Conditions: Iron Deficiency Anemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 371
Healthy volunteers: no

Brief summary:
The primary objective is to demonstrate the efficacy of ferric carboxymaltose (FCM) given in a simple dosing regimen in correcting iron deficiency anaemia (IDA), by demonstrating non-inferiority to treatment with the currently approved intravenous (IV) iron therapy of iron sucrose (IS, Venofer™) in the Chinese population. The secondary objectives are to assess the safety of FCM compared to IS in the Chinese population and to evaluate the effect of FCM compared to IS on relevant laboratory parameters (haematology, chemistry, iron parameters) in the Chinese population.

Detailed description:
This is an open-label, randomised controlled study to assess the impact of FCM in correcting iron deficiency anaemia compared with Venofer™ (IS).

All subjects, after providing written informed consent and meeting the eligibility assessments, will receive a first dose of IV iron as either FCM or IS. A total of approximately 368 subjects (184 per group) will be enrolled. All subjects will have iron deficiency anaemia as measured by haemoglobin (Hb), serum ferritin and transferrin saturation (TSAT) at screening.

Ferric carboxymaltose will be administered as either a diluted infusion or undiluted injection (at Investigator discretion) and IS will be administered as a slow intravenous injection at a rate of 1 ml undiluted solution per minute (with each single injection of 200 mg iron) or by drip infusion. Note, for subjects randomised to receive IS dosing visits are required three times a week to achieve total iron repletion dosing as calculated using the Ganzoni formula.

For subjects randomised to FCM, the total iron requirements will be calculated at screening based on the screening Hb and subject weight. Dosing will be at baseline and, if required, at day 8 and day 15. All subjects will attend study visits at screening, baseline and thereafter at Weeks 2, 4 and 6. All subjects will attend an end of study visit (at Week 8 - or earlier if discontinued prematurely).

Arms:
arm 1: Subjects treated with FCM given by IV injection or drip infusion arm 2: Subjects treated with IS given by IV injection or drip infusion

Interventions: intervention 1: Ferric carboxymaltose intervention 2: Iron sucrose
Intervention descriptions: intervention 1: Dosage Form: Injection, Sterile FCM solution as a 5% w/v iron solution in water for injection Strength: 10 mL vials containing 500 mg iron per vial Dosage: 500mg/week or 1000mg/week (based on subject BW and Hb value at screening) Route of administration: IV injection (undiluted solution) or drip infusion (500 mg iron diluted in 100 mL 0.9% w/v physiological saline or 1,000 mg iron diluted in 250 mL 0.9% w/v physiological saline) Dosing schedules: baseline (Day 1) and, if required, at Day 8 and Day 15. intervention 2: Dosage Form: Sterile solution for injection containing 2% w/v iron Strength: 5 mL ampoules containing 100 mg iron per ampoule Dosage: single doses of IS of 200mg iron based on the formula of Ganzoni: Cumulative iron deficit \[mg\] = BW \[kg\] x (target Hb- actual Hb) \[g/dL\] x 2.4 + 500 mg, up to 11 IS injections will be given Route of administration: IV injection or drip infusion Dosing schedules: three times a week, with an initial dose at baseline and will receive iron, as per approved label, until the subject has received the calculated iron dose.

Protocol document:
Prot_000.pdf: 
 
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. 
 
 
An Open-label, Randomised Controlled Multi-centre Study 
to Assess the Impact of Ferric Carboxymaltose in Correcting 
Iron Deficiency Anaemia Compared to Venofer® (Iron 
Sucrose) in Chinese Subjects 
 
Clinical Protocol Number: 
VIT-IRON-2011-004 
 
 
Date: 
 14 August 2017 
 
 
Version Number: 
5.0 
 
 
Prior Amendments: 
Amendment 1, 9 April 2014 
Amendment 2, 4 May 2016 
Amendment 3, 2 September 2016 
 
 
Co-ordinating Investigator: 
 
 
 
 
Sponsor Contact: 
 
 
 
Sponsor Address:  
Vifor International Inc. 
Rechenstrasse 37 
P.O. Box 
9001 St. Gallen 
Switzerland 
 
Sponsor Medical Expert 
 
 
 
 
 
Fax: 
+41 58 851 80 01 
  
 
Clinical Research 
Organisation 
Tigermed Consulting Ltd. 
Fl.15 Dongguan Building  
618 Jiangnan Road 


Binjiang District 
Hangzhou, Zhejiang Prov., 310052, 
P.R. China 




 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 3 of 75 
 
INVESTIGATOR AGREEMENT AND SIGNATURE PAGE 
I have read the attached protocol entitled “An Open-label, Randomised Controlled 
Multi-centre Study to Assess the Impact of Ferric Carboxymaltose in Correcting Iron 
Deficiency Anaemia Compared to Venofer® (Iron Sucrose) in Chinese Subjects”, 
Amendment 4 dated 14 August 2017, and agree to abide by all provisions set forth 
therein. 
I agree to comply with the current International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline 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 
 
Date (DD.MMM.YYYY) 
 
 
 
Name of Principal Investigator 
 
 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 4 of 75 
 
SYNOPSIS 
VIT-IRON-2011-004 
Title: 
An open-label, randomised controlled multi-centre study to assess the impact of 
ferric carboxymaltose in correcting iron deficiency anaemia compared with 
Venofer® (Iron Sucrose) in Chinese subjects 
Short Title: 
China Phase 3 Study 
Study Product(s): 
Ferinject® (ferric carboxymaltose, FCM) 
Indication: 
Iron deficiency anaemia (IDA)  
Phase: 
3 
Sponsor: 
Vifor Pharma 
Study Code: 
VIT-IRON-2011-004 
Co-ordinating 
Investigator:  
 
 
 
Objectives: 
Primary Objective(s): 
• 
To demonstrate the efficacy of ferric carboxymaltose (FCM) given in a 
simple dosing regimen in correcting IDA, by demonstrating non-inferiority 
to treatment with the currently approved intravenous (IV) iron therapy of 
Iron Sucrose (IS, Venofer) in the Chinese population. 
Secondary Objective(s): 
• 
To assess the safety of FCM compared to IS in the Chinese population. 
• 
To evaluate the effect of FCM compared to IS on relevant laboratory 
parameters (haematology, chemistry, iron parameters) in the Chinese 
population. 
Design: 
Open-label, randomised controlled study to assess the impact of FCM in 
correcting IDA compared with Venofer (IS). 
All subjects, after providing written informed consent and meeting the 
eligibility criteria, will receive a first dose of IV iron as either FCM or IS. A 
total of approximately 368 subjects (184 per group) will be randomised. All 
subjects will have IDA as measured by haemoglobin (Hb), serum ferritin and 
transferrin saturation (TSAT) at screening. 
Ferric carboxymaltose will be administered as either a diluted infusion or 
undiluted injection (at Investigator’s discretion) at single, maximum daily doses 
of 500 or 1,000 mg iron) and IS will be administered as an undiluted bolus push 
injection or diluted infusion (with each single injection/infusion of 200 mg 
iron). Note, for subjects randomised to receive IS, dosing visits are required 
three times a week to achieve total iron repletion dosing as calculated using the 
Ganzoni formula. 
For subjects randomised to FCM, the total iron requirement will be calculated 
at baseline based on the screening Hb and body weight (BW). Dosing will be at 
baseline (Day 1) and, if required, at Day 8 and Day 15.. 
 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 5 of 75 
 
Design (Cont’d): 
All subjects will attend study visits at screening, baseline and thereafter at 
Weeks 2, 4 and 6. All subjects will attend an end of study visit (at Week 8 – or 
earlier if discontinued prematurely). Additional dosing visits may be required 
for subjects receiving IS three times weekly   up to Week 4. 
Treatment: 
Arm A: Ferric Carboxymaltose 
Dosing to be based on subject Hb and BW at screening as per table below: 
 
Total Iron (mg) as FCM 
 
BW 35-<70 kg1 
BW ≥70 kg 
 
 
Hb <10 
g/dL 
Hb ≥10-<14 
g/dL 
Hb <10 
g/dL 
Hb ≥10-
<14  g/dL 
 
Day 1 
 
1,000 mg 
1,000 mg 
1,000 mg 
1,000 mg 
 
Day8 
 
500 mg 
No dose 
1,000 mg 
500 mg 
 
1. 
Notes: 
BW = Body weight; FCM = Ferric carboxymaltose; Hb = Haemoglobin.The 
maximum  single dose that should be given to a subject is 20 mg/kg BW, therefore for 
subjects with BW 35 - <50kg and Hb ≥ 10 g/dL,  the 1,000 mg  dose should be split into 2 x 
500 mg (one 500 mg dose on Day 1 and one 500 mg dose on Day 8. Subjects with BW 35 - 
<50 kg and Hb < 10g/dL should receive 3 doses of 500 mg (on Day 1, 8 and 15) . 
 
To be administered as undiluted injection or diluted infusion (500 mg iron 
diluted in 100 mL 0.9% w/v physiological saline or 1,000 mg iron diluted in 
250 mL 0.9% w/v physiological saline) over at least 5 minutes for the 500 mg 
dose and over at least 15 minutes for the 1,000 mg dose. Administration time 
should not exceed 30 minutes for either the 500 or the 1,000 mg dose. 
Arm B: Venofer (Iron Sucrose) 
Required total iron dose to be calculated per label (Ganzoni formula): 
Cumulative iron deficit [mg] (calculated from screening values)= 
BW [kg] x (target Hb(1) - actual Hb) [g/dL](2) x 2.4(3) + 500 mg(4) 
(1) Target Hb for BW >35 kg = 15 g/dL, respectively 9.3 mmol/L 
(2) To convert mmol/L to g/dL: multiply Hb (mmol/L) by the factor 1.61145 
(3) Factor 2.4 = 0.0034 (iron content Hb = 0.34%) x 0.07 (blood volume = 7% 
of BW) x 10,000 (conversion g/dL to mg/L x 10) 
(4) Storage iron 
Note: BW = Body weight. 
The calculated iron dose will be split into doses of 200 mg iron administered by 
slow intravenous injection at a rate of 1 ml undiluted solution per minute (10 ml 
of the product in at least 10 minutes; administration time should not exceed 60 
minutes) or by drip infusion in a dilution of 1 ml of Venofer in a maximum of 
20 ml 0.9% w/v physiological saline (10 ml of the product in maximum 200 ml 
of saline). The drip infusion rate should be 200 ml solution in at least 30 
minutes and should not exceed 60 minutes. The subjects will be administered 
Venofer  three times a week, with an initial dose at baseline and will receive 
iron, as per approved label, until the subject has received the calculated iron 
dose. The calculated cumulative Venofer dose will rounded up or down to the 
nearest 200 mg. 
Inclusion Criteria: 
1. At least 18 years of age 
2. Hb <11 g/dL (females) or Hb <12 g/dL (males) at the screening visit  
3. Serum ferritin <100 ng/mL for subjects with underlying inflammatory 
disease (e.g., inflammatory bowel disease (IBD), chronic kidney disease 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 6 of 75 
 
(CKD) or chronic heart failure (CHF), as determined by high sensitive C-
reactive protein [hsCRP] levels above the normal range) otherwise serum 
ferritin ≤14 ng/mL in subjects with no apparent underlying inflammatory 
disease (as determined by hsCRP levels within normal range) at the 
screening visit 
4. TSAT <16% (any subject) at the screening visit 
5. Microcytic, hypochromic anaemia at the screening visit, defined as: 
a. 
Mean corpuscular Hb concentration (MCHC) <32% 
b. Mean corpuscular volume (MCV) < 80 fL 
c. 
Mean corpuscular Hb (MCH) <27 pg 
6. Subjects with the ability to understand the requirements of the study and 
abide by the study restrictions, and who agree to return for the required 
assessments 
7. Before any study-specific procedure is conducted, the appropriate written 
informed consent must be obtained 
 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 7 of 75 
 
Exclusion Criteria: 
1. Subject has known hypersensitivity to any of the products to be 
administered during dosing 
2. Any history of iron storage diseases such as haemochromatosis 
3. Any history or clinical findings of iron utilisation disorders such as 
sideroachrestic anaemia 
4. Known haemoglobinopathy (e.g. thalassaemia) 
5. Any history or clinical findings of anaemia associated with: 
a. 
Haematuria 
b. Vitamin B12 or folic acid deficiency that requires treatment 
(subjects can be included after deficiency is corrected) 
6. Any allergic predispositions, i.e. any history of asthma or atopic allergy. 
This includes drug allergies.  
7. Planned surgery with anticipated blood loss (defined as Hb drop >2 g/dL) 
in the 3 months post randomisation 
8. Subject has known malignancy (with or without current treatment), except 
basal cell or squamous cell carcinoma of the skin or  cervical intra-
epithelial neoplasia 
9. Haemodialysis (current or planned within the next 3 months) 
10. History of IV iron therapy, erythropoiesis stimulating agent (ESA) therapy 
and/or blood transfusion in previous 4 weeks prior to baseline, and oral 
iron or oral iron-containing products including Chinese herbal medicines  
(>75mg iron/day) in the 7 days prior to baseline 
11. Body weight <35 kg 
12. Chronic liver disease and/or screening alanine transaminase (ALT) or 
aspartate transaminase (AST) above 3 times the upper limit of the normal 
range 
13. Known 
human 
immunodeficiency 
virus 
infection, 
acquired 
immunodeficiency syndrome, tuberculosis 
14. Known active hepatitis B or C or other active infection (acute or chronic) 
15. Subject currently is enrolled in or has not yet completed at least 30 days 
since ending other investigational device or drug study(ies), or subject is 
receiving other investigational agent(s) 
16. Subject is pregnant or is breast feeding 
17. Female subject of childbearing potential not using adequate contraceptive 
methods during the study and for up to 1 month after the last dose of the 
study medication. Adequate contraceptive methods are defined as those 
which result in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly such as implants, injectables, combined oral 
contraceptives, 
some 
intra-uterine 
devices, 
sexual 
abstinence 
or 
vasectomised partner. Non-childbearing potential includes being surgically 
sterilised at least 6 months prior to the study or post-menopausal, defined 
as amenorrhoea for at least 12 months 
18. Male subjects planning to father a child within 7 days from the last study 
drug administration. 
19. Subject has any kind of disorder that compromises the ability of the subject 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 8 of 75 
 
to give written informed consent and/or to comply with study procedures 
and/or other reason(s) that render subject not appropriate for study 
participation in the opinion of the treating physician 
Primary and 
Secondary 
Endpoints: 
Primary Endpoint: 
• 
Percentage of subjects achieving an increase in Hb of ≥ 2 g/dL 
(responders) from baseline at any time up to Week 8 
Secondary Endpoints: 
Efficacy: 
• 
Percentage of subjects achieving an increase in Hb ≥ 2 g/dL from baseline 
at Weeks 2, 4, 6 and 8 
• 
Change in Hb from baseline to Weeks 2, 4, 6 and 8 
• 
The percentage of subjects with TSAT ≥ 16% and serum ferritin ≥100 
ng/mL (for subjects with underlying inflammatory disease as determined 
by hsCRP levels above the normal range) or serum ferritin > 14ng/mL (in 
subjects with no apparent underlying inflammatory disease as determined 
by hsCRP levels within normal range at screening) at Weeks 2, 4, 6 and 8 
• 
Change in TSAT from baseline to Weeks 2, 4, 6 and 8 
• 
Change in serum ferritin from baseline to Weeks 2, 4, 6 and 8 
 
 
Secondary Endpoints (Cont’d): 
Safety: 
• 
Change in laboratory parameters (haematology, clinical chemistry and iron 
status) from baseline over the study duration 
• 
Summary of all treatment emergent adverse events (TEAE): type, nature, 
incidence and outcome overall and by underlying disease aetiology 
• 
Summary of changes in vital signs from baseline to Weeks 2, 4, 6  and 8 
Summary of changes in electrocardiogram (ECG) and physical 
examination (including BW) from baseline to Week 4 (for ECG only) and 
Week 8  
Procedures: 
All subjects will be screened (following written informed consent) to assess 
eligibility for the study. 
At the screening visit, all subjects will have a physical examination and an 
ECG performed and blood parameters assessed. If the subject is eligible, they 
will be randomised at the Baseline visit to receive FCM or IS (with dose as 
described in the Treatment Section). Study subjects may be hospitalised for 
study drug application, if needed, at the discretion of the Investigator. 
Subjects randomised to receive FCM will receive a second and third 
administration on Day 8 and Day 15, if needed. For subjects randomised to 
receive Venofer additional dosing visits are required three times a week up to 
Week 4 to achieve total iron repletion.  
All subjects will be required to attend follow-up visits at Weeks 2, 4, 6 and an 
end of study visit at Week 8 (or earlier if discontinued prematurely). At each 
visit, all subjects will have their vital signs and blood parameters assessed 
(using central laboratory). An ECG will be performed at Week 4 and Week 8.  


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 9 of 75 
 
Data will be recorded in the case report form (CRF)  after each visit. 
See Schedule of Events for full details of protocol required procedures and 
applicable visits (and timings). 
Sample Size: 
A total of 368 subjects will be randomised (i.e. 184 per treatment group) 
The sample size is based on showing non-inferiority in the difference in the 
proportion of subjects achieving an increase in Hb of ≥ 2g/dL at any time up to 
Week 8 between FCM and IS. Applying a test at a one sided alpha level of 
2.5%, and a -15% non-inferiority margin,  147 subjects per-group will have a 
80% power to detect whether FCM is non-inferior to IS with an expected IS 
responder proportion of 70%. The total sample size is 368, which allows for an 
estimated drop-out rate of 20% of the randomised subjects.  
Statistical Methods: 
Primary endpoint: 
Non-inferiority of FCM versus IS will be assessed by the difference in the 
proportion of subjects achieving an increase in Hb of ≥ 2g/dL at any time up to 
Week 8. The analysis will be performed for the Per Protocol set (PPS) and 
tested at a one sided alpha level of 2.5% with a 15% non-inferiority margin. A 
sensitivity analysis will be performed on the Full Analysis Set (FAS).   
Secondary endpoints for efficacy: 
All secondary endpoints will be analysed on the FAS and the PPS. All 
statistical tests will be performed at a 5% level. 
Safety analysis 
All safety analyses will be performed on the Safety Set.Further details will be 
specified in the Statistical Analysis Plan (SAP).  
 




 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 11 of 75 
 
 
Table 1: Schedule of Events 
 
Visit 
Procedures 
Visit 1 
Screen 
Visit 2 
Baseline 
Visit 3-5 
Visit 6 
End of study/ 
Early 
Termination 
 
Day -7 
to Day -1 
Day 1 
Weeks 2, 4, 
6 
±3 Days 
Week 8 
±4 Days 
Informed consent 
 
 
 
 
Eligibility criteria 
 
(1) 
 
 
Demographics 
 
 
 
 
Medical history 
 
 
 
 
Physical examination and 
weight 
 
 
 
 
Height 
 
 
 
 
Vital signs (blood pressure, 
heart rate, temperature) 
 
 
 
 
Electrocardiogram 
 
 
(6) 
 
Laboratory assessments 
(haematology/ 
biochemistry/iron 
parameters)(2) 
 
 
 
 
Hepatitis B and C screening(3) 
 
 
 
 
Urinalysis(4) 
 
 
 
 
Serum pregnancy test(5) 
 
 
 
 
Adverse events 
 
 
 
 
Prior & Concomitant 
medications 
 
 
 
 
Randomisation 
 
 
 
 
Administration of study drug 
 
 
((7)) 
 
1. Laboratory parameters will be tested at Baseline but will not be used  for eligibility because the results will not be available on 
time. Laboratory parameters taken at screening will be checked for eligibility at Baseline  
2. Laboratory assessments include:  
• Haematology: Hb, haematocrit, red blood cell count, MCV, MCH, MCHC, reticulocyte count, Hb content in reticulocytes, 
white blood cell count with differential and platelet count.  
• Iron status parameters: serum  iron, serum ferritin, serum transferrin, UIBC and TSAT.  
• Biochemistry parameters: electrolyte status (sodium, potassium, magnesium, calcium, chloride, phosphorus), AST, ALT, 
gamma-glutamyl transpeptidase (GGT), glucose, alkaline phosphatase (AP), lactate dehydrogenase (LDH), hsCRP. 
3. Hepatitis screening consists of Hepatitis B antigen, Hepatitis B virus DNA  and  Hepatitis C virus antibody  
4. Urinalysis includes:  phosphorus, protein, glucose, bilirubin, pH, nitrite, ketone, urobilinogen, blood, leukocytes 
5. For women of childbearing potential only. 
6. ECG is only performed at Week 4. 
7. Subjects randomised to receive  FCM will receive a maximum of 1,000 mg at Baseline (Day 1),   a second administration of a 
maximum of 1,000 mg at Day 8 and a third administration of a maximum of 500 mg at Day 15, if applicable. Subjects 
randomised to Venofer will need to come to the study centre to receive further Venofer dosing  three times  a week. All study 
procedures must be conducted prior to dosing. 
 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 12 of 75 
 
Notes: ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; hsCRP = high sensitive 
C-reactive protein; ECG = Electrocardiogram; FCM = ferric carboxymaltose; GGT = gamma glutamyl transpeptidase, 
Hb = Haemoglobin; LDH =lactate dehydrogenase,MCH = Mean corpuscular Hb; MCHC = Mean corpuscular 
haemoglobin concentration; MCV = Mean corpuscular volume; TSAT = Transferrin saturation, UIBC= unsaturated iron 
binding capacity. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 13 of 75 
 
TABLE OF CONTENTS 
Page 
SIGNATURE PAGE .................................................................................................... 2 
INVESTIGATOR AGREEMENT AND SIGNATURE PAGE ............................... 3 
SYNOPSIS .................................................................................................................... 4 
SCHEMA .................................................................................................................... 10 
TABLE OF CONTENTS .......................................................................................... 13 
LIST OF ABBREVIATIONS ................................................................................... 18 
1. 
INTRODUCTION AND BACKGROUND ...................................................... 20 
1.1 
Background of the Disease and Treatment Options ........................................ 20 
1.2 
Summary of Ferric Carboxymaltose Nonclinical and Clinical Data ............... 21 
 
Pharmacology ............................................................................................... 21 
1.2.1
 
Preclinical and Pharmacokinetic Studies ...................................................... 21 
1.2.2
 
Efficacy ......................................................................................................... 22 
1.2.3
 
Safety ............................................................................................................ 23 
1.2.4
2. 
RATIONALE ..................................................................................................... 25 
2.1 
Design .............................................................................................................. 26 
2.2 
Dose and Drug Selection ................................................................................. 26 
2.3 
Endpoint and Procedures ................................................................................. 27 
 
Primary Endpoint .......................................................................................... 27 
2.3.1
 
Secondary Endpoints .................................................................................... 28 
2.3.2
2.4 
Key Inclusion and Exclusion Criteria .............................................................. 28 
3. 
STUDY OBJECTIVES ...................................................................................... 29 
3.1 
Primary Objective ............................................................................................ 29 
3.2 
Secondary Objectives....................................................................................... 29 
4. 
INVESTIGATIONAL PLAN ........................................................................... 30 
4.1 
Overall Study Design ....................................................................................... 30 
4.2 
Duration of Subject Participation and Study ................................................... 30 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................. 31 
5.1 
Number of Subjects.......................................................................................... 31 
5.2 
Inclusion Criteria ............................................................................................. 31 
5.3 
Exclusion Criteria ............................................................................................ 31 
5.4 
Withdrawal of Subjects .................................................................................... 33 
 
Withdrawal of Subjects from Study Drug .................................................... 33 
5.4.1
 
Withdrawal of Subjects from Study Visits ................................................... 33 
5.4.2
6. 
RANDOMISATION, 
BLINDING 
AND 
UNBLINDING 
PROCEDURES .................................................................................................. 36 
6.1 
Randomisation ................................................................................................. 36 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 14 of 75 
 
6.2 
Blinding............................................................................................................ 36 
6.3 
Unblinding ....................................................................................................... 36 
7. 
STUDY TREATMENTS ................................................................................... 37 
7.1 
Dosage Forms/Formulation ............................................................................. 37 
 
Ferric Carboxymaltose .................................................................................. 37 
7.1.1
 
Iron Sucrose .................................................................................................. 37 
7.1.2
7.2 
Drug Dosage and Administration .................................................................... 38 
 
Arm A: Ferric Carboxymaltose .................................................................... 38 
7.2.1
 
Arm B: Iron Sucrose ..................................................................................... 38 
7.2.2
 
IV Administration of Drug (Both Arms) ...................................................... 39 
7.2.3
7.3 
Package and Labelling ..................................................................................... 40 
7.4 
Study Treatment Allocation ............................................................................. 40 
7.5 
Site Supply, Storage, Accountability ............................................................... 40 
 
Site Supply .................................................................................................... 40 
7.5.1
 
Storage .......................................................................................................... 40 
7.5.2
 
Accountability ............................................................................................... 41 
7.5.3
7.6 
Drug Dose Modification .................................................................................. 41 
 
Procedures for Overdose ............................................................................... 41 
7.6.1
7.7 
Prohibited Therapy and Concomitant Treatment ............................................. 41 
8. 
RISKS/PRECAUTIONS ................................................................................... 43 
8.1 
IV irons ............................................................................................................ 43 
8.2 
Ferric Carboxymaltose ..................................................................................... 43 
8.3 
Iron Sucrose ..................................................................................................... 44 
9. 
STUDY PROCEDURES ................................................................................... 45 
9.1 
Description of Study Assessments ................................................................... 45 
 
Vital Signs..................................................................................................... 45 
9.1.1
 
Physical Examination ................................................................................... 45 
9.1.2
 
Laboratory Parameters .................................................................................. 45 
9.1.3
 
Electrocardiogram ......................................................................................... 46 
9.1.4
 
Urinalysis ...................................................................................................... 46 
9.1.5
9.2 
Schedule of Assessments ................................................................................. 46 
 
Screening and Baseline Procedures .............................................................. 46 
9.2.1
 
Treatment Procedures ................................................................................... 47 
9.2.2
 
End of Study (or Early Discontinuation) Procedures ................................... 48 
9.2.3
 
Unscheduled Visits ....................................................................................... 48 
9.2.4
10. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES .................................................................................................................... 49 
10.1 
Definitions........................................................................................................ 49 
 
Reference Safety Information ....................................................................... 49 
10.1.1
 
Adverse Event ............................................................................................... 49 
10.1.2
 
Adverse Drug Reaction ................................................................................. 49 
10.1.3
 
Unexpected AE/ADR ................................................................................... 49 
10.1.4
 
Serious Adverse Event .................................................................................. 49 
10.1.5


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 15 of 75 
 
 
Suspected Unexpected Serious Adverse Reaction........................................ 50 
10.1.6
 
Special Situations .......................................................................................... 51 
10.1.7
10.2 
Adverse Event Descriptors .............................................................................. 51 
 
Intensity/Severity Categorisation .................................................................. 51 
10.2.1
 
Causal Relationship Categorisation .............................................................. 52 
10.2.2
 
Outcome Categorisation ............................................................................... 53 
10.2.3
 
Pre-existing Medical Conditions .................................................................. 53 
10.2.4
 
Signs and Symptoms of the Disease Under Study ........................................ 53 
10.2.5
 
Clinical Laboratory Evaluations ................................................................... 53 
10.2.6
 
Special Situations .......................................................................................... 55 
10.2.7
10.3 
Reporting Procedure for AEs, SAEs, Special Situationsand Pregnancy ......... 55 
 
Adverse Events ............................................................................................. 55 
10.3.1
 
Serious Adverse Events and Special Situations ............................................ 56 
10.3.2
10.3.2.1 
Elective Surgery/Routine Examination...................................................... 59 
 
Pregnancy...................................................................................................... 59 
10.3.3
11. STATISTICAL ANALYSIS ............................................................................. 61 
11.1 
Statistical Methods ........................................................................................... 61 
11.2 
Sample Size and Power Calculations ............................................................... 61 
11.3 
Analysis Set ..................................................................................................... 62 
 
Full Analysis Set ........................................................................................... 62 
11.3.1
 
Per-Protocol Set ............................................................................................ 62 
11.3.2
 
Safety Set ...................................................................................................... 62 
11.3.3
11.4 
Background and Demographic Characteristics ................................................ 62 
11.5 
Study Medication ............................................................................................. 62 
11.6 
Concomitant Therapy....................................................................................... 63 
11.7 
Efficacy Evaluations ........................................................................................ 63 
 
Primary.......................................................................................................... 63 
11.7.1
 
Secondary...................................................................................................... 63 
11.7.2
11.8 
Safety Evaluations ........................................................................................... 64 
11.9 
Interim Analyses .............................................................................................. 64 
11.10 Other Evaluations............................................................................................. 65 
 Pharmacokinetics .......................................................................................... 65 
11.10.1
12. STUDY ETHICAL CONSIDERATIONS ....................................................... 66 
12.1 
Ethical Conduct of the Study ........................................................................... 66 
12.2 
Informed Consent............................................................................................. 66 
12.3 
Institutional Review Board or EC/IEC ............................................................ 66 
13. QUALITY CONTROL AND QUALITY ASSURANCE ............................... 67 
14. ADMINISTRATIVE PROCEDURES ............................................................. 68 
14.1 
Sponsor’s Responsibilities ............................................................................... 68 
 
Study Supplies .............................................................................................. 68 
14.1.1
 
Insurance ....................................................................................................... 68 
14.1.2
 
Investigator Training..................................................................................... 68 
14.1.3
 
Study Monitoring .......................................................................................... 68 
14.1.4


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 16 of 75 
 
14.2 
Investigator’s Responsibilities ......................................................................... 69 
 
Reporting and Recording of Data ................................................................. 69 
14.2.1
 
Source Documentation .................................................................................. 69 
14.2.2
 
Records Retention ......................................................................................... 70 
14.2.3
 
Site Documentation....................................................................................... 70 
14.2.4
15. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY ....................................... 71 
15.1 
Protocol Waivers, Deviations and Violations .................................................. 71 
15.2 
Protocol Amendments ...................................................................................... 71 
15.3 
Study Termination ........................................................................................... 71 
16. POLICY FOR PUBLICATION AND PRESENTATION OF DATA .......... 72 
17. REFERENCES ................................................................................................... 73 
 
 
 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 17 of 75 
 
LIST OF TABLES 
 
Table 1: Schedule of Events ........................................................................................ 11 
Table 2: FCM Dosing Schedule ................................................................................... 38 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 18 of 75 
 
 LIST OF ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
BW 
Body weight 
CFDA 
Chinese Food and Drug Administration 
CHF 
Chronic heart failure 
CI 
Confidence interval 
CKD 
Chronic kidney disease 
CRF 
Case report form 
CRO 
Contract research organisation 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ESA 
Erythropoiesis stimulating agent 
FAS 
Full analysis set 
FCM 
Ferric carboxymaltose 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMP 
Good Manufacturing Practice 
hsCRP 
High sensitive C-reactive protein 
Hb 
Haemoglobin 
HUB 
Heavy uterine bleeding 
IB 
Investigator’s Brochure 
IBD 
Inflammatory bowel disease 
ICF 
Informed consent form 
ICH 
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements for Pharmaceuticals for Human Use 
ID 
Iron deficiency 
IDA 
Iron deficiency anaemia 
IEC 
Independent Ethics Committee 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 19 of 75 
 
IRB 
Institutional Review Board 
IS 
Iron Sucrose 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetics 
PPS 
Per-protocol set 
RES 
Reticuloendothelial system 
RSI 
Reference safety information 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SMC 
Standard Medical Care 
SmPC 
Summary of Product Characteristics 
TEAE 
Treatment-emergent adverse event 
TSAT 
Transferrin saturation 
WMA 
World Medical Association 
 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 20 of 75 
 
1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options 
Iron deficiency (ID) is one of the most commonly known forms of nutritional 
deficiencies. Iron deficiency is a state in which there is insufficient iron to maintain 
the normal physiological function of tissues such as the blood, brain, and muscles. As 
iron is present in all cells and, as part of enzymes, is essential for numerous vital 
functions, such as oxygen transport, transport of electrons in the form of cytochromes, 
impaired physical condition, cognitive impairment, disturbed thermoregulation and 
fatigue have been described in patients with ID [1]. 
Iron deficiency is usually only detected when untreated ID has led to anaemia. Iron 
deficiency is considered the primary cause of anaemia in approximately 50% of cases 
[3]. Low haemoglobin (Hb) levels, in conjunction with a decrease in erythrocyte 
volume and a low erythrocyte Hb concentration (microcytic, hypochromic anaemia), 
are indicative of iron deficiency anaemia (IDA). Additional assessments include iron 
makers, such as serum ferritin, a cellular iron-binding protein which is also secreted 
into the blood, providing the most reliable indirect measure of body iron stores in the 
absence of infection or inflammation. Serum ferritin levels below 15 ng/mL are 
highly specific for empty iron stores. Values from 15-30 ng/mL correspond to empty 
to limited iron stores; values from 30 to 50 ng/mL are borderline and values above 
50 ng/mL without coexisting inflammation/infection are evidence of sufficient iron 
reserves [3].  
Although a modern diet and the use of iron supplements have reduced the incidence 
and degree of ID in industrialised countries, iron supply is still a problem in certain 
subgroups of the population, namely young children, pregnant and menstruating 
women. The prevalence of iron deficiency that resulted in iron deficiency anaemia 
(IDA) in China, is estimated to range from 19.9% to 28.9%, dependent on the 
population studied, and considered a moderate public health concern [3]. Additionally, 
ID may be observed in patients with chronic diseases where hepcidin is upregulated 
and appears to decrease absorption of iron from the gastrointestinal tract (e.g., chronic 
kidney disease (CKD), chronic heart failure (CHF) or inflammatory bowel disease 
(IBD)). For instance, it has been demonstrated that ID alone is an independent risk 
factor for mortality in patients with CHF [4].  
Mild ID (i.e., plasma ferritin <30 ng/mL, transferrin saturation (TSAT) <20% [5]) can 
be prevented or corrected by eating iron-rich foods. However, as ID can have serious 
health consequences that diet may not be able to quickly correct, iron supplementation 
may be necessary. Initial treatment options usually include oral iron replacement 
therapies. Unfortunately, there is a subset of patients where oral iron is ineffective or 
cannot be tolerated and intravenous (IV) iron replacement is required.  
Typically, oral iron is not effective in populations that have an underlying chronic 
disease that may be impairing absorption of iron from food (or other oral supplements) 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 21 of 75 
 
or where the loss is greater than amount that can be replaced or there is a need for a 
more rapid repletion than can be achieved with oral iron. Diseases that may lead to 
impaired absorption have resulted in numerous international guidelines being 
developed to aid in guiding physicians for appropriate correction measures. Examples 
of where IV iron is recommended include CKD [6], IBD [7] and oncology [8]. 
Iron Sucrose (IS, Venofer®) is an IV iron replacement therapy approved in China. 
This was first approved in China in 2008 and is used in patients in whom the results 
following oral administration of iron preparations are not good and who require IV 
iron therapy. It is recommended that the iron deficit is calculated with the Ganzoni 
formula [9] and thereafter corrected with individual bolus IV injections/ infusions of 
up to 200 mg iron administered.  
1.2 
Summary of Ferric Carboxymaltose Nonclinical and Clinical 
Data 
 
Pharmacology 
1.2.1
Ferric carboxymaltose (FCM, Ferinject®) is a polynuclear iron(III)-hydroxide 
carboxymaltose complex with a molecular weight of about 150,000 Daltons.  
 
 
 
 
. 
 
Preclinical and Pharmacokinetic Studies 
1.2.2
In pharmacokinetic (PK) studies after IV administration in Caucasian subjects, iron 
provided by FCM was rapidly cleared from the serum and efficiently incorporated 
into erythrocytes [10]. Iron from FCM was distributed predominantly to the liver, 
spleen and bone marrow [11]. Non-clinical studies showed that, in the liver, which is 
a primary site for iron storage, IV administration of FCM resulted in iron localisation 
predominantly in cells of the reticuloendothelial system (RES), with minor amounts in 
the parenchyma [12]. The deposition of iron in the RES (phagocytes/monocytes) is 
preferred as it minimises the potential for iron-induced oxidative damage to the 
parenchyma, as described in mice with different IV iron preparations [13].  
It is to be considered that the findings observed in the various toxicological studies 
resulted from iron overload in healthy iron-replete animals. Iron accumulation could 
be seen predominantly in the liver, spleen and kidneys when repeated high doses were 
administered to rats and dogs. Repeated-dose toxicity studies in rats and dogs indicate 
that in terms of total iron dose, there is about a 3- to 8-fold safety margin to the 
human dose based on the no observed adverse effect level. 
Data from reproductive and developmental toxicity studies indicate that there is a 
minimal risk associated with administration of FCM during pregnancy and lactation. 
Nonclinical studies suggested that there is limited placental or milk transfer of iron 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 22 of 75 
 
from FCM after maternal exposure to FCM. Therefore, the use of FCM is 
contraindicated in the first trimester of pregnancy, and the potential risks and benefits 
should be carefully balanced when considering use of FCM in pregnant women in the 
second and third trimester, or lactating women. 
Ferric carboxymaltose did not demonstrate genotoxic potential in a standard battery of 
tests. 
Ferric carboxymaltose did not exhibit cross reactivity with anti-dextran antibodies in a 
guinea pig passive cutaneous anaphylaxis model. Administration of a challenge dose 
of FCM to previously treated rats did not result in a hypersensitivity reaction. 
Based on these nonclinical studies, FCM is considered to have a suitable 
pharmacologic, toxicologic and safety profile for IV dosing in humans for the 
treatment of ID/IDA. 
 
Efficacy 
1.2.3
In general, clinical safety and efficacy studies have been conducted in numerous 
settings representative of underlying diseases that may lead to ID; i.e., diseases with 
increased inflammatory status impairing iron absorption as well as diseases with 
increased losses of iron that cannot be compensated via dietary iron. Single iron doses 
administered to subjects ranged from 100 mg to 1,000 mg iron, with cumulative iron 
doses of up to 6,500 mg administered for repletion and maintenance of iron stores. 
More specifically, studies have been conducted in conditions leading to ID/IDA using 
distinct populations in nephrology, women’s health, gastroenterology, cardiology, and 
neurology, as well as combinations of various populations. Data of 7,300 subjects 
treated with FCM in 38 clinical trials have been generated so far. No studies have 
been performed in healthy volunteers due to the fact that FCM is designed to 
replenish deficient iron deposits, and as iron cannot be excreted, administration to 
healthy non-iron deficient volunteers may be toxic.  
Across the various clinical studies performed, effective 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 with associated anaemia, 
correction of ID using FCM has consistently resulted in significant increases in Hb 
values (correction of anaemia). An increase in Hb values was usually seen within 4 
weeks of FCM administration. In addition to the correction of laboratory parameters, 
iron replacement therapy has demonstrated significant improvements in quality of life 
and functional and symptomatic status in some patient populations. Of importance, 
these latter improvements were also seen when FCM was administered to ID subjects 
without anaemia, with no significant changes (either increase or decrease) to Hb 
values.  
Ferric carboxymaltose first received marketing authorisation in The Netherlands in 
July 2007, and since then, in over 60 countries worldwide. The total exposure of 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 23 of 75 
 
patients since the introduction of FCM into the market up to 1 January 2015 
corresponds to over 2,179,768 patient years. The total number of adverse drug 
experience cases reported is considered small with respect to the overall drug 
exposure. The reports confirm the known adverse event (AE) profile and the positive 
benefit/risk ratio of FCM. 
 
Safety 
1.2.4
Ferric carboxymaltose was well tolerated by study participants. In completed clinical 
studies, up to 1 January 2015, approximately 50% of the subjects experienced at least 
one treatment-emergent adverse event (TEAE), and events considered related to 
treatment occurred in 17.5% of subjects who received FCM. Overall, the most 
commonly reported adverse drug reactions (ADR) in the FCM group were nausea, 
headache, 
dizziness, 
hypertension, 
injection/infusion 
site 
reactions, 
hypophosphataemia  and flushing. Only 1.7% of subjects had severe TEAEs. 
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 (AST 
and alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT and alkaline 
phosphatase (AP, 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 only observed in very few cases, and was of short duration.  
A human breast milk excretion sub-study suggests a low toxic potential for infants 
breastfed by mothers receiving FCM (Study VIT-IV-CL-009). Higher iron levels in 
breast milk were measured 24 and 48 hours after IV administration of FCM compared 
with ferrous sulphate, however all levels of iron measured were considerably lower 
than toxic levels that could result in iron intoxication of the newborn. Transfer of iron 
from FCM to human milk was ≤1%. Based on limited data on nursing women, it is 
unlikely that FCM represents a risk to the nursing child. 
The safety profile of FCM in the first trimester of pregnancy has not been 
demonstrated in a clinical trial. There is, however, a limited amount of data from a 
recent clinical study (FER-ASAP-2009-01) in which no new safety signals were 
observed for mother and child after administration of FCM (n=123) for the treatment 
of IDA in the second and/or third trimester of pregnancy.  A careful benefit/risk 
evaluation is required before FCM use during pregnancy. If the benefit of FCM 
treatment is judged to outweigh the potential risk to the foetus, it is recommended that 
treatment be confined to the second and third trimester of pregnancy. 
As with all parenteral iron preparations the absorption of oral iron is reduced when 
administered concomitantly. No formal interaction studies have been performed.  


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 24 of 75 
 
Refer to the Investigator’s Brochure (IB) for further details. 
 
 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 25 of 75 
 
2. RATIONALE 
Ferric carboxymaltose has been developed by Vifor Pharma – Vifor International Inc. 
as a formulation enabling the application of high iron doses of up to 20 mg/kg body 
weight as infusion, and as undiluted injection of up to 15 mg/kg body weight. Ferric 
carboxymaltose has a low immunogenic potential and does not exhibit cross-reactivity 
to anti-dextran antibodies. The application of high doses of IV iron in 1 single 
administration with the potential to replenish the iron stores has multiple advantages 
over multiple smaller doses. Compared to other IV iron products, FCM can be given 
in a short time (6 minutes instead of 3.5 hours for a 500 mg iron dose) and in iron 
doses of up to 1,000 mg, which reduced the need for the subject for multiple and long 
stays at the hospital. This reduces hospital costs [5]. Also, especially in rural regions, 
a single administration for replenishing the iron stores may help to increase subject 
compliance, and might make long journeys to the hospital unnecessary. A single 
administration versus multiple infusions additionally reduces the risks associated with 
the administration procedure, such as phlebitis, infection, extravasation, of other 
infusion-related AEs [5]. 
It has been seen that interethnic variability in PKs of certain drugs can cause 
unexpected outcomes, such as therapeutic failure, adverse effects, and toxicity in 
subjects of different ethnic origin, which can be both due to genetic and 
environmental factors. The International Conference on Harmonisation (ICH) 
published a guidance to facilitate the registration of drugs among ICH regions 
(European Union, Japan, the United States), recommending a framework for 
evaluating the impact of ethnic factors on efficacy and safety of drugs at a particular 
dosage and dosage regimen. Especially drugs metabolised via the Phase 1 enzymes of 
the cytochrome group are prone to ethnical and/or genetic variability [14].Ferric 
carboxymaltose is not metabolised via cytochrome and constitutes a delivery system 
for the trace element iron. Based on limited data from Asian subjects who participated 
in the global registration studies conducted in Europe, genetic or interracial 
differences are not expected. 
According to the “ Reform Plan for Chemical Drug Registration Classification 
([2016] No. 51)” issued by the China Food and Drug Administration (CFDA) and 
effective since 04 March 2016, FCM constitutes a Category 5.1 drug, Originators 
marketed overseas under application for being listed in China. And according to 
requirement of clinical trials for products that are marketed overseas but not in China 
(CFDA order 28, Provisions for Drug Registration), a PK study should be conducted 
together with a 100-pair phase 3 study. This Phase 3 bridging study is designed to 
assess safety of FCM in the Chinese population, and to show efficacy by 
demonstrating non-inferiority to IS (Venofer), an IV iron product which is currently 
available on the Chinese market. A Phase 1, ascending dose study, VIT-IRON-2011-
003, will be conducted in parallel to this Phase 3 study. The objective of this study is 
to evaluate the PK and pharmacodynamics of FCM in Chinese subjects with IDA.  


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 26 of 75 
 
2.1 
Design 
An efficacy study in Caucasian subjects by Evstatiev et al, 2011 [15] demonstrated 
that FCM administered using a simplified dosing formula (as proposed in this study) 
was superior to IS dosed using the Ganzoni formula (at multiple 200 mg iron doses). 
However, since no data are available on the use of FCM in Chinese patients, a non-
inferiority design has been chosen for this study, assuming that FCM treatment is at 
least as good as IS in Chinese subjects. A randomised design was chosen to reduce 
bias in baseline differences between the treatment groups. 
Due to the differences in posology between the study drug (FCM) and the comparator 
(IS) additional administrations may be required for subjects receiving IS. In a 65 kg 
subject with Hb of 9 g/dL at screening, FCM would require 2 individual doses of 
FCM (1,000 mg iron followed by a single dose of 500 mg iron 1 week later). 
However, if the same subject was randomised to receive IS, the cumulative dose 
required (as per label) would be 1,436 mg iron which would require 7 individual 200 
mg iron doses (i.e., bi-weekly dosing) starting on Day 1. 
Therefore, this study will utilise an open-label design to avoid unnecessary IV 
placebo injections. This reduces the burden of requiring additional subject visits to 
both groups (as subjects receiving IS will need more dosing visits than subjects in the 
FCM group) as well as removing the potential for infection and other side-effects that 
may result from an IV placebo injection.  
IV iron products are designed to deliver, in a controlled way, iron to the body and to 
replenish iron stores and as a consequence increase Hb concentration. Therefore, the 
study primary endpoint is the percentage of subjects achieving an increase in Hb ≥ 
2g/dL (responders) from baseline at any time up to Week 8. Since knowledge of the 
study drug will not impact this objective parameter, in addition to the fact that all 
subjects will be receiving IV iron, the open-label design is considered to be the most 
appropriate design for this study. 
2.2 
Dose and Drug Selection 
Ferric carboxymaltose is an IV iron preparation which, in Europe, is indicated for 
subjects with ID when oral iron preparations are ineffective or cannot be used. It is a 
Type 1 iron complex with a low risk of toxicity as Type 1 iron complexes are stable 
and robust complexes [13]. As such, FCM provides iron for the endogenous iron 
transport and storage proteins in a controlled manner. This permits FCM to be 
administered in individual dosing at up to 1,000 mg iron at relatively short time 
intervals. Moreover, being free of dextran or dextran derivatives, FCM has no risk of 
dextran-induced immunogenicity. Nevertheless, as with all IV iron preparations, FCM 
may induce hypersensitivity reactions (see Section 8.1). 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 27 of 75 
 
The IB summarises data from over 30 completed clinical trials with FCM which 
supports the administration of doses of up to 1,000 mg per administration, with an 
approved maximum single dose of 20 mg iron/kg BW.  
Traditionally the Ganzoni formula has been used to calculate total iron requirements 
[9]. However, Evstatiev et al, 2011 [15] have recently demonstrated that FCM dosed 
using a simplified dosing formula (as proposed in this study) is superior in efficacy to 
dosing using the Ganzoni formula (using Venofer at multiple 200 mg iron doses). The 
simplified dosing formula (Table 2) is calculated based on subject BW and Hb. Using 
this standard formula, the heaviest subjects with low Hb receive the highest 
cumulative iron doses.  
As such, FCM will be administered using this simplified formula for calculating the 
total iron dose to achieve appropriate repletion of iron requirements. 
An IV iron preparation is deemed most appropriate as a comparator arm within this 
study. Iron Sucrose (Venofer) manufactured by Vifor Pharma is an IV iron 
preparation available on the Chinese market and was selected as the comparator 
product. Iron Sucrose has a favourable and well documented safety profile. 
Alternative products at higher doses are all dextran-based with risk of dextran-
induced anaphylactic reactions and other non-dextran based IV irons were less stable 
than IS and therefore would have required lower maximal single iron doses with an 
additional visit burden on subjects and participating sites. Additionally, there are 
numerous studies comparing FCM and IS that confirm the choice as an appropriate 
comparator. For subjects randomised to the IS arm, dosing (including calculation of 
the total dose) will be per the approved Chinese label.  
2.3 
Endpoint and Procedures 
 
Primary Endpoint 
2.3.1
As IV iron products are designed to deliver, in a controlled way, iron to the body and 
to replenish iron stores, and as a consequence increase Hb concentration, the study 
primary endpoint is the percentage of subjects with an increase in Hb ≥ 2g/dL 
(responders) from baseline at any time up to Week 8.  
The aim is to demonstrate non-inferiority of FCM given in a standardised dosing 
regimen to the currently approved formulation (IS) given according to the Ganzoni 
formula with respect to increase in Hb ≥ 2g/dL  from baseline at any time up to Week 
8. As IS is given in doses of 200 mg iron, it might take longer for the subject to 
receive the complete iron dose (e.g., 3 weeks with 3 injections per week if 1,800 mg 
are needed), as compared to FCM. To allow for the control subjects to respond to IV 
iron treatment, an 8 week study duration is chosen, which is expected to be within 5 
weeks after the last treatment received for the majority of the control subjects. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 28 of 75 
 
 
Secondary Endpoints 
2.3.2
In addition to demonstrating an increase in Hb ≥ 2g/dL (responders) from baseline at 
any time up to Week 8, the study will summarise the absolute and change from 
baseline of key laboratory parameters, such as Hb, TSAT and serum ferritin as well as 
the percentage of subjects achieving TSAT ≥16 % and serum ferritin ≥ 100 ng/mL 
(for subjects with underlying inflammation) or serum ferritin > 14 ng/mL (for subjects 
with no underlying inflammation). This will permit for confirmation of the 
replenishment of iron stores as well as to document if Hb will increase to values 
above the normal range and will allow the physician to determine appropriateness of 
medication.  
2.4 
Key Inclusion and Exclusion Criteria 
The inclusion criteria match the key population where the drug could be utilised. The 
excluded population reflects known and/or theoretical high-risk populations and/or 
those with ID due to other causes and are hence excluded from this study.  
Due to the wide number of underlying diseases or general population that may suffer 
from IDA, there are no specific criteria for disease aetiology. However, when 
including subjects and summarising safety aspects, the underlying disease will be 
included as a key variable due to the significant impact it may have on serum ferritin 
levels (inclusion criteria and known to be elevated in subjects with chronic disease) 
and on the AEs that are reported (as the underlying disease may increase the risk of 
events including risk of morbidity). Note, all safety events will have physician 
assessed relationship to study drug recorded to permit distinguishing between events 
due to disease and those related to drug – with drug related events also presented for 
the overall population.  
Subjects with IDA (defined as Hb <11 g/dL for females and <12 g/dL for males, 
serum ferritin <100 ng/mL (if subject has concomitant inflammation) or ≤14 ng/mL 
(in non-inflamed subjects), TSAT <16%, mean corpuscular Hb concentration (MCHC) 
<32%, mean corpuscular volume (MCV) <80 fl, and mean corpuscular Hb (MCH) 
<27 pg) will be included. Success of IDA treatment will be assessed by comparing 
change from baseline in Hb as well as serum ferritin (as marker for iron stores) and 
TSAT (as marker for circulatory iron pool) between treatment groups. Subjects with 
hypersensitivity to FCM or any of its excipients, subjects with evidence of iron 
overload or disturbances in utilisation of iron (i.e. sideroachrestic anaemia) and 
subjects with anaemia not attributed to ID are excluded as IV iron administration is 
contraindicated. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 29 of 75 
 
3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To demonstrate the efficacy of FCM given in a simple dosing regimen in 
correcting IDA, by demonstrating non-inferiority to treatment with the currently 
approved IV iron therapy of IS (Venofer) in the Chinese population. 
3.2 
Secondary Objectives 
• To assess the safety of FCM compared to IS in the Chinese population. 
• To evaluate the effect of FCM compared to IS on relevant laboratory parameters 
(haematology, chemistry, iron parameters) in the Chinese population. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 30 of 75 
 
4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is an open-label, randomised controlled study to assess the impact of FCM in 
correcting IDA compared to Venofer (IS) in Chinese subjects. The study will 
randomise approximately 368 subjects (184 per group) suffering from different 
underlying diseases leading to IDA. It is expected that approximately 850 subjects 
need to be screened to randomise 368 subjects. 
After an initial screening period (up to 7 days), eligible subjects will undergo baseline 
assessments and will be randomised (1:1) to receive either FCM or IS at study Day 1.  
In the FCM group, study drug administration will occur on Day 1 and, if needed, on 
Day 8 and Day 15. Subjects randomised to IS will receive injections/infusions of a 
maximum of 200 mg iron three times a week until the calculated total iron dose is 
administered.  
All subjects will return for assessment of efficacy and safety at Weeks 2, 4, 6 and 8. 
The schedule of assessments is provided in Table 1: Schedule of Events. 
Randomised subjects who terminate their study participation for any reason regardless 
of whether the study drug was taken or not, will retain their randomisation number. 
The next subject will be given the next randomisation number. 
The Investigator is responsible for ensuring that consideration is given to the post 
study care of the subject's medical condition. 
 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is a maximum of 10 weeks: Screening 
period duration is up to 1 week; treatment period duration including follow up is 8 
weeks (±4 days). 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 31 of 75 
 
5. SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 
Number of Subjects 
Approximately 368 subjects will be randomised into this study. It is expected that 
approximately 850 subjects will need to be screened to achieve 368 randomised 
subjects. For detailed justification of the sample size please refer to Section 11.2, 
Sample Size and Power Calculations. 
5.2 
Inclusion Criteria 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes minimum key 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. At least 18 years of age. 
2. Hb < 11 g/dL (females) or <12 g/dL (males) at screening visit 
3. Serum ferritin <100 ng/mL for subjects with underlying inflammatory disease (e.g. 
IBD, CKD or CHF, as determined by high sensitive C-reactive protein (hsCRP) 
levels above the normal range) otherwise serum ferritin ≤14 ng/mL in subjects 
with no apparent underlying inflammatory disease (as determined by hsCRP 
levels within normal range) at the screening visit 
4. TSAT <16% (any subject) at the screening visit. 
5. Microcytic, hypochromic anaemia at the screening visit, defined as: 
a. MCHC < 32% 
b. MCV < 80 fL 
c. MCH < 27 pg 
6. Subjects with the ability to understand the requirements of the study and abide by 
the study restrictions, and who agree to return for the required assessments 
7. Before any study-specific procedure is conducted, the appropriate written 
informed consent must be obtained. 
5.3 
Exclusion Criteria 
1. Subject has known hypersensitivity to any of the products to be administered 
during dosing. 
2. Any history of iron storage diseases such as haemochromatosis. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 32 of 75 
 
3. Any history or clinical findings of iron utilisation disorders such as sideroachrestic 
anaemia 
4. Known haemoglobinopathies (e.g. thalassaemia).  
5. Any history or clinical findings of anaemia associated with: 
a. Haematuria 
b. Vitamin B12 or folic acid deficiency that requires treatment (subjects 
can be included after deficiency is corrected) 
6. Any allergic predispositions, i.e. any history of asthma or atopic allergy. This 
includes drug allergies. 
7. Planned surgery with anticipated blood loss (defined as Hb drop  >2 g/dL) in the 
3 months post-randomisation. 
8. Subject has known malignancy (with or without current treatment), except basal 
cell or squamous cell carcinoma of the skin or cervical intra-epithelial neoplasia. 
9. Haemodialysis (current or planned within the next 3 months). 
10. History of IV iron therapy, erythropoiesis stimulating agent (ESA therapy and/or 
blood transfusion in previous 4 weeks prior to baseline, and oral iron or iron-
containing products including Chinese herbal medicines (>75mg iron/day) in the 
7 days prior to baseline. 
11. Body weight <35 kg. 
12. Chronic liver disease and/or screening ALT or AST above 3 times the upper limit 
of the normal range.  
13. Known human immunodeficiency virus infection, acquired immunodeficiency 
syndrome, tuberculosis.  
14. Known active hepatitis B or C or other active infection (acute or chronic).  
15. Subject currently is enrolled in or has not yet completed at least 30 days since 
ending other investigational device or drug study(ies), or subject is receiving other 
investigational agent(s). 
16. Subject is pregnant or is breast feeding. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 33 of 75 
 
17. Female subject of childbearing potential is not using adequate contraceptive 
methods during the study and for up to 1 month after the last dose of the study 
medication. Adequate contraceptive methods are defined as those which result in a 
low failure rate (i.e., less than 1% per year) when used consistently and correctly 
such as implants, injectables, combined oral contraceptives, some intra-uterine 
devices, sexual abstinence or vasectomised partner. Non-childbearing potential 
includes being surgically sterilised at least 6 months prior to the study or 
post-menopausal, defined as amenorrhoea for at least 12 months. 
18. Male subjects planning to father a child within 7 days from the last study drug 
administration. 
19. Subject has any kind of disorder that compromises the ability of the subject to 
give written informed consent and/or to comply with study procedures and/or 
other reason(s) that render subject not appropriate for study participation in the 
opinion of the treating physician. 
5.4 
Withdrawal of Subjects 
 
Withdrawal of Subjects from Study Drug 
5.4.1
Study drug must be stopped if the subject experiences any kind of hypersensitivity 
reaction related to the study drug during administration. The subject may remain in 
the study and continue to attend study visits. Whether the subject will receive 
additional doses of study drug will be discussed with the Medical Monitor and will be 
decided on a case by case basis.  
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. If the subjects are withdrawn from study drug 
they may remain in the study and continue to attend study visits. 
Subjects discontinuing study drug will not be replaced. 
 
Withdrawal of Subjects from Study Visits 
5.4.2
Subjects may voluntarily withdraw from study participation at any time without 
having to provide a reason. Subjects may be withdrawn because of the appearance of 
a new health condition which may require care or medications prohibited by the 
protocol, unacceptable AEs, refusal to continue treatment, or at the Investigator’s 
discretion if it is in the subject’s best interest. 
If a subject withdraws from the study at any time either at his or her request or at the 
Investigator’s discretion, the reason(s), including the primary reason for withdrawal, 
if provided by the subject, should be recorded. Subjects who discontinue the study 
prematurely should undergo all End of Study assessments, if possible. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 34 of 75 
 
Subjects may be withdrawn by the Investigator and their study participation 
discontinued prematurely for several reasons. Discontinuation from the study is 
mandatory in the following circumstances:  
• The subject requires blood transfusion or ESA treatment (e.g. for excessive acute 
bleeding) or intake of iron preparations other than the study drug. If possible, 
discontinuation assessments should take place before transfusion or treatment. The 
reason for discontinuation and the date must be recorded on the appropriate page 
of the case report form (CRF). The date on which the procedure actually took 
place should also be recorded on the CRF. 
• Surgery with expected significant blood loss. 
• Development of an illness, condition, or procedural complication, which would 
interfere with the subject’s continued participation. 
• The Investigator/study physician feels it is medically in the best interest of the 
subject to discontinue the subject’s participation in the study. 
• Pregnancy (to be recorded on the specific pregnancy reporting form). 
Subjects may be discontinued from the study for the following reasons (reason to be 
recorded on the appropriate page of the CRF): 
• Subject does not comply with study procedures. 
Appropriate documentation will be kept for all subjects who are enrolled into the 
study (i.e., who provide written informed consent). All subjects who discontinue from 
the study will be strongly encouraged to have all assessments for the End of Study 
visit (Visit 6) performed.  
If a subject refuses to continue in the study, the reason for refusal must be fully 
documented in the subject’s source document and recorded in the study-specific CRF. 
It is the subject’s right to withdraw from the trial without providing a reason. In this 
case, the source documents and the CRF must document the reason for 
discontinuation as “withdrawal by subject”. 
It is essential 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 must be followed-up 
by the investigator through contact with the subject until resolution or stabilisation has 
occurred. All AEs must be followed-up until resolution, stabilisation or the subject is 
lost to follow-up and cannot be contacted.   
Reasons for discontinuations will be documented in the CRFs. Subjects who 
discontinue prematurely will not be replaced. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 35 of 75 
 
The Sponsor may discontinue the study for any reason at any time. In this case, all 
subjects, after a final visit, will be withdrawn from the study and study treatment 
discontinued.  


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 36 of 75 
 
6. RANDOMISATION, BLINDING AND UNBLINDING 
PROCEDURES 
6.1 
Randomisation 
An Interactive Response Technology (IRT) system will be used in the study. A 
separate user manual that outlines the details of IRT will be provided to the sites. 
All subjects screened must be identifiable throughout the study and will be given a 
unique study subject number. Each site will be identified by a 3 digit number, and 
subject numbering will be assigned by IRT. The Investigator will maintain a list of 
subject numbers and subject names to enable records to be matched at a later date. 
Randomisation of eligible subjects will be performed before start of treatment with 
study drug. Randomisation will be performed based on a pre-defined, computer 
generated randomisation list. The subjects will be randomised 1:1 to receive either 
FCM administration(s) or IS.  IRT will be contacted for treatment assignment 
following confirmation of eligibility at the Baseline visit.  
6.2 
Blinding 
Due to the differences in posology between the study drug (FCM) and the comparator 
(IS) more injections/infusions may be required for subjects receiving IS. 
Therefore, the study will utilise an open-label design to avoid unnecessary IV placebo 
injections/infusions. This reduces the burden of requiring additional subject visits to 
both groups as well as removing potential infections and other side-effects that may 
result from a placebo IV injection/infusion.  
6.3 
Unblinding 
As this is an open-label study, unblinding procedures are not applicable. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 37 of 75 
 
7. STUDY TREATMENTS 
7.1 
Dosage Forms/Formulation 
All investigational medicinal products used in this study have been manufactured in 
accordance with current Good Manufacturing Practice (GMP). 
 
Ferric Carboxymaltose 
7.1.1
Ferric carboxymaltose will be provided by Vifor Pharma – Vifor (International) Inc. 
for this study. 
Strength: 
Sterile FCM solution as a 5% w/v iron solution in water for 
injection.  
Excipients: 
 
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: 
 
Note: 
For drip infusions, FCM must be diluted only in sterile 0.9% 
sodium chloride solution. 
 
Iron Sucrose 
7.1.2
Iron Sucrose (Venofer) will be provided by Vifor Pharma – Vifor (International) Inc. 
for this study. 
Strength: 
Sterile solution for injection containing 2% w/v iron. 1 mL of 
Venofer contains 20 mg of iron. 
Excipients: 
Water for injection, sodium hydroxide (for pH adjustment). 
Appearance: 
Dark brown, non-transparent aqueous solution. 
Dosage Form: 
5 mL ampoules containing 100 mg iron per ampoule. 
Manufacturer: 
Vifor Pharma – Vifor (International) Inc., Switzerland. 
Storage: 
Store between 4°C and 25°C. Do not freeze. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 38 of 75 
 
7.2 
Drug Dosage and Administration 
 
Arm A: Ferric Carboxymaltose  
7.2.1
Study drug should be administered in doses based on subject BW and Hb value at 
screening as per Table 2.  
Subjects will receive study drug as undiluted injection or infusion. The individual 
dose requirement (in mg of iron) per visit is described below: 
 
 
Table 2: FCM Dosing Schedule 
 
Total Iron (mg) as FCM 
 
BW 35 - <70 kg1 
BW ≥70 kg 
 
 
Hb <10 g/dL 
Hb ≥10- <14 
g/dL 
Hb <10 g/dL 
Hb ≥10- <14 
g/dL 
 
Day  1 
 
1,000 mg 
1,000 mg 
1,000 mg 
1,000 mg 
 
Day 8 
 
500 mg 
No dose 
1,000 mg 
500 mg 
 
Notes: BW = Body weight; FCM = Ferric carboxymaltose; Hb = Haemoglobin. 
1.The maximum single dose that should be given to a subject  is 20 mg/kg BW, therefore for subjects with BW 35 - <50kg and 
Hb ≥ 10 g/dL, the 1,000 mg  dose should be split into 2 x 500 mg (one 500 mg dose on Day 1 and one 500 mg dose on Day 8. 
Subjects with BW 35 - <50 kg and Hb < 10g/dL should receive 3 doses of 500 mg (on Day 1, 8 and 15) . 
 
 
For IV injection, the required amount of FCM solution will be drawn from the vial 
into a syringe and injected as an undiluted solution.   
For drip infusion, FCM solution must be diluted only in sterile 0.9% m/V sodium 
chloride solution (500 mg iron diluted in 100 mL 0.9% w/v physiological saline, for a 
total volume of 110 ml or 1,000 mg iron diluted in 250 mL 0.9% w/v physiological 
saline, for a total volume of 270 ml). For stability reasons, dilutions to concentrations 
less than 2 mg iron/mL are not permitted. 
From a microbial point of view, FCM preparations for parenteral administration must 
be used immediately after dilution with sterile 0.9% m/V sodium chloride solution.  
For both injection and infusion, FCM should be administered up to a maximum single 
dose of 1,000 mg iron (up to a maximum of 20 mg/kg BW) over at least 5 minutes for 
the 500 mg dose and over at least 15 min for the 1,000 mg dose. Administration time 
should not exceed 30 minutes for either the 500 or the 1,000 mg dose. 
 
Arm B: Iron Sucrose 
7.2.2
For subjects in the individually calculated IS dosage regimen group, the individual 
iron deficit will be calculated using the formula of Ganzoni [9]: 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 39 of 75 
 
Cumulative iron deficit [mg] = 
BW [kg] x (target Hb(1) - actual Hb) [g/dL](2) x 2.4(3) + 500 mg(4) 
(1) Target Hb for BW >35 kg = 15 g/dL, respectively 9.3 mmol/L 
(2) To convert mmol/L to g/dL: multiply Hb (mmol/L) by the factor 1.61145 
(3) Factor 2.4 = 0.0034 (iron content Hb = 0.34%) x 0.07 (blood volume = 7% of BW) x 10,000 
(conversion g/dL to mg/L) 
(4) Iron storage depot 
Note: BW = Body weight. 
 
The calculated cumulative IS dose is to be rounded up or down to the nearest 200 mg. 
Subjects will receive single doses of IS of up to a maximum single dose of 200mg 
iron three times a week. Depending on the calculated iron deficit, up to 11 IS 
injections will be given.  
Iron Sucrose (Venofer) will be administered by slow IV push injection at a rate of 1 
ml undiluted solution per minute (10 ml of the product in at least 10 minutes; 
administration time should not exceed 60 minutes) or by drip infusion in a dilution of 
1 ml of Venofer in maximum 20 ml 0.9% w/v physiological saline (10 ml of the 
product in maximum 200 ml saline).  Venofer must be used immediately after dilution. 
The drip infusion rate should be 200 ml solution in at least 30 minutes, and should not 
exceed 60 minutes. 
 
IV Administration of Drug (Both Arms) 
7.2.3
Study personnel responsible for study drug application will apply a tourniquet, seek a 
suitable vein, disinfect injection site and perform the vein puncture. It is 
recommended to use a blue catheter 22 gauge (or pink catheter 20 gauge) and secure 
it with duct tape. The use of blue butterfly needle is possible.  
After the puncture, the correct position of the needle can be reviewed in the vein by 
flushing with 10 mL NaCl 0.9%. Connect the syringe or infusion set to the needle and 
slowly inject or infuse the FCM (see Section 7.2.1, Arm A: Ferric Carboxymaltose) or 
IS (see Section 7.2.2, Arm B: Iron Sucrose). The vein should then be flushed with 5-
10 mL saline.  
Study medication should only be administered when staff trained to evaluate and 
manage anaphylactic reactions are immediately available, in an environment where 
full resuscitation facilities can be assured. Each subject should be observed for 
adverse effects during and for at least 30 minutes following each injection. 
Hospitalisation for study drug administration is not a requirement of the study. 
However, Investigators might choose to hospitalise subjects while they receive study 
drug as a precautionary measure. Hospitalisation for this purpose does not fulfil the 
criteria of a serious adverse event (SAE) and will not be recorded as such. If an 
AE/SAE occurs before, during or after administration of study drug during 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 40 of 75 
 
hospitalisation, this shall be assessed and recorded as per seriousness criteria for 
AE/SAEs.  
Since FCM has a physiological pH, pain at the injection site is very unlikely, therefore 
caution should be given to avoid paravenous injections. The choice of an appropriate 
needle for the IV access should minimise the potential risk of a paravenous injection 
of FCM or IS. Iron Sucrose has a basic pH and therefore, if paravenous leakage 
occurs, a burning sensation is felt by the subject. 
Treatment administration of FCM or IS must be discontinued immediately if swelling 
(paravenous injection) is observed, which can cause irritation and a brown 
discolouration of the skin which can be long-lasting. No rinsing or pressure bandage 
should be used, in order to prevent distribution and extension of extravasations.  
Study treatment can be re-administered in a different location (i.e. other arm). 
7.3 
Package and Labelling 
Both FCM and IS will be supplied to each site already packaged and labelled. All 
packaging and labelling operations will be performed according to GMP and Good 
Clinical Practice (GCP) guidelines. Labelling will be in accordance with local study 
site regulations for investigational products. Ferric carboxymaltose will be packaged 
in kits containing 1 labelled FCM vial (500 mg per 10 ml). Venofer will be packaged 
in kits containing 2 ampoules of Venofer (100 mg per 5 ml). Kits will be numbered 
for tracking purposes. The kit box as well as the vial/ampoule in the kit box will be 
labelled with the same kit number. 
7.4 
Study Treatment Allocation 
Each eligible subject will be assigned to 1 of the treatment arms using IRT. 
7.5 
Site Supply, Storage, Accountability 
 
Site Supply 
7.5.1
Once a site has been approved to receive study drug, the site will be supplied with an 
initial stock of study drug. The need for drug resupply will be assessed on a regular 
basis taking into account the number of subjects enrolled, and the number of subjects 
in screening, at the site. 
 
Storage 
7.5.2
 
 
Use of a calibrated thermometer and maintenance of a temperature log is mandatory. 
The log should be updated by site personnel at least once weekly with the minimum 
and maximum temperatures for the week being recorded. This log must be available 
for review by the Monitor during on-site monitoring visits. Should the storage 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 41 of 75 
 
temperature be outside the range, the medication must be quarantined immediately 
and the Sponsor must be contacted for guidance. 
 
Accountability 
7.5.3
The Investigator at each site is responsible for study drug supplies. The Investigator 
will ensure that adequate records of the receipt, preparation, administration and return 
of the study drug are kept and that the study drug is used only for subjects enrolled in 
the study. All data regarding the study drug must be recorded on the relevant forms 
provided. 
Each study site will maintain a drug inventory/dispensing record for all drugs 
dispensed and returned. At the end of the study, 1 copy of the drug 
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 materials will be 
returned to the Sponsor. If the study medication is destroyed at site, the Investigator 
will forward the certificate of destruction to the Sponsor. The decision to destroy 
study medication at site must be made by the Sponsor. 
7.6 
Drug Dose Modification 
If extravasation is noted during administration of FCM or IS, dosing should be ceased 
immediately. Study drug administration may be completed using a different injection 
site to complete the required dosage. If it is not possible to administer the full dose to 
a subject, the amount of actual dose administered must be documented on the relevant 
page of the CRF. 
In case of severe anaemia (Hb <6 g/dL), the subject is to be discontinued from the 
study. Further management of anaemia is at the Investigator’s discretion.  
 
Procedures for Overdose 
7.6.1
If an inadvertent overdosing of a subject (e.g., by a calculation error of the required 
iron dose) is detected, this must be reported as an AE (see Section 10, Evaluation, 
Recording and Reporting of AEs and SAEs). 
Post-baseline iron parameters will be assessed at each visit using the central 
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, if 
necessary. 
7.7 
Prohibited Therapy and Concomitant Treatment 
Prohibited therapies in this study will include the following drugs: 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 42 of 75 
 
• Oral or other IV iron therapy (other than the study medication). Note: Ongoing 
use of multivitamins or nutritional supplements containing iron are permitted 
when doses are lower than 75 mg per day. If the dose of iron in these products is 
unknown, they should not be administered during the study. 
• ESAs 
• Blood transfusions 
Note: Blood transfusions and ESAs might be used as rescue medication if the subject 
requires such treatment for symptomatic anaemia therapy. In this case, the subject 
must be withdrawn from the study and end of study procedures must be completed 
before transfusion or treatment. The reason for discontinuation and the date must be 
recorded on the appropriate page of the CRF. The date on which the procedure 
actually took place must also be recorded in the CRF. 
If symptoms of acute iron intoxication occur, treatment will be according to standard 
medical practice, e.g. consider the use of an iron chelator such as deferoxamine 
mesylate. 
In case of hypersensitivity reactions (including anaphylactoid reactions) or signs of 
intolerance, an appropriate therapy will be started according to the Investigator’s 
judgement. 
Any concomitant treatment given for any reason during the course of the study must 
be recorded on the CRF and in the subject’s medical records, including dosage, start 
and stop dates and reason for use. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 43 of 75 
 
8. RISKS/PRECAUTIONS 
8.1 
IV irons 
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 also been reported after previously uneventful doses 
of any parenteral iron complexes, including FCM and IS. Each subject should be 
observed for adverse effects during and for at least 30 minutes following each study 
drug (FCM or IS) application. 
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 
or Venofer 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 or IS solution at the 
injection/infusion site may lead to irritation of the skin and potentially long-lasting, 
brown discolouration at the site of injection/infusion. In the event of paravenous 
leakage, administration of FCM or IS must be stopped immediately. Study treatment 
may be re-administered in a different location (i.e. other arm), but extra care needs to 
be taken to make sure that paravenous leakage does not occur again. This also needs 
to be clearly documented in the CRF and the source data. If a subject did not receive 
the full dose, this also needs to be recorded. 
 
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 1% to 10% of subjects were 
headache, dizziness, hypertension, nausea, injection/infusion site reactions, flushing 
and hypophosphataemia. No reported ADRs were very common (≥10%). 
Please refer to the latest version of the IB for a full list and description of risks and 
precautions.  


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 44 of 75 
 
8.3 
Iron Sucrose 
Subjects administered IS commonly (between 1% and 10%) experience dysgeusia, 
hypertension, hypotension, nausea, injection/infusion site pain.  
Hypotensive episodes following administration of IS have been reported and will be 
caused if injection/infusion is administered too rapidly. For further details on risks 
and precautions, please refer to the currently approved Insert Sheet for China. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 45 of 75 
 
9. STUDY PROCEDURES 
9.1 
Description of Study Assessments 
 
Vital Signs 
9.1.1
To be performed per Table 1: Schedule of Events. Body temperature, resting blood 
pressure (systolic and diastolic) and heart rate will be measured with the subject in a 
sitting position. 
 
Physical Examination 
9.1.2
To be performed per Table 1: Schedule of Events. 
A full physical examination will be performed at screening and End of Study/ Early 
Withdrawal visit. Any clinically significant abnormalities occurring before signature 
of informed consent should be recorded on the medical history page of the CRF and 
any clinically significant abnormalities occurring or worsening after signature of 
informed consent should be recorded on the AE page.  
 
Laboratory Parameters 
9.1.3
All blood samples (total blood volume approximately 46ml) will be analysed at a 
central laboratory, Teddy Clinical Research laboratory,  
3rd floor, Building 12  
Xiangyin Road No 128  
Yangpu District 
Shanghai 200433  
China. 
 
Blood for clinical chemistry and haematology does not have to be drawn under fasting 
conditions.  
Haematology parameters to be analysed are Hb, haematocrit, red blood cell count, 
MCV, MCH, MCHC, reticulocyte count, Hb content of reticulocytes, white blood cell 
count with differential (absolute and percentage) and platelet count. 
Iron status parameters include serum iron, serum ferritin, serum transferrin, UIBC and 
TSAT. 
Clinical chemistry parameters to be analysed are electrolyte status (sodium, potassium, 
magnesium, calcium, chloride, phosphorus), glucose, AST, ALT, GGT, AP, lactate 
dehydrogenase and hsCRP.  
Blood for safety laboratory assessments will be collected at screening, baseline, 
Weeks 2, 4, 6 and 8. Blood samples must always be collected prior to study drug 
administration. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 46 of 75 
 
A serum pregnancy test (for women of childbearing potential only) will be performed 
at screening and End of Study visit. 
 
Electrocardiogram 
9.1.4
A 12-lead electrocardiogram (ECG) will be performed locally at each participating 
site at screening, Week 4 and End of Study visit/Early Withdrawal. Heart rate, QT, 
QTcF, RR interval, QRS complex duration and PR interval values will be assessed. 
Absolute and change from baseline data will be analysed for interval data, any 
clinically significant abnormal findings will be recorded in the source documents and 
as an AE in the CRF. QT and QTc will be analysed in accordance with ICH E14 
guidance [16]. 
The 12-lead ECGs will be recorded and assessed according to local clinical practice. 
All original ECG traces must be stored in the subject’s medical record as source 
documents. In cases where thermal paper will be used for ECG traces an ECG copy 
on permanent paper must be produced and also stored in the subject’s medical record. 
 
Urinalysis 
9.1.5
A urine sample will be collected during the study visits as per Table 1: Schedule of 
Events, and analysed in the central laboratory to measure urine phosphate, protein, 
glucose, bilirubin, pH, nitrite, ketone, urobilinogen, blood, leukocytes.  
9.2 
Schedule of Assessments 
For detailed schedule of assessments (including all protocol required assessments, 
visits and visit windows) please refer to Table 1: Schedule of Events. 
 
Screening and Baseline Procedures 
9.2.1
After signing the informed consent and within 7 days prior to the initial treatment 
administration, relevant demographic (including age, sex and race), key information 
on IDA (including underlying cause for IDA and date of diagnosis, and previous 
treatments), and baseline medical history data, including concomitant medications 
will be collected. Study procedures will be performed per  
Table 1: Schedule of Events, to assess subject eligibility for the study. 
Consent must be received prior to any procedure completed only for the study and 
before randomisation or administration of study drug. 
Screening laboratory values will be used to assess for subject eligibility (including 
serum pregnancy tests for females at screening) on relevant blood parameters. 
Laboratory assessments will be repeated at the baseline visit but not assessed to 
confirm eligibility criteria. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 47 of 75 
 
Eligible subjects will be randomised at the baseline visit to one of the two treatment 
arm. 
Subjects failing to meet eligibility will be considered screen failures and will 
discontinue study participation. Subjects may be re-screened once. Any subject that is 
rescreened must have all tests and procedures completed to permit inclusion into the 
study (i.e., all screening tests and procedures must be completed as per the Schedule 
of Events with the exception of any inclusion criteria, exclusion criteria and 
procedures that can use historical results.  In case of re-screening, documented 
informed consent must be obtained again, and the date of informed consent must be a 
minimum of 4 weeks after the date when the subject was declared a screen failure. 
The subject will keep their unique subject number. 
 
Treatment Procedures 
9.2.2
Subjects randomised to receive FCM will receive the first administration of FCM at 
baseline (Day 1), and the second and third dose at Day 8 and Day 15, if needed 
according to the dosing matrix (see Table 2, Section 7.2.1, Arm A: Ferric 
Carboxymaltose).  
Subjects randomised to IS will have their iron deficit calculated according to the 
Ganzoni formula (see Section 7.2.2, Arm B: Iron Sucrose). The doses will be split 
into injections of 200 mg iron and administered three times a week until the calculated 
dose has been given to the subject. The cumulative Venofer dose is to be rounded up 
or down to the nearest 200 mg. During these dosing visits, no additional data will be 
collected or procedures performed, except for ongoing information on AEs or change 
in concomitant medications, including dose. Note: Application of IS and FCM at any 
visit should be done after all assessments as per Schedule of Event, Table 1, 
especially blood draw for laboratory assessments, have been performed. 
For both treatment groups, time of start and end of administration (including any 
interruptions) and volume administered (i.e. incomplete dose including reason) must 
be recorded. 
During post-baseline visits at 2, 4 and 6 weeks (±3 days), the following assessments 
will be performed: 
• Vital signs 
• Laboratory assessments (haematology, chemistry, iron parameters, urinalysis) 
• AEs and concomitant medications 
• ECG (only Week 4) 
See  
Table 1: Schedule of Events for full details of protocol required procedures and 
applicable visits (and timings). 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 48 of 75 
 
 
End of Study (or Early Discontinuation) Procedures 
9.2.3
On completion of the study (i.e., last study visit – Week 8 ±4 days), or if subject is 
discontinued/withdrawn early, all assessments for Week 8 per  
Table 1: Schedule of Events should be performed. This includes the following: 
• Physical Examination + BW 
• Vital signs 
• ECG 
• Laboratory assessments (haematology, chemistry, iron parameters, urinalysis) 
• Pregnancy test (for women of childbearing potential only) 
• AEs and concomitant medications 
 
Unscheduled Visits 
9.2.4
Subjects may be seen at the out-patient clinic for a medical reason related to the VIT-
IRON-2011-004 study outside the scheduled visits defined by the protocol. Data 
collected during such visits must 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 on the AE pages of the CRF (see 
Section 10).  
 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 49 of 75 
 
10. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES 
10.1 Definitions 
 Reference Safety Information 
10.1.1
The reference safety information (RSI) is a document covering information relating to 
safety, indications, dosing, pharmacology, warnings, precautions, contraindications 
and other information concerning the product. As a minimum, it contains the 
Company Core Safety Information, which consists of the information on 
contraindications, warnings and precautions, use in special populations, undesirable 
effects and overdose from the Company Core Data Sheet. For this study, the current 
version of the IB is considered the RSI for FCM and for Venofer the Chinese SmPC is 
considered the RSI. 
 Adverse Event 
10.1.2
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. 
 Adverse Drug Reaction 
10.1.3
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.  
 Unexpected AE/ADR 
10.1.4
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., IB for an 
unapproved investigational product, or package insert/SmPC 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 adverse reaction also 
constitute unexpected events. 
 Serious Adverse Event 
10.1.5
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 50 of 75 
 
• 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 refer to an event which hypothetically might have caused death if it was 
more severe) 
• 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 should also usually be considered 
serious.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalisation; or development of drug dependency or drug abuse. 
Conversely, some hospitalisations, particularly those which are the result of elective 
or previously scheduled surgery for pre-existing conditions, which have not worsened 
after initiation of treatment, should not automatically be classed as SAEs. In addition, 
hospitalisation for the purpose of study drug administration, should not be recorded as 
an SAE. 
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. 
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 CRO/Sponsor any AEs for which 
the issue of seriousness is unclear or questionable. 
 Suspected Unexpected Serious Adverse Reaction 
10.1.6
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. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 51 of 75 
 
 Special Situations 
10.1.7
The following are defined as special situations: 
• Exposure of a medicinal product during pregnancy  
• Medication error: any unintentional error in the prescribing, dispensing or 
administration of a medicinal product during the study 
• Medication overdose: the administration of a quantity of study medication 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) are also 
considered as ADRs. Any special situation occurring with/without ADR/AE shall be 
recorded in the study specific documentation. 
10.2 Adverse Event Descriptors 
 Intensity/Severity Categorisation 
10.2.1
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. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 52 of 75 
 
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: 
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. 
 Causal Relationship Categorisation 
10.2.2
An Investigator who is qualified in medicine 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 as 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 reporting form.  
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Certain 
Yes 
• 
Event or laboratory test abnormality, with plausible time 
relationship to drug 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 drug intake 
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Rechallenge not required 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 53 of 75 
 
Possible 
Yes 
• 
Event or laboratory test abnormality, with reasonable time 
relationship to drug 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 drug intake. 
 
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 investigational product for the purposes of expedited 
regulatory reporting. In circumstances where the Investigator is not providing his/her 
assessment about the relationship, the event will be considered as “related” and 
qualify for expedited regulatory reporting. 
 Outcome Categorisation 
10.2.3
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 the outcome is reported as recovered/resolved with sequelae, the 
Investigator should specify the kind of sequelae on the AE/SAE form. If the outcome 
of an AE/SAE is reported as unknown, the Investigator should specify (on the 
AE/SAE form) the rationale why unknown was selected. 
 Pre-existing Medical Conditions 
10.2.4
A pre-existing medical condition is one that is present at the screening visit for this 
study (such as IDA or the underlying cause for IDA (i.e. heavy menstrual bleeding or 
IBD)). Such conditions should be recorded on the medical history CRF page. 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 CRF page, it is important to convey the concept that the pre-existing 
condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”, “worsening of back pain”). 
 Signs and Symptoms of the Disease Under Study 
10.2.5
Signs or symptoms of IDA and the underlying disease (e.g., heavy uterine bleeding 
(HUB), CKD) should not be classed as AEs as long as they are within the normal day-
to-day fluctuation of the disease. 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 CRF. 
 Clinical Laboratory Evaluations 
10.2.6
A change in the value of a safety laboratory investigation can represent an AE if the 
change is clinically significant and clinically relevant or if, during treatment with the 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 54 of 75 
 
investigational product, a shift of a parameter is observed from a normal value to a 
pathological value, 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 into consideration. 
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 
clinically relevant and therefore represents an AE. If the Investigator considers such 
an AE as serious (e.g., medically significant event fulfilling criteria as per Section 
10.1.5, Serious Adverse Event) it must be reported as an SAE. 
Iron parameters such as serum iron, TSAT, UIBC, serum ferritin, serum transferrin, 
Hb, and reticulocytes are expected to be out of range after administration of IV iron 
products, and will therefore not be considered as AEs. They can be classed as 
clinically significant but are usually not clinically relevant and therefore are not 
reported as AEs. 
If a laboratory abnormality meeting the above criteria is a sign of a disease or 
syndrome only the diagnosis should be recorded in the CRF.  
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 CRF, 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 CRF, 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. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 55 of 75 
 
 Special Situations 
10.2.7
All special situations (Section 10.1.7)  have to be documented in the subject’s CRF as 
well as on the form “Documentation of Special Situations”. If any overdose, and 
medication errors leads to any event that fulfils any seriousness criteria (see 
Section 10.1.5, Serious Adverse Event), the event has to be reported as an SAE. 
 
10.3 Reporting Procedure for AEs, SAEs, Special Situationsand 
Pregnancy 
 Adverse Events 
10.3.1
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 CRF and source document. This applies to all 
AEs regardless of presumed relationship to the study treatment, and to the 
investigational product as well as AEs that occurred before randomisation. Adverse 
events leading to discontinuation of study treatment should also be collected. 
If any AE is reported, the date of onset and time (only for AEs that start on dosing 
days), relationship to study medication or 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 is 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.  
Where possible, the Investigator should report a diagnosis rather than 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 CRF. 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 and abbreviations. Only 1 AE term should be recorded in each event 
field in the CRF. 
The AE reporting period begins at the time the ICF is signed by the subject. The AE 
reporting period ends at the End of Study visit (Week 8 ± 4 days). Adverse events that 
extend continuously, without resolution, between trial assessments should only be 
recorded once in the CRF. 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.  
Adverse events that resolve and subsequently recur should have each recurrence 
recorded separately in the CRF. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 56 of 75 
 
Adverse events 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. 
 Serious Adverse Events and Special Situations 
10.3.2
The occurrence of any SAE must be reported immediately (i.e., within 24 hours of 
awareness) to Vifor Pharma (or its delegate; e.g., contract research organisation 
(CRO)) by email, facsimile (fax) or telephone. In addition, SAEs must also be 
reported to CFDA, ECs, Province and Municipality.  
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. 
Full contact details to report SAEs will be provided in the study-specific documents 
(SAE Processing and Reporting Plan). The SAE must be reported to Vifor Pharma (or 
Tigermed) using the Vifor Pharma SAE reporting form provided by Vifor Pharma and 
at the same time the CFDA form for SAE reporting to the concerned authorities. The 
Investigator must complete, sign and date the SAE pages, and verify the accuracy of 
the information recorded on the SAE pages with the corresponding source documents. 
The Vifor Pharma SAE reporting form must be completed in capital letters, in 
medical terms, in English and to the best extent possible given the time constraints.  
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.  


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 57 of 75 
 
Where the SAE reporting form cannot be transmitted due to technical problems, the 
Investigator must inform the CRO/Vifor Pharma about the SAE by phone. As soon as 
technical problems are resolved, the Investigator will send a copy of the SAE 
reporting form to the CRO/Vifor Pharma.  
All SAEs (regardless of the causal relationship), from the time the informed consent is 
signed until 30 days  following the End of study/Early Withdrawal visit, as well as 
any medication given/taken for these events, must be reported in the CRF.  
No formal study visit is required but the Investigator must report any SAEs that occur 
during this period using the SAE form. SAEs starting before first administration of 
study drug must be identified as such on the CRF and source documentation. The 
onset date of the AE is defined as the onset of signs and symptoms or a change in 
baseline. 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 ICH criteria for serious 
(see section 10.1.5). 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.  Serious adverse events that are ongoing 
events 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 CRF after the completion of the final follow-up 
visit, 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, 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.  
Any SAE considered to have a causal relationship (i.e., “certainly, probably/likely, 
possibly” 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 together with the Vifor Pharma SAE 
reporting form. Any safety information that is obtained after clinical database lock 
will be documented only in the safety database and implications for handling the data 
in the clinical database assessed on an individual basis. 
A death occurring during the study or which comes to the attention of the Investigator 
within 30 days after the End of Study visit/Early Withdrawal visit, whether 
considered treatment-related or not, must be reported to the CRO/Vifor Pharma using 
the Vifor Pharma and the CFDA SAE reporting forms. Preliminary reports will be 
followed by detailed descriptions which will include copies of hospital case reports, 
autopsy reports/certificates and other documents when requested and applicable.  
The occurrence of any special situation (see Section 10.2.7) at the investigational site 
must be documented by completing the form “Documentation of Special Situations”. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 58 of 75 
 
This must be reported by the investigator to the CRO/Vifor Pharma within 5 working 
days after awareness, if the special situation does not fulfil a SAE criterion, and 
within 24 hours if after awareness if it does fulfil a SAE criterion. 
 
NOTE: Drug exposure during pregnancy always has to be reported within 24 hours 
after awareness (Section 10.3.3). 
 
 
Contact information for reporting of SAEs/Special Situation Reports: 
Pharmacovigilance Officer 
Hangzhou Tigermed Consulting Co. Ltd. 
Room 813, 999 West Zhongshan Road, 
Shanghai, 200051 
P.R. China 
 
24-hour SAE reporting fax: +86-21-33275864  
Email: PV@tigermed.net 
 
The detailed SAE reporting procedures will be provided to the investigators in the 
study documentation (SAE Processing and Reporting Plan).  
 
At a minimum the following should be provided at the time of the initial SAE report: 
• Study name and/or number 
• Subject number, year of birth and gender/sex 
• Event description (including onset date of the event, outcome and reason for it 
being considered serious) 
• Relationship to investigational product (i.e., causality) 
• Name of the investigational product (including drug dose and administration dates) 
• 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. 
Additional follow-up information, if required or available, must be faxed immediately 
(within 24 hours of awareness) following Investigator (or site) awareness of the 
information. The follow-up information must be completed on a Vifor Pharma SAE 
reporting form (marked follow-up) and placed with the original in the appropriate 
section of the study file. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 59 of 75 
 
The Investigator is encouraged to discuss with CRO/Sponsor any AEs for which the 
issue of seriousness is unclear or questionable. 
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 (IRB)/Ethics Committee (EC)/Independent Ethics Committee (IEC) as per 
local regulations.  
Additional details regarding SAE reporting is available in the document “SAE 
Processing and Reporting Plan. 
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. In addition, hospitalisation for the purpose of study drug 
administration should not be recorded as an SAE. However, AEs which occur during 
the (elective) hospitalisation will need to be collected and reported. 
 Pregnancy 
10.3.3
The safety of study treatment in pregnant women needs to be monitored once study 
treatment has been administered to them (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.  
Women of childbearing potential should have a negative serum pregnancy test at 
screening and at the End of Study Visit. Study medication should not be initiated by 
the Investigator until a report of a negative pregnancy test has been obtained. 
Effective contraception must be used before beginning study medication, during study 
dosing, and for 1 month following discontinuation of study medication. 
A female subject must immediately inform the Investigator if she becomes pregnant 
during the study and be instructed to stop taking study medication. 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. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 60 of 75 
 
A male subject must immediately inform the Investigator if his female partner 
becomes pregnant during the study. The female partner of a male subject should also 
be counselled and followed-up as described above. 
Any report of pregnancy recorded for any female subject or for a female partner of a 
male 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  
and forward to the CRO/Vifor Pharma. Complications of pregnancy such as abortion 
(spontaneous or induced), premature birth or congenital abnormality are considered 
SAEs and should be reported using the Vifor Pharma SAE form. 
All pregnancies occurring in a female subject or the female partner of a male subject 
within 90 days after discontinuation of investigational product should be reported as 
though they were an SAE to the CRO/Vifor Pharma. 
 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 61 of 75 
 
11. STATISTICAL ANALYSIS 
11.1 Statistical Methods 
All statistical analyses will be performed using SAS Version 9.0 or later (SAS 
Institute Inc. SAS/STAT, Cary, NC). 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 database lock. Any deviation 
from the SAP will be noted and explained in the final study report. All individual data 
will be listed as measured. 
11.2 Sample Size and Power Calculations 
To assess the non-inferiority of FCM compared to IS in the proportion of subjects 
who will have an increase from baseline in Hb of ≥ 2g/dL at any time up to Week 8 
(responders), the following assumptions have been made: 
• Subjects that will be included in the study will be mainly subjects with GI 
disorders and women with HUB. The responder rate after IS treatment is expected 
to be 70%. This is based on the mean of the proportion of responders in the 2 
studies described below in IDA subjects with IBD and IDA subjects with HUB 
respectively. 
In study FER-IBD-07-COR, which compared FCM to IS in IDA subjects with 
IBD, the proportion of subjects who had an increase from baseline in Hb ≥ 2g/dL 
at Week 8 was 72% in FCM group and 55% in IS group (Per Protocol Set (PPS)).  
Seventy three percent in the FCM group and 58% in the IS group had an increase 
of at least ≥ 2g/dL at any time up to Week 8.  
In study 1VIT04002/1VIT04003, which compared FCM to oral iron in IDA 
subjects with HUB, 82% of subjects in the FCM group had an increase from 
baseline in Hb ≥ 2g/dL at any time up to Week 6. Although no subjects in this 
study were treated with Venofer, and no other data are available from studies in 
which HUB patients are treated with Venofer, it has been assumed that Venofer 
would have the same response rate as FCM in this patient population. 
• The non-inferiority margin for the difference in the proportion of responders 
between FCM and IS was set to -15%. This margin will ensure a treatment effect 
for FCM (70 – 15 = 55) greater than 33%, the upper bound of the 95% confidence 
interval (CI) of the proportion of responder of an estimated placebo effect, by 
more than half the effect  itself (33 + 16.5 = 49.5). The placebo effect was 
estimated as follows: 
In study 1VIT07017 which compared FCM to Standard Medical Care (SMC) in 
IDA subjects with HUB or post-partum, there were 55 subjects in the SMC group 
who did not receive any Iron treatment. Of these, 50 had a Hb assessment at Day 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 62 of 75 
 
30. At Day 30 the proportion of non-treated subjects with an Hb increase ≥ 2 g/dL 
was 22% (11/50) with a 95% CI from 11% to 33%. 
The sample size is based on showing non-inferiority in the difference in the 
proportion of subjects achieving an increase in Hb of ≥ 2g/dL at any time up to Week 
8 between FCM and IS. Applying a test at a one-sided alpha level of 2.5%, and a -15% 
non-inferiority margin, 147 subjects per group will have 80% power to detect that 
FCM is non-inferior to IS with an expected IS responder proportion of 70%. The total 
sample size is 368 (184 per treatment group), taking into account an estimated drop-
out rate of 20% of the randomised subjects. 
11.3 Analysis Set 
 Full Analysis Set  
11.3.1
The full analysis set (FAS) consists of all subjects who satisfy the following criteria: 
• Randomised to treatment 
• Received at least 1 dose of study treatment 
• Had at least 1 baseline and post-baseline Hb value. 
Subjects will be analysed in the treatment group they were randomised to. 
 Per-Protocol Set 
11.3.2
The PPS consists of all subjects who, in addition to the FAS criteria, had no major 
protocol violations (as defined in the SAP).  
 Safety Set 
11.3.3
The safety set consists of all randomised subjects who have received at least 1 dose of 
study medication. The subjects in this group will be analysed based on the treatment 
they received.  
11.4 Background and Demographic Characteristics 
All background and demographic data will be described by mean tables (continuous 
variables) or frequency tables (categorical variables). Medical history will be coded 
according to a standard dictionary (Medical Dictionary for Regulatory Activities 
(MedDRA)) and tabulated according to system organ class and preferred term. The 
MedDRA version to be used will be the latest version available at the time of study 
initiation. 
11.5 Study Medication 
Doses of study drug are defined in Table 2 Iron dosing Schedule for FCM subjects 
and by the Ganzoni formula for IS subjects. If an incomplete dose of study drug was 
given to the subject for any reason (e.g.: due to leakage or AE) or a different dose 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 63 of 75 
 
from the planned dose was administered, this should be recorded in the CRF together 
with the reason. The dose of study drug received and the number of 
injections/infusions received will be tabulated for each subject and summarised by 
treatment group, by visit and overall. Treatment compliance will be calculated for 
each subject by the percentage of study drug received compared to the planned dose 
and summarised by treatment group by visit and overall. 
11.6 Concomitant Therapy 
At each visit, the Investigator will obtain and record any information about 
concomitant illnesses and any therapeutic interventions (e.g., drug therapy, surgery, 
etc.) Concomitant medications will be coded using the World Health Organization 
Anatomical Therapeutic Chemical Drug Reference List classifications (ATC). Counts 
and percentages of subject use for each medication by ATC Level 2 and 4 and 
preferred term will be computed and summarised by treatment group. 
11.7 Efficacy Evaluations 
 Primary 
11.7.1
The primary endpoint is the percentage of subjects achieving an increase in Hb of ≥ 
2g/dL (responders) from baseline at any time up to Week 8. The non-inferiority test 
will be applied to the difference between the proportions of subjects meeting the 
primary endpoint using the PPS. Non-inferiority will be determined if the lower 
bound of the 95% CI of this difference is above the non-inferiority margin as defined 
in Section 11.2. Further details will be specified in the SAP. 
 Secondary 
11.7.2
The secondary efficacy endpoints for this study are as follows: 
• Percentage of subjects achieving an increase in Hb ≥2 g/dL from baseline at 
Weeks 2, 4, 6 and 8. 
• Change in Hb from baseline to Weeks 2, 4, 6 and 8. 
• The percentage of subjects with TSAT ≥ 16% and serum ferritin ≥100 ng/mL (for 
subjects with underlying inflammatory disease as determined by hsCRP levels 
above the normal range) or serum ferritin >14ng/mL (in subjects with no apparent 
underlying inflammatory disease as determined by hsCRP levels within normal 
range at screening) at Weeks 2, 4, 6 and 8. 
• Change in TSAT from baseline to Weeks 2, 4, 6 and 8. 
• Change in serum ferritin from baseline to Weeks 2, 4, 6 and 8. 
Appropriate summary descriptive statistics will be determined for all secondary 
endpoints at each visit for the FAS population using raw scores. Where appropriate, 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 64 of 75 
 
methods for imputing missing values for both primary and secondary analyses will be 
described in the SAP. If any spurious data have been identified during the data review 
process they will be flagged and considered as missing in the analyses. All spurious 
and unused data will be included and identified in individual data listings. Missing 
data will be shown as missing in the listings. For continuous secondary endpoints, 
either analysis of variance or analysis of covariance models will be used and where 
necessary, the repeated measures procedure will be implemented. Where appropriate, 
terms for treatment, gender, age and respective baseline characteristics will be 
included. For non-continuous endpoints, more non-parametric methods will be used to 
make treatment comparisons, details of which will be fully specified in the SAP. 
Significance level is set at an alpha of 0.05 and no adjustment will be made for testing 
multiple secondary outcomes. Some significant findings are expected to occur by 
chance so undue consideration will not be given to any particular significant 
difference. Moreover, interpretation of the results will be based on patterns of 
differences and in conjunction with the results of the primary analyses. 
11.8 Safety Evaluations 
The safety analyses will be performed on the safety population.. The following safety 
evaluations will be performed: 
Change in laboratory parameters (haematology, clinical chemistry and iron status) 
over the study duration. Absolute and change from baseline values will be tabulated 
with descriptive statistics by treatment group across the course of the study. Clinically 
significant values outside the laboratory criterion values will be tabulated and/or listed 
for each treatment group.  
• Summary of all TEAEs: type, nature, incidence and outcome overall and by 
underlying disease aetiology All AEs will be coded using the most current version 
of  MedDRA at study initiation and tabulated according to system organ class, 
preferred term, severity and relationship to study medication. Serious adverse 
events and AEs leading to premature study withdrawal will be counted as they 
occur and listed or summarised. 
• Summary of changes in vital signs from baseline to Weeks 2, 4, 6 and 8: Blood 
pressure, temperature and heart rate will be tabulated by treatment group and visit.  
Summary of changes in ECG and physical examination (including BW) from 
baseline to Week 4 (for ECG only) and Week 8: Abnormal features on ECG will 
be tabulated and listed by treatment group. 
11.9 Interim Analyses 
There is no planned interim analysis for this study. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 65 of 75 
 
11.10 Other Evaluations 
Additional exploratory analyses not described above may be performed if indicated in 
the medical review(s) of the data.
 
 
 
 
 Pharmacokinetics 
11.10.1
There will be no PK assessments in this study. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 66 of 75 
 
12. STUDY ETHICAL CONSIDERATIONS 
12.1 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 the64th WMA General 
Assembly, Fortaleza, Brazil, October 2013), and the ICH guidelines for GCP. 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. 
12.2 Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, Chinese 
regulations, and ICH guidelines; and must have been approved by the 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. 
12.3 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. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 67 of 75 
 
13. 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 CRFs against the Investigator’s records by the Study Monitor (source document 
verification), and the maintenance of a drug dispensing log by the Investigator. The 
data collected will be entered (electronic data capture) into the study database once it 
has been 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.  


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 68 of 75 
 
14. ADMINISTRATIVE PROCEDURES 
14.1 Sponsor’s Responsibilities 
 Study Supplies 
14.1.1
Sites will be provisioned with all supplies required to manage this study. This will 
include but is not be limited to:  
• Investigator file(s) (for filing of all study related documentation) 
• Contact list of all relevant study personnel, including a 24/7 available Sponsor 
contact for urgent medical questions 
• CRF and completion guidelines 
• Study Reference Manuals 
• All study forms (e.g., SAE, special situations, pregnancy, drug accountability, etc.) 
 Insurance 
14.1.2
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 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 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 drug or failure to follow 
the Investigator’s instructions. 
 Investigator Training 
14.1.3
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.  
 Study Monitoring 
14.1.4
The study will be monitored by representatives of Vifor Pharma (or designee) which 
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 (CRFs and other pertinent data) provided that subject 
confidentiality is maintained in accordance with local requirements. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 69 of 75 
 
It will be the Monitor's responsibility to inspect the CRFs at frequent regular intervals 
throughout the study, to verify the adherence to the protocol and the completeness, 
consistency and accuracy of the data being entered on them. The Monitor should have 
access to laboratory test reports and other subject records needed to verify the entries 
on the CRF. 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. 
14.2 Investigator’s Responsibilities 
 Reporting and Recording of Data 
14.2.1
All required study data must be entered in the electronic CRF (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. 
 Source Documentation 
14.2.2
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 
CRFs. These records should include detailed notes on: 
• The medical history prior to participation in the study. 
• The basic identifying information, such as demographics, that link the subject’s 
source documents with the CRFs. 
• 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 documentation on reportable events (see Section 10.2.7) and 
pregnancies (see Section 10.3.3). 
• 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. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 70 of 75 
 
• 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. 
• For some data elements, direct data entry into specified pages of the subject’s 
CRF is acceptable without other source document (or these data elements, the 
CRFs will be considered source document).  
 Records Retention 
14.2.3
The Investigator must arrange for the retention of all study documentation (such as 
CRFs, research files, and Investigator site file) for the duration specified in their 
respective site contract. 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 back-up 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. 
 Site Documentation 
14.2.4
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. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 71 of 75 
 
15. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
15.1 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. 
15.2 Protocol Amendments 
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, will only be introduced by Vifor Pharma. Each IRB/EC/IEC will review and 
approve 
amendments 
prior 
to 
their 
implementation. 
Institutional 
Review 
Board/EC/IEC approval need not be obtained prior to removal of an immediate hazard 
to subjects. 
15.3 Study Termination 
Vifor Pharma reserves the right to terminate the study in its entirety or at a site at any 
time. The reasons for site 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. 
In terminating the study, Vifor Pharma and the Investigator will assure that adequate 
consideration is given to the protection of the subject’s interests. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 72 of 75 
 
16. 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 [17]. 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. 
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 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 (ICMJE) criteria for 
authorship [18]. That is, all authors must meet each of the following 4 criteria: 
1. Substantial contribution to the conception and design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2. Drafting the work or revising it critically for important intellectual content; AND 
3. Final approved of the version to be published; AND 
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.  
Members of the study steering committee 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. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 73 of 75 
 
17. REFERENCES 
1. 
Pantopoulos K (2005) Regulation of Iron Metabolism. In: Weiss G VRG, 
Hershko C (eds) Anemia of chronic disease, Vol 30. CRC Press, Taylor & 
Francis Group, Boca Raton, p 1. 
2. 
De Benoist B, Mc Lean E, Egli I, Cogswell M. Worldwide prevalence of 
anaemia 1993–2005 : WHO global database on anaemia, WHO 2008, ISBN 
978 92 4 159665 7. 
3. 
Guyatt GH, Oxman AD, Ali M, Willan A, McIlroy W, Patterson C. 
Laboratory diagnosis of iron deficiency anaemia: an overview. J Gen Int Med. 
1992;7:145-53. 
4. 
Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, 
Ponikowska B, Borodulin-Nadzieja L, Banasiak W, Polonski L, Filippatos G, 
McMurray JJ, Anker SD, Ponikowski P. Iron deficiency: an ominous sign in 
patients 
with 
systolic 
chronic 
heart 
failure. 
Eur 
Heart 
J. 
2010 
Aug;31(15):1872-80. 
5. 
Huch R, Schaefer R. Iron Deficiency and Iron Deficiency Anemia. Thieme 
2006, p 5, ISBN 1-58890-578-0. 
6. 
Madore F, White CT, Foley RN, Barrett BJ, Moist LM, Klarenbach SW, 
Culleton BF, Tonelli M, Manns BJ. Clinical practice guidelines for assessment 
and management of iron deficiency. Canadian Society of Nephrology. Kidney 
Int Suppl. 2008 Aug;(110):S7-S11. 
7. 
Gasche C, Evstatiev R, Haas T, Kaser A, Knoflach P, Petritsch W, Weiss G, 
Reinisch W. [Diagnosis and treatment of iron deficiency and anaemia in 
inflammatory bowel diseases. Consensus of the Austrian IBD Working Party]. 
Z Gastroenterol. 2011 May;49(5):627-32. 
8. 
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, 
Cella DF, Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, 
Lichtin AE; American Society of Clinical Oncology; American Society of 
Hematology. Use of epoetin and darbepoetin in patients with cancer: 2007 
American Society of Clinical Oncology/American Society of Hematology 
clinical practice guideline update. J Clin Oncol. 2008 Jan 1;26(1):132-49. 
9. 
Ganzoni AM. Eisen-dextran intravenös: therapeutische und experimentelle 
Möglichkeiten. Schweiz Med Wochenschr. 1970;100:301-3. 
10. 
Geisser P, Banké-Bochita J. Pharmacokinetics, safety and tolerability of 
intravenous ferric carboxymaltose: dose-escalation study in volunteers with 
mild iron –deficiency anaemia. Drug Res 2010; 60 (6a): 362-72. 
11. 
Beshara, S, Sörensen J, Lubberink M, Tolmachev V, Långström B, Antoni G, 
Danielson BG, Lundqvist H. Pharmacokinetics and red cell utilization of 
52Fe/59Fe-labellediron polymaltose in anaemic patients using positron 
emission tomography. British J Haematolol, 2003; 120: 853–859. 


 
 
VIT-IRON-2011-004 Protocol Amendment 4 
Confidential  
Version 5.0, 14 August 2017 
Page 74 of 75 
 
12. 
Funk F, Ryle P, Canclini C, Neiser S, Geisser P. The new generation of 
intravenous iron: chemistry, pharmacology, and toxicology of ferric 
carboxymaltose. Drug Res 2010; 60(6a): 345–353 
13. 
Geisser P, Baer M, Schaub E. Structure/Histotoxicity relationship of parenteral 
iron preparations. Drug Res 1992; 42(II); 12: 1439-1452. 
14. 
Kim K, Johnson JA, Derendorf H. Differences in Drug Pharmacokinetics 
Between East Asians and Caucasians and the Role of Genetic Polymorphisms 
J Clin Pharmacol 2004,44;10:1083-1105. 
15. 
Evstatiev R, Marteau P, Iqbal T, Khalif IL, Stein J, Bokemeyer B, Chopey IV, 
Gutzwiller FS, Riopel L, Gasche C; FERGI Study Group. FERGIcor, a 
randomized controlled trial on ferric carboxymaltose for iron deficiency 
anemia 
in 
inflammatory 
bowel 
disease. 
Gastroenterology. 
2011 
Sep;141(3):846-853. 
16. 
Guidance for the Industry, E14 Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. 
October 2005. Available from: http://www.fda.gov 
17. 
PhRMA principles and guidelines: public disclosure of clinical trial results. 
Pharmaceutical Research and Manufacturers of America [Internet]. 2009. 
Available from: http://www.phrma.org/principles_and_guidelines. 
18. 
[International Committee of Medicinal Journal Editors (ICMJE) guidelines]. 
Recommendations for the Conduct, Reporting, Editing and Publication of 
Scholarly Work in Medical Journals, Updated December 2016. Available from: 
http://www.icmje.org. 
 

SAP_001.pdf: 
Protocol VIT-IRON-2011-004                                                                                                          Page 1 of 35 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
 
Treatment: Ferric Carboxymaltose in Iron Deficiency Anaemia 
 
 
 
Study Phase: Phase III 
 
Study Title: An Open-label, Randomised Controlled Multi-centre Study to 
Assess the Impact of Ferric Carboxymaltose in Correcting Iron Deficiency 
Anaemia Compared to Venofer® (Iron Sucrose) in Chinese Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Number: 
VIT-IRON-2011-004 
SAP Final Version: 
1.0 
Date: 
19 July 2019 
Author: 
[
, Statistician/Stat] 


APPROVAL SIGNATURES FOR SAP
Study Title: An Open-label, Randomised Controlled Multi-centre Study to Assess the 
Impact of Ferric Carboxymaltose in Correcting Iron Deficiency Anaemia Compared to 
Venofer* (Iron Sucrose) in Chinese Subjects
Protocol Number: 
Protocol Version: 
Date:
SAP Final Version: 
Date:
VIT-IRON-2011-004
5.0
14 August 2017
1.0
19 July 2019
This Statistical Analysis Plan was subjected to critical review and complies with the statistical 
principles set out in the ICH E9 and E3, and the guidelines on Good Clinical Practice.
Prepared by:
_____________
____
 
Date
Stat/Statistician
Tigermed Consulting Ltd.
Senior Clinical Research Manager 
Vifor Pharma - Vifor Pharma Group.
Head of Clinical Drug Safety
Vifor Pharma - Vifor Pharma Group.
Principal Statistician
Vifor Pharma - Vifor Pharma Group.
Date
Date
Protocol VIT-IRON-2011-004
Page 2 of 35


Protocol VIT-IRON-2011-004                                                                                                         Page 3 of 35 
TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................................................ 6 
1.1 
STUDY RATIONALE ....................................................................................................................................... 6 
2 
STUDY SUMMARY .................................................................................................................................... 6 
2.1 
OBJECTIVES ................................................................................................................................................ 6 
2.1.1 
Primary Objective ............................................................................................................................... 6 
2.1.2 
Secondary Objectives .......................................................................................................................... 6 
2.2 
STUDY DESIGN ............................................................................................................................................ 6 
2.3 
SCHEDULE OF EVENTS ................................................................................................................................... 7 
2.4 
SAMPLE SIZE DETERMINATION ....................................................................................................................... 8 
2.5 
RANDOMISATION AND BLINDING .................................................................................................................... 9 
2.5.1 
Interim Analysis .................................................................................................................................. 9 
2.6 
STUDY ENDPOINTS ....................................................................................................................................... 9 
2.6.1 
Primary endpoint for efficacy ........................................................................................................... 10 
2.6.2 
Secondary endpoints for efficacy ...................................................................................................... 10 
2.6.3 
Endpoint for safety ........................................................................................................................... 10 
3 
ANALYSIS SETS ....................................................................................................................................... 10 
3.1 
SAFETY SET ............................................................................................................................................... 10 
3.2 
FULL ANALYSIS SET .................................................................................................................................... 10 
3.3 
PER PROTOCOL SET .................................................................................................................................... 10 
4 
DESCRIPTION OF THE STATISTICAL ANALYSIS ......................................................................................... 11 
4.1 
GENERAL CONSIDERATIONS ......................................................................................................................... 11 
4.1.1 
Standard descriptive statistics .......................................................................................................... 11 
4.1.2 
Definition of baseline, visits and visit windows ................................................................................ 11 
4.1.3 
Planned Assessment Windows ......................................................................................................... 12 
4.1.4 
Treatment start/stop dates .............................................................................................................. 12 
4.1.5 
Tables and listings presentation ....................................................................................................... 12 
4.1.6 
Analysis Sets ..................................................................................................................................... 12 
4.1.7 
Analysis of Subgroups ....................................................................................................................... 12 
4.1.8 
Methods for Handling and imputation of Missing Data ................................................................... 13 
4.2 
SUBJECT DISPOSITION, RANDOMISATION ASSIGNMENT AND SUBJECT POPULATIONS ............................................... 13 
4.3 
DEMOGRAPHICS AND BASELINE SUBJECT CHARACTERISTICS................................................................................ 13 
4.4 
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS ............................................................................ 13 
4.5 
STUDY DRUG EXPOSURE AND COMPLIANCE .................................................................................................... 14 
4.6 
EFFICACY ANALYSIS .................................................................................................................................... 15 
4.6.1 
Primary Efficacy Analysis .................................................................................................................. 15 
4.6.2 
Secondary Efficacy Analysis .............................................................................................................. 15 
4.7 
SAFETY ANALYSES ...................................................................................................................................... 16 
4.7.1 
Adverse Events ................................................................................................................................. 16 
4.7.2 
Clinical Laboratory Evaluations ........................................................................................................ 18 
4.7.3 
Electrocardiogram (ECG) Evaluations ............................................................................................... 19 
4.7.4 
Vital Signs Evaluations...................................................................................................................... 19 
4.7.5 
Other measures ................................................................................................................................ 19 
4.7.5.1 
Concomitant Medications and procedures and medication history ............................................ 19 
4.8 
PHYSICAL EXAMINATIONS ............................................................................................................................ 20 
4.9 
OTHER ANALYSES ...................................................................................................................................... 20 
APPENDICES ...................................................................................................................................................... 22 


Protocol VIT-IRON-2011-004                                                                                                         Page 4 of 35 
APPENDIX 1: MAJOR OR MINOR PDS ......................................................................................................................... 22 
APPENDIX 2: DECIMAL PLACE .................................................................................................................................... 26 
APPENDIX 3: LIST OF TFLS ........................................................................................................................................ 27 
APPENDIX 4: LABORATORY ASSESSMENTS: CTC CRITERIA (CTCAE V4.0) .......................................................................... 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 5 of 35 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
%  
 
Percentage 
AE                 Adverse event 
CI  
 
Confidence interval 
CRF   
Case report form 
ECG              Electrocardiogram 
FAS   
 Full analysis set 
FCM              Ferric carboxymaltose 
GCP   
Good clinical practice 
GI                  Gastro Intestinal 
Hb                 Haemoglobin 
HUB              Heavy uterine bleeding 
IBD                Inflammatory bowel disease 
ICF                Informed consent form 
ICH   
International conference on harmonization 
IDA               Iron deficiency anemia 
IRT 
 
Interactive response technology 
IS 
           Iron Sucrose 
MedDRA  
Medical dictionary for regulatory activities 
N  
 
Number 
PP  
 
Per protocol 
PPS  
Per protocol set 
PV  
 
Protocol violation 
SAE   
Serious adverse event 
SS 
 
Safety set 
TEAE  
Treatment emergent adverse event 
SAP   
Statistical analysis plan 
SOP   
Standard operating procedure 
TFL 
 
Tables, figures and listings 
TOC  
Table of content 
 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 6 of 35 
1 INTRODUCTION 
 
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting 
and analyses of data collected under protocol VIT-IRON-2011-004 version 5.0 dated 14 August 2017. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This 
version of the plan has been developed using protocol version 5.0 dated 14 August 2017 and CRF 
version 5.0 dated 17 January 2018. Any further changes to the protocol or CRF may necessitate 
updates to the SAP. 
1.1 
Study Rationale 
Ferric carboxymaltose (FCM) has been developed by Vifor Pharma – Vifor International Inc. as a 
formulation enabling the application of high iron doses up to 1000 mg in a single dose with a maximum 
of 20 mg/kg body weight.  FCM has a low immunogenic potential and does not exhibit cross-reactivity 
to anti-dextran antibodies.  The application of high doses of IV iron in 1 single administration with the 
potential to replenish the iron stores has multiple advantages over multiple smaller doses.  Compared 
to other IV iron products, FCM can be given in a short time (6 minutes instead of 3.5 hours (as for 
Venofer) for a 500 mg iron dose) and in iron doses of up to 1,000 mg, which reduced the need for the 
subject for multiple and long stays at the hospital.  This reduces hospital costs.  Also, especially in 
rural regions, a single administration for replenishing the iron stores may help to increase subject 
compliance, and might make long journeys to the hospital unnecessary.  A single administration 
versus multiple infusions additionally reduces the risks associated with the administration procedure, 
such as phlebitis, infection, extravasation, of other infusion-related AEs. 
It has been seen that interethnic variability in PKs of certain drugs can cause unexpected outcomes, 
such as therapeutic failure, adverse effects, and toxicity in subjects of different ethnic origin, which can 
be both due to genetic and environmental factors.  The International Council on Harmonisation (ICH) 
published a guidance to facilitate the registration of drugs among ICH regions (European Union, 
Japan, the United States), recommending a framework for evaluating the impact of ethnic factors on 
efficacy and safety of drugs at a particular dosage and dosage regimen.  Especially drugs metabolised 
via the Phase 1 enzymes of the cytochrome group are prone to ethnical and/or genetic variability. 
FCM is not metabolised via cytochrome and constitutes a delivery system for the trace element iron.  
Based on limited data from Asian subjects who participated in the global registration studies conducted 
in Europe, genetic or interracial differences are not expected. 
2 STUDY SUMMARY 
2.1 
Objectives 
2.1.1 
Primary Objective 
The primary objective of the study is to demonstrate the efficacy of FCM given in a simple dosing 
regimen in correcting Iron deficiency anaemia (IDA), by demonstrating non-inferiority to treatment with 
the currently approved intravenous (IV) iron therapy of iron sucrose (IS, Venofer) in the Chinese 
population. 
2.1.2 
Secondary Objectives 
The secondary objectives of the study are as follows: 
 
To assess the safety of FCM compared to IS in the Chinese population 
 
To evaluate the effect of FCM compared to IS on relevant laboratory parameters 
(haematology, chemistry, iron parameters) in the Chinese population 
2.2 
Study Design 


Protocol VIT-IRON-2011-004                                                                                                         Page 7 of 35 
This is an open-label, randomised controlled study to assess the impact of FCM in correcting IDA 
compared to Venofer (IS) in Chinese subjects.  The study will randomise approximately 368 subjects 
(184 per group) suffering from different underlying diseases leading to IDA.  It is expected that 
approximately 850 subjects need to be screened to randomise 368 subjects. 
After an initial screening period (up to 7 days), eligible subjects will undergo baseline assessments and 
will be randomised (1:1) to receive either FCM or IS at study Day 1.  
In the FCM group, study drug administration will occur on Day 1 and, if needed, on Day 8 and Day 15. 
Subjects randomised to IS will receive injections/infusions of a maximum of 200 mg iron three times a 
week until the calculated total iron dose is administered.  
All subjects will return for assessment of efficacy and safety at Weeks 2, 4, 6 and 8. 
 
 
2.3 
Schedule of Events 
 
Visit 
Procedures 
Visit 1 
Screen 
Visit 2 
Baseline 
Visit 3-5 
Visit 6 
End of study/ 
Early 
Termination 
 
Day -7 
to Day -1 
Day 1 
Weeks 2, 4, 6 
3 Days 
Week 8 
4 Days 
Informed consent 
 
 
 
 
Eligibility criteria 
 
(1) 
 
 
Demographics 
 
 
 
 
Medical history 
 
 
 
 
Physical examination and weight 
 
 
 
 
Height 
 
 
 
 
Vital signs (blood pressure, heart 
rate, temperature) 
 
 
 
 
Electrocardiogram 
 
 
(6) 
 
Laboratory assessments 
 
 
 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 8 of 35 
 
Visit 
Procedures 
Visit 1 
Screen 
Visit 2 
Baseline 
Visit 3-5 
Visit 6 
End of study/ 
Early 
Termination 
 
Day -7 
to Day -1 
Day 1 
Weeks 2, 4, 6 
3 Days 
Week 8 
4 Days 
(haematology/ biochemistry/iron 
parameters)(2) 
Hepatitis B and C screening(3) 
 
 
 
 
Urinalysis(4) 
 
 
 
 
Serum pregnancy test(5) 
 
 
 
 
Adverse events 
 
 
 
 
Prior & Concomitant medications 
 
 
 
 
Randomisation 
 
 
 
 
Administration of study drug 
 
 
((7)) 
 
1. Laboratory parameters will be tested at Baseline but will not be used for eligibility because the results will not be available on 
time.  Laboratory parameters taken at screening will be checked for eligibility at Baseline. 
2. Laboratory assessments include:  
 Haematology: Hb, haematocrit, red blood cell count, MCV, MCH, MCHC, reticulocyte count, Hb content in reticulocytes, 
white blood cell count with differential and platelet count.  
 Iron status parameters: serum iron, serum ferritin, serum transferrin, UIBC and TSAT.  
 Biochemistry parameters: electrolyte status (sodium, potassium, magnesium, calcium, chloride, phosphorus), AST, ALT, 
gamma-glutamyl transpeptidase (GGT), glucose, alkaline phosphatase (AP), lactate dehydrogenase (LDH), C-reactive 
protein (CRP). 
3. Hepatitis screening consists of Hepatitis B antigen, Hepatitis B virus DNA  and  Hepatitis C virus antibody  
4. Urinalysis includes:  phosphorus, protein, glucose, bilirubin, pH, nitrite, ketone, urobilinogen, blood, leukocytes 
5. For women of childbearing potential only. 
6. ECG is only performed at Week 4. 
7. Subjects randomised to receive FCM will receive a maximum of 1,000 mg at Baseline (Day 1), a second administration of a 
maximum of 1,000 mg at Day 8 and a third administration of a maximum of 500 mg at Day 15, if applicable. Subjects 
randomised to Venofer will need to come to the study centre to receive further Venofer dosing three times a week. All study 
procedures must be conducted prior to dosing. 
 
Notes: ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; CRP = C-reactive 
protein; ECG = Electrocardiogram; FCM = ferric carboxymaltose; GGT = gamma glutamyl transpeptidase; Hb = 
Haemoglobin; LDH = lactate dehydrogenase; MCH = Mean corpuscular Hb; MCHC = Mean corpuscular haemoglobin 
concentration; MCV = Mean corpuscular volume; TSAT = Transferrin saturation; UIBC = unsaturated iron binding 
capacity. 
 
2.4 
Sample Size Determination 
To assess the non-inferiority of FCM compared to IS in the proportion of subjects who will have an 
increase from baseline in Hb of ≥ 2g/dL at any time up to Week 8 (responders), the following 
assumptions have been made: 
 
Subjects that will be included in the study will be mainly subjects with Gastro Intestinal (GI) 
disorders and women with heavy uterine bleeding (HUB).  The responder rate after IS treatment is 
expected to be 70%.  This is based on the mean of the proportion of responders in the 2 studies 
described below in IDA subjects with inflammatory bowel disease (IBD) and IDA subjects with 
HUB respectively. 
In study FER-IBD-07-COR, which compared FCM to IS in IDA subjects with IBD, the proportion of 
subjects who had an increase from baseline in Hb ≥ 2g/dL at Week 8 was 72% in FCM group and 
55% in IS group (Per Protocol Set (PPS)).  Seventy three percent in the FCM group and 58% in 
the IS group had an increase of at least ≥ 2g/dL at any time up to Week 8.  
In study 1VIT04002/1VIT04003, which compared FCM to oral iron in IDA subjects with HUB, 82% 
of subjects in the FCM group had an increase from baseline in Hb ≥ 2g/dL at any time up to Week 
6.  Although no subjects in this study were treated with Venofer, and no other data are available 
from studies in which HUB subjects are treated with Venofer, it has been assumed that Venofer 
would have the same response rate as FCM in this subject population. 


Protocol VIT-IRON-2011-004                                                                                                         Page 9 of 35 
 
The non-inferiority margin for the difference in the proportion of responders between FCM and IS 
was set to -15%.  This margin will ensure a treatment effect for FCM (70 - 15 = 55) greater than 
33%, the upper bound of the 95% confidence interval (CI) of the proportion of responder of an 
estimated placebo effect, by more than half the effect  itself (33 + 16.5 = 49.5).  The placebo effect 
was estimated as follows: 
In study 1VIT07017 which compared FCM to Standard Medical Care (SMC) in IDA subjects with 
HUB or post-partum, there were 55 subjects in the SMC group who did not receive any Iron 
treatment. Of these, 50 had an Hb assessment at Day 30.  At Day 30 the proportion of non-treated 
subjects with an Hb increase ≥ 2 g/dL was 22% (11/50) with a 95% CI from 11% to 33%. 
The sample size is based on showing non-inferiority in the difference in the proportion of subjects 
achieving an increase in Hb of ≥ 2g/dL at any time up to Week 8 between FCM and IS.  Applying a test 
at a one-sided alpha level of 2.5%, and a -15% non-inferiority margin, 147 subjects per group will have 
80% power to detect that FCM is non-inferior to IS with an expected IS responder proportion of 70%.  
The total sample size is 368 (184 per treatment group), taking into account an estimated drop-out rate 
of 20% of the randomised subjects. 
 
2.5 
Randomisation and Blinding 
 
This study is an open-label, randomised controlled study to assess the impact of FCM in correcting 
IDA compared with Venofer. 
Subjects will be allocated one of the following treatments: FCM or IS.  The randomisation allocation 
ratio will be 1:1 and the randomisation will be blocked by centre.  They will be assigned to site via 
Interactive Response Technology system during study.  Totally, there will be 600 blocks with 4 as 
block size (15 block per centre).  The randomisation schedule was generated and maintained by 
Tigermed according to Tigermed SOPs. 
Table 1 presents the treatment group labels and Table 2 presents the visit labels that will be used in all 
output. 
Table 1: Study Treatments 
Studied Treatment 
Treatment Label 
FCM 
FCM 
Venofer 
IS 
 
Table 2: Study Visits 
Visit Number (title) 
Visit Label 
Visit 1 (Screening) 
Screening 
Visit 2 (Day 1) 
Baseline 
Visit 3 (Week 2) 
Week 2 
Visit 4 (Week 4) 
Week 4 
Visit 5 (Week 6) 
Week 6 
Visit 6 (Follow-Up, Week 8)  
End of study 
 
2.5.1 
Interim Analysis 
No interim analyses are planned. 
2.6 
Study endpoints 


Protocol VIT-IRON-2011-004                                                                                                         Page 10 of 35 
2.6.1 
Primary endpoint for efficacy 
Percentage of subjects achieving an increase in Hb of ≥ 2 g/dL (responders) from baseline at any time 
up to Week 8. 
2.6.2 
Secondary endpoints for efficacy 
 
Percentage of subjects achieving an increase in Hb ≥ 2 g/dL from baseline at Weeks 2, 4, 6 and 8. 
 
Change in Hb from baseline to Weeks 2, 4, 6 and 8. 
 
The percentage of subjects with TSAT ≥ 16% and serum ferritin ≥100 ng/mL (for subjects with 
underlying inflammatory disease as determined by hsCRP levels above the normal range) or > 
14ng/mL (in subjects with no apparent underlying inflammatory disease as determined by hsCRP 
levels within normal range) at Weeks 2, 4, 6 and 8. 
 
Change in TSAT from baseline to Weeks 2, 4, 6 and 8. 
 
Change in serum ferritin from baseline to Weeks 2, 4, 6 and 8. 
2.6.3 
Endpoint for safety 
 
Change in laboratory parameters (haematology, clinical chemistry and iron status) from baseline 
over the study duration. 
 
Summary of all treatment emergent adverse events (TEAE): type, nature, incidence and outcome 
overall and by underlying disease aetiology. 
 
Summary of changes in vital signs from baseline to Weeks 2, 4, 6 and 8. 
 
Summary of changes in electrocardiogram (ECG) and physical examination (including body weight) 
from baseline to Week 4 (for ECG only) and Week 8. 
3 ANALYSIS SETS 
3.1 
Safety Set 
All randomised subjects who have received at least one dose of study medication will be in the Safety 
Set (SS).  The subjects in the SS will be analysed based on the treatment that they received. 
3.2 
Full Analysis Set 
The Full Analysis Set (FAS) consists of those subjects who satisfy the following criteria: 
 
Randomised to treatment 
 
Received at least one dose of study treatment 
 
Had at least 1 baseline and post-baseline efficacy parameter (Hb, Ferritin or TSAT) value 
The FAS will be created in accordance with the Intent-To-Treat principles.  
The subjects in the FAS will be analysed based on the treatment that they were randomised to. 
3.3 
Per Protocol Set 
The Per-Protocol Set (PPS) is defined as all subjects in the FAS with a study drug compliance 
between 80 and 120% and do not have any major protocol violations (appendix 1). 
The subjects in the PPS will be analysed based on the treatment that they were randomised to. 
As per protocol, blood samples had to be drawn before study drug administration (when planned). All 
laboratory efficacy assessments (Hb, Ferritin, and TSAT) that are measured from a blood sample 


Protocol VIT-IRON-2011-004                                                                                                         Page 11 of 35 
taken after the study drug administration will not be considered for any efficacy analysis for both PPS 
and FAS.  The subjects will still be in the PPS if they do not have a major protocol deviation. 
For subjects who took prohibited concomitant medication, all laboratory efficacy assessments (Hb, 
Ferritin, and TSAT) will be censored after the prohibited medication start date for both PPS and FAS. 
The subjects will still be in the PPS if they do not have a major protocol deviation. 
4  DESCRIPTION OF THE STATISTICAL ANALYSIS 
This section describes the statistical analyses, presentation of the results, and the study 
endpoints/measures that will be collected and/or derived during the study at the time points specified 
in the Schedule of Events (see Section 2.3). 
4.1 
 General Considerations 
 
All confidence intervals (CI) and statistical tests will be 2-sided unless otherwise specified.  P-values 
which are greater than or equal to 0.001, and less than or equal to 0.999, will be presented to 3 
decimal places.  All other p-values which are less than 0.001 will be presented as <0.001, while p-
values greater than 0.999 will be presented as >0.999.  Confidence intervals will be presented to 1 
more decimal place than the raw data.  In general, the maximum number of decimal places reported 
shall be four. 
The software used for all summary statistics and statistical analyses will be SAS® Version 9.2 or later 
(SAS Institute, Inc.).  
4.1.1 
Standard descriptive statistics 
 
Continuous variables 
Unless specified otherwise, the following standard descriptive statistics by treatment group will be 
obtained for continuous variables: number, mean, standard deviation, median, quartiles (Q1, Q3), 
minimum, and maximum.  The minimum and maximum will be reported to the same number of decimal 
places as the raw data recorded in the database.  The Q1, Q3, mean and median will be reported to 
one more decimal place than the raw data recorded in the database.  The SD will be reported to two 
more decimal places than the raw data recorded in the database.  In general, the maximum number of 
decimal places reported shall be four for any summary statistic. 
Categorical variables 
Unless specified otherwise, the following standard descriptive statistics by treatment group will be 
presented for categorical values: total number, number of values in each class of the variable and the 
corresponding percentage of the total number of values available will be calculated. 
4.1.2 
Definition of baseline, visits and visit windows 
 
The baseline will be defined as the last available (non-missing) value before or on the day of the first 
administration of study drug.  Study day 1 is defined as the day of the first study drug administration.  
For analysis relative day, if considered date less than first study drug administration date, then 
analysis relative day will be considered date minus first study drug administration date, otherwise, it 
will be considered date minus first study drug administration date + 1. 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 12 of 35 
4.1.3 
Planned Assessment Windows 
 
Table 3 describes the Planned Assessment Windows that will be used in all analyses. 
Table 3: Planned Assessment Windows 
Visit Label 
Planned Visits (Protocol 
Specified) 
Analysis Assessment Window 
Target Day 
Baseline (Day 1) 
-- 
<=1 Day 
1 
Week 2 
± 3 days 
from Day 2 to Day 21 
14 
Week 4 
± 3 days 
from Day 22 to Day 35 
28 
Week 6 
± 3 days 
from Day 36 to day 49 
42 
Week 8 
± 4 days 
>= Day 50 
56 
 
All assessments will be re-mapped into the analysis windows.  For a parameter, if several 
assessments fall into the same analysis window, the closest to the target day will be considered for the 
analysis.  When there are 2 assessments closest to the target day, the latest one will be considered for 
the analysis. 
4.1.4 
Treatment start/stop dates 
 
If there are no treatment dates available in the administration page of the CRF, date of randomisation 
will be imputed as the start of treatment date, if it is known that the subject received study drug 
(information recorded in the administration page of the CRF or any information from monitoring). 
If the end of treatment date is missing in the administration page of the CRF, it will be imputed with the 
start date + administration duration of the same administration record. 
If the end of treatment date is missing in the treatment termination page of the CRF, the latest stop 
date from administration page (including imputed ones) would be imputed. 
 
4.1.5 
Tables and listings presentation 
 
The treatment groups will be displayed as in table 1. 
Listings will display all data contained in the CRF, excluding collected information on the screen failure 
subjects and subjects randomised and not treated. Screen failure and not treated subjects will be 
displayed in a separate listing.  Listings will be ordered by treatment, centre, subject ID, and visit date 
or event/medication start date. 
4.1.6 
Analysis Sets 
 
The analysis of the primary endpoint will be performed for the Per Protocol set (PPS) and tested at a 
one sided alpha level of 2.5% with a 15% non-inferiority margin.  A sensitivity analysis will be 
performed on the Full Analysis Set (FAS).  All secondary endpoints will be analysed on the FAS and 
the PPS. All statistical tests will be performed at a 5% level (2-sided). 
All safety analyses will be performed on the Safety Set. 
4.1.7 
Analysis of Subgroups 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 13 of 35 
 
 
 
 
4.1.8 
Methods for Handling and imputation of Missing Data 
 
Incomplete or missing data will not be imputed unless otherwise specified (Treatment start date (see 
4.1.4.), medical history and concomitant medications (see 4.4), adverse events (see 4.7.1)). 
 
4.2 
Subject Disposition, Randomisation Assignment and Subject Populations 
Subject disposition data will be collected on the study termination CRF page when a subject complete 
or discontinue from the study.  The subject disposition data will be summarised.  The following data 
will also be presented in the listings: 
 
Date of randomisation, randomisation number, planned treatment group, actual treatment 
received, and first administration date and time in the randomisation listing. 
 
Data of subjects included and excluded in FAS, PPS, and Safety Set with the reason of 
exclusion of any analysis set in the analysis population listing. 
 
4.3 
Demographics and Baseline Subject Characteristics 
 
Subject demographic and baseline characteristics data (sex, race, age, weight, and height) will be 
collected on the demographics CRF. The following baseline laboratory parameters Hb, TSAT, Serum 
ferritin, hsCRP will be collected on the laboratory CRF. 
The demographics will be summarised and listed (demographic listing includes dates of informed 
consent). 
Body mass index (BMI) will be calculated from weight and height as below 
 
BMI = weight(kg)/[height(m)]2 
 
4.4 
Medical History and Concurrent Medical Conditions 
 
All medical history (stopped prior to study drug administration) and concurrent medical conditions 
(started before dosing and ongoing or started after dosing) will be coded using the MedDRA (version 
19.1).   
Medical history identified as cause of IDA will be summarised separately by system organ class and 
preferred term. 
All medical history and concurrent medical conditions (including the ones identified as cause of IDA) 
will be summarised by system organ class and preferred term.  Also all medical history and concurrent 
medical conditions will be listed separately (Medical history identified as cause of IDA will be flagged).  
Prior and Concomitant Procedures will be listed separately. 
Missing dates/partial dates will be handled per below. 
Imputation of Start Dates: 
 
If only the month and year are specified, 1st of the month will be used. 


Protocol VIT-IRON-2011-004                                                                                                         Page 14 of 35 
 
If only the year is specified, January 01 will be used. 
 
If the start date is completely unknown, no imputation will be performed. 
Imputation of Stop Dates: 
 
If only the month and year are specified, then use the last day of the month. 
 
If only the year is specified, then use December 31 of that year. 
 
If the stop date is completely unknown, no imputation will be performed. 
 
4.5 
Study Drug Exposure and Compliance 
 
All individual dosing information will be listed and will include planned dose, dose form, Planned 
/Actual kit No., the start/end date and time of study drug administration, duration of administration, arm 
used for injection/infusion and actual volume administered.  Any reasons for incomplete dose will be 
listed if applicable.  A subject is defined as treatment compliant if he or she has taken at least 80% and 
not more than 120% of the investigational product dosage planned for that interval.  The dose of study 
drug information (cumulative planned dose, cumulative actual dose, days on treatment, duration of 
study participation, Total no. of injections/infusions received, treatment compliance rate, and 
compliance rate category (<80%, 80 to <120 %, >=120 %)) will also be summarised by treatment 
group. 
Cumulative treatment compliance percentage will be calculated as: 
Cumulative treatment compliance = 100 × Total Iron administered (mg)
Total Iron planned (mg) (1)  
(1) For subjects who withdraw the study the Total planned Iron is the Iron they should receive up to 
their discontinuation day. 
For subjects in FCM arm with a body weight <50kg and who withdrew on Day 8 or Day 15, they may 
have withdrawn the study before or after drug administration and therefore, will be considered 
compliant in either case unless consideration is required for under or over dosing (if they received the 
dose planned that day, the dose of the day should be added to the Total planned Dose, If they did not 
received it, the dose of the day should not be added to the Total planned dose.) 
For subjects in the IS arm, drug administrations could happen on any day within each week windows. 
The following table shows the total doses a subject could have received by day of withdrawal.  If a 
subject has a Total Iron received equal to any possible total dose or equal to the calculated Total 
planned Iron (by Ganzoni formula) if he/she withdrew after day 28, he should be considered as 
compliant.  Otherwise, if the total received dose is different to all possible doses at the time of 
withdrawal, the possible dose which is the closest to the received dose should be considered as the 
total planned dose. 
Day of study 
withdrawal 
Possible Total doses* 
1 
200 
  
  
  
2 
200 
400 
  
  
3 to 6 
200 
400 
600 
  
7 
400 
600 
  
  
8 
600 
800 
  
  
9 
600 
800 
1000 
  
10 to 12 
600 
800 
1000 
1200 
13 
800 
1000 
1200 
  
14 
1000 
1200 
  
  
15 
1200 
1400 
  
  


Protocol VIT-IRON-2011-004                                                                                                         Page 15 of 35 
16 
1200 
1400 
1600 
  
17 to 19 
1200 
1400 
1600 
1800 
20 
1400 
1600 
1800 
  
21 
1600 
1800 
  
  
22 
1800 
2000 
  
  
23 
1800 
2000 
2200 
  
24 to 26 
1800 
2000 
2200 
2400 
27 
2000 
2200 
2400 
  
28 
2200 
2400 
  
  
*: If the minimal possible dose is greater than the planned dose calculated by Ganzoni formula, the 
planned dose by Ganzoni formula should be consider as the total planned dose. 
 
4.6 
Efficacy Analysis 
 
4.6.1 
Primary Efficacy Analysis 
The primary endpoint is the percentage of subjects achieving an increase in Hb of ≥ 2g/dL 
(responders) from baseline at any time up to Week 8.  The non-inferiority test will be applied to the 
difference (FCM - IS) between the proportions of subjects meeting the primary endpoint using the PPS 
and FAS.  Non-inferiority will be determined if the lower bound of the 95% CI of this difference is above 
the non-inferiority margin as defined -15%.  The difference in proportions between the FCM and 
Venofer groups from baseline at any time up to Week 8 and its one‑sided 97.5% confidence intervals 
(CIs) will be computed using the Wilson score method with continuity correction described by 
Newcombe (1998). 
4.6.2 
Secondary Efficacy Analysis 
All secondary endpoints will be analysed on the FAS and the PPS.  All statistical tests will be 
performed at a 5% level (2-sided). 
Percentage of subjects achieving an increase in Hb ≥ 2 g/dL from baseline at Weeks 2, 4, 6 and 8. 
The difference in proportions between the FCM and Venofer groups from baseline at Weeks 2, 4, 6 
and 8 and its two‑sided 95% confidence intervals (CIs) will be computed using the Wilson score 
method with continuity correction described by Newcombe (1998). 
Change in Hb from baseline to Weeks 2, 4, 6 and 8.  Summary statistics will be presented at baseline, 
Weeks 2, 4, 6 and 8.  Treatment comparisons for change in Hb from baseline will also be assessed 
using an analysis of MMRM model including treatment, haemoglobin baseline, site and visit as factors. 
Interaction between visit and treatment is also included in the model.  The covariance structure to 
model the within-subject errors will be unstructured.  The REML will be used.  The Kenward-Roger 
method will be used to estimate the denominator degrees of freedom.  Type III tests for the least-
squares (LS) means will be used for the statistical comparison; the 95% CI will also be reported.  
Treatment group comparisons at each visits will be reported.  If the unstructured covariance matrix 
results in a lack of convergence, the heterogeneous Toeplitz covariance structure, followed by the 
heterogeneous autoregressive covariance structure, followed by the compound symmetry will be used.  
This order is specified according to a decreasing number of covariance parameters in the structure. 
The percentage of subjects with ID correction defined as TSAT ≥ 16% and serum ferritin ≥ 100 ng/mL 
(for subjects with underlying inflammatory disease as determined by hsCRP levels above the normal 
range) or > 14ng/mL (in subjects with no apparent underlying inflammatory disease as determined by 
hsCRP levels within normal range) at Weeks 2, 4, 6 and 8. The difference in proportions between the 
FCM and Venofer groups at Weeks 2, 4, 6 and 8 and its two‑sided 95% confidence intervals (CIs) will 
be computed using the Wilson score method with continuity correction described by Newcombe 


Protocol VIT-IRON-2011-004                                                                                                         Page 16 of 35 
(1998).  Treatment comparisons of subjects with ID correction variable will be assessed using a 
logistic regression analysis with treatment, baseline serum ferritin, baseline TSAT, and site in the 
model.   
Change in TSAT from baseline to Weeks 2, 4, 6 and 8.  Summary statistics will be presented at 
baseline, Weeks 2, 4, 6 and 8.  Treatment comparisons for Change in TSAT from baseline will also be 
assessed using an analysis of MMRM model including treatment, haemoglobin baseline, site and visit 
as factors. Interaction between visit and treatment is also included in the model. The covariance 
structure to model the within-subject errors will be unstructured.  The REML will be used.  The 
Kenward-Roger method will be used to estimate the denominator degrees of freedom.  Type III tests 
for the least-squares (LS) means will be used for the statistical comparison; the 95% CI will also be 
reported.  Treatment group comparisons at each visits will be reported.  If the unstructured covariance 
matrix results in a lack of convergence, the heterogeneous Toeplitz covariance structure, followed by 
the heterogeneous autoregressive covariance structure, followed by the compound symmetry will be 
used.  This order is specified according to a decreasing number of covariance parameters in the 
structure. 
Change in serum ferritin from baseline to Weeks 2, 4, 6 and 8.  Summary statistics will be presented at 
baseline, Weeks 2, 4, 6 and 8.  Treatment comparisons for Change in serum ferritin from baseline will 
also be assessed using an analysis of MMRM model including treatment, haemoglobin baseline, site 
and visit as factors. Interaction between visit and treatment is also included in the model.  The 
covariance structure to model the within-subject errors will be unstructured.  The REML will be used.  
The Kenward-Roger method will be used to estimate the denominator degrees of freedom.  Type III 
tests for the least-squares (LS) means will be used for the statistical comparison; the 95% CI will also 
be reported.  Treatment group comparisons at each visits will be reported.  If the unstructured 
covariance matrix results in a lack of convergence, the heterogeneous Toeplitz covariance structure, 
followed by the heterogeneous autoregressive covariance structure, followed by the compound 
symmetry will be used.  This order is specified according to a decreasing number of covariance 
parameters in the structure. 
4.7 
Safety Analyses 
Safety evaluations will be performed using the safety set.  Missing values will not be imputed unless 
otherwise decided and specified before database locked. 
4.7.1 
Adverse Events 
Adverse events data was collected from the time informed consent was obtained until the end of last 
study visit.  Missing AE data will be handled according to the rules specified in below. 
 
Adverse Event Definitions 
Adverse events reported after the time the ICF is signed until the end of study visit (Week 8 ± 4 days).  
A treatment-emergent adverse event (TEAE) is defined as an AE that occurred or increased in severity 
after the first dose of study medication was taken. 
A serious treatment-emergent adverse event (TEAE) is defined as a SAE occurring or increasing in 
severity after the first dose of study medication was taken, including SAEs occurring up to 30 days 
after the End of study/Early Withdrawal visit.  An AE will be classified as related to study medication if 
the relationship to study medication was recorded as “certain”, “probable/likely”, “possible”.  An AE will 
be classified as unrelated to study medication if the relationship to study medication was recorded as 
“unrelated”. 
An AE leading to study discontinuation will be defined as an AE where the reason for study withdrawal 
was recorded as being due to an AE on the Study Termination CRF page and the response to “Action 
taken with study drug” on the “Adverse Events” CRF page, was recorded as “Drug withdrawn”. 


Protocol VIT-IRON-2011-004                                                                                                         Page 17 of 35 
An AE leading to treatment discontinuation is defined as an AE where the outcome of the event was 
recorded as ‘Drug withdrawn’ on the ‘Adverse Events’ CRF page. 
Special Situations, the following are defined as special situations: 
 
Exposure of a medicinal product during pregnancy  
 
Medication error: any unintentional error in the prescribing, dispensing or administration of a 
medicinal product during the study 
 
Medication overdose: the administration of a quantity of study medication 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) are also considered as ADRs.  
Any special situation occurring with/without ADR/AE shall be recorded in the study specific 
documentation. 
All special situations have to be documented in the subject’s CRF as well as on the form 
“Documentation of Special Situations”.  If any overdose, or medication error leads to any event that 
fulfils any seriousness criteria, the event has to be reported as an SAE. 
Coding of Adverse Event Terms 
The AE term (Investigator term) will be assigned to the lowest level term (LLT), and a preferred term 
(PT) will be classified by a high level term (HLT), a high level group term (HLGT) and a system organ 
class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA) thesaurus, the 
MedDRA version to be used will be the latest version available at the time of study initiation. 
Although there can be multiple SOCs for a PT, each PT will be linked with one SOC, namely the 
primary SOC which is automatically assigned by MedDRA via one HLT, HLGT route. 
The following coding data will be presented: 
 
PT. 
 
primary SOC. 
 
Adverse events will be reported on a per-subject basis and per-event.  On a per-subject basis this 
means that even if a subject reported the same event repeatedly (i.e., events mapped to the same PT) 
during the study period, the event will be counted only once.  In the latter case the event will be 
assigned the worst severity and the strongest relationship to the study medication when summarised.  
The earliest date will be regarded as start date of the event and the latest date/time will be regarded as 
stop date of the event within the assigned study period. 
Missing and/or incomplete dates/times for AEs are imputed in a manner resulting in the earliest onset 
or the longest duration during the treatment period, taking additionally into account that the start 
date/time should not be after the stop date/time.  Stop dates/times will not be imputed if the AE is 
ongoing. This will be done as follows: 
For a missing/incomplete start date/time the minimum of the following will be imputed: 
 
The maximum of the earliest possible start date/time and the date/time of first study 
medication administration. 
 
The latest possible start date/time. 
 
The latest possible stop date/time. 
 
For a missing/incomplete stop date/time the maximum of the following will be imputed: 


Protocol VIT-IRON-2011-004                                                                                                         Page 18 of 35 
 
The minimum of the latest possible stop date/time and the date/time of last study medication 
administration. 
 
The earliest possible stop date/time. 
 
The earliest possible start date/time. 
 
The earliest (latest) possible date is defined as: 
 
The date itself if it is complete. 
 
The date of the first (last) day of the month, if month and year are available but day is missing. 
 
The date of the first (last) day of the year, if year is available but day and month are missing. 
 
A very early (late) date, e.g., 01JAN2000 (01JAN2100), if the date is completely missing. 
 
The imputation method will only be used to determine treatment emergence and to determine the time 
of the event relative to the first administration of study medication.  A worst-case approach will be 
followed in the event of missing severity or causality data.  If the severity is missing, ‘Severe’ will be 
imputed.  If causality data is missing, ‘Certain’ will be imputed.  In the event that no coding information 
is available for a specific AE, the AE will be presented as an ‘Uncoded’ in summary tables. 
The following listings will also be generated:  
 
Treatment Emergent Adverse Events Listing  
 
Non-Treatment Emergent Adverse Events 
 Adverse Events (Screened Only/Not Treated) 
 
Treatment Emergent Treatment Related Adverse Events 
 
Treatment Emergent Serious Adverse Events 
 
Treatment Emergent Adverse Events Leading to Premature Study Withdrawal 
 
Treatment Emergent Adverse Event Leading to Death 
 
Special Situations 
The following summary tables will be provided:  
 
Overall Summary of Treatment Emergent Adverse Events 
 
Treatment Emergent Adverse Events by Primary System Organ Class and Preferred Term 
 
Treatment Emergent Treatment Related Adverse Events by Primary System Organ Class and 
Preferred Term 
 
Treatment Emergent Serious Adverse Events by Primary System Organ Class and Preferred 
Term 
 
Treatment Emergent Treatment Related Serious Adverse Events by Primary System Organ Class 
and Preferred Term 
 
Treatment Emergent Adverse Events Leading to Premature Study Withdrawal by Primary System 
Organ Class and Preferred Term 
 
Treatment Emergent Adverse Events Leading to Death by Primary System Organ Class and 
Preferred Term 
 
Treatment Emergent Adverse Events Leading to Study Drug Interruption by Primary System 
Organ Class and Preferred Term 
 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term, and Relationship 
to Study Medication 
 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term, and Maximum 
Severity 
 
Treatment Emergent Adverse Events by Preferred Term 
Each summary table will include incidences of adverse events.  
 
4.7.2 
Clinical Laboratory Evaluations 
Descriptive statistics will be performed for laboratory parameters on a continuous scale for the 
absolute and change from baseline for each visit split by treatment group.  Subjects with Potential 
clinical significance will be summarised by treatment group.  
If multiple tests were performed at baseline, the latest non-missing measurement prior to the first 
administration of study treatment will be used for the baseline value.  For multiple tests at post-
baseline visits occurring during the same visit window, the closest measurement will be used for the 


Protocol VIT-IRON-2011-004                                                                                                         Page 19 of 35 
analyses and summary tables. When two measurements are exactly equidistant to the exact visit date, 
the later will be used for the analyses and summary tables.  Laboratory values expressed as ‘less 
than” or “greater than” will be imputed using the next numerical value (i.e. ‘<2.00’ imputed as 1.99, 
“>0.3” imputed as 0.4). 
Shift tables for the hematology and biochemistry laboratory parameters comparing values low, normal 
and high using the standard reference ranges will be presented for the baseline laboratory 
measurement versus the endpoint measurement for each subject.  The number and percentage of 
subjects with abnormal values for each analyte will be summarised at each analysis visit.  Abnormal 
values for each analyte will be determined using normal ranges provided by the central laboratory.   
All laboratory results will be listed, including all unscheduled visits.  Decimal place for each parameter 
is described in appendix 2. 
4.7.3 
Electrocardiogram (ECG) Evaluations 
A summary of abnormal clinically significant and abnormal not clinically significant electrocardiogram 
(ECG) results will be presented by treatment and visit.  Absolute and change from baseline ECG 
results will be tabulated (Heart Rate, PR interval, QRS interval, RR interval, QT interval, QTcF interval) 
by treatment group and overall.  QT and QTc will be analyzed in accordance with ICH E14 guidance.  
All ECG tests and results will be listed.  A summary of Electrocardiogram Abnormal Results (QT and 
QTcF) will be presented by treatment and visit.  Also a shift table for QT and QTcF for interval class 
will be presented for the baseline measurement versus the endpoint measurement by treatment and 
visit. 
If multiple ECG evaluations were performed at baseline, the latest non-missing measurement prior to 
the first administration of study treatment will be used for the baseline value.  For multiple ECG 
evaluations at post-baseline visits occurring during the same visit window, the closest measurement to 
the actual visit date will be used for the analyses and summary tables.  When two measurements are 
exactly equidistant to the exact visit date, the later will be used for the analyses and summary tables.   
All ECG tests and results will be listed. 
4.7.4 
Vital Signs Evaluations 
The raw scores and change from baseline results of blood pressure, heart rate, temperature, body 
weight and BMI will be summarised by treatment and visit.  
For each vital signs variable, the Baseline value is defined as the last non-missing measurement 
collected/derived prior to the first study medication administration at Baseline visit. 
Vital signs will be presented for individual subjects in data listings. 
If multiple Vital signs evaluations were performed at baseline, the latest non-missing measurement 
prior to the first administration of study treatment will be used for the baseline value.  For multiple Vital 
signs evaluations at post-baseline visits occurring during the same visit window, the closets 
measurement to the actual visit date will be used for the analyses and summary tables.  When two 
measurements are exactly equidistant to the exact visit date, the later will be used for the analyses 
and summary tables. 
4.7.5 
Other measures 
 
4.7.5.1 
Concomitant Medications and procedures and medication history 
Medication history refers to the medications that the study subjects stopped taking before or at 
baseline.  Concomitant medications are defined as medications taken from baseline through the end of 
the study.  Counts and percentages of subject used for each medication will be computed and 


Protocol VIT-IRON-2011-004                                                                                                         Page 20 of 35 
summarised by ATC level 2, level 4 and preferred term for each treatment and overall.  If coding levels 
are empty, text “Uncoded” will be displayed. 
All procedures will be listed. 
4.8 
Physical Examinations 
 
Data has been documented into AE or medical history.  No separate analysis will be performed. 
4.9 
Other Analyses 
 
Not applicable. 


Protocol VIT-IRON-2011-004                                                                                                         Page 21 of 35 
REFERENCES 
1. ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95- adopted 
December 1995). 
2. ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted March 
1998). 
3. Guidance on Statistical Principles for Clinical Trials in Pharmaceutical Development. China 
Food and Drug Administration, P. R. China; Jun 2016. 
4. Newcombe, R. G. (1998), Interval Estimation for the Difference between Independent 
Proportions: Comparison of Eleven Methods, Statistics in Medicine. 1998: 17, 873–890. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 22 of 35 
APPENDICES 
 
Appendix 1: Major or Minor PDs 
Vifor DVSCAT 
  (Categories of 
PDs) 
Vifor DVDECOD 
(Sub-Categories of 
PDs) 
Details 
Major or 
Minor 
ICF PROCEDURE 
ERROR 
ICF PROCEDURE 
ERROR 
Written informed consent obtained after study 
specific procedure conducted 
Major 
 
PRE-ICF 
PROCEDURE 
Written informed consent not obtained and study 
specific procedure conducted 
Major 
INCLUSION 
CRITERIA 
INCLUSION 
CRITERION # 1 
At least 18 years of age   
 
Deviation: <18 years 
Major 
 
INCLUSION 
CRITERION # 2 
Hb <11 g/dL (females) or Hb <12 g/dL (males) at the 
screening visit 
 
Deviation: Hb >=11 g/dL (females) or Hb >=12 
g/dL (males)  at screening visit 
Major 
 
INCLUSION 
CRITERION # 3 
Serum ferritin <100 ng/mL for subjects with 
underlying inflammatory disease (e.g., inflammatory 
bowel disease (IBD), chronic kidney disease (CKD) 
or chronic heart failure (CHF), as determined by C-
reactive protein [CRP] levels above the normal 
range) otherwise ≤14 ng/mL in subjects with no 
apparent underlying inflammatory disease (as 
determined by CRP levels within normal range) at 
the screening visit 
 
Deviation:  
Serum ferritin >=100 ng/mL for subjects with 
underlying inflammatory disease (CRP level 
above NR)  at screening visit 
Serum ferritin >14 ng/mL for subjects without 
underlying inflammatory disease (CRP level 
within NR)  at screening visit 
Major 
 
INCLUSION 
CRITERION # 4 
TSAT <16% (any subject) at the screening visit 
 
Deviation: TSAT >=16 % at screening visit 
Major 
 
INCLUSION 
CRITERION # 5 
Microcytic, hypochromic anaemia defined as: 
a. Mean corpuscular Hb concentration (MCHC) 
<32% 
b. Mean corpuscular volume (MCV) < 80 fL 
c. Mean corpuscular Hb (MCH) <27 pg  
 
Deviation: MCHC >=32% or MCV >= 80fL or 
MCH >=27 pg at screening 
Major 
EXCLUSION 
CRITERIA 
EXCLUSION 
CRITERION # 1 
Subject has known hypersensitivity to any of the 
products to be administered during dosing 
Major 
 
EXCLUSION 
CRITERION # 2 
Any history of iron storage diseases such as 
haemochromatosis 
Major 
 
EXCLUSION 
CRITERION # 3 
Any history or clinical findings of iron utilisation 
disorders such as sideroachrestic anaemia 
Major 
 
EXCLUSION 
CRITERION # 4 
Known haemoglobinopathy (e.g. thalassaemia) 
Major 
 
EXCLUSION 
CRITERION # 5 
Any history or clinical findings of an anaemia 
associated with: 
a. Haematuria 
b. Vitamin B12 or folic acid deficiency that requires 
treatment (subjects can be included after deficiency 
Major 


Protocol VIT-IRON-2011-004                                                                                                         Page 23 of 35 
Vifor DVSCAT 
  (Categories of 
PDs) 
Vifor DVDECOD 
(Sub-Categories of 
PDs) 
Details 
Major or 
Minor 
is corrected) 
 
EXCLUSION 
CRITERION # 6 
Any allergic predisposition, ie any history of asthma 
or atopic allergy. This includes drug allergies.  
Major 
 
EXCLUSION 
CRITERION # 7 
Planned surgery with anticipated blood loss (defined 
as Hb drop >2 g/dL) in the 3 months post 
randomisation 
Major 
 
EXCLUSION 
CRITERION # 8 
Subject has known malignancy (with or without 
current treatment), except basal cell or squamous 
cell carcinoma of the skin or cervical intra-epithelial 
neoplasia 
Major 
 
EXCLUSION 
CRITERION # 9 
Haemodialysis (current or planned within the next 3 
months) 
Major 
 
EXCLUSION 
CRITERION # 10 
History of IV iron therapy, erythropoiesis stimulating 
agent (ESA) therapy and/or blood transfusion in 
previous 4 weeks prior to screening, and oral iron or 
oral iron-containing products including Chinese 
herbal medicines  (>75mg iron/day) in the 7 days 
prior to screening 
Major 
 
EXCLUSION 
CRITERION # 11 
Body weight <35 kg 
Major 
 
EXCLUSION 
CRITERION # 12 
Chronic liver disease and/or screening alanine 
transaminase (ALT) or aspartate 
transaminase (AST) above 3 times the upper limit of 
the normal range 
Major 
 
EXCLUSION 
CRITERION # 13 
Known human immunodeficiency virus infection, 
acquired immunedeficiency syndrome, tuberculosis 
Major 
 
EXCLUSION 
CRITERION # 14 
Known active hepatitis B or C or other active 
infection (acute or chronic) 
Major 
 
EXCLUSION 
CRITERION # 15 
Subject currently is enrolled in or has not yet 
completed at least 30 days since ending other 
investigational device or drug study(ies), or subject is 
receiving other investigational agent(s)  
Major 
 
EXCLUSION 
CRITERION # 16 
Subject is pregnant or is breast feeding 
Major 
 
EXCLUSION 
CRITERION # 17 
Female subject of childbearing potential not using 
adequate contraceptive methods during the study 
and for up to 1 month after the last dose of the study 
medication. Adequate contraceptive methods are 
defined as those which result in a low failure rate 
(I.e., less than 1% per year) when used consistently 
and correctly such as implants, injectables, combined 
oral contraceptives, some intra-uterine devices, 
sexual abstinence or vasectomised partner. Non-
childbearing potential includes being surgically 
sterilised at least 6 months prior to the study or post-
menopausal, defined as amenorrhoea for at least 12 
months. 
Major 
 
EXCLUSION 
CRITERION # 18 
Male subjects fathering a child within 7 days from the 
last study drug administration 
Major 
 
EXCLUSION 
CRITERION # 19 
Subject has any kind of disorder that compromises 
the ability of the subject to give written informed 
consent and/or to comply with study procedures 
and/or other reason(s) that render subject not 
appropriate for study participation in the opinion of 
the treating physician 
TBD* 
NON-
COMPLIANCE 
WITH STUDY 
NON-COMPLIANCE 
WITH STUDY DRUG 
# 1 
Incomplete FCM dose administered on Day 1, Day 8 
or Day 15 
TBD* 


Protocol VIT-IRON-2011-004                                                                                                         Page 24 of 35 
Vifor DVSCAT 
  (Categories of 
PDs) 
Vifor DVDECOD 
(Sub-Categories of 
PDs) 
Details 
Major or 
Minor 
DRUG 
 
NON-COMPLIANCE 
WITH STUDY DRUG 
# 2 
Incomplete IS dose administered 
TBD* 
STUDY DRUG 
ADMINISTRATIO
N/TECHNICAL 
ERROR 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 1 
FCM Dose not administered  according to visit 
schedule (as per table 2 in protocol) 
TBD* 
 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 2 
Total daily FCM Dose not administered  according to 
body weight and Hb  
TBD* 
 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 3 
Incorrect FCM administration times  
 (infusion of 500 mg < 5 min OR infusion of 1000mg 
< 15 min AND for both doses >30 min) 
Major for rapid administration (< 5min for 500 mg 
dose or <15 min for1000mg dose); 
Minor for longer administration (>30 min) 
Major/Minor 
 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 4 
FCM diluted with the incorrect volume 
 (infusion of 500 mg NOT diluted in 100mL OR 
infusion of 1000mg NOT diluted in 250mL) 
For over dilution in larger volume: Major  
For dilution in smaller volume(<100ml for 500mg 
dose or <250ml for 1000mg dose: Minor 
Major/Minor 
 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 5 
IS Dose not administered  according to Ganzoni 
formula 
TBD* 
 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 6 
 IS Dose not administered  according to visit 
schedule 
Major for overdose (> 3 doses per week)  Minor for 
dose omission 
Major/Minor 
 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 7 
Maximum daily IS dose exceeded(> 200mg) 
Major 
 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 8 
IS diluted with the incorrect volume 
(Dilution of 10 ml of the product intended for slow IV 
push injection OR drip infusion of 10 ml diluted in > 
200ml) 
Major 
 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 9 
Incorrect IS administration time (infusion >60 mins) 
Minor 
 
STUDY DRUG 
ADMINISTRATION/T
ECHNICAL ERROR 
# 10 
Incorrect IS administration time (for undiluted 
injection< 10 mins OR for diluted drip infusion < 30 
mins) 
Major 
STUDY DRUG 
DEVIATION 
STUDY DRUG 
DEVIATION # 1 
Incorrect IMPs storage condition (FCM store > 30°C 
or freeze / IS store < 4°C or > 25°C or freeze) 
TBD* 
 
STUDY DRUG 
DEVIATION # 2 
Incorrect treatment administration vs randomization 
Major 
 
STUDY DRUG 
DEVIATION # 3 
Study drug not stopped when subject experienced 
any kind of hypersensitivity reaction related to the 
study drug during administration 
Major 


Protocol VIT-IRON-2011-004                                                                                                         Page 25 of 35 
Vifor DVSCAT 
  (Categories of 
PDs) 
Vifor DVDECOD 
(Sub-Categories of 
PDs) 
Details 
Major or 
Minor 
PROHIBITED 
MEDICATION 
PROHIBITED 
MEDICATION 
Prohibited Therapy and Concomitant Treatment (Oral 
or other IV iron therapy (other than the study 
medication), multivitamins or nutritional supplements 
containing iron > 75 mg per day, ESAs, Blood 
transfusions) 
Major 
PROCEDURE/TE
ST NOT DONE 
PROCEDURE/TEST 
NOT DONE # 1 
Vital Signs missing 
Major 
 
PROCEDURE/TEST 
NOT DONE # 2 
Physical Examination  missing (Fully missing is Major 
at Screening/Fully missing is Minor at EOS/Partially 
missing is Minor at Screening and EOS) 
Major/Minor 
 
PROCEDURE/TEST 
NOT DONE # 3 
Laboratory tests: Haematology & Iron status missing 
from Visit 2 to Visit 6(Missing assessment is 
major/Missing parameter is minor 
Major/Minor 
 
PROCEDURE/TEST 
NOT DONE # 4 
Laboratory tests: Haematology & Iron status missing 
at Visit 1(Missing assessment is major/Parameters 
Hb, MCH, MCV, MCHC, Serum Ferritin, TSAT 
missing is major/Other parameters missing is minor) 
Major/Minor 
 
PROCEDURE/TEST 
NOT DONE # 5 
Laboratory tests : Chemistry missing from Visit 2 to 
Visit 6 (Missing assessment is major/Missing 
parameter is minor) 
Major/Minor 
 
PROCEDURE/TEST 
NOT DONE # 6 
Laboratory tests: Chemistry missing at Visit 
1(Missing assessment is major/Parameters CRP, 
ALT, AST missing is major 
/Other parameters missing is minor) 
Major/Minor 
 
PROCEDURE/TEST 
NOT DONE # 7 
Laboratory tests at planned visits: Urinalysis missing 
(Missing assessment is major/Missing parameter is 
minor ) 
Major/Minor 
 
PROCEDURE/TEST 
NOT DONE # 8 
Laboratory tests: Hepatitis B and C missing at Visit 1 
(Any parameters missing is major) 
Major 
 
PROCEDURE/TEST 
NOT DONE # 9 
ECG missing 
Minor 
 
PROCEDURE/TEST 
NOT DONE # 10 
Laboratory tests: Pregnancy Test at Screening 
missing 
Major 
 
PROCEDURE/TEST 
NOT DONE # 11 
Laboratory tests: Pregnancy Test at Visit 6 missing 
Major 
PROCEDURE 
OUTSIDE 
WINDOW 
PROCEDURE 
OUTSIDE WINDOW 
# 1 
Laboratory tests Out Of planned Window 
Minor 
 
PROCEDURE 
OUTSIDE WINDOW 
# 2 
Vital Signs out of planned window 
Minor 
 
PROCEDURE 
OUTSIDE WINDOW 
# 3 
ECG Out Of planned Window (Not done at Screening 
& Week 4 & EOS) 
Minor 
NON-
COMPLIANCE 
WITH 
PROCEDURE 
NON-COMPLIANCE 
WITH PROCEDURE 
#1 
Dosing NOT performed after all study assessments 
for the visit( Out of chronological order is minor) 
Minor 
 
NON-COMPLIANCE 
WITH PROCEDURE 
#2 
Missing reporting of SAEs to sponsor within the 
agreed timeframe "within 24 hours of awareness" 
Major 
VISIT OUTSIDE 
WINDOW 
VISIT OUTSIDE 
WINDOW # 1 
Screening duration > 7 days 
Minor 
 
VISIT OUTSIDE 
WINDOW # 2 
visits out of window (Planned chronological visits 
schedule not respected is major) 
Major 
VIST NOT DONE 
VISIT NOT DONE 
Visits NOT done 
Major 


Protocol VIT-IRON-2011-004                                                                                                         Page 26 of 35 
Vifor DVSCAT 
  (Categories of 
PDs) 
Vifor DVDECOD 
(Sub-Categories of 
PDs) 
Details 
Major or 
Minor 
SUBJECT NOT 
WITHDRAWN AS 
PER PROTOCOL 
SUBJECT NOT 
WITHDRAWN AS 
PER PROTOCOL 
Site satff failed to take the appropriate action in 
response to protocol-specific 
discontinuation/withdraw criteria 
such as:severe anaemia (Hb <6 g/dL) and the 
subject continued the study 
Major 
OTHER 
NON-COMPLIANCE 
WITH PROCEDURE 
# 1 
Rescreening within 4 weeks of original screening 
visit(minor) 
Minor 
 
NON-COMPLIANCE 
WITH PROCEDURE 
# 2 
Race is not Chinese and subject randomized (minor) 
Minor 
  
OTHER 
Any other protocol deviation (e.g., as outlined in the 
monitoring plan): 
TBD* 
NOTE 
  
*TBD(to be discussed): PDs will be determined of 
major or minor by TMM and consult with Sponsor if 
necessary                                                                       
CRA will submit the signed and dated major protocol 
deviation to local EC within 15 working days. 
  
 
Appendix 2: Decimal place 
Category for 
Lab 
Lab Test 
Short Name 
Lab Test Name 
Original 
Units 
Standard 
Units 
Conversion 
Factor 
Decimal 
Place 
CHEMISTRY 
ALP 
Alkaline Phosphatase 
U/L 
U/L 
1 
0 
CHEMISTRY 
ALT 
Alanine Aminotransferase 
U/L 
U/L 
1 
0 
CHEMISTRY 
AST 
Aspartate Aminotransferase 
U/L 
U/L 
1 
0 
CHEMISTRY 
CA 
Calcium 
mmol/L 
mmol/L 
1 
2 
CHEMISTRY 
CL 
Chloride 
mmol/L 
mmol/L 
1 
1 
CHEMISTRY 
CRP 
C Reactive Protein 
mg/L 
mg/L 
1 
2 
CHEMISTRY 
GGT 
Gamma Glutamyl 
Transferase 
U/L 
U/L 
1 
0 
CHEMISTRY 
GLUC 
Glucose 
mmol/L 
mmol/L 
1 
2 
CHEMISTRY 
K 
Potassium 
mmol/L 
mmol/L 
1 
2 
CHEMISTRY 
LDH 
Lactate Dehydrogenase 
U/L 
U/L 
1 
0 
CHEMISTRY 
MG 
Magnesium 
mmol/L 
mmol/L 
1 
2 
CHEMISTRY 
PHOS 
Phosphate 
mmol/L 
mmol/L 
1 
2 
CHEMISTRY 
SODIUM 
Sodium 
mmol/L 
mmol/L 
1 
0 
HEMATOLOGY 
BASO 
Basophils 
10^9/L 
10^9/L 
1 
2 
HEMATOLOGY 
BASOLE 
Basophils/Leukocytes 
% 
% 
1 
1 
HEMATOLOGY 
EOS 
Eosinophils 
10^9/L 
10^9/L 
1 
2 
HEMATOLOGY 
EOSLE 
Eosinophils/Leukocytes 
% 
% 
1 
1 
HEMATOLOGY 
HBDNA 
Hepatitis B DNA 
IU/mL 
IU/mL 
1 
0 
HEMATOLOGY 
HBSAG 
Hepatitis B Virus Surface 
Antigen 
IU/mL 
IU/mL 
1 
3 
HEMATOLOGY 
HCT 
Hematocrit 
% 
% 
1 
1 
HEMATOLOGY 
HGB 
Hemoglobin 
g/L 
g/dL 
0.1 
1 
HEMATOLOGY 
LYM 
Lymphocytes 
10^9/L 
10^9/L 
1 
2 
HEMATOLOGY 
LYMLE 
Lymphocytes/Leukocytes 
% 
% 
1 
1 
HEMATOLOGY 
MCH 
Ery. Mean Corpuscular 
Hemoglobin 
pg 
pg 
1 
1 
HEMATOLOGY 
MCHC 
Ery. Mean Corpuscular 
HGB Concentration 
g/L 
g/L 
1 
0 
HEMATOLOGY 
MCV 
Ery. Mean Corpuscular 
Volume 
fL 
fL 
1 
1 


Protocol VIT-IRON-2011-004                                                                                                         Page 27 of 35 
Category for 
Lab 
Lab Test 
Short Name 
Lab Test Name 
Original 
Units 
Standard 
Units 
Conversion 
Factor 
Decimal 
Place 
HEMATOLOGY 
MONO 
Monocytes 
10^9/L 
10^9/L 
1 
2 
HEMATOLOGY 
MONOLE 
Monocytes/Leukocytes 
% 
% 
1 
1 
HEMATOLOGY 
NEUT 
Neutrophils 
10^9/L 
10^9/L 
1 
2 
HEMATOLOGY 
NEUTLE 
Neutrophils/Leukocytes 
% 
% 
1 
1 
HEMATOLOGY 
PLAT 
Platelets 
10^9/L 
10^9/L 
1 
0 
HEMATOLOGY 
RBC 
Erythrocytes 
10^12/L 
10^12/L 
1 
2 
HEMATOLOGY 
RETI 
Reticulocytes 
10^9/L 
10^9/L 
1 
1 
HEMATOLOGY 
RETICH 
Ret. Corpuscular 
Hemoglobin Content 
pg 
pg 
1 
1 
HEMATOLOGY 
WBC 
Leukocytes 
10^9/L 
10^9/L 
1 
2 
IRON INDICES 
FERRITIN 
Ferritin 
ug/L 
ng/mL 
1 
1 
IRON INDICES 
IBCU 
Unsaturated Iron Binding 
Capacity 
umol/L 
umol/L 
1 
1 
IRON INDICES 
IRON 
Iron 
umol/L 
umol/L 
1 
1 
IRON INDICES 
TFERRIN 
Transferrin 
g/L 
g/L 
1 
2 
IRON INDICES 
TFRRNSAT 
Transferrin Saturation 
% 
% 
1 
1 
URINALYSIS 
PH 
pH 
  
  
  
0 
URINALYSIS 
PHOS 
Phosphate 
mmol/L 
mmol/L 
1 
2 
 
 
Appendix 3: List of TFLs 
 
Table 14.1.1 Subject Enrollment 
 
Table 14.1.2 Number of Subjects Randomised by Site and Treatment Group 
 
Table 14.1.3 Subject Disposition 
 
Table 14.1.4 Subject Populations 
 
Table 14.1.5.1 Demographic and Baseline Characteristics (SS)  
Table 14.1.5.2 Demographic and Baseline Characteristics (FAS) 
 
Table 14.1.6.1 Underlying Cause for IDA 
 
Table 14.1.6.2 Medical History 
Table 14.1.7.1 Medication History 
 
Table 14.1.7.2 Concomitant Medication  
Table 14.1.8.1 Study Drug Exposure 
 
Table 14.1.8.2 Study Drug Compliance  
Table 14.2.1.1 Analysis of Percentage of Subjects Achieving an Increase in Hb≥ 2g/dL (Responders) 
- Baseline to any Time up to Week 8 (PPS) 
Table 14.2.1.2 Analysis of Percentage of Subjects Achieving an Increase in Hb≥ 2g/dL (Responders) 
- Baseline to any Time up to Week 8 (FAS) 


Protocol VIT-IRON-2011-004                                                                                                         Page 28 of 35 
Table 14.2.2.1 Summary of Subjects Achieving an Increase of Hb≥2 g/dL from Baseline to Weeks 2, 
4, 6, and 8 (PPS) 
 
 
Table 14.2.2.3 Summary of Subjects Achieving an Increase in Hb≥2 g/dL from Baseline at Weeks 2, 
4, 6, and 8 (FAS) 
 
 
Table 14.2.2.2 Analysis of Percentage of Subjects Achieving an Increase in Hb≥2 g/dL from Baseline 
to Weeks 2, 4, 6, and 8 (PPS)  
Table 14.2.2.4 Analysis of Percentage of Subjects Achieving an Increase in Hb≥2 g/dL from Baseline 
at Weeks 2, 4, 6, and 8 (FAS)  
Table 14.2.3.1 Summary of Haemoglobin (g/dL) Data (Absolute and Change from Baseline) Over Time 
(PPS)  
Table 14.2.3.3 Summary of Haemoglobin (g/dL) Data (Absolute and Change from Baseline) Over Time 
(FAS)  
Table 14.2.5.1 Summary of Transferrin Saturation (%) Data (Absolute and Change from Baseline) 
Over Time (PPS) 
 
Table 14.2.5.3 Summary of Transferrin Saturation (%) Data (Absolute and Change from Baseline) 
Over Time (FAS) 
 
Table 14.2.6.1 Summary of Serum Ferritin (ng/mL) Data (Absolute and Change from Baseline) Over 
Time (PPS) 
 
Table 14.2.6.3 Summary of Serum Ferritin (ng/mL) Data (Absolute and Change from Baseline) Over 
Time (FAS) 
 
Table 14.2.3.2 Analysis of Change in Haemoglobin (g/dL) Over Time (Observed Values, Repeated 
Measures Model) (PPS) 
 
 
Table 14.2.3.4 Analysis of Change in Haemoglobin (g/dL) Over Time (Observed Values, Repeated 
Measures Model) (FAS) 
 
Table 14.2.5.2 Analysis of Change in Transferrin Saturation (%) Over Time (Observed Values, 
Repeated Measures Model) (PPS) 
 
Table 14.2.5.4 Analysis of Change in Transferrin Saturation (%) Over Time (Observed Values, 
Repeated Measures Model) (FAS) 
 
Table 14.2.6.2 Analysis of Change in Serum Ferritin (ng/mL) Over Time (Observed Values, Repeated 
Measures Model) (PPS) 
 
Table 14.2.6.4 Analysis of Change in Serum Ferritin (ng/mL) Over Time (Observed Values, Repeated 
Measures Model) (FAS) 
Table 14.2.4.1 Summary of Subjects with Iron Deficiency Correction Over Time by Treatment (PPS)
 
 
Table 14.2.4.3 Summary of Subjects with Iron Deficiency Correction Over Time by Treatment (FAS)
 
 
Table 14.2.4.2 Analysis of Iron Deficiency Correction Over Time (Observed Values, logistic Model) 
(PPS)  


Protocol VIT-IRON-2011-004                                                                                                         Page 29 of 35 
Table 14.2.4.4 Analysis of Iron Deficiency Correction Over Time (Observed Values, Repeated 
Measures Model) (FAS) 
 
Table 14.3.1.1 Overall Summary of Treatment Emergent Adverse Events 
 
Table 14.3.1.2 Treatment Emergent Adverse Events by Primary System Organ Class and Preferred 
Term 
 
Table 14.3.1.3 Treatment Emergent Treatment Related Adverse Events by Primary System Organ 
Class and Preferred Term 
 
 
Table 14.3.1.4 Treatment Emergent Serious Adverse Events by Primary System Organ Class and 
Preferred Term  
Table 14.3.1.5 Treatment Emergent Treatment Related Serious Adverse Events by Primary System 
Organ Class and Preferred Term 
 
Table 14.3.1.6 Treatment Emergent Adverse Events Leading to Premature Study Withdrawal by 
Primary System Organ Class and Preferred Term 
 
Table 14.3.1.7 Treatment Emergent Adverse Events Leading to Death by Primary System Organ 
Class and Preferred Term 
 
 
Table 14.3.1.8 Treatment Emergent Adverse Events Leading to Study Drug Interruption by Primary 
System Organ Class and Preferred Term 
 
Table 14.3.1.9 Treatment Emergent Adverse Events by Primary System Organ Class, Preferred Term, 
and Relationship to Study Medication 
 
Table 14.3.1.10 Treatment Emergent Adverse Events by Primary System Organ Class, Preferred 
Term, and Maximum Severity 
 
Table 14.3.1.11 Treatment Emergent Adverse Events by Preferred Term 
 
Table 14.3.2.1.1 Summary of Laboratory Haematology Data (Absolute and Change from Baseline) 
Over Time 
 
Table 14.3.2.2.1 Summary of Laboratory Biochemistry Data (Absolute and Change from Baseline) 
Over Time 
 
Table 14.3.2.3 Summary of Laboratory Iron Parameters Data (Absolute and Change from Baseline) 
Over Time 
 
Table 14.3.2.4.1 Summary of Laboratory Urinalysis Data (Absolute and Change from Baseline) Over 
Time 
 
Table 14.3.2.1.2 Laboratory Data - Haematology Shift over Time by Treatment  
Table 14.3.2.2.2 Laboratory Data - Biochemistry Shift over Time by Treatment  
Table 14.3.2.1.3 Potentially Clinically Significant Post-Baseline Haematology Results 
 
Table 14.3.2.2.3 Potentially Clinically Significant Post-Baseline Biochemistry Results 
 
Table 14.3.2.4.2 Potentially Clinically Significant Post-Baseline Urinalysis Results 
 
Table 14.3.3.1 Vital Signs Data (Absolute and Change from Baseline) Over Time 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 30 of 35 
Table 14.3.4.1 12-Lead Electrocardiogram Data (Absolute and Change from Baseline) Over Time
 
 
Table 14.3.4.2 12-Lead ECG by Visit and Overall Interpretation 
Table 14.3.4.3 Summary of Electrocardiogram Abnormal Results (QT and QTcF) by Treatment Group 
and Visit 
Table 14.3.4.4 Electrocardiogram - QT and QTcF Shift Over Time by Treatment 
Listing 16.2.1.1.1 Subjects Disposition (Safety)  
Listing 16.2.1.1.2 Subjects Disposition (Screened Only/Not Treated) 
 
Listing 16.2.1.2 Randomisation Assignments 
 
Listing 16.2.2.1 Inclusion/Exclusion Criteria Description  
Listing 16.2.2.2.1 Inclusion/Exclusion Criteria Failed (Safety) 
 
Listing 16.2.2.2.2 Inclusion/Exclusion Criteria Failed (Screened Only/Not Treated) 
 
Listing 16.2.3 Protocol Deviations 
 
Listing 16.2.4 Subject Populations 
 
Listing 16.2.5.1 Demographic and Baseline Characteristics (Safety) 
 
Listing 16.2.5.2 Demographic and Baseline Characteristics (Screened Only/Not Treated) 
 
Listing 16.2.6.1 Medical History (Safety) 
Listing 16.2.6.2 Medical History (Screened Only/Not Treated) 
 
Listing 16.2.7.1 Prior and Concomitant Medications (Safety) 
 
Listing 16.2.7.2 Prior and Concomitant Medications (Screened Only/Not Treated) 
 
Listing 16.2.8.1 Prior and Concomitant Procedures (Safety) 
 
Listing 16.2.8.2 Prior and Concomitant Procedures (Screened Only/Not Treated) 
 
Listing 16.2.9.1 Study Medication Exposure 
 
Listing 16.2.9.2 Study Medication Compliance  
Listing 16.2.10.1 Efficacy Haemoglobin (g/dL)  
Listing 16.2.10.2 Efficacy Transferrin Saturation (%) 
 
Listing 16.2.10.3 Efficacy Serum Ferritin (ng/mL) 
 
Listing 16.2.10.4 Listing of Iron Deficiency Correction Data 
 
Listing 16.2.11.1.1 Treatment Emergent Adverse Events 
 
Listing 16.2.11.1.2 Non-Treatment Emergent Adverse Events 
 
Listing 16.2.11.1.3 Adverse Events (Screened Only/Not Treated) 
 
Listing 16.2.11.2 Treatment Emergent Treatment Related Adverse Events 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 31 of 35 
Listing 16.2.11.3 Treatment Emergent Serious Adverse Events  
Listing 16.2.11.4 Treatment Emergent Adverse Events Leading to Premature Study Withdrawal  
Listing 16.2.11.5 Treatment Emergent Adverse Event Leading to Death  
Listing 16.2.11.6 Special Situations 
 
Listing 16.2.12.1 Laboratory Reference Ranges  
Listing 16.2.12.2 Haematology Results  
Listing 16.2.12.3 Biochemistry Results  
Listing 16.2.12.4 Iron Parameters Results 
 
Listing 16.2.12.5 Urinalysis Results 
 
Listing 16.2.12.6 Hepatitis B and C Results 
 
Listing 16.2.12.7 Serum Pregnancy Test 
 
Listing 16.2.12.8 Subjects with Potentially Clinically Significant Assessment 
 
Listing 16.2.12.9 Laboratory Data 
 
Listing 16.2.13.1 Vital Signs (Safety) 
 
Listing 16.2.13.2 Vital Signs (Screened Only/Not Treated) 
 
Listing 16.2.14.1.1 12-Lead Electrocardiogram Results (Safety)  
Listing 16.2.14.1.2 12-Lead Electrocardiogram Results (Screened Only/Not Treated) 
 
Listing 16.2.14.2.1 Overall Interpretation of 12-Lead Electrocardiogram Results (Safety)  
Listing 16.2.14.2.2 Overall Interpretation of 12-Lead Electrocardiogram Results (Screened Only/Not 
Treated) 
 
Appendix 4: Laboratory assessments: CTC criteria (CTCAE V4.0) 
 
Note: all laboratory PCS or CTC grading is provided for use in medical monitoring/on site monitoring 
and will not be used for reporting or severity classification of any adverse events/findings. 
 
 
 
CTC Grade  
Laboratory 
Sub 
Category 
Laboratory 
Parameter 
PCS Criteria 
1 
2 
3 
4 
5 
Haematology 
Erythrocytes 
Below LLN  
 
 
 
 
 
Mean 
corpuscular 
volume 
Below LLN>week 
4 
 
 
 
 
 
Mean 
corpuscular 
haemoglobin 
Below LLN>week 
4 
 
 
 
 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 32 of 35 
 
 
 
CTC Grade  
Laboratory 
Sub 
Category 
Laboratory 
Parameter 
PCS Criteria 
1 
2 
3 
4 
5 
Mean 
corpuscular 
haemoglobin 
concentration 
Below LLN>week 
4 
 
 
 
 
 
Haemoglobin 
Increase of two 
CTC grade or to 
grade 4 
LLN-
100.0 g/L 
LLN-6.2 
mmol/L 
<100.0-
80.0 g/L 
<6.2-4.9 
mmol/L- 
<80.0 – 65 
g/L 
<4.9- 
mmol/L 
Life-
Threatening 
consequenc
es, urgent 
intervention 
indicated  
Death 
Haematocrit 
Below LLN>week 
4 
 
 
 
 
 
Reticulocyte 
count 
Below LLN>week 
4 
 
 
 
 
 
HbA1C 
Below LLN>week 
4 
 
 
 
 
 
Leukocytes 
Increase of two 
CTC grades or to 
grade 4 
<LLN - 
3.0 x 
109/L 
<3.0 - 2.0  
x 109/L 
<2.0 - 1.0  x 
109/L 
<1.0 x 109/L 
Death 
 
 
 
 
 
 
 
Neutrophils 
Increase of two 
CTC grades or to 
grade 4 
<LLN - 
1500/mm
3; <LLN - 
1.5 
x 10e9 /L 
<1500 - 
1000/mm3; 
<1.5 - 1.0 
x 10e9 /L 
<1000 - 
500/mm3; 
<1.0 - 0.5 x 
10e9 /L 
<500/mm3; 
<0.5 x 10e9 
/L 
 
Eosinophils 
Below LLN 
 
 
 
 
 
Basophils 
Below LLN 
 
 
 
 
 
Lymphocytes 
Increase of two 
CTC grades or to 
grade 4 
<LLN - 
800/mm3; 
<LLN - 
0.8 
x 10e9 /L 
<800 - 
500/mm3; 
<0.8 - 0.5 x 
10e9 /L 
<500 - 
200/mm3; 
<0.5 - 0.2 x 
10e9 /L 
<200/mm3; 
<0.2 x 10e9 
/L 
 
Lymphocytes 
Above ULN 
 
>4000/mm
3 - 
20,000/mm
3 
>20,000/mm
3 
 
 
Monocytes 
Below LLN 
 
 
 
 
 
Platelets 
Increase of two 
CTC grade or to 
grade 4 
<LLN -  
75.0 x 
109/L 
<75.0 – 
50.0 x 
109/L 
<50.0 – 25.0 
x 109/L 
<25.0 x 
109/L 
Death 
Serum 
Chemistry 
Phosphorus - 
low 
Grade 2 or above 
<LLN - 
2.5 
mg/dL; 
<LLN - 
0.8 
mmol/L 
<2.5 - 2.0 
mg/dL; 
<0.8 - 0.6 
mmol/L 
<2.0 - 1.0 
mg/dL; <0.6 
- 0.3 mmol/L 
<1.0 mg/dL; 
<0.3 mmol/L; 
lifethreatenin
g 
consequenc
es 
Death 
Calcium 
(total, 
corrected and 
ionised) - 
Grade 2 or above 
Corrected 
serum 
calcium of 
>ULN - 
Corrected 
serum 
calcium of 
>11.5 - 
Corrected 
serum 
calcium of 
>12.5 - 13.5 
Corrected 
serum 
calcium of 
>13.5 
Death 


Protocol VIT-IRON-2011-004                                                                                                         Page 33 of 35 
 
 
 
CTC Grade  
Laboratory 
Sub 
Category 
Laboratory 
Parameter 
PCS Criteria 
1 
2 
3 
4 
5 
High 
11.5 
mg/dL; 
>ULN - 
2.9 
mmol/L; 
Ionised 
calcium 
>ULN - 
1.5 
mmol/L 
12.5 
mg/dL; 
>2.9 - 3.1 
mmol/L; 
Ionised 
calcium 
>1.5 
- 1.6 
mmol/L; 
symptomati
c 
mg/dL; >3.1 
- 3.4 
mmol/L; 
Ionised 
calcium >1.6 
- 1.8 
mmol/L; 
hospitalisatio
n 
indicated 
mg/dL; >3.4 
mmol/L; 
Ionised 
calcium >1.8 
mmol/L; 
life-
threatening 
consequenc
es 
Calcium 
(total, 
corrected and 
ionised) - low 
Grade 2 or above 
Corrected 
serum 
calcium of 
<LLN - 
8.0 
mg/dL; 
<LLN - 
2.0 
mmol/L; 
Ionised 
calcium 
<LLN - 
1.0 
mmol/L 
Corrected 
serum 
calcium of 
<8.0 - 7.0 
mg/dL; 
<2.0 - 1.75 
mmol/L; 
Ionised 
calcium 
<1.0 
- 0.9 
mmol/L; 
symptomati
c 
Corrected 
serum 
calcium of 
<7.0 - 6.0 
mg/dL; 
<1.75 - 1.5 
mmol/L; 
Ionised 
calcium <0.9 
- 0.8 
mmol/L; 
hospitalisatio
n 
indicated 
Corrected 
serum 
calcium of 
<6.0 mg/dL; 
<1.5 mmol/L; 
Ionised 
calcium <0.8 
mmol/L; 
life-
threatening 
consequenc
es 
Death 
Glucose 
Increase by two 
CTC grades or to 
grade 4 
<LLN - 55 
mg/dL; 
<LLN - 
3.0 
mmol/L 
<55 - 40 
mg/dL; 
<3.0 - 2.2 
mmol/L 
<40 - 30 
mg/dL; <2.2 
- 1.7 mmol/L 
<30 mg/dL; 
<1.7 mmol/L; 
lifethreatenin
g 
consequenc
es; seizures 
Death 
Hs C-reactive 
protein 
Above ULN and 
greater than 
baseline result* 
 
 
 
 
 
Sodium - 
high 
Increase by two 
CTC grades or to 
grade 4 
>ULN – 
150 
mmol/L 
>150 – 155 
mmol/L 
>155 – 160 
mmol/L 
>160 mmol/L 
Death 
Sodium - low 
Increase by two 
CTC grades or to 
grade 4 
<LLN – 
130 
mmol/L 
- 
<130 – 120 
mmol/L 
<120 mmol/L 
Death 
Potassium - 
high 
Increase by two 
CTC grades or to 
grade 4 
>ULN - 
5.5 
mmol/L 
>5.5 - 6.0 
mmol/L 
>6.0 - 7.0 
mmol/L; 
hospitalisatio
n indicated 
>7.0 mmol/L; 
life-
threatening 
consequenc
es 
Death 
Potassium - 
low 
Increase by two 
CTC grades or to 
grade 4 
<LLN - 
3.0 
mmol/L 
<LLN - 3.0 
mmol/L; 
symptomati
c; 
intervention 
indicated 
<3.0 - 2.5 
mmol/L; 
hospitalisatio
n  indicated 
<2.5 mmol/L; 
life-
threatening 
consequenc
es 
Death 
Magnesium - 
High 
Increase by two 
CTC grades or to 
>ULN - 
3.0 
- 
>3.0 - 8.0 
mg/dL; 
>8.0 mg/dL; 
>3.30 
Death 


Protocol VIT-IRON-2011-004                                                                                                         Page 34 of 35 
 
 
 
CTC Grade  
Laboratory 
Sub 
Category 
Laboratory 
Parameter 
PCS Criteria 
1 
2 
3 
4 
5 
grade 4 
mg/dL; 
>ULN - 
1.23 
mmol/L 
>1.23 - 3.30 
mmol/L 
mmol/L;life-
threatening 
consequenc
es 
Magnesium - 
low 
Increase by two 
CTC grades or to 
grade 4 
<LLN - 
1.2 
mg/dL; 
<LLN - 
0.5 
mmol/L 
<1.2 - 0.9 
mg/dL; 
<0.5 - 0.4 
mmol/L 
<0.9 - 0.7 
mg/dL; <0.4 
- 0.3mmol/L 
<0.7 mg/dL; 
<0.3 mmol/L; 
lifethreatenin
g 
consequenc
es 
Death 
Chloride 
Below LLN or 
above ULN 
 
 
 
 
 
Liver 
Enzymes 
(Serum) 
Alkaline 
phosphatase 
(ALP) 
increase of two 
CTC grade or to 
grade 4 
>ULN – 
2.5 x ULN 
>2.5 – 5.0 
x ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
- 
Aspartate 
transaminase 
(AST) 
increase of two 
CTC grade or to 
grade 4 
>ULN – 
3.0 x ULN 
>3.0 – 5.0 
x ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
- 
Alanine 
transaminase 
(ALT) 
Increase of two 
CTC grade or to 
grade 4 
>ULN – 
3.0 x ULN 
>3.0 – 5.0 
x ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
- 
Lactate 
dehydrogena
se (LDH) 
Above ULN 
 
 
 
 
 
Gamma-
glutamyl 
transpeptidas
e (GGT) 
Increase of one 
CTC grade or to 
grade 4 
>ULN – 
2.5 x ULN 
>2.5 – 5.0 
x ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
- 
Iron Status 
Parameters 
Serum Iron 
n/a 
 
 
 
 
 
Total Iron 
n/a 
 
 
 
 
 
UIBC 
n/a 
 
 
 
 
 
Ferritin 
Above 800 ng/ml 
at consecutive 
visits 
 
 
 
 
 
Transferrin 
n/a 
 
 
 
 
 
Transferrin 
saturation 
n/a 
 
 
 
 
 
Urinalysis 
Urobilinogen 
n/a 
 
 
 
 
 
 
Leucocytes 
n/a 
 
 
 
 
 
 
Protein 
Positive 
 
 
 
 
 
 
Glucose 
Positive 
 
 
 
 
 
 
Bilirubin 
Positive 
 
 
 
 
 
 
Nitrite 
Positive 
 
 
 
 
 


Protocol VIT-IRON-2011-004                                                                                                         Page 35 of 35 
 
 
 
CTC Grade  
Laboratory 
Sub 
Category 
Laboratory 
Parameter 
PCS Criteria 
1 
2 
3 
4 
5 
 
Ketone 
Positive 
 
 
 
 
 
 
Blood 
Trace/positive 
 
 
 
 
 
 
Phosphorus 
n/a 
 
 
 
 
 
“*” Subjects are permitted to have a hsCRP above the ULN at baseline per protocol.