Clinical trial NCT03238911
Conditions: Iron Deficiency Anaemia Iron Deficiency Anemia
Keywords: Iron Deficiency Anaemia Iron Deficiency Anemia IDA Intravenous iron replacement therapy Iron deficiency Iron isomaltoside Ferric derisomaltose Monofer Monoferric Monover Monofar Monoferro Hypophosphatemia Ferric carboxymaltose
Sponsor: Pharmacosmos A/S
Start date: 2017-10-24; Completion date: 2018-06-19
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The trial was designed to evaluate the incidence of unintended hypophosphatemia (low level of phosphate in the blood) in subjects with iron deficiency anaemia (IDA).

Detailed description:
This trial was designed to evaluate the effect of IV iron isomaltoside/ferric derisomaltose compared with IV ferric carboxymaltose on s-phosphate in subjects with IDA caused by different etiologies.

The subjects received either a single intravenous (IV) dose of iron isomaltoside/ferric derisomaltose (1000 mg at baseline) or two IV doses of ferric carboxymaltose (one dose 750 mg at baseline and a second dose 750 mg on day 7; cumulative dose: 1500 mg). The study subjects were monitored for up to 35 days from baseline.

Arms: arm 1: Administered IV arm 2: Administered IV
Interventions: intervention 1: Iron isomaltoside/ferric derisomaltose intervention 2: Ferric carboxymaltose
Intervention descriptions: intervention 1: Iron isomaltoside/ferric derisomaltose (Monofer®/Monoferric®; 100 mg/mL) was the test product in this trial.

The dose of iron isomaltoside/ferric derisomaltose for the individual subject was a single IV infusion of 1000 mg (10 mL containing 1000 mg iron isomaltoside/ferric derisomaltose diluted in 100 mL 0.9 % sodium chloride), given over approximately 20 minutes (50 mg iron/min) at baseline (cumulative dose: 1000 mg). intervention 2: Ferric carboxymaltose (Injectafer®; 50 mg/mL) was the comparator in this trial.

Ferric carboxymaltose was administered as 750 mg, infused over at least 15 minutes at baseline and on day 7 (cumulative dose: 1500 mg).

Protocol documents:
Prot_000.pdf: 
Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
Confidential 
 
 Page 1 of 56 
 
CLINICAL TRIAL PROTOCOL 
A randomized, open-label, comparative trial comparing the in-
cidence of hypophosphatemia in relation to treatment with 
iron isomaltoside and ferric carboxymaltose in subjects with 
iron deficiency anaemia  
 
Trial ID: 
P-Monofer-IDA-04 
 
 
 
Sponsor: 
Pharmacosmos A/S, Rørvangsvej 30, DK-4300 Holbæk, Denmark 
 
Protocol Version: 
Version 1.0, 02 May 2017 
 
Protocol Version: 
Version 2.0 (amendment 1), 14 June 2017 
 
Protocol Version: 
Version 3.0 (amendment 2), 29 November 2017 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information of Pharmacosmos A/S. This document must 
not be disclosed to anyone other than the trial staff and members of the Independent Ethics 
Committee/Institutional Review Board or Competent Authorities. The information in this 
document cannot be used for any purpose other than the conduct or evaluation of the clinical 
investigation without the prior written consent of Pharmacosmos A/S. 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
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Date of Document : 
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PROTOCOL PREPARED AND APPROVED BY 
Protocol prepared by: 
Sponsor’s Medical 
Writing responsible 
person: 
Name: 
, PhD 
Address: Pharmacosmos A/S, Rørvangsvej 30, DK-4300 Holbæk, 
Denmark 
Phone: +45 5948 5959 
E-mail: 
 
Protocol approved by: 
Pharmacosmos A/S, 
CMO: 
Name: 
, MD 
Address: Pharmacosmos A/S, Rørvangsvej 30, DK-4300 Holbæk, 
Denmark 
Phone: +45 5948 5959 
E-mail: 
 
Date and signature: 
Biostatistician: 
Name: 
, MSc 
Address: 
  
Phone: 
 
E-mail: 
 
Date and signature: 
Pharmacosmos A/S, 
QPPV: 
Name: 
, MD 
Address: Pharmacosmos A/S, Rørvangsvej 30, DK-4300 Holbæk, 
Denmark 
Phone: +45 5948 5959 
E-mail: 
 
Date and signature: 
 
 
 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
Confidential 
 
 Page 3 of 56 
INVESTIGATOR’S STATEMENT 
 
The Principal Investigator agrees to conduct the trial as outlined in this protocol and in ac-
cordance with global/local regulations and current International Conference on Harmonization 
Good Clinical Practise (ICH-GCP) guidelines. Any modification to the protocol must be ap-
proved in writing by Pharmacosmos A/S, Competent Authorities, and the Institutional Review 
Board (IRB)/ Independent Ethics Committee (IEC) as may be required by applicable regula-
tions.  
The Principal Investigator agrees, by written consent to this protocol, to fully co-operate with 
monitoring and audit checks by allowing direct access to subject’s records, including source 
data, by authorised individuals representing Pharmacosmos A/S or Competent Authorities. 
 
Approved consent in writing by Principal Investigator: 
 
Date:______________________________________ 
 
Name in print:_______________________________ 
 
Signature:__________________________________ 
 
 
 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
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PROTOCOL SUMMARY 
Trial title  
A randomized, open-label, comparative trial comparing the incidence of hypophosphatemia 
in relation to treatment with iron isomaltoside and ferric carboxymaltose in subjects with iron 
deficiency anaemia  
Trial design 
The trial is a randomized, open-label, comparative trial. Subjects with Iron Deficiency 
Anaemia (IDA) will be randomized 1:1 to one treatment course of one of the following 
treatments: 
 Group A: iron isomaltoside 1000 (Monofer®, Pharmacosmos, Holbæk, Denmark, 
termed iron isomaltoside in the following), 1000 mg at baseline 
 Group B: ferric carboxymaltose (Ferinject®/Injectafer®, Vifor Inc, Switzerland), 750 
mg at baseline and day 7, cumulative dose: 1500 mg 
It is intended that 50 % of the recruited subjects are women with IDA due to gynaecological 
blood losses. 
Phase of trial 
The trial is a phase III trial. 
Background  
IDA is highly prevalent in subjects with gastrointestinal diseases and cancer, menstruating or 
pregnant women, and subjects who have undergone bariatric procedure. IDA can have a sub-
stantial medical and Quality of Life (QoL) burden on the subjects and the treatment of these 
subjects includes controlling the bleeding and replenishing lost iron. 
Oral iron administration is used in the clinical practice primarily because of its convenience. 
However, oral iron may not be tolerated by all subjects and iron loss may exceed the capacity 
for iron absorption. Hence, there is a need of an alternative in subjects, who do not tolerate 
oral iron or who require rapid repletion of iron stores, and intravenous (IV) iron is being in-
creasingly used in patients not responding to oral iron. 
Existing IV iron complexes differ in relation to the compounds capability to induce unintend-
ed hypophosphatemia to a degree defined as medical significant (i.e. serum (s-) phosphate < 
2 mg/dL as defined in the Common Terminology Criteria for Adverse Events (CTCAE) Ver-
sion 4.0), and in the medical review of ferric carboxymaltose performed by the Food and 
Drug Administration (FDA) in the USA it is stated that ferric carboxymaltose is associated 
with clinical significant hypophosphatemia. The effect of iron isomaltoside on s-phosphate 
has therefore been evaluated in several trials, showing a low frequency of hypophosphatemia 
in iron isomaltoside treated subjects.  
It seems as the frequency of hypophosphatemia is highest in gynaecology patients and fre-
quencies up to 50-70 % have been reported for ferric carboxymaltose in gynaecology patients 
with heavy uterine bleeding.  
This trial is planned to evaluate the effect of IV iron isomaltoside compared to IV ferric car-
boxymaltose on phosphate in subjects with IDA, and it is intended that 50 % of the recruited 
subjects are women with IDA due to gynaecological blood losses. 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
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Date of Document : 
29 November 2017 
 
 
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Objectives 
The primary objective of the trial is to compare the incidence of hypophosphatemia in sub-
jects with IDA treated with iron isomaltoside or ferric carboxymaltose. 
The secondary safety objective of the trial is to compare the effects of iron isomaltoside and 
ferric carboxymaltose treatment in subjects with IDA on the following:  
(1) 
Incidence of severe hypophosphatemia  
(2) 
Time with hypophosphatemia  
(3) 
Proportion of subjects with hypophosphatemia at the last visit 
(4) 
S-phosphate (absolute [∆] and relative [%] changes) 
(5) 
Fractional phosphate urinary excretion 
(6) 
Intact Fibroblast Growth Factor 23 (iFGF23), C-terminal FGF23 (cFGF23), vitamin D 
(25, 1.25, 24.25), Parathyroid Hormone (PTH), and ionized calcium  
(7) 
Adverse Events (AEs) and biochemical safety parameters 
The secondary efficacy objective of the trial is to compare the effects of iron isomaltoside 
and ferric carboxymaltose treatment in subjects with IDA on Haemoglobin (Hb), s-ferritin, 
and Transferrin Saturation (TSAT). 
In addition to the primary and secondary objectives, the effect of iron isomaltoside and ferric 
carboxymaltose will be investigated purely exploratory on the following: 
(1) 
Biochemical bone/muscle markers  
(2) 
Fatigue symptoms  
(3) 
QoL 
(4) 
Bone pain 
(5) 
Muscle strength 
Endpoints 
The primary endpoint is the incidence of hypophosphatemia (defined as s-phosphate < 2 
mg/dL) at any time from baseline to day 35. 
The secondary safety endpoints are the following: 
 
Incidence of s-phosphate < 1.0 mg/dL at any time from baseline to day 35 
 
Time with hypophosphatemia (i.e. time with s-phosphate < 2.0 mg/dL) from baseline 
to day 35 
 
Proportion of subjects with hypophosphatemia at day 35 
 
Absolute [∆] and relative [%] changes in s-phosphate from baseline to 1, 7, 8, 14, 21, 
and 35 
 
Fractional phosphate urinary excretion at 1, 7, 8, 14, 21, and 35 
 
Change in iFGF23, cFGF23, vitamin D (25, 1.25, 24.25), PTH, and ionized calcium 
from baseline to 1, 7, 8, 14, 21, and 35 
 
Type and incidence of AEs  


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 
Serious or severe hypersensitivity reaction starting on or after the first dose of ran-
domized treatment (i.e. treatment emergent). The hypersensitivity terms are defined 
as standardised Medical Dictionary for Regulatory Activities query (SMQ) terms (in-
cluding four additional terms) in Appendix A. 
In addition, physical examinations and measurements of vital signs, height, weight, electro-
cardiogram (ECG), and safety laboratory parameters will be measured as part of standard 
safety assessments.  
The secondary efficacy endpoints are the following: 
 Change in Hb, s-ferritin, and TSAT from baseline to day 1, 7, 8, 14, 21, and 35  
The exploratory endpoints are the following:  
 Change in biochemical bone/muscle markers (serum N-terminal Propeptide of Type I 
Collagen (PINP), Carboxy-terminal Collagen Crosslinks (CTx), s-alkaline phosphatase 
(bone specific and total), and creatine kinase) from baseline to day 1, 7, 8, 14, 21, and 
35 
 Change in fatigue symptoms from baseline to day 14 and 35 measured by the Func-
tional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
 Change in QoL from baseline to day 14 and 35 measured by Short Form (SF)-36 ques-
tionnaire 
 Change in bone pain from baseline to day 14 and 35 measured on a Visual Analogue 
Scale (VAS)  
 Change in muscle strength from baseline to day 14 and 35 measured by grip strength 
 Change in upper and lower limb proximal muscle function from baseline to day 14 and 
35 measured by the "1 kg arm lift" test and the "30 sec chair stand" test. 
 Change in respiratory muscles strength from baseline to day 14 and 35 measured by 
Maximal Inspiratory Pressure (MIP) and Maximal Expiratory Pressure (MEP) 
Safety assessments 
The trial includes the following safety assessments: 
 Measurements of s-phosphate (blood and urine), iFGF23, cFGF23, vitamin D (25, 
1.25, 24.25), PTH, and ionized calcium  
 AEs will be collected and evaluated for relatedness, severity, seriousness, and expect-
edness. They will be reported to authorities and followed-up according to international 
and local requirements 
 Physical examinations, measurements of vital signs, ECG, height, weight, and safety 
laboratory parameters 
Efficacy assessments 
The trial includes the following efficacy assessments:  
 Hb, s-ferritin, TSAT, and s-iron 
Exploratory assessments 
The exploratory assessments include the following:  
 Measurement of serum N-terminal PINP, CTx, s-alkaline phosphatase (bone specific 
and total), and creatine kinase  


Trial ID: 
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Protocol Version: 
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 FACIT Fatigue Scale 
 SF-36 questionnaire 
 Bone pain assessed by a VAS  
 Grip strength test 
 "1 kg arm lift" test and "30 sec chair stand" test 
 MIP and MEP 
Participating countries 
An updated list of the participating countries and sites will be kept in the trial master file. 
Trial duration and number of visits 
For the individual subject, duration of the trial will be approximately 9 weeks (including a 28 
days screening period) and each subject will attend 8 visits. 
Subject population 
Subjects, who fulfil the following eligibility criteria, will be included. 
Inclusion criteria: 
A subject will be eligible for inclusion in the trial if he/she fulfils the following criteria: 
1. Men or women > 18 years having IDA caused by different aetiologies* such as ab-
normal uterine bleeding, gastrointestinal diseases, cancer, bariatric procedures (gastric 
bypass operations), and other conditions leading to significant blood loss  
2. Hb ≤ 11 g/dL  
3. Body weight > 50 kg 
4. S-ferritin  100 ng/mL 
5. Estimated Glomerular Filtration Rate (eGFR) ≥ 65 mL/min/1.73 m2 
6. S-phosphate > 2.5 mg/dL  
7. Documented history of intolerance or unresponsiveness to oral iron therapy** for at 
least one month*** prior to trial enrolment 
8. Willingness to participate and signing the Informed Consent Form (ICF) 
*The aetiology (also if unknown) for IDA should be documented in the medical history and 
verified in the source documents. 
**The intolerance and non-response to oral iron treatment should be documented with sign 
and symptoms in the medical history and verified in the source document. 
***There should be a documentation of intolerance or unresponsiveness to at least one month 
of prescribed oral iron therapy per investigator’s judgment within the last 9 months and they 
would not be candidates for oral iron again. 
Exclusion criteria: 
A subject will not be eligible for inclusion in this trial if he/she fulfils any of the following 
criteria: 
1. Acute bleeding > 500 mL within 72 hours 
2. Anaemia predominantly caused by factors other than IDA according to Investigator's 
judgment  


Trial ID: 
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Protocol Version: 
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3. Hemochromatosis or other iron storage disorders 
4. Known hypersensitivity reaction to any component of iron isomaltoside or ferric car-
boxymaltose 
5. Previous serious hypersensitivity reactions to any IV iron compounds (seriousness 
criteria are defined in Section 12.2) 
6. Treatment with IV iron within the last 30 days prior to screening 
7. Treatment with erythropoietin or erythropoietin-stimulation agents, red blood cell 
transfusion, radiotherapy, and/or chemotherapy within the last 30 days prior to screen-
ing 
8. Received an investigational drug within the last 30 days prior to screening 
9. Planned surgical procedure within the trial period 
10. Alanine Aminotransferase (ALAT) and/or Aspartate Aminotransferase (ASAT) > 3 
times upper limit of normal (e.g. decompensated liver cirrhosis or active hepatitis)  
11. Surgery under general anaesthesia within the last 30 days prior to screening 
12. Any non-viral infection within the last 30 days prior to screening 
13. Alcohol or drug abuse within the past 6 months  
14. Untreated hyperparathyroidism 
15. Kidney transplantation  
16. Estimated life expectancy of < 6 months or, for cancer patients, an Eastern Coopera-
tive Oncology Group (ECOG) performance status > 1 
17. Conditions that interfere with the subject's ability to understand the requirements of 
the trial and/or presumable non-compliance 
18. Any other laboratory abnormality, medical condition, or psychiatric disorders which, 
in the opinion of the Investigator, will put the subject’s disease management at risk or 
may result in the subject being unable to comply with the trial requirements 
19. Pregnant or nursing women. In order to avoid pregnancy, women of childbearing po-
tential have to use adequate contraception (e.g. intrauterine devices, hormonal contra-
ceptives, or double barrier method) during the whole trial period and 7 days after the 
last dosing 
Trial treatment 
The subjects will be dosed with either one treatment course of iron isomaltoside (group A) or 
one treatment course of ferric carboxymaltose (group B) as described below. 
Group A: iron isomaltoside will be administered as a single IV infusion of 1000 mg at base-
line diluted in 100 mL 0.9 % sodium chloride and given over approximately 20 minutes (50 
mg iron/min, cumulative dose: 1000 mg).  
Group B: ferric carboxymaltose will be administered as 750 mg infused over at least 15 
minutes at baseline and day 7 (cumulative dose: 1500 mg).  
No premedication (e.g. antihistamine or steroids) is allowed before administration of the trial 
drug. If the subject is in daily treatment for e.g. allergy or asthma this is not considered as 
"premedication" and may be continued. 
 


Trial ID: 
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Protocol Version: 
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Sample size calculations 
Data from a previous trial conducted with iron isomaltoside 1000 mg suggests that the inci-
dence of hypophosphatemia in a gynaecology population with/without heavy uterine bleeding 
can be expected to be approximately 10 % (P-Monofer-IDA-01, 1000 mg; n=3/29=10.3 %, 
95 % Confidence Interval (CI) = 2-27 %, gynaecology subgroup; n = 1/10 = 10.0 %, 95 % CI 
= 0-45 %). For ferric carboxymaltose the incidence has been observed to be 40-70 % (e.g. 
Wolf et al., 2013; n = 10/17 = 59 %, 95 % CI = 33-82 %).  
The significance level is set to 5 %, and the power is set to 80 %. Assuming incidences of 15 
% for iron isomaltoside and 40 % for ferric carboxymaltose, 49 subjects in each treatment 
group is required to detect a difference between the treatment groups (based on chi-square 
test). 
To account for the uncertainty, and to gain more safety information, 60 subjects per treatment 
group will be randomized in this trial.  
In addition to the efficacy and safety analyses performed for this trial alone, an efficacy and 
safety assessment will be performed for the P-Monofer-IDA-04 and P-Monofer-IDA-05 trials 
combined. This is briefly described in Section 15.6.  
Statistical analyses 
The primary endpoint, incidence of hypophosphatemia (defined as s-phosphate < 2 mg/dL) at 
any time from baseline to day 35, will be tabulated and exact 95 % CI will be estimated for 
each treatment group.  
Iron isomaltoside will be compared to ferric carboxymaltose by estimation of the risk differ-
ence and the associated 95 % CI, adjusting for strata (type of underlying disease (women 
with IDA due to gynaecological blood losses; yes/no) and screening s-phosphate level (< or ≥ 
3.5 mg/dL)) using the Cochran-Mantel-Haenszel method.  
As sensitivity, the treatment groups will be compared between the treatment groups by a lo-
gistic regression model with treatment and type of underlying disease as factors and baseline 
s-phosphate as covariate and by Fisher’s exact tests. 
All subjects in the safety analysis set will be included in the analysis. The first post-baseline 
phosphate measurement will be taken at day 1; hence, very few missing values are expected. 
If there are subject(s), for whom no post-baseline phosphate measurement(s) are available, 
these subjects will be set as having s-phosphate < 2 mg/dL in the primary analysis. 
All the statistical analyses will be described in a statistical analysis plan. 
Ethical aspects 
The trial will follow International Conference on Harmonization-Good Clinical Practice 
(ICH-GCP) guidelines and the Helsinki Declaration, and all subjects will sign informed con-
sent before inclusion. 
The protocol will be submitted to relevant authorities (Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC), Competent Authorities, and Data Protection 
Agencies) according to local regulatory requirements prior to trial initiation. 
 


Trial ID: 
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Protocol Version: 
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TABLE OF CONTENTS 
1 
ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 15 
1.1 
ABBREVIATIONS ............................................................................................................ 15 
1.2 
DEFINITION OF TERMS ................................................................................................... 16 
2 
INTRODUCTION ...................................................................................................... 17 
2.1 
BACKGROUND ............................................................................................................... 17 
2.2 
IRON ISOMALTOSIDE ..................................................................................................... 18 
2.3 
TRIAL RATIONALE ......................................................................................................... 18 
3 
TRIAL DESIGN ......................................................................................................... 19 
4 
TRIAL OBJECTIVES ............................................................................................... 19 
4.1 
PRIMARY OBJECTIVES ................................................................................................... 19 
4.2 
SECONDARY SAFETY OBJECTIVES ................................................................................. 19 
4.3 
SECONDARY EFFICACY OBJECTIVES ............................................................................. 19 
4.4 
ADDITIONAL OBJECTIVES.............................................................................................. 19 
5 
TRIAL ENDPOINTS ................................................................................................. 20 
5.1 
PRIMARY ENDPOINT ...................................................................................................... 20 
5.2 
SECONDARY SAFETY ENDPOINTS .................................................................................. 20 
5.3 
SECONDARY EFFICACY ENDPOINT ................................................................................ 20 
5.4 
EXPLORATORY ENDPOINTS ........................................................................................... 20 
6 
TRIAL VISITS ........................................................................................................... 21 
6.1 
PRE-SCREENING (OPTIONAL) ......................................................................................... 21 
6.2 
TRIAL VISITS ................................................................................................................. 21 
6.3 
VISIT 1 (SCREENING) ..................................................................................................... 22 
6.4 
VISIT 2 (BASELINE) ....................................................................................................... 23 
6.5 
VISIT 3, VISIT 5, AND VISIT 7 ........................................................................................ 23 
6.6 
VISIT 4 .......................................................................................................................... 24 
6.7 
VISIT 6 .......................................................................................................................... 24 
6.8 
VISIT 8 .......................................................................................................................... 24 
7 
TRIAL ASSESSMENTS............................................................................................ 25 
7.1 
DEMOGRAPHIC AND BASELINE ASSESSMENTS .............................................................. 25 
7.2 
PREGNANCY TEST ......................................................................................................... 25 
7.3 
RELEVANT MEDICAL HISTORY...................................................................................... 25 
7.4 
CONCOMITANT MEDICATION ........................................................................................ 25 


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7.5 
PHYSICAL EXAMINATION .............................................................................................. 26 
7.6 
HEIGHT ......................................................................................................................... 26 
7.7 
WEIGHT ......................................................................................................................... 26 
7.8 
VITAL SIGNS ................................................................................................................. 26 
7.9 
ELECTROCARDIOGRAM ................................................................................................. 26 
7.10 FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY FATIGUE SCALE ............... 26 
7.11 SHORT FORM-36 QUESTIONNAIRE ................................................................................. 26 
7.12 BONE PAIN MEASUREMENT .......................................................................................... 27 
7.13 MUSCLE STRENGTH....................................................................................................... 27 
7.14 UPPER AND LOWER LIMB PROXIMAL MUSCLE FUNCTION ............................................. 27 
7.15 RESPIRATORY MUSCLES STRENGTH .............................................................................. 27 
7.16 LABORATORY ASSESSMENTS ........................................................................................ 28 
7.16.1 
Eligibility Laboratory Assessments ............................................................ 28 
7.16.2 
Vitamin E ................................................................................................... 28 
7.16.3 
Safety Laboratory Assessments .................................................................. 28 
7.16.4 
Efficacy Laboratory Assessments .............................................................. 29 
7.16.5 
Exploratory Laboratory Assessments ........................................................ 29 
7.16.6 
Urine Assessments ..................................................................................... 29 
7.17 ADVERSE EVENTS ......................................................................................................... 29 
8 
TRIAL POPULATION.............................................................................................. 29 
8.1 
NUMBER OF SUBJECTS .................................................................................................. 29 
8.2 
INCLUSION CRITERIA ..................................................................................................... 29 
8.3 
EXCLUSION CRITERIA ................................................................................................... 30 
8.4 
SUBJECT RECRUITMENT ................................................................................................ 31 
9 
SUBJECT COMPLETION AND WITHDRAWAL ............................................... 31 
9.1 
SCREEN FAILURES ......................................................................................................... 31 
9.2 
RE-SCREENING .............................................................................................................. 31 
9.3 
SUBJECT WITHDRAWAL ................................................................................................ 31 
9.4 
SUBJECT COMPLETION .................................................................................................. 32 
9.5 
TREATMENT AFTER THE TRIAL ...................................................................................... 32 
9.6 
EARLY TRIAL TERMINATION ......................................................................................... 32 
10 
INVESTIGATIONAL PRODUCTS ......................................................................... 32 
10.1 DESCRIPTION OF INVESTIGATIONAL PRODUCTS ............................................................ 32 


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10.2 DOSAGE, ADMINISTRATION AND BLINDING OF TRIAL DRUG ........................................ 33 
10.3 DOSE RATIONALE .......................................................................................................... 33 
10.4 SIDE EFFECTS OF IRON ISOMALTOSIDE .......................................................................... 34 
10.5 SIDE EFFECTS OF FERRIC CARBOXYMALTOSE ............................................................... 34 
10.6 PREPARATION, HANDLING, AND LABELLING ................................................................. 34 
10.7 HANDLING AND STORAGE ............................................................................................. 34 
10.8 PRODUCT ACCOUNTABILITY ......................................................................................... 34 
11 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ................ 35 
11.1 PERMITTED MEDICATIONS ............................................................................................ 35 
11.2 PROHIBITED MEDICATIONS AND NON-DRUG THERAPIES ............................................... 35 
12 
ADVERSE EVENTS .................................................................................................. 35 
12.1 DEFINITION OF ADVERSE EVENTS ................................................................................. 35 
12.2 DEFINITION OF SERIOUS ADVERSE EVENTS ................................................................... 36 
12.3 DEFINITION OF AN ADVERSE DRUG REACTION ............................................................. 36 
12.4 COLLECTION OF ADVERSE EVENTS ............................................................................... 36 
12.5 REPORTING OF SAES ..................................................................................................... 38 
13 
PREGNANCIES ......................................................................................................... 38 
14 
OVERDOSE ............................................................................................................... 39 
15 
STATISTICAL ANALYSES ..................................................................................... 39 
15.1 HYPOTHESES ................................................................................................................. 39 
15.2 SAMPLE SIZE DETERMINATION ..................................................................................... 39 
15.3 DATA ANALYSIS SETS ................................................................................................... 39 
15.4 INTERIM ANALYSIS ....................................................................................................... 40 
15.5 KEY ELEMENTS OF THE ANALYSIS PLAN ....................................................................... 40 
15.5.1 
Safety Analyses ........................................................................................... 40 
15.5.2 
Efficacy Analyses ....................................................................................... 42 
15.5.3 
Exploratory Analyses ................................................................................. 42 
15.6 COMBINED ANALYSIS OF P-MONOFER-IDA-04 AND P-MONOFER-IDA-05 .................. 42 
16 
DATA MANAGEMENT AND DATA COLLECTION ......................................... 43 
16.1 DEFINITION OF SOURCE DATA ....................................................................................... 43 
16.2 DATA MANAGEMENT .................................................................................................... 43 
17 
TRIAL MONITORING ............................................................................................. 43 
17.1 TRIAL MONITORING ...................................................................................................... 43 


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17.2 QUALITY ASSURANCE ................................................................................................... 44 
17.3 PROTOCOL DEVIATIONS ................................................................................................ 44 
18 
TRIAL ADMINISTRATION .................................................................................... 44 
18.1 TRIAL CORE TEAM, GCP QUALITY STEERING COMMITTEE, AND GCP QUALITY BOARD
 
……………………………………………………………………………………….44 
18.2 DIRECT ACCESS ............................................................................................................ 45 
18.3 TRIAL AND SITE CLOSURE ............................................................................................. 45 
18.4 RECORDS RETENTION .................................................................................................... 45 
18.5 PROVISION OF TRIAL RESULTS AND INFORMATION TO PRINCIPAL INVESTIGATORS ...... 46 
18.6 FINANCE AND INSURANCE ............................................................................................. 46 
19 
ETHICAL CONSIDERATIONS .............................................................................. 46 
19.1 REGULATORY AND ETHICAL CONSIDERATIONS ............................................................. 46 
19.2 CHANGES TO THE PROTOCOL ........................................................................................ 46 
20 
PUBLICATION PLAN .............................................................................................. 47 
20.1 UPLOADING OF DATA ON PUBLIC WEBSITES ................................................................. 47 
21 
REFERENCES ........................................................................................................... 47 
APPENDIX A ........................................................................................................................ 51 
APPENDIX B ......................................................................................................................... 54 
APPENDIX C ........................................................................................................................ 55 
 
 
 
 


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LIST OF APPENDICES 
Appendix A: Standardised MedDra query (SMQ) terms (including four additional terms) for 
definition of hypersensitivity events 
Appendix B: Southampton protocol for adult grip strength measurement 
Appendix C: Tests of upper and lower limb proximal muscle function 
 
 
 
 


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1 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
1.1 
Abbreviations 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALAT 
Alanine Aminotransferase 
ASAT 
Aspartate Aminotransferase 
BMW 
Biometrics and Medical Writing  
cFGF23 
C-terminal Fibroblast Growth Factor 23   
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organizations 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTx 
Carboxy-terminal Collagen Crosslinks  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FGF23 
Fibroblast Growth Factor 23  
GCP 
Good Clinical Practice 
Hb 
Haemoglobin 
ICF 
Informed Consent Form 
ICH-GCP  
International Conference on Harmonization-Good Clinical Practice 
IDA 
Iron Deficiency Anaemia 
IEC 
Independent Ethics Committee 
iFGF23 
Intact Fibroblast Growth Factor 23 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
IV 
Intravenous 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume  
MedDRA 
Medical Dictionary for Regulatory Activities 
MEP 
Maximal Expiratory Pressure  
MIP 
Maximal Inspiratory Pressure 
MMRM 
Mixed Models for Repeated Measures  
NMR 
Nuclear magnetic resonance 
PI 
Principal Investigator 


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PINP 
Propeptide of Type I Collagen   
PP 
Per Protocol 
PTH 
Parathyroid hormone 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
REML 
Restricted Maximum Likelihood  
s- 
Serum 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SF-36 
Short Form-36 
SmPC 
Summary of Product Characteristics 
SMQ 
Standardised Medical Dictionary for Regulatory Activities Query 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCT 
Trial Core Team 
TSAT 
Transferrin Saturation  
VAS 
Visual Analogue Scale  
WBC 
White Blood Cells 
 
1.2 
Definition of Terms 
Baseline values 
The “baseline” values are the values measured at the baseline visit, before first administra-
tion of the trial drug. For variables/assessments not performed on the baseline visit, the 
baseline value is the value from the screening period measured closest to the baseline 
visit. 
Completed subject  
A subject, who is enrolled in the trial after signing informed consent, exposed to trial 
drug, and not withdrawn or lost to follow up during the trial. 
Documented          
history 
The subject's own description is adequate to be entered in the medical file as source. Thus, 
no medical files from the referring physician or other are necessary. 
End of trial 
The end of trial is the last subject last visit date. 
Final subject visit 
The final trial visit for a subject. No trial related procedure is performed after this visit. 
Iron isomaltoside 
Iron isomaltoside 1000 (Monofer®) 
Subject withdrawal 
Time point when the subject exits from the trial prior to the planned completion of all trial 
drug administrations or assessments.  
Screening period 
The time period from signed informed consent until inclusion or exclusion from the trial. 
 
 
 


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2 
INTRODUCTION 
2.1 
Background 
Iron Deficiency Anaemia (IDA) is highly prevalent in subjects with gastrointestinal diseases 
such as inflammatory bowel diseases [Wilson et al., 2004] and cancer [Aapro et al., 2012], 
menstruating or pregnant women [WHO, 2008], and subjects who have undergone bariatric 
procedure [Muñoz et al., 2009]. IDA can have a substantial medical and Quality of Life 
(QoL) burden on the subjects, and treatment of these subjects includes controlling the bleed-
ing and replenishing lost iron. 
Oral iron administration is used in the clinical practice primarily because of its convenience. 
However, oral iron may not be tolerated by all subjects and iron loss may exceed the capacity 
for iron absorption. Hence, there is a need of an alternative in subjects, who do not tolerate 
oral iron or who require rapid repletion of iron stores, and intravenous (IV) iron is being in-
creasingly used in patients not responding to oral iron. Moreover, some international guide-
lines recommend IV iron as the preferred option in the treatment of IDA in circumstances 
where there is decreased transport capacity and a high iron demand, as it is more effective and 
better tolerated than oral iron [Dignass et al., 2015; KDIGO guideline, 2012; Gasche et al., 
2007]. 
Existing IV iron complexes differ in relation to the compounds capability to induce unintend-
ed hypophosphatemia [Food and Drug Administration (FDA) Advisory Committee Briefing 
Document, 2008; Okada et al., 1983; Schouten et al., 2009a; Schouten et al., 2009b; Van 
Wyck et al., 2009; Wolf et al., 2013] to a degree defined as medical significant (i.e. s-
phosphate < 2 mg/dL as defined in the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0), and in the medical review of ferric carboxymaltose performed by the 
FDA in the USA it is stated that ferric carboxymaltose is associated with clinical significant 
hypophosphatemia [FDA, 2013]. 
Mild to moderate severe hypophosphatemia is usually asymptomatic, and major clinical se-
quelae usually occur only with severe hypophosphatemia. Severe hypophosphatemia is asso-
ciated with various complications including fatigue [Liu & Jeng, 2004], seizures [De Oliveira 
Iglesias et al., 2009], osmotic demyelination syndrome [Turnbull et al., 2013], myocardial 
depression [O'Connor et al., 1977], ventricular tachycardia [Ognibene et al., 1994], proximal 
myopathy [Russell, 1994], respiratory muscle weakness [Gravelyn et al., 1988], rhabdomyol-
ysis [Singhal et al., 1992], haemolytic anaemia [Poesen et al., 2012], muscle weakness, and 
bone pain [Schubert & DeLuca, 2010]. 
The effect of iron isomaltoside on serum (s-) phosphate has been evaluated in several trials. 
The frequency of transient hypophosphatemia in iron isomaltoside treated subjects is low; 0-
1.8 % in chronic kidney disease patients [Bhandari et al., 2015; Gupta et al., 2013; Kalra et 
al., 2016], 0-10 % in inflammatory bowel disease patients [Reinisch et al., 2013; Reinisch et 
al., 2015; Dahlerup et al., 2016], 0 % in cardiology patients [Johansson et al., 2015], 5 % in 
women with post-partum [Holm et al., 2017], and 8 % in cancer patients [Birgegard et al., 
2016].  
It has been suggested that hypophosphatemia associated with parenteral iron could be mediat-
ed by Fibroblast Growth Factor 23 (FGF23) [Durham et al., 2007; Imel et al., 2011; Schouten 
et al., 2009a; Schouten et al., 2009b; Shimizu et al., 2009; Wolf et al., 2013] which is a phos-
phate regulating peptide hormone secreted by osteocytes. Although the mechanism is poorly 


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understood, it has been suggested that FGF23 leads to a suppression of renal tubular phos-
phate reabsorption and 1α-hydroxylation of vitamin D, leading to hypophosphatemia [Schou-
ten et al., 2009b]. 
It seems as the frequency of hypophosphatemia is highest in gynaecology patients and fre-
quencies up to 50-70 % have been reported for ferric carboxymaltose in gynaecology patients 
with heavy uterine bleeding [van Wyck et al., 2009].  
This trial is planned to evaluate the effect of IV iron isomaltoside 1000 (Monofer®, Pharma-
cosmos, Holbæk, Denmark, termed iron isomaltoside in the following) compared to IV ferric 
carboxymaltose (Ferinject®/Injectafer®, Vifor Inc, Switzerland) on phosphate in subjects with 
IDA, and it is intended that 50 % of the recruited subjects are women with IDA due to gynae-
cological blood losses. 
2.2 
Iron Isomaltoside  
Iron isomaltoside is a complex between iron and a carbohydrate moiety. The carbohydrate 
isomaltoside 1000 is a purely linear chemical structure as shown by 13C Nuclear Magnetic 
Resonance (NMR) of repeating α-(1-6) linked glucopyranose residues. Thus, it is structurally 
different from the branched dextran polysaccharides present in iron dextran. Isomaltoside 
1000 consists predominantly of 3-5 glucose units and is prepared from oligomers used for 
prevention of dextran-induced anaphylactic reaction. These oligomers have been chemically 
modified to further reduce the potential for anaphylactic/anaphylactoid reaction. Thus, iso-
maltoside 1000 is not a dextran [Jahn et al., 2011]. 
Iron isomaltoside has strongly bound iron within the iron isomaltoside formulation, which 
enables a controlled, slow release of bioavailable iron to the iron-binding proteins with only a 
little risk of free iron toxicity [Jahn et al., 2011]. This allows flexible dosing, including high 
and rapid dosing. 
Following IV administration, iron isomaltoside is rapidly taken up by the cells in the reticulo-
endothelial system, particularly in the liver and spleen. Due to its molecular weight it is not 
eliminated by the kidneys [Monofer® Investigator's Brochure, current version]. 
Iron isomaltoside is available as aqueous solution for injection containing 100 mg iron/ml 
with pH between 5.0 and 7.0.    
2.3 
Trial Rationale 
Among the various formulations of parenteral iron available on the market, iron isomaltoside 
may allow flexibility in terms of high and rapid dosing. The use of parenteral iron, especially 
in high doses, may result in better compliance, fewer visits to the medical practitioner, and 
overall improvement in QoL. However, IV iron complexes differ in relation to the compounds 
capability to induce unintended hypophosphatemia and frequencies up to 70 % have been 
reported for ferric carboxymaltose in gynaecology patients. Thus, this trial is planned to eval-
uate the effect of IV iron isomaltoside compared to IV ferric carboxymaltose on phosphate in 
subjects with IDA, and it is intended that 50 % of the recruited subjects are women with IDA 
due to gynaecological blood losses. 


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3 
TRIAL DESIGN 
The trial is a randomized, open-label, comparative trial. The trial duration for the individual 
subject will be approximately 9 weeks (including a 28 days screening period) and each sub-
ject will attend 8 visits. Subjects with IDA will be randomized 1:1 to one treatment course of 
one of the following treatments: 
 Group A: iron isomaltoside (1000 mg infusion at baseline, cumulative dose: 1000 
mg) 
 Group B: ferric carboxymaltose (750 mg infusion at baseline and day 7, cumula-
tive dose: 1500 mg) 
It is intended that 50 % of the recruited subjects are women with IDA due to gynaecological 
blood losses. 
4 
TRIAL OBJECTIVES 
4.1 
Primary Objectives 
The primary objective of the trial is to compare the incidence of hypophosphatemia in sub-
jects with IDA treated with iron isomaltoside or ferric carboxymaltose. 
4.2 
Secondary Safety Objectives 
The secondary safety objective of the trial is to compare the effects of iron isomaltoside and 
ferric carboxymaltose treatment in subjects with IDA on the following:  
(1) 
Incidence of severe hypophosphatemia  
(2) 
Time with hypophosphatemia  
(3) 
Proportion of subjects with hypophosphatemia at the last visit 
(4) 
S-phosphate (absolute [∆] and relative [%] changes) 
(5) 
Fractional phosphate urinary excretion 
(6) 
Intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23), vitamin D (25, 1.25, 24.25), 
Parathyroid Hormone (PTH), and ionized calcium  
(7) 
Adverse Events (AEs) and biochemical safety parameters 
4.3 
Secondary Efficacy Objectives 
The secondary efficacy objective of the trial is to compare the effects of iron isomaltoside and 
ferric carboxymaltose treatment in subjects with IDA on Haemoglobin (Hb), s-ferritin, and 
Transferrin Saturation (TSAT). 
4.4 
Additional Objectives 
In addition to the primary and secondary objectives, the effect of iron isomaltoside and ferric 
carboxymaltose will be investigated purely exploratory on the following: 
(1) 
Biochemical bone/muscle markers  
(2) 
Fatigue symptoms  


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(3) 
QoL 
(4) 
Bone pain 
(5) 
Muscle strength 
5 
TRIAL ENDPOINTS 
5.1 
Primary Endpoint 
The primary endpoint is the incidence of hypophosphatemia (defined as s-phosphate < 2 
mg/dL) at any time from baseline to day 35. 
5.2 
Secondary Safety Endpoints 
The secondary safety endpoints are the following: 
 Incidence of s-phosphate < 1.0 mg/dL at any time from baseline to day 35 
 Time with hypophosphatemia (i.e. time with s-phosphate < 2.0 mg/dL) from baseline to 
day 35 
 Proportion of subjects with hypophosphatemia at day 35 
 Absolute [∆] and relative [%] changes in s-phosphate from baseline to day 1, 7, 8, 14, 
21, and 35 
 Fractional phosphate urinary excretion at day 1, 7, 8, 14, 21, and 35 
 Change in iFGF23, cFGF23, vitamin D (25, 1.25, 24.25), PTH, and ionized calcium 
from baseline to day 1, 7, 8, 14, 21, and 35 
 Type and incidence of AEs  
 Serious or severe hypersensitivity reaction starting on or after the first dose of random-
ized treatment (i.e. treatment emergent). The hypersensitivity terms are defined as 
standardised Medical Dictionary for Regulatory Activities query (SMQ) terms (includ-
ing four additional terms) in Appendix A. 
In addition, physical examinations and measurements of vital signs, height, weight, electro-
cardiogram (ECG), and safety laboratory parameters will be measured as part of standard 
safety assessments.  
5.3 
Secondary Efficacy Endpoint 
The secondary efficacy endpoints are the following: 
 Change in Hb, s-ferritin, and TSAT from baseline to day 1, 7, 8, 14, 21, and 35  
5.4 
Exploratory Endpoints 
The exploratory endpoints are the following:  
 Change in biochemical bone/muscle markers (serum N-terminal Propeptide of type I 
Collagen (PINP), Carboxy-terminal Collagen Crosslinks (CTx), s-alkaline phosphatase 
(bone specific and total), and creatine kinase) from baseline to day 1, 7, 8, 14, 21, and 
35 
 Change in fatigue symptoms from baseline to day 14 and 35 measured by the Functional 
Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 






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6.4 
Visit 2 (Baseline) 
Visit 2 (baseline) will be conducted a maximum of 28 days after visit 1 (screening). The fol-
lowing will be assessed: 
 Inclusion and exclusion criteria reviewed to confirm that no change has occurred since 
screening 
 Pregnancy test, if applicable 
 Recording of relevant medical history  
 Recording of concomitant medication  
 Physical examination (not performed later than the baseline visit) 
 Measurement of height 
 Measurement of weight 
 Examination of vital signs  
 Randomization 
 ECG 
 Assessment of fatigue by FACIT Fatigue Scale 
 Assessment of QoL by SF-36 questionnaire  
 Assessment of pain intensity by a VAS 
 Assessment of grip strength by Jamar hand dynamometer 
 Assessment of upper limb proximal muscle function by the "1 kg arm lift" test  
 Assessment of lower limb proximal muscle function by the "30 sec chair stand" test 
 Assessment of respiratory muscles strength by MIP and MEP 
 Measurement of vitamin E  
 Safety laboratory tests 
 Efficacy laboratory tests 
 Exploratory laboratory tests 
 Spot urine sampling 
 Treatment with iron isomaltoside (group A only) 
 Treatment with ferric carboxymaltose (group B only) 
 AE evaluation and recording   
6.5 
Visit 3, Visit 5, and Visit 7 
The following will be assessed: 
 Changes in concomitant medication and medical history (worsening of symptoms or 
diseases shall be recorded as AEs) 
 ECG 
 Safety laboratory tests 
 Efficacy laboratory tests 
 Exploratory laboratory tests 


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 Spot urine sampling 
 AE evaluation and recording 
6.6 
Visit 4 
The following will be assessed: 
 Changes in concomitant medication and medical history (worsening of symptoms or 
diseases shall be recorded as AEs) 
 Examination of vital signs (group B only) 
 ECG 
 Safety laboratory tests 
 Efficacy laboratory tests 
 Exploratory laboratory tests 
 Spot urine sampling 
 Treatment with ferric carboxymaltose (group B only) 
 AE evaluation and recording 
6.7 
Visit 6 
The following will be assessed: 
 Changes in concomitant medication and medical history (worsening of symptoms or 
diseases shall be recorded as AEs) 
 ECG 
 Assessment of fatigue by FACIT Fatigue Scale 
 Assessment of QoL by SF-36 questionnaire  
 Assessment of pain intensity by a VAS 
 Assessment of grip strength by Jamar hand dynamometer 
 Assessment of upper limb proximal muscle function by the "1 kg arm lift" test  
 Assessment of lower limb proximal muscle function by the "30 sec chair stand" test 
 Assessment of respiratory muscles strength by MIP and MEP 
 Safety laboratory tests 
 Efficacy laboratory tests 
 Exploratory laboratory tests 
 Spot urine sampling 
 AE evaluation and recording 
6.8 
Visit 8 
The following will be assessed: 
 Changes in concomitant medication and medical history (worsening of symptoms or 
diseases shall be recorded as AEs) 
 Physical examination 


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 Measurement of weight 
 ECG 
 Assessment of fatigue by FACIT Fatigue Scale 
 Assessment of QoL by SF-36 questionnaire  
 Assessment of pain intensity by a VAS 
 Assessment of grip strength by Jamar hand dynamometer 
 Assessment of upper limb proximal muscle function by the "1 kg arm lift" test  
 Assessment of lower limb proximal muscle function by the "30 sec chair stand" test 
 Assessment of respiratory muscles strength by MIP and MEP 
 Safety laboratory tests 
 Efficacy laboratory tests 
 Exploratory laboratory tests 
 Spot urine sampling 
 AE evaluation and recording 
 Completing the final visit form 
7 
TRIAL ASSESSMENTS 
7.1 
Demographic and Baseline Assessments 
Date of birth, gender, race, ethnicity, and smoking habits will be collected. A current smoker 
is defined as a subject who has been smoking within the last 6 months. 
7.2 
Pregnancy Test 
A urine pregnancy test will be performed for all women of childbearing potential. The test 
will be handled and interpreted by the site personnel. 
7.3 
Relevant Medical History  
Relevant medical history will be recorded. Changes in medical history will be recorded at the 
subsequent visits during the trial (worsening of symptoms or diseases shall be recorded as 
AEs). The following will be collected: disease and start and stop date. Except for underlying 
disorder causing IDA, start dates occurring > 12 months before the enrolment into the trial 
should be set as > 12 months. 
7.4 
Concomitant Medication 
If the subject is receiving any concomitant medication it will be recorded at the baseline visit. 
Changes in concomitant medication will be recorded in the subsequent visits during the trial. 
The following will be collected: brand name, indication, route, dose, frequency, unit, and start 
and stop date. Start dates occurring > 12 months before the enrolment into the trial should be 
set as > 12 months. 


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7.5 
Physical Examination 
A physical examination will be performed based upon the Investigator’s judgement and may 
include the following: 
 Head-Eyes-Ear-Nose-Throat  
 Cardiovascular system 
 Respiratory system 
 Nervous system 
 Gastrointestinal system 
 Musculo-skeletal system 
 Urogenital system 
 Dermatology system 
 Others, if required 
7.6 
Height 
Height will be measured without shoes. 
7.7 
Weight 
Weight will be measured. 
7.8 
Vital Signs  
Heart rate and blood pressure will be measured at the following time points when a subject 
receives trial drug: approximately 0-10 minutes before infusion, during infusion, 5-15 
minutes, and 20-40 minutes after the infusion has ended. If vital signs are measured more than 
once in the given time interval, the lowest measurement of diastolic blood pressure (including 
the attendant systolic blood pressure and heart rate) for the period should be noted in the elec-
tronic Case Report Form (eCRF). 
7.9 
Electrocardiogram 
A standard 12 lead ECG will be recorded (including date, time, and signature). At baseline 
and other treatment visits, two ECGs will be recorded; one before administration of the trial 
drug and one approximately 30 minutes after start of the dosing. Only one ECG should be 
recorded at the follow-up visits. 
The ECGs do not need to be evaluated by a cardiologist. 
7.10 
Functional Assessment of Chronic Illness Therapy Fatigue Scale 
The FACIT Fatigue Scale is used to measure fatigue symptoms of the subjects [Cella et al., 
2005]. It is a self-administered questionnaire which will be filled in by the subject. 
7.11 
Short Form-36 Questionnaire 
The SF-36 questionnaire is used to measure QoL. SF-36 is a 36 item questionnaire developed 
from the Medical Outcomes Study in the United States [Brazier et al., 1992]. The SF-36 com-


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prises eight health scales, covering functional status, well-being, and overall evaluation of 
health. It is a self-administered questionnaire which will be filled in by the subject. 
7.12 
Bone Pain Measurement 
Bone pain is measured as pain intensity on a VAS [Woodforde & Merskey, 1972]. It is a 100 
mm length continuous scale anchored by two verbal descriptors, one for each symptom ex-
treme; “no pain” (score of 0) and “worst imaginable pain” (score of 100). Thus, a higher score 
indicates greater pain intensity. 
Based on the distribution of pain VAS scores in postsurgical patients (knee replacement, hys-
terectomy, or laparoscopic myomectomy), who described their postoperative pain intensity as 
none, mild, moderate, or severe, the following cut points on the pain VAS have been recom-
mended: no pain (0–4 mm), mild pain (5–44 mm), moderate pain (45–74 mm), and severe 
pain (75–100 mm) [Jensen et al., 2003]. 
7.13 
Muscle Strength 
Muscle strength is measured by grip strength. Grip strength can be measured quantitatively 
using a hand dynamometer. The Jamar hand dynamometer (Lafayette Instrument Company, 
USA) will be used as this is the most widely cited in the literature and accepted as the gold 
standard. The standardized Southampton protocol for adult grip strength measurement will be 
followed [Roberts et al. 2011]. Details of the measurement can be found in Appendix B. 
7.14 
Upper and Lower Limb Proximal Muscle Function 
The upper and lower limb proximal muscle function is measured by the "1 kg arm lift" test 
and the "30 sec chair stand" test as described in Agarwal and Kiely, 2006.  
For the "1 kg arm lift" test, the number of times the weight is lifted above the head in a 30 sec 
period is recorded for each arm individually and the final score is the mean of the two meas-
urements. For the "30 sec chair stand" test, the final test score is the number of times that the 
subject rises to a full stand from the seated position with arms folded within 30 sec. Both tests 
provide a numerical score on a continuous scale that is operator independent. Neither test ex-
hibits a ceiling effect, as the upper limit of repetitions for each test is infinite. If the subjects 
have severe weakness and are unable to perform the tests at all, the score is 0 [Agarwal & 
Kiely, 2006]. Details of the measurement can be found in Appendix C. 
7.15 
Respiratory Muscles Strength 
The measurements of MIP and MEP provide a non-invasive clinical method for evaluating the 
strength of respiratory muscles, and it is the most widely used test to assess muscle pressures 
[ATS/ERS statement, 2002]. The MIP reflects the strength of the diaphragm and other in-
spiratory muscles, while the MEP reflects the strength of the abdominal muscles and other 
expiratory muscles. MIP and MEP will be measured by MicroRPM (CareFusion Germany 
234 GmbH, Hoechberg, Germany). Three tests should be performed for both MIP and MEP 
with the highest value from the three tests taken as the achieved result. Details of the meas-
urement 
can 
be 
found 
in 
the 
following 
instruction 
video: 
http://www.bd-
horizon.com/micro/modules/rpm/index.html.  


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7.16 
Laboratory Assessments 
It is requested that the blood samples are drawn before administering the trial drug, and, if 
possible, that they are drawn at the same time of the day at all visits in order to reduce any 
diurnal fluctuation in the parameters. 
Laboratory assessments will be performed at a central laboratory. A Laboratory Manual will 
be provided to each site in which all laboratory procedures will be described. 
7.16.1 
Eligibility Laboratory Assessments 
The following eligibility laboratory assessments will be performed: 
 
Complete haematology set: Hb, leucocytes/White Blood Cells (WBC), erythro-
cytes/Red Blood Cells (RBC), haematocrit, platelets, neutrophil granulocytes, lym-
phocytes, monocytes, eosinophils, basophils, Mean Corpuscular Haemoglobin (MCH), 
Mean Corpuscular Volume (MCV), Mean Corpuscular Haemoglobin Concentration 
(MCHC), and reticulocyte count 
 Biochemistry: 
o S-ferritin 
o S-phosphate 
o Alanine Aminotransferase (ALAT) and Aspartate Aminotransferase (ASAT) 
o C-reactive Protein (CRP)  
o Estimated Glomerular Filtration Rate (eGFR) 
o PTH 
7.16.2 
Vitamin E 
Vitamin E will be measured at baseline visit as part of the demographic data. 
7.16.3 
Safety Laboratory Assessments 
The following safety laboratory assessments will be analysed: 
 S-phosphate  
 iFGF23 and cFGF23 
 Vitamin D (25, 1.25, 24.25) 
 PTH 
 Ionized calcium  
 Complete haematology set: Leucocytes/WBC, erythrocytes/RBC, haematocrit, plate-
lets, neutrophil granulocytes, lymphocytes, monocytes, eosinophils, basophils, MCH, 
MCV, MCHC, and reticulocyte count 
 Biochemistry: 
o S-sodium, s-potassium, s-calcium, s-urea, s-creatinine, s-albumin 
o S-bilirubin, ASAT, ALAT 
o CRP  


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7.16.4 
Efficacy Laboratory Assessments 
 The following efficacy laboratory parameters will be analysed: 
 Hb  
 S-ferritin 
 TSAT (s-iron and transferrin will be collected to calculate the TSAT) 
7.16.5 
Exploratory Laboratory Assessments 
The following exploratory laboratory assessments will be analysed: 
 Serum N-terminal PINP 
 CTx 
 S-alkaline phosphatase (bone specific and total) 
 Creatine kinase 
7.16.6 
Urine Assessments 
A spot urine sampling will be collected in order to assess the level of fractional s-phosphate 
excretion.  
7.17 
Adverse Events 
AEs will be collected and evaluated for relatedness to trial drug, seriousness, severity, and 
expectedness. They will be reported to the authorities and followed-up according to local re-
quirements (described in Section 12). 
8 
TRIAL POPULATION 
8.1 
Number of Subjects 
A minimum of 120 subjects will be recruited, and they will be randomized 1:1 to one treat-
ment course of one of the following treatments: 
 Group A: iron isomaltoside (60 subjects) 
 Group B: ferric carboxymaltose (60 subjects) 
The blocked randomization of subjects to treatment arms will be stratified in order to balance 
the type of underlying disease (women with IDA due to gynaecological blood losses; yes/no) 
and screening s-phosphate level (< or ≥ 3.5 mg/dL). 
The procedure for preparing the randomization list will be approved by the Global Trial Re-
sponsible Statistician before the randomization is performed. 
8.2 
Inclusion Criteria 
A subject will be eligible for inclusion in the trial if he/she fulfils the following criteria: 
1. Men or women > 18 years having IDA caused by different aetiologies* such as ab-
normal uterine bleeding, gastrointestinal diseases, cancer, bariatric procedures (gastric 
bypass operations), and other conditions leading to significant blood loss  
2. Hb ≤ 11 g/dL  


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3. Body weight > 50 kg 
4. S-ferritin  100 ng/mL 
5. eGFR ≥ 65 mL/min/1.73 m2 
6. S-phosphate > 2.5 mg/dL  
7. Documented history of intolerance or unresponsiveness to oral iron therapy** for at 
least one month*** prior to trial enrolment 
8. Willingness to participate and signing the Informed Consent Form (ICF) 
*The aetiology (also if unknown) for IDA should be documented in the medical history and 
verified in the source documents. 
**The intolerance and non-response to oral iron treatment should be documented with sign 
and symptoms in the medical history and verified in the source document. 
***There should be a documentation of intolerance or unresponsiveness to at least one month 
of prescribed oral iron therapy per investigator’s judgment within the last 9 months and they 
would not be candidates for oral iron again. 
8.3 
Exclusion Criteria 
A subject will not be eligible for inclusion in this trial if he/she fulfils any of the following 
criteria: 
1. Acute bleeding > 500 mL within 72 hours 
2. Anaemia predominantly caused by factors other than IDA according to Investigator's 
judgment  
3. Hemochromatosis or other iron storage disorders 
4. Known hypersensitivity reaction to any component of iron isomaltoside or ferric car-
boxymaltose 
5. Previous serious hypersensitivity reactions to any IV iron compounds (seriousness cri-
teria are defined in Section 12.2) 
6. Treatment with IV iron within the last 30 days prior to screening 
7. Treatment with erythropoietin or erythropoietin-stimulation agents, red blood cell 
transfusion, radiotherapy, and/or chemotherapy within the last 30 days prior to screen-
ing 
8. Received an investigational drug within the last 30 days prior to screening 
9. Planned surgical procedure within the trial period 
10. ALAT and/or ASAT > 3 times upper limit of normal (e.g. decompensated liver cirrho-
sis or active hepatitis)  
11. Surgery under general anaesthesia within the last 30 days prior to screening 
12. Any non-viral infection within the last 30 days prior to screening 
13. Alcohol or drug abuse within the past 6 months  
14. Untreated hyperparathyroidism 
15. Kidney transplantation  
16. Estimated life expectancy of < 6 months or, for cancer patients, an Eastern Coopera-
tive Oncology Group (ECOG) performance status > 1 


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17. Conditions that interfere with the subject's ability to understand the requirements of 
the trial and/or presumable non-compliance 
18. Any other laboratory abnormality, medical condition, or psychiatric disorders which, 
in the opinion of the Investigator, will put the subject’s disease management at risk or 
may result in the subject being unable to comply with the trial requirements 
19. Pregnant or nursing women. In order to avoid pregnancy, women of childbearing po-
tential have to use adequate contraception (e.g. intrauterine devices, hormonal contra-
ceptives, or double barrier method) during the whole trial period and 7 days after the 
last dosing 
8.4 
Subject Recruitment 
Informed consent must be obtained from the subject before any trial related procedures are 
carried out. 
In obtaining and documenting informed consent, the Investigator should comply with any 
applicable regulatory requirements, and should adhere to International Conference on Harmo-
nization-Good Clinical Practice (ICH-GCP) and the Declaration of Helsinki. 
Before informed consent is obtained the subject should be allowed ample time and opportuni-
ty to read the subject information sheet, to enquire about details of the trial, and to decide 
whether or not to participate. 
If the subject wishes to participate, the written ICF should be completed as appropriate and 
then signed and personally dated by the subject and the Investigator who conducted the in-
formed consent discussions. The procedure for obtaining the informed consent must follow 
the local requirements and legislation.  
9 
SUBJECT COMPLETION AND WITHDRAWAL 
9.1 
Screen Failures 
The PI will maintain a list of screening numbers and names of the subjects who have been 
screened at the site in order to allow for identification of records at a later date. The reasons 
for failure should be noted in the screening log of the site file and the final visit form.  
9.2 
Re-screening 
Subjects may be re-screened three times at the discretion of the PI. Each subject re-screened 
must be re-consented and allocated a new subject number. All required screening assessments 
must be repeated in accordance with the protocol. 
9.3 
Subject Withdrawal 
The subject has the right to withdraw from the trial at any time and for any reason without 
prejudice to his/her future medical care by the physician or at the institution. The PI can with-
draw subjects from the trial in the following situations; treatment failure, safety reasons, and 
protocol violations. 
The subject may also withdraw the consent if he/she does not wish to or is unable to continue 
in the trial. The Investigator will discuss with the subject the most appropriate way to with-
draw in order to ensure the subject’s health. If a subject withdraws from the trial, the Investi-


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gator will perform all final visit assessments, besides the scheduled trial assessments for that 
visit. Upon subject withdrawal, the Investigator will fill in the final visit form including the 
reason for withdrawal. 
A subject who withdraws from the trial will not be re-enrolled or replaced with a new subject. 
9.4 
Subject Completion 
When the subject has completed the trial, the Investigator will fill in the final visit form.  
9.5 
Treatment after the Trial 
When the trial has ended or if the subject is withdrawn from the trial, the subject will be treat-
ed according to standard hospital practice. 
9.6 
Early Trial Termination 
Pharmacosmos A/S reserves the right to temporarily suspend or prematurely discontinue the 
trial at any time for reasons including, but not limited to; safety or ethical issues, severe non-
compliance, and insufficient subject enrolment. For multi-centre trials, this can occur at one 
or more sites. If Pharmacosmos A/S decides that such action is needed, Pharmacosmos A/S or 
its designee will discuss this with the PI including the reasons for taking such action. The PI 
also has the right to temporarily suspend or prematurely discontinue this trial for mutually 
agreed reason(s) with Pharmacosmos A/S.  
Pharmacosmos A/S or its designee will promptly inform all other PIs and/or institutions con-
ducting the trial if the trial is suspended or terminated due to safety reasons. 
Pharmacosmos A/S or its designee will promptly inform the Competent Authorities of the 
suspension or termination of the trial and the reason(s) for the action. If required by applicable 
regulations, the PI must inform the Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC) promptly and provide the reason for the suspension or termination.  
10 
INVESTIGATIONAL PRODUCTS 
10.1 
Description of Investigational Products 
Iron isomaltoside 
Iron isomaltoside is a complex between iron and a carbohydrate moiety. The carbohydrate 
isomaltoside 1000 is a purely linear chemical structure as shown by 13C NMR of repeating α-
(1-6) linked glucopyranose residues. Thus, it is structurally different from the branched dex-
tran polysaccharides present in iron dextran. Isomaltoside 1000 consists predominantly of 3-5 
glucose units and is prepared from oligomers used for prevention of dextran-induced anaphy-
lactic reaction. These oligomers have been chemically modified to further reduce the potential 
for anaphylactic/anaphylactoid reaction. Thus, isomaltoside 1000 is not a dextran [Jahn et al., 
2011]. 
Iron isomaltoside has strongly bound iron within the iron isomaltoside formulation, which 
enables a controlled, slow release of bioavailable iron to the iron-binding proteins with only a 
little risk of free iron toxicity [Jahn et al., 2011]. This allows flexible dosing, including high 
dose and rapid dosing. 


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Following IV administration, iron isomaltoside is rapidly taken up by the cells in the reticulo-
endothelial system, particularly in the liver and spleen. Due to its molecular weight, it is not 
eliminated by the kidneys [Monofer® Investigator's Brochure, current version]. 
Iron isomaltoside is available as aqueous solution for injection/infusion containing 100 mg 
iron/mL with pH between 5.0 and 7.0. 
Ferric carboxymaltose 
Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose, a 
carbohydrate polymer that releases iron. It is  an aqueous complex with the chemical name 
polynuclear 
iron 
(III) 
hydroxide 
4(R)-(poly-(1→4)-O-α-D-glucopyranosyl)-oxy-
2(R),3(S),5(R),6-tetrahydroxy-hexanoate. It has a relative molecular weight of approximately 
150,000 Daltons [Injectafer® prescribing information (USA), 07/2013].  
Ferric carboxymaltose is provided as a dark brown, sterile, aqueous, isotonic colloidal solu-
tion for IV injection. Each mL contains 50 mg iron as ferric carboxymaltose in water for in-
jection. Ferric carboxymaltose is available in 15 mL single-use vials. Sodium hydroxide 
and/or hydrochloric acid may have been added to adjust the pH to 5.0-7.0. Ferric carboxy-
maltose will be administered as 750 mg infused over at least 15 minutes at baseline and day 7 
(cumulative dose: 1500 mg), which is an approved treatment course [Injectafer® prescribing 
information (USA), 07/2013]. 
10.2 
Dosage, Administration and Blinding of Trial Drug 
The subjects will be randomized 1:1 to one treatment course of one of the following treat-
ments: 
 Group A, iron isomaltoside will be administered as a single IV infusion of 1000 mg 
diluted in 100 mL 0.9 % sodium chloride and given over approximately 20 minutes 
(50 mg iron/min) at baseline (cumulative dose: 1000 mg) 
 Group B, ferric carboxymaltose will be administered as 750 mg infused over at least 
15 minutes at baseline and day 7 (cumulative dose: 1500 mg) 
No premedication (e.g. antihistamine or steroids) is allowed before administration of the trial 
drug. If the subject is in daily treatment for e.g. allergy or asthma this is not considered as 
"premedication" and may be continued. 
The subjects must be observed for signs and symptoms of hypersensitivity during and after 
trial drug administration for at least 30 minutes and until clinically stable following comple-
tion of each administration. 
Details of administration and storage of iron isomaltoside and ferric carboxymaltose are fur-
ther described in the Drug Handling Plan.  
10.3 
Dose Rationale 
In the present trial, subjects will be given a cumulative dose of 1000 mg iron isomaltoside 
administered as a single infusion. Justification for this single dose regime is found in recent 
safety data. Up to 31 December 2016, more than 1700 subjects have been treated with iron 
isomaltoside including bolus injections and high single dose infusions up to 2500 mg adminis-
tered over 2 minutes for bolus injections and 15-60 minutes for infusions without a test dose. 
No safety concerns were found with these single dose levels.  


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In this trial we have included single doses of 1000 mg iron isomaltoside in order to elucidate 
the safety and effect of high doses of iron isomaltoside since higher dosing would result in 
better compliance and increased convenience due to fewer visits necessary to make the sub-
jects iron replete. 
In the majority of the trials with iron isomaltoside, single dose infusions of up to 1000 mg 
have been administered over 15 minutes. There is no apparent indication that there are any 
specific safety concerns related to this speed of administration of iron isomaltoside. In the 
present trial, iron isomaltoside will be administered over 20 minutes. 
Ferric carboxymaltose will be administered as 750 mg infused over at least 15 minutes at 
baseline and day 7 (cumulative dose: 1500 mg), which is an approved treatment course [In-
jectafer® prescribing information (USA), 07/2013]. 
10.4 
Side Effects of Iron Isomaltoside 
Side effects for iron isomaltoside are described in the Investigator's Brochure for iron iso-
maltoside (current version). 
10.5 
Side Effects of Ferric Carboxymaltose  
Side effects for ferric carboxymaltose are described in Injectafer® prescribing information 
(USA), 07/2013. 
10.6 
Preparation, Handling, and Labelling 
Pharmacosmos A/S or its designee will be responsible for preparation and packaging of all 
trial medication. No trial product will be used after its expiry date. The contents of the label 
will be in accordance with all applicable regulatory requirements. 
Details of administration and storage of iron isomaltoside and ferric carboxymaltose are fur-
ther described in the Drug Handling Plan.  
10.7 
Handling and Storage 
The investigational product must be dispensed or administered according to procedures de-
scribed herein. Only subjects enrolled in the trial may receive the investigational product, and 
it must be administered in accordance with all applicable regulatory requirements. Only au-
thorised site staff may supply or administer the investigational product. All investigational 
products must be stored in a secure area with access limited to the authorised site staff and 
under physical conditions that are consistent with investigational product-specific require-
ments. 
10.8 
Product Accountability 
The PI is responsible for investigational product accountability, reconciliation, and record 
maintenance throughout the course of the trial in accordance with all applicable regulatory 
requirements.  
The responsible person(s) will document the amount of investigational products received from 
and returned to Pharmacosmos A/S or its designee, and the amount supplied and/or adminis-
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11 
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
11.1 
Permitted Medications 
Throughout the trial, the subject may take any concomitant medications or treatments deemed 
necessary to provide adequate supportive care except for those listed in Section 11.2. Any 
concomitant medications administered while the subject is participating in the trial must be 
recorded on the source document and transcribed into the concomitant medication form.  
11.2 
Prohibited Medications and Non-drug Therapies 
No premedication (e.g. antihistamine or steroids) is allowed before administration of the trial 
drug. If the subject is in daily treatment for e.g. allergy or asthma this is not considered as 
"premedication" and may be continued. 
The following medication and non-drug therapy are not allowed during the trial period since 
they could potentially have an impact on the endpoints: 
 Any iron supplementation other than investigational drug (nutritional supplementation 
including iron is allowed unless it is assumed as treatment of the subject's anaemia) 
 Blood transfusion 
 Erythropoietin or erythropoietin-stimulation agents 
 Radiotherapy  
 Chemotherapy 
12 
ADVERSE EVENTS 
12.1 
Definition of Adverse Events 
An AE is defined in the ICH-GCP guideline as “any untoward medical occurrence in a subject 
or clinical investigation subject administered a pharmaceutical product and that does not nec-
essarily have a causal relationship with this treatment” (ICH E6:1.2). An AE can therefore be 
any unfavourable and unintended sign, symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. A clin-
ically significant abnormal laboratory finding is also regarded as an AE if the effect is unfa-
vourable for the subject. It is the responsibility of the Investigator to review the laboratory test 
results and determine whether an abnormal laboratory value is clinically significant. In gen-
eral, a clinically significant laboratory value which suggests disease progression and/or re-
quires active management is considered as an AE. Clinical significant efficacy laboratory pa-
rameters (including related parameters) are not to be recorded as AEs unless these are consid-
ered lack of efficacy or overdose.     
Clinical significant findings in physical examinations and ECGs are to be recorded as medical 
history if they are observed at baseline. Otherwise they should be recorded as AEs.  
Worsening of a pre-existing medical condition (e.g. cancer or diabetes) must also be recorded 
as an AE (e.g. if there is an increase in severity, frequency, duration of the condition or wors-
ening of outcome). Pre-planned procedures and pre-existing medical conditions (planned or 


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present at the time of signing the ICF) that have not worsened are not considered AEs. These 
are recorded on the medical history pages of the eCRF.  
12.2 
Definition of Serious Adverse Events 
A Serious Adverse Event (SAE) is defined as an AE that  
 is fatal 
 is life threatening (places the subject at immediate risk of death) 
 requires in-patient hospitalization or prolongation of existing hospitalisation (a mini-
mum of an overnight stay in a health care facility) 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is a medically important event or reaction 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious such as important medical events that might not be immediately 
life-threatening or result in death or hospitalisation but might jeopardise the subject or might 
require intervention to prevent one of the other outcomes listed in the definition above.  
If the above interventions are performed as standard of care and not associated with an AE, 
the health issue for which the intervention is being performed will not be considered an SAE. 
If there is a complication as a result of the procedure and the complication meets at least 1 
serious criterion, that complication would be reported as an SAE. 
12.3 
Definition of an Adverse Drug Reaction 
An Adverse Drug Reaction (ADR) is an AE that is judged by the Investigator or Pharmacos-
mos A/S to be “related” or “possible related” to the trial drug (see classification of relatedness 
in Section 12.4).  
If the ADR fulfils at least 1 of the criterion for an SAE, it is considered a Serious Adverse 
Reaction (SAR). If the SAR is not listed as an expected side effect for iron isomaltoside 
[Monofer® Investigator’s Brochure, current version] or for ferric carboxymaltose [Injectafer® 
prescribing information (USA), 07/2013], it is considered a Suspected Unexpected Serious 
Adverse Reaction (SUSAR).  
It is the responsibility of Pharmacosmos A/S to evaluate the SARs for expectedness. 
12.4 
Collection of Adverse Events 
The Investigator is responsible for ensuring that all AEs (as defined in Section 12.1) observed 
by the Investigator or reported by the subject are properly collected and recorded in the sub-
ject’s medical record as well as in the AE pages of the eCRF. 
AEs/SAEs occurring before administration of the trial drug are considered as non-treatment 
emergent, and those occurring after administration of the trial drug are considered as treat-
ment emergent. Non-treatment emergent AEs/SAEs which are worsened after treatment with 
trial drug will be assessed as treatment emergent.  
Non-treated subjects: All SAEs will be reported in the eCRF from the time a subject has 
signed the ICF and until he/she exits the trial. Non-serious AEs occurring in subjects who are 
never treated with the trial drug will not be collected. 


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Treated subjects: From the time a subject has signed the ICF and until he/she exits the trial, 
all AEs/SAEs will be reported in the eCRF.  
If a subject is permanently withdrawn from the trial because of an AE, this information must 
be included in the final visit form. 
An AE should be described in the following manner: The nature of the event will be described 
in precise, standard medical terminology (i.e. not necessarily the exact words used by the sub-
ject). If known, a specific diagnosis should be stated. Furthermore, the Investigator should 
describe an AE regarding seriousness (see Section 12.2), severity, relatedness, action taken, 
and outcome.  
Severity 
 Mild: The AE does not interfere in a significant manner with the subject’s normal 
functioning level, but may be an annoyance 
 Moderate: The AE produces some impairment of functioning but is not hazardous to 
health, but is uncomfortable and/or an embarrassment 
 Severe: The AE produces significant impairment of functioning or incapacitation and 
is a hazard to the subject 
Relatedness 
 Related: The AE is related to the medicinal product 
 Possible related: A causal relationship is conceivable and cannot be dismissed 
 Unlikely related: The event is most likely related to an aetiology other than the medic-
inal product 
 Not related: No relatedness to the medicinal product 
The categories "related" and "possible related" will be classified as related AEs and the cate-
gories "unlikely related" and "not related" will be classified as unrelated AEs in the Clinical 
Study Report (CSR). 
Outcome 
 Recovered/resolved: Complete clinical recovery without any sequel attributable to the 
event as per Investigator’s discretion 
 Recovered/resolved with sequelae: Complete clinical recovery but with one or more 
sequels attributable to the event as per Investigator’s discretion   
 Recovering/resolving: The condition is improving and the subject is expected to re-
cover from the event. This term should only be used when the subject has completed 
the trial 
 Not recovered/not resolved: The subject’s condition has not improved and the symp-
toms are unchanged 
 Fatal 
 Unknown: The subject’s condition is unknown. This term should only be used when 
no other definition is possible e.g. the subject is lost to follow-up 
For the purpose of medical management, all AEs and laboratory abnormalities that occur dur-
ing the trial must be evaluated by the Investigator. Each of these will be followed to satisfac-
tory clinical resolution. Insofar as possible, all AEs should be followed-up to determine the 


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final outcome of the event. The Investigator must follow-up all subjects with SAEs until the 
event has subsided (or disappeared), the condition has stabilised, the event is otherwise ex-
plained, or the subject is lost to follow-up. 
12.5 
Reporting of SAEs 
The Investigator must report all SAEs promptly and within 24 hours to Drug Safety at Phar-
macosmos A/S after obtaining knowledge of the event.  
The Investigator should report the SAEs by filling out the SAE form and report to Pharma-
cosmos A/S either by e-mail at pv@pharmacosmos.com or fax number +45 5948 6082.  
Contact details:  Drug Safety, Pharmacosmos A/S 
Roervangsvej 30, DK-4300 Holbaek, Denmark 
Phone: 
  
Fax: +45 5948 60 82 
E-mail: pv@pharmacosmos.com 
After the initial SAE report, the Investigator is required, proactively, to provide further infor-
mation regarding the subject’s condition. All follow-up information must be forwarded to 
Pharmacosmos A/S as it becomes available.  
For all AEs with fatal outcome, autopsy reports (if available) and relevant medical reports 
should be reported to Pharmacosmos A/S, as described above.  
SAEs occurring after trial termination must be reported if considered related to the trial treat-
ment. 
Pharmacosmos A/S will report SUSARs to the Competent Authorities within 7 calendar days 
for fatal and life threatening SUSARs and follow-up information within the next 8 calendar 
days. All other SUSARs are submitted as soon as possible within 15 calendar days and rele-
vant follow-up information is subsequently communicated as soon as possible.  
Pharmacosmos A/S will inform any SUSARs to all PI(s) within 15 calendar days by circulat-
ing the Council for International Organizations of Medical Sciences (CIOMS-I) form.  
All SAEs including expected SARs will be reported by Pharmacosmos A/S to the Competent 
Authorities by the annually Development Safety Update Report. 
In addition, 6-monthly safety reports will be prepared by Pharmacosmos A/S and submitted to 
the Investigators for information. 
13 
PREGNANCIES 
Subjects who become pregnant during the trial should continue the trial but cannot receive 
more trial drug. 
If a subject becomes pregnant during the trial, they will be required to inform the Investigator 
about the pregnancy, delivery, and the health of the infant until 1 month of age. The Investiga-
tor must report the pregnancy and follow-up within 14 calendar days of obtaining the infor-
mation. Pregnancy complications must be recorded as an AE. If the infant has a congenital 
anomaly/birth defect, this must be reported and followed up as an SAE. 
The site will send a copy of the pregnancy form to Pharmacosmos A/S within 1 working day 
to Drug Safety, contact details in Section 12.5. 


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14 
OVERDOSE 
Overdose may lead to accumulation of iron in storage sites eventually leading to haemosider-
osis. Monitoring of iron parameters such as s-ferritin may assist in recognising iron accumula-
tion. Supportive measures such as chelating agents can be used. 
An overdose must be reported as an AE. 
15 
STATISTICAL ANALYSES 
15.1 
Hypotheses 
The following hypotheses will be tested:  
The incidence of hypophosphatemia is not different in the two treatment groups.  
H0: πiron isomaltoside - πferric carboxymaltose = 0 
against the alternative:  
HA: πiron isomaltoside - πferric carboxymaltose ≠ 0 
where, πiron isomaltoside and πferric carboxymaltose denote the incidence of hypophosphatemia.  
The null hypothesis will be tested against the alternative by estimation of the risk difference 
using the Cochran-Mantel-Haenszel method.  
15.2 
Sample Size Determination 
Data from a previous trial conducted with iron isomaltoside 1000 mg suggests that the inci-
dence of hypophosphatemia in a gynaecology population with/without heavy uterine bleeding 
can be expected to be approximately 10 % (P-Monofer-IDA-01, 1000 mg; n=3/29=10.3 %, 95 
% Confidence Interval (CI) = 2-27 %, gynaecology subgroup; n = 1/10 = 10.0 %, 95 % CI = 
0-45 %). For ferric carboxymaltose the incidence has been observed to be 40-70 % (e.g. Wolf 
et al., 2013; n = 10/17 = 59 %, 95 % CI = 33-82 %). The significance level is set to 5 %, and 
the power is set to 80 %. Assuming incidences of 15 % for iron isomaltoside and 40 % for 
ferric carboxymaltose, 49 subjects in each treatment group is required to detect a difference 
between the treatment groups. 
To account for the uncertainty, and to gain more safety information, 60 subjects per treatment 
group will be randomized in this trial.  
15.3 
Data Analysis Sets 
The following data analysis sets will be used in the analyses of the data: 
Intention to Treat (ITT) analysis set: The ITT analysis set will include all randomized sub-
jects. This will be the primary analysis set for evaluating efficacy. Subjects will be included as 
randomized. 
Safety analysis set: The safety analysis set will include all subjects who received at least one 
dose of the trial drug. This will be the analysis set for evaluating safety. Subjects will be in-
cluded as treated. 


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Full Analysis Set (FAS): The FAS will consist of all randomized subjects, received at least 
one dose of the trial drug, and have at least one post baseline Hb assessment. Subjects will be 
included as randomized. 
Per Protocol (PP) analysis set: The PP analysis set will include all subjects in the FAS who do 
not have any major protocol deviation of clinical or statistical significance. Major protocol 
deviations are defined in Section 17.3. 
The classification of the subjects will be performed before database lock. 
15.4 
Interim Analysis 
No interim analysis will be performed.  
15.5 
Key Elements of the Analysis Plan 
The statistical analyses will be described in detail in a statistical analyses plan. 
15.5.1 
Safety Analyses 
15.5.1.1 Primary Analysis 
The incidence of hypophosphatemia (defined as s-phosphate < 2 mg/dL) at any time from 
baseline to day 35 will be tabulated and exact 95 % CI will be estimated for each treatment 
group.  
Iron isomaltoside will be compared to ferric carboxymaltose by estimation of the risk differ-
ence and the associated 95 % CI, adjusting for strata (type of underlying disease (women with 
IDA due to gynaecological blood losses; yes/no) and screening s-phosphate level (< or ≥ 3.5 
mg/dL)) using the Cochran-Mantel-Haenszel method. 
As sensitivity, the treatment groups will be compared between the treatment groups by a lo-
gistic regression model with treatment and strata as factors and baseline s-phosphate as co-
variate and by Fisher’s exact tests. 
All subjects in the safety analysis set will be included in the analysis. The first post-baseline s-
phosphate measurement will be taken at day 1; hence, very few missing values are expected. 
If there are subject(s), for whom no post-baseline s-phosphate measurement(s) are available, 
these subjects will be set as having s-phosphate < 2 mg/dL in the primary analysis. 
15.5.1.2 Secondary Analyses 
The incidence of s-phosphate < 1.0 mg/dL at any time from baseline to day 35 and the inci-
dence of s-phosphate < 2 mg/dL at day 35 will be presented similar to the primary endpoint. 
The time with hypophosphatemia from baseline to day 35 will be presented by a Kaplan-
Meier plot, and compared between the two groups by a log-rank test. Only subjects who have 
one or more s-phosphate value(s) < 2 mg/dL will be included. The time with s-
hypophosphatemia will be calculated as the actual number of days from the first day where s-
phosphate < 2 mg/dL until the first day where s-phosphate ≥ 2 mg/dL. If a subject experiences 
more than one period with s-phosphate < 2 mg/dL, the longest period will be used in the anal-
ysis. All periods will be tabulated. 
The absolute and percentage change in s-phosphate from baseline to day 1, 7, 8, 14, 21, and 
35 will be analysed using a Restricted Maximum Likelihood (REML)-based Mixed Models 
for Repeated Measures (MMRM) approach. All subjects in the safety analysis set with post-


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baseline s-phosphate data will be included with their observed data. For subjects without post-
baseline s-phosphate values will have change from baseline set to 0 at the first post-baseline 
visit. The model will include the fixed, categorical effects of treatment (iron isomaltoside and 
ferric carboxymaltose), strata, week, treatment-by-week interaction, as well as the continuous, 
fixed covariates of baseline s-phosphate value and base-line s-phosphate-by-week interaction. 
The fractional phosphate urinary excretion at day 1, 7, 8, 14, 21, and 35 will be tabulated. 
The change in iFGF23, cFGF23, vitamin D (25, 1.25, 24.25), PTH, and ionized calcium from 
baseline to day 1, 7, 8, 14, 21, and 35 will be analysed by a MMRM model similar to s-
phosphate. 
15.5.1.3 Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) current 
version.  
Treatment emergent AEs will be summary tabulated by body system and preferred term indi-
cating number and percentage of subjects and number of events. Number of subjects who ex-
perience an ADR including SUSARs will be compared between treatment groups.  
The following AE listings will be made as a minimum: 
 The following list will be made for subjects who never received trial drug: 
o Non-treatment emergent SAEs  
 The following lists will be made for the safety analysis set: 
o Non-treatment emergent AEs and SAEs 
o Treatment emergent AEs (non-serious and serious) 
o Treatment emergent SAEs 
o ADRs 
o AEs leading to dose reduction or withdrawal from treatment 
o Serious or severe hypersensitivity reactions 
o Fatal SAEs 
The incidence of serious or severe hypersensitivity reaction starting on or after the first dose 
of randomized treatment will be tabulated. The hypersensitivity terms are defined as SMQ 
terms (including four additional terms) in Appendix A. 
15.5.1.4 Additional Safety Analyses 
Vital signs, ECG, and standard laboratory data will be presented by descriptive statistics. The 
incidence of treatment emergent potentially clinically significant laboratory and vital sign 
values will be tabulated. 
Physical examination will be tabulated (by body system) as described for categorical data 
above.  


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15.5.2 
Efficacy Analyses 
The change in Hb, s-ferritin, and TSAT from baseline to day 1, 7, 8, 14, 21, and 35 will be 
analysed by a MMRM model similar to s-phosphate. All subjects in the ITT analysis set will 
be included. 
15.5.3 
Exploratory Analyses 
The following exploratory endpoints will be analysed similar with a MMRM model similar to 
s-phosphate:  
 Change in biochemical bone/muscle markers (serum N-terminal PINP, CTx, s-alkaline 
phosphatase (bone specific and total), and creatine kinase) from baseline to day 1, 7, 8, 
14, 21, and 35 
 Change in fatigue symptoms from baseline to day 14 and 35 measured by the FACIT 
Fatigue Scale 
 Change in QoL from baseline to day 14 and 35 measured by SF-36 questionnaire 
 Change in bone pain from baseline to day 14 and 35 measured on a VAS  
 Change in muscle strength from baseline to day 14 and 35 measured by grip strength 
 Change in upper and lower limb proximal muscle function from baseline to day 14 
and 35 measured by the "1 kg arm lift" test and the "30 sec chair stand" test 
 Change in respiratory muscles strength from baseline to day 14 and 35 measured by 
MIP and MEP 
15.6 
Combined Analysis of P-Monofer-IDA-04 and P-Monofer-IDA-05 
The two trials P-Monofer-IDA-04 and P-Monofer-IDA-05 will run in parallel. With n = 60 
treated with iron isomaltoside and n = 60 treated with ferric carboxymaltose, each trial has 
more than 80% power to detect a difference in the incidence of hypophosphatemia, defined as 
s-phosphate < 2 mg/dL at any point from day 1 to day 35.  
In P-Monofer-IDA-04 and P-Monofer-IDA-05 the same dosing regimens are investigated: 
 Group A: iron isomaltoside (1000 mg infusion at baseline, cumulative dose: 1000 
mg) 
 Group B: ferric carboxymaltose (750 mg infusion at baseline and day 7, cumula-
tive dose: 1500 mg) 
Pooled analyses of safety and efficacy endpoints will be performed for the two trials. 
The analyses will be performed similar to those specified for the individual trials, with the 
addition of trial in the models, i.e. the strata in the Cochran-Mantel-Haenszel method will be a 
combination of baseline s-phosphate and trial.  
Using the assumptions of incidences of 15 % for iron isomaltoside and 40 % for ferric car-
boxymaltose, with n = 120 for iron isomaltoside 1000 mg and n = 120 for ferric carboxymalt-
ose, there is 99 % power to detect this difference. 
The assumption of the incidence of s-phosphate < 2 mg/dL for iron isomaltoside is based on 
the subgroup in the trial P-Monofer-IDA-01 receiving 1000 mg (n = 29). For this subgroup, 
no subject experienced s-phosphate < 1 mg/dL. For ferric carboxymaltose, there has been ob-
served incidences of 9 % [Bager & Dahlerup, 2016].  


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Using assumptions of incidences of 1 % for iron isomaltoside and 9 % for ferric carboxymalt-
ose, with n = 120 for iron isomaltoside 1000 mg and n = 120 for ferric carboxymaltose, there 
is 82% power to detect this difference. 
Also, the overall incidence of treatment emergent AEs and ADRs will be compared between 
the treatments. 
The CSR can be finalised without the combined analysis, which will be done when both trials 
are finalised. The combined analysis will be included as an appendix to the CSR. 
16 
DATA MANAGEMENT AND DATA COLLECTION 
16.1 
Definition of Source Data 
Source data is defined as all information in original records or certified copies of original rec-
ords of clinical findings, observations, or other activities in a clinical trial necessary for recon-
struction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies). Source data location list needs to be filled in and maintained by 
the Investigator during the trial. 
16.2 
Data Management 
Data management will be outsourced. The data collection tool for this trial will be an eCRF, 
which is compliant with 21 CFR Part 11 regulations. Subject data necessary for analyses and 
reporting will be entered into a validated database or data system. Clinical data management 
will be performed in accordance with applicable standards and data cleaning procedures.  
The site staff will be trained before they have access to the eCRF and an eCRF guideline will 
be available.  
17 
TRIAL MONITORING 
17.1 
Trial Monitoring 
In accordance with applicable regulations and ICH-GCP guidelines, Pharmacosmos A/S or its 
designee will contact the site prior to the start of the trial to review with the site staff the pro-
tocol, trial requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing the data collection procedures, the discussion will also include 
identification, agreement, and documentation of data items for which the eCRF may serve as 
the source document. 
Pharmacosmos A/S and or its designee will monitor the trial for protocol compliance verify-
ing the following, but not limited to:  
 Safety and rights of subjects are being protected 
 Trial is conducted in accordance with the currently approved protocol and any other 
trial agreements, ICH-GCP guidelines, and all applicable regulatory requirements 
 Data are authentic, accurate, and complete 
Risk based monitoring will be used and is described further in the Global Monitoring Plan. 
The PI agrees to allow the Clinical Research Associate (CRA) direct access to all relevant 
documents for the purpose of verification of available data. 


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17.2 
Quality Assurance 
To ensure compliance with ICH-GCP guidelines and all applicable regulatory requirements, 
Pharmacosmos A/S or its designee may conduct a quality assurance audit following intima-
tion and appointment. Regulatory agencies may also conduct a regulatory inspection of this 
trial. Such audits/inspections can occur at any time during or after completion of the trial. 
17.3 
Protocol Deviations 
Deviations from the protocol will be registered as protocol deviations which will be classified 
as minor, major, or Good Clinical Practice (GCP) deviations.  
The following will be assessed as major protocol deviation: 
 Out of visit window at three visits 
 Intake of prohibited medication 
 Treatment compliance outside the 80-120 % range  
 Other protocol deviations which are assessed as having a clinically or statistically 
significant effect 
18 
TRIAL ADMINISTRATION 
Pharmacosmos A/S will be responsible for trial administration as described in this section.  
A list of laboratories, Contract Research Organizations (CROs), and other vendors will be 
kept in the trial master file. 
18.1 
Trial Core Team, GCP Quality Steering Committee, and GCP Quality Board 
A Trial Core Team (TCT) will be established for the trial consisting of the following Sponsor 
personnel: 
 Chief Medical Officer  
 Quality Assurance 
 Global Trial Management 
  
 
 Global Medical Monitoring  
 Quality Control 
 Regulatory  
 
 
 Biometrics and Medical Writing (BMW) 
The purpose of the TCT is to ensure high quality, regulatory compliance, scientific validity, 
and transparency in all activities of the trial via robust planning and timely action. Regular 
meeting will be held.   
Issues which have a general impact on GCP will be escalated to the GCP Quality Steering 
Committee consisting of: 
 Chief Medical Officer 
 Quality Assurance 
 
  
 Head of Clinical Trial Management   
 


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 Head of Drug Safety  
 
 
 Quality Control 
 Regulatory  
 
 
 
 BMW 
Serious GCP breach and GCP related issues of broad impact to Pharmacosmos A/S could be 
escalated to the GCP Quality Board consisting of: 
 Chief Medical Officer 
 
 
 
 Quality and Regulatory Affairs  
 
 Medical Affairs 
 
 
 
 Chief Executive Officer 
 
 
 
18.2 
Direct Access 
Direct access to all source data and documents will be mandatory for representatives from 
Pharmacosmos A/S, Contract Research Organizations, IRB/IEC, Competent Authorities, and 
other national authorities (e.g. Data Protection Agency) for the purpose of verification of 
available data. 
If an audit or inspection occurs, the PI and institution agree to allow the auditor/inspector di-
rect access to all relevant documents and to allocate his/her time and the time of his/her staff 
to the auditor/inspector to discuss findings and any relevant issues. 
18.3 
Trial and Site Closure 
Upon completion or premature discontinuation of the site or trial, the CRA will conduct site 
closure activities with the PI or site staff, as appropriate, in accordance with applicable regula-
tions, ICH-GCP guidelines, and Pharmacosmos A/S or its designee’s procedures.  
18.4 
Records Retention 
Following closure of the trial, the PI must maintain all site trial records in a safe and secure 
location mutually agreeable to the PI, Pharmacosmos A/S, or its designee. The records must 
be maintained to allow easy and timely retrieval when needed (e.g. audit or inspection) and, 
whenever feasible, to allow any subsequent review of data in conjunction with assessment of 
the facility, supporting systems, and staff. Where permitted by local laws/regulations or insti-
tutional policy, some or all of these records can be maintained in a format other than hard 
copy (e.g. microfiche, scanned, and electronic); however, caution needs to be exercised before 
such action is taken. The PI must assure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including re-
generating a hard copy, if required. Furthermore, the PI must ensure there is an acceptable 
back-up of these reproductions and that an acceptable quality control process exists for mak-
ing these reproductions. 
Pharmacosmos A/S or its designee will inform the PI of the time period for retaining these 
records to comply with all applicable regulatory requirements. The minimum retention time 
will meet the strictest standard applicable to that site for the trial, as dictated by any institu-
tional requirements, local laws or regulations, or Pharmacosmos A/S or its designee standard 
procedures; otherwise the retention period will by default be 25 years.  


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The PI must notify Pharmacosmos A/S or its designee of any changes in the archival ar-
rangements, including, but not limited to, the following: archival at an off-site facility and 
transfer of ownership of the records if the PI leaves the site.  
18.5 
Provision of Trial Results and Information to Principal Investigators 
When the CSR is completed, Pharmacosmos A/S or its designee will provide the PI with a 
summary of the trial results. The PI is encouraged to share the summary results with the sub-
jects, as appropriate. In addition, the PI will be given reasonable access to review the relevant 
statistical tables, figures, and reports and will be able to review the results for the entire trial at 
a Pharmacosmos A/S site or other mutually agreeable location. 
18.6 
Finance and Insurance 
All agreements between the PI and Pharmacosmos A/S or designee must be signed prior to 
screening of the first subject in the clinical trial. The agreement must clearly state the rights 
and obligations of the parties concerned and include a detailed financial settlement. 
Every subject participating in the trial will be insured in accordance with the local legal re-
quirements against trial related injuries to health, which may occur during the trial. 
Excluded from this, however, are injuries to health and deteriorations of illnesses already in 
existence which would have occurred or continued to exist even if the subject had not taken 
part in the clinical trial. 
The insurance cover is jeopardised if the subject fails to report immediately to the PI or re-
sponsible physician any injury to health, which might have resulted from participation in the 
clinical trial, or if the subject undergoes any other medical treatment without their consent 
before the clinical trial has been completely finished, insofar as the individual subject is con-
cerned. 
The subject insurance will be arranged by Pharmacosmos A/S on the basis of the final trial 
protocol. 
19 
ETHICAL CONSIDERATIONS 
19.1 
Regulatory and Ethical Considerations 
Pharmacosmos A/S or its designee will obtain favourable opinion/approval to conduct the 
trial from the IRB/IEC, Competent Authorities, and the Data Protection Agency in accordance 
with the local requirements prior to initiating the trial. 
The trial will be conducted in accordance with all applicable regulatory requirements. The 
trial will also be conducted in accordance with ICH-GCP guidelines, all applicable subject 
privacy requirements, and the guiding principles of the Declaration of Helsinki.  
19.2 
Changes to the Protocol 
The clinical trial procedures may be changed, and if the changes are substantial, both the 
IRB/IEC and Competent Authorities, as applicable, must approve/acknowledge the changes 
before they can be implemented. All substantial changes must be documented by protocol 
amendments, if applicable. 


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20 PUBLICATION PLAN 
A CSR will be prepared by Pharmacosmos A/S or its designee and reviewed by Pharmacos-
mos A/S. The CSR or a summary of the CSR should be sent to the IRB/IEC and Competent 
Authorities according to local legislation. 
No data from the clinical trial may be published, presented, or communicated, except to Com-
petent Authorities, prior to the release of the CSR, unless approved by Pharmacosmos A/S in 
writing. The PIs agree not to discuss externally or publish any result from the trial without the 
possibility of Pharmacosmos A/S to give comments for up to 90 days after receipt of the 
manuscript. 
The trial will be registered at Clinicaltrials.gov. 
The results of the trial, positive as well as negative, will be published by the end of the trial. 
If the results of the trial are to be published in a journal, the authorship credit should be based 
on (1) substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data; (2) drafting the article or revising it critically for important intellectual 
content; (3) final approval of the version to be published. Authors should meet conditions 1, 
2, and 3. 
20.1 
Uploading of Data on Public Websites 
The primary and secondary endpoints will be uploaded on ClinicalTrial.gov in according to 
national requirements.  
21 
REFERENCES 
Aapro M, Österborg A, Gascón P, Ludwig H, Beguin Y. Prevalence and management of can-
cer-related anaemia, iron deficiency and the specific role of i.v. iron. Ann Oncol 2012;23: 
1954-1962 
Agarwal S, Kiely PDW. Two simple, reliable and valid tests of proximal muscle function, 
and their application to the management of idiopathic inflammatory myositis. Rheumatology 
2006;45:874-879 
ATS/ERS statement on respiratory muscle testing. Am J Respir Crit Care Med 2002;166:518-
624 
Bager P, Dahlerup JF. Hypophosphataemia after different intravenous iron infusion drugs. 
Poster 538, Congress of ECCO, Amsterdam 16-19 March 2016 
Bhandari S, Kalra PA, Kothari J, et al. A randomized, open-label trial of iron isomaltoside 
1000 (Monofer®) compared with iron sucrose (Venofer®) as maintenance therapy in haemodi-
alysis patients. NDT 2015;30:1577-1589 
Birgegard G, Henry D, Glaspy J, et al. A randomized, noninferiority trial of intravenous iron 
isomaltoside versus oral iron sulfate in patients with nonmyeloid malignancies and anemia 
receiving chemotherapy, the PROFOUND trial. Pharmacotherapy 2016;36:402-414  
Brazier JE, Harper R, Jones NMB, et al. Validating the SF-36 health survey questionnaire: 
new outcome measure for primary care. BMJ 1992;305:160-164 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
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 Page 48 of 56 
Cella D, Yount S, Sorensen M, Chartash E, Sengupta N, Grober J. Validation of the Func-
tional Assessment of Chronic Illness Therapy Fatigue Scale relative to other instrumentation 
in patients with rheumatoid arthritis. J Rheumatol 2005;32:811-819 
Dahlerup JF, Jacobsen BA, van der Woude J, et al. High-dose fast infusion of parenteral iron 
isomaltoside is efficacious in inflammatory bowel disease patients with iron-deficiency anae-
mia without profound changes in phosphate or fibroblast growth factor 23. Scand J Gastroen-
terol 2016;51:1332-1338 
De Oliveira Iglesias SB, Pons Leite H, De Carvalho WB. Hypophosphatemia-induced sei-
zure in a child with diabetic ketoacidosis. Pediatric Emergency Care 2009;25:859-861 
Dignass AU, Gasche C, Bettenworth D, et al. European consensus on the diagnosis and man-
agement of iron deficiency and anaemia in inflammatory bowel diseases. J Crohns Colitis 
2015;9:211-222 
Durham BH, Joseph F, Bailey LM, Fraser WD. The association of circulating ferritin with 
serum concentrations of fibroblast growth factor-23 measured by three commercial assays. 
Ann Clin Biochem 2007;44:463-466 
FDA. Advisory Committee Briefing Document, Drug Safety and Risk Management Commit-
tee, and 1 February. Division of Medical Imaging and Hematology Products and Office of 
Oncology Drug Products and Office of New Drugs, New Drug Application (NDA) 22-054 for 
Injectafer (Ferric Carboxymaltose) for the treatment of iron deficiency anemia in patients with 
heavy uterine bleeding or postpartum patients. 2008;1-63  
FDA. Medical review of ferric carboxymaltose, application number 203565Orig1s000, Center 
for Drug Evaluation and Research, Food and Drug Administration, 21 July 2013   
Gasche C, Berstad A, Befrits R, et al. Guidelines on the diagnosis and management of iron 
deficiency and anemia in inflammatory bowel diseases. Inflamm Bowel Dis 2007;13:1545-
1553 
Gravelyn TR, Brophy N, Siegert C, Peters-Golden M. Hypophosphatemia-associated respira-
tory muscle weakness in a general inpatient population. Am J Med 1988;84:870-876 
Gupta DR, Larson DS, Thomsen LL, Coyne DW. Pharmacokinetics of iron isomaltoside 
1000 in patients with stage 5 chronic kidney disease on dialysis therapy. J Drug Metab Toxi-
col 2013;4:152. doi: 10.4172/2157-7609.1000152 
Holm, C, Thomsen LL, Norgaard A, Langhoff-Roos J. Single-dose intravenous iron infusion 
or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled 
trial. Vox Sang 2017;112:219-228 
Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 
differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin En-
docrinol Metab 2011;96:3541-3549 
Injectafer® prescribing information (USA), 07/2013 
Jahn MR, Andreasen HB, Futterer S et al. A comparative study of the physicochemical prop-
erties of iron isomaltoside 1000 (Monofer®), a new intravenous iron preparation and its clini-
cal implications. Eur J Pharm Biopharm 2011;78:480-491 
Jensen MP, Chen C, Brugger AM. Interpretation of visual analog scale ratings and change 
scores: a reanalysis of two clinical trials of postoperative pain. J Pain 2003;4:407-414 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
Confidential 
 
 Page 49 of 56 
Johansson PI, Rasmussen AS, Thomsen LL. Intravenous iron isomaltoside 1000 (Monofer®) 
reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or 
subacute coronary artery bypass graft, valve replacement or a combination thereof: a random-
ized double-blind placebo-controlled clinical trial (the PROTECT trial). Vox Sang 
2015;109:257-266 
Kalra PA, Bhandari S, Saxena S, et al. A randomized trial of iron isomaltoside 1000 versus 
oral iron in non-dialysis-dependent chronic kidney disease patients with anaemia. NDT 
2016;3:646-655 
KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. 2012;2 
http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO-Anemia%20GL.pdf (accessed 
the 1 May 2017) 
Liu PY, Jeng CY. Severe hypophosphatemia in a patient with diabetic ketoacidosis and acute 
respiratory failure. J Chinese Medical Association 2004;67:355-359 
Muñoz M, Botella-Romero F, Gómez-Ramírez S, Campos A, García-Erce JA: Iron deficien-
cy and anaemia in bariatric surgical patients: causes, diagnosis and proper management. Nutr 
Hosp 2009;24:640-654 
O'Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphatemia on myocardial per-
formance in man. The New England J Medicine 1977;297:901-903 
Ognibene A, Ciniglio R, Greifenstein A, et al. Ventricular tachycardia in acute myocardial 
infarction: the role of hypophosphatemia. Southern Medical J 1994;87:65-69  
Okada M, Imamura K, Iida M, Fuchigami T, Omae T. Hypophosphatemia induced by intra-
venous administration of Saccharated iron oxide. Klin Wochenschr 1983;61:99-102 
Poesen R, Dierickx D, Evenepoel P. Hemolytic anemia associated with severe hypophos-
phatemia in a renal transplant recipient. Transplant International 2012;25:e27-e28 
Reinisch W, Staun M, Tandon RK, et al. A randomized, open-label, non-inferiority study of 
intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of ane-
mia in IBD (PROCEED). Am J Gastroenterol 2013;108:1877-1888 
Reinisch W, Altorjay I, Zsigmond F, et al. A 1-year trial of repeated high-dose intravenous 
iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease. 
Scand J Gastroenterol 2015;2015:50:1226-1233 
Roberts HC, Denison HJ, Martin HJ et al. A review of the measurement of grip strength in 
clinical and epidemiological studies: towards a standardised approach. Age and Ageing 
2011;40:423-429 
Russell JA. Osteomalacic myopathy. Muscle and Nerve 1994;17:578-580  
Schouten  BJ, Doogue MP, Soule SG, Hunt PJ. Iron polymaltose-induced FGF23 elevation 
complicated by hypophosphataemic osteomalacia. Ann Clin Biochem 2009a;46:167-169 
Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypo-
phosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol 
Metab 2009b;94:2332-2337 
Schubert L, DeLuca HF. Hypophosphatemia is responsible for skeletal muscle weakness of 
vitamin D deficiency Arch Biochem Biophys 2010;500:157-161 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
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 Page 50 of 56 
Shimizu Y, Tada Y, Yamauchi M, Okamoto T, Suzuki H, Ito N, Fukumoto S, Sugimoto T,  
Fujita T. Hypophosphatemia induced by intravenous administration of saccharated ferric ox-
ide: another form of FGF23-related hypophosphatemia. Bone 2009;45:814-816 
Singhal PC, Kumar A, Desroches L, Gibbons N, Mattana J. Prevalence and predictors of 
rhabdomyolysis in patients with hypophosphatemia. Am J Med 1992;92:458-464  
Turnbull J, Lumsden D, Siddiqui A, Lin JP, Lim M. Osmotic demyelination syndrome asso-
ciated with hypophosphataemia: 2 cases and a review of literature. Acta Paediatrica 
2013;102:e164-e168 
Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose 
intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleed-
ing: a randomized, controlled trial. Transfusion 2009;49:2719-2728 
WHO. Worldwide prevalence of anaemia 1993-2005, WHO Global Database on Aneamia, 
Center for Disease Control and Prenention, 2008  
Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anaemia in inflammatory bowel 
disease: a systematic review of the literature. Am J Med 2004;116:44S-49. 
Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fi-
broblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res 
2013;28:1793-1803 
Woodforde JM, Merskey H. Some relationships between subjective measures of pain. J Psy-
chosom Res 1972;16:173-178 
 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
Confidential 
 
 Page 51 of 56 
APPENDIX A 
Standardised MedDra query (SMQ) terms (including four additional terms) for definition of 
hypersensitivity events  
Group A: Narrow terms pertaining to hypersensitivity reactions 
 Anaphylactic reaction 
 Anaphylactic shock 
 Anaphylactic transfusion reaction 
 Anaphylactoid reaction 
 Anaphylactoid shock 
 Circulatory collapse 
 First use syndrome 
 Kounis syndrome 
 Shock 
 Type I hypersensitivity 
 
Group B: Broad terms pertaining to respiratory reactions potentially related to hypersensitivi-
ty 
 Acute respiratory failure 
 Asthma 
 Bronchial oedema 
 Bronchospasm 
 Cardio-respiratory distress 
 Chest discomfort 
 Choking 
 Choking sensation 
 Circumoral oedema 
 Cough 
 Cyanosis 
 Dyspnoea 
 Hyperventilation 
 Laryngeal dyspnoea 
 Laryngeal oedema 
 Laryngospasm 
 Laryngotracheal oedema 
 Mouth swelling 
 Nasal obstruction 
 Oedema mouth 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
Confidential 
 
 Page 52 of 56 
 Oropharyngeal spasm 
 Oropharyngeal swelling 
 Respiratory arrest 
 Respiratory distress 
 Respiratory failure 
 Reversible airways obstruction  
 Sensation of foreign body 
 Sneezing 
 Stridor 
 Swollen tongue 
 Tachypnoea 
 Throat tightness 
 Throat oedema 
 Tracheal obstruction 
 Tracheal oedema 
 Upper airway obstruction 
 Wheezing 
 
Group C: Broad terms pertaining to skin reactions potentially related to hypersensitivity 
 Allergic oedema 
 Angioedema 
 Erythema 
 Eye oedema 
 Eye pruritus 
 Eye swelling 
 Eyelid oedema 
 Face oedema 
 Flushing 
 Generalised erythema 
 Injection site urticaria 
 Lip oedema 
 Lip swelling 
 Ocular hyperaemia 
 Oedema 
 Periobital oedema 
 Pruritus 
 Pruritus allergic 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
Confidential 
 
 Page 53 of 56 
 Pruritus generalised 
 Rash 
 Rash erythematous 
 Rash generalised 
 Rash pruritic 
 Skin swelling 
 Swelling 
 Swelling face 
 Urticaria 
 Urticaria papular 
 
Group D: Broad terms pertaining to cardiovascular reaction potentially related to hypersensi-
tivity 
 Blood pressure decreased 
 Blood pressure diastolic decreased 
 Blood pressure systolic decreased 
 Cardiac arrest 
 Cardio-respiratory arrest 
 Cardiovascular insufficiency 
 Diastolic hypotension 
 Hypotension 
 
Group E: Additional terms defined by the Food and Drug Administration (FDA) 
 Syncope 
 Unresponsiveness 
 Loss of consciousness 
 Seizure 
 
 
 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
Confidential 
 
 Page 54 of 56 
APPENDIX B  
Southampton protocol for adult grip strength measurement (equipment: Model J00105 
JAMAR Hydraulic Hand Dynamometer or similar model) [Roberts et al. 2011]. 
(1)  Sit the participant comfortably in a standard chair with legs, back support, and fixed 
arms. Use the same chair for every measurement.  
(2)   Ask them to rest their forearms on the arms of the chair with their wrist just over the end 
of the arm of the chair—wrist in a neutral position, thumb facing upwards.  
(3)   Demonstrate how to use the Jamar handgrip dynamometer to show that gripping very 
tightly registers the best score.  
(4)   Start with the right hand.  
(5)   Position the hand so that the thumb is round one side of the handle and the four fingers 
are around the other side. The instrument should feel comfortable in the hand. Alter the 
position of the handle if necessary.  
(6)   The observer should rest the base of the dynamometer on the palm of their hand as the 
subject holds the dynamometer. The aim of this is to support the weight of the dyna-
mometer (to negate the effect of gravity on peak strength), but care should be taken not 
to restrict its movement.  
(7)   Encourage the participant to squeeze as long and as tightly as possible or until the nee-
dle/measurement stops rising/increasing. Once the needle/measurement stops ris-
ing/increasing the participant can be instructed to stop squeezing.  
(8)   Read grip strength in kilograms from the outside dial and record the result to the nearest 
1 kg on the data entry form.  
(9)   Repeat measurement in the left hand.  
(10)  Do two further measurements for each hand alternating sides to give three readings in 
total for each side.  
(11)  The best of the six grip strength measurements is used in statistical analyses so as to 
encourage the subjects to get as high a score as possible.  
(12)  Also record hand dominance, i.e. right, left or ambidextrous (people who can genuinely 
write with both hands).  
Figure 1. Southampton protocol for 
adult grip strength measurement. 
 
 
 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
Confidential 
 
 Page 55 of 56 
APPENDIX C  
Tests of upper and lower limb proximal muscle function [Agarwal and Kiely, 2006]. 
The subject sits in a chair holding a 1 kg weight with the shoulder adducted, the elbow in full 
flexion, and the forearm in supination (Figure 1). He/she is asked to lift the arm above the 
head until the elbow is fully extended, then to lower the arm back to the starting position, and 
then repeat the action at his/her own pace. This devised test has been called the "1 kg arm lift" 
test. It is important that the emphasis is not on achieving a maximum possible number of repe-
titions within the time, but instead that the test is performed at a comfortable pace according 
to the subject’s own rhythm. The number of times the weight is lifted above the head in a 30 s 
period is recorded for each arm individually and the final score is the mean of the two meas-
urements. When the test cannot be performed in one arm, for reasons other than the muscle 
disease in question, such as elbow or shoulder arthritis, the score from the contralateral arm 
alone is used. 
 
 
 
Figure 1. Photograph demonstrating the "1 kg arm lift" test. The subject sits in a chair holding 
the 1 kg weight with the shoulder adducted, the elbow in full flexion, and the forearm in supi-
nation. He/she is asked to lift the arm above the head until the elbow is fully extended, then to 
drop the arm back to the starting position, and then repeat the action at his/her own pace for a 
30 s period. 
 
 
 


Trial ID: 
P-Monofer-IDA-04 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
29 November 2017 
 
 
Confidential 
 
 Page 56 of 56 
The "30 s chair stand" test is a valid and reliable measure of proximal lower limb strength in 
older adults. The subject is asked to stand upright from a chair with their arms folded across 
the chest, then to sit down again and then repeat the action at his/her own pace over a 30 s 
period (Figure 2). Again it is important to emphasize that the subject does not need to achieve 
a maximum possible number of repetitions within the time allocated, but that the test is per-
formed at a comfortable pace according to the subject’s own rhythm. It is important that the 
same or a similar chair is used on each occasion, as the score may be influenced by the height 
of the chair. The final test score is the number of times that the subject rises to a full stand 
from the seated position with arms folded within 30 s.  
 
 
Figure 2. Photograph demonstrating the "30 s chair stand" test. The subject is asked to stand 
upright from a chair with their arms folded across the chest, then to sit down again, and then 
repeat the action at his/her own pace for a 30 s period. 
 

SAP_001.pdf: 
Sponsor:  
Drug/Project:  
Pharmacosmos A/S 
Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
Statistical Analysis Plan 
 
Trials: 
P-Monofer-IDA-04 
P-Monofer-IDA-05 
 
 
 
 
 
P_monofer_IDA_04_05_SAP_Final_20171127 
Confidential 
Page 1 of 22 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
Trial IDs: 
P-Monofer-IDA-04 and P-Monofer-IDA-05 
 
Randomized, open-label, comparative trials comparing the incidence of hypophosphatemia in 
relation to treatment with iron isomaltoside and ferric carboxymaltose in subjects with iron 
deficiency anaemia 
 
 
 
 
 
Phase III Trials 
 
Author: 
  
Principal Biostatistician 
 
 
 
The content of this document is confidential and must not be communicated to a third party and must not be 
reproduced or quoted without the written consent of Pharmacosmos A/S. 
 
 




Sponsor:  
Drug/Project:  
Pharmacosmos A/S 
Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
Statistical Analysis Plan 
 
Trials: 
P-Monofer-IDA-04 
P-Monofer-IDA-05 
 
 
 
 
 
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Confidential 
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Table of Contents 
List of Tables .................................................................................................................................. 4 
1 
List of Abbreviations ................................................................................................................ 4 
2 
Introduction ............................................................................................................................ 6 
3 
Trial Characteristics ................................................................................................................. 7 
3.1 
Trial Objectives ........................................................................................................................................ 7 
3.1.1 
Primary objective ....................................................................................................................................... 7 
3.1.2 
Secondary safety objectives ....................................................................................................................... 7 
3.1.3 
Secondary efficacy objectives .................................................................................................................... 7 
3.1.4 
Additional objectives .................................................................................................................................. 7 
3.2 
Trial Design .............................................................................................................................................. 8 
3.3 
Subject included ...................................................................................................................................... 9 
3.3.1 
Sample Size Determination ........................................................................................................................ 9 
4 
Analysis Populations .............................................................................................................. 10 
5 
Planned Statistical Methods ................................................................................................... 10 
5.1 
Statistical Considerations ...................................................................................................................... 10 
5.1.1 
Key methods ............................................................................................................................................. 11 
5.2 
Subject Disposition ................................................................................................................................ 11 
5.3 
Baseline Characteristics and Demographics ......................................................................................... 12 
5.4 
Medical History and IDA-Underlying Disease ....................................................................................... 12 
6 
Exposure and Other Dosing Information ................................................................................. 12 
6.1 
Exposure ................................................................................................................................................ 12 
6.2 
Concomitant medication ....................................................................................................................... 12 
7 
Statistical Methodology ......................................................................................................... 13 
7.1 
Analysis and Presentation of the Primary Endpoint ............................................................................. 13 
7.1.1 
Incidence of hypophosphatemia at any time from baseline to day 35 .................................................... 13 
7.2 
Analysis and Presentation of the Secondary Safety Endpoints ............................................................. 13 
7.2.1 
Incidence of s-phosphate < 1.0 mg/dL at any time from baseline to day 35 ........................................... 14 
7.2.2 
Time with hypophosphatemia from baseline to day 35 ........................................................................... 14 
7.2.3 
Proportion of hypophosphatemia at day 35 ............................................................................................ 14 
7.2.4 
Absolute [∆] and relative [%] changes in s-phosphate from baseline to day 1, 7, 8, 14, 21, and 35 ....... 14 
7.2.5 
Fractional phosphate urinary excretion at day 1, 7, 8, 14, 21, and 35 ..................................................... 14 
7.2.6 
Change in iFGF23, cFGF23, vitamin D (25, 1.25, 24.25), PTH, and ionized calcium from baseline to 
day 1, 7, 8, 14, 21, and 35 ......................................................................................................................... 15 
7.2.7 
Type and incidence of AEs ........................................................................................................................ 15 
7.2.8 
Serious or severe hypersensitivity reaction ............................................................................................. 16 
7.3 
Analysis and Presentation of the Secondary Efficacy Endpoints .......................................................... 16 
7.3.1 
Change in Hb per gram iron ..................................................................................................................... 16 
7.3.2 
Change in s-ferritin ................................................................................................................................... 16 
7.3.3 
Change in TSAT ......................................................................................................................................... 16 
7.4 
Analysis and Presentation of Other Safety Assessments ...................................................................... 16 
7.4.1 
Vital signs and weight ............................................................................................................................... 17 
7.4.2 
ECG 
17 
7.4.3 
Laboratory data ........................................................................................................................................ 17 
7.4.4 
Physical examination ................................................................................................................................ 17 
7.5 
Exploratory endpoints ........................................................................................................................... 17 
7.5.1 
Change in biochemical bone/muscle markers ......................................................................................... 18 
7.5.2 
Change in Hb ............................................................................................................................................ 18 
7.5.3 
Change in fatigue symptoms .................................................................................................................... 18 
7.5.4 
Change in QoL........................................................................................................................................... 19 
7.5.5 
Change in bone pain ................................................................................................................................. 20 
7.5.6 
Change in muscle strength ....................................................................................................................... 20 


Sponsor:  
Drug/Project:  
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7.5.7 
Change in upper and lower limb proximal muscle function ..................................................................... 20 
7.5.8 
Change in respiratory muscles strength ................................................................................................... 20 
7.6 
Handling of Missing Values ................................................................................................................... 20 
7.7 
Multiplicity adjustments ....................................................................................................................... 21 
7.8 
Sub-group and Centre Effects ............................................................................................................... 21 
7.9 
Interim Analysis ..................................................................................................................................... 21 
7.10 
Combined Analysis of P-Monofer-IDA-04 and P-Monofer-IDA-05 ........................................................ 21 
8 
Deviations from Protocol ....................................................................................................... 21 
9 
Software ............................................................................................................................... 22 
10 Reference List ........................................................................................................................ 22 
 
List of Tables 
Table 1: Activities Flow Chart .......................................................................................................... 8 
Table 2 Visit schedule ................................................................................................................... 10 
 
1 List of Abbreviations 
ADR 
Adverse Drug Reaction  
AE 
Adverse Event 
cFGF23 
C-terminal Fibroblast Growth Factor 23 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTx 
Carboxy-terminal Collagen Crosslinks 
ECG 
Electrocardiogram 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAS 
Full Analysis Set 
Hb 
Haemoglobin  
IDA 
Iron Deficiency Anaemia 
iFGF23 
Intact Fibroblast Growth Factor 23 
ITT 
Intention-To-Treat 
LLOQ 
Lower Limit Of Quantification 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEP 
Maximal Expiratory Pressure 
MIP 
Maximal Inspiratory Pressure 
MMRM 
Mixed Models for Repeated Measures 
PCS 
Physical Component Summary 
PINP 
Propeptide of Type I Collagen 
PP 
Per Protocol  


Sponsor:  
Drug/Project:  
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Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
Statistical Analysis Plan 
 
Trials: 
P-Monofer-IDA-04 
P-Monofer-IDA-05 
 
 
 
 
 
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PT 
Preferred Term 
PTH 
Parathyroid Hormone 
QoL 
Quality of Life 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan   
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SF-36 
Short Form - 36 
S-ferritin 
Serum-ferritin 
SMQ 
Standardised Medical Dictionary for Regulatory Activities Query 
SOC 
System Organ Class 
S-phosphate 
Serum-phosphate 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TEAE 
Treatment Emergent Adverse Event 
TSAT 
Transferrin Saturation 
VAS 
Visual Analogue Scale 
 
 


Sponsor:  
Drug/Project:  
Pharmacosmos A/S 
Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
Statistical Analysis Plan 
 
Trials: 
P-Monofer-IDA-04 
P-Monofer-IDA-05 
 
 
 
 
 
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2 Introduction 
The generic statistical analysis plan (SAP) for the identical trials P-Monofer-IDA-04 and P-Monofer-IDA-
05 is based on the final protocols, both version 3.0 including amendment 2 dated 29 November 2017. 
Reporting of each trial will be done individually after the date of last subject last visit of the trials.  
A combined analysis is planned, which will be done when both trials are finalised. The trials will be 
reported without the combined analysis, which will be included as an appendix to both clinical study 
reports (CSRs). 
The SAP describes in detail the analyses to be conducted and highlights any deviations from the 
analysis described in the protocols (see section 8). Deviations from methods described in this SAP, if 
any, will be specified in the CSRs. 
Before releasing data for final analysis, one or more data review and classification meeting will be held 
to review protocol deviations in order to classify subjects with respect to analysis populations. The 
product of the classification meetings will be a detailed description of the analysis populations, and 
the number and nature of unresolved data queries will also be reported. 
The analysis is performed based on: 
 
The clinical database, which includes the electronic Case Report Forms (CRF)  
 
List of protocol deviations 
 
Analysis populations documented in the data base lock minutes. 
 
 


Sponsor:  
Drug/Project:  
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Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
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P-Monofer-IDA-05 
 
 
 
 
 
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3 Trial Characteristics 
3.1 Trial Objectives 
3.1.1 Primary objective 
The primary objective of the trials is to compare the incidence of hypophosphatemia in subjects with 
Iron Deficiency Anaemia (IDA) treated with iron isomaltoside or ferric carboxymaltose. 
3.1.2 Secondary safety objectives 
The secondary safety objectives of the trials are to compare the effects of iron isomaltoside and ferric 
carboxymaltose treatment in subjects with IDA on the following:  
(1) 
Incidence of severe hypophosphatemia  
(2) 
Time with hypophosphatemia  
(3) 
Proportion of subjects with hypophosphatemia at the last visit 
(4) 
Absolute [∆] and relative [%] changes in serum-phosphate (s-phosphate) 
(5) 
Fractional phosphate urinary excretion 
(6) 
Intact Fibroblast Growth Factor 23 (iFGF23), C-terminal FGF23 (cFGF23), vitamin D (25, 1.25, 
24.25), Parathyroid Hormone (PTH), and ionized calcium  
(7) 
Adverse Events (AEs) and biochemical safety parameters 
3.1.3 Secondary efficacy objectives 
The secondary efficacy objective of the trials is to compare the effects of iron isomaltoside and ferric 
carboxymaltose treatment in subjects with IDA on Haemoglobin (Hb), serum-ferritin (s-ferritin), and 
Transferrin Saturation (TSAT). 
3.1.4 Additional objectives 
In addition to the trials primary and secondary objectives, the effect of iron isomaltoside and ferric 
carboxymaltose will be investigated purely exploratory on the following: 
(1) 
Biochemical bone/muscle markers  
(2) 
Fatigue symptoms  
(3) 
Quality of Life (QoL) 
(4) 
Bone pain 
(5) 
Muscle strength 
 
 
 






Sponsor:  
Drug/Project:  
Pharmacosmos A/S 
Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
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Trials: 
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P-Monofer-IDA-05 
 
 
 
 
 
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4 Analysis Populations 
The following data analysis sets are defined in the protocol: 
 
Intention to Treat (ITT) analysis set: The ITT analysis set will include all randomized subjects. 
This will be the primary analysis set for evaluating efficacy. Subjects will be included as 
randomized. 
 
Safety analysis set: The safety analysis set will include all subjects who received at least one 
dose of the trial drug. This will be the analysis set for evaluating safety. Subjects will be 
included as treated. 
 
Full Analysis Set (FAS): The FAS will consist of all randomized subjects who received at least 
one dose of the trial drug and have at least one post baseline Hb assessment. Subjects will be 
included as randomized. 
 
Per Protocol (PP) analysis set: The PP analysis set will include all subjects in the FAS who do 
not have any major protocol deviation of clinical or statistical significance. Major protocol 
deviations are defined in the trial protocols Section 17.3. 
The primary analysis population is the safety analysis set, which will be used for all safety evaluations. 
ITT analysis set will be used for all efficacy evaluations. FAS and PP analysis set will be used for the 
analysis of Hb.  
5 Planned Statistical Methods 
5.1 Statistical Considerations 
Baseline is defined as the last assessment with available data prior to the first administration of trial 
medication. The following visits are scheduled: 
Table 2 Visit schedule 
Visit 
1 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
Time (days) 
Max -28 
0 
1 
7 
8 
14 
21 
35 
Visit window 
(days) 
- 
- 
+ 1 
+ 1 
+ 1 
± 2 
± 3 
± 3 
 
The visits will be labelled by screening, baseline and scheduled day. Categorical data will be 
summarized by treatment, using number and percentages of subjects. For calculation of percentages, 
the denominator will either be the number of subjects in the analysis set or the number of subjects in 
the analysis set with non-missing values. Continuous data will be presented using the number of 
subjects (n), mean, standard deviation (SD), median, lower quartile, upper quartile, minimum and 
maximum. Both the absolute values and the change from baseline will be presented. 


Sponsor:  
Drug/Project:  
Pharmacosmos A/S 
Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
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Descriptive statistics for all endpoints will be presented by treatment group and day, if applicable, 
using observed cases, i.e. no imputation of missing data will be performed. Missing data for time to 
event endpoints is handled using censoring. 
Values below lower limit of quantification (LLOQ) will be substituted by 0.5*LLOQ in tables and figures. 
In the following, strata are defined as Type of underlying disease: women with IDA due to 
gynaecological blood losses (yes or no) and screening s-phosphate level (< 3.5 mg/dL or ≥ 3.5 mg/dL). 
5.1.1 Key methods 
The following two methods will be used for several endpoints. 
Cochran-Mantel-Haenszel 
Iron isomaltoside will be compared to ferric carboxymaltose by estimation of the risk difference of a 
parameter and the associated 95 % Newcombe CI adjusting for strata using the Cochran-Mantel-
Haenszel (CMH) method. The risk difference, 95 % CIs and the corresponding p-value will be 
presented. 
Mixed Models for Repeated Measures  
Change in a parameter from baseline will be analysed using a Restricted Maximum Likelihood (REML)-
based Mixed Models for Repeated Measures (MMRM) approach. All subjects with post-baseline data 
will be included with their observed data. Subjects without post-baseline values will have change from 
baseline set to 0 at the first post-baseline visit.  
The model will include the fixed, categorical effects of treatment (iron isomaltoside and ferric 
carboxymaltose), strata, day, treatment-by-day interaction, as well as the continuous, fixed covariates 
of the parameters baseline value and baseline value-by-day interaction. An unstructured covariance 
matrix will be used to model the within-subject errors. If, unexpectedly, this analysis fails to converge, 
the following structures will be applied, in the following order; first-order ante-dependence, 
heterogeneous compound symmetry, compound symmetry. The comparisons will be the contrasts 
between iron isomaltoside and ferric carboxymaltose at the day or days in question based on the least 
squares means for the treatment-by-day interaction effect. The estimated mean differences based on 
this model will be reported with two-sided symmetric 95 % CIs and corresponding p-values. The 
Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. 
5.2 Subject Disposition 
A summary table of the subject disposition by planned treatment and overall and also by strata will be 
prepared with number and percentage of subjects in the following categories (and sub-categories): 
 
Screened, randomised and exposed subjects 
 
Analysis sets (ITT,safety, FAS and PP analysis set) 
 
End of study:  
o Completed 
o Withdrawn 


Sponsor:  
Drug/Project:  
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 
Reason for withdrawal: 
o Adverse event 
o Screen failure 
o Withdrawal by subject 
o Lost to follow-up 
o Protocol deviation 
o Investigator decision 
o Sponsor request 
o Other 
All randomised subjects by planned treatment will be used as denominator in the table.  
All disposition information will be listed. Screening failures and major protocol deviations will be listed 
by subject. Visits outside visit window will be listed. Subjects with at least three visits outside visit 
window will be listed. 
5.3 Baseline Characteristics and Demographics 
Demographics and baseline characteristics consist of age, gender, race, ethnicity, height, smoking 
habits, and strata. Demographics and baseline characteristics will be listed and summarized using 
descriptive statistics, by treatment, and by treatment and strata for the safety and if different, then 
also for the ITT analysis set. 
5.4 Medical History and IDA-Underlying Disease 
Relevant medical history is collected. Changes in medical history will be recorded at the subsequent 
visits during the trials. Worsening of symptoms or diseases is recorded as AEs. 
Medical history and IDA-underlying disease will be summarised and will also be listed by subject for 
the safety analysis set. 
6 Exposure and Other Dosing Information 
All descriptive data will be presented by treatment for the safety analysis set. 
6.1 Exposure 
Dose and compliance will be summarised. Planned and actual dose in mg, number of doses and 
compliance will be presented. Treatment interruptions and restarts will be listed. 
Compliance will be calculated as 
100∗𝑎𝑐𝑡𝑢𝑎𝑙 𝑑𝑜𝑠𝑒
𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 
All information will be listed. Also subjects out of the treatment compliance range of 80-120 % will be 
listed. 
6.2 Concomitant medication 
Concomitant medication is recorded at baseline and during the trial.  


Sponsor:  
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Concomitant medication will be summarised and will also listed by subject. Subjects using prohibited 
medication during the trials will be listed. 
7 Statistical Methodology 
The safety analysis set will be used for all safety endpoints and the ITT analysis set will be used for all 
efficacy endpoints if nothing else is stated. 
7.1 Analysis and Presentation of the Primary Endpoint 
The primary endpoint is  
 
Incidence of hypophosphatemia, defined as s-phosphate < 2 mg/dL, at any time from baseline 
to day 35. 
7.1.1 Incidence of hypophosphatemia at any time from baseline to day 35 
The incidence of hypophosphatemia at any time from baseline to day 35 will be tabulated and exact 
95 % CI will be estimated for each treatment group.  
Iron isomaltoside will be compared to ferric carboxymaltose by CMH as described in section 5.1.1..  
Two sensitivity analyses will be presented: 
 
The treatment groups will be compared by a logistic regression model with treatment and 
strata as factors and baseline s-phosphate as covariate. The estimated treatment ratio of iron 
isomaltoside versus ferric carboxymaltose will be presented with 95 % CIs and corresponding 
p-value.  
 
The treatment groups will also be compared by Fisher’s exact tests where the p-value will be 
presented 
All subjects in the safety analysis set will be included in the analyses.  
If very few subjects are present in one of the strata, similar analyses will be presented, but where two 
of the categories are grouped. 
The number and percentage of subjects with hypophosphatemia will be presented by treatment and 
visit, and by treatment, strata and visit using bar chart. The s-phosphate data will be listed by subject. 
Subjects with s-phosphate < 2 mg/dL will be listed. 
7.2 Analysis and Presentation of the Secondary Safety Endpoints 
The secondary safety endpoints are the following: 
 Incidence of s-phosphate < 1.0 mg/dL at any time from baseline to day 35 
 Time with hypophosphatemia (i.e. time with s-phosphate < 2.0 mg/dL) from baseline to day 35 
 Proportion of hypophosphatemia at day 35 
 Absolute [∆] and relative [%] changes in s-phosphate from baseline to day 1, 7, 8, 14, 21, and 35 
 Fractional phosphate urinary excretion at day 1, 7, 8, 14, 21, and 35 
 Change in iFGF23, cFGF23, vitamin D (25, 1.25, 24.25), PTH, and ionized calcium from baseline 
to day 1, 7, 8, 14, 21, and 35 
 Type and incidence of AEs  
 Serious or severe hypersensitivity reaction starting on or after the first dose of randomized 
treatment (i.e. treatment emergent). The hypersensitivity terms are defined as standardised 
Medical Dictionary for Regulatory Activities query (SMQ) terms (including four additional terms) 
in the protocol in Appendix A. 


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7.2.1 Incidence of s-phosphate < 1.0 mg/dL at any time from baseline to day 35 
The incidence of s-phosphate < 1.0 mg/dL at any time from baseline to day 35 will be analysed and 
presented like the primary endpoint using CMH as described in section 5.1.1 and the sensitivity 
analyses described in section 7.1.1. 
The number and percentage of subjects with s-phosphate < 1.0 mg/dL will be summarised by 
treatment and day. The s-phosphate data will be listed by subject as mentioned in section 7.1.1. 
7.2.2 Time with hypophosphatemia from baseline to day 35 
The time with s-hypophosphatemia will be calculated as the actual number of days from the first day 
where s-phosphate < 2 mg/dL until the first day where s-phosphate ≥ 2 mg/dL. If the subject does not 
reach s-phosphate ≥ 2 mg/dL then it will be treated as censored at day 35. If a subject experiences 
more than one period with s-phosphate < 2 mg/dL, the longest period will be used in the analysis.  
The time with hypophosphatemia from baseline to day 35 will be presented by a Kaplan-Meier plot. 
The treatment groups will be compared by a log-rank test. Only subjects who have one or more s-
phosphate value(s) < 2 mg/dL will be included.  
Plots including the Kaplan-Meier curves, log-rank test and median time with hypophosphatemia will 
be presented overall by treatment. All periods will be presented by subject in a swimmer plot. 
7.2.3 Proportion of hypophosphatemia at day 35 
The proportion of subjects with hypophosphatemia at day 35 will be analysed and presented like the 
primary endpoint using the CMH described in section 5.1.1. for observed cases only. 
The number and percentage of subjects with hypophosphatemia will be summarised by treatment and 
listed by subject as described in section 7.1.1. 
7.2.4 Absolute [∆] and relative [%] changes in s-phosphate from baseline to day 
1, 7, 8, 14, 21, and 35 
The change in s-phosphate from baseline to day 1, 7, 8, 14, 21, and 35 will be analysed and presented 
using the MMRM described in section 5.1.1. 
The change in s-phosphate will be summarised by treatment and visit, and mean plot of absolute 
change over time will be presented.  
The percentage change in s-phosphate from baseline to day 1, 7, 8, 14, 21, and 35 will be analysed and 
presented using the MMRM described in section 5.1.1.  
The percentage change in s-phosphate will be summarised by treatment and visit, and mean plot of 
percentage change over time will be presented.  
7.2.5 Fractional phosphate urinary excretion at day 1, 7, 8, 14, 21, and 35 
The fractional phosphate urinary excretion at day 1, 7, 8, 14, 21, and 35 including change from 
baseline will be summarised by treatment and visit. All data will be listed by subject. 
 
 


Sponsor:  
Drug/Project:  
Pharmacosmos A/S 
Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
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7.2.6 Change in iFGF23, cFGF23, vitamin D (25, 1.25, 24.25), PTH, and ionized 
calcium from baseline to day 1, 7, 8, 14, 21, and 35 
The change in each of the following 7 endpoints  
 
iFGF23 
 
cFGF23 
 
vitamin D (25) 
 
vitamin D (1.25) 
 
vitamin D (24.25) 
 
PTH 
 
ionized calcium  
from baseline to day 1, 7, 8, 14, 21, and 35 will be analysed using the MMRM described in section 
5.1.1..  
A summary of absolute values and change from baseline by treatment and visit, and mean plots of 
change over time will be presented for each endpoint. All data will be listed by subject. 
7.2.7 Type and incidence of AEs  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) current version. AEs 
will be regarded as treatment emergent AEs (TEAEs) if they either occur after administration of 
randomised treatment or occur before and are worsened after randomised treatment. Related or 
possible related AEs are defined as Adverse Drug Reactions (ADRs). 
Summary by system organ class (SOC) and preferred term (PT) indicating number and percentage of 
subjects and number of events will be presented for: 
 
TEAEs 
 
Treatment emergent serious adverse events (SAEs) 
 
TEAEs by severity (mild, moderate, severe) 
 
TEAEs by relationship (related, possible, unlikely, not related, unknown) 
An overall summary table by treatment will present number of events, number of subjects, and 
proportion of subjects reporting Non-TEAEs, TEAEs, Treatment emergent SAEs, Fatal SAEs, ADRs, 
Suspected Unexpected Serious Adverse Reaction (SUSARs), TEAEs by severity, and TEAEs by outcome. 
Number of subjects who experience an ADR including SUSARs will be compared between treatment 
groups using Fisher's Exact test.  
Non-treatment emergent SAEs for subjects who never received trial drug will be listed.  
The following lists will be made for the safety analysis set: 
 
Non-treatment emergent AEs and SAEs 
 
TEAEs  
 
Treatment emergent SAEs 
 
ADRs 
 
AEs leading to dose reduction or withdrawal from treatment 
 
Fatal SAEs 


Sponsor:  
Drug/Project:  
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7.2.8 Serious or severe hypersensitivity reaction 
The hypersensitivity reactions are defined by the SMQs but including four additional terms, see the 
protocol Appendix A.  
The number of events, number of subjects, and proportion of subjects reporting serious or severe 
hypersensitivity reaction starting on or after the first dose of randomized treatment will be 
summarised by SMQ and PT. Serious or severe hypersensitivity reactions will be listed. 
7.3 Analysis and Presentation of the Secondary Efficacy Endpoints 
The secondary efficacy endpoints are  
 
Change in Hb per gram iron in dose of randomised treatment from baseline to day 1, 7, 8, 14, 
21, and 35 
 
Change in s-ferritin from baseline to day 1, 7, 8, 14, 21, and 35 
 
Change in TSAT from baseline to day 1, 7, 8, 14, 21, and 35 
7.3.1 Change in Hb per gram iron 
The absolute change in Hb per gram iron in planned dose of randomised treatment from baseline to 
day 1, 7, 8, 14, 21, and 35 will be analysed and presented using the MMRM described in section 5.1.1. 
for ITT analysis set and FAS.   
The absolute change in Hb per gram iron in actual dose of randomised treatment from baseline to day 
1, 7, 8, 14, 21, and 35 will be analysed and presented using the MMRM described in section 5.1.1. for 
the PP analysis set. 
The absolute values and change from baseline will be summarised by treatment and, and mean plot of 
change over time will be presented. All data will be listed by subject. 
7.3.2 Change in s-ferritin 
The absolute change in s-ferritin from baseline to day 1, 7, 8, 14, 21, and 35 will be analysed and 
presented using the MMRM described in section 5.1.1. 
The absolute values and change from baseline will be summarised by treatment and visit, and mean 
plot of change over time will be presented. All data will be listed by subject. 
7.3.3 Change in TSAT  
The absolute change in TSAT from baseline to day 1, 7, 8, 14, 21, and 35 will be analysed and 
presented using the MMRM described in section 5.1.1. 
The absolute values and change from baseline will be summarised by treatment and visit, and mean 
plot of change over time will be presented. All data will be listed by subject. 
7.4 Analysis and Presentation of Other Safety Assessments 
Other safety assessments are 
 
Vital signs and weight 
 
Electrocardiogram (ECG) 
 
Standard laboratory data 
 
Physical examination 


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7.4.1 Vital signs and weight 
Vital signs, i.e. heart rate, and systolic and diastolic blood pressure, is assessed at baseline and for 
ferric carboxymaltose also at day 7. Vital signs will be summarised by treatment, visit and time point 
(before/during/5-15 minutes after infusion /20-40 minutes after infusion), including change from pre- 
infusion at the treatment visit. Weight is assessed at baseline and day 35 and will be summarised 
including change from baseline by treatment and visit. All data will be listed by subject. 
7.4.2 ECG 
A standard 12 lead ECG is recorded. All ECGs will be evaluated as normal or abnormal, and if abnormal 
then also evaluated as clinical significant or not. At treatment visits, which is at baseline and for ferric 
carboxymaltose also at day 7, two ECGs are recorded; one before administration of the trial drug and 
one approximately 30 minutes after start of the dosing. Only one ECG is recorded at the other visits. 
The 3 categories for the standard 12 lead ECG will be summarised by treatment, visit and time point. 
Shift tables of ECG before and after treatment will be presented at the treatment visits. All data will be 
listed by subject. 
7.4.3 Laboratory data 
Eligibility laboratory assessments are performed at screening. Safety laboratory data is assessed at 
baseline and day 1, 7, 8, 14, 21, and 35. Vitamin E is assessed at baseline. 
The number and percentage of subjects and number of events will be presented by visit for subjects 
experiencing treatment emergent clinically significant laboratory values. In addition, laboratory data 
will be plotted using boxplots by treatment and visit. 
Values outside normal ranges will be flagged. Laboratory reference ranges will be listed. All safety 
laboratory data will be listed by subject, including eligibility and exploratory laboratory assessments. 
7.4.4 Physical examination 
A physical examination is performed at baseline and day 35 based upon the Investigator’s judgement 
and might include Head-Eyes-Ear-Nose-Throat, Cardiovascular system, Respiratory system, Nervous 
system, Gastrointestinal system, Musculoskeletal system, Urogenital system, Dermatology system, 
and Others if required.  
A summary table of physical examination will be presented by body system and visit. All data will be 
listed by subject. 
7.5 Exploratory endpoints 
The exploratory endpoints are the following:  
 
Change in biochemical bone/muscle markers: 
o Serum N-terminal Propeptide of Type I Collagen (PINP) 
o Carboxy-terminal Collagen Crosslinks (CTx) 
o Plasma alkaline phosphatase (bone specific) 
o Plasma alkaline phosphatase (total) 
o Creatine kinase 
from baseline to day 1, 7, 8, 14, 21, and 35 
 
Change in Hb from baseline to day 1, 7, 8, 14, 21, and 35 


Sponsor:  
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Monofer 
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 
Change in fatigue symptoms from baseline to day 14 and 35 measured by the Functional 
Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
 
Change in QoL from baseline to day 14 and 35 measured by Short Form - 36 (SF-36) 
questionnaire 
 
Change in bone pain from baseline to day 14 and 35 measured on a Visual Analogue Scale (VAS) 
scale 
 
Change in muscle strength from baseline to day 14 and 35 measured by grip strength 
 
Change in 
o Upper limb proximal muscle function measured by the "1 kg arm lift" test 
o Lower limb proximal muscle function measured by the "30 sec chair stand" test 
from baseline to day 14 and 35 
 
Change in 
o respiratory muscles strength measured by Maximal Inspiratory Pressure (MIP) 
o respiratory muscles strength measured by Maximal Expiratory Pressure (MEP) 
from baseline to day 14 and 35 
7.5.1 Change in biochemical bone/muscle markers  
Change in Biochemical bone/muscle markers 
 
Serum N-terminal PINP 
 
CTx 
 
Plasma alkaline phosphatase (bone specific) 
 
Plasma alkaline phosphatase (total) 
 
Creatine kinase 
from baseline to day 1, 7, 8, 14, 21, and 35 will be analysed and presented using the MMRM described 
in section 5.1.1.. A summary of absolute values and change from baseline by treatment and visit will 
be presented for each endpoint. All data will be listed by subject. 
7.5.2 Change in Hb 
The absolute change in Hb from baseline to day 1, 7, 8, 14, 21, and 35 will be analysed and presented 
using the MMRM described in section 5.1.1. 
The absolute values and change from baseline will be summarised by treatment and, and mean plot of 
change over time will be presented. All data will be listed by subject. 
7.5.3 Change in fatigue symptoms 
The FACIT fatigue scale consists of 13 items ranging from 0 (not at all) to 4 (very much). All items, 
except items An5 and An7 are reversed scored from 4 to 0. The total score range is 0-52. A score of 
less than 30 indicates severe fatigue, and the higher the score, the better QoL. If more than 50 % of 
the items for a subject at a given visit are missing, the total score will not be calculated. If less than 50 
% (6 out of 13) of the items are missing, the scores are prorated using the average of the other 
answers in the scale. 
𝑇𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒= 𝑆𝑢𝑚 𝑜𝑓 𝑖𝑛𝑑𝑖𝑣𝑖𝑑𝑢𝑎𝑙 𝑠𝑐𝑜𝑟𝑒𝑠 𝑥 13
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑡𝑒𝑚𝑠 𝑎𝑛𝑠𝑤𝑒𝑟𝑒𝑑 


Sponsor:  
Drug/Project:  
Pharmacosmos A/S 
Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
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Trials: 
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P-Monofer-IDA-05 
 
 
 
 
 
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Change in fatigue symptoms from baseline to day 14 and 35 measured by the FACIT Fatigue Scale will 
be considered a continuous measure and will be analysed and presented using the MMRM described 
in section 5.1.1. 
A summary of absolute values and change from baseline by treatment and visit will be presented. All 
data will be listed by subject. 
7.5.4 Change in QoL 
The SF-36 survey consists of the following eight scales with a total of 35 items: 
 
General health (GH, based on 5 items) 
 
Physical function (PF, based on 10 items) 
 
Physical role limitations (RP, based on 4 items) 
 
Emotional role limitations (RE, based on 3 items) 
 
Social function (SF, based on 2 items) 
 
Bodily pain (BP, based on 2 items) 
 
Vitality (VT, based on 4 items) 
 
Mental health (MH, based on 5 items), 
plus, a self-evaluated transition (SET) scale (1 item). 
Ten of the 35 items should be reversed to ensure the highest number indicates best possible health. 
The 10 items are GH item 1, 11b, and 11d, SF item 6, BP item 7 and 8, VT item 9a and 9e, and MH item 
9d and 9h (please refer to the SF-36 questionnaire for the numbering of items). GH item 1 and BP item 
7 and 8 will be scored using recommended scoring (please refer to the SF-36 Users Guide, Appendix 
D). Note: Item 7 and 8 belongs to the same scale, but of different length. To obtain the same length, 
the first category in item 8, “Not at all” are split into two, by those who answers “None” in item 7 and 
those who answer “very mild” to “very severe” in item 7. The combination “Not at all” and “None” is 
then the best possible category with a raw score of 6. 
The items within each of the eight scales are then summarized to achieve the Raw Scores. The Raw 
Scores are transformed in to a scale from 0 to 100 using the following formula: 
Transformed scale score = ((Actual raw score-lowest possible raw score)) / (possible raw score range) x 
100. 
The transformed scale scores are then further transformed into a z-score by subtracting each of the 
eight scale’s 2009 U.S. general population mean from the score and then divide by the given scales 
standard deviation.  
Each of the z-scores can then be transformed into T-scores with mean 50 and SD 10, i.e. each z-score is 
multiplied with 10 and then 50 is added. 
Furthermore, a Physical Component Summary (PCS) and a Mental Component Summary (MCS) are 
derived, both based on the eight z-scores. For deriving PCS each of the z-scores is multiplied by its 
respective physical factor score coefficient and then the eight products are summarized. Similar the 
MCS are calculated using the mental factor score coefficients. The two scores are transformed into T-
scores by multiplying by 10 and then adding 50. Note: a PCS and a MCS score can be computed if at 
least seven scales have been scored, one of which being the PF and MH scale, respectively. 
Change in the eight health domain T-scores, and PCS T-score and MCS T-score from baseline to day 14 
and day 35 will be considered continuous measures and will be analysed and presented using the 
MMRM described in section 5.1.1. 
A summary of absolute values and change from baseline by treatment and visit will be presented. All 
data will be listed by subject. 
Missing items will be imputed, please refer to section 7.6 for details. 


Sponsor:  
Drug/Project:  
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Monofer 
Date:                             12MAR2018 
Version:                              Final 2.0 
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7.5.5 Change in bone pain 
Bone pain is measured on a Visual Analogue Scale (VAS) and recorded on a scale ranging from 0 to 
100, where a higher score indicates greater pain intensity. 
Change in bone pain from baseline to day 14 and day 35 will be considered continuous and will be 
analysed and presented using the MMRM described in section 5.1.1. A summary of absolute values 
and change from baseline by treatment and visit will be presented. All data will be listed by subject. 
7.5.6 Change in muscle strength 
Muscle strength is measured by grip strength in kg with Jamar hand dynamometer. Three readings for 
each hand are done and the best of the six readings is recorded. Change in muscle strength from 
baseline to day 14 and 35 is considered continuous and will be analysed and presented using the 
MMRM described in section 5.1.1. A summary of absolute values and change from baseline by 
treatment and visit will be presented. All data will be listed by subject. 
7.5.7 Change in upper and lower limb proximal muscle function 
Upper limb proximal muscle function is measured by the "1 kg arm lift" test, where the number of times 
the weight is lifted above the head in a 30 second period is recorded for each arm individually and the 
final score is the mean of the two measurements.  
Lower limb proximal muscle function is measured by the "30 sec chair stand" test, where the number 
of times that the subject rises to a full stand from the seated position with arms folded within 30 s is 
recorded. 
Change in 
 
Upper limb proximal muscle function  
 
Lower limb proximal muscle function  
from baseline to day 14 and 35 is considered continuous and will be analysed and presented using the 
MMRM described in section 5.1.1. A summary of absolute values and change from baseline by 
treatment and visit will be presented. All data will be listed by subject. 
7.5.8 Change in respiratory muscles strength 
Maximal Inspiratory Pressure (MIP) reflects the strength of the diaphragm and other inspiratory 
muscles. Maximal Expiratory Pressure (MEP) reflects the strength of the abdominal muscles and other 
expiratory muscles. Both are measured in cmH2O as continuous variables by a Micro Respiratory 
Pressure Meter (MicroRPM). 
Change in 
 
MIP 
 
MEP 
from baseline to day 14 and 35 will be analysed and presented using the MMRM described in section 
5.1.1. 
A summary of absolute values and change from baseline by treatment and visit will be presented. All 
data will be listed by subject. 
7.6 Handling of Missing Values 
For the primary endpoint, the first post-baseline s-phosphate measurement is taken at day 1, hence, 
very few missing values are expected. If there are subject(s), for whom no post-baseline s-phosphate 


Sponsor:  
Drug/Project:  
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Monofer 
Date:                             12MAR2018 
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measurement(s) are available, these subjects will be set as having s-phosphate < 2 mg/dL in the 
primary analysis.  
In the MMRM analyses subjects without post-baseline values will have change from baseline set to 0 
at the first post-baseline visit.  
Missing values for the SF-36 questionnaires will be handled using the Half-scale rule, i.e. a score will be 
calculated if at least 50 % of the items are answered by a subject at a given visit. The missing items will 
be imputed by the average score of the non-missing items. The PCS score can be computed if at least 
seven scales have been scored, one of which being the PF scale; similarly, the MCS score can be 
computed if at least seven scales have been scored, one of which being the MH scale. 
Besides from this no imputation of missing values will be applied. 
7.7 Multiplicity adjustments 
These trials are two-armed with one primary endpoint, so no multiplicity exists. For the secondary 
endpoints, treatment differences, CIs and corresponding p-values are presented, but no adjustment 
for multiplicity will be done.  
7.8 Sub-group and Centre Effects 
No sub-group analyses are planned. The trials are multi centre trials, but no adjustment for centre 
effects is planned. 
7.9 Interim Analysis 
No interim analysis is planned. 
7.10 Combined Analysis of P-Monofer-IDA-04 and P-Monofer-IDA-05 
The two trials P-Monofer-IDA-04 and P-Monofer-IDA-05 is planned to run in parallel and the same 
dosing regimens are investigated. 
Pooled analyses of primary and secondary safety and efficacy endpoints will be performed for the two 
trials. 
The analyses will be performed similar to those specified for the individual trials, with the addition of 
trial in the models, i.e. the CMH method will be stratified by strata and trial and the MMRM will 
include the fixed, categorical effects of trial, treatment, strata, day, treatment-by-day interaction.  
Also, the overall incidence of TEAEs and ADRs will be compared between the treatment groups using 
Fisher's Exact test. 
The CSRs will be finalised without the combined analyses, which will be done when both trials are 
finalised. The combined analysis will be included as an appendix to the CSRs. 
8 Deviations from Protocol 
 
If very few subjects are present in one of the strata, similar analyses to the primary analysis 
will be presented as additional analyses, where two of the categories are grouped. 


Sponsor:  
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Date:                             12MAR2018 
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 
The wording “the proportion of subjects with hypophosphatemia” is used for a secondary 
endpoint where the intention was to evaluate on “the incidence of hypophosphatemia”. 
 
In the description of how time with hypophosphatemia from baseline to day 35 is presented it 
is stated “All periods will be tabulated”. This will be presented by a swimmer lane plot.  
 
In the description of combined analysis of P-Monofer-IDA-04 and P-Monofer-IDA-05 it is 
specified “The analyses will be performed similar to those specified for the individual trials, 
with the addition of trial in the models, i.e. the strata in the Cochran-Mantel-Haenszel method 
will be a combination of baseline s-phosphate and trial”. Here the strata to be used is type of 
underlying disease and screening s-phosphate level together with trial and not baseline s-
phosphate together with trial as specified in the protocol. 
 
The secondary efficacy endpoint Change in Hb from baseline to day 1, 7, 8, 14, 21, and 35 will 
be evaluated per gram iron as described in section 7.3.1. in order to align with Hb data 
included in the label of another IV iron product (Ferumoxytol). Change in Hb will also be 
evaluated based on full iron dose as an exploratory endpoint. 
 
The exploratory endpoint Change in Pyridinoline in the urine from baseline to day 1, 7, 8, 14, 
21, and 35 has been omitted since it was an exploratory endpoint with a limited value, which 
showed to be quite challenging to both site and subjects due to very specific requirements of 
the urine sample. Instead the focus will be on the bone marker CTx. 
9  Software 
All statistical calculations described in this SAP will be done by 
 using SAS, release 9.4 or 
later (SAS Institute, Cary, NC, USA). SF-36 will be scored using QualityMetric Health Outcome Scoring 
Software version 5.1. 
10 Reference List 
Not applicable.