Conditions: Iron Deficiency Anaemia Iron Deficiency Anemia
Keywords: Iron Deficiency Anaemia Iron Deficiency Anemia IDA Intravenous iron replacement therapy Iron isomaltoside Ferric derisomaltose Monofer Monoferric Monover Monofar Monoferro
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1512
Healthy volunteers: no

Brief summary:
Evaluate safety and efficacy of iron isomaltoside/ferric derisomaltose (Monofer®/Monoferric®) compared with iron sucrose (Venofer®), in subjects diagnosed with IDA.

Detailed description:
IDA is highly prevalent condition in subjects with cancer and gastrointestinal diseases such as inflammatory bowel diseases, menstruating or pregnant women, and subjects who have undergone bariatric procedure or surgery. IDA can have a substantial medical and quality of life (QoL) burden. Treatment of subjects diagnosed with IDA includes controlling the bleeding and replenishing lost iron.

This study was designed to evaluate the safety and efficacy of iron isomaltoside/ferric derisomaltose compared with iron sucrose in subjects diagnosed with IDA. In a subfraction of 35 subjects treated with iron isomaltoside/ferric derisomaltose, ECG and iron will be frequently measured.

The study subjects received either a single intravenous (IV) dose of iron isomaltoside/ferric derisomaltose (1000 mg at baseline) or iron sucrose (200 mg IV injections at baseline and repeated according to standard practice or physician choice up to a maximum of five times within the first two weeks starting at baseline; a cumulative dose of 1000 mg was recommended). The study subjects were monitored for up to 8 weeks from baseline.

Arms:
arm 1: Administered IV arm 2: Administered IV

Interventions: intervention 1: Iron isomaltoside/ferric derisomaltose intervention 2: Iron sucrose
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 set to 1000 mg. The dose was diluted in 100 mL 0.9 % sodium chloride (100 mL bags) and administered as a single IV infusion over approximately 20 minutes. intervention 2: Iron sucrose (Venofer®; 20 mg elemental iron/mL) was the comparator in this trial.

Iron sucrose was administered as 200 mg undiluted IV injections over approximately 2-5 minutes and repeated according to standard practice or physician choice up to a maximum of five times within the first two weeks starting at baseline. A cumulative dose of 1000 mg was recommended.

Protocol document:
Prot_000.pdf: 
Trial ID: 
P-Monofer-IDA-03 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
14 June 2017 
 
 
Confidential 
 
 Page 1 of 59 
 
CLINICAL TRIAL PROTOCOL 
A phase III, randomised, open-label, comparative safety and efficacy trial of in-
travenous iron isomaltoside (Monofer®) and iron sucrose in subjects with iron 
deficiency anaemia who are intolerant or unresponsive to oral iron therapy or in 
whom the haemoglobin measurement in Investigators' opinion were sufficiently 
low as to require rapid repletion of iron stores to minimize the risk of receiving a 
blood transfusion 
 
Trial ID: 
P-Monofer-IDA-03 
 
 
 
Sponsor: 
Pharmacosmos A/S, Rørvangsvej 30, DK-4300 Holbæk, Denmark 
 
Protocol Version: 
Version 1.0, 7 June 2016 
 
Protocol Version: 
Version 2.0 (amendment 1), 26 July 2016 
 
Protocol Version: 
Version 3.0 (amendment 2), 14 June 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: 
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Protocol Version: 
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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: 
 Den-
mark  
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-03 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
14 June 2017 
 
 
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 Page 3 of 59 
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-03 
 
Protocol Version: 
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Date of Document : 
14 June 2017 
 
 
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PROTOCOL SUMMARY 
Trial title  
A phase III, randomised, open-label, comparative safety and efficacy trial of intravenous iron 
isomaltoside (Monofer®) and iron sucrose in subjects with iron deficiency anaemia who are 
intolerant or unresponsive to oral iron therapy or in whom the haemoglobin measurement in 
Investigators' opinion were sufficiently low as to require rapid repletion of iron stores to min-
imize the risk of receiving a blood transfusion 
Trial design 
The trial is a randomised, comparative, open-label trial. Subjects with iron deficiency anae-
mia (IDA) who are intolerant or unresponsive to oral iron therapy or in whom the screening 
haemoglobin (Hb) measurement in Investigators' opinion were sufficiently low as to require 
rapid repletion of iron stores to minimize the risk of receiving a blood transfusion will be 
randomised 2:1 to 1 of the following treatment groups: 
 Group A: iron isomaltoside 1000 (Monofer®, Pharmacosmos, Holbæk, Denmark, 
termed iron isomaltoside in the following)  
 Group B: iron sucrose (Venofer®) 
Phase of trial 
The trial is a phase III trial. 
Background  
IDA is highly prevalent in subjects with cancer and gastrointestinal diseases such as inflam-
matory bowel diseases, menstruating or pregnant women, and subjects who have undergone 
bariatric procedure. IDA can have a substantial medical and quality of life (QoL) burden on 
the subjects, and treatment of these subjects includes controlling the bleeding and replenish-
ing 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.  
Iron sucrose is a widely used parenteral iron product and therefore this product has been cho-
sen as comparator in this trial which is planned to evaluate the safety and efficacy of intrave-
nous (IV) iron isomaltoside compared to IV iron sucrose in subjects with IDA who are intol-
erant or unresponsive to oral iron therapy or in whom the Hb measurement in the Investiga-
tors' opinion were sufficiently low as to require rapid repletion of iron stores to minimize the 
risk of receiving a blood transfusion. 
Objectives 
The primary safety objective of the trial is to evaluate the safety of IV iron isomaltoside 
compared to iron sucrose in subjects with IDA when oral iron preparations are ineffective or 
cannot be used or in whom the screening Hb measurement in Investigators' opinion were suf-
ficiently low as to require rapid repletion of iron stores. 
The primary efficacy objective of the trial is to evaluate and compare the effect of iron iso-
maltoside to iron sucrose in its ability to increase Hb in subjects with IDA when oral iron 


Trial ID: 
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preparations are ineffective or cannot be used or in whom the screening Hb measurement in 
Investigators' opinion were sufficiently low as to require rapid repletion of iron stores. 
The secondary efficacy objective of the trial is to evaluate and compare the effect of iron 
isomaltoside to iron sucrose on:  
 Other relevant iron related biochemical parameters  
 Fatigue symptoms 
 Pharmacoeconomics 
Endpoints 
The co-primary safety endpoint is serious or severe hypersensitivity reaction starting on or 
after the first dose of randomised 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 Appendix A. 
 
The adverse events (AEs) will be adjudicated in a blinded fashion by an independent Clinical 
Endpoint Adjudication Committee (CEAC) (described in a separate adjudication charter). 
The specified definition of adjudicated endpoints will be given in the charter. 
 
The secondary safety endpoints are the following: 
 Composite cardiovascular AEs starting on or after the first dose of randomised treat-
ment (i.e. treatment-emergent). The adjudicated composite AEs includes the follow-
ing: 
 Death due to any cause 
 Non-fatal myocardial infarction 
 Non-fatal stroke 
 Unstable angina requiring hospitalization 
 Congestive heart failure requiring hospitalization or medical intervention 
 Arrhythmias 
 Hypertension 
 Hypotension 
 
The AEs will be adjudicated in a blinded fashion by an independent CEAC (described 
in a separate adjudication charter). The specified definition of adjudicated endpoints 
is given in Appendix B. 
 Time to first composite cardiovascular safety AE  
 Serum (s-) phosphate < 2 mg/dL at any time from baseline to weeks 1, 2, 4, or 8 
 
Physical examinations and measurements of vital signs, height, weight, and safety laboratory 
parameters will be measured as part of standard safety assessments. Furthermore, intensive 
electrocardiogram (ECG) monitoring for evaluation of QTc prolongations will be performed 
in 35 subjects. 


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The co-primary efficacy endpoint is change in Hb from baseline to week 8. 
The secondary efficacy endpoints are the following:  
 Hb increase of ≥ 2 g/dL from baseline to weeks 1, 2, 4, or 8 
 Time to change in Hb ≥ 2 g/dL 
 Hb level of > 12 g/dL at any time from week 1 to week 8 
 Increase in Hb concentration ≥ 2 g/dL at any time from week 1 to week 8 
 S-ferritin level of ≥ 100 ng/mL and transferrin saturation (TSAT) of 20-50 % at any 
time from week 1 to week 8 
 Change in concentrations of Hb from baseline to weeks 1, 2, and 4 
 Change in concentrations of s-ferritin, TSAT, and s-iron from baseline to weeks 1, 2, 
4, and 8 
 Change in fatigue symptoms from baseline to weeks 1, 2, and 8 measured by the 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
 Resources used by the subject (per visit) and health care staff (per administration) 
measured by the ISDR questionnaire and health care resource use questionnaire, re-
spectively  
Safety assessments  
The trial includes the following safety assessments: 
 AEs will be collected and evaluated for relatedness, severity, seriousness, and expect-
edness. They will be reported to authorities and followed-up according to internation-
al and local requirements. Events will be adjudicated in a blinded fashion by an inde-
pendent CEAC (described in a separate adjudication charter) 
 Intensive ECG monitoring for evaluation of QTc prolongations in 35 subjects 
 Physical examinations, measurements of vital signs, height, weight, and safety labora-
tory parameters 
Efficacy assessments 
The trial includes the following efficacy assessments: 
 Measurements of Hb, s-ferritin, TSAT, and s-iron  
 FACIT Fatigue Scale 
 ISDR questionnaire and health care resource use questionnaire  
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 10-15 weeks and each 
subject will attend 6-12 visits (3 visits are conducted by telephone). 
Subject population 
Subjects, who fulfil the following eligibility criteria, will be included. 
Inclusion criteria: 


Trial ID: 
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A subject will be eligible for inclusion in the trial if he/she fulfils the following criteria: 
1. Men or women ≥ 18 years  
2. Subjects having IDA caused by different aetiologies* such as abnormal uterine bleed-
ing, gastrointestinal diseases, cancer, bariatric procedures (gastric bypass operations), 
and other conditions leading to significant blood loss.  
3. Subjects with: 
a. Up to 1 month run-in phase indicating intolerance or lack of response to oral iron 
or  
b. A documented history of intolerance to oral iron therapy to at least one month of 
ordinated oral iron therapy within 9 months** prior to trial enrolment or  
c. Screening Hb measurement in Investigators' opinion was sufficiently low as to re-
quire rapid repletion of iron stores to minimize the risk of eventual blood transfu-
sion*** 
4. Hb ≤ 11 g/dL 
5. TSAT < 20 % 
6. S-ferritin < 100 ng/mL 
7. Willingness to participate and signing the informed consent form 
*The aetiology for IDA should be documented in the medical history and verified in the 
source document. 
**The intolerance to oral iron treatment within the last 9 months should be documented in the 
medical history and verified in the source document with signs and symptoms that lead to 
discontinuation of the oral iron therapy and precluded further use of oral iron therapy.  
*** The Hb measurement that in Investigators' opinion was sufficiently low as to require 
rapid repletion of iron stores to minimize the risk of receiving a blood transfusion should be 
documented in the source document. 
 
Additional inclusion criteria after the run-in period: 
After the run-in period, subjects who fulfil the following additional eligibility criteria will be 
included: 
1. Hb level ≤ 11 g/dL  
2. S-ferritin ≤ 800 ng/mL  
3. Lack of efficacy: Hb increase < 1 g/dL at visit R4 (i.e. inadequate response to oral 
iron) and compliance to oral iron (pill counts), which needs to be ≥ 67 % 
Or 
1. Hb level ≤ 11 g/dL  
2. S-ferritin ≤ 800 ng/mL  
3. Inability to tolerate oral iron, as per discretion of the Investigator 
Exclusion criteria: 
A subject will not be eligible for inclusion in this trial if he/she fulfils any of the following 
criteria: 


Trial ID: 
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Protocol Version: 
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1. Anaemia predominantly caused by factors other than IDA according to Investigator's 
judgment  
2. Hemochromatosis or other iron storage disorders 
3. Known hypersensitivity reaction to any component of iron isomaltoside or iron su-
crose 
4. Previous serious hypersensitivity reactions to any IV iron compounds 
5. Previously randomised in a clinical trial with iron isomaltoside  
6. Received an investigational drug within 30 days of screening 
7. During 10-day period prior to screening; has been treated with IV iron 
8. Erythropoiesis stimulating agent (ESA) treatment within 30 days before the screening 
visit  
9. During 30-day period prior to screening or during the trial period; has or will be treat-
ed with a red blood cell transfusion, radiotherapy, and/or chemotherapy 
10. During 30-day period prior to screening or during the trial period; has or will require a 
surgical procedure that necessitated general anaesthesia 
11. Alanine aminotransferase (ALAT) and/or aspartate aminotransferase (ASAT) > 3 
times upper limit of normal (e.g. decompensated liver cirrhosis or active hepatitis)  
12. Any non-viral infection 
13. Required dialysis for treatment of CKD 
14. Alcohol or drug abuse within the past 6 months 
15. Estimated life expectancy of < 6 months or, for cancer patients, an Eastern Coopera-
tive Oncology Group (ECOG) performance status > 1 
16. 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 
17. 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 iron isomaltoside (group A) or iron sucrose (group B) 
as described below. 
In group A, iron isomaltoside will be administered as a single IV infusion of 1000 mg at 
baseline diluted in 100 mL 0.9 % sodium chloride and given over approximately 20 minutes 
(50 mg iron/min).  
In group B, iron sucrose will be administered as 200 mg undiluted IV push injections over 
approximately 2-5 minutes and repeated according to standard practice or physician choice 
up to a maximum of five times (1000 mg) within the first two weeks starting at baseline. A 
cumulative dose of 1000 mg is recommended. The cumulative dose of iron sucrose should be 
specified and documented at baseline. 
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 


Trial ID: 
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Protocol Version: 
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"premedication" and may be continued. 
Sample size calculations 
The co-primary endpoints are treatment-emergent serious and/or severe non-serious 
hypersensitivity AEs and change in Hb from baseline to week 8.  
Safety: 
Data from previous trials conducted with iron isomaltoside suggests that the incidence of 
treatment-emergent serious and/or severe non-serious hypersensitivity AEs for an IDA popu-
lation can be expected to be approximately 1 % (IBD-01/IBD-02/CIA-01/PP-01: n = 3/341 = 
0.9 %, 95 % confidence interval (CI): 0.2 %; 2.5 %), and similar for iron sucrose (CKD-03: n 
= 1/114 = 0.9 %, 95 % CI: 0.0 %; 4.8 %). A common incidence of 1.5 % will be assumed for 
the current trial. 
As these are relatively rare events, an incidence of 0 % for placebo is assumed. Iron iso-
maltoside should be at most 50 % worse than the difference between iron sucrose and place-
bo, corresponding to a maximum relative risk of 2 (1.5 %/(1.5 %-0 %)2). 
This trial will primarily assess the risk of the test drug under investigation. Arguing back 
from a relative risk of 2 gives that the upper bound of the 95 % CI for the incidence of treat-
ment-emergent serious and/or severe non-serious hypersensitivity AEs should be at most 3 % 
(2×1.5 %) for the iron isomaltoside treatment group. 
Efficacy: 
IDA-301 was a double-blind, placebo-controlled trial designed to compare the safety and 
efficacy of 1000 mg IV ferumoxytol to placebo. In this trial, 608 subjects were treated with 
ferumoxytol and 200 received placebo. The change in Hb from baseline to week 5 was the 
primary efficacy endpoint for the European Union regulators, and one of the secondary end-
points for U.S. regulators. The mean change was 2.6 g/dL (standard deviation (SD): 1.5) for 
IV ferumoxytol and 0.1 g/dL (SD: 0.9) for placebo. The estimated treated effect of IV fer-
umoxytol (i.e. the difference between ferumoxytol and placebo) was estimated to be approx-
imately 2.5 g/dL with a 95 % CI ranging from 2.3 to 2.7 g/dL. The point estimate will be 
used as estimate of the treatment effect. Preserving 80 % of this effect is believed to provide 
reasonable assurance that iron isomaltoside is efficacious. Hence, the non-inferiority margin 
is set to (1-0.8) × 2.5 g/dL ~ 0.5 g/dL. 
Power: 
The significance level is set to 5 %. With n = 1000 in the iron isomaltoside treatment group, 
there is 88 % power for demonstrating that the upper bound of the 95 % CI of the incidence 
of treatment-emergent serious and/or severe non-serious hypersensitivity AEs is less than 3 
%. And with n = 500 in the iron sucrose treatment group, assuming no difference between the 
treatment groups, and assuming a common SD = 1.5 g/dL, there is 100 % power for demon-
strating non-inferiority of the change in Hb from baseline to week 8, using a non-inferiority 
margin of -0.5 g/dL.  
This yields a total power for demonstrating both co-primary endpoints of 88 % in the trial. 
The CKD-04 trial will run in parallel with this trial and the sample size is the same, yielding a 
total of 2000 subjects to be treated with iron isomaltoside and 1000 with iron sucrose. In ad-
dition to the efficacy and safety analyses performed for this trial alone, an efficacy and safety 


Trial ID: 
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assessment will be performed for the two trials combined. This is briefly described in Section 
0. 
Subjects will be stratified according to type of underlying disease (gastroenterology, gynae-
cology, oncology, and ‘other’) and baseline cardiovascular risk (history of myocardial infarc-
tion, stroke, or congestive heart failure, yes/no). 
Statistical analyses 
The co-primary safety endpoint will be analysed by constructing an exact two-sided 95 % CI 
of the incidence of treatment-emergent serious and/or severe non-serious hypersensitivity 
AEs in the iron isomaltoside treatment group. If the upper bound of the 95 % CI is <3 %, the 
safety objective has been met. 
The co-primary efficacy endpoint will be analysed using a restricted maximum likelihood 
(REML)-based mixed model for repeated measures (MMRM) approach. All subjects in the 
intention to treat (ITT) analysis set with post baseline Hb data will be included with their ob-
served data. For subjects without post baseline Hb 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 iron sucrose), week, treatment-by-week interaction, strata, 
as well as the continuous, fixed covariates of baseline Hb value and baseline Hb-by-week 
interaction. An unstructured (co)variance structure will be used to model the within-subject 
errors. If, unexpectedly, this analysis fails to converge, the following structures will be ap-
plied, in the following order; first-order ante-dependence, heterogeneous compound sym-
metry, compound symmetry. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. The primary comparisons will be the contrasts between iron 
isomaltoside and iron sucrose at week 8 based on the least squares means for the treatment-
by-week interaction effect. The estimated mean difference based on this model will be re-
ported with two-sided symmetric 95 % CI, and if the lower bound of the 95 % CI is > -0.5 
g/dL, the efficacy objective has been met. 
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. 
 
 


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TABLE OF CONTENTS 
1 
ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 16 
1.1 
ABBREVIATIONS ............................................................................................................ 16 
1.2 
DEFINITION OF TERMS ................................................................................................... 17 
2 
INTRODUCTION ...................................................................................................... 18 
2.1 
BACKGROUND ............................................................................................................... 18 
2.2 
IRON ISOMALTOSIDE ..................................................................................................... 18 
2.3 
TRIAL RATIONALE ......................................................................................................... 18 
3 
TRIAL DESIGN ......................................................................................................... 19 
4 
TRIAL OBJECTIVES ............................................................................................... 19 
4.1 
SAFETY OBJECTIVES ..................................................................................................... 19 
4.2 
EFFICACY OBJECTIVES .................................................................................................. 19 
5 
TRIAL ENDPOINTS ................................................................................................. 20 
5.1 
PRIMARY SAFETY ENDPOINT ......................................................................................... 20 
5.2 
SECONDARY SAFETY ENDPOINTS .................................................................................. 20 
5.2.1 
Additional Safety Analyses ............................................................................ 20 
5.3 
PRIMARY EFFICACY ENDPOINT ..................................................................................... 20 
5.4 
SECONDARY EFFICACY ENDPOINTS ............................................................................... 20 
6 
TRIAL VISITS ........................................................................................................... 21 
6.1 
PRE-SCREENING (OPTIONAL) ......................................................................................... 21 
6.2 
TRIAL VISITS ................................................................................................................. 21 
6.3 
RUN-IN PERIOD ............................................................................................................. 27 
6.4 
VISIT 1 (SCREENING) ..................................................................................................... 27 
6.5 
VISIT 2 (BASELINE) ....................................................................................................... 28 
6.6 
VISIT 3 .......................................................................................................................... 28 
6.7 
VISIT 4 .......................................................................................................................... 28 
6.8 
VISIT 5 .......................................................................................................................... 29 
6.9 
VISIT 6 (FINAL VISIT) ..................................................................................................... 29 
6.10 OPTIONAL TREATMENT VISIT (TV1-TV2) .................................................................... 29 
7 
TRIAL ASSESSMENTS............................................................................................ 30 
7.1 
DEMOGRAPHIC AND BASELINE ASSESSMENTS .............................................................. 30 
7.2 
PREGNANCY TEST ......................................................................................................... 30 
7.3 
RELEVANT MEDICAL HISTORY...................................................................................... 30 


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7.4 
CONCOMITANT MEDICATION ........................................................................................ 30 
7.5 
PHYSICAL EXAMINATION .............................................................................................. 30 
7.6 
HEIGHT ......................................................................................................................... 31 
7.7 
WEIGHT ......................................................................................................................... 31 
7.8 
VITAL SIGNS ................................................................................................................. 31 
7.9 
ELECTROCARDIOGRAM ................................................................................................. 31 
7.10 FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY FATIGUE SCALE ............... 31 
7.11 PHARMACOECONOMICS ................................................................................................. 31 
7.12 LABORATORY ASSESSMENTS ........................................................................................ 32 
7.12.1 
Eligibility Laboratory Assessments ............................................................ 32 
7.12.2 
Safety Laboratory Assessments .................................................................. 32 
7.12.3 
Efficacy Laboratory Assessments .............................................................. 32 
7.12.4 
Pharmacokinetic Assessments ................................................................... 33 
7.13 ADVERSE EVENTS ......................................................................................................... 33 
8 
TRIAL POPULATION.............................................................................................. 33 
8.1 
NUMBER OF SUBJECTS .................................................................................................. 33 
8.2 
INCLUSION CRITERIA ..................................................................................................... 33 
8.3 
EXCLUSION CRITERIA ................................................................................................... 34 
8.4 
SUBJECT RECRUITMENT ................................................................................................ 35 
9 
SUBJECT COMPLETION AND WITHDRAWAL ............................................... 35 
9.1 
SCREEN FAILURES ......................................................................................................... 35 
9.2 
RE-SCREENING .............................................................................................................. 36 
9.3 
SUBJECT WITHDRAWAL ................................................................................................ 36 
9.4 
SUBJECT COMPLETION .................................................................................................. 36 
9.5 
TREATMENT AFTER THE TRIAL ...................................................................................... 36 
9.6 
EARLY TRIAL TERMINATION ......................................................................................... 36 
10 
INVESTIGATIONAL PRODUCTS ......................................................................... 36 
10.1 DESCRIPTION OF INVESTIGATIONAL PRODUCTS ............................................................ 36 
10.2 DOSAGE, ADMINISTRATION AND BLINDING OF TRIAL DRUG ........................................ 37 
10.3 DOSE RATIONALE .......................................................................................................... 38 
10.4 SIDE EFFECTS OF IRON ISOMALTOSIDE .......................................................................... 38 
10.5 SIDE EFFECTS OF IRON SUCROSE ................................................................................... 38 
10.6 PREPARATION, HANDLING, AND LABELLING ................................................................. 38 


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10.7 HANDLING AND STORAGE ............................................................................................. 38 
10.8 PRODUCT ACCOUNTABILITY ......................................................................................... 39 
11 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ................ 39 
11.1 PERMITTED MEDICATIONS ............................................................................................ 39 
11.2 PROHIBITED MEDICATIONS AND NON-DRUG THERAPIES ............................................... 39 
12 
ADVERSE EVENTS .................................................................................................. 39 
12.1 DEFINITION OF ADVERSE EVENTS ................................................................................. 39 
12.2 DEFINITION OF SERIOUS ADVERSE EVENTS ................................................................... 40 
12.3 DEFINITION OF AN ADVERSE DRUG REACTION ............................................................. 40 
12.4 COLLECTION OF ADVERSE EVENTS ............................................................................... 41 
12.5 REPORTING OF SAES ..................................................................................................... 42 
13 
PREGNANCIES ......................................................................................................... 43 
14 
OVERDOSE ............................................................................................................... 43 
15 
STATISTICAL ANALYSES ..................................................................................... 43 
15.1 HYPOTHESES ................................................................................................................. 43 
15.2 SAMPLE SIZE DETERMINATION ..................................................................................... 44 
15.3 DATA ANALYSIS SETS ................................................................................................... 45 
15.4 INTERIM ANALYSIS ....................................................................................................... 45 
15.5 KEY ELEMENTS OF THE ANALYSIS PLAN ....................................................................... 45 
15.5.1 
Safety Analyses ........................................................................................... 45 
15.5.2 
Efficacy Analyses ....................................................................................... 46 
15.6 COMBINED ANALYSIS OF IDA-03 AND CKD-04 ........................................................... 47 
16 
DATA MANAGEMENT AND DATA COLLECTION ......................................... 48 
16.1 DEFINITION OF SOURCE DATA ....................................................................................... 48 
16.2 DATA MANAGEMENT .................................................................................................... 48 
17 
TRIAL MONITORING ............................................................................................. 49 
17.1 TRIAL MONITORING ...................................................................................................... 49 
17.2 QUALITY ASSURANCE ................................................................................................... 49 
17.3 PROTOCOL DEVIATIONS ................................................................................................ 49 
18 
TRIAL ADMINISTRATION .................................................................................... 49 
18.1 TRIAL CORE TEAM, GCP QUALITY STEERING COMMITTEE, AND GCP QUALITY BOARD
 
……………………………………………………………………………………..50 
18.2 DIRECT ACCESS ............................................................................................................ 50 
18.3 TRIAL AND SITE CLOSURE ............................................................................................. 51 


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18.4 RECORDS RETENTION .................................................................................................... 51 
18.5 PROVISION OF TRIAL RESULTS AND INFORMATION TO PRINCIPAL INVESTIGATORS ...... 51 
18.6 FINANCE AND INSURANCE ............................................................................................. 51 
19 
ETHICAL CONSIDERATIONS .............................................................................. 52 
19.1 REGULATORY AND ETHICAL CONSIDERATIONS ............................................................. 52 
19.2 CHANGES TO THE PROTOCOL ........................................................................................ 52 
20 
PUBLICATION PLAN .............................................................................................. 52 
20.1 UPLOADING OF DATA ON PUBLIC WEBSITES ................................................................. 53 
21 
REFERENCES ........................................................................................................... 53 
APPENDIX A ........................................................................................................................ 54 
APPENDIX B ......................................................................................................................... 57 
 
 
 
 


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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: Adjudicated composite cardiovascular endpoints 
 
 
 


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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 
CEAC 
Clinical Endpoint Adjudication Committee 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CRA 
Clinical Research Associate 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ESA 
Erythropoiesis Stimulating Agent 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAS 
Full Analysis Set 
Hb 
Haemoglobin 
ICF 
Informed Consent Form 
ICH-GCP  
International Conference on Harmonization-Good Clinical Practice 
IDA 
Iron Deficiency Anaemia 
IEC 
Independent Ethics Committee 
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 
NMR 
Nuclear magnetic resonance 
PI 
Principal Investigator 
PP 
Per Protocol 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
s- 
Serum 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SMQ 
Standardised Medical Dictionary for Regulatory Activities Query 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCT 
Trial Core Team 
TEAE 
Treatment Emergent Adverse Event 


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TSAT 
Transferrin Saturation  
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. 
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 cancer [Aapro et al., 2012] 
and gastrointestinal diseases such as inflammatory bowel diseases [Wilson et al., 2004], men-
struating or pregnant women [WHO, 2008], and subjects who have undergone bariatric pro-
cedure [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 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.  
Iron sucrose (Venofer®) is a widely used parenteral iron products and therefore this product 
has been chosen as comparator in this trial which is planned to evaluate the safety and effica-
cy of intravenous (IV) iron isomaltoside 1000 (Monofer®, Pharmacosmos, Holbæk, Denmark, 
termed iron isomaltoside in the following) compared to IV iron sucrose in subjects with IDA 
who are intolerant or unresponsive to oral iron therapy or in whom the haemoglobin (Hb) 
measurement in the Investigators' opinion were sufficiently low as to require rapid repletion 
of iron stores to minimize the risk of receiving a blood transfusion. 
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 res-
onance (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. 


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Thus, this trial is planned to compare the safety and efficacy of iron isomaltoside with another 
parenteral iron preparation (iron sucrose) in subjects with IDA and who are intolerant or unre-
sponsive to oral iron therapy or who need iron rapidly. 
3 
TRIAL DESIGN 
The trial is a randomised, comparative, open-label trial. The trial duration for the individual 
subject will be approximately 10-15 weeks and each subject will attend a minimum of 6 vis-
its.  
Subjects who have not a documented intolerance of oral iron for at least 1 month within the 
last 9 months should have up to 1 month of run-in period of oral iron in order to document 
intolerance or lack of response to oral iron (see details in Section 6.3). Subjects enrolled in the 
run-in period will attend 1-4 additional visits (R1-R4). Visits R1-R3 are conducted by tele-
phone. 
The subject in group B may attend additional 2 treatment visits (TV1-TV2) if deemed neces-
sary by the Investigator in order to achieve the cumulative dose of iron sucrose. The subjects 
will be randomised 2:1 to 1 of the following treatment groups: 
 Group A: Iron isomaltoside (1000 mg infusion) 
 Group B: Iron sucrose (200 mg push injection up to 5 times), a cumulative dose of 
1000 mg is recommended 
4 
TRIAL OBJECTIVES 
4.1 
Safety Objectives 
The primary safety objective of the trial is to evaluate the safety of IV iron isomaltoside com-
pared to iron sucrose in subjects with IDA when oral iron preparations are ineffective or can-
not be used or in whom the screening Hb measurement in Investigators' opinion were suffi-
ciently low as to require rapid repletion of iron stores. 
4.2 
Efficacy Objectives 
The primary efficacy objective of the trial is to evaluate and compare the effect of iron iso-
maltoside to iron sucrose in its ability to increase Hb in subjects with IDA when oral iron 
preparations are ineffective or cannot be used or in whom the screening Hb measurement in 
Investigators' opinion were sufficiently low as to require rapid repletion of iron stores. 
The secondary efficacy objective of the trial is to evaluate and compare the effect of iron 
isomaltoside to iron sucrose on:  
 Other relevant iron related biochemical parameters  
 Fatigue symptoms 
 Pharmacoeconomics 


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5 
TRIAL ENDPOINTS 
5.1 
Primary Safety Endpoint 
The co-primary safety endpoint is serious or severe hypersensitivity reaction starting on or 
after the first dose of randomised 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 Appendix A. 
The adverse events (AEs) will be adjudicated in a blinded fashion by an independent Clinical 
Endpoint Adjudication Committee (CEAC) (described in a separate adjudication charter). The 
specified definition of adjudicated endpoints will be given in the charter. 
5.2 
Secondary Safety Endpoints 
The secondary safety endpoints are the following: 
 Composite cardiovascular AEs starting on or after the first dose of randomised treat-
ment (i.e. treatment-emergent). The adjudicated composite AEs includes the follow-
ing: 
 Death due to any cause 
 Non-fatal myocardial infarction 
 Non-fatal stroke 
 Unstable angina requiring hospitalization 
 Congestive heart failure requiring hospitalization or medical intervention 
 Arrhythmias 
 Hypertension 
 Hypotension 
 
The AEs will be adjudicated in a blinded fashion by an independent CEAC (described 
in a separate adjudication charter). The specified definition of adjudicated endpoints is 
given in Appendix B. 
 Time to first composite cardiovascular safety AE 
 Serum (s-) phosphate < 2 mg/dL at any time from baseline to weeks 1, 2, 4, or 8 
5.2.1 
Additional Safety Analyses 
Physical examinations and measurements of vital signs, height, weight, and safety laboratory 
parameters will be measured as part of standard safety assessments. Furthermore, intensive 
electrocardiogram (ECG) monitoring for evaluation of QTc prolongations will be performed 
in 35 subjects. 
5.3 
Primary Efficacy Endpoint 
The co-primary efficacy endpoint is change in Hb from baseline to week 8. 
5.4 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following:  


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 Hb increase of ≥ 2 g/dL from baseline to weeks 1, 2, 4, or 8 
 Time to change in Hb ≥ 2 g/dL 
 Hb level of > 12 g/dL at any time from week 1 to week 8 
 Increase in Hb concentration ≥ 2 g/dL at any time from week 1 to week 8 
 S-ferritin level of ≥ 100 ng/mL and transferrin saturation (TSAT) of 20-50 % at any 
time from week 1 to week 8 
 Change in concentrations of Hb from baseline to weeks 1, 2, and 4 
 Change in concentrations of s-ferritin, TSAT, and s-iron from baseline to weeks 1, 2, 
4, and 8 
 Change in fatigue symptoms from baseline to weeks 1, 2, and 8 measured by the Func-
tional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
 Resources used by the subject (per visit) and health care staff (per administration) 
measured by the ISDR questionnaire and health care resource use questionnaire, re-
spectively  
6 
TRIAL VISITS 
6.1 
Pre-screening (optional) 
The Principal Investigator (PI) will have the option of pre-screening potential trial candidates 
if the candidate’s Hb value is unknown to the Investigator and Hb testing is not part of stand-
ard care. This should be done by using a HemoCue Hb test, which will give an indication of 
whether the inclusion criteria could be fulfilled. It is up to the Investigator to decide if the 
candidate should proceed to screening. If the candidates continue into a regular screening visit 
all screening procedures including informed consent should be done according to the protocol. 
The candidates should sign a separate pre-screening consent form prior to the HemoCue test.  
6.2 
Trial Visits 
The subjects will attend a minimum of 6 visits.  
Subjects who have not a documented intolerance of oral iron for at least 1 month within the 
last 9 months should have up to 1 month of run-in period of oral iron in order to document 
intolerance or lack of response to oral iron. Subjects enrolled in the run-in period will attend 
1-4 additional visits (R1-R4). Visits R1-R3 are conducted by telephone. 
The subject in group B may attend additional 2 treatment visits (TV1-TV2) if deemed neces-
sary by the Investigator in order to achieve the cumulative dose of iron sucrose.  
A trial flowchart of the trial assessments performed at the visits is shown in Table 1a (patients 
enrolled in the run-in period) and Table 1b (patients with documented intolerance of oral 
iron). 










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f. Subjects in group B may attend up to 2 additional treatment visits (TV1-TV2). The TV visits are optional treatment visit for dosing with iron sucrose, if in the opinion of the Investigator 
required in order to achieve the cumulative dose of iron sucrose.  


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6.3 
Run-in Period 
Subjects who do not have a documented history of intolerance of oral iron for at least 1 month 
within the last 9 months should have a run-in period. In the run-in period, the subject will re-
ceive oral iron for up to 1 month in order to document intolerance or lack of response to oral 
iron. If the subject fulfils the inclusion/exclusion criteria he/she will be enrolled into the run-
in period after a telephone confirmation call at day -42 (visit R1). In the run-in period, the 
subject has to take 325 mg oral iron sulphate (Ferrous Sulphate 325 mg) three times daily. 
The oral iron sulphate will be provided by Pharmacosmos A/S. The subjects will have a tele-
phone call at day -35 (visit R2) and day -28 (visit R3) in order to assess compliance (via pill 
counts) and tolerance of oral iron. At day -14, the subjects will have a visit (visit R4) in order 
to assess compliance (via pill counts) and tolerance of oral iron, and a blood sample will be 
drawn in order to assess the Hb and s-ferritin levels. 
Subjects who report severe diarrhoea, constipation, vomiting, or abdominal pain with oral iron 
at the telephone calls after 7 and 14 days of oral iron treatment (day -35 and day -28) or be-
fore are withdrawn from the run-in and may continue directly to visit R4 (day -14). If all in-
clusion/exclusion criteria are fulfilled at visit R4 (day-14) the subject may be enrolled in the 
trial. Subjects who report other side effects are to reduce the oral iron dose to 325 mg once 
daily for the remaining run-in period. 
If the subject experience severe diarrhoea, constipation, vomiting, or abdominal pain at any 
time during the run-in period, he/she should contact the site. The subjects are withdrawn from 
the run-in and if all other inclusion/exclusion criteria are fulfilled at visit R4 (day-14) the sub-
ject may be enrolled in the trial.  
After 28-30 days treatment with oral iron, the subject will attend visit R4 (day -14). If a sub-
ject has been withdrawn during the run-in period due to intolerance, the subject may attend 
visit R4 before day -14. Subjects who respond adequately to oral iron during run-in (Hb in-
crease ≥ 1 g/dL) are excluded from the trial. Subjects who have a Hb level ≤ 11 g/dL and s-
ferritin ≤ 800 ng/mL after the run-in period and either an inadequate response to oral iron (i.e. 
Hb increase < 1 g/dL at visit R4 and a compliance of ≥ 67 % to oral iron) or an inability to 
tolerate oral iron, as per discretion of the Investigator, are enrolled into the trial if all inclu-
sion/exclusion criteria are fulfilled. The following will be assessed during and/or after the run-
in period: 
 Compliance to oral iron (pill counts), which needs to be ≥ 67 % 
 Severe intolerance defined as severe diarrhoea, constipation, vomiting, or abdominal 
pain 
 Response to oral iron (Hb and ferritin) 
6.4 
Visit 1 (Screening) 
The following will be assessed: 
 Subject is informed about the trial and signs the informed consent 
 Collection of demographic information 
 Inclusion and exclusion criteria checked 
 Eligibility laboratory assessments 


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6.5 
Visit 2 (Baseline) 
The following 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, including history of myocardial infarction, 
stroke, or congestive heart failure  
 Recording of concomitant medication 
 Physical examination (not performed later than the baseline visit)  
 Measurement of height 
 Measurement of weight 
 Examination of vital signs  
 Randomisation 
 ECG (intensive ECG monitoring for evaluation of QTc prolongations will be per-
formed in 35 subjects treated with iron isomaltoside) 
 Assessment of fatigue by FACIT Fatigue Scale 
 Assessment of pharmacoeconomics by the ISDR questionnaire and health care re-
source use questionnaire  
 Safety laboratory tests 
 Efficacy laboratory tests 
 Treatment with iron isomaltoside (group A only) 
 Treatment with iron sucrose (group B only) 
 AE evaluation and recording 
6.6 
Visit 3 
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  
 ECG  
 Assessment of fatigue by FACIT Fatigue Scale 
 Safety laboratory tests 
 Efficacy laboratory tests  
 Treatment with iron sucrose (group B only), if required  
 AE evaluation and recording 
6.7 
Visit 4 
The following will be assessed: 


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 Changes in concomitant medication and medical history (worsening of symptoms or 
diseases shall be recorded as AEs) 
 Examination of vital signs  
 ECG  
 Assessment of fatigue by FACIT Fatigue Scale 
 Safety laboratory tests 
 Efficacy laboratory tests  
 Treatment with iron sucrose (group B only), if required  
 AE evaluation and recording 
6.8 
Visit 5 
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  
 ECG  
 Safety laboratory tests 
 Efficacy laboratory tests  
 AE evaluation and recording 
6.9 
Visit 6 (final visit) 
The following will be assessed: 
 Changes in concomitant medication and medical history (worsening of symptoms or 
diseases shall be recorded as AEs) 
 Physical examination 
 Measurement of weight 
 Examination of vital signs  
 ECG  
 Assessment of fatigue by FACIT Fatigue Scale 
 Safety laboratory tests 
 Efficacy laboratory tests  
 AE evaluation and recording 
 Completing the final visit form 
6.10 
Optional Treatment Visit (TV1-TV2) 
Subjects in group B may attend up to 2 additional treatment visits (TV1-TV2). The TV visits 
are optional treatment visit for dosing with iron sucrose, if in the opinion of the Investigator 
required in order to achieve the cumulative dose of iron sucrose. The following will be as-
sessed: 
 Examination of vital signs  


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 ECG  
 Treatment with iron sucrose  
 AE evaluation and recording 
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 including history of myocardial infarction, stroke, 
or congestive heart failure. Intolerance and non-response to oral iron treatment as well as the 
underlying disorder causing IDA should be documented in the medical history. Changes in 
medical history will be recorded at the subsequent visits during the trial (worsening of symp-
toms 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: generic name, indication, dose, and start and stop date. Start 
dates occurring > 12 months before the enrolment into the trial should be set as > 12 months. 
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 (HEENT) 
 Cardiovascular system 
 Respiratory system 
 Nervous system 
 Gastrointestinal system 
 Musculo-skeletal system 
 Urogenital system 
 Dermatology system 
 Others, if required 


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7.6 
Height 
Height will be measured. 
7.7 
Weight 
Weight will be measured. 
7.8 
Vital Signs  
Heart rate and blood pressure will be measured. 
At the treatment visits, heart rate and blood pressure will be measured at the following time 
points: 
 For subjects receiving an infusion of iron isomaltoside: approximately 0-10 minutes 
before infusion, during infusion, 5-15 minutes, and 20-40 minutes after the infusion 
has ended 
 For subjects receiving a push injections of iron sucrose: approximately 0-10 minutes 
before injection, 5-15 minutes, and 20-40 minutes after the injection has ended 
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. In addition, intensive ECG monitor-
ing for evaluation of QTc prolongations as well as pharmacokinetic assessments (described in 
Section 7.12.4) will be performed at baseline in 35 consecutive subjects in relation to treat-
ment with iron isomaltoside at selected sites. The intensive ECGs will be described in a spe-
cific procedure description (sub-protocol). The intensive ECGs will be evaluated centrally 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 out by the subject. 
7.11 
Pharmacoeconomics 
The ISDR questionnaire will be used to measure the resources used to receive treatment at 
one visit by the subject. Questions 5 and 10 of the questionnaire have been rephrased so that 
the questionnaire only includes resources used on preparation for the visit, travel time, and 
receiving the trial drug. Thus, resources used on other trial activities are not included. The 
questionnaire is based on independent research funded by the National Institute for Health 
Research under the Program Grants for Applied Research program (RP-PG-1210-12016). 
The health care resource use questionnaire will include questions regarding time used by the 
health care staff during administration of the trial drug and the administration time (including 
the observational time). The questions will include the following: 
 What is your profession (nurse, doctor, etc.)? 


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 How much time did you use on administration of the trial drug including preparing for 
the administration, administration time, and observation time? 
7.12 
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. 
7.12.1 
Eligibility Laboratory Assessments 
The following eligibility laboratory assessments will be performed at screening: 
 
Complete haematology set: Hb, leucocytes/white blood cells (WBC), erythrocytes/red 
blood cells (RBC), haematocrit, platelets, neutrophil granulocytes, lymphocytes, mon-
ocytes, eosinophils, basophils, mean corpuscular haemoglobin (MCH), mean corpus-
cular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), and re-
ticulocyte count 
 Biochemistry: 
o S-ferritin 
o TSAT 
o Alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) 
o C-reactive protein (CRP)  
The following eligibility laboratory assessments will be performed at visit R4: 
 
Hb 
 
S-ferritin 
7.12.2 
Safety Laboratory Assessments 
The following safety laboratory assessments will be analysed: 
 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-phosphate, s-urea, s-creatinine, s-albumin 
o S-bilirubin, ASAT, ALAT 
o CRP  
7.12.3 
Efficacy Laboratory Assessments 
 The following efficacy laboratory parameters will be analysed: 
 Hb  
 S-ferritin 
 TSAT 


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 S-iron 
7.12.4 
Pharmacokinetic Assessments 
Blood for pharmacokinetic assessments will be obtained at baseline from 35 consecutive sub-
jects in relation to treatment with iron isomaltoside and intensive ECG monitoring at selected 
sites. The time points for such sampling will be: pre-dose (at approximately -15 minutes), and 
post-dose at: 0.5, 1, 1.5, 2, 3, 4, 6, and 24 hours post-dose. The assessments and analyses will 
be described in a specific procedure description (sub-protocol).  
7.13 
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 1500 subjects will be recruited, and they will be randomised 2:1 to 1 of the 
following treatment groups: 
 Group A: iron isomaltoside 
 Group B: iron sucrose  
The blocked randomisation of subjects to treatment arms will be stratified in order to balance 
the following: type of underlying disease (gastroenterology, gynaecology, oncology, and ‘oth-
er’) and baseline cardiovascular risk (history of myocardial infarction, stroke, or congestive 
heart failure, yes/no). 
The procedure for preparing the randomisation list will be approved by the Global Trial Re-
sponsible Statistician before the randomisation 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  
2. Subjects having IDA caused by different aetiologies* such as abnormal uterine bleed-
ing, gastrointestinal diseases, cancer, bariatric procedures (gastric bypass operations), 
and other conditions leading to significant blood loss.  
3. Subjects with: 
a. Up to 1 month run-in phase indicating intolerance or lack of response to oral iron 
or  
b. A documented history of intolerance to oral iron therapy to at least one month of 
ordinated oral iron therapy within 9 months** prior to trial enrolment or  
c. Screening Hb measurement in Investigators' opinion was sufficiently low as to re-
quire rapid repletion of iron stores to minimize the risk of eventual blood transfu-
sion*** 


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4. Hb ≤ 11 g/dL 
5. TSAT < 20 % 
6. S-ferritin < 100 ng/mL 
7. Willingness to participate and signing the informed consent form (ICF) 
*The aetiology for IDA should be documented in the medical history and verified in the 
source document. 
**The intolerance to oral iron treatment within the last 9 months should be documented in the 
medical history and verified in the source document with signs and symptoms that lead to 
discontinuation of the oral iron therapy and precluded further use of oral iron therapy.  
*** The Hb measurement that in Investigators' opinion was sufficiently low as to require rap-
id repletion of iron stores to minimize the risk of receiving a blood transfusion should be doc-
umented in the source document. 
 
Additional inclusion criteria after the run-in period: 
After the run-in period, subjects who fulfil the following additional eligibility criteria will be 
included: 
4. Hb level ≤ 11 g/dL  
5. S-ferritin ≤ 800 ng/mL  
6. Lack of efficacy: Hb increase < 1 g/dL at visit R4 (i.e. inadequate response to oral 
iron) and compliance to oral iron (pill counts), which needs to be ≥ 67 % 
Or 
4. Hb level ≤ 11 g/dL  
5. S-ferritin ≤ 800 ng/mL  
6. Inability to tolerate oral iron, as per discretion of the Investigator 
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. Anaemia predominantly caused by factors other than IDA according to Investigator's 
judgment  
2. Hemochromatosis or other iron storage disorders 
3. Known hypersensitivity reaction to any component of iron isomaltoside or iron su-
crose 
4. Previous serious hypersensitivity reactions to any IV iron compounds 
5. Previously randomised in a clinical trial with iron isomaltoside  
6. Received an investigational drug within 30 days of screening 
7. During 10-day period prior to screening; has been treated with IV iron 
8. Erythropoiesis stimulating agent (ESA) treatment within 30 days before the screening 
visit  


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9. During 30-day period prior to screening or during the trial period; has or will be treat-
ed with a red blood cell transfusion, radiotherapy, and/or chemotherapy 
10. During 30-day period prior to screening or during the trial period; has or will require a 
surgical procedure that necessitated general anaesthesia 
11. ALAT and/or ASAT > 3 times upper limit of normal (e.g. decompensated liver cirrho-
sis or active hepatitis)  
12. Any non-viral infection 
13. Required dialysis for treatment of CKD 
14. Alcohol or drug abuse within the past 6 months 
15. Estimated life expectancy of < 6 months or, for cancer patients, an Eastern Coopera-
tive Oncology Group (ECOG) performance status >1 
16. 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 
17. 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.  


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9.2 
Re-screening 
Subjects may be re-screened 3 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-
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  


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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. 
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. 
Iron sucrose 
Iron sucrose (Venofer®) is an aqueous complex of polynuclear iron (III)-hydroxide in sucrose 
for IV use. Iron sucrose injection has a molecular weight of approximately 34,000-60,000 
Daltons [Venofer® prescribing information (USA), 01/2014 or local Summary of Product 
Characteristics (SmPC)].  
Iron sucrose is provided as a brown, sterile solution in 5 mL single dose vials (100 mg ele-
mental iron per 5 mL) and 10 mL single dose vials (200 mg elemental iron per 10 mL). Iron 
sucrose must be administered intravenously by push injections over approximately 2-5 
minutes in this trial, which is an approved treatment course.  
10.2 
Dosage, Administration and Blinding of Trial Drug 
The subjects will be randomised 2:1 to 1 of the following treatment groups: 
 Group A, iron isomaltoside will be administered as a single IV infusion of 1000 mg at 
baseline diluted in 100 mL 0.9 % sodium chloride and given over approximately 20 
minutes (50 mg iron/min).  
 Group B, iron sucrose will be administered as 200 mg undiluted IV push injections 
over approximately 2-5 minutes and repeated according to standard practice or physi-
cian choice up to a maximum of five times (1000 mg) within the first two weeks start-
ing at baseline. A cumulative dose of 1000 mg is recommended. The cumulative dose 
of iron sucrose should be specified and documented at baseline. 
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. 


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Details of administration and storage of iron isomaltoside and iron sucrose are further de-
scribed 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 2015, more than 1700 patients 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. 
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. 
10.4 
Side Effects of Iron Isomaltoside  
Side effect for iron isomaltoside is described in Investigator's Brochure (current version). 
10.5 
Side Effects of Iron Sucrose  
Side effects for iron sucrose are described in Venofer® prescribing information (USA), 
01/2014 or local SmPC. 
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 iron sucrose are further de-
scribed 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. 


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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-
tered to subjects. 
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, except oral iron during the 
run-in period (nutritional supplementation including iron is allowed unless it is as-
sumed as treatment of the subject's anaemia) 
 ESA 
 Blood transfusion 
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-


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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 
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 electronic case report form (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 Pharmacosmos 
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 reac-
tion (SAR). If the SAR is not listed as an expected side effect for iron isomaltoside [Monofer® 
Investigator’s Brochure, current version], for iron sucrose [Venofer® prescribing information 
(USA), 01/2014 or local SmPC], or for oral iron [prescribing information (USA), version ap-
plicable at the time of approval of the protocol] it is considered a suspected unexpected seri-
ous adverse reaction (SUSAR).  
It is the responsibility of Pharmacosmos A/S to evaluate the SARs for expectedness. 


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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. 
Screen failures: 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. 
Randomised 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. AEs/SAEs occurring before administration 
of the trial drug are considered as non-treatment emergent, and those occurring after admin-
istration of the trial drug are considered as treatment emergent.  
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 


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 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 
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. 
Collection of AEs during the run-in period 
During the run-in period only the following common AEs for iron sulphate will be collected 
and recorded as described above: Constipation, vomiting, abdominal pain, and diarrhoea. 
All SAEs must be collected and recorded as described below. 
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.  


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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. Thus, the subjects may attend visit 3, 4, 5, and 6. 
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. 
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 co-primary endpoints are treatment-emergent serious and/or severe non-serious hypersen-
sitivity AEs and change in Hb from baseline to week 8.  
The following hypotheses will be tested: 
Safety: 
The incidence of treatment-emergent serious and/or severe non-serious hypersensitivity AEs 
in the iron isomaltoside treatment group is less than 3 %. 
H01: πiron isomaltoside ≥ 3 % 
against the alternative: 
HA1: πiron isomaltoside < 3 %, 
where, πiron isomaltoside denote the incidence of treatment-emergent serious and/or severe non-
serious hypersensitivity AEs. 
The null hypothesis will be tested against the alternative by constructing an unadjusted two-
sided exact 95 % confidence interval (CI) of the incidence. 
Efficacy: 


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H02: µiron isomaltoside - µiron sucrose ≤ -0.5 g/dL 
against the alternative: 
HA2: µiron isomaltoside - µiron sucrose > -0.5 g/dL, 
where, µiron isomaltoside and µiron sucrose denote the change from baseline to week 8 in Hb. 
The null hypothesis will be tested against the alternative by constructing a two-sided 95 % CI 
of the difference in change in Hb, deducted at week 8 from mixed model for repeated 
measures (MMRM). 
15.2 
Sample Size Determination 
Safety: 
Data from previous trials conducted with iron isomaltoside suggests that the incidence of 
treatment-emergent serious and/or severe non-serious hypersensitivity AEs for an IDA popu-
lation can be expected to be approximately 1 % (IBD-01/IBD-02/CIA-01/PP-01: n=3/341=0.9 
%, 95% CI: 0.2 %; 2.5 %). And similar for iron sucrose (CKD-03: n=1/114=0.9 %, 95% CI: 
0.0 %; 4.8 %). A common incidence of 1.5 % will be assumed for the current trial. 
As these are relatively rare events, an incidence of 0 % for placebo is assumed. Iron isomalto-
side should be at most 50 % worse than the difference between iron sucrose and placebo, cor-
responding to a maximum relative risk of 2 (1.5 %/(1.5 %-0 %)2). 
This trial will primarily assess the risk of the test drug under investigation. Arguing back from 
a relative risk of 2, gives that the upper bound of the 95 % CI for the incidence of treatment-
emergent serious and/or severe non-serious hypersensitivity AEs should be at most 3 % 
(2×1.5 %) for the iron isomaltoside treatment group. 
Efficacy: 
IDA-301 was a double-blind, placebo-controlled trial designed to compare the safety and effi-
cacy of 1000 mg IV ferumoxytol to placebo. In this trial, 608 subjects were treated with fer-
umoxytol and 200 received placebo. The change in Hb from baseline to week 5 was the pri-
mary efficacy endpoint for the European Union regulators, and one of the secondary end-
points for U.S. regulators. The mean change was 2.6 g/dL (standard deviation (SD): 1.5) for 
IV ferumoxytol and 0.1 g/dL (SD: 0.9) for placebo. The estimated treated effect of IV fer-
umoxytol (i.e. the difference between ferumoxytol and placebo) was estimated to be approxi-
mately 2.5 g/dL with a 95 % CI ranging from 2.3 to 2.7 g/dL. The point estimate will be used 
as estimate of the treatment effect. Preserving 80 % of this effect is believed to provide rea-
sonable assurance that iron isomaltoside is efficacious. Hence, the non-inferiority margin is 
set to (1-0.8) × 2.5 g/dL ~ 0.5 g/dL. 
Power: 
The significance level is set to 5 %. With n = 1000 in the iron isomaltoside treatment group, 
there is 88 % power for demonstrating that the upper bound of the 95 % CI of the incidence of 
treatment-emergent serious and/or severe non-serious hypersensitivity AEs is less than 3 %. 
And with n = 500 in the iron sucrose treatment group, assuming no difference between the 
treatment groups, and assuming a common SD = 1.5 g/dL, there is 100 % power for demon-
strating non-inferiority of the change in Hb from baseline to week 8, using a non-inferiority 
margin of -0.5 g/dL.  


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This yields a total power for demonstrating both co-primary endpoints of 88 %. 
The CKD-04 trial will run in parallel with this trial and the sample size is the same, yielding a 
total of 2000 subjects to be treated with iron isomaltoside and 1000 with iron sucrose. In addi-
tion to the efficacy and safety analyses performed for this trial alone, an efficacy and safety 
assessment will be performed for the two trials combined. This is briefly described in Section 
0. 
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 randomised subjects. 
Subjects will be included as randomised. This will be the primary analysis set for evaluating 
efficacy. 
Safety analysis set: The safety analysis set will include all randomised subjects who received 
at least one dose of the trial drug. This will be the analysis set for evaluating safety. 
Full analysis set (FAS): The FAS will consist of all randomised subjects, received at least one 
dose of the trial drug, and have at least one post baseline Hb assessment. Subjects will be in-
cluded as randomised. 
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 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) current 
version. An AE will be regarded as treatment emergent AEs (TEAEs) if it occurs after admin-
istration of randomised treatment. Related or possible related AE’s are defined as ADRs. 
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: 
 Non-treatment emergent AEs (defined as AEs collected before dosing including AEs 
reported for subjects never exposed to trial drug) in randomised subjects 
 Treatment emergent AEs (non-serious and serious) in randomised subjects 
 Treatment emergent SAEs in randomised subjects 
 SAEs in non-randomised subjects 
 ADRs 


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 AEs leading to dose reduction or withdrawal from treatment 
 Fatal SAEs 
 Serious or severe hypersensitivity reactions 
 Composite cardiovascular AEs 
15.5.1.1 Primary Analysis 
The co-primary safety endpoint is treatment-emergent serious and/or severe non-serious hy-
persensitivity AEs. The SMQs/preferred terms are listed in Appendix A. 
An exact two-sided 95 % CI of the incidence of treatment-emergent serious and/or severe 
non-serious hypersensitivity AEs in the iron isomaltoside treatment group will be constructed. 
If the upper bound of the 95 % CI is <3 %, the safety objective has been met. 
In addition, as supportive information, the risk difference between iron isomaltoside and iron 
sucrose will be assessed by constructing a 95 % CI of the risk difference. Both an unadjusted 
CI (with continuity correction), and a CI adjusted for strata using the Cochran-Mantel-
Haenszel method will be produced. 
15.5.1.2 Secondary Analyses 
The incidence of composite cardiovascular safety AEs will be tabulated and compared be-
tween the treatment groups by a Fisher’s exact test. 
The time to first composite cardiovascular safety AEs will be presented by a Kaplan-Meier 
plot, and the treatment groups will be compared by a log-rank test. 
The incidence of treatment-emergent AEs, SAEs, ADR, and SARs will be tabulated and com-
pared between the treatment groups by a Fisher’s Exact Test. 
15.5.1.3 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.  
15.5.2 
Efficacy Analyses 
The co-primary efficacy endpoint will be analysed using a restricted maximum likelihood 
(REML)-based MMRM approach. All subjects in the ITT with post baseline Hb data will be 
included with their observed data. For subjects without post baseline Hb 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 iron sucrose), week, treatment-by-week 
interaction, strata, as well as the continuous, fixed covariates of baseline Hb value and base-
line Hb-by-week interaction. An unstructured (co)variance structure 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 Kenward-Roger approximation will be used to estimate 
the denominator degrees of freedom. The primary comparisons will be the contrasts between 
iron isomaltoside and iron sucrose at week 8 based on the least squares means for the treat-
ment-by-week interaction effect. The estimated mean difference based on this model will be 
reported with two-sided symmetric 95 % CI, and if the lower bound of the 95 % CI is > -0.5 


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g/dL, the efficacy objective has been met. If the lower bound of the two-sided 95 % CI is > 0 
g/dL superiority will be declared, and the p-value for the test of superiority will be presented. 
As sensitivity, the analysis above will be repeated for the FAS and PP analysis sets.  
Some level of data missingness is expected, and the primary analysis (MMRM) is valid under 
the assumption that the data is Missing at Random (MAR). Simulation trials do suggest that 
MMRM is robust to accommodate some level of data Missing Not at Random. Since it is un-
clear how the level of missingness of this type of data will influence the outcome at this stage, 
choosing a pre-specified primary analysis valid under MNAR accurately will be very difficult. 
As such, sensitivity analyses valid under relevant cases of data MNAR will be performed. In 
particular, pattern-mixture models will be used. Different delta (imputation of how much 
worse response subjects who discontinue would have compared to those who complete the 
trial and who have the same profile up to time to withdrawal) will be applied as described by 
C. H. Mallinckrodt, Q. Lin, and G. Molenberghs [Mallinckrodt et al., 2012]. These analyses 
will be performed for the ITT, FAS, and PP analysis sets.  
The proportion of subjects with an Hb increase of ≥ 2 g/dL from baseline to any time from 
week 1 to week 8 will be compared between treatment groups using a logistic regression 
model with treatment and strata as fixed effects. Subjects without post baseline Hb values will 
be set as failures. The estimated treatment ratio of iron isomaltoside versus iron sucrose will 
be presented with 95 % CIs and corresponding p-value. 
Time to change in Hb increase ≥ 2 g/dL will be presented by a Kaplan-Meier plot, and the 
treatment groups will be compared by a log-rank test. Subjects without post baseline Hb val-
ues will be set as censored at day 0. 
The proportion of subjects who achieve Hb level of > 12 g/dL at any time from week 1 to 
week 8, the proportion of subjects who achieve an increase in Hb concentration ≥ 2 g/dL at 
any time from week 1 to week 8, and the proportion of subjects who achieve s-ferritin level of 
≥ 100 ng/mL and TSAT of 20-50 % at any time from week 1 to week 8 will be analysed by a 
logistic regression model similar to above. Subjects without Hb values at week 1-8 will be set 
as failures. 
The change in concentrations of Hb to weeks 1, 2, and 4, and change in s-ferritin, TSAT, and 
s-iron from baseline to weeks 1, 2, and 8, and change in fatigue symptoms (FACIT) will be 
estimated by MMRM models similar to the one described for the co-primary efficacy end-
point. 
Pharmacoeconomics will be assessed by the ISDR questionnaire and health care resource use 
questionnaire and summarised descriptively.  
15.6 
Combined Analysis of IDA-03 and CKD-04 
The two trials IDA-03 and CKD-04 will run in parallel. With n=1000 treated with iron iso-
maltoside and n=500 treated with iron sucrose, each trial is powered to show that the inci-
dence of serious and/or severe hypersensitivity AEs in the iron isomaltoside group is less than 
3 % and, with a non-inferiority margin of -0.5 g/dL, to demonstrate non-inferiority of iron 
isomaltoside versus iron sucrose for change in Hb to week 8. 
Pooled analyses will be performed of the two trials.  
For safety, in addition to estimating the absolute risk (incidence and 95 % CI) of iron iso-
maltoside, a non-inferiority analysis will be performed of iron isomaltoside versus iron su-


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crose. For iron sucrose, a similar rate of 1.5 % will be assumed. As iron isomaltoside should 
be no worse than 3 %, the non-inferiority margin will be set to 1.5 % points. The non-
inferiority assessment will be performed by estimation of the risk difference and the associat-
ed 95 % CI, adjusting for trial using the Cochran-Mantel-Haenszel method. With a total of 
2000 subjects treated with iron isomaltoside, and 1000 subjects treated with iron sucrose, as-
suming common incidences of 1.5 %, and using a significance level of 5 %, the power to 
demonstrate non-inferiority is 87 %. 
As sensitivity, the incidence will be estimated from a Kaplan-Meier curve of time to serious 
and/or severe hypersensitivity AEs. The log-log transformation will be used to estimate the 
standard errors for each treatment group, and the 95 % CI will be constructed by pooling these 
standard errors. 
For efficacy, the same non-inferiority assessment as in the individual trials will be performed, 
including the specified sensitivity analyses. A similar MMRM model as for the individual 
trials will be applied, with trial added as fixed factor. The power for demonstrating efficacy is 
100 %. 
Hence, with a total of 2000 subjects treated with iron isomaltoside, and 1000 subjects treated 
with iron sucrose, the combined power of demonstrating the two primary endpoints is 87 %. 
Similar to the individual trials, if the upper bound of two-sided 95 % CI of the risk difference 
(iron isomaltoside - iron sucrose) < 0 for the incidence of serious and/or severe hypersensitivi-
ty, or the lower bound of two-sided 95 % CI of the mean difference (iron isomaltoside - iron 
sucrose) in change in Hb from baseline to week 8 is 0 g/dL superiority will be declared, and 
the p-values for the test of superiority will be presented. 
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 the 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 a eCRF guideline will 
be available.  


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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 doc-
uments for the purpose of verification of available data. 
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 GCP deviations.  
Out of visit windows will be registered as minor deviations if they are < 14 days. 
The following will be assessed as major protocol deviation: 
 Out of visit window of ≥ 14 days after the final visit (i.e. ≥ 70 days after baseline) 
 Intake of prohibited medication 
 Treatment compliance outside the 80-120 % range (the calculation of compliance for 
iron sucrose is based upon the cumulative dose recorded at baseline) 
 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. 


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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  
 Global trial management 
  
 
 Global medical monitoring 
 
 QC/Regulatory  
 
 
 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 on a monthly basis.   
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   
 
 Head of Drug Safety  
 
 
 QC/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 
 
 
 
 Pharmacosmos CEO   
 
 
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. 


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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 15 years.  
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. 


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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. 
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. 


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20.1 
Uploading of Data on Public Websites 
The co-primary endpoints and key secondary endpoints will be uploaded on public websites 
in according to national requirements. Key secondary endpoints in the trial are the following: 
 Change in concentrations of Hb from baseline to weeks 1, 2, and 4 
 Change in concentrations of s-ferritin and TSAT from baseline to weeks 1, 2, 4, and 8 
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 
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 
Jahn MR, Andreasen HB, Futterer S, Nawroth T, Schunemann V, Kolb U et al. A compara-
tive study of the physicochemical properties of iron isomaltoside 1000 (Monofer®), a new 
intravenous iron preparation and its clinical implications. Eur J Pharm Biopharm 
2011;78:480-491 
Mallinckrodt CH, Lin Q, Molenberghs M. A structured framework for assessing sensitivity 
to missing data assumptions in longitudinal clinical trials. Pharmaceutical Statistics 
2012;12:1-6 
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 
Venofer® prescribing information (USA), 01/2014 
Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anaemia in inflammatory bowel 
disease: a systematic review of the literature. American Journal of Medicine 2004;116:44S-
49. 
WHO. Worldwide prevalence of anaemia 1993-2005, WHO Global Database on Aneamia, 
Center for Disease Control and Prenention, 2008  
 
 
 
 


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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 


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 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 


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 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-03 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
14 June 2017 
 
 
Confidential 
 
 Page 57 of 59 
APPENDIX B 
Adjudicated composite cardiovascular endpoints  
1. Death due to any cause will be adjudicated as the date the subject is pronounced dead. 
  
2. Myocardial infarction: A myocardial infarction (MI) will be defined as the presence of 
the characteristic changes in cardiac enzyme markers in the setting of either temporally relat-
ed symptoms of an acute coronary syndrome or electrocardiographic (ECG) changes con-
sistent with either ischemia or infarction. 
Cardiac enzyme markers indicative of an MI will include: 
 An appropriate rise and fall in serum troponin (I or T) or creatine kinase-MB where at 
least 1 value is ≥ 2 × upper limit of normal (ULN). Where only 1 value has been 
measured, if it is ≥ 2 × ULN, an event may be adjudicated based on the totality of the 
clinical evidence. 
 Where only total creatine phosphokinase is measured, serial changes (i.e. at least 2 
values) need to be ≥ 2 × ULN. 
Symptoms indicative of ischemia will need to have been present for > 10 minutes and may 
include chest pain, chest pressure, or chest tightness. Dyspnoea, diaphoresis, or nausea may 
be considered symptoms of ischemia and will be judged based on the totality of the clinical 
evidence. 
ECG changes will be defined as: 
 New Q waves in 2 or more contiguous leads 
 Evolving ST-segment to T-wave changes in 2 or more contiguous leads + (such as ≥ 
0.5 mm transient ST-segment depression) 
 New left bundle branch block 
 1 mm ST-segment elevation in 2 or more contiguous leads 
 
3. Stroke: A stroke is defined as a focal neurological deficit of sudden onset that is not re-
versible within 24 hours that results from a vascular cause involving the central nervous sys-
tem and is not due to another readily identifiable cause (i.e. brain tumour or trauma). Strokes 
will be sub-classified as haemorrhagic, ischaemic, or unknown. 
 
4. Unstable angina requiring hospitalization: Unstable angina requiring hospitalization will 
be defined as ischemic symptoms meeting the following criteria: 
1. Lasting  10 minutes and considered to be myocardial ischemia on final diagnosis 
AND 
2. Requiring an unscheduled visit to a health care facility and overnight admission (does 
not include chest pain observation units) 
AND 
3. At least one of the following: 
 New dynamic ECG changes 


Trial ID: 
P-Monofer-IDA-03 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
14 June 2017 
 
 
Confidential 
 
 Page 58 of 59 
 Ischemia evidence on stress testing with or without cardiac imaging 
 Angiographic evidence of ≥ 70 % lesion and/or thrombus in an epicardial cor-
onary artery 
 
5. Congestive heart failure requiring hospitalization or medical intervention will meet 
the following criteria: 
1. Requires hospitalization defined as an admission to an inpatient unit or a visit to an 
emergency department that results in at least a 12-hour stay (or a date change if the 
time of admission/discharge is not available) 
AND 
2. Clinical manifestation of congestive heart failure including at least one of the follow-
ing: new or worsening dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea, oede-
ma, pulmonary basilar crackles, jugular venous distension, or radiological evidence of 
worsening heart failure 
AND 
3. Additional/increased therapy 
a. Intravenous treatment with diuretic, inotrope, or vasodilator therapy  
OR 
b. Mechanical or surgical intervention (mechanical circulatory support, heart 
transplantation, or ventricular pacing to improve cardiac function) or the use of 
ultrafiltration, hemofiltration, or dialysis that is specifically directed at 
treatment of heart failure 
 
6. Arrhythmia will be defined as any symptomatic deviation from normal sinus rhythm expe-
rienced by the subject that results in an evaluation by a health care provider. The evaluation 
may include a physical exam during an outpatient visit, an ECG, or a hospital admission. Ar-
rhythmias may include any conduction abnormality, atrioventricular heart block, prolongation 
of QTc interval, supraventricular/nodal arrhythmia, vasovagal episode, ventricular arrhyth-
mia, or other cardiovascular arrhythmia. 
 
7. Hypertension 
 During the observation period immediately following trial drug administration, hyper-
tension will be defined as an increase in systolic blood pressure > 20 mm Hg that re-
sults in a value > 180 mm Hg or an increase in diastolic blood pressure > 15 mm Hg 
that results in a value > 105 mm Hg  
 Following the release of a subject from the trial visit during which they are receiving 
medication, hypertension will be defined as requiring an unscheduled outpatient health 
care visit, a hospital admission, or a change in medical therapy (e.g. administration of 
antihypertensives) in conjunction with the objective criteria, a rise in blood pressure 
(an increase in systolic blood pressure > 20 mm Hg that results in a value > 180 mm 
Hg or an increase in diastolic blood pressure > 15 mm Hg that results in a value > 105 
mm Hg) 


Trial ID: 
P-Monofer-IDA-03 
 
Protocol Version: 
3.0 (amendment 2) 
Date of Document : 
14 June 2017 
 
 
Confidential 
 
 Page 59 of 59 
8. Hypotension 
 During the observation period immediately following trial drug administration, hypo-
tension will be defined as a decrease in systolic blood pressure > 20 mm Hg that re-
sults in a value < 90 mm Hg or a decrease in diastolic blood pressure > 15 mm Hg that 
results in a value < 50 mm Hg. 
 Following the release of a subject from the trial visit during which they are receiving 
medication, hypotension will be defined as requiring an unscheduled outpatient health 
care visit, a hospital admission, or a change in medical therapy (e.g. fluid/volume re-
pletion, holding of antihypertensives) in conjunction with the objective criteria, a dec-
rement in blood pressure (a decrease in systolic blood pressure > 20 mm Hg that re-
sults in a value < 90 mm Hg or a decrease in diastolic blood pressure > 15 mm Hg that 
results in a value < 50 mm Hg). 
 
 

SAP_001.pdf: 
Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
P-CDK-04_IDA-03_SAP_V2_20180412.docx 
Confidential 
Page 1 of 25 
 
 
 
 
Statistical Analysis Plan 
Trial IDs: 
 
P-Monofer-CKD-04 and P-Monofer-IDA-03 
 
 
 
 
Phase III Trials 
 
 
 
 
 
 
 
 
 
 
Author: 
 
Principal Statistician 
 
 
 
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. 




Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
P-CDK-04_IDA-03_SAP_V2_20180412.docx 
Confidential 
Page 3 of 25 
 
Table of Contents 
List of Tables .................................................................................................................................. 4 
1 
List of Abbreviations ................................................................................................................ 5 
2 
Introduction ............................................................................................................................ 6 
3 
Trial Characteristics ................................................................................................................. 7 
3.1 
Trial Objectives ........................................................................................................................................ 7 
3.1.1 
Primary Objective .................................................................................................................... 7 
3.1.2 
Secondary Objectives .............................................................................................................. 7 
3.2 
Trial Design .............................................................................................................................................. 8 
3.3 
Subject included ...................................................................................................................................... 9 
3.3.1 
Sample Size Determination ..................................................................................................... 9 
4 
Analysis Populations .............................................................................................................. 10 
4.1 
Major protocol deviations ..................................................................................................................... 11 
4.1.1 
Prohibited Medication........................................................................................................... 11 
5 
Planned Statistical Methods ................................................................................................... 12 
5.1 
Statistical Considerations ...................................................................................................................... 12 
5.2 
Subject Disposition ................................................................................................................................ 12 
5.3 
Baseline Characteristics and Demographics ......................................................................................... 13 
5.4 
Medical History ..................................................................................................................................... 13 
6 
Exposure and Other Dosing Information ................................................................................. 13 
6.1 
Exposure ................................................................................................................................................ 13 
6.2 
Concomitant medication ....................................................................................................................... 13 
7 
Statistical Methodology for Co-Primary and Secondary Endpoints........................................... 14 
7.1 
Analysis and Presentation of the Co-Primary Endpoints ...................................................................... 14 
7.1.1 
Co-primary Safety Endpoint .................................................................................................. 14 
7.1.2 
Co-primary efficacy endpoint ................................................................................................ 15 
7.2 
Analysis and Presentation of the Secondary Efficacy Endpoints .......................................................... 17 
7.2.1 
Haemoglobin ......................................................................................................................... 18 
7.2.2 
s-ferritin, TSAT, and s-iron ..................................................................................................... 19 
7.2.3 
FACIT fatigue scale ................................................................................................................ 19 
7.2.4 
Other Assessments ................................................................................................................ 20 
7.3 
Handling of Missing Values ................................................................................................................... 20 
7.4 
Multiplicity adjustments ....................................................................................................................... 20 
7.5 
Sub-group and Centre Effects ............................................................................................................... 20 
8 
Statistical Methodology for Safety Endpoints ......................................................................... 21 
8.1 
Safety Endpoints ................................................................................................................................... 21 
8.1.1 
Analysis and Presentation of Safety Endpoints ..................................................................... 21 
8.1.2 
Adverse Events ...................................................................................................................... 21 
8.1.3 
Composite cardiovascular AEs............................................................................................... 22 
8.1.4 
Serum Phosphate .................................................................................................................. 22 
8.1.5 
Other Safety Assessments ..................................................................................................... 22 
8.1.6 
Laboratory Safety Data .......................................................................................................... 23 
8.2 
Interim Analysis ..................................................................................................................................... 23 
9 
Combined Analyses ............................................................................................................... 24 
9.1 
Pooled analyses of the co-primary safety endpoint ............................................................................. 24 
9.2 
Pooled analyses of the co-primary efficacy endpoint ........................................................................... 24 
9.3 
Pooled Analyses of the Secondary Efficacy Endpoints .......................................................................... 24 
9.4 
Pooled Analyses of the Composite Cardiovascular AEs ........................................................................ 25 
10 Software ............................................................................................................................... 25 
11 Reference List ........................................................................................................................ 25 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
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Confidential 
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List of Tables 
Table 1: Activities Flow Chart .................................................................................................................. 8 
 
 
 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
P-CDK-04_IDA-03_SAP_V2_20180412.docx 
Confidential 
Page 5 of 25 
 
1 List of Abbreviations 
ADR 
Adverse Drug Reaction  
AE 
Adverse Event 
CEAC 
Clinical Endpoint Adjudication Committee 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
CRF 
Case Report Form 
CSR 
Clinical Trial Report 
DBL 
Data Base Lock 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
ESA 
Erythropoiesis Stimulating Agents 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAS 
Full Analysis Set 
IDA 
Iron Deficiency Anaemia 
ITT 
Intention-To-Treat 
Hb 
Haemoglobin 
LLOQ 
Lower Limit of Quantification 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measurements 
MNAR 
Missing Not at Random 
N 
Number of Subjects 
NDD 
Non-Dialysis-Dependent 
PP 
Per Protocol  
PT 
Preferred Term 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan   
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SOC 
System Organ Class 
SMQ 
Standardised Medical Dictionary for Regulatory Activities Query 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TEAE 
Treatment Emergent Adverse Event 
TSAT 
Transferrin Saturation 
 
 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
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Confidential 
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2 Introduction 
The statistical analysis plan (SAP) is a generic SAP for the two trials; P-Monofer-CKD-04, based on the 
final protocol 4.0 dated 14 June 2017 and P-Monofer-IDA-03, based on the final protocol 3.0 dated 14 
June 2017.  
The SAP describes in detail the analyses to be conducted and highlights any deviations from the 
analysis described in the protocols (see section Error! Reference source not found.). Deviations from 
methods described in this SAP, if any, will be specified in the clinical trial reports (CSRs).  
All endpoints, analysis and presentation of data will be handled the same way for the two trials, unless 
otherwise specified. Any differences in endpoints, analysis or presentations will be clearly described. 
Before releasing data for final analysis, one or more data review and classification meetings will be 
held 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 at the classification meetings 
Reporting of the individual trials will be after the date of last subject last visit for each trial. Reporting 
of combined analyses of the two trials may be done after finalizing of the individual CSRs, and included 
as appendixes to the CSRs. 
 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
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Confidential 
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3 Trial Characteristics 
3.1 Trial Objectives 
3.1.1 Primary Objective 
Trial P-Monofer-CKD-04 
The primary safety objective of the trial is to evaluate the safety of IV iron isomaltoside compared to 
iron sucrose in subjects with iron deficiency anaemia (IDA) and non-dialysis-dependent chronic kidney 
disease (NDD-CKD). The evaluation will be based on the iron isomaltoside arm only, and conclusion 
will be drawn regardless of the safety observed in the iron sucrose arm. 
The primary efficacy objective of the trial is to evaluate and compare the effect of iron isomaltoside to 
iron sucrose in its ability to increase haemoglobin (Hb) in subjects with IDA and NDD-CKD. 
Trial P-Monofer-IDA-03 
The primary safety objective of the trial is to evaluate the safety of IV iron isomaltoside compared to 
iron sucrose in subjects with IDA when oral iron preparations are ineffective or cannot be used or in 
whom the screening Hb measurement in Investigators' opinion were sufficiently low as to require 
rapid repletion of iron stores. The evaluation will be based on the iron isomaltoside arm only, and 
conclusion will be drawn regardless of the safety observed in the iron sucrose arm. 
The primary efficacy objective of the trial is to evaluate and compare the effect of iron isomaltoside to 
iron sucrose in its ability to increase Hb in subjects with IDA when oral iron preparations are 
ineffective or cannot be used or in whom the screening Hb measurement in Investigators' opinion 
were sufficiently low as to require rapid repletion of iron stores. 
3.1.2 Secondary Objectives  
The secondary efficacy objectives of the trials are to evaluate and compare the effect of iron 
isomaltoside to iron sucrose on: 
 
Other relevant iron related biochemical parameters 
 
Fatigue symptoms 
 
Pharmacoeconomics 
 
Note: Assessments related to pharmacoeconomics are only performed at baseline and it will not be 
possible to estimate a treatment effects. 
 
 




Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
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Confidential 
Page 9 of 25 
 
Vital signsb1 
  
 
X  
(X)  
X  
(X)  
X  
X  
X  
Oral iron (only 
patients included in 
the run-in period) 
 
R1-R3 
 
 
 
 
 
 
 
Compliance to oral 
iron 
 
R2-R4 
 
 
 
 
 
 
 
Tolerance to oral 
iron 
 
R2-R4g 
 
 
 
 
 
 
 
Randomisation  
  
 
X  
  
  
  
  
  
  
ECG b1, b2 
  
 
X  
(X)  
X  
(X)  
X  
X  
X  
FACIT Fatigue Scale  
  
 
X  
  
X  
  
X  
  
X  
ISDR questionnaire   
  
 
X  
  
  
  
  
  
  
Health care 
resource use 
questionnaire  
  
 
X  
  
  
  
  
  
  
Safety lab tests  
  
 
X  
  
X  
  
X  
X  
X  
Efficacy lab tests  
  
 
X  
  
X  
  
X  
X  
X  
Treatment with iron 
isomaltosidec or  
  
 
X  
  
  
  
  
  
  
Treatment with iron 
sucrosec  
  
 
X  
(X)  
(X)  
(X)  
(X)  
  
  
Adverse events   
  
 
X  
(X)  
X  
(X)  
X  
X  
X  
Final visit formd  
  
 
  
  
  
  
  
  
X  
a. 
Physical examination, height, and weight may be measured between the screening and baseline visit 
b1. For details of the assessment, please see Section 8.1.5. 
b2. An ECG will be taken for all subjects. In addition, intensive ECG monitoring for evaluation of QTc prolongations will be performed at           
baseline in 35 subjects in trial P-Monofer-IDA-03. 
c. 
All trial assessments should be done before administration of the trial drug unless otherwise stated in Section 8.1.5. 
d. 
The final visit form may be filled in at any time of the trial if the subject is withdrawn. 
e. 
Subjects in group B may attend up to 2 additional treatment visits (TV1-TV2). The TV visits are optional treatment visit for dosing with 
iron sucrose, if in the opinion of the Investigator required in order to achieve the cumulative dose of iron sucrose. 
f. 
Subjects who do not have a documented intolerance of oral iron for at least 1 month within the last 9 months or had a screening Hb        
measurement which in Investigators' opinion was sufficiently low as to require rapid repletion of iron stores to minimize the risk of        
eventual blood transfusion should have up to 1 month of run-in period of oral iron in order to document intolerance or lack of response 
to oral iron. Subjects enrolled in the run-in period will have 1-4 additional visits (R1-R4). Visits R1-R3 are conducted by telephone. 
g. 
If a subject has been withdrawn during the run-in period due to intolerance, the subject may attend visit R4 before day -14. 
 
3.3 Subject included 
3.3.1 Sample Size Determination 
Safety:  
Data from previous trials conducted with iron isomaltoside suggests that the incidence of treatment-
emergent serious and/or severe non-serious hypersensitivity adverse events (AEs) for an IDA 
population can be expected to be approximately 1 % (IBD-01/IBD-02/CIA-01/PP-01: n=3/341=0.9 %, 
95% confidence interval (CI): 0.2 %; 2.5 %). And similar for iron sucrose (CKD-03: n=1/114=0.9 %, 95% 
CI: 0.0 %; 4.8 %). A common incidence of 1.5 % will be assumed for the current trial.  


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
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Confidential 
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As these are relatively rare events, an incidence of 0 % for placebo is assumed. Iron isomaltoside 
should be at most 50 % worse than the difference between iron sucrose and placebo, corresponding 
to a maximum relative risk of 2 (1.5 % / (1.5 %-0 %)2).  
This trial will primarily assess the risk of the test drug under investigation. Arguing back from a relative 
risk of 2, gives that the upper bound of the 95 % CI for the incidence of treatment emergent serious 
and/or severe non-serious hypersensitivity AEs should be at most 3 % (2×1.5 %) for the iron 
isomaltoside treatment group.  
Efficacy:  
IDA-301 was a double-blind, placebo-controlled trial designed to compare the safety and efficacy of 
1000 mg IV ferumoxytol to placebo. In this trial, 608 subjects were treated with ferumoxytol and 200 
received placebo. The change in Hb from baseline to week 5 was the primary efficacy endpoint for the 
European Union regulators, and one of the secondary endpoints for U.S. regulators. The mean change 
was 2.6 g/dL (standard deviation (SD): 1.5) for IV ferumoxytol and 0.1 g/dL (SD: 0.9) for placebo. The 
estimated treated effect of IV ferumoxytol (i.e. the difference between ferumoxytol and placebo) was 
estimated to be approximately 2.5 g/dL with a 95 % CI ranging from 2.3 to 2.7 g/dL. The point estimate 
will be used as estimate of the treatment effect. Preserving 80 % of this effect is believed to provide 
reasonable assurance that iron isomaltoside is efficacious. Hence, the non-inferiority margin is set to 
(1-0.8) × 2.5 g/dL ~ 0.5 g/dL.  
Power:  
The significance level is set to 5 %. With n = 1000 in the iron isomaltoside treatment group, there is 88 
% power for demonstrating that the upper bound of the 95 % CI of the incidence of treatment-
emergent serious and/or severe non-serious hypersensitivity AEs is less than 3 %. And with n = 500 in 
the iron sucrose treatment group, assuming no difference between the treatment groups, and 
assuming a common SD = 1.5 g/dL, there is 100 % power for demonstrating non-inferiority of the 
change in Hb from baseline to week 8, using a non-inferiority margin of -0.5 g/dL.   
This yields a total power for demonstrating both co-primary endpoints of 88 %.  
The IDA-03 and CKD-04 trials will run in parallel with identical sample sizes, yielding a total of 2000 
subjects to be treated with iron isomaltoside and 1000 with iron sucrose. In addition to the efficacy 
and safety analyses performed for this trial alone, an efficacy and safety assessment will be performed 
for the two trials combined. This is briefly described in Section 9. 
4 Analysis Populations 
The following 4 analysis sets are defined and will be used in the analyses of the data:  
 
Intention to treat (ITT) analysis set: The ITT analysis set will include all randomised subjects. 
Subjects will be included as randomised.  
 
Safety analysis set: The safety analysis set will include all randomised subjects who received at 
least one dose of the trial drug. This will be the analysis set for evaluating safety.  
 
Full analysis set (FAS): The FAS will consist of all randomised 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 randomised.  
 
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 4.1. Subjects will be included as randomised. 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
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Confidential 
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The classification of the subjects will be performed before database lock. 
Subjects included in the Safety analysis set will be evaluated according to treatment actually received. 
The primary analysis population for efficacy evaluation is the ITT analysis set, and all efficacy 
endpoints will be analysed using the ITT and the subjects will be evaluated according to randomised 
treatment.  
The primary efficacy endpoint will in addition be analysed using the FAS and PP. The analysis specified 
for the FAS and PP are to be regarded as supportive evidence. 
4.1 Major protocol deviations 
Deviations from the protocol will be registered as protocol deviations. Before data base lock (DBL) all 
protocol deviations will be evaluated and classified as minor, major, or GCP deviations. Protocol 
deviations classified as major will lead to exclusion from PP analysis set. The decisions will be 
documented. 
The following will be assessed as major protocol deviation:  
 
Out of visit window of ≥ 14 days after the final visit (i.e. ≥ 70 days after baseline)  
 
Intake of prohibited medication (see section 4.1.1 for a list of prohibited medication) 
 
Treatment compliance outside the 80-120 % range (the calculation of compliance for iron 
sucrose is based upon the cumulative dose recorded at baseline) 
 
Other protocol deviations which are assessed as having a clinically or statistically significant 
effect (e.g. did not receive treatment as randomised) 
All major protocol deviations will be listed by subject. Separate listings will be made for the safety 
analysis set of all visits outside window, intake of prohibited medication and treatment compliance 
outside range. Protocol deviations will be summarised by classification and category. The summary 
table will present number and percentages of subjects with a deviation and number of deviations. 
4.1.1 Prohibited Medication 
The following medication and non-drug therapy is not allowed in both trials: 
 
Any premedication (e.g. antihistamine or steroids) before administration of the trial drug 
 
Any iron supplementation other than investigational drug, except oral iron during the run-in 
period of trial P-Monofer-IDA-03 (nutritional supplementation including iron is allowed unless 
it is assumed as treatment of the subject's anaemia)  
 
Blood transfusion  
P-Monofer-IDA-03 only: 
 
Erythropoiesis Stimulating Agents (ESA) 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
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Confidential 
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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. No statistical tests comparing treatment groups at baseline will be performed. 
Categorical data will be summarised by treatment, using number and percentages of subjects. For 
calculation of percentages the denominator will be the number of subjects in the analysis set, unless 
otherwise stated. Numerical data will be presented using the number of subjects (N), mean, SD, 
median, lower quartile, upper quartile, minimum and maximum. Both the absolute values and the 
change from baseline will be presented. 
Descriptive statistics for all endpoints will be presented by treatment group and week (if applicable) 
using observed cases, i.e. no imputation of missing data will be performed, except for subject in the 
ITT with no post baseline measurements of the co-primary efficacy endpoint. For these cases the 
change to first post baseline visit will be set to 0. Missing data for time to event endpoints is handled 
using censoring. 
Throughout this SAP, stratum or strata refer to the stratum the subject was randomised in. This might 
be different from the stratum the subject truly belongs to.  
For the logistic regressions, it might be necessary to pool strata in case one or more strata are very 
sparse. If needed to the two smallest strata will be pooled, and if necessary the pooling will be 
repeated for the two smallest strata after the initial pooling. 
For all analyses and presentations of efficacy endpoints scheduled time will be used, and trial visits will 
be labeled as follows: 
Visit  
Label 
2 Baseline 
3 
4 
5 
6 
Baseline 
Week 1 
Week 2 
Week 4 
Week 8 
 
5.2 Subject Disposition 
An overall summary table of the subject disposition will be prepared with number and percentages of 
subjects in the following categories (and sub-categories): 
 
Screened and randomised subjects 
 
Analysis sets (ITT, safety analysis set, FAS, and PP analysis set) 
 
End of study status 
 
Withdrawn from trial including reasons 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
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For calculation of the percentages the denominator will be number of randomised subjects and 
relative to planned treatment. 
Subject disposition will in addition be presented by stratum. All information will be listed. Separate 
listings will be made for subjects withdrawn from treatment and for screening failures.  
5.3 Baseline Characteristics and Demographics 
Demographics and baseline characteristics consist of age, gender, race, ethnicity, and smoking habits. 
Age will in addition be grouped into: 18-64 years, 65-84 years and above 84 years. Demographics will 
be listed and summarised using descriptive statistics, by treatment and by treatment and strata for the 
ITT and for the PP analysis set. 
5.4 Medical History 
Relevant medical history including history of myocardial infarction, stroke, or congestive heart failure, 
intolerance and non-response to oral iron treatment (P-Monofer-IDA-03 only) as well as underlying 
disorder causing IDA is collected.  
Medical history will be summarised and listed. Intolerance and non-response to oral iron treatment, 
and underlying disorder causing IDA will be summarised separately. 
6 Exposure and Other Dosing Information 
6.1 Exposure 
Dose and compliance will be summarised using descriptive statistics and presented for the safety 
analysis set by treatment, and by treatment and underlying disease causing IDA. 
For both treatments, planned and actual dose in mg, number of doses and compliance will be 
presented. 
 
Compliance will be calculated as: 
 
100∗actual dose
planned dose  
 
All information will be listed. Furthermore, subjects out of the treatment compliance range of 80-120 
% will be listed. 
 
6.2 Concomitant medication 
Concomitant medication at baseline and changes in concomitant medication during the trial will be 
recorder. All concomitant medication will be summarised and listed using the IIT analysis set. 
 
 
 


Sponsor: Pharmacosmos  
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7 Statistical Methodology for Co-Primary and Secondary Endpoints 
7.1 Analysis and Presentation of the Co-Primary Endpoints 
The primary safety objective of each trial is to evaluate the safety of IV iron isomaltoside compared to 
iron sucrose. The primary safety analysis will be based on the iron isomaltoside arm alone, and 
conclusion will be drawn regardless of the safety observed in the iron sucrose arm.  
The co-primary endpoints for evaluation of the primary safety and efficacy objectives are: 
 
Serious or severe hypersensitivity reaction starting on or after the first dose of randomised 
treatment (i.e. treatment emergent) 
 
Change in Hb from baseline to week 8 
7.1.1 Co-primary Safety Endpoint 
The co-primary safety endpoint will be summarised and analysed using the safety analysis set. 
The hypersensitivity terms are defined as standardised Medical Dictionary for Regulatory Activities 
query (SMQ) terms (including four additional terms), please refer to the protocols Appendix A.  
The AEs will be adjudicated in a blinded fashion by an independent Clinical Endpoint Adjudication 
Committee (CEAC) (described in a separate adjudication charter). Only the adjudicated serious (fatal) 
or severe hypersensitivity reaction as judged by the CEAC will be considered as co-primary endpoint. 
The treatment emergent serious or severe hypersensitivity reactions starting on or after the first dose 
of treatment will be summarised by SMQ term and preferred term (PT). The summary will include 
number of events, number of subjects, and proportion of subjects reporting serious or severe 
hypersensitivity reactions. 
The following hypothesis will be tested: 
The number of subjects reporting treatment-emergent serious or severe non-serious hypersensitivity 
reactions in the iron isomaltoside treatment group is less than 3 %.  
H01: πiron isomaltoside ≥ 3 % against the 
alternative:  
HA1: πiron isomaltoside < 3 %,  
where, πiron isomaltoside denote the number of subjects reporting of treatment-emergent serious or severe 
non-serious hypersensitivity reactions.  
The null hypothesis will be tested against the alternative by constructing an unadjusted two-sided 
exact 95 % CI of the number of subjects. If the upper bound of the 95 % CI is <3 %, the safety objective, 
is considered met.  
Note, In the protocols section 15.1 it is stated that the hypotheses that the incidence of treatment-
emergent serious and/or severe non-serious hypersensitivity reactions in the iron isomaltoside 
treatment group is less than 3 % will be tested. The intension was to evaluate on the number of 
subjects, i.e. the hypotheses that the number of subjects, and not number of events, reporting 


Sponsor: Pharmacosmos  
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Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
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treatment-emergent serious or severe non-serious hypersensitivity AEs in the iron isomaltoside 
treatment group is less than 3 % will be tested. 
In addition, as supportive information, the risk difference between iron isomaltoside and iron sucrose 
will be assessed by constructing a 95 % CI of the risk difference. Both an unadjusted CI (with continuity 
correction), and a 95 % Newcombe CI adjusted for strata using the Cochran-Mantel-Haenszel method 
will be produced (ref. Yeonhee K. and Seunghyun W. 2013). 
7.1.2 Co-primary efficacy endpoint 
Change from baseline in Hb will be summarised by treatment and week using ITT, FAS and PP, 
respectively. Furthermore, the change from baseline in Hb will be summarised by strata, treatment 
and week using ITT, FAS and PP, respectively. 
All subjects in the ITT with post baseline Hb data will be included with their observed data. For 
subjects without post baseline Hb values, the change from baseline will be set to 0 at the first post-
baseline visit. This imputation will be included in the summary tables as well as in the primary analysis. 
Number of subjects without post baseline Hb values will be summarised.  
The co-primary efficacy endpoint will be analysed using a mixed model for repeated measurement 
(MMRM) with a restricted maximum likelihood (REML)-based approach.  
The following hypothesis will be tested: 
H02: µiron isomaltoside - µiron sucrose ≤ -0.5 g/dL  
against the alternative:  
HA2: µiron isomaltoside - µiron sucrose > -0.5 g/dL,  
where, µiron isomaltoside and µiron sucrose denote the change from baseline to week 8 in Hb. 
The model will include the fixed, categorical effects of treatment (iron isomaltoside and iron sucrose), 
week, treatment-by-week interaction, strata, as well as the continuous, covariates of baseline Hb 
value and baseline Hb-by-week interaction. The treatment effect will be estimated using SAS Proc 
Mixed: 
proc mixed data=_data method=reml cl ; 
  class trtp strata avisit subjid ; 
  model chg = trtp*avisit base*avisit avisit trtp strata base  / cl ddfm=kr noint ; 
  repeated avisit / type=un subject=subjid ; 
  estimate 'Visit 6, Iron Isomaltoside - Iron Sucrose' trtp 1 -1  trtp*avisit 0 0 0 1 0 0 0 -1 / cl ;   
run ; 
An unstructured covariance structure 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.  


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
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IDA-03 
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Version:                             Final 2.0    
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The Kenward-Roger approximation will be used to estimate the denominator degrees of freedom.  
The primary comparisons will be the contrasts between iron isomaltoside and iron sucrose at week 8 
based on the least squares means for the treatment-by-week interaction effect. The estimated mean 
difference based on this model will be reported with two-sided symmetric 95 % CI. 
Non-inferiority of iron isomaltoside 1000 against iron sucrose can be claimed if the lower bound of the 
95% CI is above -0.5 g/dL. The hypothesis is tested by evaluating the lower CI, and p-value for the non-
inferiority test will not be given. 
If non-inferiority is claimed it will be investigated if iron isomaltoside 1000 is superior to iron sucrose. 
If the lower bound of the two-sided 95 % CI is above 0 g/dL superiority will be declared, and the p-
value associated with a test of superiority will be presented.  
As sensitivity, the analysis above will be repeated for the FAS and the PP population.   
Sensitivity to missing data 
Some level of data missingness is expected, and the primary analysis (MMRM) is valid under the 
assumption that the data is Missing at Random (MAR). Simulation trials do suggest that MMRM is 
robust to accommodate some level of data Missing Not at Random (MNAR). Since it is unclear how the 
level of missingness of this type of data will influence the outcome at this stage, choosing a pre-
specified primary analysis valid under MNAR accurately will be very difficult. As such, sensitivity 
analyses valid under relevant cases of data MNAR will be performed.  
In particular, a pattern mixture model approach mimicking an ITT scenario where withdrawn subjects 
are assumed to be switched to a treatment inferior to the treatment with iron sucrose after 
withdrawal will be applied. With 5 visits (including baseline) there are 25 = 32 possible missing data 
patterns.  
In order to reduce the number of pattern groups and obtain a monotone missing data pattern, 
intermittent missing values (i.e. missing values followed by a non-missing value) will initially be 
imputed using a Markov Chain Monte Carlo (MCMC) method. This imputation is done for each 
treatment group separately and 100 copies of the dataset will be generated. 
For the below imputations, it might be necessary to pool strata in case one or more strata are very 
sparse. If needed to the two smallest strata will be pooled, and if necessary the pooling will be 
repeated for the two smallest strata after the initial pooling. 
In the first step, for each of the 100 copies of the dataset, an analysis of variance model with strata as 
factor, and baseline Hb as covariate is fitted to the Hb value at week 1 for each treatment arm. The 
estimated parameters, and their variances, from this model are used to impute missing values at week 
1 for subjects in both treatment groups, based on their strata and Hb at baseline. 
In the second step, for each of the 100 copies of the dataset, an analysis of variance model with strata 
as factor, and baseline Hb and Hb at 1 week as covariates is fitted to Hb at 2 weeks for each treatment 
arm. The estimated parameters, and their variances, from this model are used to impute missing 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
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values at 2 weeks for subjects in both treatment groups, based on their strata and Hb at baseline and 
1 week. 
Missing values at 4 and 8 weeks are imputed using a similar approach. 
Now in step five, for each withdrawn subject in the iron isomaltoside treatment group, a value of 0.5 
g/dL (the non-inferiority limit as penalty) is subtracted from the change in Hb at 8 weeks. This 
corresponds to the assumption that a subject that withdraws from the iron isomaltoside is switched to 
a treatment that is inferior to iron isomaltoside. 
Step six: For each of the complete data sets, the change from baseline to visit 8 is analysed using an 
analysis of variance model with treatment, site, and strata as factors and the baseline Hb value as a 
covariate. The estimates and standard deviations for the 100 data sets are pooled to one estimate and 
associated standard deviation using Rubin’s formula: 
 
where 𝑚𝑖 and 𝑆𝐷𝑖 are the estimated means and standard deviations for the 100 copies of the dataset, 
and 𝑚𝑀𝐼, 𝑆𝐷𝑀𝐼 are the pooled estimates. 
In the final step, then from 𝑚𝑀𝐼 and 𝑆𝐷𝑀𝐼, the 95% confidence interval for the treatment difference 
and the associated p-value are calculated. 
Mean plots of Hb from baseline to week 8 will be presented by monotone missing pattern group and 
treatment. 
Step five will be repeated using different delta (penalties) and the tipping-point, where the results no 
longer fulfil non-inferiority, will be calculated if applicable. The pattern mixture models with multiple 
imputations are described by C. H. Mallinckrodt, Q. Lin, and G. Molenberghs [Mallinckrodt et al., 
2012]. These analyses will be performed for the ITT and for the FAS, and PP analysis sets, if applicable. 
Other penalties may be explored.  
7.2 Analysis and Presentation of the Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following:   
Trial P-Monofer-CKD-04: 
 
Hb increase of ≥ 1 g/dL from baseline to weeks 1, 2, 4, or 8  
 
Time to change in Hb ≥ 1 g/dL  
 
Trial P-Monofer-IDA-03: 
 
Hb increase of ≥ 2 g/dL from baseline to weeks 1, 2, 4, or 8  
 
Time to change in Hb ≥ 2 g/dL  
 
Both trials: 
 
Hb level of > 12 g/dL at any time from week 1 to week 8  


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
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 
Increase in Hb concentration ≥ 2 g/dL at any time from week 1 to week 8  
 
S-ferritin level of ≥ 100 ng/mL and transferrin saturation (TSAT) of 20-50 % at any time from 
week 1 to week 8  
 
Change in concentrations of Hb from baseline to weeks 1, 2, and 4  
 
Change in concentrations of s-ferritin, TSAT, and s-iron from baseline to weeks 1, 2, 4, and 8  
 
Change in fatigue symptoms from baseline to weeks 1, 2, and 8 measured by the Functional 
Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
 
Resources used by the subject (per visit) and health care staff (per administration) measured 
by the ISDR questionnaire and health care resource use questionnaire, respectively 
Note, the ISDR questionnaire and the health care resource use questionnaire are only filled in at 
baseline. 
7.2.1 Haemoglobin 
HB responder 
In trial P-Monofer-CKD-04 a subject is considered a Hb responder to a certain week if an increase in Hb 
of at least 1 g/dL from baseline to the week in question is observed. In trial P-Monofer-IDA-03 a 
subject is considered a Hb responder to a certain week if an increase in Hb of at least 2 g/dL from 
baseline to the week in question is observed. Hb response will be evaluated against the weeks 1, 2, 4 
and 8. Subjects without baseline- or post baseline Hb values will be set as non-responders at the first 
post-baseline week. 
Number and percentage of responders will be summarised by treatment and week. 
Proportion of Hb responders to each week will be analysed using a repeated measures logistic 
regression model with treatment, visit, strata and treatment by visit interaction as fixed effects and 
baseline value as covariate. An unstructured covariance structure will be used to model the within-
subject errors. If the model does not converge one of the following covariance structures will be 
applied; exchangeable, m-dependent or independent. For each visit the estimated treatment ratio of 
iron isomaltoside versus iron sucrose will be presented with 95 % CIs and corresponding p-value.  
Time to Hb response 
Time to Hb response is considered the key secondary endpoint. 
For responders, time to Hb response is defined as the scheduled time from baseline until the visit 
where the first Hb response were measured. For non-responders, time to response will be censored at 
the visit with the last known Hb measurement. Subjects without baseline- or post baseline Hb values 
will be censored at visit 2, Baseline. 
Time to Hb response will be estimated using the Kaplan-Meier method and the hypothesis of no 
treatment difference will be assessed by a 2-sided log-rank test. Plots including the Kaplan-Meier 
curves, log-rank test and median survival time will be presented overall by treatment. 
Hb level of > 12 g/dL 
The proportion of subjects who achieve Hb level of > 12 g/dL at any time from week 1 to week 8 will 
be analysed using a logistic regression model with treatment and strata as fixed effects. The estimated 
treatment ratio of iron isomaltoside versus iron sucrose will be presented with 95 % CIs and 
corresponding p-value. Subjects without postbaseline Hb values will be set as failures. 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
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Increase in Hb concentration ≥ 2 g/dL from week 1 to week 8 
The proportion of subjects who achieve an increase in Hb concentration ≥ 2 g/dL at any time from 
week 1 to week 8 will be analysed using a logistic regression model with treatment and strata as fixed 
effects. The estimated treatment ratio of iron isomaltoside versus iron sucrose will be presented with 
95 % CIs and corresponding p-value. 
Change in concentrations of Hb 
Change in concentrations of Hb from baseline to weeks 1, 2, and 4 will be analysed using a MMRM 
including treatment, week, treatment-by-week interaction, and strata as factors and baseline Hb, and 
baseline Hb-by-week interaction as covariates. An unstructured covariance structure will be used to 
model the within-subject errors and the estimation method will be a REML-based approach.  
The estimated treatment differences based on the least square means of the treatment-by-week 
interaction effects will be presented by week including 95% CIs and corresponding p-values. 
Change in Hb concentrations from baseline to week 1, 2, 4, and 8 will be summarised by treatment 
and week using descriptive statistics. Furthermore, absolute Hb values will be presented by treatment 
and week. 
Change in Hb concentrations over time by treatment will be presented using mean plots.  
7.2.2 s-ferritin, TSAT, and s-iron 
Proportion of subject who achieve a s-ferritin level of ≥ 100 ng/mL and a TSAT of 20-50 % at any time 
from week 1 to week 8 will be analysed using a logistic regression model with treatment and strata as 
fixed effects. The estimated treatment ratio of iron isomaltoside versus iron sucrose will be presented 
with 95 % CIs and corresponding p-value. 
Change in concentrations of s-ferritin from baseline to weeks 1, 2, 4 and 8 will be analysed using a 
MMRM including treatment, week, treatment-by-week interaction, and strata as factors and baseline 
valeu, and baseline value-by-week interaction as covariates. An unstructured covariance structure will 
be used to model the within-subject errors and the estimation method will be a REML-based 
approach. Change in concentrations of TSAT and s-iron will be analysed using similar models. 
The estimated treatment differences based on the least square means of the treatment-by-week 
interaction effects will be presented by week including 95% CIs and corresponding p-values. 
Concentrations of s-ferritin will be summarised by treatment and week using descriptive statistics, 
including change from baseline. Change in concentrations of s-ferritin over time by treatment will be 
presented using mean plots. Change in concentrations of TSAT and s-iron will be presented in a similar 
way. 
7.2.3 FACIT fatigue scale 
The FACIT fatigue scale consist of 13 items ranging from 0 (not at all) to 4 (very much). All items, 
except items 7 and 8 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 the 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. 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
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𝑇𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒= 𝑆𝑢𝑚 𝑜𝑓 𝑖𝑛𝑑𝑖𝑣𝑖𝑑𝑢𝑎𝑙 𝑠𝑐𝑜𝑟𝑒𝑠 𝑥 13
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑡𝑒𝑚𝑠 𝑎𝑛𝑠𝑤𝑒𝑟𝑒𝑑 
Change in fatigue symptoms will be considered a continuous measure and will be analysed and 
presented similar to change in Hb except that treatment differences will be given for week 1, 2 and 8. 
A sensitivity analysis will be performed using observed cases only, i.e. without imputation of missing 
items. 
7.2.4 Other Assessments 
Pharmacoeconomics is assessed at baseline by the ISDR questionnaire and the health care resource 
use questionnaire.  
The health care resource use questionnaire includes the following items: 
 
What is your profession (nurse, doctor, etc.)? 
 
How much time did you use on administration of the trial drug including preparing for the 
administration, administration time, and observation time? 
The items of the two questionnaires will be summarised using descriptive statistics. All information 
will be listed. 
7.3 Handling of Missing Values 
The co-primary efficacy endpoint is analysed using a MMRM based on the MAR assumption and 
performed using observed cased, except for subject in the ITT set with no post baseline data. For these 
subjects change to first post baseline week is set to 0. Sensitivity analyses using pattern mixture 
models and MI are performed to evaluate the robustness of the MAR assumptions. Please refer to 
section 7.1.2 for details. 
For endpoints describing time to response missing values will be handled using censoring. 
If less than 50 % of the items in the FACIT questionnaire are missing the scores are prorated using the 
average of the other answers in the scale. 
7.4 Multiplicity adjustments 
In these two-armed trials there is no multiplicity issue with more comparators. The trials contain two 
co-primary endpoints and both needs to be fulfilled in order to claim overall success of the individual 
trials. Superiority for the will only be tested if non-inferiority has been claimed. 
For the limited number of secondary endpoints, no adjustment for multiplicity will be done. For 
secondary efficacy endpoints analysed using MMRM estimated treatment differences, CIs and 
corresponding p-values are presented for each week, but no adjustment for multiplicity is applied. 
7.5 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. 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
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8 Statistical Methodology for Safety Endpoints 
Safety will be considered for subjects included in the Safety Analysis Set and reported by actual 
received treatment, unless otherwise stated. No imputation of missing data is planned for safety 
endpoints. 
8.1 Safety Endpoints 
The secondary safety endpoints are the following: 
 
Composite cardiovascular AEs starting on or after the first dose of randomised treatment. The 
adjudicated composite AEs includes the following: 
 
Death due to any cause  
 
Non-fatal myocardial infarction  
 
Non-fatal stroke  
 
Unstable angina requiring hospitalization  
 
Congestive heart failure requiring hospitalization or medical intervention  
 
Arrhythmias  
 
Hypertension  
 
Hypotension 
 
Time to first composite cardiovascular safety AE  
 
Serum (s-) phosphate < 2 mg/dL at any time from baseline to weeks 1, 2, 4, or 8  
 
Additional safety assessments are physical examinations and measurements of vital signs, height, 
weight, electrocardiogram (ECG), and safety laboratory parameters will be measured as part of 
standard safety assessments. Furthermore, in trial P-Monofer-IDA-03, intensive ECG monitoring for 
evaluation of QTc prolongations will be performed in 35 subjects treated with iron isomaltoside. 
8.1.1 Analysis and Presentation of Safety Endpoints 
8.1.2 Adverse Events 
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 occur after administration of randomised 
treatment. Non-treatment emergent AEs (Non-TEAE) are defined as AEs collected before dosing 
including AEs reported in randomised subjects never exposed to trial drug. Related or possible related 
AEs are defined as adverse drug reactions (ADRs). 
An overall summary table by treatment will be made. The overall summary table will include number 
of events, number of subjects, and proportion of subjects reporting Non-TEAEs, TEAEs, Treatment 
emergent serious adverse events (SAEs), Fatal SAEs, ADRs, serious adverse reactions (SAR), TEAEs by 
severity, and TEAEs by outcome. The number of TEAEs, SAEs, ADRs, and SARs will be compared 
between treatment groups using a Fishers Exact test. 
All TEAEs will be summarised by system organ class (SOC) and PT. The summaries will include number 
of events, number of subjects, and proportion of subjects reporting these events and will be 
tabulated, by treatment for: 
 
TEAEs 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
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 
Non-serious TEAEs, frequency ≥ 5% (or lower frequency as applicable) 
 
Treatment emergent SAEs 
 
TEAEs by severity (mild, moderate, severe) 
 
TEAEs by relationship (related, possible, unlikely, not related, unknown) 
 
Composite cardiovascular TEAEs 
 
Serious or severe hypersensitivity reactions 
The following listings of AEs will be made based on the safety analysis set: 
 
Non-TEAEs 
 
TEAEs (non-serious and serious)  
 
TESAEs  
 
ADRs (including SUSARs) 
 
AEs leading to dose reduction or withdrawal from treatment  
 
Fatal SAEs  
 
Serious or severe hypersensitivity reactions  
 
Composite cardiovascular AEs 
 
In addition, a listing of SAEs for subjects not in the safety analysis set will be made. 
All data from adjudication review will be listed. 
8.1.3 Composite cardiovascular AEs 
The overall incidence of adjudicated composite cardiovascular AEs will be tabulated and compared 
between the treatment groups by a Fisher’s exact test. 
Time to first composite cardiovascular AE is defined as the actual time in days from first dose of 
treatment till the date of the adjudicated AE. For subjects not reporting a composite cardiovascular 
AE, the time will be censored at the date of the last attended visit.  
The time to first composite cardiovascular AEs will be estimated using the Kaplan-Meier method and 
the hypothesis of no treatment difference will be assessed by a log-rank test. Plots including the 
Kaplan-Meier curves, and log-rank test will be presented.  
8.1.4 Serum Phosphate 
Subjects with serum (s-) phosphate < 2 mg/dL at any time from baseline to weeks 1, 2, 4, or 8 will be 
listed. The listing will include phosphate values for all weeks. 
8.1.5 Other Safety Assessments 
Vital Signs 
Vital signs (heart rate, systolic and diastolic blood pressure) will be measured at baseline, weeks 1, 2, 4 
and 8, and at the additional treatment visits, if applicable. 
At the treatment visits, vital signs will be measured at the following time points:  
 
For subjects receiving an infusion of iron isomaltoside: approximately 0-10 minutes before 
infusion, during infusion, 5-15 minutes, and 20-40 minutes after the infusion has ended  


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
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 
For subjects receiving a push injections of iron sucrose: approximately 0-10 minutes before 
injection, 5-15 minutes, and 20-40 minutes after the injection has ended 
Vital signs will be summarised by week and time point, including change from pre- infusion/injection 
at treatment visits. 
Height and Weight 
Height is measured at baseline. Weight is measured at baseline and at the final visit.  
ECG  
Standard 12 lead ECG is assessed at baseline, weeks 1, 2, 4 and 8, and at the additional treatment 
visits, if applicable. At the treatment visits, two ECGs will be recorded; one before administration 
of the trial drug and one approximately 30 minutes after start of the dosing.  
In addition, for P-Monofer IDA-03, intensive ECG monitoring for evaluation of QTc prolongations will 
be performed at baseline in 35 consecutive subjects in relation to treatment with iron isomaltoside at 
selected sites.  
All ECG will be evaluated as normal or abnormal, and if abnormal clinical significant or not. 
The 3 categories for the standard 12 lead ECG will be summarised by week, time point and treatment. 
All data will be listed. 
Physical Examination 
Physical examination is assessed at baseline and at week 8. Each body system of the physical 
examination will be evaluated as normal or abnormal, and if abnormal clinical significant or not. 
The body system is not collected in the CRF and physical examination will be presented as an overall 
worst case of the 3 categories by treatment using shift tables from baseline till week 8. All data will be 
listed. 
8.1.6 Laboratory Safety Data  
Eligibility laboratory haematology and biochemistry parameters are measured at screening. Safety 
laboratory parameters (haematology and biochemistry) are measured at baseline and weeks 1, 2, 4, or 
8. 
Laboratory safety data will be summarised using descriptive statistics, including means, medians, SDs, 
quartiles, and minimum and maximum by week and treatment, including changes from baseline. In 
addition, laboratory safety data will be plotted using boxplots by week and treatment. For the 
summary tables and boxplots, values below lower limit of quantification (LLOQ) will be set to half 
times the limit. 
Values outside normal ranges will be flagged. All safety laboratory data will be listed by subject, 
including eligibility laboratory assessments. Clinical significant laboratory will be listed including 
corresponding AEs. 
8.2 Interim Analysis 
No interim analysis is planned. 
 
 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
P-CDK-04_IDA-03_SAP_V2_20180412.docx 
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9 Combined Analyses 
Data for the two trials, P-Monofer IDA-03 and P-Monofer CKD-04 will be pooled and combined 
analyses will be performed for the co-primary endpoints, and all secondary efficacy endpoints that 
appears in both trials.  
9.1 Pooled analyses of the co-primary safety endpoint 
The primary safety analysis described in section 7.1.1 will be repeated on the pooled data.  
For safety, in addition to estimating the absolute risk (number of subjects and 95 % CI) of iron 
isomaltoside, a non-inferiority analysis will be performed of iron isomaltoside versus iron sucrose. For 
iron sucrose, a similar rate of 1.5 % will be assumed. As iron isomaltoside should be no worse than 3 
%, the non-inferiority margin will be set to 1.5 % points. The non-inferiority assessment will be 
performed by estimation of the risk difference and the associated 95 % CI, adjusting for trial using the 
Cochran-Mantel-Haenszel method. With a total of 2000 subjects treated with iron isomaltoside, and 
1000 subjects treated with iron sucrose, assuming common incidences of 1.5 %, and using a 
significance level of 5 %, the power to demonstrate non-inferiority is 87 %. 
As sensitivity, the cumulative incidence will be estimated from a Kaplan-Meier curve of actual time 
from first treatment to serious and/or severe hypersensitivity AEs. Subjects without serious and/or 
serious hypersensitivity AEs will be censored at the last know time point without event. The log-log 
transformation will be used to estimate the standard errors for each treatment group, and the 95 % CI 
will be constructed by pooling these standard errors. 
9.2 Pooled analyses of the co-primary efficacy endpoint 
For efficacy, the same non-inferiority assessment as in the individual trials will be performed, including 
the specified sensitivity analyses. A similar MMRM model as for the individual trials will be applied, 
with trial added as fixed factor. The power for demonstrating efficacy is 100 %. 
Hence, with a total of 2000 subjects treated with iron isomaltoside, and 1000 subjects treated with 
iron sucrose, the combined power of demonstrating the two co-primary endpoints is 87 %. 
Similar to the individual trials, if the upper bound of two-sided 95 % CI of the risk difference (iron 
isomaltoside - iron sucrose) < 0 for the incidence of serious and/or severe hypersensitivity, or the 
lower bound of two-sided 95 % CI of the mean difference (iron isomaltoside - iron sucrose) in change 
in Hb from baseline to week 8 is 0 g/dL superiority will be declared, and the p-values for the test of 
superiority will be presented. 
9.3 Pooled Analyses of the Secondary Efficacy Endpoints 
Analyses combining data from the two trials will be made for the following secondary endpoints: 
 
Hb responder from baseline to weeks 1, 2, 4, or 8 (see section 7.2.1 for the definition of a 
responder) 
 
Hb level of > 12 g/dL at any time from week 1 to week 8  
 
Increase in Hb concentration ≥ 2 g/dL at any time from week 1 to week 8  


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trials: P-Monofer-CKD-04, P-Monofer-
IDA-03 
Date:                            12 Apr 2018 
Version:                             Final 2.0    
Statistical Analysis Plan 
 
 
 
 
 
 
P-CDK-04_IDA-03_SAP_V2_20180412.docx 
Confidential 
Page 25 of 25 
 
 
S-ferritin level of ≥ 100 ng/mL and transferrin saturation (TSAT) of 20-50 % at any time from 
week 1 to week 8  
 
Change in concentrations of Hb from baseline to weeks 1, 2, and 4  
 
Change in concentrations of s-ferritin, TSAT, and s-iron from baseline to weeks 1, 2, 4, and 8  
 
Change in fatigue symptoms from baseline to weeks 1, 2, and 8 measured by the FACIT 
Fatigue Scale  
 
The analyses for the individual endpoints will be performed as described in section 7.2.1 to 7.2.3 
above. For each analysis trial will be added as fixed factor in the models. 
9.4 Pooled Analyses of the Composite Cardiovascular AEs 
The overall incidence of adjudicated composite cardiovascular AEs will be tabulated and compared 
between the treatment groups by a Fisher’s exact test. 
The time to first composite cardiovascular AEs will be estimated using the Kaplan-Meier method and 
the hypothesis of no treatment difference will be assessed by a log-rank test. Plots including the 
Kaplan-Meier curve and log-rank test will be presented.  
10 Software  
All statistical calculations described in this SAP will be done by 
 Aps using SAS, release 9.4 or 
later (SAS Institute, Cary, NC, USA).  
11 Reference List 
Yeonhee K. and Seunghyun W. (2013). “Adjusted proportion difference and confidence interval in 
stratified randomized trials”, PharmaSUG 2013 – Paper SP04. 
Mallinckrodt CH, Lin Q, Molenberghs M. (2012). A structured framework for assessing sensitivity to 
missing data assumptions in longitudinal clinical trials. Pharmaceutical Statistics; 12:1-6