Conditions: Iron Deficiency Anemia Iron Deficiency Anaemia
Keywords: Iron Deficiency Anemia Iron Deficiency Anaemia IDA Intravenous iron replacement therapy Chronic Kidney Disease CKD Iron isomaltoside Ferric derisomaltose Monofer Monoferric Monover Monofar Monoferro
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 103
Healthy volunteers: no

Brief summary:
Evaluate safety and efficacy of intravenous (IV) iron isomaltoside/ferric derisomaltose re-dosing, in subjects who were previously treated with iron isomaltoside/ferric derisomaltose.

Detailed description:
Among the various formulations of parenteral iron that are currently available, iron isomaltoside/ferric derisomaltose may allow flexibility in terms of high and rapid dosing. Up to now, most clinical trials with intravenous (IV) iron treatment were of 4-12 weeks in duration; longer trials are warranted to follow-up on long-term safety.

The aim of the trial was to evaluate the safety and efficacy of IV iron isomaltoside/ferric derisomaltose re-dosing in subjects who were previously treated with iron isomaltoside/ferric derisomaltose in lead-in trials.

This was a 6-months extension trial lasting 26 weeks. Eligible subjects attended 5 visits: screening, baseline (subjects treated with a single IV dose of 1000 mg iron isomaltoside/ferric derisomaltose), and follow-up visits at week 2, 13, and 26 weeks after the IV dose, for safety and efficacy assessments.

Arms:
arm 1: Administered IV

Interventions: intervention 1: Iron isomaltoside/ferric derisomaltose
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 from the site's supply and administered over approximately 20 minutes using IV infusion.

Protocol document:
Prot_000.pdf: 
Trial ID: 
P-Monofer-IDA/CKD-EXT-01 
 
Protocol Version: 
2.0 (amendment 1) 
Date of Document : 
14 June 2017 
 
 
Confidential 
 
 Page 1 of 43 
 
CLINICAL TRIAL PROTOCOL 
An open-label, multicentre, extension trial to assess the safety of re-
dosing of intravenous iron isomaltoside (Monofer®)  
 
Trial ID: 
P-Monofer-IDA/CKD-EXT-01  
 
 
Sponsor: 
Pharmacosmos A/S, Rørvangsvej 30, DK-4300 Holbæk, Denmark 
 
Protocol Version: 
Version 1, 7 June 2016 
 
Protocol Version: 
Version 2 (amendment 1), 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. 
 
 
 


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


Trial ID: 
P-Monofer-IDA/CKD-EXT-01 
 
Protocol Version: 
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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:__________________________________ 
 
 
 


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PROTOCOL SUMMARY 
Trial title  
An open-label, multicentre, extension trial to assess the safety of re-dosing of intravenous 
iron isomaltoside (Monofer®)  
Trial design 
The trial is a prospective, open-label, multi-centre, extension trial of the lead-in trials P-
Monofer-IDA-01, P-Monofer-IDA-03, and P-Monofer-CKD-04 to assess the safety profile of 
iron isomaltoside 1000 (Monofer®, Pharmacosmos, Holbæk, Denmark) in subjects at 3 and 6 
months after re-dosing. 
Subjects will be re-dosed with 1000 mg iron isomaltoside. 
Phase of trial 
The trial is a phase III trial. 
Background  
Iron deficiency anaemia (IDA) is often associated with many chronic diseases such as renal 
diseases, cancer, infections, chronic heart failure, and inflammatory bowel disease.  
Subjects are often treated with erythropoiesis stimulating agents (ESAs) in order to stimulate 
erythropoiesis. This therapy requires rapid mobilisation of iron reserves in order to meet the 
demands of new red blood cell (RBC) growth. Despite normal or even increased iron stores, 
the demands of this therapy can outstrip the body’s ability to mobilise iron stores resulting in 
“functional iron deficiency”. 
IDA can have a substantial medical and quality of life (QoL) burden on the subjects, and 
treatment of these subjects includes treatment of its underlying cause and restoration of nor-
mal haemoglobin (Hb) concentrations and iron stores. Iron replacement can be accomplished 
by the oral or parenteral routes. Intravenous (IV) iron offers a rapid and efficient means of 
iron correction, and it is superior to oral iron therapy in many circumstances. Treatment with 
oral iron may be adequate for some patients, but intolerance, abnormal absorption due to in-
flammation, noncompliance, and large iron deficits may lead to an inadequate treatment of 
the anemia with oral iron. International guidelines recommend IV iron preparations as the 
preferred option in the correction of IDA in several of these circumstances and when there is 
a high iron demand, since it is more effective, better tolerated, and improves QoL to a greater 
extent than oral iron supplements. 
Most trials with IV iron have been 4-12 weeks trials and long-term trials are warranted to 
follow-up on long-term safety. This trial is a 6-months extension trial of P-Monofer-IDA-01, 
P-Monofer-IDA-03, and P-Monofer-CKD-04 trials where the aim is to evaluate the safety 
and efficacy of IV iron isomaltoside re-dosing. 
Objectives 
The primary objective of the trial is to evaluate the safety of IV iron isomaltoside after re-
dosing. 
The efficacy objective of the trial is to evaluate the effect of iron isomaltoside on:  
 Increase in Hb  


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 Other relevant iron related biochemical parameters  
Endpoints 
The primary endpoint is the number of adverse drug reaction (ADR). 
The secondary safety endpoints are the following: 
 Serious or severe hypersensitivity reaction starting on or after the treatment with iron 
isomaltoside (i.e. treatment-emergent). The hypersensitivity terms are defined as 
standardised Medical Dictionary for Regulatory Activities query (SMQ) terms (in-
cluding four additional terms) in Appendix A. 
 Composite cardiovascular adverse events (AEs) starting on or after the treatment with 
iron isomaltoside (i.e. treatment-emergent). 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 
 
The AEs will be adjudicated by an independent clinical events classification commit-
tee (described in a separate adjudication charter). The specified definition of adjudi-
cated 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 month 6 
 
In addition, physical examinations and measurements of vital signs, height, weight, electro-
cardiogram (ECG), and safety laboratory parameters will be measured as part of standard 
safety assessments.  
The efficacy endpoints are the following:  
 Change in Hb from baseline to week 2 and months 3 and 6 
 Change in s-ferritin, transferrin saturation (TSAT), and s-iron from baseline to week 2 
and months 3 and 6 
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 by an independent clinical 
events classification committee (described in a separate adjudication charter) 
 Physical examinations, measurements of vital signs, height, weight, ECG, and safety 


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laboratory parameters 
Efficacy assessments 
The trial includes the following efficacy assessments: 
 Measurements of Hb, s-ferritin, TSAT, and s-iron  
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 6 months including 5 
visits; screening visit, baseline visit, 2 weeks visit, 3 months visit, and 6 months visit. 
Subject population 
Subjects from selected sites in the lead-in trials will be offered to participate in this extension 
trial if they fulfil the following eligibility criteria: 
Inclusion criteria: 
A subject will be eligible for inclusion in the trial if he/she fulfils the following criteria: 
1. Completed one of the lead-in trials 
2. Randomised and dosed with iron isomaltoside in one of the lead-in trials. The dose 
given needs to be in compliance, i.e. within 80-120 % of the cumulative dose.  
3. Having a Hb of ≤ 11 g/dL  
4. Screening s-ferritin  100 ng/mL, or  300 ng/mL if TSAT  30 % 
5. Life expectancy beyond 18 months by Investigator’s judgement 
6. Willingness to participate and signing the informed consent form 
Exclusion criteria: 
A subject will not be eligible for inclusion in this trial if he/she fulfils any of the following 
criteria: 
1. IV iron treatment between the lead-in trial and screening 
2. 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 
3. Received an investigational drug within 30 days of screening 
4. Alanine aminotransferase (ALAT) and/or aspartate aminotransferase (ASAT) > 3 
times upper limit of normal (e.g. decompensated liver cirrhosis or active hepatitis)  
5. Undergoing dialysis for treatment of CKD or under consideration for dialysis during 
the trial period 
6. 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  
7. 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 


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Trial treatment 
Subjects will be dosed with a single infusion of 1000 mg iron isomaltoside diluted in 100 mL 
0.9 % sodium chloride and given over approximately 20 minutes. No test dose will be ap-
plied. 
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. 
Statistical analyses 
No sample size calculations have been performed for this extension trial. It is anticipated that 
100 subjects will be recruited with at least 25 subjects with IDA and at least 25 NDD-CKD 
subjects with IDA from the three lead-in trials, P-Monofer-IDA-01, P-Monofer-IDA-03, and 
P-Monofer-CKD-04, and followed for 6 months safety follow-up.  
The incidence of treatment-emergent ADRs and SARs will be presented, including two-sided 
95 % confidence interval (CI). 
Safety and efficacy assessments will be summarised descriptively. 
Summaries will be prepared with respect to two baselines: Baseline in lead-in trial, and base-
line in this extension trial. Summaries will be prepared overall and by lead-in trial.  
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 ......................................... 13 
1.1 
ABBREVIATIONS ............................................................................................................ 13 
1.2 
DEFINITION OF TERMS ................................................................................................... 14 
2 
INTRODUCTION ...................................................................................................... 15 
2.1 
BACKGROUND ............................................................................................................... 15 
2.2 
IRON ISOMALTOSIDE ..................................................................................................... 15 
2.3 
TRIAL RATIONALE ......................................................................................................... 16 
3 
TRIAL DESIGN ......................................................................................................... 16 
4 
TRIAL OBJECTIVES ............................................................................................... 16 
4.1 
PRIMARY SAFETY OBJECTIVES ...................................................................................... 16 
4.2 
SECONDARY EFFICACY OBJECTIVES ............................................................................. 16 
5 
TRIAL ENDPOINTS ................................................................................................. 17 
5.1 
PRIMARY SAFETY ENDPOINT ......................................................................................... 17 
5.2 
SECONDARY SAFETY ENDPOINTS .................................................................................. 17 
5.3 
EFFICACY ENDPOINTS ................................................................................................... 17 
6 
TRIAL VISITS ........................................................................................................... 18 
6.1 
PRE-SCREENING (OPTIONAL) ......................................................................................... 18 
6.2 
TRIAL VISITS ................................................................................................................. 18 
6.3 
VISIT 1 (SCREENING) ..................................................................................................... 19 
6.4 
VISIT 2 (BASELINE) ....................................................................................................... 19 
6.5 
VISIT 3 .......................................................................................................................... 19 
6.6 
VISIT 4 .......................................................................................................................... 20 
6.7 
VISIT 5 .......................................................................................................................... 20 
7 
TRIAL ASSESSMENTS............................................................................................ 20 
7.1 
DEMOGRAPHIC AND BASELINE ASSESSMENTS .............................................................. 20 
7.2 
PREGNANCY TEST ......................................................................................................... 20 
7.3 
RELEVANT MEDICAL HISTORY...................................................................................... 20 
7.4 
CONCOMITANT MEDICATION ........................................................................................ 21 
7.5 
PHYSICAL EXAMINATION .............................................................................................. 21 
7.6 
HEIGHT ......................................................................................................................... 21 
7.7 
WEIGHT ......................................................................................................................... 21 
7.8 
VITAL SIGNS ................................................................................................................. 21 


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7.9 
ELECTROCARDIOGRAM ................................................................................................. 21 
7.10 LABORATORY ASSESSMENTS ........................................................................................ 21 
7.10.1 
Eligibility Laboratory Assessments ............................................................ 22 
7.10.2 
Safety Laboratory Assessments .................................................................. 22 
7.10.3 
Efficacy Laboratory Assessments .............................................................. 22 
7.11 ADVERSE EVENTS ......................................................................................................... 22 
8 
TRIAL POPULATION.............................................................................................. 23 
8.1 
NUMBER OF SUBJECTS .................................................................................................. 23 
8.2 
INCLUSION CRITERIA ..................................................................................................... 23 
8.3 
EXCLUSION CRITERIA ................................................................................................... 23 
8.4 
SUBJECT RECRUITMENT ................................................................................................ 23 
9 
SUBJECT COMPLETION AND WITHDRAWAL ............................................... 24 
9.1 
SCREEN FAILURES ......................................................................................................... 24 
9.2 
RE-SCREENING .............................................................................................................. 24 
9.3 
SUBJECT WITHDRAWAL ................................................................................................ 24 
9.4 
SUBJECT COMPLETION .................................................................................................. 24 
9.5 
TREATMENT AFTER THE TRIAL ...................................................................................... 24 
9.6 
EARLY TRIAL TERMINATION ......................................................................................... 24 
10 
INVESTIGATIONAL PRODUCTS ......................................................................... 25 
10.1 DESCRIPTION OF INVESTIGATIONAL PRODUCTS ............................................................ 25 
10.2 DOSAGE, ADMINISTRATION AND BLINDING OF TRIAL DRUG ........................................ 25 
10.3 DOSE RATIONALE .......................................................................................................... 26 
10.4 SIDE EFFECTS OF IRON ISOMALTOSIDE .......................................................................... 26 
10.5 PREPARATION, HANDLING, AND LABELLING ................................................................. 26 
10.6 HANDLING AND STORAGE ............................................................................................. 26 
10.7 PRODUCT ACCOUNTABILITY ......................................................................................... 26 
11 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ................ 27 
11.1 PERMITTED MEDICATIONS ............................................................................................ 27 
11.2 PROHIBITED MEDICATIONS AND NON-DRUG THERAPIES ............................................... 27 
12 
ADVERSE EVENTS .................................................................................................. 27 
12.1 DEFINITION OF ADVERSE EVENTS ................................................................................. 27 
12.2 DEFINITION OF SERIOUS ADVERSE EVENTS ................................................................... 28 
12.3 DEFINITION OF AN ADVERSE DRUG REACTION ............................................................. 28 


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12.4 COLLECTION OF ADVERSE EVENTS ............................................................................... 28 
12.5 REPORTING OF SAES ..................................................................................................... 30 
13 
PREGNANCIES ......................................................................................................... 30 
14 
OVERDOSE ............................................................................................................... 31 
15 
STATISTICAL ANALYSES ..................................................................................... 31 
15.1 HYPOTHESES ................................................................................................................. 31 
15.2 SAMPLE SIZE DETERMINATION ..................................................................................... 31 
15.3 DATA ANALYSIS SETS ................................................................................................... 31 
15.4 INTERIM ANALYSIS ....................................................................................................... 31 
15.5 STATISTICAL ANALYSES ............................................................................................... 31 
15.6 SAFETY ANALYSES........................................................................................................ 32 
EFFICACY ANALYSES ............................................................................................................... 32 
16 
DATA MANAGEMENT AND DATA COLLECTION ......................................... 32 
16.1 DEFINITION OF SOURCE DATA ....................................................................................... 32 
16.2 DATA MANAGEMENT .................................................................................................... 33 
17 
TRIAL MONITORING ............................................................................................. 33 
17.1 TRIAL MONITORING ...................................................................................................... 33 
17.2 QUALITY ASSURANCE ................................................................................................... 33 
17.3 PROTOCOL DEVIATIONS ................................................................................................ 33 
18 
TRIAL ADMINISTRATION .................................................................................... 34 
18.1 TRIAL CORE TEAM, GCP QUALITY STEERING COMMITTEE, AND GCP QUALITY BOARD
 
…………………………………………………………………………………………34 
18.2 DIRECT ACCESS ............................................................................................................ 35 
18.3 TRIAL AND SITE CLOSURE ............................................................................................. 35 
18.4 RECORDS RETENTION .................................................................................................... 35 
18.5 PROVISION OF TRIAL RESULTS AND INFORMATION TO PRINCIPAL INVESTIGATORS ...... 35 
18.6 FINANCE AND INSURANCE ............................................................................................. 36 
19 
ETHICAL CONSIDERATIONS .............................................................................. 36 
19.1 REGULATORY AND ETHICAL CONSIDERATIONS ............................................................. 36 
19.2 CHANGES TO THE PROTOCOL ........................................................................................ 36 
20 
PUBLICATION PLAN .............................................................................................. 36 
20.1 UPLOADING OF DATA ON PUBLIC WEBSITES ................................................................. 37 
21 
REFERENCES ........................................................................................................... 37 
APPENDIX A ........................................................................................................................ 38 


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APPENDIX B ......................................................................................................................... 41 
 
 
 
 


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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 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
Chronic Kidney Disease 
CRA 
Clinical Research Associate 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ESA 
Erythropoiesis Stimulating Agents 
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 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCT 
Trial Core Team 
TEAE 
Treatment Emergent Adverse Event 
TSAT 
Transferrin Saturation  
WBC 
White Blood Cells 
 


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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 a common problem associated with many chronic diseases 
such as chronic kidney disease (CKD), cancer, infections, chronic heart failure (CHF), and 
inflammatory bowel disease (IBD). It is also common in pregnant women and occurs in the 
elderly. IDA is primarily caused by chronic blood loss, poor diet, or impaired gastrointestinal 
iron absorption. The major causes of anaemia in CKD subjects are iron and erythropoietin 
deficiencies and a decreased responsiveness to the actions of erythropoietin [Mehdi & Toto, 
2009].  
Subjects are often treated with erythropoiesis stimulating agents (ESAs) in order to stimulate 
erythropoiesis. This therapy requires rapid mobilisation of iron reserves in order to meet the 
demands of new red blood cell (RBC) growth. Despite normal or even increased iron stores, 
the demands of this therapy can outstrip the body’s ability to mobilise iron stores resulting in 
“functional iron deficiency” [Hotta et al., 1991]. 
IDA can have a substantial medical and quality of life (QoL) burden on the subjects, and 
treatment of these subjects includes treatment of its underlying cause and restoration of nor-
mal haemoglobin (Hb) concentrations and iron stores. Iron replacement can be accomplished 
by the oral or parenteral routes. Intravenous (IV) iron offers a rapid and efficient means of 
iron correction, and it is superior to oral iron therapy in many circumstances [Dignass et al., 
2015]. Treatment with oral iron may be adequate for some patients, but intolerance, abnormal 
absorption due to inflammation, noncompliance, and large iron deficits may lead to an inade-
quate treatment of the anemia with oral iron [Henry, 2006]. International guidelines recom-
mend IV iron preparations as the preferred option in the correction of IDA in several of these 
circumstances and when there is a high iron demand, since it is more effective, better tolerat-
ed, and improves QoL to a greater extent than oral iron supplements [Charytan et al., 2005; 
Gasche et al., 2007; KDIGO guideline, 2012; Dignass et al., 2015]. 
Most trials with IV iron have been 4-12 weeks trials and long-term trials are warranted to fol-
low-up on long-term safety after re-dosing. One randomised, comparative, open-label, 5-
weeks trial with iron isomaltoside 1000 (Monofer®, Pharmacosmos, Holbæk, Denmark) has 
been carried out (P-Monofer-IDA-01) and two randomised, comparative, open-label, 8-weeks 
trials are going to be initiated in subjects with IDA (P-Monofer-IDA-03) and NDD-CKD sub-
jects with IDA (P-Monofer-CKD-04). This trial is a 6-months extension trial of P-Monofer-
IDA-01, P-Monofer-IDA-03, and P-Monofer-CKD-04 trials where the aim is to evaluate the 
safety and efficacy of IV iron isomaltoside re-dosing. 
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]. 


Trial ID: 
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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. 
Most trials with IV iron have been 4-12 weeks trials and long-term trials are warranted to fol-
low-up on long-term safety. One randomised, comparative, open-label, 5-weeks trial with iron 
isomaltoside 1000 has been carried out (P-Monofer-IDA-01) and two randomised, compara-
tive, open-label, 8-weeks trials with iron isomaltoside is going to be initiated in subjects with 
IDA (P-Monofer-IDA-03) and NDD-CKD subjects with IDA (P-Monofer-CKD-04). This 
trial is a 6-months extension trial of P-Monofer-IDA-01, P-Monofer-IDA-03, and P-Monofer-
CKD-04 trials where the aim is to evaluate the safety and efficacy of IV iron isomaltoside re-
dosing. Some subjects from the lead-in trials (P-Monofer-IDA-01, P-Monofer-IDA-03, and P-
Monofer-CKD-04) will need re-dosing in order to maintain their Hb above a certain thresh-
old. Hence, the intention in this trial is to re-dose subjects when Hb is going down, but not 
necessarily to a more severe stage of anaemia. On the other hand it is the intention not to ex-
pose subjects if there is an indication that there iron related parameters are too high. 
3 
TRIAL DESIGN 
The trial is a prospective, open-label, multi-centre, extension trial of the lead-in trials P-
Monofer-IDA-01, P-Monofer-IDA-03, and P-Monofer-CKD-04 to assess the safety profile of 
iron isomaltoside in subjects at 3 and 6 months after re-dosing. For the individual subject, 
duration of the trial will be approximately 6 months including 5 visits; screening visit, base-
line visit, 2 weeks visit, 3 months visit, and 6 months visit. 
Subjects will be re-dosed with 1000 mg iron isomaltoside. 
4 
TRIAL OBJECTIVES 
4.1 
Primary Safety Objectives 
The primary objective of the trial is to evaluate the safety of IV iron isomaltoside after re-
dosing. 
4.2 
Secondary Efficacy Objectives 
The efficacy objective of the trial is to evaluate the effect of iron isomaltoside on:  


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 Increase in Hb  
 Other relevant iron related biochemical parameters  
5 
TRIAL ENDPOINTS 
5.1 
Primary Safety Endpoint 
The primary endpoint is the number of adverse drug reaction (ADR). 
5.2 
Secondary Safety Endpoints 
The secondary safety endpoints are the following: 
 Serious or severe hypersensitivity reaction starting on or after the treatment with iron 
isomaltoside (i.e. treatment-emergent). The hypersensitivity terms are defined as 
standardised Medical Dictionary for Regulatory Activities query (SMQ) terms (includ-
ing four additional terms) in Appendix A. 
 Composite cardiovascular adverse events (AEs) starting on or after the treatment with 
iron isomaltoside (i.e. treatment-emergent). 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 
 
The AEs will be adjudicated by an independent clinical events classification commit-
tee (described in a separate adjudication charter). The specified definition of adjudi-
cated 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 month 6 
 
In addition, physical examinations and measurements of vital signs, height, weight, electro-
cardiogram (ECG), and safety laboratory parameters will be measured as part of standard 
safety assessments. 
5.3 
Efficacy Endpoints 
The efficacy endpoints are the following:  
 Change in Hb from baseline to week 2 and months 3 and 6 
 Change in s-ferritin, transferrin saturation (TSAT), and s-iron from baseline to week 2 
and months 3 and 6 




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b. All trial assessments should be done before administration of the trial drug unless otherwise stated in Section 7. 
c. The final visit form may be filled in at any time of the trial if the subject is withdrawn.  
d. Laboratory tests taken at visit 6 of the lead-in trials P-Monofer-IDA-03 and P-Monofer-CKD-04 will be considered as 
screening values for the extension trial if they are collected ≤14 days before the screening visit. 
6.3 
Visit 1 (Screening) 
Visit 1 (screening) will be conducted within 14 days prior to visit 2 (baseline). The following 
will be done: 
 Subject is informed about the trial and signs the informed consent 
 Collection of demographic information 
 Inclusion and exclusion criteria checked 
 Eligibility laboratory assessments 
6.4 
Visit 2 (Baseline) 
Visit 2 (baseline) will be conducted a maximum of 14 days after the screening visit. The fol-
lowing will be assessed: 
 Inclusion and exclusion criteria checked 
 Pregnancy test, if applicable 
 Recording of relevant medical history, including specific assessment of history of my-
ocardial 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  
 ECG 
 Safety laboratory tests 
 Efficacy laboratory tests 
 Treatment with iron isomaltoside  
 AE evaluation and recording  
6.5 
Visit 3 
Visit 3 will be conducted 2 weeks (± 2 days) after baseline. 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 


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6.6 
Visit 4 
Visit 4 will be conducted 13 weeks (± 3 days) after baseline. 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 
6.7 
Visit 5 
Visit 5 will be conducted 26 weeks (± 4 days) after baseline. 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 
 Safety laboratory tests 
 Efficacy laboratory tests  
 AE evaluation and recording 
 Completing the final visit form 
7 
TRIAL ASSESSMENTS 
7.1 
Demographic and Baseline Assessments 
Date of birth, gender, race, ethnicity, and smoking habits will be collected. A current smoker 
is defined as a subject who has been smoking within the last 6 months. 
7.2 
Pregnancy Test 
A urine pregnancy test will be performed for all women of childbearing potential. The test 
will be handled and interpreted by the site personnel. 
7.3 
Relevant Medical History  
Relevant medical history will be recorded. Changes in medical history will be recorded at the 
subsequent visits during the trial (worsening of symptoms or diseases shall be recorded as 
AEs). The following will be collected: disease and start and stop date. Except for underlying 
disorder causing IDA, start dates occurring > 12 months before the enrolment into the trial 
should be set as > 12 months. 


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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 
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 during infusion of iron isomaltoside: approximately 0-10 minutes before infusion, dur-
ing infusion, 5-15 minutes, and 20-40 minutes after the infusion has ended. 
7.9 
Electrocardiogram 
A standard 12 lead ECG will be recorded (including date, time, and signature). At baseline, 
two ECGs will be recorded; one before administration of the trial drug and one approximately 
30 minutes after start of the dosing. Only one ECG should be recorded at the follow-up visits. 
The ECGs do not need to be evaluated by a cardiologist.  
7.10 
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. 


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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. 
7.10.1 
Eligibility Laboratory Assessments 
The following eligibility laboratory assessments will be performed: 
 
Complete haematology set: Hb, leucocytes/white blood cells (WBC), erythro-
cytes/RBC, haematocrit, platelets, neutrophil granulocytes, lymphocytes, monocytes, 
eosinophils, basophils, mean corpuscular haemoglobin (MCH), mean corpuscular vol-
ume (MCV), mean corpuscular haemoglobin concentration (MCHC), and reticulocyte 
count 
 Biochemistry: 
o S-ferritin 
o TSAT 
o Aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) 
 
Laboratory tests taken at visit 6 of the lead-in trials P-Monofer-IDA-03 and P-Monofer-CKD-
04 will be considered as screening values for the extension trial if they are collected ≤ 14 days 
before the screening visit. 
7.10.2 
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 C-reactive protein (CRP)  
7.10.3 
Efficacy Laboratory Assessments 
 The following efficacy laboratory parameters will be analysed: 
 Hb  
 S-ferritin 
 TSAT 
 S-iron 
7.11 
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). 


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8 
TRIAL POPULATION 
8.1 
Number of Subjects 
A target of 100 subjects will be recruited at selected sites with at least 25 subjects from P-
Monofer-IDA-01/P-Monofer-IDA-03 and at least 25 from P-Monofer-CKD-04. The distribu-
tion of subjects from each of the three trials does not need to be equal and the subjects will be 
enrolled consecutively based on the enrolment criteria until 100 subjects have been enrolled. 
8.2 
Inclusion Criteria 
A subject will be eligible for inclusion in the trial if he/she fulfils the following criteria: 
1. Completed one of the lead-in trials 
2. Randomised and dosed with iron isomaltoside in one of the lead-in trials. The dose 
given needs to be in compliance, i.e. within 80-120 % of the cumulative dose.   
3. Having a Hb of ≤ 11 g/dL  
4. Screening s-ferritin  100 ng/mL, or  300 ng/mL if TSAT  30 % 
5. Life expectancy beyond 18 months by Investigator’s judgement 
6. Willingness to participate and signing the informed consent form (ICF) 
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. IV iron treatment between the lead-in trial and screening 
2. 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 
3. Received an investigational drug within 30 days of screening 
4. ALAT and/or ASAT > 3 times upper limit of normal (e.g. decompensated liver cirrho-
sis or active hepatitis)  
5. Undergoing dialysis for treatment of CKD or under consideration for dialysis during 
the trial period 
6. 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  
7. 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 
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. 


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Before informed consent is obtained the subject should be allowed ample time and opportuni-
ty to read the subject information sheet, to enquire about details of the trial, and to decide 
whether or not to participate. 
If the subject wishes to participate, the written ICF should be completed as appropriate and 
then signed and personally dated by the subject and the Investigator who conducted the in-
formed consent discussions. The procedure for obtaining the informed consent must follow 
the local requirements and legislation.  
9 
SUBJECT COMPLETION AND WITHDRAWAL 
9.1 
Screen Failures 
The PI will maintain a list of screening numbers and names of the subjects who have been 
screened at the site in order to allow for identification of records at a later date. The reasons 
for failure should be noted in the screening log of the site file and the final visit form.  
9.2 
Re-screening 
If a subject does not fulfil the inclusion/exclusion criteria (screen failure), they may be re-
screened up to three times. 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-


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compliance, and insufficient subject enrolment. For multi-centre trials, this can occur at one 
or more sites. If Pharmacosmos A/S decides that such action is needed, Pharmacosmos A/S or 
its designee will discuss this with the PI including the reasons for taking such action. The PI 
also has the right to temporarily suspend or prematurely discontinue this trial for mutually 
agreed reason(s) with Pharmacosmos A/S.  
Pharmacosmos A/S or its designee will promptly inform all other PIs and/or institutions con-
ducting the trial if the trial is suspended or terminated due to safety reasons. 
Pharmacosmos A/S or its designee will promptly inform the Competent Authorities of the 
suspension or termination of the trial and the reason(s) for the action. If required by applicable 
regulations, the PI must inform the Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC) promptly and provide the reason for the suspension or termination.  
10 
INVESTIGATIONAL PRODUCTS 
10.1 
Description of Investigational Products 
Iron isomaltoside 
Iron isomaltoside is a complex between iron and a carbohydrate moiety. The carbohydrate 
isomaltoside 1000 is a purely linear chemical structure as shown by 13C NMR of repeating α-
(1-6) linked glucopyranose residues. Thus, it is structurally different from the branched dex-
tran polysaccharides present in iron dextran. Isomaltoside 1000 consists predominantly of 3-5 
glucose units and is prepared from oligomers used for prevention of dextran-induced anaphy-
lactic reaction. These oligomers have been chemically modified to further reduce the potential 
for anaphylactic/anaphylactoid reaction. Thus, isomaltoside 1000 is not a dextran [Jahn et al., 
2011]. 
Iron isomaltoside has strongly bound iron within the iron isomaltoside formulation, which 
enables a controlled, slow release of bioavailable iron to the iron-binding proteins with only a 
little risk of free iron toxicity [Jahn et al., 2011]. This allows flexible dosing, including high 
dose and rapid dosing. 
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. 
10.2 
Dosage, Administration and Blinding of Trial Drug 
Subjects will be dosed with a single infusion of 1000 mg iron isomaltoside diluted in 100 mL 
0.9 % sodium chloride and given over approximately 20 minutes. No test dose will be ap-
plied. 
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. 


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The subjects must be observed for signs and symptoms of hypersensitivity during and after 
trial drug administration for at least 30 minutes and until clinically stable following comple-
tion of each administration. 
Details of administration and storage of iron isomaltoside are further described in the Drug 
Handling Plan.  
10.3 
Dose Rationale 
In the present trial, subjects will be given 1000 mg iron isomaltoside administered as a single 
infusion. Justification for this single dose regime is found in recent safety data. Up to 31 De-
cember 2015, more than 1700 patients have been treated with iron isomaltoside including 
bolus injections and high single dose infusions up to 2500 mg administered 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 
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 are further described in the Drug 
Handling Plan.  
10.6 
Handling and Storage 
The investigational product must be dispensed or administered according to procedures de-
scribed herein. Only subjects enrolled in the trial may receive the investigational product, and 
it must be administered in accordance with all applicable regulatory requirements. Only au-
thorised site staff may supply or administer the investigational product. All investigational 
products must be stored in a secure area with access limited to the authorised site staff and 
under physical conditions that are consistent with investigational product-specific require-
ments. 
10.7 
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.  


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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.  
ESA may be administered to the subjects if they were receiving ESA treatment in the lead-in 
trial. ESA treatment must be kept stabile (+/- 20%) both in the lead-in trial and during the 
extension trial. If the ESA treatment is terminated between the lead-in trial and this extension 
trial, the wash-out period is 4 weeks before the screening visit in this trial. 
11.2 
Prohibited Medications and Non-drug Therapies 
No premedication (e.g. antihistamine or steroids) is allowed before administration of the trial 
drug. If the subject is in daily treatment for e.g. allergy or asthma this is not considered as 
"premedication" and may be continued. 
The following medication and non-drug therapy are not allowed during the trial period since 
they could potentially have an impact on the endpoints: 
 Any iron supplementation other than investigational drug (nutritional supplementation 
including iron is allowed unless it is assumed as treatment of the subject's anaemia) 
 Blood transfusion 
ESAs are also prohibited medication unless the subject was treated with ESA in the lead-in 
trial or has received a stable dose (+/- 20 %) 4 weeks before the screening visit in this trial.  
12 
ADVERSE EVENTS 
12.1 
Definition of Adverse Events 
An AE is defined in the ICH-GCP guideline as “any untoward medical occurrence in a subject 
or clinical investigation subject administered a pharmaceutical product and that does not nec-
essarily have a causal relationship with this treatment” (ICH E6:1.2). An AE can therefore be 
any unfavourable and unintended sign, symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. A clin-
ically significant abnormal laboratory finding is also regarded as an AE if the effect is unfa-
vourable for the subject. It is the responsibility of the Investigator to review the laboratory test 
results and determine whether an abnormal laboratory value is clinically significant. In gen-
eral, a clinically significant laboratory value which suggests disease progression and/or re-
quires active management is considered as an AE. Clinical significant efficacy laboratory pa-
rameters (including related parameters) are not to be recorded as AEs unless these are consid-
ered lack of efficacy or overdose.  


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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 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], it is considered a suspected unexpected serious ad-
verse reaction (SUSAR).  
It is the responsibility of Pharmacosmos A/S to evaluate the SARs for expectedness. 
12.4 
Collection of Adverse Events 
The Investigator is responsible for ensuring that all AEs (as defined in Section 12.1) observed 
by the Investigator or reported by the subject are properly collected and recorded in the sub-
ject’s medical record as well as in the AE pages of the eCRF. 
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. 


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Treated subjects: From the time a subject has signed the ICF and until he/she exits the trial, 
all AEs/SAEs will be reported in the eCRF. AEs/SAEs occurring before administration of the 
trial drug are considered as non-treatment emergent, and those occurring after administration 
of the trial drug are considered as 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 
 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 


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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. 
12.5 
Reporting of SAEs 
The Investigator must report all SAEs promptly and within 24 hours to Drug Safety at Phar-
macosmos A/S after obtaining knowledge of the event.  
The Investigator should report the SAEs by filling out the SAE form and report to Pharma-
cosmos A/S either by e-mail at pv@pharmacosmos.com or fax number +45 5948 6082.  
Contact details:  Drug Safety, Pharmacosmos A/S 
Roervangsvej 30, DK-4300 Holbaek, Denmark 
Phone: +
  
Fax: +45 5948 60 82 
E-mail: pv@pharmacosmos.com 
After the initial SAE report, the Investigator is required, proactively, to provide further infor-
mation regarding the subject’s condition. All follow-up information must be forwarded to 
Pharmacosmos A/S as it becomes available.  
For all AEs with fatal outcome, autopsy reports (if available) and relevant medical reports 
should be reported to Pharmacosmos A/S, as described above.  
SAEs occurring after trial termination must be reported if considered related to the trial treat-
ment. 
Pharmacosmos A/S will report SUSARs to the Competent Authorities within 7 calendar days 
for fatal and life threatening SUSARs and follow-up information within the next 8 calendar 
days. All other SUSARs are submitted as soon as possible within 15 calendar days and rele-
vant follow-up information is subsequently communicated as soon as possible.  
Pharmacosmos A/S will inform any SUSARs to all PI(s) within 15 calendar days by circulat-
ing the Council for International Organizations of Medical Sciences (CIOMS-I) form.  
All SAEs including expected SARs will be reported by Pharmacosmos A/S to the Competent 
Authorities by the annually Development Safety Update Report. 
In addition, 6-monthly safety reports will be prepared by Pharmacosmos A/S and submitted to 
the Investigators for information. 
13 
PREGNANCIES 
Subjects who become pregnant during the trial should continue the trial but cannot receive 
more trial drug. Thus, the subjects may attend visit 3, 4, and 5. 
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-


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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 
No formal hypotheses will be tested in this 6 months safety extension trial. 
15.2 
Sample Size Determination 
No sample size calculations have been performed for this extension trial. It is anticipated that 
100 subjects will be recruited with at least 25 subjects with IDA and at least 25 NDD-CKD 
subjects with IDA from the three lead-in trials, P-Monofer-IDA-01, P-Monofer-IDA-03, and 
P-Monofer-CKD-04, and followed for 6 months safety follow-up 
15.3 
Data Analysis Sets 
The following data analyses sets will be used in the analyses of the data: 
Safety analysis set: The safety analysis set will include all subjects who received at least one 
dose of the trial drug. 
Intention to treat (ITT) analysis set: The ITT analysis set will include all subjects. This will be 
the primary analysis set for evaluating efficacy. 
Full Analysis Set (FAS): The FAS will consist of all subjects who received at least one dose 
of the trial drug in the lead-in trial, and have at least one post baseline Hb assessment.  
Per protocol (PP) analysis set: The PP analysis set will include all the 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 
Statistical Analyses 
Summary tables and descriptive statistics will be applied to demographics, efficacy, and safe-
ty data. Concomitant medications and medical history will be listed by subject. 


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Summaries will be prepared with respect to two baselines: Baseline in lead-in trial, and base-
line in this extension trial. Summaries will be prepared overall and by lead-in trial. 
The statistical analyses will be described in a statistical analyses plan. 
15.6 
Safety Analyses 
The incidence of treatment-emergent ADRs and SARs will be presented, including two-sided 
95 % confidence interval (CI). 
AEs will be classified according to the time of onset: 
 Non-treatment emergent AE – an AE that starts after the subject has signed the ICF but 
before the subject receives iron isomaltoside in this extension trial 
 Treatment emergent AE (TEAE) – an AE that starts after the subject receives iron 
isomaltoside in this extension trial  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) current 
version. Related or possible related AE’s are defined as ADRs. 
AEs will be summary tabulated by body system and preferred term indicating number and 
percentage of subjects and number of events. Number of subjects who experience an ADR 
including SUSARs will be compared between treatment groups.  
The following AE listings will be made as a minimum: 
 Non-treatment emergent AEs in treated subjects 
 TEAEs (non-serious and serious)  
 Treatment emergent SAEs  
 SAEs in subjects not receiving treatment in the extension trial (e.g. screen failures) 
 ADRs 
 AEs leading to dose reduction or withdrawal from treatment 
 Fatal SAEs 
 Serious or severe hypersensitivity reactions 
 Composite cardiovascular AEs 
Physical examinations and measurements of vital signs, height, weight, ECG, and safety la-
boratory parameters will be tabulated by visit. 
Efficacy Analyses 
Change in Hb, s-ferritin, TSAT, and s-iron from baseline (lead-in and extension) to week 2 
and months 3 and 6 will be tabulated. 
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-


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struction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies). Source data location list needs to be filled in and maintained by 
the Investigator during the trial. 
16.2 
Data Management 
Data management will be outsourced. The data collection tool for this trial will be an eCRF, 
which is compliant with 21 CFR Part 11 regulations. Subject data necessary for analyses and 
reporting will be entered into a validated database or data system. Clinical data management 
will be performed in accordance with applicable standards and data cleaning procedures.  
The site staff will be trained before they have access to the eCRF and a eCRF guideline will 
be available.  
17 
TRIAL MONITORING 
17.1 
Trial Monitoring 
In accordance with applicable regulations and ICH-GCP guidelines, Pharmacosmos A/S or its 
designee will contact the site prior to the start of the trial to review with the site staff the pro-
tocol, trial requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing the data collection procedures, the discussion will also include 
identification, agreement, and documentation of data items for which the eCRF may serve as 
the source document. 
Pharmacosmos A/S and or its designee will monitor the trial for protocol compliance verify-
ing the following, but not limited to:  
 Safety and rights of subjects are being protected 
 Trial is conducted in accordance with the currently approved protocol and any other 
trial agreements, ICH-GCP guidelines, and all applicable regulatory requirements 
 Data are authentic, accurate, and complete 
Risk based monitoring will be used and is described further in the Global Monitoring Plan. 
The PI agrees to allow the clinical research associate (CRA) direct access to all relevant 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 < 30 days. 
The following will be assessed as major protocol deviation: 


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 Out of visit window of ≥ 30 days after the final visit (i.e. ≥ 212 days after baseline) 
 Intake of prohibited medication 
 Treatment compliance outside the 80-120 % range  
 Other protocol deviations which are assessed as having a clinically or statistically 
significant effect 
18 
TRIAL ADMINISTRATION 
Pharmacosmos A/S will be responsible for trial administration as described in this section.  
A list of laboratories, Contract Research Organizations (CROs), and other vendors will be 
kept in the trial master file. 
18.1 
Trial Core Team, GCP Quality Steering Committee, and GCP Quality Board 
A Trial Core Team (TCT) will be established for the trial consisting of the following Sponsor 
personnel: 
 Chief medical officer  
 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   
 
 


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


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18.6 
Finance and Insurance 
All agreements between the PI and Pharmacosmos A/S or designee must be signed prior to 
screening of the first subject in the clinical trial. The agreement must clearly state the rights 
and obligations of the parties concerned and include a detailed financial settlement. 
Every subject participating in the trial will be insured in accordance with the local legal re-
quirements against trial related injuries to health, which may occur during the trial. 
Excluded from this, however, are injuries to health and deteriorations of illnesses already in 
existence which would have occurred or continued to exist even if the subject had not taken 
part in the clinical trial. 
The insurance cover is jeopardised if the subject fails to report immediately to the PI or re-
sponsible physician any injury to health, which might have resulted from participation in the 
clinical trial, or if the subject undergoes any other medical treatment without their consent 
before the clinical trial has been completely finished, insofar as the individual subject is con-
cerned. 
The subject insurance will be arranged by Pharmacosmos A/S on the basis of the final trial 
protocol. 
19 
ETHICAL CONSIDERATIONS 
19.1 
Regulatory and Ethical Considerations 
Pharmacosmos A/S or its designee will obtain favourable opinion/approval to conduct the 
trial from the IRB/IEC, Competent Authorities, and the Data Protection Agency in accordance 
with the local requirements prior to initiating the trial. 
The trial will be conducted in accordance with all applicable regulatory requirements. The 
trial will also be conducted in accordance with ICH-GCP guidelines, all applicable subject 
privacy requirements, and the guiding principles of the Declaration of Helsinki.  
19.2 
Changes to the Protocol 
The clinical trial procedures may be changed, and if the changes are substantial, both the 
IRB/IEC and Competent Authorities, as applicable, must approve/acknowledge the changes 
before they can be implemented. All substantial changes must be documented by protocol 
amendments, if applicable. 
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. 


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The trial will be registered at Clinicaltrials.gov. 
The results of the trial, positive as well as negative, will be published by the end of the trial. 
If the results of the trial are to be published in a journal, the authorship credit should be based 
on (1) substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data; (2) drafting the article or revising it critically for important intellectual 
content; (3) final approval of the version to be published. Authors should meet conditions 1, 
2, and 3. 
20.1 
Uploading of Data on Public Websites 
The primary endpoint 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 Hb from baseline to week 2 and months 3 and 6 
 Change in s-ferritin and TSAT from baseline to week 2 and months 3 and 6 
21 
REFERENCES 
Charytan C, Qunibi W, Bailie GR. Comparison of intravenous iron sucrose to oral iron in the 
treatment of anemic patients with chronic kidney disease not on dialysis. Nephron Clin Pract 
2005; 100: c55-c62 
Dignass AU, Gasche C, Bettenworth D, et al. European consensus on the diagnosis and 
management of iron deficiency and anaemia in inflammatory bowel diseases. J Crohns Colitis 
2015;9(3):211-222 
Gasche C, Berstad A, Befrits R et al. Guidelines on the diagnosis and management of iron 
deficiency 
and 
anemia in 
inflammatory 
bowel 
diseases. 
Inflamm Bowel 
Dis. 
2007;13(12):1545-1553 
Henry DH. The role of intravenous iron in cancer-related anemia. Oncology. (Williston Park) 
2006;20(8 Suppl 6):21-24 
Hotta T, Ogawa H, Saito A, et al. Iron balance following recombinant human erythropoietin 
therapy for anemia associated with chronic renal failure. Int J Hematol 1991; 54:195-200. 
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 
KDIGO Clinical practice guideline for anemia in chronic kidney disease. 2012;2(4). 
Available from: http://kdigo.org/home/guidelines/anemia-in-ckd/ 
Mehdi U, Toto RD. Anemia, diabetes, and chronic kidney disease. Diabetes Care 
2009;32(7):1320-1326 
 
 


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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 
 
 
 


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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 


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 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/CKD-EXT-01 
 
Protocol Version: 
2.0 (amendment 1) 
Date of Document : 
14 June 2017 
 
 
Confidential 
 
 Page 43 of 43 
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 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
Version:                              Final 2.0 
Statistical Analysis Plan 
 
 
 
 
 
 
P-IDA_CDK-EXT_SAP_V2_201807018.docx 
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Page 1 of 14 
 
 
 
 
Statistical Analysis Plan 
Trial Title: 
An open-label, multicentre, extension trial to assess the safety of 
redosing of intravenous iron isomaltoside (Monofer®)   
 
Trial ID: 
 
P-Monofer-IDA/CKD-EXT-01 
 
 
 
 
Phase III Trial 
 
 
 
 
 
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 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
Version:                              Final 2.0 
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Table of Contents 
List of Tables .................................................................................................................................. 3 
1 
List of Abbreviations ................................................................................................................ 4 
2 
Introduction ............................................................................................................................ 5 
3 
Trial Characteristics ................................................................................................................. 6 
3.1 
Trial Objectives ........................................................................................................................................ 6 
3.1.1 
Primary Objective .................................................................................................................... 6 
3.1.2 
Secondary Objectives .............................................................................................................. 6 
3.2 
Trial Design .............................................................................................................................................. 6 
3.3 
Subject included ...................................................................................................................................... 7 
3.3.1 
Sample Size Determination ..................................................................................................... 7 
4 
Analysis Populations ................................................................................................................ 7 
4.1 
Major protocol deviations ....................................................................................................................... 8 
4.1.1 
Prohibited Medication............................................................................................................. 8 
5 
Planned Statistical Methods ..................................................................................................... 8 
5.1 
Statistical Considerations ........................................................................................................................ 8 
5.2 
Subject Disposition .................................................................................................................................. 9 
5.3 
Baseline Characteristics and Demographics ........................................................................................... 9 
5.4 
Medical History ....................................................................................................................................... 9 
6 
Exposure and Other Dosing Information ................................................................................... 9 
6.1 
Exposure .................................................................................................................................................. 9 
6.2 
Concomitant medication ....................................................................................................................... 10 
7 
Statistical Methodology for Primary and Secondary Endpoints ................................................ 10 
7.1 
Analysis and Presentation of the Primary Endpoint ............................................................................. 10 
7.2 
Secondary Safety Endpoints .................................................................................................................. 10 
7.3 
Analysis and Presentation of the Safety Endpoints .............................................................................. 10 
7.3.1 
Adverse Events ...................................................................................................................... 10 
7.3.2 
Serum Phosphate .................................................................................................................. 12 
7.3.3 
Other Safety Assessments ..................................................................................................... 12 
7.4 
Analysis and Presentation of the Secondary Efficacy Endpoints .......................................................... 13 
7.5 
Handling of Missing Values ................................................................................................................... 13 
7.6 
Multiplicity adjustments ....................................................................................................................... 13 
7.7 
Sub-group and Centre Effects ............................................................................................................... 13 
7.8 
Interim Analysis ..................................................................................................................................... 13 
8 
Deviations from Protocol ....................................................................................................... 13 
9 
Software ............................................................................................................................... 14 
10 Reference List ........................................................................................................................ 14 
List of Tables 
Table 1: Flow Chart .................................................................................................................. 6 
 
 
 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
Version:                              Final 2.0 
Statistical Analysis Plan 
 
 
 
 
 
 
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1 List of Abbreviations 
ADR 
Adverse Drug Reaction  
AE 
Adverse Event 
ASAT 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CI 
Confidence Interval 
CRF 
Case Report Form 
DBL 
Data Base Lock 
ECG 
Electrocardiogram 
ESA 
Erythropoiesis Stimulating Agents 
FAS 
Full Analysis Set 
ITT 
Intention-To-Treat 
Hb 
Haemoglobin 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number of Subjects 
PP 
Per Protocol  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan   
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TEAE 
Treatment Emergent Adverse Event 
 
 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
Version:                              Final 2.0 
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2 Introduction 
The statistical analysis plan (SAP) for the P-Monofer-IDA/CKD-EXT-01 trial is based on the final 
protocol 2.0 dated 14 June 2017.  
The SAP describes in detail the analyses to be conducted and highlights any deviations from the 
analysis described in the protocol (see section 8). Deviations from methods described in this SAP, if 
any, will be specified in the clinical trial report. 
Throughout this SAP treatment and baseline refers to treatment and baseline, respectively in this 
extension trial, unless otherwise specified. 
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 analyses will be 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 trials will be after the date of last subject last visit. 
 




Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
Version:                              Final 2.0 
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Safety lab tests  
  
X  
X  
X  
X  
Efficacy lab tests  
  
X  
X  
X  
X  
Treatment with iron 
isomaltoside   
  
X  
  
  
  
Adverse events   
  
X  
X  
X  
X  
Final visit formb 
  
  
  
  
X  
a. 
For details of the assessment, please see Section 7.3.3. 
b. 
The final visit form may be filled in at any time of the trial if the subject is withdrawn.   
c. 
Laboratory tests taken at visit 6 of the lead-in trials P-Monofer-IDA-03 and P-Monofer-CKD-04 will be considered as 
screening values for the extension trial if they are collected ≤14 days before the screening visit.  
3.3 Subject included 
3.3.1 Sample Size Determination 
No sample size calculations have been performed for this extension trial.  
A target of 100 subjects will be recruited at selected sites with at least 25 subjects from P-Monofer-
IDA-01 and P-Monofer-IDA-03 combined and at least 25 from P-Monofer-CKD-04. The distribution of 
subjects from each of the three trials does not need to be equal and the subjects will be enrolled 
consecutively based on the enrolment criteria until 100 subjects have been enrolled. 
4 Analysis Populations 
The following 4 analysis sets for subjects requited in this extension trial are defined and will be used in 
the analyses of the data:  
 
Safety analysis set: The safety analysis set will include all subjects who received at least one 
dose of the trial drug. 
 
Intention to treat (ITT) analysis set: The ITT analysis set will include all subjects, with the 
exception of screening failures. 
 
Full Analysis Set (FAS): The FAS will consist of all subjects who received at least one dose of the 
trial drug in the lead-in trial (i.e. does not violate inclusion criteria 2), and have at least one post 
baseline Hb assessment.  
 
Per protocol (PP) analysis set: The PP analysis set will include all the 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. 
The classification of the subjects will be performed before database lock (DBL). 
The primary analysis population for efficacy evaluation is the ITT analysis set. All efficacy endpoints 
will be presented using the ITT. If the FAS contains less than 90% of the subjects in the ITT set, then Hb 
will in addition be presented using FAS. Similar if the PP set contains less than 90% of the subjects in 
FAS (or ITT, if FAS is not presented), then Hb will in addition be presented using the PP analysis set.  


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
Version:                              Final 2.0 
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4.1 Major protocol deviations 
Deviations from the protocol will be registered as protocol deviations. Before 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 ≥ 30 days after the final visit (i.e. ≥ 212 days after baseline)  
 
Intake of prohibited medication 
 
Treatment compliance outside the 80-120 % range 
 
Other protocol deviations which are assessed as having a clinically or statistically significant 
effect 
All major protocol deviations will be listed by subject and lead-in trial. Separate listings will be made 
for the ITT analysis set of visits 6 outside window of 14 days or more, 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: 
 
Any premedication (e.g. antihistamine or steroids) before administration of the trial drug. Daily 
treatment for e.g. allergy or asthma this is not considered as "premedication" 
 
Any iron supplementation other than investigational drug (nutritional supplementation 
including iron is allowed unless it is assumed as treatment of the subject's anaemia)  
 
Blood transfusion  
 
Erythropoiesis Stimulating Agents (ESA), unless the subject was treated with ESA in the lead-in 
trial or has received a stable dose (+/- 20 %) 4 weeks before the screening visit in this trial. 
5 Planned Statistical Methods 
5.1 Statistical Considerations 
No formal hypotheses will be tested in this 6 months, one-armed, safety extension trial.  
Baseline is defined as the last assessment with available data prior to the first administration of trial 
medication.  
Categorical data will be summarized, 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, standard deviation 
(SD), median, lower quartile, upper quartile, minimum and maximum. Both the absolute values and 
the change from baseline will be presented, unless stated otherwise. 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
Version:                              Final 2.0 
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Descriptive statistics for all endpoints will be presented overall and by lead-in trial and by week (if 
applicable) using observed cases, i.e. no imputation of missing data will be performed. All listings will 
be by lead-in trial and subject id unless stated otherwise. 
 
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 subjects 
 
Analysis sets (ITT, safety analysis set, FAS, and PP analysis set) 
 
End of study status 
 
Withdrawn from trial including reasons 
For calculation of the percentages the denominator will be number of subjects in the ITT. 
Subject disposition will in addition be presented by lead-in trial. All information will be listed. 
Screening failures will be listed.  
5.3 Baseline Characteristics and Demographics 
Demographics and baseline characteristics consist of age, gender, ethnic origin, 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 summarized using descriptive statistics, overall and by lead-in trial for the ITT analysis 
set. Age, Age groups and sex will in addition be presented by the FAS, safety analysis set and PP 
population. 
5.4 Medical History 
Relevant medical history is collected and will be summarised and listed. The summaries will be made 
by system organ class (SOC) and preferred term and by preferred term for the ITT analysis set. 
Separate summary and listing will be made of underlying disorder causing IDA. 
6 Exposure and Other Dosing Information 
6.1 Exposure 
Dose and compliance will be summarized using descriptive statistics and presented for the safety 
analysis set overall and by lead-in trial. 
For actual dose will be presented including dose category, dose in mg, number of doses and 
compliance. 
 
Compliance will be calculated as: 
 
100∗actual dose
planned dose  
 
All information will be listed by lead-in trial and subject. Furthermore, subjects out of the treatment 
compliance range of 80-120 % will be listed. 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
Version:                              Final 2.0 
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6.2 Concomitant medication 
Concomitant medication at baseline and changes in concomitant medication during the trial will be 
recorded. All concomitant medication will be summarised and listed using the ITT analysis set. The 
summaries will be made by anatomical therapeutic chemical (ATC) term The listing will be by lead-in 
trial and subject.  
7 Statistical Methodology for Primary and Secondary Endpoints 
7.1 Analysis and Presentation of the Primary Endpoint 
The primary endpoint is the number of adverse drug reaction (ADR), defined as adverse events (AEs) 
that are related or possible related to trial drug. 
Overall number and percentages of subjects with ADRs and number of ADRs will be summarized 
overall and by lead-in-trial, including two-sided 95 % exact Clopper-Pearson confidence limits (CL) for 
the number of subjects reporting ADRs.  
7.2  Secondary Safety Endpoints 
The secondary safety endpoints are the following: 
 
Serious or severe hypersensitivity reaction starting on or after the treatment with iron 
isomaltoside (i.e. treatment-emergent). The hypersensitivity terms are defined as standardised 
Medical Dictionary for Regulatory Activities query (SMQ) terms (including four additional 
terms) in protocol Appendix A.  
 
Composite cardiovascular AEs starting on or after the treatment with iron isomaltoside (i.e. 
treatment-emergent). 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 month 6  
 
Additional safety assessments are physical examinations and measurements of vital signs, height, 
weight, electrocardiogram (ECG), and safety laboratory parameters. 
7.3 Analysis and Presentation of the Safety Endpoints 
7.3.1 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 iron 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
Version:                              Final 2.0 
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isomaltoside or occur before dosing and increase in severity after dosing. AEs that increase in severity 
from before till after dosing will be identified by means of Data Management Audit Trail. Non-
treatment emergent AEs (Non-TEAE) are defined as AEs collected in the current trial, before dosing 
and does not increase in severity from before till after dosing. There will be more than 5 half-lives 
between dosing in the lead-in trial and screening in the current trial, thus none of the AEs will be 
regarded as related to previous treatment. 
An overall summary table by treatment will be made. The overall summary table will include total 
number of events, total number of subjects, and proportion of subjects reporting AEs, non-TEAEs, 
TEAEs, Treatment emergent serious adverse events (SAEs), Fatal SAEs, ADRs, serious adverse reactions 
(SAR), TEAEs by severity, and TEAEs by outcome. 
All TEAEs will be summarised by SOC and preferred term (PT). The summaries will include number of 
events, number of subjects, and proportion of subjects reporting these events and will be tabulated 
overall and by lead-in-trial for: 
 
TEAEs 
 
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) 
 
ADRs 
 
SARs  
 
Composite cardiovascular TEAEs 
 
Serious or severe hypersensitivity reactions 
 
Hypersensitivity reactions 
A two-sided 95 % exact Clopper-Pearson confidence limit (CL) for the overall number of subjects 
reporting SARs will be constructed. 
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  
 
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. 


Sponsor: Pharmacosmos  
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Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
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Time to first composite cardiovascular AE is defined as the actual time in days from date 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 
presented in a plot.  
7.3.2 Serum Phosphate 
Subjects with serum (s-) phosphate < 2 mg/dL at any time from baseline to month 6 will be listed. The 
listing will include phosphate values for all weeks. The data will in addition be presented in a 
longitudinal plot. 
7.3.3 Other Safety Assessments 
ECG and Physical Examination 
Standard 12 lead ECG and Physical examination is assessed at baseline and at week 26. At baseline, 
two ECGs will be recorded; one before administration of the trial drug and one approximately 30 
minutes after start of the dosing. ECG and each body system of the physical examination will be 
evaluated as normal or abnormal, and if abnormal clinical significant or not. 
The 3 categories of ECG will be presented overall by shift tables from baseline (before treatment) till 
after dosing and week 26. The shift tables will be repeated by lead in trial. Similar shift tables from 
baseline till week 26 will be made for physical examination worst case. All data will be listed. 
Vital Signs 
Vital signs (heart rate, systolic and diastolic blood pressure) will be measured at baseline, weeks 2, 13, 
and 26. At baseline, vital signs will be measured at the following time points:  
 
Approximately 0-10 minutes before infusion, during infusion, 5-15 minutes, and 20-40 minutes 
after the infusion has ended  
Vital signs will be summarized by treatment, week and time point, including change from pre- infusion 
at the treatment visit. The summary tables will be repeated by lead in trial. Vital signs will be listed by 
subject. 
Height and Weight 
Height is measured at baseline. Weight is measured at baseline and at the final visit.  
Height will be summarised by treatment for the pooled data overall, and by lead in trial. 
Weight will be presented in summary tables by treatment and week including change from baseline. 
This will be made for the pooled data overall, and by lead in trial. All data will be listed by subject. 
Laboratory Safety Data 
Safety laboratory parameters (haematology and biochemistry) are measured at baseline and at week 
2, 13, and 26. 
Laboratory safety data will be summarised using descriptive statistics, including means, medians, SDs, 
and minimum and maximum by week, overall and by lead-in-trial. Furthermore, changes from baseline 
will summarised. In addition, laboratory safety data will be plotted using boxplots by week. 


Sponsor: Pharmacosmos  
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Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
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Values outside normal ranges will be flagged. All safety laboratory data will be listed by lead-in-trial 
and subject including eligibility laboratory assessments. Clinical significant laboratory will be listed 
including the corresponding AE. 
7.4 Analysis and Presentation of the Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
 
Change in Hb from baseline to week 2 and months 3 and 6  
 
Change in s-ferritin, transferrin saturation (TSAT), and s-iron from baseline to week 2 and 
months 3 and 6 
Change in Hb from baseline to week 2 and months 3 and 6 will be summarised by week using 
descriptive statistics overall and by lead-in trial for the ITT, and for the FAS and PP analysis sets, if 
applicable. Furthermore, change from baseline for the lead-in trial to current baseline, week 2 and 
months 3 and 6 including absolute Hb values will be summarised. Change in Hb concentrations over 
time will be presented using mean plots overall and by lead-in trial. Serum (s)-ferritin, TSAT and s-iron 
will be presented in similar ways using the ITT analysis set, only. 
The efficacy data will be listed by lead-in-trial, subject and time point. 
7.5 Handling of Missing Values 
No imputation of missing values will be applied. 
7.6 Multiplicity adjustments 
In this one-armed extension trial, no formal statistical analyses will be performed and there will be no 
adjustment for multiplicity. 
7.7 Sub-group and Centre Effects 
Summary tables of demographics, efficacy and secondary safety endpoints will be prepared overall 
and by lead-in trial. 
No effect of centres will be evaluated. 
7.8 Interim Analysis 
No interim analysis is planned. 
8 Deviations from Protocol 
The below describes the deviation in statistical methods as compared to the protocol text.   
 
In the protocol section 15.3 it is stated that the ITT analysis set will include all subjects. This has 
been changed to: The ITT analysis set will include all subjects, with the exception of screening 
failures. 


Sponsor: Pharmacosmos  
Drug/Project: Monofer 
Trial: P-Monofer-IDA/CKD-EXT-01 
Date:                            18-Jul-2018 
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 
In the protocol section 15.5 it is stated that summaries will be prepared with respect to two 
baselines: Baseline in lead-in trial, and baseline in this extension trial. This will only be 
applied to the efficacy endpoints. 
 
In the protocol section 15.6 it is stated that the incidence of treatment-emergent ADRs and 
SARs will be presented, including two-sided 95 % CI. Instead a two-sided CI around the number 
of subjects with ADRs and SARs, respectively will be constructed. 
 
In the protocol section 15.6 it is stated that number of subjects who experience an ADR 
including SUSARs will be compared between treatment groups. This is not applicable in this 
one-armed trial. 
9 Software  
All statistical calculations described in this SAP will be done by 
 using SAS, release 9.4 or 
later (SAS Institute, Cary, NC, USA).  
10 Reference List 
Not applicable.