
(i.e., normal saline) according to a computer generated randomisation plan. 
Each eligible subject will be randomised to either FCM or placebo using a validated 
centralised procedure (IWRS) that automates the random assignment of treatment groups 
to randomisation numbers. Subject randomisation (1:1) will be determined by a 
minimisation algorithm including a random variable and accounting for the following 
stratification factors: sex, age (<70 years/≥70 years), HF aetiology (ischemic/ 
non-ischemic), HF duration (newly diagnosed at Index hospitalisation/known 
documented HF prior to Index hospitalisation), country and centre. The system will 
allocate study treatment pack number(s) which should be used for the subject concerned. 
Details on how to randomise a subject will be found in the respective user manual. 
The randomisation plan will be kept strictly confidential, accessible only to authorised 
persons, until the time of unblinding. If a subject discontinues from the study, neither the 
subject identification number nor the allocated study treatment pack numbers will be 
reused, and the subject will not be allowed to be re-randomised in the study. 
6.2 
Blinding 
This is a double-blind trial with randomisation concealment and neither the Investigator, 
the subject nor Sponsor (or representative) will be aware of the administered study 
treatment to each subject. The Vifor Pharma Safety Department will have access to the 
randomisation codes as will investigational sites should the need to unblind a subject arise. 
As the FCM and placebo solutions differ in appearance and the study treatment boxes will 
not be blinded, unblinded study personnel not involved in any study assessments (other 
than assessment and interpretation of post-randomisation laboratory test results) will be 
responsible for handling the study treatment boxes, and preparing and administering the 
study treatment injections in black syringes and using a curtain (or similar) to maintain 
subject blinding. Unblinded personnel will make sure the subject is not able to observe 
the preparation of study treatment injections. 
Post-baseline iron values should be seen only by the unblinded study physician, who will 
then be responsible for evaluating the parameters. This physician must review the 
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6.3 
Unblinding 
In an emergency situation where knowledge of a subject’s study treatment allocation must 
be present in order to determine the further medical management of the subject concerned, 
or if knowledge of a subject’s treatment allocation is required for safety regulatory 
reporting purposes, the blinded Investigator or the Sponsor pharmacovigilance officer, 
respectively (as appropriate) will have access to the study treatment code for the subject 
concerned via the secure, web-based trial-specific treatment allocation system. 
Instructions for access (which is password protected) and use may be found in the 
respective user manual. All information (i.e., the name of the person who has accessed the 
treatment code, the reason, date and time and subject for whom the code was accessed) 
concerning study treatment code access will be tracked and stored in the web-based 
system. 
If a study treatment code is broken, the subject concerned must discontinue study 
treatment. Further medical management is at the discretion of the Investigator. However, 
clinical status permitting, all remaining planned outpatient clinic visits and telephone calls 
must be completed in accordance with the protocol schedule unless the subject refuses 
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7. STUDY TREATMENTS 
7.1 
Dosage Forms/Formulation 
All investigational medicinal products to be used in this study have been manufactured in 
accordance with current Good Manufacturing Practice (GMP). FCM will be provided by 
Vifor Pharma. 
7.1.1 
Formulation of Ferric Carboxymaltose 
Active Ingredient: 
Ferric carboxymaltose 
Strength: 
Sterile FCM solution as a 5% weight/volume (w/v) iron solution in 
water for injection 
Excipients: 
Sodium hydroxide, hydrochloric acid, water for injections 
Appearance: 
Dark brown, non-transparent aqueous solution 
Dosage Form: 
10 mL vials containing 500 mg iron per vial 
Manufacturer: 
Vifor Pharma – Vifor (International) Inc., Switzerland 
Storage: 
As indicated on the label 
7.1.2 
Formulation of Normal Saline 
Normal saline will be provided by Vifor Pharma for this study. 
Active Ingredient: 
NaCl (normal saline) 
Strength/packaging: 10 mL container with 10 mL normal saline 
Excipients: 
Water for injections 
Appearance: 
Clear aqueous solution 
Dosage Form: 
0.9% w/v NaCl as sterile solution in water for injections 
Manufacturer: 
B. Braun Melsungen AG 
Storage: 
As indicated on the label 
7.2 
Study Treatment Dosage and Administration 
7.2.1 
Treatment Arms 
Eligible subjects will be randomised (1:1) to either FCM or placebo using a validated 
centralised procedure (IWRS). 

 
 
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7.2.2 
Dosing and Administration Guidelines 
The dose of study treatment to be administered will be determined using the subject’s 
body weight and Hb values based on a repletion and maintenance dosing scheme. 
Subjects will be administered study treatment as an undiluted bolus IV injection - a 
10-mL vial of FCM contains 500 mg iron. The individual dose requirements (in mL) per 
visit are detailed in Table 1. The doses of study treatment administered at Visits 2 and 3 
are considered the repletion phase and any subsequent administrations (if ID persists) will 
be considered the maintenance phase. All administrations, including duration of injection, 
will be documented in the site source data and in the eCRF. Each administration of study 
treatment will be documented in the treatment accountability log kept by the unblinded 
person on site. 
The IV bolus injection will be done using a black syringe. A curtain (or similar) will be 
used in addition to ensure that blinding of the subject is maintained. Injections will have a 
volume of 20 mL (1,000 mg iron or normal saline) or 10 mL (500 mg iron or normal 
saline) depending on the subject’s Hb value and body weight. 
In case a site has local regulations that prevent the use of a black syringe then the 
investigational site needs to provide an alternative acceptable procedure that will maintain 
the blind, whilst satisfying their local procedures. This alternative procedure must receive 
approval by the Sponsor on a site-by-site basis. 
The following describes the procedure for the preparation and administration of study 
treatment. 
7.2.2.1 
Preparation of Study Treatment 
Study treatment must be prepared by an unblinded member of the site study team using 
black syringes. The volume of study treatment to administrate must follow the 
instructions in Table 1. When preparing the FCM solution, the vials should be visually 
inspected for sediment and damage before use and only those containing sediment-free, 
homogeneous solution should be used. Once prepared, study treatment should be 
administered immediately thereafter. 
7.2.2.2 
Administration of Ferric Carboxymaltose and Placebo 
Study treatment should only be administered when staff trained to evaluate and manage 
anaphylactic reactions is immediately available, in an environment where full 
resuscitation facilities can be assured. 
Unblinded study personnel will administer study treatment. He/she should apply 
tourniquet, identify a suitable vein, disinfect the injection site and perform the venous 
puncture. It is recommended to use a blue catheter 22 G or pink catheter 20 G and secure 
it with duct tape. The use of blue butterfly needle is possible but a curtain (or similar) 
must be used to maintain blinding of the subject during the administration of study 
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After the venous puncture is performed, the correct positioning of the needle (within the 
vein) can be checked by flushing with 10 mL NaCl 0.9%. Thereafter, the study personnel 
should then connect the syringe containing the study treatment to the needle and slowly 
inject the study treatment over at least 5 minutes for the 500 mg dose and over at least 
15 minutes for the 1,000 mg dose). 
After administration, the vein should then be flushed with 5-10 mL saline. Each subject 
should be observed for adverse effects for at least 30 minutes following each injection. 
Since FCM has a physiological pH, pain at the injection site is unlikely, therefore caution 
should be exercised to avoid paravenous injections. The choice of an appropriate needle 
(i.e., a blue catheter 22 G or pink catheter 20 G) for the IV access should minimise the 
potential risk of a paravenous injection of FCM or placebo. 
The administration of study treatment should be discontinued immediately if swelling 
(paravenous injection) is observed at or around the injection site which can cause 
irritation and a brown discolouration of the skin which can be long-lasting. Please refer to 
Section 7.6 for more details. No rinsing or pressure bandage should be used, in order to 
prevent distribution and extension of extravasations. 
7.3 
Package and Labelling 
Study drug will be supplied to each site already packaged and labelled. The packaging 
and labelling of study treatment will be performed according to GMP and GCP (Good 
Clinical Practice). In addition, the content of the labels to be affixed on the study 
treatment packs will be in accordance with local regulations for clinical trials. Each study 
treatment pack and its content will be identified by a treatment number. Once allocated to 
a subject, the content from a specific study treatment pack should not be used for another 
subject.  
7.4 
Study Treatment Allocation 
Each eligible subject will be randomised to either FCM or placebo using a secure 
validated centralised (IWRS) system. The system will allocate a study treatment pack 
number which should be used for the subject concerned. Details how to randomise a 
subject will be found in the respective user manual. Numbered study treatment packs will 
contain either FCM solution or placebo (normal saline) according to a computer 
generated randomisation plan. 
7.5 
Site Supply, Storage, Accountability 
7.5.1 
Site Supply 
Once a site has been approved to receive study treatment, the site will be supplied with an 
initial stock of study treatment. The need for treatment resupply will be assessed on a 
regular basis taking into account the number of subjects enrolled, and the number of 
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7.5.2 
Storage 
Study treatment must be stored in a locked and temperature controlled area. Each site 
should have a thermometer that records minimum and maximum temperatures daily. 
Maintenance of a temperature log is mandatory. The log should be updated by site 
personnel daily. This log must be available for review by the Monitor during on-site 
monitoring visits. 
7.5.3 
Accountability 
The unblinded study personnel at each site is responsible for study treatment supplies. 
The study personnel will ensure that adequate records of the receipt, preparation, 
administration and return of the study treatment are kept and that the study treatment is 
used only for subjects enrolled in the study. All data regarding the study treatment 
(including kit and batch numbers) must be recorded in the eCRF and on any other 
relevant forms provided. 
Each study site will maintain a treatment inventory/dispensing record for all treatments 
dispensed and returned. At the end of the study, 1 copy of the treatment 
inventory/dispensing record should be sent to the Sponsor for the central study file. The 
original will be kept in the site files. 
After completion of the study, or if it is prematurely terminated, all unused materials will 
be returned to the Sponsor. The decision to destroy study treatment at site must be made 
by the Sponsor. If the study treatment is destroyed at site, the Investigator will forward 
the certificate of destruction to the Sponsor. 
7.6 
Study Treatment Dose Modification 
If extravasation is noted during administration of study treatment, the administration 
should be ceased immediately. Study treatment administration may be completed using a 
different injection site to complete the required dosage. 
7.6.1 
Procedures for Overdose 
If an inadvertent overdosing of a subject (e.g., by a calculation error of the required iron 
dose) is detected, this will be reported as a special situation. If associated with any 
signs/symptoms, this will be reported as an AE (see Section 10). 
Post-baseline iron parameters will be assessed by the unblinded Investigator at each visit 
using the local laboratory. In the case of iron accumulation the Investigator at the site will 
initiate corrective measures according to local guidelines for treatment of iron overload. 
7.7 
Prohibited Therapy and Concomitant Treatment 
All medications and treatments prescribed for a subject at the time of or during screening, 
and all additional medications or dose changes made during follow-up, are considered to 
be concomitant treatments. In addition, all treatments prescribed up to at least 3 months 

 
 
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prior to informed consent must also be documented in the eCRF, irrespective if the 
treatment is still on-going or not. This includes the treatments prescribed to treat the AHF 
episode during the Index hospitalisation. 
7.7.1 
Basic Regimen 
In this trial, study treatment (i.e., FCM or placebo) is given in addition to the basic HF 
treatment regimen. Anti-coagulants and/or platelet aggregation inhibiting drugs may be 
used according to local routine. No trial-specific dietary requirements are mandated by 
the protocol and other medications to treat concurrent diseases can be prescribed as 
required provided that the restrictions given in Section 7.7.2 are adhered to. 
As of randomisation, the aim should be to keep the prescribed basic regimen for HF as 
stable as the subject’s clinical presentation permits over the 52-week follow-up period. 
However, if symptoms or signs develop which suggest a worsening of HF, the 
management and treatment of subjects is at the discretion of the Investigator. 
Any other clinically relevant diagnosis or finding(s) which develops or worsens during 
the subject’s participation in the trial may be treated as indicated, provided that the 
restrictions given in Section 7.7.2 are observed. Any new clinically relevant symptom, 
diagnosis or finding must be reported as an event on the appropriate SAE or AE report 
form (see Section 10). 
7.7.2 
Concomitant Treatment Restrictions 
The following therapies or treatments must not be given, or must not be performed, 
concurrently with study treatment (if needed, subject has to be withdrawn from study 
treatment): 
• Immunosuppressive or myelosuppressive therapy 
• Erythropoietin 
• Oral or IV iron therapy (other than study medication). Note: Ongoing use of 
multivitamins containing iron <75 mg/day are permitted. 
• Blood transfusion 
• Surgery that may result in significant blood loss (>100 mL or >1 g/dL Hb) 
• Renal dialysis 
• Heart transplant 
7.7.3 
Treatment in the Case of an Emergency 
The Investigator is responsible for ensuring that appropriate processes, procedures and 
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Medical emergencies should be treated according to local routine. Continuation of the 
study treatment is at the discretion of the Investigator beside in cases of an emergency 
that involves any kind of hypersensitivity reaction related to the study drug during 
administration. The latter case will be discussed with the Medical Monitor and a case by 
case decision will be made, whether the subject should receive additional doses of study 
treatment (Section 5.4.1). The guidelines and restrictions given in Section 7.7.2 must be 
adhered to as long as the subject is still on study treatment. 
An emergency situation constitutes an immediately reportable SAE (see Section 10). 

 
 
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8. RISKS/PRECAUTIONS 
8.1 
IV Iron Risks  
Parenterally administered iron preparations can cause hypersensitivity reactions including 
anaphylactoid reactions, which may be fatal. Therefore, facilities for cardiopulmonary 
resuscitation must be available. If allergic reactions or signs of intolerance occur during 
administration, the treatment must be stopped immediately. Hypersensitivity reactions 
have been reported after previously uneventful doses of any parenteral iron complexes, 
including FCM. Each subject should be observed for adverse effects for at least 
30 minutes following administration of the study treatment. 
In subjects with liver dysfunction, parenteral iron should only be administered after 
careful benefit/risk assessment. Parenteral iron administration should be avoided in 
subjects with hepatic dysfunction where iron overload is a precipitating factor, in 
particular porphyria cutanea tarda. Careful monitoring of iron status is recommended to 
avoid iron overload. 
Parenteral iron must be used with caution in cases of acute or chronic infection, asthma, 
eczema or atopic allergies. It is recommended that the administration of FCM be stopped 
in subjects with ongoing bacteraemia. In subjects with chronic infection, a benefit/risk 
evaluation has to be performed, taking into account the suppression of erythropoiesis (due 
to chronic infection). 
Paravenous leakage must be avoided because leakage of FCM solution at the injection 
site may lead to irritation of the skin and potentially long-lasting, brown discolouration at 
the site of injection. In the event of paravenous leakage, administration of FCM must be 
stopped immediately. Study treatment administration may be completed using a different 
injection site to complete the required dosage. 
8.2 
Ferric Carboxymaltose 
One mL of undiluted FCM solution contains up to 5.5 mg (0.24 mmol) of sodium. This 
has to be taken into account in subjects on a sodium-controlled diet. 
To date, over 7,300 subjects have received FCM in completed clinical studies. The most 
commonly reported ADRs that have occurred in between 1% and 10% of subjects were 
headache, dizziness, hypertension, nausea, injection site reactions, flushing and 
hypophosphataemia. No reported ADRs were very common (≥10%). 
Please refer to the Investigator’s Brochure for full list and description of risks and 
precautions. 
8.3 
Sodium Chloride (NaCl 0.9%) 
One mL of NaCl 0.9% solution contains 9 mg (0.39 mmol) of sodium. This has to be 
taken into account in subjects on a sodium-controlled diet. 

 
 
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9. STUDY PROCEDURES 
9.1 
Description of Study Assessments 
The visit schedule and procedures to be carried out at each visit are shown in the flow 
chart (see Table 2). 
9.2 
Schedule of Assessments 
For a detailed schedule of assessments (including all protocol required assessments, visits 
and visit windows) please refer to Table 2. 
9.2.1 
Screening Procedures 
9.2.1.1 
Screening Visit 
The AHF hospitalisation will be considered as the Index hospitalisation. The screening 
visit will be performed in-hospital. The following will be done at the screening visit: 
• Obtain written informed consent from potentially eligible subjects and complete 
subject demographics. 
The Investigator will obtain written informed consent from potentially eligible 
subjects before any trial-related procedure is performed. The informed consent 
information in addition to the subject demographics will be reported in the eCRF. 
• A blood test which will be analysed locally will be performed to determine if the 
subject is iron deficient and if the Hb ≥8 g/dL* and ≤15 g/dL. The assays to be 
performed are: serum ferritin, TSAT and Hb. In addition, serum phosphorus levels 
analysed locally from the same blood draw will be documented in the eCRF. 
*Following section in italics is applicable for The Netherlands, Spain and Singapore 
only (NL, ES and SG only): 
The lower threshold of Hb values is set to 10 g/dL. 
• During the same blood draw, a serum pregnancy test will be taken for females of 
childbearing potential. 
• The date when the blood tests were performed will be reported in the eCRF. 
• If available in the subject clinical records within the Index hospitalisation, the latest 
serum creatinine value measured before randomisation will be collected.  
• The Investigator will review the main eligibility criteria to determine the potential 
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• As of the signing of informed consent for each subject, AEs and changes/additions 
made to concomitant medications must be documented in the eCRF. Serious adverse 
events will be reported as they occur but no later than 24 hours after the Investigator’s 
awareness of the event. 
9.2.1.2 
Baseline Visit, Randomisation and Administration of the First Dose of 
Study Treatment 
The baseline visit will be performed in-hospital for subjects from whom the screening 
visit blood test results confirm ID and Hb ≥8 g/dL* and ≤15 g/dL. For females of 
childbearing potential, the serum pregnancy test must be negative.  
*Following section in italics is applicable for The Netherlands, Spain and Singapore only 
(NL, ES and SG only): 
The lower threshold of Hb values is set to 10 g/dL. 
The following assessments will be performed for the baseline visit: 
• Completion of the self-administered KCCQ-12 and European quality of life – 5 
dimensions questionnaire (EQ-5D) (see Section 9.2.3.10) 
• Physical examination (see Section 9.2.3.2) 
• Recording of body height and weight (see Section 9.2.3.3) 
• Recording of vital signs (i.e. seated blood pressure, pulse rate, and rhythm (see 
Section 9.2.3.3) 
• 12-lead electrocardiogram (ECG) (see Section 9.2.3.7) 
• Recording of the appropriate medical history (see Section 9.2.3.1) 
• Assessment of symptoms and signs related to HF (see Section 9.2.3.5) 
• Assessment of NYHA class (see Section 9.2.3.6) 
• Documentation of prior and current concomitant treatments (see Section 9.2.3.8) 
• Check for the occurrence of AEs since the signing of informed consent (see 
Section 10) 
• Final review of inclusion/exclusion criteria and confirmation of eligibility (see 
Sections 5.2 and 5.3) 
• Randomisation (see Section 9.2.3.12) 

 
 
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• Blood sampling for biomarkers in a subset of subjects (see Section 9.2.3.11) 
• Prepare and administer first dose of study treatment (see Section 9.2.3.13) 
• Hand-out subject identification card at hospital discharge 
• Provision of the self-administered questionnaire (KCCQ-12) for completion at 
Telephone Call 1 (Week 2) and Telephone Call 2 (Week 4) 
9.2.2 
Post-randomisation Visits 
9.2.2.1 
Outpatient Clinic Visits 
All subjects will be followed for a maximum of 52 weeks (after randomisation). During 
the follow-up phase, subjects will come to the outpatient clinic at Week 6 (Visit 3), 
Week 12 (Visit 4), Week 24 (Visit 5) and Week 52 (Visit 6) after randomisation.  
Note: due to the COVID-19 pandemic situation the Investigator can perform the 52 week 
visit (Visit 6) via remote methods (such as phone calls, video calls, etc.) to ensure 
collecting at a minimum subject’s health status, AEs and concomitant medications. 
The following will be done during the outpatient clinic visits: 
• At Week 6 (Visit 3) and Week 52 (Visit 6) only: Collect the self-administered (paper) 
questionnaires (KCCQ-12 and EQ-5D) completed by the subject at Week 2, Week 4 
and at Week 36 respectively 
• Completion of the self-administered KCCQ-12 (see Section 9.2.3.10) 
• Completion of EQ-5D at Week 6 (Visit 3), Week 24 (Visit 5) and Week 52 (Visit 6) 
(see Section 9.2.3.10) 
• Assessment of symptoms and signs related to HF (see Section 9.2.3.5) 
• Assessment of NYHA class (see Section 9.2.3.6) 
• Body weight (see Section 9.2.3.3) 
• Vital signs (i.e., seated blood pressure, pulse rate and rhythm) (see Section 9.2.3.3) 
• Documentation of changes made to/additions of concomitant treatments (see 
Section 9.2.3.8) 
• Blood test to determine if ID persists. The following assays should be performed: 
serum ferritin, TSAT and Hb. In addition, serum phosphorus levels analysed locally 
from the same blood draw will be documented in the eCRF (see Section 9.2.3.11). 

 
 
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• Serum pregnancy test (except at Week 52 (Visit 6) for females of childbearing 
potential (see Section 9.2.3.11) 
• Blood test for biomarkers at Week 6 (Visit 3), Week 24 (Visit 5) and Week 52 
(Visit 6) in a subset of subjects (see Section 9.2.3.11) 
• At Week 6 (Visit 3) only: Administer the repletion dose of study treatment based on 
the iron need as assessed at the baseline visit. Dosing only in subjects for whom Hb at 
Week 6 (Visit 3) ≤15 g/dL and if serum pregnancy test is negative in women of 
childbearing potential (see Section 9.2.3.13) 
• At Weeks 12 (Visit 4) and 24 (Visit 5) only: Administer study treatment ONLY if ID 
persists and Hb ≥8 g/dL* and ≤15 g/dL and serum pregnancy test negative for women 
of childbearing potential (see Section 9.2.3.13) 
*Following section in italics is applicable for The Netherlands, Spain and Singapore only 
(NL, ES and SG only): 
The lower threshold of Hb values is set to 10 g/dL. 
• Assessment of and reporting of events suggestive of the study outcomes (see 
Section 9.2.3.14) 
• 12-lead ECG at Week 52 (Visit 6) only (see Section 9.2.3.7) 
• Physical examination at Week 52 (Visit 6) only (see Section 9.2.3.2) 
• Check for the occurrence of AEs. Document the events accordingly (see Section 10) 
• At Week 24 (Visit 5) only: Provision of the self-administered questionnaire 
(KCCQ-12) for completion at Week 36 (Telephone Call 3) 
• If ID persists at Week 52 (Visit 6), subjects should be treated in accordance with local 
routine/standard care 
9.2.2.2 
Refusal of Subjects to Come to the Outpatient Clinic Visits 
If subjects refuse to come in person to the outpatient clinic visit, at the very least, they 
should be contacted by telephone to ascertain whether they have experienced a 
deterioration of their disease, if they were hospitalised since the last visit and whether the 
subject experienced any other AE. In case of a deterioration of the subject’s clinical status, 
the subject will be asked to consult the investigational site personally for further 
investigations and/or further treatment. The outcome/findings of the telephone call will be 
documented in the subject’s source data and in addition, the required data will be entered 
in the eCRF. If the subject reports a hospitalisation, the Investigator must verify this 
information and must report the SAE as per the protocol requirements (see Section 10). 

 
 
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9.2.2.3 
Telephone Contact 
The site will contact the subject by telephone at Week 2 (Telephone Call 1), Week 4 
(Telephone Call 2), and Week 36 (Telephone Call 3), after randomisation to enquire 
about the subject’s health status and enquire if the subjects experienced a deterioration of 
their condition or if they were hospitalised since the last visit contact and/or if there were 
changes made to their concomitant treatments. The latter will be reported in the eCRF. 
The subjects will be requested to complete the KCCQ-12 questionnaire at home on the 
same day as the Week 2, Week 4 and Week 36 telephone call. The subjects will be 
instructed to return the completed questionnaires at the following outpatient clinic visit. 
Adverse events will also be reported in the eCRF. If the subject reports a hospitalisation, 
the Investigator must report the SAE as per the protocol requirements (see Section 10). 
9.2.2.4 
Extra Visits 
Subjects may be seen at the out-patient clinic for a medical reason related to the 
AFFIRM-AHF trial outside the scheduled visits defined by the protocol. Data collected 
during such visits will be recorded on the Unscheduled Visit eCRFs designed for this 
purpose. If the reason for performing an extra visit constitutes a (serious) AE, this 
information must be documented as an event (see Section 10). 
9.2.2.5 
Premature Termination of Follow-up 
Subjects who withdraw informed consent for further follow-up prior to Week 52 (Visit 6), 
should be requested to return to the outpatient clinic as soon as possible after the date 
when the informed consent was withdrawn. The assessments as shown in Table 2 should 
be performed and reported in the eCRF. 
9.2.3 
Clinical and Laboratory Assessments 
9.2.3.1 
Medical History 
A medical history will be taken during the baseline visit. Information to be collected will 
include the aetiology of HF, the date when HF was first diagnosed, and other clinically 
relevant past and present medical conditions which were diagnosed/occurred up to at least 
12 months prior to signing the informed consent and/or for which the subject is currently 
treated. Any medically important conditions sustained by the subject which extend 
beyond 12-months prior to informed consent, should also be reported in the medical 
history eCRF. If available in the subject clinical records within the Index hospitalisation, 
the latest serum creatinine value measured before randomisation visit will be collected.  
9.2.3.2 
General Physical Examination 
A routine general physical examination must be performed at the baseline visit and at 
Week 52 (Visit 6). Any clinically relevant abnormalities or findings must be recorded in 
the baseline visit section of the eCRF. Any new clinically relevant finding as assessed by 
the Investigator, must be reported as an AE (see Section 10). 

 
 
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9.2.3.3 
Body Height, Weight 
Body height (in cm, without shoes) must be measured at the baseline visit only. Body 
weight must be measured in underwear or light clothing without shoes. The same 
calibrated scale must be used throughout the trial. Any new clinically relevant change in 
body weight must be reported as an AE (see Section 10). 
9.2.3.4 
Vital Signs 
The subject’s seated systolic and diastolic blood pressure in addition to pulse rate and 
rhythm must be measured after at least 10 minutes of rest. If blood pressure is measured 
manually, the diastolic blood pressure must be read at the disappearance of sounds 
(Korotkoff Phase V). If the disappearance of sound is not detectable, Korotkoff Phase IV 
should be used for manual measurements; care must be taken not to miss a “silent gap”. 
Any new clinically relevant change as assessed by the Investigator, in blood pressure 
readings, pulse rhythm or rate must be reported as an AE (see Section 10). 
9.2.3.5 
Symptoms and Signs of Heart Failure 
The Investigator must assess the following HF symptoms: 
• Dyspnoea on exertion, 
• Dyspnoea at rest while sitting, 
• Orthopnoea, and paroxysmal nocturnal dyspnoea. 
The Investigator must assess the following clinical signs for HF: 
• Peripheral oedema, 
• Pulmonary congestion (crackles, rales), 
• Liver enlargement, 
• Presence of a third heart sound (S3 gallop), 
• Jugular venous distension. 
Any new clinically relevant symptom or sign of worsening HF, as assessed by the 
Investigator, must be reported as an AE (see Section 10). 
The HF symptoms and findings which are part of the inclusion criteria must be 
documented in the Source Data (see Section 5.2). 
9.2.3.6 
New York Heart Association Functional Classification 
NYHA functional classification [34] will be done using the classification as shown 
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Table 3 
New York Heart Association Classification 
Class 
Description 
Class I  
Patients have cardiac disease but without the resulting limitations of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea, or anginal 
pain. 
Class II 
Patients have cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea, or 
anginal pain. 
Class III  
Patients have cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, 
dyspnoea, or anginal pain. 
Class IV 
Patients have cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may 
be present even at rest. If any physical activity is undertaken, discomfort is increased. 
 
Any new clinically relevant change in the NYHA class as assessed by the Investigator, 
must be must be reported as an AE (see Section 10). 
9.2.3.7 
12-lead Electrocardiogram 
A 12-lead ECG must be performed at baseline and Week 52 (Visit 6). A scanned image 
of the ECG will be uploaded in the eCRF. 
At baseline, the Investigator must document clinically relevant ECG findings on the 
appropriate Baseline eCRF pages and in the subject’s hospital records. Any new clinically 
relevant ECG finding or aggravation/worsening of an already existing finding as assessed 
by the Investigator, must be reported as an AE (see Section 10). 
9.2.3.8 
Documentation of Concomitant Treatments 
All medications and treatments prescribed at the moment of informed consent must be 
documented on the appropriate eCRF pages. In addition, treatments prescribed up to at 
least 3 months prior to obtaining the informed consent must be documented on the 
appropriate eCRF pages, irrespective if the treatment is still ongoing at the time of 
screening. This includes the recording in the eCRF of all medications/treatments 
prescribed for the AHF episode. 
All changes to or addition of concomitant treatments as of informed consent must be 
recorded (including changes in dose, change in formulation, starting or stopping 
medications) in the eCRF. If the indication for changing a subject’s concomitant 
treatment constitutes a new medical condition or a worsening of an existing clinical 
condition which is considered by the Investigator as being clinically relevant, the 
indication must be documented as an AE (see Section 10). 
9.2.3.9 
Final Review of the Inclusion/Exclusion Criteria 
Before randomising the subject, the Investigator must ensure that all of the inclusion 
criteria are present and that none of the exclusion criteria are present. 

 
 
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9.2.3.10 
Health-related Quality of Life 
KCCQ-12 – Kansas City Cardiomyopathy Questionnaire 
Health-related quality of life (HRQoL) will be assessed using the validated KCCQ-12. 
The KCCQ-12 is a self-administered, disease-specific instrument for measuring HRQoL 
in subjects with HF regardless of aetiology. It is a 12-item questionnaire that quantifies 
physical function, symptoms (frequency, severity and recent change), social function, 
self-efficacy and knowledge, and QoL [35]. Validated official translations in the local 
language versions will be used. The subject should complete the paper-based KCCQ-12 
before any other assessment or procedure for the visit concerned is performed. The 
subject should complete the questionnaires in a quiet environment. 
Source data verification will be performed for paper-based questionnaires. Once 
completed by the subjects, data will be entered into the eCRF by site staff. The manual of 
operations will detail how the data flow will be handled. 
EQ-5D – European Quality of Life – 5 Dimensions 
The EQ-5D questionnaire is a brief, utility-based generic HRQoL instrument. It consists 
of a health descriptive system and a visual analogue scale (VAS) for respondents to 
self-classify and rate their health status on the day of administration of the instrument. [36] 
The descriptive system has 5 items/dimensions (i.e. mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression). The VAS is a vertical, graduated (0-100 points) 
20 cm “thermometer”, with 100 at the top representing “best imaginable health state” and 
0 at the bottom representing “worst imaginable health state”. The VAS records the 
respondent’s self-rated health on a 20 cm vertical, VAS with endpoints labelled “the best 
health you can imagine” and “the worst health you can imagine”. This information can be 
used as a quantitative measure of health as judged by the individual respondents. 
Validated official translations in the local language versions will be used. The subject 
should complete the paper-based EQ-5D after the KCCQ-12 but before any other 
assessment or procedure for the visit concerned is performed. The subject should 
complete the questionnaires in a quiet environment. 
Source data verification will be performed for paper-based questionnaires. Once 
completed by the subjects, data will be entered into the eCRF by site staff. The manual of 
operations will detail how the data flow will be handled. 
9.2.3.11 
Laboratory Tests Mandated by the Study Protocol 
The laboratory tests mandated by the trial protocol to be transferred into the eCRF will be 
analysed locally. The assays to be performed are Hb, serum ferritin, TSAT, serum 
phosphorus and serum pregnancy tests in females of childbearing potential. 
If available in the subject clinical records within the Index hospitalisation, the latest 
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Iron status blood test reports and serum phosphorus levels received after randomisation 
must be provided directly to the unblinded Investigator. This person must enter the results 
in the eCRF page provided for this purpose. 
In addition, blood samples for biomarkers will be taken in a subset of subjects. The 
baseline biomarker blood sample will be drawn just prior to the injection of study 
treatment. Blood samples will be stored for up to three years after the end of the trial for 
future analyses of biomarkers of scientific interest. Details concerning the blood samples 
storage will be provided in an instruction manual and results of these exploratory analyses 
will be not part of the clinical study report of the main study. 
9.2.3.12 
Randomisation 
Upon completion of the baseline visit procedures/assessments, eligible subjects will be 
randomised using a validated centralised procedure (IWRS) to either FCM or placebo. 
Study treatment must be administered on the same day as randomisation. To 
accommodate local hospital practice, the first dose of study treatment may be 
administered either on the same day or the day before the planned discharge day. Note 
that a planned overnight stay following study treatment administration does NOT fulfil 
the criteria of an SAE unless there is a medical reason for doing this. The randomisation 
system will allocate the study treatment pack number(s) which should be used for the 
subject concerned. 
9.2.3.13 
Administration of Study Treatment 
The unblinded Investigator will determine the dose of study treatment to be administered 
as shown in Table 1. After administration of the first dose of study treatment by the 
unblinded study personnel, each subject should be observed for adverse effects for at least 
30 minutes following each injection of study treatment. Thereafter, at the discretion of the 
Investigator, subjects may then be discharged from hospital (i.e., following the Index 
hospitalisation) and for the follow-up visits, may leave the outpatient clinic at the 
discretion of the Investigator. The complete details concerning the study drug 
administration procedures will be detailed in the manual of operations. 
9.2.3.14 
Reporting of Events Suggestive of the Study Outcomes 
Reported AEs will be assessed to determine if they are suggestive of the study outcomes 
– this includes emergency room admissions and unscheduled outpatient clinic visits to 
treat worsening HF. For such events, the sites will be requested to provide additional 
information and source documentation (e.g., discharge letters, laboratory/investigational 
test results) concerning the event which will be used by the CEC to adjudicate the event 
concerned. All source documentation provided to the CEC will be anonymised. 
9.2.4 
Treatment Procedures 
Details concerning the preparation and administration of study treatment may be found in 
Section 7.2.2. 

 
 
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9.2.5 
Data Which Must be Available in Source Data 
9.2.5.1 
Laboratory Test Results 
The blood test results for assays performed under normal routine and/or during the Index 
hospitalisation and which determine the subject’s eligibility must be available in the 
source data. The assays concerned are: BNP or NT-proBNP performed ≤72 hours of the 
AHF admission (i.e., Index hospitalisation), alanine transaminase and aspartate 
transaminase. The BNP or NT-proBNP value used to determine eligibility will be 
documented in the eCRF. 
Any new clinically relevant changes, as assessed by the Investigator, in laboratory tests 
performed under normal routine during the follow-up period of the trial must be reported 
as an AE (see Section 10). The results of the laboratory tests concerned must be available 
in the source data. 
9.2.5.2 
Symptoms and Clinical Findings Relating to Heart Failure 
The symptoms and signs with which the subject presented at the Index hospitalisation 
must be documented in the subject’s source data. 
The date for the LVEF measurement used to determine eligibility must be <12 months 
prior the randomisation date. The LVEF may have been measured by echocardiography, 
computerised tomography (CT scan), magnetic resonance imaging (MRI) or ventricular 
gated single-photon emission computed tomography (SPECT) or radionuclide 
angiography (MUGA). 
9.2.6 
End of Treatment Procedures 
Not applicable. 
9.2.7 
End of Study (or Early Discontinuation) Procedures 
Upon completion of the study (i.e., at Week 52 (Visit 6)), or if subject is 
discontinued/withdrawn prior to Week 52 (Visit 6), all assessments should be performed 
as detailed in Table 2 for such scenarios. 

 
 
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10. EVALUATION, RECORDING AND REPORTING OF AES, SAES 
AND SPECIAL SITUATIONS 
10.1 Definitions 
10.1.1 Reference Safety Information 
The Reference Safety Information (RSI) presents the basis for expectedness assessment 
of an adverse reaction for expedited reporting and annual safety reporting, as well as 
surveillance of subject’s safety in a clinical trial by regulatory (and ethic) bodies. In the 
context of this study, the RSI is contained in Appendix 2 of the Investigator’s Brochure. 
10.1.2 Adverse Event 
Any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
10.1.3 Adverse Drug Reaction 
In the pre-approval clinical experience with a new medical product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all noxious and unintended 
responses to a medicinal product related to any dose should be considered ADRs. The 
phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out. 
10.1.4 Unexpected Adverse Event/Adverse Drug Reaction 
An AE/ADR, the nature (i.e., specificity/seriousness/outcome/frequency) or severity of 
which is not consistent with the applicable product information (e.g., Investigator’s 
Brochure for an unapproved investigational product, or Package Insert/Summary of 
Product Characteristics for an approved product). Reports which add significant 
information on the specificity, increase in the rate of occurrence, or severity of a known, 
already documented serious adverse reaction also constitute unexpected events. 
10.1.5 Serious Adverse Event 
A SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (the term life-threatening in the definition of serious refers to an 
event in which the subject was at risk of death at the time of the event; it does not 
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• Requires inpatient hospitalisation or prolongation of existing hospitalisation (unless 
elective surgery (a planned, non-emergency medical procedure)) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event (i.e., medically significant) 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events should also be considered as serious. 
Conversely, some hospitalisations, particularly those which are the result of elective or 
previously scheduled surgery for pre-existing conditions, treatment on an emergency 
outpatient basis not resulting in hospital admission or inpatient hospitalisation for social 
reasons in the absence of any deterioration in the subject’s general condition should not 
automatically be classed as SAEs. Also, a planned overnight stay following study 
treatment administration does NOT fulfil the criteria of an SAE unless there is a medical 
reason for doing this.  
Any worsening of a pre-existing medical condition or any new medical condition that 
meets the above SAE criteria should be considered as an SAE. 
In case of any worsening of a pre-existing medical condition or any new medical 
condition occurring that meets the above SAE criteria should be considered as an SAE. 
Any suspected transmission of any infectious agent via a medicinal product should be 
considered as an important medical event (i.e., medically significant) and therefore 
documented as an SAE. 
The Investigator is encouraged to discuss with the Contract Research Organisation 
(CRO)/Sponsor any AEs for which the issue of seriousness is unclear or questionable. 
10.1.6 Suspected Unexpected Serious Adverse Reaction 
Any ADR that is both serious and unexpected (per the RSI) that, based on the opinion of 
the Investigator or Sponsor, is felt to have a reasonable suspected causal relationship to a 
medicinal product. 
Based on the specific study design and the advanced underlying disease state of the 
recruited subject population, events suggestive of the study outcomes i.e., a 
re-hospitalisation for an episode of acutely decompensated HF or a CV event leading to 
death which occurs after discharge for the Index hospitalisation would automatically 

 
 
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qualify to meet the criteria of seriousness in this study. These events would be reported as 
suspected unexpected serious adverse reactions in cases where there is reasonable 
suspected causal relationship to a medicinal product. 
10.1.7 Special Situations 
The following are defined as special situations: 
• Use of a medicinal product during pregnancy or breastfeeding 
• Medication abuse: the persistent or sporadic, intentional excessive use of study 
medication 
• Medication error: any unintentional error in the prescribing, dispensing or 
administration of a medicinal product during the study 
• Medication misuse: an intentional and inappropriate use of a medicinal product not in 
accordance with the protocol dose, route of administration, and/or the indication(s) 
• Medication overdose: the administration of a quantity of study treatment given per 
administration or per day which is above the protocol maximum permitted dose 
• Occupational exposure: an exposure to a medicinal product for human use as a result 
of one’s professional or non-professional occupation 
• Drug interaction 
• Unexpected therapeutic or clinical benefit from product use 
Suspected adverse reactions associated with medication errors of the investigational 
medicinal product or use outside that foreseen in the protocol (e.g., overdose or misuse) 
are also considered as ADRs. Any special situation occurring with/without ADR/AE shall 
be recorded in the study-specific documentation. 
10.2 AE Descriptors 
10.2.1 Intensity/Severity Categorisation 
The term severe is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); however the event itself may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
serious, which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
In general, the intensity of a particular AE to be recorded is the worst intensity 
experienced by the subject during the course of the event. The medical assessment of 
intensity will be determined by using the following definitions: 

 
 
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Mild: 
The AE is easily tolerated and does not interfere with usual activity. 
Moderate: 
The AE interferes with daily activity, but the subject is still able to 
function. 
Severe: 
The AE is incapacitating and the subject is unable to work or complete 
usual activity. 
10.2.2 Causal Relationship Categorisation 
An Investigator who is qualified in medicine (or dentistry, if appropriate) must make the 
determination of relationship to investigational product for each AE and SAE. The 
Investigator should decide whether, in his or her medical judgement, there is a reasonable 
possibility that the event may have been caused by the investigational product. If there is 
no valid reason for suggesting a relationship, then the AE/SAE should be classified as 
unrelated. Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a cause-and-effect relationship between the investigational product and the 
occurrence of the AE/SAE, then the AE/SAE should be considered certainly, 
probably/likely, or possibly related. For SAEs, the Investigator must provide a brief 
comment explaining the rationale of his/her assessment of causal relationship on the SAE 
form. 
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Certain 
Yes 
• Event or laboratory test abnormality, with plausible time relationship to 
study treatment intake 
• Cannot be explained by disease or other drugs 
• Response to withdrawal plausible (pharmacologically, pathologically) 
• Event definitive pharmacologically or phenomenologically (i.e., an 
objective and specific medical disorder or a recognised pharmacological 
phenomenon) 
• Rechallenge satisfactory, if necessary 
Probable/ 
Likely 
Yes 
• Event or laboratory test abnormality, with reasonable time relationship to 
study treatment intake 
• Unlikely to be attributed to disease or other drugs 
• Response to withdrawal clinically reasonable 
• Rechallenge not required 
Possible 
Yes 
• Event or laboratory test abnormality, with reasonable time relationship to 
study treatment intake 
• Could also be explained by disease or other drugs 
• Information on drug withdrawal may be lacking or unclear 
Unrelated 
No 
• Event or laboratory test abnormality which is clearly related to 
circumstances not connected with the study treatment intake 
 

 
 
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If the causal relationship between an AE/SAE and the investigational product is 
determined to be “certainly, probably/likely, or possibly related”, the event will be 
considered to be related to the investigational product for the purposes of expedited 
regulatory reporting. In circumstances where the Investigator has not provided his/her 
assessment about the relationship, the event will be considered as related and qualify for 
expedited regulatory reporting. 
10.2.3 Outcome Categorisation 
Outcome may be classified 
as: 
recovered/resolved 
(i.e., 
without 
sequelae); 
recovered/resolved with sequelae; recovering/resolving; not recovered/not resolved; fatal; 
or unknown (if follow-up is not possible). 
If the outcome of an SAE is reported as recovered/resolved with sequelae, the 
Investigator should specify the kind of sequelae on the SAE form. If the outcome of an 
SAE is reported as unknown, the Investigator should specify (on the SAE form) the 
rationale why unknown was selected. 
10.2.4 Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the medical history eCRF. A pre-existing medical 
condition should be recorded as an AE only if the frequency, severity, or character of the 
condition worsens during the study. When recording such events on the AE eCRF, it is 
important to convey the concept that the pre-existing condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
10.2.5 Worsening of the Disease Under Study 
Symptoms and signs of the disease under study should not be considered AEs as long as 
they are not regarded as worsening of the clinical features of the disease under study. If a 
sign or symptom of the disease has unexpectedly worsened in severity or frequency or 
changed in nature at any time during the study, the symptoms and signs should be 
recorded as AEs, and clearly marked as worsening of the signs or symptoms in the eCRF. 
10.2.6 Clinical Laboratory Evaluations 
A change in the value of a safety laboratory investigation can represent an AE if the 
change is clinically relevant or if, during treatment with the investigational product, a 
shift of a parameter is observed from a normal value to a pathological value, or results in 
a deterioration of Common Terminology Criteria grade, or a further worsening of an 
already pathological value. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while 
continuing treatment or after the end of treatment with the investigational product, and the 
range of variation of the respective parameter within its reference range, must be taken 
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If, at the end of the treatment phase, there are pathological laboratory values which were 
not present at baseline, further clinical or laboratory investigations should be performed 
until the values return to within reference range or until a plausible explanation 
(e.g., concomitant disease) is found for the pathological laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. If the Investigator considers such an AE as serious (e.g., medically 
significant event fulfilling criteria per Section 10.1.5), it must be reported as an SAE. 
If a laboratory abnormality meeting the above criteria is a sign of a disease or syndrome 
only the diagnosis should be recorded in the eCRF. 
If a laboratory abnormality meeting the above criteria is not a sign of a disease or 
syndrome, the abnormality itself should be recorded in the eCRF, along with a descriptor 
indicating if the test result is above or below the normal range (e.g., “elevated potassium” 
as opposed to “abnormal potassium”). 
If the laboratory abnormality can be characterised by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE. For example, hyperkalaemia 
or hypoglycaemia. Observations of the same laboratory abnormality from visit to visit 
should not be repeatedly recorded in the eCRF, unless the aetiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be 
updated any time the event worsens. 
At the end of the study period, all pathological laboratory findings/values diagnosed 
throughout the treatment period should be reviewed by the Investigator to provide a final 
clinical assessment in view of the dynamic of laboratory changes/abnormalities. 
10.2.7 Abnormal Vital Signs 
Not every vital sign abnormality qualifies as an AE. A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• Accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• Results in a medical intervention or a change in concomitant therapy 
• Clinically significant in the Investigator’s judgment 
It is the Investigator’s responsibility to review all vital sign findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated vital sign 
abnormality should be classified as an AE. 

 
 
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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded in 
the eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded in the eCRF, unless the aetiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be 
updated any time the event worsens. 
10.2.8 Special Situations 
All special situations (see Section 10.1.7) such as study treatment overdose and 
medication errors including injection rate errors have to be documented in the subject’s 
eCRF (investigational medicinal product accountability and special situations pages as 
appropriate) and source documents. All special situations, e.g., overdose, or medication 
errors have to be reported per standard guidelines. 
10.3 Reporting Procedure for AEs, SAEs and Pregnancy 
10.3.1 Adverse Events 
All AEs either observed by the Investigator or one of his/her medical collaborators, or 
reported by the subject spontaneously, or in response to a direct question, will be noted in 
the AE section of the subject's eCRF and source documentation. This applies to all AEs 
regardless of presumed relationship to the study. AEs leading to discontinuation of study 
treatment should also be collected. 
If any AE is reported, the date of onset, relationship to study treatment, any action taken, 
date of resolution (or the fact that it is still continuing or has become chronic), outcome, 
intensity (worst at any point during the event) and whether the AE was serious or not at 
any time during the event will be recorded. In order to establish the duration of any SAE, 
the dates of hospitalisation and discharge or dates of meeting other SAE criteria will be 
recorded in the eCRF. 
Where possible, the Investigator should report a diagnosis rather than individual signs and 
symptoms or abnormal laboratory values. However, if a constellation of signs and/or 
symptoms cannot be medically characterised as a single diagnosis or syndrome at the 
time of reporting, each individual event should be recorded in the eCRF. If a diagnosis is 
subsequently established, all previously reported AEs based on signs and symptoms 
should be nullified and replaced by 1 AE report based on the single diagnosis, with a 
starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis. 
The Investigator should use standard medical terminology/concepts; avoid colloquialisms 
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The AE reporting period begins at the time the ICF is signed by the subject. The AE 
reporting period ends at the last study/follow-up visit (Week 52 – Visit 6). 
AEs that extend continuously, without resolution, between trial assessments should only 
be recorded once in the eCRF. The initial severity of the event should be recorded, and 
the severity should be updated to reflect the most extreme severity any time the event 
worsens. 
AEs that resolve and subsequently recur should have each recurrence recorded separately 
in the eCRF. 
All AEs persisting at the time of study completion will be followed by the Investigator 
through contact with the subject until resolution or stabilisation, or the subject is lost to 
follow-up and cannot be contacted. The outcome must be documented in the subject’s 
source documents. 
If the subject reports an AE, it is the Investigator’s responsibility to acquire sufficient 
information in order to assess causality. This may require additional laboratory testing, 
physical examinations, telephone contacts, etc. 
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, 
such as “How are you feeling?” It is also important to question the subject in a 
non-leading way about changes in their health or concomitant medication usage since 
their last visit. This information should be collected prior to completion of assessments at 
all study visits. In addition, any symptoms/conditions reported during assessments and 
deemed to be clinically significant by the Investigator will be assessed as AEs. 
10.3.2 Serious Adverse Events 
The occurrence of an SAE must be immediately reported to Vifor Pharma (or its delegate; 
e.g., CRO) within 24 hours of awareness. This includes all SAEs (independent of 
relationship to study treatment) occurring from the time the informed consent is signed 
until 30 days following the last study visit or until 30 days after last study drug 
administration, whichever is longer. The final follow-up may be conducted as a telephone 
call rather than a formal visit, but the Investigator must report any SAEs that occur during 
this period. SAEs starting before first administration of study treatment must be identified 
as such.  
A death occurring during the study or which comes to the attention of the Investigator 
within 30 days after the last study visit or until 30 days after the last study treatment 
administration, whichever is longer, whether considered treatment-related or not, must be 
reported to the CRO/Vifor Pharma. 
SAEs must be reported by entering the SAE information into the eCRF. CRO (Worldwide 
Clinical Trial Pharmacovigilance department) will receive notification of the initial SAE 
via an email alert generated from the electronic data capture system. 

 
 
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The electronic SAE form will be completed with the following information at a minimum: 
• Event description/verbatim (including onset date of the SAE, outcome and reason for 
it being considered serious) 
• Relationship to investigational product (i.e., causality) 
• Name of the investigational product (including study treatment dose and 
administration dates) 
• Action taken with the investigational product  
• Severity of the event 
Additional information must be uploaded to the eCRF when available including any 
relevant records (e.g., hospital discharge summary, autopsy report/death certificate, etc.). 
Any supporting information provided should not reveal a subject’s identity beyond the 
agreed study identifier. The Investigator should ensure that information reported is 
accurate and consistent. 
If the Investigator is unable to access the eCRF, the report may be done by facsimile or 
email using the study-specific Vifor Pharma SAE form provided by Vifor Pharma (see 
Appendix 1). The Investigator must complete, sign and date the SAE pages, and verify 
the accuracy of the information recorded on the SAE pages with the source documents. 
The Vifor Pharma SAE form must be completed in capital letters, in medical terms, in 
English and to the best extent possible given the time constraints. Any supporting 
documentation should be sent along with the Vifor Pharma SAE form. 
At a minimum the following should be provided at the time of the initial SAE report: 
• Study name and/or number 
• Subject number, age and sex 
• Event description/verbatim (including onset date of the SAE, outcome and reason for 
it being considered serious) 
• Relationship to investigational product (i.e., causality) 
• Name of the investigational product (including study treatment dose and 
administration dates) 
• Action taken with the investigational product  
• Severity of the event 

 
 
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• Investigator name and address 
• Name of the reporter (including site name or number and country), and 
• Dated signature of the Investigator or Sub-/Co-Investigator 
A safety contact sheet will be provided by the Sponsor to the Investigator (prior to first 
subject providing informed consent) detailing all applicable contact information. This will 
be kept up to date with any changes being provided to the Investigator immediately. 
Pharmacovigilance Department 
Worldwide Clinical Trials 
Fax:
 
Email address: 
 
The SAE information must be entered onto the SAE eCRF as soon as the web-based 
system becomes accessible. 
Follow-up information must be handled in the same way and reported within the same 
time frame as the initial report. 
Where possible, the Investigator should report a diagnosis rather than signs and 
symptoms. 
Death should be considered an outcome and not a distinct event. In case of a fatal 
outcome, the Investigator should provide a working diagnosis (event which caused 
outcome, e.g., death due to fatal myocardial infarction) instead of reporting only death; 
and an autopsy report should be provided where possible. If the cause of death later 
becomes available (e.g., after autopsy), this working diagnosis should be replaced by the 
established cause of death. 
The onset date of the SAE is defined as the date the signs and symptoms/diagnosis 
became serious, i.e., met at least 1 of the International Council for Harmonisation (ICH) 
criteria for seriousness. The resolution date of the SAE is defined as when the symptoms 
resolve, or the event is considered chronic (e.g., sequelae) or stable, and/or if the 
seriousness criteria are no longer applicable. SAEs that are ongoing at the time of death 
are considered unresolved. 
All recorded SAEs, regardless of relationship to investigational product, will be followed 
up until resolution, stabilisation, or the subject is lost to follow-up and cannot be 
contacted. No further updates should be entered into the eCRF after the completion of the 
final safety follow-up period, but should be notified to the CRO/Vifor Pharma using the 
Vifor Pharma SAE form. In circumstances where the Investigator is unable to make 
contact with the subject (or his/her relatives), the Investigator must provide a written 
statement (recorded in the subject’s source documents) to the CRO/Vifor Pharma, 
confirming that the subject is lost to follow-up.  

 
 
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Vifor Pharma, or its delegate, is responsible for expedited reporting to the relevant 
Regulatory Authorities, to Investigators and to local and central Institutional Review 
Board/Ethics Committee/Independent Ethics Committee (IRB/EC/IEC) as per local 
regulations. 
Any SAE considered to have a causal relationship (i.e., related) to the investigational 
product and discovered by the Investigator at any time after the study should be reported. 
A rationale for the assessment of a causal relationship must be provided by the 
Investigator. Any safety information that is obtained after database lock of the clinical 
database will be documented in the safety database and implications for handling the data 
in the clinical database assessed on an individual case basis. 
Additional detail regarding SAE reporting procedures and management is available in the 
study-specific SAE Processing and Reporting Plan, which will be provided in the study 
documentation. 
10.3.2.1 
Elective Surgery/Routine Examination 
Elective surgery (a planned, non-emergency medical procedure) and in-patient routine 
examination for a pre-existing condition (i.e., recorded in the medical history) do not 
qualify as SAEs as long as the procedure was not performed as a result of a worsening of 
the condition. However, AEs which occur during any elective hospitalisation will need to 
be collected and reported. 
10.3.3 Pregnancy 
When a female subject becomes pregnant during the study and study treatment has been 
administered to the subject, the outcome of the pregnancy needs to be monitored and the 
safety of the mother and unborn child need to be safeguarded (as per protocol, pregnancy 
is an exclusion criteria). Therefore, the outcome of all such pregnancies (including normal 
births) must be followed up and documented, even if the subject was withdrawn from the 
study or the study has been completed. 
Women of childbearing potential should have a negative serum pregnancy test prior to 
randomisation. Study treatment should not be initiated by the Investigator until a report of 
a negative pregnancy test has been obtained. 
A highly effective contraception must be used in female subjects of childbearing potential 
before beginning study treatment, during study dosing, and for 30 days following 
discontinuation of study treatment. 
Following sections in italics are applicable for United Kingdom only (UK only):  
Highly effective birth control methods include: 
• Combined (oestrogen and progestogen containing) hormonal contraception 
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− 
Oral 
− 
Intravaginal 
− 
Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
− 
Oral 
− 
Injectable 
− 
Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomised partner 
• Sexual abstinence 
Due to the follow-up of 52 weeks per patient after randomisation in the present study, 
sexual abstinence is only acceptable as ‘true abstinence’ when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of 
exposure to IMP, and withdrawal are not acceptable methods of contraception. 
A female subject must immediately inform the Investigator if she becomes pregnant 
during the study and no further study treatment shall be administered. The Medical 
Monitor must be contacted immediately to break the blind (if applicable). The 
Investigator should counsel the subject and discuss the risks of continuing with the 
pregnancy and the possible effects on the foetus. 
The Investigator/Sponsor is responsible for monitoring the subject and pregnancy 
outcome. Every effort should be made to gather information regarding the pregnancy 
outcome until 90 days postpartum (or otherwise as appropriate). It will be the 
responsibility of the Sponsor, together with the appropriate support of the Investigator, to 
obtain this information. 
Any report of pregnancy recorded for any female subject should be reported to the 
CRO/Vifor Pharma within the same timelines as a SAE, i.e., immediately (within 
24 hours of awareness). The Investigator should complete a Vifor Pharma Report on 
Exposure to Medicines During Pregnancy form (see Appendix 2) and forward to the 
CRO/Vifor Pharma. Complications of pregnancy such as abortion (spontaneous or 

 
 
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induced), premature birth (before 37 weeks gestational age) or congenital abnormality are 
considered SAEs and should be reported using the study-specific Vifor Pharma SAE form. 
All pregnancies occurring in a female subject within 90 days after discontinuation of 
investigational product should be reported within the same timelines as a SAE to the 
CRO/Vifor Pharma. 

 
 
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11. STUDY COMMITTEES 
11.1 DSMB/DMC Procedures 
A DSMB/DMC will be constituted to protect the safety of study participants. A 
DSMB/DMC is a group of independent experts external to a study assessing the progress, 
safety data and, if needed critical efficacy endpoints of a clinical study. Most 
DSMBs/DMCs are composed of clinicians with expertise in relevant clinical specialties 
and at least 1 biostatistician knowledgeable about statistical methods for clinical trials and 
sequential analysis of trial data. For trials with unusually high risks or with broad public 
health implications, the DSMB/DMC may include a medical ethicist knowledgeable 
about the design, conduct, and interpretation of clinical trials. For practical reasons the 
number of members of a DSMB/DMC should be limited. 
The DSMB/DMC will receive blinded eCRF data in the form of tables and listings 
(prepared by an independent statistician), and adjudicate on subject status changes and 
dosing decisions (where appropriate). Where appropriate, the DSMB/DMC may receive 
unblinded data (on a subject level or treatment group level) that should be reviewed in a 
closed session. The data should include, but is not limited to, demographics, subject 
enrolment, baseline characteristics, AE data, SAE data (by severity and causality), 
laboratory data, dose adjustments, protocol adherence, and subject withdrawals. The 
DSMB/DMC will evaluate the progress of the trial, assess data quality and timeliness, 
participant recruitment, accrual and retention, and participant benefit/risk. In addition the 
DSMB/DMC will monitor external factors relevant to the trial, for example scientific and 
therapeutic developments that may affect participant safety or ethical status. Based on the 
observed benefits or adverse effects, the DSMB/DMC will make recommendations to the 
Sponsor concerning continuation, termination or modifications of the trial. 
The Sponsor will establish a charter document explaining the working procedures and 
responsibilities of the DSMB/DMC. The charter should be agreed to by the DSMB/DMC. 
11.2 Steering Committee 
The Steering Committee (SC), chaired by Co-ordinating Investigator, will be responsible 
for maintaining the scientific integrity of the trial. Members will be selected investigators 
from the participating countries/regions. The Co-ordinating Investigator will review and 
approve the trial protocol and subsequent protocol amendments, taking into account also 
feedback from other SC members, if applicable. The SC will be blinded to study 
treatment allocation while the trial is ongoing. Each SC member is expected to discuss 
with the SC Chairman any activities that might constitute a conflict of interest for the 
AFFIRM-AHF trial. 
SC meetings will be attended by, in addition, representatives of the Sponsor and 
coordinating personnel (if applicable), in a non-voting capacity. 

 
 
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11.3 Clinical Endpoint Committee 
An independent CEC will be formed to adjudicate all events suggestive of the study 
endpoints using prospectively defined criteria which will be detailed in the CEC charter. 
Members of the CEC will not be employees of Sponsor. This committee will be 
composed of at least three members including at least one cardiologist specialising in HF. 
The CEC will adjudicate the events blinded to study treatment group allocation. Endpoint 
adjudication will be done, using a web-based adjudication system, on an ongoing basis 
throughout the duration of the trial. The adjudicated events will be used for the analyses 
of the primary endpoint, secondary and other endpoints. 

 
 
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12. STATISTICAL ANALYSIS 
12.1 Statistical Methods 
All statistical analyses will be performed using SAS Version 9.3 or later (SAS 
Institute Inc. SAS/STAT, Cary, NC, United States). The level of significance to be used 
will be 0.05. Detailed methodology for summary and statistical analyses of the data 
collected in this trial will be documented in a Statistical Analysis Plan (SAP), which will 
be finalised prior to unlocking of the study data base. A general description of the planned 
methods is provided below. Any deviation from the SAP will be noted and explained in 
the final study report. 
12.2 Sample Size and Power Calculations 
The recurrent HF hospitalisation and CV death rates in the control group was extrapolated 
as 0.9 events/year using the data from the EVEREST study [37] and as 0.61 events/year 
using the data from the ESC-HF study [38]. For this study, it is anticipated that 
approximately 35% of subjects will sustain either a CV death or will sustain at least one 
HF hospitalisation. It is also anticipated that 12% of subjects will sustain a CV death. 
Assuming that 50% of subjects who sustain a CV death will not undergo any prior HF 
hospitalisation and that the average number of HF hospitalisations per subject with at 
least one HF hospitalisation will be estimated as 2, the number of events per 100 years 
has been estimated as follows: 12 CV deaths + 2*(35-6) HF hospitalisations, which 
equates to approximately 70 events/100 years of follow-up for HF hospitalisations and 
CV death. 
Concerning the event rate ratio, it is assumed that there will be a 30% reduction in HF 
hospitalisations for subjects allocated to FCM and that CV death rates will be similar 
between the FCM and placebo groups. It is therefore assumed that the rate ratio between 
FCM and placebo for the composite of recurrent HF hospitalisations and CV deaths will 
be approximately 25%. 
The dispersion factor used in negative binomial regression is a measure of the mean-
variance. There is currently insufficient data to estimate the negative binomial dispersion. 
For this sample size calculation, a dispersion factor (K) of 1 was assumed. 
The sample size calculation was done in the software NCSS PASS-14 [39] using the 
sample size formula proposed by Zhu and Lakkis 2014 [40] to compare two negative 
binomial rates. 
Assuming a recurrent HF hospitalisation and CV death of 0.7 events/year the placebo 
group, in total, 1,000 subjects (500 per study treatment group) would be required to 
demonstrate a statistically significant rate ratio of 0.75 (i.e., 25% reduction of recurrent 
events between the FCM and placebo groups) with a power of 80% and a 2-sided alpha of 
0.05. Taking into account 9% loss to follow-up, a sample size of 1,100 subjects (550 per 
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12.3 Analysis Sets 
12.3.1 Full Analysis Set 
The full analysis set (FAS) will consist of all subjects who satisfy the following criteria: 
• Randomised to either of the two treatment groups 
• The administration of study treatment was started 
The FAS data set will be analysed based on the randomised treatment arm. 
12.3.2 Per-protocol Set 
The per-protocol (PP) analysis set will consist of all subjects who, in addition to the FAS 
criteria, had no major protocol violations (as defined in the SAP). 
12.3.3 Safety Set 
The safety set will consist of all randomised subjects administered at least 1 dose of study 
treatment. The subjects in this group will be analysed based on the treatment received. 
12.4 Background and Demographic Characteristics 
The baseline and demographic characteristics will be summarised per treatment group. 
12.5 Study Treatment 
The total amount of study treatment given will be calculated for each subject and will be 
compared to the amount expected to be given for each subject. Treatment compliance will 
be calculated for each subject and summarised by treatment group. 
12.6 Concomitant Therapy 
Concomitant medications will be categorised according to a standard dictionary (World 
Health Organization Drug Classification). Counts and percentages of subject use for each 
medication will be computed and summarised by treatment group. 
12.7 Efficacy Evaluations 
12.7.1 Primary 
The primary outcome is the composite of recurrent HF hospitalisations and CV death up 
to 52 weeks after randomisation. 
The HF hospitalisation and CV death rates per 100 patient-years of follow-up as 
adjudicated by the CEC, will be calculated by dividing the total number of HF 
hospitalisations, and CV deaths by the total follow-up duration of all subjects in each 
group. The rate ratio (95% CI and p-value) for this analysis will be analysed using a 
negative binomial model. Compared to the Poisson distribution, the negative binomial 

 
 
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distribution allows for different individual tendencies (frailties) with respect to their risks 
of repeat hospitalisations [41]. 
The negative binomial model will be adjusted for the following baseline covariates: sex, 
age, HF aetiology (ischemic/non-ischemic), HF duration (newly diagnosed at Index 
hospitalisation/known documented HF prior to Index hospitalisation) and country. A 
sensitivity analyses will be performed using an unadjusted model. 
The primary outcome analysis will be performed on the FAS will use the CEC 
adjudicated events. A sensitivity analysis will be performed on the PP population set. 
Descriptive statistics will provide, per treatment group, the total number of events and the 
number (%) of subjects with at least one event. 
A graphical representation of the estimated cumulative hazard rate will also be provided. 
As the analysis of HF hospitalisations could be confounded by the competing risk of 
death, a confirmatory analysis will be performed on the FAS population set using the 
joint frailty model in order to analyse repeat hospitalisation rate whilst accounting for 
their associated mortality rate [42]. 
12.7.2 Secondary and Other Endpoints 
The secondary endpoints will evaluate, relative to placebo, the effect of IV FCM. 
Hochberg’s procedure will be used to control the overall Type I error for the evaluation of 
the secondary endpoints. The secondary endpoints are the following: 
• The composite of recurrent CV hospitalisations and CV death up to 52 weeks after 
randomisation. 
• HF hospitalisations up to 52 weeks after randomisation (analysed as recurrent event). 
• CV mortality analysed as time to first event at 52 weeks after randomisation. 
• The composite of HF hospitalisations or CV death analysed as time to first event at 
52 weeks after randomisation.  
• Days lost due to HF hospitalisations or CV death at 52 weeks after randomisation. 
Complete details concerning the analyses of the secondary endpoints and the statistical 
tests to be performed will be detailed in the SAP – the latter will be finalised prior to 
unblinding of the trial database. 

 
 
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The other endpoints will evaluate, relative to placebo, the effect of IV FCM on: 
• The composite of recurrent HF hospitalisations and CV death up to 30 days after 
randomisation. 
• The composite of recurrent CV hospitalisations and CV death up to 30 days after 
randomisation. 
• The composite of HF hospitalisations or CV death analysed as time to first event at 
30 days after randomisation. 
• The composite of CV hospitalisations or CV death analysed as time to first event at 
30 days after randomisation.  
• HF hospitalisations up to 30 days after randomisation (analysed as recurrent event). 
• HF hospitalisations up to 30 days and 52 weeks after randomisation (analysed as time 
to first event). 
• CV hospitalisations up to 30 days and 52 weeks after randomisation (analysed as 
recurrent event and time to first event). 
• The composite of CV hospitalisations or CV death analysed as time to first event at 
30 days and 52 weeks after randomisation.  
• Cardiovascular mortality analysed as time to first event at 30 days after randomisation. 
• All-cause mortality analysed as time to first event at 30 days and 52 weeks after 
randomisation. 
• Proportion of patients with an event (HF hospitalisations, CV hospitalisations, CV 
mortality, composite and individual categories). 
• Change from baseline in NYHA functional class as assessed at 6, 12, 24 and 52 weeks 
after randomisation. 
• Change from baseline in the Kansas City Cardiomyopathy Questionnaire-12 up to 
52 weeks after randomisation. 
• Change from baseline in the European quality of life – 5 dimensions questionnaire up 
to 52 weeks after randomisation. 
• Days lost due to HF hospitalisations or CV death at 30 days after randomisation. 
The analyses of secondary and other endpoints will be performed on the FAS and will use 
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For the recurrent event analysis, the same analysis as that described for the primary 
outcome will be performed. 
For the time to first event analysis, the incidence of events will be documented by 
treatment group with the total number of events, the number of subjects with at least 1 
event and the event hazard rate per 100 patient years “at risk” (estimated as the number of 
patients with at least 1 event divided by the patient years at risk of event). Patient years at 
risk of event will be taken as the sum of the observation time from start of study treatment 
until the first occurrence of the event concerned, or until censoring. The hazard ratio 
(relative to placebo), its 95% CI and the p-value test will be provided using Cox 
regression. The proportion of patients with an event (HF hospitalisations, CV 
hospitalisations, CV mortality; composite and individual categories) will also be reported. 
The change in NYHA class will be analysed using a repeated measurement analysis of the 
ordered polytomous regression adjusted for treatment, time and the baseline NYHA value. 
Complete details concerning the analyses of the other endpoints and the statistical tests to 
be performed will be detailed in the SAP – the latter will be finalised prior to unblinding 
of the trial database. 
12.8 Safety Evaluations 
The safety analysis will be performed on the Safety analysis set. The following safety 
outcomes will be analysed: 
• Clinical laboratory panels (iron status, serum phosphorus and cardiac biomarkers) 
• Summary of AEs: by system organ class (SOC) and preferred term (PT) (Medical 
Dictionary for Regulatory Activities (MedDRA) coded term), by severity and relation 
to study product 
• Summary of SAEs: by SOC and PT (MedDRA coded term), by severity and relation 
to study product 
All data will be presented in a descriptive manner by providing mean tables (continuous 
variables) or frequency tables (discrete variables and AEs). Laboratory data will also be 
presented by shift tables. 
For AEs, the total number of events and number (%) of subjects with event will be 
presented by MedDRA SOC and PT by treatment group. 
Complete details concerning the analyses and statistical tests to be performed will be 
detailed in the SAP. 
12.9 Interim Analyses 
No interim analyses are planned. 

 
 
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12.10 Other Evaluations 
12.10.1 Exploratory Analyses 
Additional exploratory analyses not described above may be performed if indicated in the 
medical review(s) of the data. Such analyses may include subgroup analyses based on 
various baseline characteristics such as Hb, HF aetiology, duration of HF, baseline serum 
creatinine and will be fully described in the final SAP. 
12.10.2 Biomarker Blood Samples 
It is planned to perform biomarker analyses in blood samples from approximately 60% of 
randomised subjects. The decision concerning which biomarkers will be analysed will be 
made by in collaboration with the SC, together with the Sponsor. If the biomarker 
samples will not be analysed, they will be destroyed. Details concerning the blood 
samples storage will be provided in an instruction manual. The statistical analysis for the 
biomarker blood samples will be detailed in a separate biomarker SAP and results of 
these exploratory analyses will be not part of the clinical study report of the main study. 
12.10.3 Quality of Life 
Quality of Life will be assessed using the KCCQ-12 and EQ-5D. The analysis of 
treatment difference on the KCCQ-12 score at Week 2, Week 4, Week 6, Week 12, 
Week 24, Week 36 and Week 52 will be done by comparing the model adjusted means of 
the corresponding visit based on a model for repeated-measures including terms for 
treatment, baseline, time and treatment-by-time with an unstructured covariance matrix to 
model the within-patient variability. The analysis of treatment difference on the EQ-5D 
score will be done in the same manner for the data collected at Week 6, Week 24 and 
Week 52. The SAP will detail the analysis to be performed. 
12.10.4 Pooling of AFFIRM-AHF, FAIR-HF2 and FAIR-HFpEF studies 
Since February 2017, a study (FAIR-HF2: ClinicalTrials.gov Identifier: NCT03036462) 
is running as multinational trial. The purpose of this study is to determine whether IV iron 
supplementation using FCM reduces hospitalisation and mortality in patients with ID and 
HF.  
Since August 2017, a study (FAIR-HFpEF: ClinicalTrials.gov Identifier: NCT03074591) 
is running in Germany. The purpose of this study is to determine whether treatment with 
IV iron for patients with HF with preserved ejection fraction and ID, both with or without 
anaemia, can improve exercise capacity as measured by 6-minute walking test and 
symptoms while being safe. 
As there are a lot of similarities between AFFIRM-AHF, FAIR-HF2 and FAIR-HFpEF 
studies, it has been decided to perform 2 integrated analyses of the 3 studies: 
• Integrated analysis 1: AFFIRM-HF and FAIR-HF2 studies 

 
 
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• Integrated analysis 2: AFFIRM-HF, FAIR-HF2 and FAIR-HFpEF studies 
For the Integrated analysis 1, the pooling of both databases (AFFIRM-HF and FAIR-HF2) 
will occur after the database lock of the second incoming study, currently projected to be 
FAIR-HF2. A specific integrated SAP will be written prior to the database lock of the 
first incoming study, currently projected to be AFFIRM-AHF. The methods for the 
Integrated data analysis 1 will be listed and detailed in an integrated SAP and the results 
reported in an integrated Clinical Study Report separate to the study report of each 
individual study. 
For the Integrated analysis 2, the pooling of the 3 databases (AFFIRM-HF, FAIR-HF2 
and FAIR-HFpEF) will occur after the database lock of the last incoming study, currently 
projected to be FAIR-HFpEF. A specific integrated SAP will be written prior to the 
database lock of the first incoming study, currently projected to be AFFIRM-AHF. The 
methods for the Integrated data analysis 2 will be listed and detailed in an integrated SAP 
and the results reported in an integrated Clinical Study Report separate to the study report 
of each individual study. 
 

 
 
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13. STUDY ETHICAL CONSIDERATIONS 
13.1 Ethical Conduct of the Study 
The study will be conducted according to the principles of the World Medical 
Association’s (WMA) Declaration of Helsinki (as amended by the 64th WMA General 
Assembly, Fortaleza, October 2013) [43], and the ICH guidelines for GCP [44]. Vifor 
Pharma will ensure that the study complies with all local, federal or country regulatory 
requirements. 
The Investigator must ensure the anonymity of all subjects participating in the study. 
Each subject will be assigned a unique subject number and this should be used on all 
forms associated with the subject’s documents or samples that will be supplied to the 
Sponsor or any party completing testing on behalf of the Sponsor (e.g., blood for central 
laboratory assessments). 
All anonymous data remains the property of Vifor Pharma. 
13.2 Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, federal 
regulations, and ICH guidelines; and must have been approved by the appropriate 
IRB/EC/IEC prior to use. The Investigator or an authorised associate must explain orally 
and in writing the nature of the study and the treatment in such a manner that the subject 
is aware of potential benefits and risks. Subjects must also be informed that participation 
is voluntary and that they may withdraw from the study at any time, without prejudice. 
Subjects must be provided sufficient time to consider participation, including discussion 
with family members prior to signing the ICF. Documentation of the discussion and the 
date of informed consent must be recorded in the source documentation. Subjects must 
give informed consent in writing. 
A guideline on how to administer informed consent is attached in Appendix 3 and should 
be followed by all site staff administering informed consent to subjects when an 
equivalent process is not available at the site. 
13.3 Institutional Review Board or EC/IEC 
The protocol, any protocol amendments and consent form for the proposed clinical study 
and any other documents required by the local IRB/EC/IEC must be submitted by the 
Investigator for review and approval to the IRB/EC/IEC. The Investigator must also 
ensure that the IRB/EC/IEC reviews the progress of the study on a regular basis and, if 
necessary, renews its approval of the study on an annual basis. A copy of the approval 
letter must be forwarded to Vifor Pharma before the study is implemented. 

 
 
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14. QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator must ensure that all trial related site source data, study related documents 
and reports will be available, and that the provision of direct access for monitoring and 
auditing by Vifor Pharma or its designees will be permitted. In addition, the Investigator 
must ensure that all trial related site source data, study related documents and reports will 
be made available for inspection by the appropriate Regulatory Authority and review by 
the IRB/EC/IEC. 
Accurate and reliable data collection will be assured by verification and cross-check of 
the eCRFs against the Investigator’s records by the Monitor (source document 
verification), and the maintenance of a study treatment dispensing log by the Investigator. 
The data collected will be entered (electronic data capture) into the study database and 
will be verified by the Monitor. A comprehensive validation check program will verify 
the data and queries will be generated for resolution by the Investigator. Throughout the 
study, Vifor Pharma or its designates may review data as deemed necessary. 

 
 
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15. ADMINISTRATIVE PROCEDURES 
15.1 Sponsor’s Responsibilities 
15.1.1 Study Supplies 
Sites will be provisioned with supplies required to manage this study. This will include 
but not be limited to: 
• Investigator file(s) (for filing of all study related documentation) 
• Contact list of all relevant study personnel 
• Access to eCRF and completion guidelines 
• Study reference manual 
• All study forms (e.g., SAE, pregnancy, drug accountability, etc.) 
15.1.2 Insurance 
Vifor Pharma confirms that it carries liability insurance which protects non-employee 
physicians or Investigators against claims for which they may become liable as a result of 
damages caused by Vifor Pharma products used in clinical studies. Insurance coverage is 
not extended to damages that the Investigators or third parties may suffer by reason of 
acts of commission or omission on the part of such Investigators or third parties and that 
are not in accordance with accepted common medical practices (lege artis procedures). 
Vifor Pharma will reimburse the subject for all study-related injuries provided that the 
injury does not arise from the subject’s misuse of the study treatment or failure to follow 
the Investigator’s instructions. 
15.1.3 Investigator Training 
All Investigators and their study personnel will receive training regarding the study 
procedures and GCP/regulations specific to the conduct of clinical trials. This training 
will take place prior to enrolment of the first subject at the study centre. 
15.1.4 Study Monitoring 
The study will be monitored by representatives of Vifor Pharma (or designee) who may 
include a CRO and/or partner company. 
It is understood that the responsible Vifor Pharma Monitor (or designee) will contact and 
visit the Investigator regularly and will be allowed, on request, to inspect the various 
records of the trial (eCRFs and other pertinent data) provided that subject confidentiality 
is maintained in accordance with local requirements. 
It will be the Monitor's responsibility to inspect the eCRFs at frequent regular intervals 
throughout the study, to verify adherence to the protocol and the completeness, 

 
 
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consistency and accuracy of the data being entered on them. The Monitor must have 
access to laboratory test reports and other subject records needed to verify the entries on 
the eCRF. The Investigator (or his/her deputy) agrees to co-operate with the Monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
15.1.5 Medical Monitoring 
Vifor Pharma (or designee) will provide a medical contact for the discussion of medical 
concerns or queries throughout this clinical study. Details of how to access the Medical 
Monitor will be provided and stored in the Investigator Site File. 
15.2 Investigator’s Responsibilities 
15.2.1 Reporting and Recording of Data 
All required study data must be entered in the eCRF created for the study. Training on the 
system will be provided to all sites, including instructions on how to address missing data, 
corrections, query procedures and electronic signatures. Only individuals who are 
identified on the authorised signature page may enter/correct data in the eCRF. For those 
subjects who withdraw before completion of the study, all available efficacy and safety 
data must be entered in the eCRF. Incomplete or inconsistent data on the eCRF will result 
in data queries addressed to the Investigator for resolution. 
15.2.2 Source Documentation 
The Investigator must maintain adequate and accurate source documents upon which case 
reports for each subject are based. They are to be separate and distinct from eCRFs. These 
records should include detailed notes on: 
• The medical history up to at least 12 months prior to participation in the study 
• The basic identifying information, such as demographics, that link the subject’s 
source documents with the eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided and 
any other data on the condition of the subject 
• The subject’s exposure to study treatment 
• All AEs, and pregnancies 
• All special situations as defined in Section 10.1.7 
• The subject’s exposure to any concomitant therapy (including date and quantity 
dispensed) 
• All relevant observations and data on the condition of the subject throughout the study 

 
 
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• The oral and written communication with the subject regarding the study treatment 
(including the risks and benefits of the study). The date of informed consent must be 
recorded in the source documentation. 
All data for the study must be available in source documentation. 
15.2.3 Records Retention 
The Investigator must arrange for the retention of all study documentation (eCRF files or 
printed forms, research files, and master files) for the duration specified in their 
respective site contract or as specified by the applicable Regulatory Authority, whichever 
is longer. The Sponsor will inform the Investigator in writing when files can be destroyed. 
Archived data may be held on microfiche or electronic record, provided that a backup 
copy exists and that a hard copy can be generated if required. 
The Investigator must inform Vifor Pharma immediately if any documents are lost, to be 
transferred to a different facility, or to be transferred to a different owner. 
15.2.4 Site Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. 

 
 
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16. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
16.1 Protocol Waivers, Deviations and Violations 
Protocol waivers shall not be permitted except where necessary to eliminate an immediate 
hazard to subjects. 
Deviations from the protocol including violations of inclusion/exclusion criteria will be 
assessed as minor or major on a case-by-case basis. The criteria describing the deviation(s) 
and how they will be handled will be documented in the SAP. 
16.2 Protocol Amendments 
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, must be made only with the prior approval of Vifor Pharma. Each applicable 
Regulatory Authority/IRB/EC/IEC will review and approve amendments prior to their 
implementation. Regulatory Authority/IRB/EC/IEC approval need not be obtained prior 
to removal of an immediate hazard to subjects. 
16.3 Study Termination 
Vifor Pharma reserves the right to terminate the study in its entirety or at a site at any 
time. Reasons for termination may include (but are not limited to) unsatisfactory subject 
enrolment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or GCP, or data recording is inaccurate and/or incomplete. 
Following sections in italics are applicable for The Netherlands only (NL only):  
The right by the Sponsor to the terminate the study is only applicable in case certain 
circumstances are applicable as follows: 
a) If the judgement of the competent medical research ethics committee that has assessed 
the study is irrevocably revoked 
b) If a reasonable case can be made for terminating the study in the interests of the 
health of the research subjects 
c) If it transpires that continuation of the study cannot serve any scientific purpose, and 
this is confirmed by the medical research ethics committee that has issued a positive 
decision on the study 
d) If one of the parties or the funder has been declared insolvent or a 
bankruptcy/winding-up petition has been filed in respect of one of the parties or the 
financier, or one of the parties or the financier is dissolved as a legal entity 
e) If circumstances beyond the control of the Sponsor, Investigator or funder make it 
unreasonable to require the study's continuation 

 
 
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In terminating the study, Vifor Pharma and the Investigator will assure that adequate 
consideration is given to the protection of the subject’s interests. Both parties will arrange 
the procedures on an individual basis after review and consultation and in accordance 
with the study contract. 

 
 
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17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
Vifor Pharma is committed to the timely communication of data from clinical research 
trials, following the Pharmaceutical Research and Manufacturers of America principles 
[45]. Where possible, authorship will be agreed at the beginning of the study. The authors 
will form a publication committee and this committee will propose and develop 
appropriate scientific manuscripts or abstracts from the study data. Investigators may not 
present or publish partial or complete study results individually.  
Following section in italics is applicable for The Netherlands only (NL only): 
In The Netherlands the previous sentence is extended with: 
[…]individually, in the initial 12 months after the study’s termination prior research 
results have been disclosed.  
Any manuscript or abstract proposed by the Investigators must be reviewed and approved 
in writing by Vifor Pharma before submission for publication. Names of all Investigators 
actively participating in the study will be included in the publication. 
The publication committee for a study will comprise of authors selected in adherence 
with the International Committee of Medical Journal Editors criteria [46] for authorship. 
That is, all authors must meet each of the following 3 criteria: 
1. Substantial contribution to conception and design or acquisition of data, or analysis 
and interpretation of data 
2. Drafted the article or revised it critically for important intellectual content 
3. Approved the final version for publication 
Members of the study SC generally fulfil the authorship criteria through their 
involvement in protocol design and review, monitoring of and sometimes direct 
involvement with recruitment, and thus they will usually be part of the publication 
committee. If studies are multicentre, it may be appropriate to assign group authorship. 
In addition, certain Vifor Pharma employees involved in the design and conception of the 
protocol, study management and data analysis and interpretation are qualified authors and 
will be included in the publication committee e.g., the lead physician, statistician and 
study project manager or their equivalents. 

 
 
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
FER-CARS-06 Version 3.1 
1 April 2020
Confidential 
Page 101 of 108


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FER-CARS-06 Version 3.1 
1 April 2020
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1 April 2020
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