Conditions: Pulmonary Arterial Hypertension Iron Deficiency
Keywords: Idiopathic pulmonary arterial hypertension (IPAH) Iron deficiency
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 56
Healthy volunteers: no

Brief summary:
This study will establish whether intravenous iron replacement has clinical benefit in idiopathic pulmonary arterial hypertension.

A 24-week double-blind, randomised, placebo-controlled, crossover study will investigate whether a single dose of 1g of Ferinject® or CosmoFer improves cardiopulmonary haemodynamics, exercise capacity and quality of life and is well-tolerated.

IV iron formulation used in Europe - Ferinject IV iron formulation used in China - CosmoFer

Detailed description:
These results represent the outcome of two separate clinical trials which were conducted in collaboration, led by Imperial College and Fuwai, China respectively. The protocols were analogous, although in China Endurance Cardio-Pulmonary Exercise Testing (CPET) was not done and instead of Ferinject/Placebo being infused over 15 minutes, Cosmofer/Placebo was infused over 4-6 hours.

The study analyses were performed as Intention to Treat, except for patients 6009-6017 as described below. The study was a cross-over design and results are presented for 2 groups based on the participants' study timepoint, and presented separately for the two study datasets (Europe and Fuwai). A meta-analysis was conducted for the combined data where possible and the relevant p-values have been provided.

Iron results in the European dataset are taken from blood results which were collected centrally and analysed by one laboratory at Imperial College London. N-Terminal B-type natriuretic peptide (NT-PRO-BNP) and Soluble Transferrin Receptors (STFR) were not done at Fuwai.

The study was conducted according to Good Clinical Practice (GCP), but there were some missing data (imputed using multiple imputation techniques), and also some significant protocol deviations which are summarised below.

Six participants (2003, 3004, 4002-4005) had their endurance CPETs set at incorrect workloads which differed significantly from that achieved at the baseline incremental CPET. These data were therefore treated as missing, and relevant values imputed as per the statistical analysis plan.

Visit 5 CPETs for participants 1008 (Incremental CPET 12 weeks later) 1018 (Endurance CPET 13 days later) and 1019 (Incremental CPET 15 days later) were performed outside the protocol-specified window.

Participant 1014 received placebo at both treatment visits in error. Participant 6017 suffered a suspected allergic reaction to their first infusion and was withdrawn from the study. There was a systemic error where participants 6009-6016 received the opposite to their random-assigned treatment at each time point. These participants were analysed according to the treatment actually received, rather than that originally assigned by randomisation.

Arms:
arm 1: IV iron formulation used in Europe - Ferinject - given over 15 minutes

IV iron formulation used in China - CosmoFer - over a period of 4 to 6 hours

IV Iron given at Week 0, Placebo (saline) given at Week 12. arm 2: Placebo comparator

Placebo (saline) given at Week 0, IV Iron given at Week 12.

Interventions: intervention 1: Saline intervention 2: Ferinject or CosmoFer
Intervention descriptions: intervention 1: intravenous, no active drug intervention 2: Intravenous, 1000 mg iron

Protocol document:
SAP_002.pdf: 


Page 2 of 5 
 
1. Introduction 
 
This Statistical Analysis Plan (SAP) describes the analyses that will be performed on 
the primary and secondary efficacy endpoints recorded in two Phase II proof-of-
concept studies of the use of intravenous iron infusion to treat iron deficient patients 
with IPAH. The SAP is based on version 9.0 of the UK/EU study protocol, which is 
dated 24th October 2016, and on version 1.0 of the China study, which is dates 8th 
August 2014. 
 
Both studies are double-blind, placebo controlled crossover trials, one of which recruits 
patients in various centres in the UK and EU, and the second of which recruits patients 
in China.  
 
The two studies are very similar in design, the major difference being that the UK/EU 
study uses Ferinject® for the treatment of iron deficiency, whereas the China study 
uses Cosmofer®. There are also some differences between the endpoints recorded in 
the two studies (documented below). 
 
In both studies patients are allocated at random to receive either active treatment or 
placebo in the first of two treatment periods, with the other treatment being 
administered, following a washout phase, in the second treatment period. 
 
 
2. Sample size 
 
The original version of both protocols contained the following statement on sample 
size: 
 
“The null hypothesis is that iron replacement has no effect on patients with iron 
deficiency and IPAH, with a two-sided alternative that iron replacement changes PVR 
in patients with iron deficiency and IPAH. Assuming a standard deviation of 250 
dynes/s/cm and a drop-out rate of 10%, 60 patients randomised 1:1 would give this 
study 80% power to detect a 194 dynes/s/cm reduction in PVR with iron treatment at a 
significance level of p=0.05 using two-sample t-test.” 
 
However, a blinded conditional power analysis of the PVR endpoint, conducted in April 
2015 for the UK/EU study only, indicated that the study had conditional power (under 
the current trend hypothesis) of less than 60% to detect a statistically significant effect. 
 
The current version of the UK/EU protocol contains an amended primary endpoint, 
applicable to the UK/EU study, and makes the following statement on power and 
sample size, which is based on a planned recruitment of 60 patients chosen on the 
basis of safety and feasibility considerations: 
 
“For the cardiopulmonary exercise tests, (with) a 12-weekly drop-out rate of 10% and 
standard deviation of 5 ml/min/kg for peak VO2 we would have 80% power to detect a 
mean change of 1.94 ml/min/kg at a significance level of alpha=0.05 using a paired 
analysis” 
 
 
3. Efficacy Endpoints 
 
For both studies, the original protocol specified the following primary endpoint: 


Page 3 of 5 
 
 
“Change in resting Pulmonary Vascular Resistance (PVR) between baseline and 12 
weeks, measured by cardiac catheterisation”. 
 
In June 2015, following the blinded conditional power calculation, a protocol 
amendment was made for the UK/EU study which changed the primary endpoint from 
PVR to Endurance Time and cardiac catheterisation was dropped from the protocol. 
The China study continues to have PVR as the primary endpoint. Apart from the 
cardiac catheterisation procedure, the other main difference between the UK/EU study 
and the China study is that the former uses both incremental and endurance exercise 
tests, whereas the latter uses incremental exercise tests only. 
 
The following efficacy endpoints are therefore specified in the UK/EU study protocol: 
 
 
Primary:  
 
• Endurance time at the end of endurance bicycle cardiopulmonary exercise testing at 
80% peak work rate determined from the incremental exercise test  
 
Secondary:  
 
• Incremental bicycle cardiopulmonary exercise testing - peak VO2 
(ml/min/kg), VO2 at metabolic threshold, VE/VCO2 slope, VO2/WR slope 
and O2 pulse.  
• VO2 at the end of endurance bicycle cardiopulmonary exercise testing at 
80% peak work rate determined from the incremental exercise test  
• Gas exchange at 3 minutes after the start of the work phase of an 
endurance exercise test at 80% peak work rate determined from the 
incremental exercise test  
• Iron indices – serum iron, transferrin saturations, ferritin, soluble 
transferrin receptor (sTfR), unsaturated iron binding capacity (UIBC), red 
cell distribution width (RDW) and erythropoietin (EPO) levels  
• 6 minute walk distance and Borg dyspnoea scale  
• NYHA WHO functional class  
• NT-pro-BNP  
• Quality of life (CAMPHOR questionnaire) and the self-reported Patient 
Global Assessment  
• Cardiac MRI - right ventricular volumes, mass, ejection fraction, stroke 
volume and diastolic function (at sites where facility is available). 
 
 
The following efficacy endpoints are specified in the China protocol: 
 
Primary: 
 
The change in resting pulmonary vascular resistance (PVR) between baseline and 12 
weeks, measured by cardiac catheterisation.  
 
Secondary: 
 


Page 4 of 5 
 
 Incremental bicycle cardiopulmonary exercise testing - peak VO2 (ml/min/kg), 
anaerobic threshold, VE/VCO2 slope, VO2/WR slope, O2 pulse and tissue 
oxygenation index. 
 Resting cardiopulmonary haemodynamics – right atrial pressure, pulmonary 
arterial pressure, pulmonary capillary wedge pressure, cardiac output and 
stroke volume 
 Iron indices – serum iron, transferrin saturations, ferritin, unsaturated iron 
binding capacity (UIBC), red cell distribution width (RDW). 
 6 minute walk distance and Borg dyspnoea scale 
 NYHA WHO functional class 
 NT-pro-BNP 
 Safety - the occurrence of adverse events 
 Cardiac MRI - right ventricular volumes, mass, ejection fraction, stroke volume 
and diastolic function 
 
 
4. Statistical Analyses 
 
The principal objective of all of the statistical analyses planned for these studies is to 
test for a treatment effect (i.e. a difference between control and test treatments) and to 
produce suitable interval estimates of the effect, for each of the efficacy endpoints. 
 
The overall strategy for the statistical analysis is that each of the two studies will first be 
analysed separately, using the methods outlined below, and results will be reported 
separately for the two studies. Following these separate analyses, and subject to 
satisfactory evidence of homogeneity, the individual results (treatment effect estimates 
and/or associated p-values) will be combined using meta-analysis techniques, in order 
to produce overall summaries of the effects of iron supplementation. If there is 
evidence that the results from the two studies cannot validly be combined, the results 
from individual studies only will be reported. 
 
In order to facilitate the planned meta-analysis of the two sets of study results, each of 
the endpoints specified above, whether in the UK/EU study or the China study, will be 
analysed for both studies (if the relevant data are available), so that the individual study 
results can be combined. This means that some endpoints will be analysed in each 
study that are not explicitly specified in the protocol for that study. 
 
All primary and secondary efficacy endpoints will be analysed using linear mixed 
models appropriate for a crossover design. The linear models will include 
administration sequence, period and treatment as fixed effects and subject as a 
random effect, and all models will include relevant and statistically significant baseline 
covariates. If the assumption of normal errors appears inappropriate for any of these 
linear models, (as evidenced by initial exploratory analyses), the linear models will use 
a suitable alternative error structure. 
 
From the linear mixed models estimates of the treatment effect (difference in mean 
outcomes between the two treatment arms) will derived. These will summarised using 
adjusted (least-squares) means and mean differences, together with 95% confidence 
intervals and associated p-values. P-values testing for sequence and period effects will 
also be derived for each of the linear mixed models.  
 


Page 5 of 5 
 
In any case in which the use of a linear mixed model appears, in initial exploratory 
analyses, to be inappropriate for the data structure, suitable nonparametric statistical 
procedures will be employed. In particular, for cardiac MRI outcomes, where the 
recorded endpoint will be multivariate in nature, the multi-response permutation 
procedure (MRPP) will be used to test for a treatment effect. 
 
The main analyses of the efficacy endpoints will be performed using the Intention-to-
treat (ITT) analysis set, with imputation of missing data, if required, carried out using 
multiple imputation (MCMC) techniques.  
 
In addition to the ITT analyses, exploratory analyses of other patient subsets, including 
centre-specific subsets, may be performed. 
 
For the meta-analysis of the two studies, treatment effect estimates will be derived by 
combination of the individual study effect estimates and/or by direct pooling of 
individual patient data, and p-value combination methodologies (i.e. combinations of 
the individual study p-values) will be used to derive an overall meta-analytic p-value 
from the combined results.  
 
 

Prot_000.pdf: 
Ferinject® for iron deficiency in IPAH patients                                                                
                Page 1 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
 
 
 
 
What is the effect of intravenous iron supplementation on exercise capacity 
and quality of life in patients with IPAH and iron deficiency? 
 
 
 
(Short title: FerinjectP®
P for iron deficiency in IPAH patients) 
 
 
 
Protocol Number: WILK3 
 
Protocol Version: 9.0  
 
Version Date: 24 October 2016 
 
EudraCT Number: 2010-024585-22 
 
 
Sponsor: Imperial College Academic Health Science Centre 
 
Chief Investigator:  
Dr Luke Howard DPhil, FRCP 
 
Co-investigators:  
Professor Martin Wilkins 
Dr John Wharton  
Dr J Simon R Gibbs 
Dr David Kiely 
Dr Karen Sheares 
Prof. Dr. med. Stephan Rosenkranz 
Prof. Dr. Ardeshir H. Ghofrani 
 
 
 
 
Protocol authorised by: 
 
Name & Role                                    Signature                                                 Date 
 
 
 
 
 
 
 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 2 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
ORGANISATION FOR THE CLINICAL TRIAL 
 
Sponsor 
Imperial College Academic Health Science Centre 
AHSC Joint Research Compliance Office  
Imperial College London and Imperial College Healthcare NHS Trust 
510C Fifth Floor, Lab Block 
Charing Cross Hospital, London 
W6 8RF 
United Kingdom 
Tel: 020 3311 0204 
Fax: 0203 311 0203 
Chief Investigator 
Dr Luke Howard DPhil, FRCP 
Consultant in Respiratory Medicine 
National Pulmonary Hypertension Service 
Hammersmith Hospital 
Du Cane Road 
London W12 0HS 
United Kingdom 
Tel: 020 8383 3171 
Fax: 020 8383 2331 
Email: l.howard@imperial.ac.uk 
Principal Investigators 
Dr David Kiely  PhD, FRCP 
Department 
of 
Respiratory 
Medicine 
Royal Hallamshire Hospital 
Glossop Road 
Sheffield S10 2JF 
United Kingdom 
Dr Karen Sheares PhD, FRCP 
Pulmonary Vascular Diseases Unit 
Papworth Hospital NHS Foundation 
Trust 
Papworth Everard 
Cambridge CB23 3RE 
United Kingdom  
Prof. Dr. med. Stephan Rosenkranz 
Klinik III für Innere Medizin und 
Zentrum für Molekulare Medizin 
Köln (ZMMK) 
Herzzentrum der Universität zu 
Köln 
Kerpener Str. 62 
50937 Köln 
Prof. Dr. Ardeshir H. Ghofrani 
Professor for Internal Medicine, 
Justus-Liebig University Giessen,  
Klinikstraße 33 
35392 GIEßEN 
 
Study Coordination 
Centre 
 
Vijaykumar Zala 
NIHR/Wellcome Trust Imperial Clinical Research Facility 
Imperial Centre for Translational and Experimental Medicine 
Hammersmith Hospital, Du Cane Road, London W12 0HS 
United Kingdom 
Tel: 020 33138070 
Fax: 020 33131763  
 
Email: V.Zala@imperial.ac.uk  


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 3 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
Central Laboratories 
 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiopulmonary 
Exercise Testing 
 
 
Dr John Wharton BSc, PhD 
Honorary Senior Lecturer 
Section for Pharmacology & Therapeutics, Department of Medicine 
Imperial College London, Hammersmith Campus 
E505 Burlington Danes Building 
Du Cane Road, London W12 0NN 
Tel: 020 7594 6819 
Fax: 020 7594 6821 
Email: 3TUj.wharton@imperial.ac.uk  
  
Professor Leong L. Ng, BA, MB, BChir, MD, FRCP  
Professor of Medicine & Therapeutics, University of Leicester 
Honorary Consultant Physician, Cardiovascular Unit, University Hospitals 
of Leicester NHS Trust 
Leicester LE2 7LX 
Tel: 0116 252 3132 
Fax: 0116 252 3108 
Email: 3TUlln1@le.ac.uk 
 
 
Dr Kevin Murphy 
Hammersmith Hospital 
Du Cane Road 
London W12 0HS 
United Kingdom 
 
Tel: 0208 8383 1233 
Drug Supply 
Vifor (International) Inc. 
Rechenstrasse 37 
CH-9014 St Gallen 
Switzerland 
Pharmacovigilance 
Vifor (International) Inc. 
Rechenstrasse 37 
CH-9014 St Gallen 
Switzerland 
Fax: +41 68 851 86 59 
Email: 3TUsafety@viforpharma.comU3T  
 
 
 
 
 
 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 4 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
 
 
I confirm agreement to conduct the study according to the protocol and in compliance with 
Good Clinical Practice standards and other applicable regulatory requirements. 
 
 
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct 
or supervise the described clinical study. 
 
 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receive the appropriate information throughout the study. 
 
 
Investigator Name: 
 
 
 
Investigator Address: 
 
 
 
 
 
 
 
 
Investigator Signature: 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 5 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
Table of Contents 
 
GLOSSARY OF ABBREVIATIONS ........................................................................................................... 8 
1. 
BACKGROUND AND RATIONALE ............................................................................................... 13 
2. 
STUDY OBJECTIVES .................................................................................................................... 14 
3. 
STUDY OUTCOME MEASURES ................................................................................................... 14 
3.1. 
Primary outcome .................................................................................................................. 14 
3.2. 
Secondary outcomes: ............................................................................................................ 14 
4. 
INVESTIGATIONAL PLAN ........................................................................................................... 14 
4.1. 
Overall study design and plan ............................................................................................... 14 
4.2. 
Discussion of study design .................................................................................................... 15 
4.3. 
Selection of Study Population ............................................................................................... 15 
4.3.1. 
Inclusion criteria: ............................................................................................................... 15 
4.3.2. 
Exclusion criteria: .............................................................................................................. 16 
4.3.3. 
Subject Completion ........................................................................................................... 17 
4.3.4. 
Withdrawal of Subjects from Study .................................................................................. 17 
4.3.5. 
Replacement policy ........................................................................................................... 17 
5. 
INVESTIGATIONAL PRODUCT(S) ................................................................................................ 17 
5.1. 
Ferinject® .............................................................................................................................. 17 
5.1.1. 
Composition, packaging and storage ................................................................................ 17 
5.2. 
IMP preparation and administration .................................................................................... 18 
5.2.1. 
IMP Preparation ................................................................................................................ 18 
5.2.2. 
IMP Administration ........................................................................................................... 18 
5.3. 
Labelling ................................................................................................................................ 18 
5.4. 
Study drug accountability ..................................................................................................... 18 
5.5. 
Treatment assignment and blinding ..................................................................................... 18 
5.5.1. 
Treatment assignment ...................................................................................................... 18 
5.5.2. 
Blinding ............................................................................................................................. 18 
5.5.3. 
Emergency unblinding procedures ................................................................................... 19 
5.6. 
Concomitant medications ..................................................................................................... 19 
5.6.1. 
Permitted concomitant medications ................................................................................ 19 
5.6.2. 
Prohibited concomitant medications................................................................................ 19 
6. 
VISIT AND ASSESSMENT SCHEDULE .......................................................................................... 19 
6.1. 
Screening Visit ....................................................................................................................... 19 
6.2. 
Baseline/Randomisation Visit (Week 0) ................................................................................ 20 
6.3. 
Week 2 (+/- 3 days) Telephone Follow up ............................................................................ 20 
6.4. 
Week 12 (+/- 3 days) ............................................................................................................. 20 
6.5. 
Week 14 (+/- 3 days) Telephone Follow up .......................................................................... 21 
6.6. 
Week 24 (+/- 3 days) ............................................................................................................. 21 
7. 
STUDY ASSESSMENTS ................................................................................................................ 21 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 6 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
7.1. 
Physical Examination and Medical History ........................................................................... 21 
7.2. 
Modified NYHA (WHO) Classification ................................................................................... 22 
7.3. 
Vital signs .............................................................................................................................. 22 
7.4. 
Endurance cardiopulmonary exercise test ........................................................................... 22 
7.5. 
Six minute walk distance: ...................................................................................................... 22 
7.6. 
Incremental cardiopulmonary exercise test: ........................................................................ 23 
7.7. 
Cardiac Magnetic Resonance (CMR) Imaging ....................................................................... 23 
7.8. 
Laboratory measurements:................................................................................................... 23 
7.8.1. 
Type of laboratory ............................................................................................................. 23 
7.8.2. 
Research samples .............................................................................................................. 24 
7.8.3. 
Volume of Blood Collection .............................................................................................. 24 
7.9. 
Quality of Life: ....................................................................................................................... 25 
7.10. 
Patient Global Assessment................................................................................................ 25 
8. 
PHARMACOVIGILANCE .............................................................................................................. 25 
8.1. 
Definitions ............................................................................................................................. 25 
8.2. 
Assigning Causality ................................................................................................................ 26 
8.2.1. 
Causality Description......................................................................................................... 26 
8.3. 
Assigning Severity ................................................................................................................. 26 
8.4. 
Adverse event reporting procedures .................................................................................... 27 
8.4.1. 
Screening period ............................................................................................................... 27 
8.4.2. 
Treatment period .............................................................................................................. 27 
8.4.2.1. 
Non serious AR/AEs....................................................................................................... 27 
8.4.2.2. 
Serious AR/AEs .............................................................................................................. 27 
8.5. 
Reporting to the Regulatory Authorities .............................................................................. 27 
8.6. 
Reporting to the Sponsor ...................................................................................................... 27 
8.7. 
Reporting to Vifor Pharma Drug Safety ................................................................................ 28 
8.8. 
Follow up of adverse events ................................................................................................. 28 
9. 
DOCUMENTATION OF DATA ..................................................................................................... 28 
9.1. 
Data collection ...................................................................................................................... 28 
9.2. 
Data monitoring .................................................................................................................... 28 
10. 
STATISITICS AND DATA ANALYSIS ......................................................................................... 28 
11. 
ADMINISTRATIVE AND LEGAL CONSIDERATIONS ................................................................. 29 
11.1. 
General Legal Requirements ............................................................................................. 29 
11.2. 
Ethics Committee/RA approvals ....................................................................................... 29 
11.3. 
Informed consent .............................................................................................................. 29 
11.4. 
Patient confidentiality ....................................................................................................... 29 
11.5. 
Protocol Amendments ...................................................................................................... 30 
11.6. 
Premature Termination of the Trial .................................................................................. 30 
11.7. 
Sponsor ............................................................................................................................. 30 
11.8. 
Indemnity .......................................................................................................................... 30 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 7 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
11.9. 
Record Retention .............................................................................................................. 30 
11.10. 
Confidentiality ................................................................................................................... 31 
11.11. 
Publications ....................................................................................................................... 31 
11.12. 
Audits and Inspections ...................................................................................................... 31 
References ........................................................................................................................................ 32 
Table 1. Visit and Assessment Schedule ........................................................................................... 33 
 
 
 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 8 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
GLOSSARY OF ABBREVIATIONS 
 
6MWT 
6 –minute walk test 
AE 
Adverse event 
AR 
Adverse reaction 
BP 
Blood pressure 
bpm 
Beats per minute 
CAMPHOR 
Cambridge Pulmonary Hypertension Outcome Review 
CMR 
Cardiac Magnetic Resonance  
CPET 
Cardiopulmonary exercise test 
CRF 
Case Report Form 
FPFV 
First patient first visit 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigation Medicinal Product 
IPAH 
Idiopathic pulmonary arterial hypertension 
i.v. 
Intravenous 
LPLV 
Last patient last visit 
NT pro-BNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
PAH 
Pulmonary arterial hypertension 
PAP 
Pulmonary arterial pressure 
PCWP 
Pulmonary capillary wedge pressure 
PH 
Pulmonary hypertension 
PVR 
Pulmonary vascular resistance 
RA 
Regulatory Authority 
REC 
Research Ethics Committee 
RHC 
Right heart catheterisation 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SPM 
Study Procedures Manual (study specific SOP binder) 
sTfR 
Soluble transferrin receptor 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SVR 
Systemic vascular resistance 
WHO 
World Health Organisation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 9 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
Study Summary 
 
TITLE 
What is the effect of intravenous iron supplementation on exercise capacity and 
quality of life in patients with idiopathic pulmonary arterial hypertension (IPAH) and 
iron deficiency? 
PHASE 
II 
DESIGN 
Multi-centre, double-blind, randomised, placebo-controlled, crossover study 
OBJECTIVES 
To assess the clinical value of using intravenous iron (ferric carboxymaltose) infusion 
(Ferinject®) in iron deficient patients with IPAH. 
 OUTCOME 
 MEASURES 
Primary: 
 Endurance time at the end of endurance bicycle cardiopulmonary exercise 
testing at 80% peak work rate determined from the incremental exercise test  
Secondary: 
 Incremental bicycle cardiopulmonary exercise testing - peak VO2 (ml/min/kg), 
VO2 at metabolic threshold, VE/VCO2 slope, VO2/WR slope and O2 pulse. 
 VO2 at the end of endurance bicycle cardiopulmonary exercise testing at 80% 
peak work rate determined from the incremental exercise test  
 Gas exchange at 3 minutes after the start of the work phase of an endurance 
exercise test at 80% peak work rate determined from the incremental exercise 
test 
 Iron indices – serum iron, transferrin saturations, ferritin, soluble transferrin 
receptor (sTfR), unsaturated iron binding capacity (UIBC), red cell distribution 
width (RDW) and erythropoietin (EPO) levels 
 6 minute walk distance and Borg dyspnoea scale 
 NYHA WHO functional class 
 NT-pro-BNP 
 Quality of life (CAMPHOR questionnaire) and the self-reported Patient Global 
Assessment 
 Safety - the occurrence of adverse events 
 Cardiac MRI - right ventricular volumes, mass, ejection fraction, stroke volume 
and diastolic function (at sites where facility is available) 
POPULATION 
An estimated 60 patients will be enrolled.  
STUDY CENTRES 
5 centres in UK/EU. 
STUDY DURATION 
FPFV: Q4 2011  
LPLV: Q4 2017 
ELIGIBILITY 
Inclusion criteria 
1. Males or females aged between 16–75 years old 
2. PAH which is idiopathic, heritable or associated with anorexigens.  
3. Iron deficiency as defined by any one of the following criteria: 
sTfR levels > 28.1 nmol/l (where sTfR analysis is available) or one of the 
following: Ferritin < 37 ug/l; transferrin saturations < 16.4%; iron < 10.3 umol/l. 
4. Documented diagnosis of PAH by right heart catheterisation performed at any 
time prior to Screening showing: resting mean pulmonary artery pressure 
>25mmHg, pulmonary capillary wedge pressure =/< 15 mm Hg and normal or 
reduced cardiac output;  
5. 6 minute walking distance greater than 50m at entry;  
6. Stable on an unchanged PAH therapeutic regime (any combination of 
endothelin receptor antagonist, phosphodiesterase inhibitor or prostacyclin 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 10 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
analogue) for at least 1 month. 
7. Able to provide written informed consent prior to any study-mandated 
procedures 
8. Female subjects of child-bearing potential are eligible to participate if they 
agree to use one of the following contraception methods: 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
o oral 
o injectable 
o implantable  
 
Intrauterine device (IUD)  
 
Intrauterine hormone-releasing system (IUS)  
 
Bilateral tubal occlusion  
 
Vasectomised partner  
 
Sexual abstinence  
 
Exclusion criteria 
 
1. Unable to provide informed consent. 
2. Clinically-significant renal disease (Creatinine clearance < 30 ml/min per 
1.73 mP2
P calculated from CKD-Epi 
3TUhttp://www.qxmed.com/renal/Calculate-
CKD-EPI-GFR.phpU3T) or liver disease (including serum transaminases > 3 times 
upper limit of normal). 
3. Haemoglobin concentration <10 g/dl. 
4. Patients will be excluded if any single parameter (iron, ferritin or transferrin 
saturation) exceeds 1x upper limit of normal (ULN) in the local lab reference 
range. 
5. Patients with moderate to severe hypophosphatemia as defined as 
<0.65mmol/L 
6. Known to have haemoglobinopathy e.g. sickle cell disease, thalassaemia. 
7. Admission to hospital related to PAH or change in PAH therapy within 1 
month prior to Screening. 
8. Evidence of left ventricular disease or significant lung disease on high-
resolution CT scanning or lung function as judged by the investigator  
9. Acute or chronic infection or inflammation. 
10. Significant uncontrolled asthma as judged by the investigator, eczema or 
atopic allergies. 
11. Females who are lactating or pregnant. 
12. Individuals known to have HIV, Hepatitis B or C or Creutzfeld-Jakob disease. 
13. Known hypersensitivity to FerinjectP®
P or any of its excipients and any other 
iron supplement preparation. 
14. Evidence of disturbances in utilisation of iron. 
15. Significant blood loss (e.g. GI bleed) within the last 3 months or history of 
menorrhagia. 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 11 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
16. Unable to perform a Cardiopulmonary Exercise Test i.e. due to syncope or 
musculoskeletal factors. 
17. Patients who have received an investigational medicinal product within 30 
days of entering the baseline visit  
TREATMENT 
All the study participants will attend a screening visit, two treatment periods at 
Week 0 and Week 12, telephone visits at Week 2 and Week 14 and a follow up visit 
at Week 24 to evaluate the kinetics of iron re-depletion.  
 
Potential participants will be screened using data collected during their routine 
outpatient appointment at the Pulmonary Hypertension Service. Any unavailable or 
missing data will be collected at the baseline visit (week 0) once the patient has 
provided written informed consent. 
 
Eligible participants will be admitted to the research unit for up to 3 days in order to 
complete the Baseline (Week 0) assessments including a physical examination, 
medical history, ECG, bloods to assess routine haematology and clinical chemistry 
and measure biomarkers, 6-Minute Walk Test, CAMPHOR questionnaire  and 
incremental and endurance cardiopulmonary exercise tests (CPET). 
 
As outlined in Figures 1, following completion of the Baseline assessments at Week 
0 patients will be randomly allocated 1:1 to receive an infusion of either Ferinject P®
P 
or saline. 
 
At Week 2, participants will attend a phone call from the research unit for a follow 
up visit. This will include any AE or medication and PGA questionnaire. 
 
At Week 12 all participants will be admitted to the research unit for up to 3 days to 
repeat the assessments done at Baseline (Week 0). Following completion of the 
Week 12 procedures, the patients will be switched to the other treatment arm (i.e. 
those who received FerinjectP®
P at baseline will be administered a saline infusion, and 
vice versa).  
 
Thereafter participants will have a telephone follow up assessments at Weeks 14. 
The assessments at these visits are the same as for Week 2.  
 
Participants will have a final hospital follow up visit at Week 24 during which the 
assessments will be the same as those performed at baseline and Week 12. 
 
At selected centres participants will be given the option to undergo additional 
cardiac MRI (Weeks 0, 12 and 24). 
 
At the Sheffield site only, if participants agree, they will have two extra blood 
samples taken (50 ml extra in total) to assess neutrophil and peripheral blood 
mononuclear cell function and expression at Week 0 and 2 or Week 0 and 12 of 
study participation. 
 
 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 12 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
  
 
 
 
 
Figure 1 – Schematic overview of study to determine the effect of intravenous iron supplementation 
on cardiopulmonary haemodynamics and exercise capacity in iron deficient patients with 
IPAH.   
1000mg IV iron (Ferinject) 
Saline 
Week 0 
Secondary endpoint measures by telephone call 
Week 2 
Primary endpoint measures 
Secondary endpoint measures 
Week 12 
Saline 
Week 14 
Secondary endpoint measures by telephone call 
Primary endpoint measures 
Secondary endpoint measures 
Week 24 
Baseline measurements 
Screening  
(during routine outpatients appointment) 
1000mg IV iron (Ferinject) 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 13 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
1. BACKGROUND AND RATIONALE 
 
Iron deficiency in the absence of anaemia is now well documented in patients with idiopathic 
pulmonary arterial hypertension, IPAH (1-3). Estimates suggest a prevalence of 43 to 60% and it is 
associated with poor survival (1). Oral iron replacement has been explored as a treatment by Ruiter 
et al (2011) with only limited response in 44% of patients, consistent with impaired absorption of 
oral iron from the gut from raised hepcidin levels (1), and the authors conclude that a trial of 
intravenous iron therapy is required. Ruiter et al (2015) have treated 15 patients with ferric 
carboxymaltose (Ferinject®) given as a single infusion and demonstrated restoration of serum iron 
levels (4). Viethen et al (2013) have treated 20 patients, again through a single infusion of 1000mg 
over 15min of ferric carboxymalose (Ferinject®), and successfully restored serum iron (5). The 
authors conclude “that parenteral iron supplementation with ferric carboxymaltose … is well 
tolerated in patients with PAH and iron deficiency”. But as these studies were open-label, a double-
blind proof-of-concept study is essential to help decide on the future use of intravenous ferric 
carboxymaltose (Ferinject®) in IPAH. This study will establish whether iron supplementation has 
clinical benefit. If there is no evidence of improvement, only a small patient population has been 
exposed and costs are kept to a minimum. If the data support a potentially useful therapeutic effect 
and suggest this drug is safe, the study will be used to power a Phase 3 study to address efficacy.  
 
A 24-week double-blind, randomised, placebo-controlled, crossover study will investigate whether a 
single dose of 1g of Ferinject® improves exercise capacity and quality of life and is well-tolerated. 
This is a multicentre study. All patients will be followed for up to 24 weeks after dosing with 
Ferinject® to measure the kinetics of iron re-depletion. 
 
Patients with IPAH and iron-deficiency, who have been stable on their current therapy for the 
preceding 1 month, will be treated with 1000 mg or 15 mg/kg (whichever is the smaller) Ferinject® in 
line with the Summary of Product Characteristics (SmPC) and clinical experience with the product. 
Soluble transferrin receptor (sTfR) is the best measure of iron deficiency in inflammatory diseases 
such as IPAH (>28.1 nmol/l). Where available, sTfR levels will be used as the screening tool to assess 
iron deficiency and inclusion in to the study. But as it is not routinely available at all participating 
centres, iron deficiency will also be defined by standard laboratory measures of ferritin < 37 ug/l, 
iron < 10.3 umol/l or transferrin saturations < 16.4%. Using these criteria, modelling of data from our 
previous work (1) show that 83% of patients will have raised sTfR levels> 28.1 nmol/l. 
 
A formula exists to guide the amount of iron replacement required to render patients with anaemia 
iron-replete. This is based on the difference between current and target haemoglobin. In IPAH, this 
formula is likely to be inappropriate since the target haemoglobin is not known as patients may be 
hypoxaemic and thus require higher levels of haemoglobin. Indeed, many patients with iron 
deficiency have normal haemoglobin levels, but increased circulating EPO levels, implying an 
ongoing drive to increased red cell mass. Patients in the FERRIC-HF trial of iron supplementation in 
congestive heart failure were defined as having iron deficiency if ferritin was less than 100 ug/l or 
between 100 and 300 ug/l with transferrin saturations < 20% (6). By 4 and 16 weeks, 781 ± 94 and 
1269 ± 297 mg iron sucrose had been given to the non-anaemic group (Hb > 12.5 g/dl) and 1051 
±219 and 1583 ± 366 mg had been given to the anaemic group. Iron sucrose can be given in doses up 
to 200mg, whereas Ferinject® can be given in doses up to 1000mg due their differing 
pharmacokinetics. We will give a single 1000mg (or 15 mg/kg) dose to answer whether this simple 
strategy is of benefit and well-tolerated. Experience from Viethen et al (2013) and Ruiter et al (2015) 
in a total of 35 patients indicate that this is well tolerated and does not lead to iron overload (4,5). 
Using full iron profiling we will be able to determine how long this dose maintains iron repletion.  
 
Ferinject® has recently been used in a large phase III trial in heart failure (7). Adverse events were 
few in 304 patients assigned to receive Ferinject® and were not significantly different from the 
placebo group (n=105). Only 2 patients reported injection site pain and no allergic reactions were 
described.  


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
2. STUDY OBJECTIVES 
 
To assess the clinical value of using intravenous iron (Ferinject®) infusion in iron deficient patients 
with IPAH. 
 
3. STUDY OUTCOME MEASURES 
3.1. Primary outcome 
 
Endurance time at the end of endurance bicycle cardiopulmonary exercise testing at 80% peak work 
rate determined from the incremental exercise test.  
3.2. Secondary outcomes: 
 
The secondary outcomes will be measured by capturing other data, particularly exercise parameters 
and NT-pro-BNP data.  
 
A summary of the measurements that will be made is as follows:  
 
Incremental bicycle cardiopulmonary exercise testing – measurements will include peak VOR2
R 
(ml/min/kg), VO2 at metabolic threshold, VE/VCO2 slope, VE/VCO2 equivalents at metabolic 
threshold, VO2/WR slope and O2 pulse. Details are described in the Study Procedures Manual 
(SPM).  
 
VO2 at the end of endurance bicycle cardiopulmonary exercise testing at 80% peak work 
rate determined from the incremental exercise test  
 
Gas exchange at 3 minutes after the start of the work phase of an endurance exercise test at 
80% peak work rate determined from the incremental exercise test 
 
Iron indices – serum iron, transferrin saturations, ferritin, soluble transferrin receptor, RDW, 
EPO, and UIBC 
 
6 minute walk distance and Borg dyspnoea scale 
 
WHO functional class 
 
NT-proBNP 
 
Quality of life (CAMPHOR questionnaire) and the self-reported Patient Global Assessment 
 
Safety - the occurrence of adverse events 
 
Cardiac MRI - right ventricular volumes, mass, ejection fraction, stroke volume and diastolic 
function. Details are described in the SPM. 
 
4. INVESTIGATIONAL PLAN 
4.1. Overall study design and plan 
 
This study is a Phase II, multicentre, double-blind, randomised, placebo-controlled, crossover study. 
 
The study consists of a screening process, two treatment periods at Week 0 and Week 12 plus a 
follow up phase to evaluate the kinetics of iron re-depletion. 
 
Potential participants will be screened using data collected during their routine outpatient 
appointment at the Pulmonary Hypertension Service or PH Clinic. Any unavailable or missing data 
will be collected at the screening visit (week 0) once the patient has provided written informed 
consent.  
 
The study will involve hospital visits at Weeks 0, 12 and 24 while participants will be followed up by 
telephone on week 2 and 14. 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
 
Eligible participants will be admitted to the research unit for up to 3 days in order to complete the 
Baseline (Week 0) assessments including a physical examination, medical history, ECG, bloods to 
assess routine haematology and clinical chemistry and measure biomarkers, 6-Minute Walk Test, 
CAMPHOR questionnaire and incremental and endurance cardiopulmonary exercise tests (CPET). 
 
As outlined in Figure 1, following completion of the Baseline assessments at Week 0 patients will be 
randomly allocated 1:1 to receive an infusion of either FerinjectP®
P or saline.  
 
At Week 2 participants will receive a telephone call from the research unit for follow up. This will 
include a general assessment of AEs, other medication and PGA questionnaire.  
 
At Week 12 participants will be admitted to the research unit for up to 3 days to repeat the 
assessments done at Baseline (Week 0). Following completion of the Week 12 procedures, the 
patients will be switched to the other treatment arm (i.e. those who received FerinjectP®
P at baseline 
will be administered a saline infusion, and vice versa). 
 
Thereafter participants will have follow up assessments by telephone at Week 14 (which will be the 
same as week 2) and a final hospital visit at week 24 (which will be the same as the Weeks 0 and 12 
visits) 
 
At the sites where facility is available, participants will be given the option to undergo additional 
cardiac MRI (Weeks 0, 12 and 24). 
 
At the Sheffield site only, if participants agree, at each of the week 0 and week 12 visits they will 
have two extra blood samples taken (50 ml extra in total) to assess neutrophil and peripheral blood 
mononuclear cell function and expression. 
4.2. Discussion of study design 
 
Patients will be randomised 1:1 to FerinjectP® 
Por saline, with a 6-minute walk test, cardiac MRI and 
incremental and endurance cardiopulmonary exercise tests to measure changes in cardiopulmonary 
performance. Patients will then receive the alternative treatment and 6-minute walk test and 
endurance and incremental cardiopulmonary exercise testing repeated after a further 12 weeks 
(Figures 1). This crossover design maximises the data available on exercise testing at 12 weeks post-
iron for analysis.  
4.3. Selection of Study Population 
 
Patients participating in this study are adult males and females with symptomatic IPAH as defined by 
the eligibility criteria below. 
4.3.1. Inclusion criteria: 
 
Eligible patients must meet all of the following inclusion criteria: 
 
1. Males or females aged between 16–75 years old. 
2. PAH which is idiopathic, heritable or associated with anorexigens.  
3. Iron deficiency as defined by any one of the following criteria: sTfR levels > 28.1 nmol/l (where 
sTfR analysis is available) or one of the following: ferritin <37 µg/l; transferrin saturations 
<16.4%; iron < 10.3 µmol/l. 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
4. Documented diagnosis of PAH by right heart catheterisation performed at any time prior to 
Screening showing: resting mean pulmonary artery pressure >25mmHg, pulmonary capillary 
wedge pressure =/< 15 mm Hg and normal or reduced cardiac output. 
5. 6 minute walking distance greater than 50m at entry. 
6. Stable on an unchanged PAH therapeutic regime (any combination of endothelin receptor 
antagonist, phosphodiesterase inhibitor or prostacyclin analogue) for at least 1 month. 
7. Able to provide written informed consent prior to any study-mandated procedures. 
8. Female subjects of child-bearing potential are eligible to participate if they agree to use one of 
the following contraception methods: 
 
combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable  
 
intrauterine device (IUD)  
 
intrauterine hormone-releasing system (IUS)  
 
bilateral tubal occlusion  
 
vasectomised partner  
 
sexual abstinence  
4.3.2. Exclusion criteria: 
 
Patients will not be enrolled into the study if they meet any of the following criteria: 
 
1. Unable to provide informed consent. 
2. Clinically-significant renal disease (Creatinine clearance < 30 ml/min per 1.73 m P2
P calculated from 
CKD-Epi 
3TUhttp://www.qxmed.com/renal/Calculate-CKD-EPI-GFR.phpU3T) or liver disease (including 
serum transaminases > 3 times upper limit of normal). 
3. Haemoglobin concentration <10 g/dl. 
4. Patients will be excluded if any single parameter (iron, ferritin or transferrin saturation) exceeds 
1x upper limit of normal (ULN) in the local lab reference range. 
5. Patients with moderate to severe hypophosphatemia as defined as <0.65mmol/L 
6. Known to have haemoglobinopathy e.g. sickle cell disease, thalassaemia. 
7. Admission to hospital related to PAH or change in PAH therapy within 1 month prior to 
Screening. 
8. Evidence of left ventricular disease or significant lung disease on high-resolution CT scanning or 
lung function as judged by the investigator.  
9. Acute or chronic infection or inflammation. 
10. Significant uncontrolled asthma as judged by the investigator, eczema or atopic allergies. 
11. Females who are lactating or pregnant. 
12. Individuals known to have HIV, Hepatitis B or C or Creutzfeld-Jakob disease. 
13. Known hypersensitivity to FerinjectP®
P or any of its excipients and any other iron preparations. 
14. Evidence of disturbances in utilisation of iron. 
15. Significant blood loss (e.g. GI bleed) within the last 3 months or history of menorrhagia. 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
16. Unable to perform a Cardiopulmonary Exercise Test i.e. due to syncope or musculoskeletal 
factors. 
17. Patients who have received an investigational medicinal product within 30 days of entering the 
baseline visit.  
4.3.3. Subject Completion 
 
Subjects will be considered complete for the purpose of this study once they have completed all 
procedures at the end of Week 24. 
 
The end of study is defined as the last visit of the last subject undergoing the trial. 
4.3.4. Withdrawal of Subjects from Study 
 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The investigator can withdraw subjects from the 
study for any of the following reasons: 
 
• 
Occurrence of an unacceptable adverse event 
• 
Subject request 
• 
Subject is lost to follow up 
• 
Administrative reasons 
• 
Development of an intercurrent illness, condition, or procedural complication, which would 
interfere with the subject’s continued participation 
• 
Patient becomes pregnant 
 
The investigator also reserves the right to withdraw subjects in the interest of subject safety and 
welfare.  
4.3.5. Replacement policy 
 
Patients who are prematurely discontinued from the study will not be replaced. 
 
5. INVESTIGATIONAL PRODUCT(S) 
 
Patients who are eligible to participate in the study will receive FerinjectP®
P and normal saline 
(placebo).  
5.1. Ferinject® 
 
FerinjectP® 
Pis currently licensed up to doses of 1000 mg as an intravenous infusion for the treatment 
of iron deficiency when oral preparations cannot be used or are ineffective. 
5.1.1. Composition, packaging and storage 
 
A dark brown, non-transparent, aqueous solution. Ferinject® is available as 50 mg iron/mL solution 
for injection/infusion.  
 
FerinjectP® 
Pwill be supplied by Vifor Pharma, Glattbrugg, Switzerland as 2ml and 10 ml solutions in a 
vial (type I glass) with bromobutyl rubber stopper and aluminium cap. One mL of solution contains 
50 mg of iron as ferric carboxymaltose. 
 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
The study drug should not be stored above 30Po
PC; it should not be refrigerated or frozen. 
 
5.2. IMP preparation and administration 
5.2.1. IMP Preparation 
 
The total dose of Ferinject® to be administered will be 1000mg or 15mg/kg, whichever is the smaller.  
 
The study treatments will be prepared either by the hospital pharmacy or as per local SOP at 
individual site. 
 
FerinjectP® 
Pwill be diluted up to 50ml in sterile 0.9% sodium chloride solution. 
 
The same volume of saline will be given as for the active drug.  
5.2.2. IMP Administration 
 
FerinjectP® 
Pwill be administered by intravenous infusion and infused over 15 minutes. The patient will 
receive a single infusion of FerinjectP®
P at either Week 0 or Week 12, depending on the treatment 
allocation. 
5.3. Labelling 
 
The study drug will be labelled in accordance with local regulatory requirements. 
5.4. Study drug accountability 
 
Accountability for the study drug at the study site is the responsibility of the Principal Investigator. 
The investigator will ensure that the study drug is used only in accordance with this protocol. Where 
allowed, the investigator may choose to assign some of the drug accountability tasks to a pharmacist 
or other appropriate individual.  
 
Drug accountability records indicating the drug’s delivery date to the site, inventory at the site, use 
by each subject, and end-of-study destruction and disposal of the drug, will be maintained by each 
clinical site. These records will adequately document that the subjects were provided the doses as 
specified in the protocol and should reconcile all study drug received from Vifor Pharma, 
Switzerland.  
5.5. Treatment assignment and blinding 
5.5.1. Treatment assignment 
 
Patients will be randomised on 1:1 ratio to each treatment arm. Randomisation will be performed at 
the Baseline (Week 0) visit using InFormPTM
P. Randomisation will be stratified by gender, with an 
appropriate fixed block size, in order to ensure equal allocation to Ferinject® and placebo. The 
computer-generated randomisation list will be prepared by a statistician independent of the study 
team and will be provided to Imperial College staff (who are not otherwise involved in the study) 
responsible for building the InFormPTM
P system.  
5.5.2. Blinding 
 
This study will be conducted as a double-blind trial therefore the investigator, study staff, and 
patients will remain blinded to the patient’s study treatment until the end of the study.  


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 19 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
 
FerinjectP® 
Pis a dark-brown solution.  To ensure that the patient remains blinded to the treatment 
they are receiving, patients will be blindfolded for a short time during the infusion. Further details 
are described in the SPM. 
 
Site personnel involved in the preparation and administration of the study drug will not be 
permitted to undertake any of the study assessments. In addition, an unblinded physician will be 
identified at each participating site and will be assigned to review iron profile results after patients 
have been dosed in order to prevent accidental unblinding of treatment allocation. 
5.5.3. Emergency unblinding procedures 
 
The identity of the study treatment may be revealed only if the patient experiences a medical 
emergency whose management would be improved by the knowledge of the treatment assignment.  
Emergency unblinding can be performed immediately by the study investigator by examination of 
the remaining solution in the syringe or infusion line. 
5.6. Concomitant medications 
5.6.1. Permitted concomitant medications 
 
Approved endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) type inhibitors 
and/or prostacyclin analogues are permitted for the treatment of PAH. The dose must be stable for 
at least 1 month prior to entry into the study. 
5.6.2. Prohibited concomitant medications 
 
Patients are not permitted to take oral iron therapy whilst on the study. 
 
6. VISIT AND ASSESSMENT SCHEDULE 
 
For a tabulated summary of all visits and assessments described in the following section see 3TUTable 1U3T. 
 
It is recognised that the schedule of investigations may be difficult for patients with severe 
pulmonary hypertension. Therefore, it will be made clear to patients that they need not see through 
every investigation if they do not feel able to. Forgoing an investigation will not prevent patients 
from continuing the study. 
6.1. Screening Visit 
 
The Screening Visit should be performed no more than 28 days prior to the Baseline/Randomisation 
Visit. 
 
Participants’ eligibility with respect to IPAH status and Iron status will usually be determined using 
from routine outpatient clinical record. The following data will be recorded during the visit or 
obtained from the hospital records where possible. 
 
 
Obtain written informed consent 
 
Demographics 
 
Medical history 
 
Physical examination 
 
Concomitant medications 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 20 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
 
Vital signs: Resting supine blood pressure (BP), pulse measurement, temperature, pulse 
oximetry, height and weight. 
 
Modified NYHA/WHO Functional Class 
 
6MWT and Borg dyspnoea index 
 
Blood samples for routine haematology, blood chemistry (including iron parameters, sTfR 
(where available) and serum pregnancy test where clinically indicated (woman of childbearing 
potential only). 
 
Any missing or unavailable data (e.g. 6MWT or pregnancy test) or data which are not collected 
during routine outpatient visit should be collected at this visit or at Visit 1 after written informed 
consent has been obtained and before confirmation of the patient’s eligibility for the trial. 
Randomisation will only occur after confirmation of eligibility. Screening and Baseline/randomisation 
procedures can be recorded in a combined visit.  
6.2. Baseline/Randomisation Visit (Week 0) 
 
The patient will be admitted to the research unit for up to 3 days in order to undergo the following 
procedures: 
 
 
Physical examination 
 
Concomitant medications 
 
Document adverse events 
 
ECG 
 
Research blood sampling (NT pro-BNP, IL-6, hepcidin, sTfR and EPO). Neutrophil and peripheral 
blood mononuclear cell function and expression (Sheffield site only) 
 
Fasting glucose and insulin  
 
Incremental Cardiopulmonary Exercise Test  
 
Endurance Cardiopulmonary Exercise Test 
 
CAMPHOR questionnaire 
 
Cardiac MRI  
 
Following completion of the above procedures, the patient will be randomised and receive an 
infusion of either the study drug (FerinjectP®
P) or placebo (saline).  
6.3. Week 2 (+/- 3 days) Telephone Follow up 
 
Patients will undergo a telephone review at week 2 to check for AEs and concomitant medication. 
The PGA questionnaire will be completed over the phone.  
6.4. Week 12 (+/- 3 days) 
 
The patient will be admitted to the research unit for up to 3 days in order to undergo the following 
procedures:  
 
 
Physical examination 
 
Concomitant medications 
 
Document adverse events 
 
Vital signs: Resting supine blood pressure (BP), pulse measurement, temperature, pulse 
oximetry and weight 
 
ECG 
 
Modified NYHA/WHO Functional Class 
 
6MWT and Borg dyspnoea index 


Ferinject® for iron deficiency in IPAH patients                                                                
                Page 21 of 33 
Protocol No: WILK3  Version 9.0 24 October 2016 
 
Blood samples for routine haematology, blood chemistry, (including iron indices), and serum 
pregnancy test (woman of childbearing potential only) 
 
Research blood sampling (NT pro-BNP, IL-6, hepcidin, sTfR and EPO; neutrophil and peripheral 
blood mononuclear cell function and expression (Sheffield site only) 
 
Fasting glucose and insulin (taken after an overnight stay and before dosing) 
 
Incremental Cardiopulmonary Exercise Test  
 
Endurance Cardiopulmonary Exercise Test 
 
Cardiac MRI (where the facility is available) 
 
CAMPHOR questionnaire 
 
Patient Global Assessment (PGA) 
 
Following completion of the above procedures, the patient will be administered either the study 
drug (FerinjectP®
P) or placebo (saline).  
6.5. Week 14 (+/- 3 days) Telephone Follow up  
 
Patients will undergo a telephone review as at week 2 to check for AEs and concomitant medication. 
The PGA questionnaire will be completed over the phone.  
6.6. Week 24 (+/- 3 days) 
 
The patient will attend the research unit in order to undergo the following procedures (these 
assessments can either be done as outpatient visits or on an inpatient basis involving an overnight 
stay at selected centres): 
 
 
Physical examination 
 
Concomitant medications 
 
Document adverse events 
 
Vital signs: Resting supine blood pressure (BP), pulse measurement, temperature, pulse 
oximetry and weight 
 
ECG 
 
Modified NYHA/WHO Functional Class 
 
6MWT and Borg dyspnoea index 
 
Blood samples for routine haematology, blood chemistry, (including iron indices), and serum 
pregnancy test (woman of childbearing potential only) 
 
Research blood sampling (NT pro-BNP, IL-6, hepcidin, sTfR and EPO) 
 
Fasting glucose and insulin (taken after an overnight stay) 
 
Incremental Cardiopulmonary Exercise Test  
 
Endurance Cardiopulmonary Exercise Test  
 
Cardiac MRI (where the facility is available) 
 
CAMPHOR questionnaire 
 
Patient Global Assessment (PGA) 
 
7. STUDY ASSESSMENTS 
7.1. Physical Examination and Medical History 
 
Physical examinations will be performed to ensure suitability according to the inclusion and 
exclusion criteria at screening and to document the health status at the time points specified in the 
Schedule of Events (Table 1). The physical examination comprises measurement of height and body 
weight and a routine medical examination. 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
A medical history will be recorded at screening or at Visit 1. The medical history will elicit 
information concerning existing medical conditions, major illnesses, and related surgical procedures. 
Any prescribed or over-the-counter medications that the subject received within the past 30 days 
should be recorded on the CRF. Medication prescribed for the treatment of PAH for the 8 weeks 
prior to enrolment should be recorded on the CRF. Subjects will be instructed to notify the study 
doctor before beginning new prescribed or over-the-counter medications. 
7.2. Modified NYHA (WHO) Classification 
 
Functional assessment of PAH will be made according to the modified New York Heart Association 
(NYHA) (WHO) classification system (World Symposium on Primary Pulmonary Hypertension, 1998, 
Evian, France, sponsored by the World Health Organization). 
 
Class I:  
Patients with PAH without limitation of physical activity. Ordinary physical activity 
does not cause increased dyspnoea or fatigue, chest pain, or near syncope. 
Class II:  
Patients with PAH resulting in slight limitation of physical activity. No discomfort at 
rest. Normal physical activity causes increased dyspnoea or fatigue, chest pain, or 
near syncope. 
Class III:  
Patients with PAH resulting in marked limitation of physical activity. There is no 
discomfort at rest. Less than ordinary activity causes increased dyspnoea or fatigue, 
chest pain, or near syncope. 
Class IV: 
Patients with PAH with inability to carry out any physical activity without discomfort. 
Indications of manifest right heart failure. Dyspnoea and/or fatigue may even be 
present at rest. Discomfort is increased by the least physical activity. 
7.3. Vital signs 
 
Systolic and diastolic systemic BP will be measured by means of either a standard manual or an 
automatic BP measuring device (cuff method). For each subject, the same method should be used 
during the entire study, and the type of device used should be recorded on the CRF. The same arm 
will be used for each measurement of BP, and BP will be measured after 5 minutes seated. 
 
At each visit heart rate (HR) and oxygen saturation will be measured by pulse oximetry after the 
subject has been at rest for at least 5 minutes. 
7.4. Endurance cardiopulmonary exercise test 
 
Endurance exercise testing has been shown to be a much more sensitive indicator of change in 
exercise capacity in studies of rehabilitation in chronic lung disease, but remains an exploratory 
endpoint in pulmonary hypertension.  Work rate will be set at 80% of the patient’s peak work rate 
achieved on the baseline CPET and patients will be asked to exercise to a point where they are 
unable to continue.  The same equipment and monitoring will be used as in the incremental test and 
end-test VO2 will be used to gauge validity of the test, as it ought to be the same as the patient’s 
maximal VO2.  Measurement of steady-state gas exchange will be made also at 3 minutes and peak. 
Details are described in the SPM. 
7.5. Six minute walk distance 
 
Distance walked during an unencouraged 6 minute walk test conducted according to American 
Thoracic Society (ATS) guidelines (8). This is a standard tool for the study of functional capacity in 
PAH patients and is primarily determined by cardiac output and hence right ventricular function. We 
are aware that a possible increase in haemoglobin might be a confounding factor, improving 6 
minute walk not because of the increase in cardiac output but because of increased oxygen delivery.  


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
This is the rationale behind assessing exercise haemodynamics. We will interpret the 6 minute walk 
in the context of the overall results. [The screening walk test may be done according to local 
protocol.] 
7.6. Incremental cardiopulmonary exercise test 
 
Exercise testing is increasingly used to evaluate the level of exercise intolerance in patients with lung 
and heart diseases (9). Patients will undergo cycle ergometry cardiopulmonary exercise testing (CPX) 
following a ramp protocol (Jaeger Masterscreen CPX) according to ATS guidelines (10). Using CPX, we 
can extract effort-independent data from exercise.  Endpoints taken from CPX will include VO R2
R at 
peak and anaerobic threshold, VE/VCOR2
R slope, VE/VCOR2
R equivalents at metabolic threshold, 
VOR2
R/WR slope and OR2
R pulse. All data will be analysed centrally to ensure similar measurement 
techniques for CPET variables. Details are described in the SPM. 
7.7. Cardiac Magnetic Resonance (CMR) Imaging 
 
Cardiac Magnetic Resonance Imaging will be performed at selected centres at Weeks 0, 12 and 24 
following a standardised clinical protocol. Patients who are unable to undergo MR scanning will be 
excluded from this part of the protocol.  This may be for reasons such as a metal implant, cardiac 
arrhythmias or claustrophobia. Using balanced steady state free precession sequences, we will 
measure right ventricular mass and function. Velocity-encoded sequences will be used to measure 
the flows through R-sided heart cavities and assess the severity of tricuspid regurgitation. Analysis of 
the acquired images will be performed using dedicated software. Tracing of epicardial and 
endocardial borders of SA slices in end-diastole (image phase with the largest cavity area) and 
endocardial border in end-systole (smallest cavity area) allows calculation of right and left 
myocardial volume, end-diastolic and end-systolic volumes. From this stroke volume and ejection 
fraction can be derived. For mass calculation, the myocardial volume is multiplied by the specific 
density of myocardium (taken as 1.05 g/cmP3
P). Cardiac output is calculated from the images using the 
left ventricular stroke volume multiplied by heart rate and cardiac index is then derived by 
normalization to body surface area. Quantification of right ventricular diastolic function will be made 
by measuring R-R interval normalised isovolumetric relaxation time on the right two-chamber view, 
and early peak filling rate (E), atrium-induced peak filling rate (A) on the short-axis images. 
 
A core lab will be established at Hammersmith Hospital to interpret the CMR scans from all sites by 
CMR trained personnel, blinded to the study timing. Further details are described in the SPM. 
7.8. Laboratory measurements 
 
Blood sampling will be performed at each visit to include: NT-pro-BNP as an indicator of cardiac 
workload; Iron status, as assessed by serum iron, UIBC or TIBC, transferrin saturation, sTfR, ferritin, 
and hepcidin levels; EPO levels and RDW to assess erythrogenesis. Inflammation status is known to 
affect hepcidin expression and will be determined by measuring CRP and IL-6 levels. Possible 
haemolysis will be assessed by measuring unconjugated bilirubin, LDH, haptoglobin and 
reticulocytes.  
7.8.1. Type of laboratory 
Central laboratories (see contact details on page 3) will be used to analyse the research bloods. All 
other routine clinical laboratory parameters (haematology, chemistry, coagulation panel, iron profile) 
will be analysed by local accredited hospital laboratories. Tests may vary slightly depending on the 
availability of local hospital assays and so some flexibility with regards to the specific tests will be 
tolerated e.g. folate or folic acid etc.  
 
Routine clinical laboratory tests include the following: 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
Haematology 
White blood cell count with differential, red blood cell count, platelet 
count, haemoglobin,  hematocrit and reticulocytes, RDW 
Standard chemistry 
Albumin, Total bilirubin, Unconjugated bilirubin, Urea, Creatinine, Glucose, 
Total protein, CRP, Urate, Serum electrolytes (Calcium, Chloride, Sodium, 
Phosphate, Potassium) Bicarbonate, Aspartate aminotransferase (AST); 
alanine aminotransferase (ALT); -glutamyl transpeptidase (Gamma-GT); 
alkaline phosphatase (ALP); lactate dehydrogenase (LDH); creatine kinase 
(CK) 
Folic acid and Vitamin B12 
Iron profile 
Transferrin saturations, ferritin, iron, UIBC/TIBC 
Serum pregnancy test 
-hCG 
Others 
EPO 
7.8.2. Research samples 
Blood samples to measure circulating factors including sTfR, IL-6, Hepcidin, NT pro-BNP haptoglobin, 
and GDF-15 will be taken at Baseline and Weeks 12  and 24 for research purposes.  
 
Detailed instructions for the preparation, labeling, storage and shipment of the samples can be 
found in the laboratory manual. 
 
Two additional research blood samples (25ml each) will be collected by the Royal Hallamshire 
Hospital site only at Week 0 (baseline) and week 12. This is to enable the isolation and study of 
neutrophil and peripheral blood mononuclear cell function (apoptosis, respiratory burst, 
phagocytosis, chemotaxis, bacterial killing, integrin expression) and expression (mRNA and protein) 
in response to iron loading. Patients at this site will be given the option to opt out of these extra 
blood collections if they wish. 
7.8.3. Volume of Blood Collection 
The approximate blood volume collected from each individual during the study will be as follows: 
 
Assessment 
mL/Collection 
Number of Collections 
Total (mL) 
Clinical chemistry 
10 
7 
70.0 
Haematology 
3.0 
7 
21.0 
Serum pregnancy test* 
1.5 
2 
3.0 
Research blood 
15.0 
6 
90.0 
25.0** 
2** 
50.0** 
 
Total blood volume : 
184.0mL 
234.0mL** 
 
* for women of childbearing potential 
** 2 extra research blood collections (25ml each) will be performed at Weeks 0 and 12 of study participation to freshly 
isolate human neutrophils and peripheral blood mononuclear cells for functional and expression studies at the Royal 
Hallamshire Hospital, Sheffield. The total volume of extra blood collection by this site will be 50 ml. Patients at this site will 
be given the option to opt out of these extra blood collections if they wish. 
 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
7.9. Quality of Life 
 
CAMPHOR is a disease-specific patient-reported outcome instrument which has been developed for 
patients with pulmonary hypertension (11). It is sensitive to small changes in health and quality of 
life in this patient group. It will be collected on Baseline, Week 12 and on Week 24. 
 
7.10. 
Patient Global Assessment 
 
The self-reported Patient Global Assessment will be used at Weeks 2, 12, 14 and 24 to assess 
patient-perceived response to the intervention. 
 
8. PHARMACOVIGILANCE 
8.1. Definitions 
 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational 
medicinal product (IMP), whether or not considered related to the IMP. 
 
Adverse Reaction (AR): all untoward and unintended responses to an IMP related to any dose 
administered. All AEs judged by either the reporting investigator or the sponsor as having reasonable 
causal relationship to a medicinal product qualify as adverse reactions. The expression reasonable 
causal relationship means to convey in general that there is evidence or argument to suggest a 
causal relationship. 
 
Unexpected Adverse Reaction: an AR, the nature or severity of which is not consistent with the 
applicable product information (e.g. investigator’s brochure for an unapproved investigational 
product or summary of product characteristics (SmPC) for an authorised product). When the 
outcome of the adverse reaction is not consistent with the applicable product information this 
adverse reaction should be considered as unexpected. Side effects documented in the SmPC which 
occur in a more severe form than anticipated are also considered to be unexpected. 
 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR): any untoward medical occurrence 
or effect that at any dose: 
 
 
Results in death 
 
Is life-threatening  
 
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE/AR is serious in other situations. 
Important AE/ARs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above, should also be considered serious. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): any suspected adverse reaction related 
to an IMP that is both unexpected and serious. 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
8.2. Assigning Causality 
 
Each adverse event must be assessed by the investigator as to whether or not there is a reasonable 
possibility of a causal relationship to the study drug.  The assignment of the causality should be 
made by the investigator responsible for the care of the participant using the definitions below. If 
any doubt about the causality exists the local investigator should inform the study coordination 
centre who will notify the Chief Investigator. Vifor Pharma and/or other clinicians may be asked to 
advise in some cases. 
 
In the case of discrepant views on causality between the investigator and others, all parties will 
discuss the case. In the event that no agreement is made, REC/Regulatory Authority will be informed 
of both points of view. 
 
8.2.1. Causality Description 
 
Unrelated: There is no evidence of any causal relationship 
 
Unlikely: 
There is little evidence to suggest there is a causal relationship (e.g. the event did not 
occur within a reasonable time after administration of the trial medication). There is 
another reasonable explanation for the event (e.g. the participant’s clinical condition, 
other concomitant treatment). 
 
Possible:  There is some evidence to suggest a causal relationship (e.g. because the event occurs 
within a reasonable time after administration of the trial medication). However, the 
influence of other factors may have contributed to the event (e.g. the participant’s 
clinical condition, other concomitant treatments). 
 
Probable: There is evidence to suggest a causal relationship and the influence of other factors is 
unlikely. 
 
Definitely: There is clear evidence to suggest a causal relationship and other possible contributing 
factors can be ruled out. 
 
Not  
assessable: There is insufficient or incomplete evidence to make a clinical judgment of the causal 
relationship. 
 
8.3. Assigning Severity 
 
For each AE intensity should be defined according to the following criteria: 
• 
Mild: Awareness of sign or symptom, but easily tolerated. 
• 
Moderate: Discomfort enough to cause interference with normal daily activities. 
• 
Severe: Inability to perform normal daily activities. 
• 
Life threatening or disabling: Immediate risk of death from the reaction as it occurred. 
• 
Death: The event resulted in death. 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
8.4. Adverse event reporting procedures 
8.4.1. Screening period 
 
All adverse events should be documented. SAEs occurring between signing the Informed Consent 
Form and study drug initiation are only required to be reported if they are considered by the 
investigator to be related to study-mandated procedures. 
8.4.2. Treatment period 
 
All adverse events should be documented. Depending on the nature of the event the reporting 
procedures below should be followed. Any questions concerning adverse event reporting should be 
directed to the study coordination centre in the first instance.  
8.4.2.1. Non serious AR/AEs 
 
All such toxicities, whether expected or not, should be recorded in the Adverse Events section of the 
case report form. 
8.4.2.2. Serious AR/AEs 
 
All SAEs must be reported to the study coordination centre within 24 hours of the investigator being 
made aware of the event.  The investigator should complete the SAE form and send it to the study 
coordination centre together with relevant treatment forms and anonymised copies of all relevant 
investigations. Follow up information about a previously reported SAE must be reported within 24 
hours of receiving it. 
 
However relapse and death due to pulmonary hypertension, and hospitalisations for elective 
treatment of a pre-existing condition do not need reporting as SAEs. 
 
8.5. Reporting to the Regulatory Authorities 
 
The Sponsor has delegated the responsibility for notifying the Regulatory authority and REC of all 
SUSARs occurring during the study to the Chief Investigator.  All SAEs and SUSARs must be reported 
in accordance with local regulatory guidelines: 
Life threatening SUSARs should be reported to the RA and REC no later than 7 days after the CI has 
first knowledge of the minimum criteria for expedited reporting. Further relevant information should 
be given within a further 8 days. 
 
Non-fatal and non-life threatening SUSARs should be reported to the RA and REC no later than 15 
days after the CI has first knowledge of the minimum criteria for expedited reporting. Further 
relevant information should be given as soon as possible.  
 
An annual safety report will be submitted on the anniversary of the Clinical Trial Application to the 
RA and REC.  
 
8.6. Reporting to the Sponsor 
 
All SAEs and SUSARs must be forwarded the Imperial College Joint Research Office within 24 hours 
of the Investigator learning of its occurrence. 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
8.7. Reporting to Vifor Pharma Drug Safety 
 
All SAEs that are considered possibly, probably or definitely related to the study drug must be 
forwarded to Vifor Pharma Pharmacovigilance by fax or e-mail within 1 business day of learning of 
the event: 
 
Fax: +41 68 851 86 59 
3TUsafety@viforpharma.comU3T 
8.8. Follow up of adverse events 
 
All adverse events that are still ongoing at the end of the study will be followed up until resolution. 
 
9. DOCUMENTATION OF DATA 
9.1. Data collection 
 
The data collection tool for this study will be electronic case report forms (eCRFs). Case report forms 
(CRFs) will be completed for each subject and will contain study data which are verifiable to the 
source data (i.e., original recordings, laboratory reports, and subject records). In addition, all source 
data should be attributable (signed and dated).  
Only the Investigator and authorized co-workers are entitled to make entries on the CRF. 
Concomitant medications may be entered as they appear in the participant’s record or as per local 
standards (generic or trade names may be entered).  
It is the responsibility of the Investigator to ensure that the CRFs are kept up-to-date so that they 
always contain the latest observations on the subjects enrolled. 
Laboratory values outside the normal range will be commented upon by the Investigator. Other 
data than those requested by this protocol may be recorded as “additional data” in the comments 
section of the case report form; the clinical significance of any additional data should be described. 
9.2. Data monitoring 
 
The Sponsor is responsible for ensuring that the study is monitored appropriately in order to ensure 
compliance with GCP and local regulatory guidelines. The monitor will check the completeness of 
medical records, verify the accuracy of entries in the CRF, and ensure adherence to the protocol and 
compliance with local regulatory requirements. 
 
10. STATISITICS AND DATA ANALYSIS 
 
This is a proof-of-concept study, thus the sample size has been chosen with respect to safety (in 
terms of exposure to the drug and investigations) and feasibility (patient population) and with the 
aim of measuring effect size. We would expect that a sample size of 60 will be sufficient to detect 
clinically meaningful changes in cardiopulmonary exercise end-points, NT-pro-BNP and quality of life 
in the direction consistent with benefit. 
 
The null hypothesis is that iron replacement has no effect on cardiopulmonary performance in 
patients with iron deficiency and IPAH, with a two-sided alternative that iron replacement changes 
cardiopulmonary performance in patients with iron deficiency and IPAH.   
 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
For the cardiopulmonary exercise tests, if  a 12-weekly drop-out rate of 10% and standard deviation 
of 5 ml/min/kg for peak VO2 we would have 80% power to detect a mean change of 1.94 ml/min/kg 
at a significance level of alpha=0.05 using a paired analysis (cf 2.2ml difference in FERRIC-HF with 35 
patients). Other pre-specified secondary endpoints will be change in CPET at 2 weeks, change in 
cardiac output at 12 weeks, and change in 6 minute walk distance and circulating biochemical 
markers at 12 weeks. A full statistical analysis plan will be developed for each endpoint, using linear 
mixed models for analysis of the crossover data. Primary analysis will be intention-to-treat, with 
sensitivity analyses to explore the effect of dropout. Due to the exploratory nature of the study no 
multiplicity adjustment will be made to p-values for secondary analyses, though results will be 
interpreted with caution if the primary endpoint does not achieve significance.  
 
It will only be possible to measure sTfR for every study participant after enrolment and thus a 
separate analysis will be performed to analyse the effect of Ferinject® in patients with sTfR > 28.1 
nmol/l.  Additionally, on recruitment of the 20Pth
P, 40Pth
P and 60Pth
P patient, serum samples will be 
analysed to establish the number of patients enrolled with sTfR > 28.1 nmol/l and an additional 
number of patients will be recruited to achieve 60 enrolled iron-deficient patients.  
 
Data from all centres will be pooled and analysed at Hammersmith. Due to the small sample sizes in 
each centre, the assessment of consistency of results amongst the centres will be made on an 
informal basis.   
 
11. ADMINISTRATIVE AND LEGAL CONSIDERATIONS 
11.1. 
General Legal Requirements 
 
This trial will adhere to the principles outlined in the Medicines for Human Use (Clinical Trials) 
Regulations 2004 (SI 2004/1031 and its amendments) or any legislation that supersedes these 
regulations and the International Conference on Harmonisation Good Clinical Practice (ICH GCP) 
guidelines. It will be conducted in compliance with the protocol, the Data Protection Act and other 
regulatory requirements as appropriate. 
11.2. 
Ethics Committee/RA approvals 
 
Approval must be obtained from a Research Ethics Committee (REC) and the Regulatory Authority 
(RA) before starting the study and must be documented in a dated letter to the investigator clearly 
identifying the trial, the documents reviews, and the date of the approval. 
A list of the Ethics Committee members must be provided. If any study staff were present, it must 
be clear that none of these persons voted. 
Modifications made to the protocol after receipt of the REC/RA approval must also be submitted as 
amendments by the investigator to the REC/RA in accordance with local procedures and regulations. 
11.3. 
Informed consent 
 
It is the Investigator’s responsibility to explain to each subject the study procedures, potential 
benefits and hazards of trial participation, the right to withdraw from the study at any time, and to 
obtain written informed consent prior to any study-specific procedures. The original copy of the 
signed and dated Informed Consent Form must be filed in the Investigator Site File. The subject, the 
subject’s legally authorised representative, or both will be given a copy of the signed and dated 
Informed Consent Form. A copy will also be placed in the subject’s medical hospital notes. 
11.4. 
Patient confidentiality 
 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
The Investigators affirm and uphold the principle of the subject’s right to protection against invasion 
of privacy. Personal health data will be kept confidential. 
On CRFs or other documents, subjects will be identified by their initials and a subject number only. 
However, each Investigator will keep in his/her file a Subject Identification List. With respect to the 
processing of data, every subject has to agree with this in writing. This agreement should be 
documented together with the written informed consent for trial participation. 
11.5. 
Protocol Amendments 
 
Any changes in the protocol will require a formal amendment. Such amendments will be agreed 
upon and approved in writing by the Investigator. Amendments to the protocol will be submitted to 
the relevant authorities and the REC for approval prior to implementation. 
Administrative changes which have no significant impact on the medical or scientific validity of the 
study will be documented in a statement. The REC will be notified of administrative changes, if 
applicable. 
11.6. 
Premature Termination of the Trial 
 
The Chief Investigator reserves the right to terminate the trial for well-documented reasons. 
Instructions will be provided in a separate document should it be determined that assessments 
beyond those defined by the protocol are required. 
Further recruitment of subjects will not take place under the following conditions: 
 
Premature termination of the trial. 
 
Drug-related events, i.e. SUSARs, emerging adverse effects that are serious and the 
risk/benefit ratio is unacceptable. 
 
Procedure-related events, i.e., the recruitment rate is too low or the number of dropouts 
for administrative reasons is too high. 
11.7. 
Sponsor 
 
Imperial College Academic Health Science Centre will act as the main Sponsor for this study. 
Delegated responsibilities will be assigned to the NHS trusts taking part in this study. 
11.8. 
Indemnity 
 
Imperial College holds Public Liability ("negligent harm") and Clinical Trial ("non-negligent harm") 
insurance policies which apply to this trial. 
11.9. 
Record Retention 
 
The PI must retain all study records by the applicable regulations in a secure and safe facility. The 
PI/institution must take measures to prevent accidental or premature destruction of essential 
documents, that is, documents that individually and collectively permit evaluation of the conduct of 
a study and the quality of the data produced, including paper copies of study records (e.g. subject 
charts) as well as any original source documents that are electronic as required by applicable 
regulatory requirements. 
The PI/institution should retain subject identifiers for at least 15 years after the completion or 
discontinuation of the study.  Subject files and other source data must be kept for the maximum 
period of time permitted by the hospital, institution or private practice, but not less than 15 years.  
These documents should be retained for a longer period, however, if required by the applicable 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
regulatory requirements.   It is the responsibility of the PI to inform the institution as to when these 
documents no longer need to be retained. 
If an Investigator moves, withdraws from an investigation, retires, requests to move records to 
another location or to assign these records to another party or (e.g. other Investigator) who will 
accept the responsibility, written notice of this transfer must be made to and agreed upon by each 
party. 
11.10. Confidentiality 
 
All information concerning this study and which was not previously published is considered 
confidential information and shall not be used except in the performance of this study. 
11.11. Publications 
 
Publication of the results of the study, whether in whole or in part, shall be within the responsibility 
of the Investigator(s).  
11.12. Audits and Inspections 
 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit in accordance with their local internal procedures.  
Audits and/or inspections may also be carried out by local authorities, or authorities to which 
information on this trial has been submitted. All documents pertinent to the trial must be made 
available for such inspection after an adequate announcement. 
 
 
 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
References 
 
1. Rhodes CJ, Howard LS, Busbridge M, Ashby D, Kondili E, Gibbs SR, Wharton J, Wilkins MR. Iron 
deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: clinical prevalence, 
outcomes and mechanistic insights. J Am Coll Cardiol 58:300–309, 2011 
2. Ruiter G, Lankhorst S, Boonstra A, Postmus PE, Zweegman S,  Westerhof N, Van Der Laarse WJ, 
Vonk-Noordegraaf A, Iron deficiency is common in idiopathic pulmonary arterial hypertension. 
The European respiratory journal, , Vol.37(6), pp.1386-91, 2011 
3. Soon E, Treacy CM, Toshner MR, MacKenzie-Ross R, Manglam V, Busbridge M, Sinclair-McGarvie 
M, Arnold J, Sheares KK, Morrell NW, Pepke-Zaba J Unexplained iron deficiency in idiopathic and 
heritable pulmonary arterial hypertension. Thorax 66:326-332, 2011 
4. Viethen T, Gerhardt F, Dumitrescu D, Knoop-Busch S, Freyhaus H, Rudolph TK, Baldus S, 
Rosenkranz S. Ferric carboxymaltose improves exercise capacity and quality of life in patients 
with pulmonary arterial hypertension and iron deficiency: A pilot study International Journal of 
Cardiology 175  233–239, 2014 
5. Ruiter G, Manders E, Happe´ CM, Schalij I, Groepenhoff H, Howard LS, Wilkins MR, Bogaard HJ, 
Westerhof N, Van Der Laarse WJ, Man FS, Vonk-Noordegraaf A, Intravenous iron therapy in 
patients with idiopathic pulmonary arterial hypertension and iron deficiency. Pulmonary 
Circulation, 5(3):466-472, 2015 
6. Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, Foldes G, Thum T, 
Majda J, Banasiak W, Missouris CG, Poole-Wilson PA, Anker SD and Ponikowski P. Effect of 
intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with 
symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, 
observer-blinded trial. J Am Coll Cardiol 51: 103-112, 2008. 
 
7. Anker SD, Comin CJ, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, 
Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart RB, Pocock SJ, Poole-Wilson PA and 
Ponikowski P. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J 
Med 361: 2436-2448, 2009. 
 
8. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 166: 111-117, 
2002. 
 
9. Arena R, Lavie CJ, Milani RV, Myers J and Guazzi M. Cardiopulmonary exercise testing in patients 
with pulmonary arterial hypertension: an evidence-based review. J Heart Lung Transplant 29: 
159-173, 2010. 
 
10. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 167: 211-
277, 2003. 
 
11. McKenna SP, Doughty N, Meads DM, Doward LC and Pepke-Zaba J. The Cambridge Pulmonary 
Hypertension Outcome Review (CAMPHOR): a measure of health-related quality of life and 
quality of life for patients with pulmonary hypertension. Qual Life Res 15: 103-115, 2006. 
 
 


Ferinject® for iron deficiency in IPAH patients                                                                
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Protocol No: WILK3  Version 9.0 24 October 2016 
Table 1. Visit and Assessment Schedule 
 
Assessment 
ScreeningP#≤ 28 
days 
before week 0 
visit 
Week 0 
Baseline/     
randomisation 
Visit 1§ 
Week 2         
(+/- 3 days) 
Telephone 
Visit 2 
Week 12 
(+/- 3 days) 
Visit 3 
Week 14 
(+/- 3 days) 
Telephone 
Visit 4 
Week 24 
(+/- 3 days) 
Visit 5 
Written informed consent 
X 
 
 
 
 
 
Medical history (incl. demographics) 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
X 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
Modified NYHA (WHO) Functional Class 
X 
 
X 
X 
X 
X 
Vital signs 
X 
X 
 
X 
 
X 
ECG 
 
X 
 
X 
 
X 
6MWT and Borg Dyspnoea Score 
X 
 
 
X 
 
X 
CAMPHOR Questionnaire 
 
X 
 
X 
 
X 
Patient Global Assessment (PGA) 
 
 
X 
X 
X 
X 
Routine laboratory assessments (e.g.  iron status) 
X 
X 
 
X 
 
X 
Research blood sampling 
 
X 
 
X 
 
X 
Serum pregnancy testing (if applicable) 
X 
 
 
X 
 
X 
Incremental Cardiopulmonary Exercise Test 
 
X 
 
X 
 
X 
Endurance Cardiopulmonary Exercise Test 
 
X 
 
X 
 
X 
Administration of  study drug or placebo   
 
X 
 
X 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
Cardiac MRI* 
 
X 
 
X 
 
X 
 
Visit 2 & 4 (Week 2 & 14) will be done by telephone call. 
#; Iron status and IPAH status will be determined from routine clinical care records. 
§; Screening procedures can be combined with Visit 1 wherever convenient for patient and where data from routine clinical visits are not available. 
*; Additional exploratory assessments, where research facility for MRI available for this protocol