Feraccru® Real World Effectiveness Study in Hospital Practice (FRESH): A Real World Study to Describe the Outcomes Associated With the Use of Ferric Maltol (Feraccru) for the Management of Iron Deficiency Anaemia in Patients With Inflammatory Bowel Disease in the UK.
Conditions: Anemia, Iron Deficiency, Inflammatory Bowel Diseases
Sponsor: Shield Therapeutics

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Feraccru® Real World Effectiveness Study in Hospital Practice (FRESH): A real 
world study to describe the outcomes associated with the use of ferric maltol 
(Feraccru®) for the management of iron deficiency anaemia in patients with 
inflammatory bowel disease in the UK 
 
STUDY PROTOCOL 
 
Sponsor Study Number ST10-01-401 
 
Chief Investigator: 
Dr Fraser Cummings 
Gastroenterology Department 
Southampton General Hospital 
Tremona Road 
Southampton 
Hampshire 
SO16 6YD 
Study Sponsor: 
Shield Therapeutics PLC 
One Euston Square 
40 Melton Street 
London, NW1 2FD 
Key Sponsor Contact: 
Dr George Stanley 
Medical Director (Interim) 
gstanley@shieldtx.com 
07824 817113 
Study Management: 
Project Manager: 
pH Associates 
The Weighbridge, 
Brewery Courtyard 
High Street 
Marlow, SL7 2FF 
Lucinda Frere-Scott 
LucindaFrere-Scott@phassociates.com 
Date: 
3 March 2017 
Version: 
FINAL 2.0 

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Confidentiality Notice 
This document contains confidential, trade secret, and/or proprietary information of 
pH Associates and Shield Therapeutics PLC. 
This document must not be disclosed to anyone other than the study staff and 
members of the independent ethics committee. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the study without the prior written consent of pH Associates 
and Shield Therapeutics PLC. 

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Contents 
 
List of tables ..................................................................................................................................... 5 
List of abbreviations ........................................................................................................................ 6 
List of definitions ............................................................................................................................. 7 
1. 
Study synopsis ...................................................................................................................... 8 
2. 
Study amendments and protocol deviations ..................................................................... 13 
3. 
Background and rationale .................................................................................................. 14 
3.1 
Rationale for study ...................................................................................................... 15 
4. 
Aim and objectives ............................................................................................................. 15 
4.1 
Aim .............................................................................................................................. 15 
4.2 
Primary objective ........................................................................................................ 15 
4.3 
Secondary objectives ................................................................................................... 16 
5. 
Hypothesis .......................................................................................................................... 17 
6. 
Study design and methodology .......................................................................................... 17 
6.1 
Study time periods ...................................................................................................... 17 
6.2 
Study population ......................................................................................................... 17 
6.2.1 Inclusion criteria .......................................................................................................... 18 
6.2.2 Exclusion (ineligibility) criteria .................................................................................... 18 
6.2.3 Participant recruitment ............................................................................................... 18 
6.3 
Data collection ............................................................................................................. 19 
6.4 
Data source.................................................................................................................. 19 
6.5 
Study endpoints and variables .................................................................................... 20 
6.5.1 Primary endpoint ......................................................................................................... 20 
6.5.2 Secondary endpoints ................................................................................................... 20 
6.5.3 Variables to be collected ............................................................................................. 21 

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7. 
Data management and quality control ............................................................................... 23 
7.1 
Database management ............................................................................................... 23 
7.2 
Data quality checks ...................................................................................................... 23 
8. 
Study sample size................................................................................................................ 24 
9. 
Statistical analysis ............................................................................................................... 25 
9.1 
Missing data ................................................................................................................ 25 
10. 
Review of study results ....................................................................................................... 26 
11. 
Study limitations ................................................................................................................. 26 
12. 
Safety .................................................................................................................................. 27 
12.1 
Definitions ................................................................................................................... 27 
12.1.1 Adverse events ............................................................................................................ 27 
12.1.2 Serious adverse events ................................................................................................ 27 
12.2 Reporting procedures for adverse events ................................................................... 28 
12.3 Special Reporting Situations ........................................................................................ 28 
13. 
Ethical and regulatory obligations ...................................................................................... 29 
13.1 
Protection of human subjects ..................................................................................... 29 
14. 
Study timelines ................................................................................................................... 31 
15. 
Administrative and legal obligations .................................................................................. 32 
15.1 
Study amendments and study termination ................................................................ 32 
15.2 
Study documentation and archive .............................................................................. 32 
15.3 
Ethical and regulatory approvals ................................................................................. 32 
15.4 
Ethical issues ............................................................................................................... 33 
16. 
Communication of study results ......................................................................................... 33 
17. 
Study support ..................................................................................................................... 34 
18. 
References .......................................................................................................................... 35 

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List of tables 
Table 1 Study amendments .......................................................................................................... 13 
Table 2 Precision calculated using a Binomial confidence interval (Wald interval, normal 
approximation) ............................................................................................................................. 25 
Table 3 Study timelines ................................................................................................................ 31 

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List of abbreviations 
 
 
Abbreviation Definition 
AE 
CD 
Adverse event 
Crohn’s disease 
CRP 
eDCF 
ENCePP 
C-reactive protein 
Electronic data collection form 
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance 
FRESH 
GafRECGI 
Hb 
HBI 
HRA 
Feraccru® Real World Effectiveness Study in Hospital Practice 
Governance Arrangements for Research Ethics Committees Gastrointestinal 
Haemoglobin 
Harvey-Bradshaw Index 
Health Research Authority 
IBD 
IDA 
ISPE 
Inflammatory bowel disease 
Iron deficiency anaemia 
International Society for Pharmacoepidemiology 
IV 
MAH 
Intravenous 
Marketing Authorisation Holder 
MCH 
MCV 
MHRA 
Mean corpuscular haemoglobin 
Mean corpuscular volume 
Medicines and Healthcare Products Regulatory Agency 
NHS 
OFPs 
National Health Service 
Oral ferrous products 
QoL 
R&D 
Quality of life 
Research and Development 
REC 
SADR 
SAE 
SCCI 
SDV 
UC 
WHO 
Research Ethics Committee 
Serious adverse drug reaction 
Serious adverse event 
Simple Clinical Colitis Index 
Source data verification 
Ulcerative colitis 
World Health Organization 

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List of definitions 
Baseline is defined as the date of initiation of Feraccru®. 
 
Iron deficiency anaemia is defined by the World Health Organization (WHO) as <12.0 g/dL in 
women and <13.0 g/dL in men1. 
Mild to moderate iron deficiency anaemia (secondary to either CD or UC) is also defined in 
this  study  as  serum  ferritin  concentration  <30  microgram/L  or  transferrin  saturation of 
<20%. 
 
Normalised hameoglobin (Hb) is defined in this study as Hb ≥12.0 g/dL for females and 
≥13.0 g/dL for males. 
 
Normalised serum ferritin is defined in this study as serum ferritin concentration ≥30 
microgram/L and ≤300 microgram/L. 
Normalised transferrin saturation is defined in this study as transferrin saturation between 
20% and 50%. 
Observation period is defined as 12 weeks after initiation of Feraccru® (permitting a window 
from 10 to 16 weeks). 

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1. Study synopsis 
 
Title 
Feraccru® Real World Effectiveness Study in Hospital 
Practice (FRESH): A real world study to describe the 
outcomes associated with the use of ferric maltol 
(Feraccru®) for the management of iron deficiency anaemia 
in patients with inflammatory bowel disease in the UK. 
Background and 
rationale for study 
Approximately 20–75% of patients with inflammatory bowel 
disease (IBD) experience iron deficiency anaemia (IDA), 
which impacts on patients’ quality of life (QoL) through a 
range of symptoms. 
Oral ferric maltol (Feraccru®) is a novel iron complex 
licensed in the UK for the treatment of IDA in patients with 
IBD. Since its launch in 2016, Feraccru® has been used in 
some secondary care gastroenterology centres. Due to its 
high bioavailability and better tolerability compared with 
ferrous iron salt complexes, Feraccru® is likely to be used in 
patients after failure of oral ferrous products (OFPs), with 
the aim of preventing the need for IV iron infusions. In the 
phase III clinical trial, approximately 70% of patients had 
normalised haemoglobin (Hb) levels after 12 weeks of 
treatment with Feraccru®. 
The aim of the study is to understand the early experiences 
of Feraccru® in patients with IBD and IDA in the UK,  
including treatment effectiveness, patterns of use and 
tolerability. By describing the characteristics of patients 
treated with Feraccru® and their outcomes, this study will 
provide the medical community with important information 
to support treatment decisions for their patients. This will 
ultimately support improvements to patient care, including 
the long-term outcomes of patients with IBD and IDA. 
Objectives 
Primary objective: 
 To describe the percentage of patients with normalised 
Hb levels at 12 weeks after initiation of Feraccru®. 
Secondary objectives: 
 To describe the clinical outcomes associated with  the 
use of Feraccru® in the real world, including: 
o Change in Hb levels at 4 and 12 weeks after initiation 
of Feraccru® 
o Time to normalisation of Hb levels after initiation of 
Feraccru® 
o Change  in  serum ferritin  levels  at 4  and  12  weeks 

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after initiation of Feraccru® 
o Percentage of patients with normalised ferritin levels 
at 12 weeks after initiation of Feraccru® 
o Time to correction of serum ferritin levels after 
initiation of Feraccru® 
o Change in transferrin saturation at 4 and 12 weeks 
after initiation of Feraccru® 
o Percentage of patients with normalised transferrin 
saturation at 12 weeks after initiation of Feraccru® 
o Time to correction of transferrin saturation after 
initiation of Feraccru® 
 
To describe the characteristics of patients receiving 
Feraccru® in the real world, including: 
o Age and sex 
o Type of IBD 
o Haematology and biochemistry parameters at 
baseline 
o Time from diagnosis of IBD to initiation of Feraccru® 
o Time from diagnosis of IDA to initiation of Feraccru® 
o Iron treatment history 
o Reason(s) for discontinuing each prior oral ferrous 
product 
o Reason(s) for initiating Feraccru® 
o Percentage of patients who discontinue Feraccru® 
o Reason(s) for discontinuing Feraccru® 
o Type, severity and time of adverse events that are 
related to and caused by (in the clinician’s opinion) 
Feraccru®, from initiation of Feraccru® 
Hypothesis 
statement 
As  the  study  is  descriptive  in  nature  there  is  no  a priori 
hypothesis to be tested. 
Study design 
An observational, multi-centre cohort study will be 
conducted in five secondary care gastroenterology centres 
in the UK. 
Patients who are prescribed Feraccru® in routine practice 
will be identified by their care team and approached and 
asked to provide consent to allow their medical records to 
be used in the study. There will be no change to the 
management of patients as a result of taking part in the 
study. No additional patient investigations or tests will be 
required. 
In order to maximise the number of eligible patients, there 
will be two methods of patient identification and consent: 
 Retrospective recruitment - Patients initiated on 
Feraccru® since June 2016 will be approached and asked 
to provide consent either by post, or when they return 

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to clinic for routine follow-up visits. 
 Prospective recruitment - Patients initiated on Feraccru® 
during the study period will be identified and asked to 
provide consent at the time of Feraccru® initiation. 
Data source(s) 
Data will be collected from hospital medical records, by a 
member of the care team or a researcher in the study 
centre. 
Number of centres Five secondary care centres in the UK. 
Number of 
subjects 
Approximately 100 patients with IBD (Crohn’s disease [CD] 
or ulcerative colitis [UC]) who are also diagnosed with IDA. 
Study time period 
12 weeks (permitting a window from 10 to 16 weeks to 
allow for routine follow up clinic visits to occur). 
Patient selection 
Inclusion criteria 
 Male and female patients aged ≥ 18 years at the time of 
initiation 
 Patient presenting with mild to moderate IDA that is 
secondary to either CD or UC defined as: 
o Hb <12.0 g/dL in females 
o Hb <13.0 g/dL in males 
o Serum ferritin concentration <30 microgram/L or 
transferrin saturation of <20% 
 Patient receiving Feraccru® since the time of UK launch 
in June 2016 
Exclusion criteria 
 Patient receiving Feraccru® as part of an interventional 
clinical trial 
 Patients with severely active IBD or requiring 
corticosteroids at the time of initiation on Feraccru® 
 Patient with an IBD flare, as determined by the clinician 
 Patient with medical records that are not available for 
review 
 Patient not willing or unable to consent to study 
participation, or patient is deceased at the start of data 
collection period 
Study endpoints 
Primary endpoint: 
 Percentage of patients with normalised Hb levels at 12 
weeks (permitting a window from 10 to 16 weeks) after 
initiation of Feraccru® 
Secondary endpoints: 
 Descriptive analyses summarising change from baseline 

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(permitting a window from -2 to 2 weeks) in Hb levels at  
4 weeks (permitting a window from 3 to 5 weeks) where 
data are available, and 12 weeks (permitting a window 
from 10 to 16 weeks) after initiation of Feraccru® 
 Time to normalisation of Hb levels after initiation of 
Feraccru® 
 Descriptive analyses summarising change from baseline 
(permitting a window from -2 to 2 weeks) in ferritin 
levels at 4 weeks (permitting a window from 3 to 5 
weeks) where data are available, and 12 weeks 
(permitting a window from 10 to 16 weeks) after 
initiation of Feraccru® 
 Percentage patients with normalised ferritin levels at 12 
weeks (permitting a window from 10 to 16 weeks) after 
initiation of Feraccru® 
 Time to correction of serum ferritin levels after initiation 
of Feraccru® 
 Descriptive analyses summarising change from baseline 
(permitting a window from -2 to 2 weeks) in transferrin 
saturation at 4 weeks (permitting a window from 3 to 5 
weeks) where data are available, and 12 weeks 
(permitting a window from 10 to 16 weeks) after 
initiation of Feraccru® 
 Percentage of patients with normalised transferrin 
saturation at 12 weeks (permitting a window from 10 to 
16 weeks) after initiation of Feraccru®. Normalised 
transferrin saturation is defined as transferrin saturation 
between 20% and 50% 
 Time to correction of transferrin saturation after 
initiation of Feraccru® 
 Patient characteristics: age, sex and type of IBD 
 Descriptive analyses of haematology and biochemistry 
parameters at baseline 
 Time from diagnosis of IBD to initiation of Feraccru® 
 Time from diagnosis of IDA to initiation of Feraccru® 
 Descriptive analyses of prior IV iron treatment, to 
include at least the percentage of patients with one or 
more prior infusions 
 Reason(s) for discontinuing each prior oral ferrous 
product 
 Reason(s) for initiating Feraccru® 
 Percentage of patients who discontinue Feraccru® 
 Reason(s) for discontinuing Feraccru® 
 Type, severity and time of adverse events that are 
related to and caused by (in the clinician’s opinion) 
Feraccru®, from initiation of Feraccru® 

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Statistical 
considerations 
Given the descriptive nature of the study, a preliminary 
estimation of the required sample size is expressed in terms 
of precision and not statistical power. The estimated 
percentage of patients treated with Feraccru® and a 
reported normalised Hb at 12 weeks is approximately 66%. 
The accuracy of this point estimate will vary according to the 
number of participants in the study. Based on this estimate, 
precision can be calculated using a Binomial confidence 
interval. With a sample size of 100 patients, the precision of 
the estimates is between 9–10%. This means that the 
percentage of patients treated with Feraccru® with a 
reported normalised Hb at 12 weeks will be within 9–10% of 
the true population percentage. 
Data from all centres will be pooled for analysis. The 
planned analysis will be descriptive in nature. 
Regulatory, ethical 
and 
administrative 
obligations 
In line with the harmonised edition of the Governance 
Arrangements for Research Ethics Committees (GAfREC) 
(effective from 1st September 2011), this study is required 
to be submitted for NHS REC review, as it is an observational 
research study involving collection of non-identifiable 
information by an external data collector. Consent will be 
sought from patients and only those who consent will be 
included in the study. 

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2. Study amendments and protocol deviations 
All amendments to the protocol will be documented in Table 1. Protocol deviations will be 
documented in a Protocol Deviation Log. 
 
 
 
Table 1 Study amendments 
Amendment 
number 
Date of 
amendment 
Amendment 
description 
Reason for 
amendment 

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3. Background and rationale 
Ulcerative colitis (UC) and Crohn’s disease (CD) are both types of inflammatory bowel 
disease (IBD) that are characterised by symptoms of bloody diarrhoea, abdominal pain and 
cramps2. Anaemia is a complication that occurs in up to 70% of patients with CD or UC3–6. 
Iron deficiency anaemia (IDA) is the most common cause of anaemia in these patients. 
Iron deficiency can result from insufficient dietary intake, chronic inflammation reducing 
absorption, malabsorption and/or intestinal bleeding3,7–9. In IBD, iron deficiency results from 
a combination of functional iron deficiency due to inflammation and chronic blood loss10. 
Approximately 20–75% of patients with IBD experience IDA3,5,11, which can impair patients’ 
quality of life (QoL) through symptoms such as fatigue, dizziness, headache, tachycardia, 
shortness of breath, depression, and reduced cognitive functioning5,12. Not only does IDA in 
IBD have a considerable impact on activities of daily living, but severe symptoms can lead to 
hospitalisation. Iron deficiency anaemia is defined by the World Health Organization (WHO) 
as haemoglobin (Hb) <12.0 g/dL in women and Hb <13.0 g/dL in men1. Laboratory 
investigations using modern automated cell counters are able to detect changes in red cell 
indices, including reduced mean corpuscular volume (MCV) and reduced mean corpuscular 
haemoglobin (Hb) (MCH), necessary for a diagnosis of IDA13. 
Treatment goals in the clinical management of IDA are to normalise Hb concentrations and 
red cell indices, as well as replenishing iron stores. Clinical guidelines recommend the 
inclusion of oral iron supplementation to correct anaemia, with oral iron continued for 3 
months after the IDA has been corrected14,15. Guidance also suggests regular patient 
monitoring; every 3 months up to a year after IDA correction then 12 months thereafter, 
and again if symptoms of anaemia develop14. For patients who are intolerant, or have an 
insufficient response to oral iron, intravenous (IV) iron is recommended which is often 
administered in a hospital setting as a day case. This results in an increased burden on 
patients and increased costs associated with both the drug and use of hospital services14. 
Oral ferric maltol (Feraccru®) is a novel iron complex consisting of a single ferric iron ion 
(Fe3+), chelated with high affinity to three maltol molecules. Maltol is a natural sugar 
derivative that binds with high affinity to ferric iron until it is released directly into the area 
of the gastrointestinal (GI) tract where it is best absorbed. This is suggested to confer high 

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bioavailability and better tolerability compared with ferrous iron salt complexes, due to the 
reduced exposure of free iron throughout the GI tract. Feraccru® is licensed in the UK for the 
treatment of IDA in patients with IBD and has been used in a number of secondary care 
gastroenterology centres since its launch in 2016. Feraccru® is likely to be used in patients 
after failure of oral ferrous products (OFPs), with the aim of preventing the need for 
intravenous (IV) iron infusions. In the phase III clinical trial, approximately 70% of patients 
had normalised haemoglobin after 12 weeks of treatment with Feraccru®3. 
 
3.1 Rationale for study 
As Feraccru® has only been on the UK market for a relatively short period of time, real world 
evidence is required to understand early experiences of Feraccru® in IBD patients with IDA  
in UK routine practice. For example, data are needed to determine whether biochemical 
outcomes seen in clinical trials can be replicated in a more diverse and representative 
population in the real world. Information is also needed about the characteristics and 
treatment history of patients who receive Feraccru®, and the tolerability that is achieved. By 
describing the characteristics of patients treated with Feraccru® and their associated 
outcomes, this study will provide the medical community with important information to 
support their treatment decisions for their patients. The findings from this study will 
ultimately support improvements to patient care, including the long-term outcomes of 
patients with IBD and IDA. 
 
4. Aim and objectives 
4.1 Aim 
To describe the real-world use of Feraccru®, and the characteristics and the clinical 
outcomes of patients with IBD and IDA who receive Feraccru®. 
 
 
4.2 Primary objective 
To describe the percentage of patients with normalised Hb levels at 12 weeks after initiation 
of Feraccru®. 

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4.3 Secondary objectives 
 To describe the clinical outcomes associated with the use of Feraccru® in the real world, 
including: 
o Change in Hb levels at 4 and 12 weeks after initiation of Feraccru® 
 
o Time to normalisation of Hb levels after initiation of Feraccru® 
 
o Change in serum ferritin levels at 4 and 12 weeks after initiation of Feraccru® 
 
o Percentage of patients with normalised ferritin levels at 12 weeks after initiation 
of Feraccru® 
o Time to correction of serum ferritin levels after initiation of Feraccru® 
 
o Change in transferrin saturation at 4 and 12 weeks after initiation of Feraccru® 
 
o Percentage of patients with normalised transferrin saturation at 12 weeks after 
initiation of Feraccru® 
o Time to correction of transferrin saturation after initiation of Feraccru® 
 
 To describe the characteristics of patients receiving Feraccru® in the real world, 
including: 
o Age and sex 
 
o Type of IBD 
 
o Haematology and biochemistry parameters at baseline 
 
o Time from diagnosis of IBD to initiation of Feraccru® 
 
o Time from diagnosis of IDA to initiation of Feraccru® 
 
o Iron treatment history 
 
o Reason(s) for discontinuing each prior oral ferrous product 
 
o Reason(s) for initiating Feraccru® 
 
o Percentage of patients who discontinue Feraccru® 
 
o Reason(s) for discontinuing Feraccru® 

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o Type, severity and time of adverse events that are related to and caused by (in 
the clinician’s opinion) Feraccru®, from initiation of Feraccru® 
 
 
5. Hypothesis 
As the study is descriptive in nature, there is no a priori hypothesis to be tested. 
 
 
 
6. Study design and methodology 
The study has been designed and will be conducted according to the requirements of the 
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP; 
http://www.encepp.eu/index.shtml) and International Society for Pharmacoepidemiology 
(ISPE; 
https://www.pharmacoepi.org/resources/guidelines_08027.cfm) 
guidance, 
as 
appropriate. 
This study will be an observational, multi-centre cohort study conducted in five secondary 
care NHS centres across the UK. Patients will be recruited using both retrospective and 
prospective approaches. 
 
 
6.1 Study time periods 
Eligible patients will be followed from the time of initiation on Feraccru® for 12 weeks, with 
a permitted window from 10 to 16 weeks. 
 
 
6.2 Study population 
The study population will be patients under the management of secondary care 
gastroenterology centres in the UK that are using Feraccru®. Study participants will be 
required to consent to study participation by the signing of a consent form before any data 
are collected. 

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The study sample will be derived from the population of patients with IBD (either CD or UC) 
who also have a clinically confirmed diagnosis of IDA and were either: 
 Initiated on Feraccru® since June 2016 (retrospectively recruited patients), or 
 Initiated on Feraccru® during the study period (prospectively recruited patients). 
 
 
6.2.1 Inclusion criteria 
 Male and female patients aged ≥ 18 years at the time of initiation 
 Patients presenting with mild to moderate IDA that is secondary to either CD or UC, 
defined as; 
o Hb <12.0 g/dL in females 
 
o Hb <13.0 g/dL in males 
 
o Serum ferritin concentration <30 microgram/L or transferrin saturation of <20% 
 
 Patients receiving Feraccru® since the time of UK launch in June 2016 
 
 
6.2.2 Exclusion (ineligibility) criteria 
 Patient receiving Feraccru® as part of an interventional clinical trial 
 Patients with severely active IBD or requiring corticosteroids at the time of initiation on 
Feraccru® 
 Patient with an IBD flare, as determined by the clinician 
 Patient with medical records that are not available for review 
 Patient not willing or unable to consent to study participation, or patient is deceased at 
the start of data collection period. 
 
 
6.2.3 Participant recruitment 
Patients who are prescribed Feraccru® and eligible for inclusion in the study will be  
identified by their care team and approached and asked to provide consent to allow their 

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medical records to be used in the study. There will be no change to the management of 
patients as a result of taking part in the study. No additional patient investigations or tests 
will be required. In order to maximise the number of eligible patients, there will be two 
methods of patient identification and consent; 
1. Retrospective recruitment - Patients who were initiated on Feraccru® since its launch 
in June 2016 will be approached and asked to complete a consent form either by 
post or when they return to the gastroenterology clinic for routine follow-up visits. 
2. Prospective recruitment - Patients initiated on Feraccru® during the study period will 
be identified and asked to provide consent (and complete a consent form) at the 
time of Feraccru® initiation. 
The study will recruit approximately 100 patients across 5 centres. 
 
 
 
6.3 Data collection 
Patients will be identified in all study records using a unique study code, which will allow 
individual patients to be identified for each of their clinic visits and allow data queries to be 
raised with centres by the data management team at pH Associates while preserving patient 
confidentiality. Further information on data collection can be found in section 7. 
Data relating to the patient’s demographics, IDA treatment history, outcomes, and 
tolerability of Feraccru®, will be collected by a member of the care team, or a researcher in 
the study centre. Data will be entered onto electronic (MACRO) data collection forms (eDCF) 
designed specifically for the study. 
 
 
6.4 Data source 
 
The study data will be derived from hospital medical records. This will include, but not be 
limited to case notes, prescribing records, laboratory reports and investigation reports. 

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6.5 Study endpoints and variables 
 
6.5.1 Primary endpoint 
 Percentage of patients with normalised Hb levels at 12 weeks (permitting a window  
from 10 to 16 weeks) after initiation of Feraccru® (normalisation of Hb defined as Hb ≥12 
g/dL for females and ≥13.0 g/dL for males) 
 
 
6.5.2 Secondary endpoints 
 Descriptive analyses summarising change from baseline (permitting a window from -2 to 
2 weeks) in Hb levels at 4 weeks (permitting a window from 3 to 5 weeks) where data 
are available, and 12 weeks (permitting a window from 10 to 16 weeks) after initiation  
of Feraccru® 
 Time to normalisation of Hb levels (normalisation of Hb defined as Hb≥ 12 g/dL for 
females and ≥13.0 g/dL for males) after initiation of Feraccru® 
 Descriptive analyses summarising change from baseline (permitting a window from -2 to 
2 weeks) in ferritin levels at 4 weeks (permitting a window from 3 to 5 weeks) where 
data are available, and 12 weeks (permitting a window from 10 to 16 weeks) after 
initiation of Feraccru® 
 Percentage of patients with normalised ferritin levels at 12 weeks (permitting a window 
from 10 to 16 weeks) after initiation of Feraccru®. Normalised serum ferritin is defined 
as serum ferritin concentration ≥30 microgram/L and ≤300 microgram/L 
 Time to correction of serum ferritin levels after initiation of Feraccru® 
 Descriptive analyses summarising change from baseline (permitting a window from -2 to 
2 weeks) in transferrin saturation at 4 weeks (permitting a window from 3 to 5 weeks) 
where data are available, and 12 weeks (permitting a window from 10 to 16 weeks) after 
initiation of Feraccru® 
 Percentage of patients with normalised transferrin saturation at 12 weeks (permitting a 
window from 10 to 16 weeks) after initiation of Feraccru®. Normalised transferrin 
saturation is defined as transferrin saturation between 20% and 50% 

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 Time to correction of transferrin saturation after initiation of Feraccru® 
 Patient characteristics: age, sex and type of IBD 
 Descriptive analyses of haematology and biochemistry parameters at baseline 
 Time from diagnosis of IBD to initiation of Feraccru® 
 Time from diagnosis of IDA to initiation of Feraccru® 
 Descriptive analyses of prior IV iron treatment, to include at least the percentage of 
patients with one or more prior infusions 
 Reason(s) for discontinuing each prior oral ferrous product 
 Reason(s) for initiating Feraccru® 
 Percentage of patients who discontinue Feraccru® 
 Reason(s) for discontinuing Feraccru® 
 Type, severity and time of adverse events that are related to and caused by (in the 
clinician’s opinion) Feraccru®, from initiation of Feraccru® 
 
 
6.5.3 Variables to be collected 
The following study variables will be collected during the observation period to measure the 
study endpoints, in order to describe the use of Feraccru® in the real world. 
 
 
Patient demographics and other characteristics: 
 Age at initiation of treatment with Feraccru® 
 Sex (Male/Female) 
 Date diagnosed with IBD 
 Type of IBD (CD/UC) 
 Date diagnosed with IDA 
 Description of IV iron treatment history, to include at least the number of prior infusions 
 Description of oral iron treatment history, where available in secondary care notes 

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o Experience of oral ferrous products (OFPs) (Yes/No), if yes: 
 
o Name(s) of OFP(s) 
 
o Reason(s) for discontinuing OFP(s) 
 
Feraccru® treatment: 
 Date initiated on Feraccru® 
 Reason(s) for initiating Feraccru® 
 Date discontinued Feraccru® 
 Reason (s) for discontinuation of Feraccru® 
 
 
Haematology and biochemistry parameters: 
 
The date(s) and result(s) of haemoglobin (Hb), ferritin and transferrin saturation will be 
collected from baseline (permitting a window from -2 to 2 weeks) to 12 weeks (permitting a 
window from 10 to 16 weeks). The date(s) and result(s) of the following haematology and 
biochemistry parameters will be collected at baseline only (permitting a window from -2 to 
2 weeks): 
 
Folate 
     B12 
 
Mean corpuscular volume 
 
Mean corpuscular Hb 
 
Platelets 
 
C-reactive protein (CRP) 
 
 
Adverse events: 
 
The details of adverse events (AEs) that are considered to be related to Feraccru® 
treatment, determined by clinical opinion, will be collected: 

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 Type, severity, start and end dates of AE/serious adverse event (SAE) with a temporal 
relationship to and caused by Feraccru®, as determined by the clinician 
 
 
 
7. Data management and quality control 
Data collection will be completed by trained staff employed by the NHS Trust or staff from 
pH Associates. All data collectors will be provided with Data Collection Guidelines to provide 
further information regarding the completion of the electronic Data Collection Form (eDCF). 
The same data collector will be used at each centre, wherever possible, to ensure 
consistency in data collection, if feasible. All data collected will be submitted regularly in 
anonymised-coded form to pH Associates for data entry, cleaning and analysis. 
 
 
7.1 Database management 
The eDCF will be developed from a paper draft and then converted to electronic form in 
MACRO, which is a web-based secure electronic data capture and data management tool. 
MACRO is compliant with FDA 21 CFR part 11 and Good Clinical Practice (GCP) and has been 
widely used in the UK NHS for complex interventional clinical trials and used by pH 
Associates on a range of real world evidence studies. A data analysis tool will be developed 
using Microsoft capabilities (Access®, Excel®). 
 
 
7.2 Data quality checks 
As this study will use both retrospective and prospective methods of data collection, the 
quality of the study dataset will depend on the accuracy and completeness of data recorded 
in patients’ medical records. Where data on study variables are not available, fields will be 
marked as ‘not known’ rather than left empty. Quantitative data collected for laboratory 
(haematology and biochemistry) parameters will be standardised per centre using 
laboratory reference ranges entered on the eDCF. This will allow pooling of these study 
parameters across centres. 

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All data submitted will be checked for accuracy and completeness. Queries will be raised by 
the pH Associates data management team. Study centres will be required to co-operate  
with the data management team in the resolution of these queries. On completion of the 
first three eDCFs from at least two centres, a pilot data review will be completed. This pilot 
will ensure that the study dataset can be captured feasibly and efficiently on the eDCF and 
the methodology for data collection is suitably robust. 
In order to confirm the accuracy and quality of the data, source data verification (SDV) will 
be completed for a randomly selected 10% of all patients. 100% of the data collected for 
these patients will be reviewed by pH Associates staff. Where data collection is completed 
by pH Associates staff, the staff member who carries out the SDV will be different to the 
person responsible for data collection at that specific centre. 
 
 
 
8. Study sample size 
Given the descriptive nature of this study, a preliminary estimation of the required sample 
size is expressed in terms of precision and not statistical power. In the literature, the 
percentage of patients treated with Feraccru® with reported normalised Hb at 12 weeks is 
approximately 66%3. However, the accuracy of such estimates will vary according to the 
number of participants in the study. Using 66% as the percentage of patients expected to 
show a normalised Hb at 12 weeks, the precision of such estimates can be calculated using a 
Binomial confidence interval (Table 2). 

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Table 2 Precision calculated using a Binomial confidence interval (Wald interval, normal 
approximation) 
Patients with normalised Hb at 12 weeks (%) 
Precision (%) 
Study patients (N) 
66% 
7% 
176 
66% 
8% 
135 
66% 
9% 
107 
66% 
10% 
87 
66% 
11% 
72 
66% 
12% 
60 
 
 
With a sample size of 100 patients, the precision of the estimates is calculated as between 
9–10%. This means that the percentage of patients treated with Feraccru® with a reported 
normalised Hb at 12 weeks in the study will be within 9–10% of the true population 
percentage. 
 
9. Statistical analysis 
Analyses will be performed by pH Associates. The planned analysis will be descriptive in 
nature. Both distributions and descriptive statistics of central tendency (arithmetic means 
and medians) and dispersion (standard deviation, interquartile range) will be presented for 
quantitative variables. Nominal variables will be described with frequencies, percentages 
and modes, while ordinal variables will also have medians and interquartile ranges 
described. Confidence intervals will be provided for means of quantitative variables. 
 
 
9.1 Missing data 
Whilst study centres will be selected to include those expected to have the most complete 
data, this study involves the retrospective collection of data from medical records. As   such, 

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it is possible that some data points will be missing. Where data are missing from the original 
medical record, the affected analyses will be conducted using only the results of those 
patients with data available (complete case analysis) and the number of patients included in 
each analysis will be stated. The percentage of data missing will be reported for each study 
variable. Missing data in itself will be of interest and should provide insight into the way 
patients are being managed in the UK outside the methodological constraints of a clinical 
trial. 
 
 
 
10. Review of study results 
No independent review of statistical data/study results is planned prior to completion of the 
study report. Investigators will be able to review the study results at the investigator 
meeting. 
 
 
 
11. Study limitations 
The quality of the dataset may be limited by the accuracy and completeness of patients’ 
medical records. It is believed that this limitation will be minimised by robust feasibility 
testing of the protocol framework during its development and additional evaluation during 
site selection. Furthermore, training of all data collectors and source data verification will 
ensure high quality data and will minimize potential bias. 

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12. Safety 
12.1 Definitions 
 
12.1.1 Adverse events 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. The definition of an AE includes worsening of a pre-existing medical 
condition. 
Adverse drug reactions (ADRs) are a subset of AEs where there is a clear causal relationship 
between the treatment and the event. This study requires the collation of all AEs, including 
ADRs. 
 
 
12.1.2 Serious adverse events 
An adverse event is considered serious (SAE) if it: 
 
 Is fatal 
 Is life threatening (places the subject at immediate risk of death) 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Other significant medical hazard 
 
 
“Other significant medical hazards” refer to important medical events that may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events could include allergic bronchospasm, convulsions, 
and blood dyscrasias, drug-induced liver injury, events that necessitate an emergency room 
visit, outpatient surgery, or other events that require other urgent intervention. 

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A serious adverse drug reaction (SADR) is a serious adverse event that is considered related 
to the medicinal product. A hospitalization meeting the regulatory definition for “serious” is 
any inpatient hospital admission that includes a minimum of an overnight stay in a 
healthcare facility. 
 
 
12.2 Reporting procedures for adverse events 
All SAEs/Special Reporting Situations related to any Shield Therapeutics PLC product(s) at 
each centre shall be reported to PrimeVigilance Limited by the Principal Investigator /pH 
Associates within 24 hours of discovery or notification. Initial SAE information and all follow- 
up information must be recorded on the SAE form and emailed to PrimeVigilance Limited. 
Investigators may be requested to provide follow-up information concerning serious 
adverse events, including an evaluation of causality and seriousness. Relatedness of the SAE 
to Shield Therapeutics PLC product(s) will be assessed by the investigator if there is doubt. 
All non-serious AEs will be captured as part of the study dataset and will be tabulated in the 
study report but will not be subject to expedited reporting. Only SAE and AEs judged to be 
related to Feraccru® will be included as a study endpoint. As all adverse events will be 
documented (and ultimately made available to the Medicines and Healthcare products 
Regulatory Agency, MHRA) by Shield Therapeutics PLC as study sponsor, there is no need for 
investigator sites to duplicate adverse event reporting through the Yellow Card Scheme. 
 
 
12.3 
Special Reporting Situations 
Any AEs in the following patient groups should be reported as if it was an SAE to 
PrimeVigilance Limited.  
 Pregnancy: Any case in which a patient is found to be pregnant or to have become 
pregnant following treatment with the Product(s). Exposure is considered either through 
maternal exposure or via semen following paternal exposure. 
 Breastfeeding: infant exposure from breastfeeding. 

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 Overdose: All information of any accidental or intentional overdose. 
 Drug abuse, misuse or medication error: All information on medicinal product abuse, 
misuse or medication error (potential or actual). 
 Suspected transmission of an infectious agent: All information on a suspected (in the 
sense of confirmed or potential) transmission of an infectious agent by a medicinal 
product. 
 Lack of effect report for the product(s). 
 Any use of the product in children. 
 Occupational exposure. 
 Use outside the terms of the marketing authorization, also known as “off-label”. 
 Use of falsified medicinal product. 
 Use of counterfeit medicinal product. 
 
 
 
 
 
13. 
Ethical and regulatory obligations 
13.1 Protection of human subjects 
This study will comply with all applicable laws, regulations, and guidance regarding patient 
protection including patient privacy. 
As this is an observational study, there is no additional risk to participants as all data are 
collected from medical records and patients will have no direct involvement in the study 
with the exception of providing their informed consent for data to be collected from their 
medical records. There will be no change to the management of patients as a result of 
taking part in the study. 
In accordance with the UK Department of Health Research Governance Framework for 
Health and Social Care this type of study, except in specific cases, must be submitted for 
review by an independent committee. This study will therefore be submitted for review by 
SAFETY CONTACT DETAILS 
 
PrimeVigilance Limited has been contracted by the Sponsor for safety reporting  
Email SAE reports to shieldpv@primevigilance.com or fax to +44 (0)1483 431831 
and copy to data@phassociates.com 

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an NHS Research Ethics Committee (REC), via the Health Research Authority (HRA). The 
study will also be submitted for inclusion in the NIHR portfolio of research studies. NHS 
management approval for local conduct of the study and the sharing of anonymised- coded 
patient data will be sought via the Research and Development (R&D) department in each 
participating Trust. 

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14. Study timelines 
 
 
Table 3 Study timelines 
Study milestone 
Expected date(s)/frequency 
Start of data collection 
May 2017 
End of data collection 
August 2017 
Data analysis 
August to September 2017 
Final report of study results 
October to November 2017 

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15. Administrative and legal obligations 
15.1 Study amendments and study termination 
Amendments must be made only by prior agreement between Shield Therapeutics PLC, pH 
Associates and Dr Fraser Cummings. The REC must be informed of all amendments and give 
approval for substantial amendments. The Chief Investigator must send a copy of the 
approval letter from the REC to Shield Therapeutics PLC. pH Associates, Shield Therapeutics 
PLC, and the investigator reserve the right to terminate participation in the study according 
to the study contract. pH Associates will notify the REC in writing of the study’s completion 
or early termination and send a copy of the notification to Shield Therapeutics PLC and the 
Chief Investigator. 
 
 
15.2 Study documentation and archive 
Completed eDCFs are transmitted over a secure connection to pH associates in real time. 
The principal investigator (PI) at each site must ensure that information entered in the eDCF 
is traceable to the source documents in the patient’s medical record (paper or electronic). 
Changes to the eDCF are recorded in the MACRO audit trail, these include changes in 
response to queries, SDV and data entry errors. 
The study documentation and electronic data will be kept after the study for 5 years and will 
then be securely destroyed according to the policy of the sponsor. 
 
 
15.3 Ethical and regulatory approvals 
In line with the harmonised edition of the Governance Arrangements for Research Ethics 
Committees (GAfREC) (effective from 1st September 2011), this study is required to be 
submitted for NHS REC review, as it is an observational research study involving collection of 
non-identifiable information collected by an external data collector. Consent will be sought 
from patients and only those who consent will be included in the study. 

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Clinical trials in the UK are regulated and require authorisation by the UK competent 
authority, Medicines and Healthcare Products Regulatory Agency (MHRA). This non- 
interventional study does not require authorisation, as The Medicines for Human Use 
(Clinical Trials) Regulations 2004 (SI 1031) do not apply. 
 
 
15.4 Ethical issues 
Patients with IBD and IDA who have been identified as being eligible for study participation 
will be provided with a patient information sheet and consent form by a member of their 
care team. This will provide written information for their consideration and discussion with 
their family and friends and as well as care team members. The patient will be allowed 
adequate time to consider whether they wish to consent for their participation in the study 
and have any questions answered by their care team. 
No patient identifiable information will be collected or removed from the NHS Trusts 
participating in the study in order to preserve patient confidentiality. Patients will be 
assigned a study-specific patient number which will be referenced in a study log.  This 
patient log will not leave the participating NHS Trust and will be the responsibility of the 
principal investigator at that study centre. 
 
 
 
16. Communication of study results 
The study will be reported according to the requirements of STROBE (Strengthening the 
reporting of observational studies in epidemiology) as specified in the appropriate checklist 
for the study design (http://www.strobe-statement.org/index.php?id=available-checklists). 
Authorship of publications arising from the study will follow the guidelines proposed by the 
International Committee of Medical Journal Editors (2015) (http://www.icmje.org/icmje- 
recommendations.pdf ). All authors will meet the criteria for authorship, and all people who 
meet the criteria will be authors. Potential conflicts of interest will be disclosed. All authors 
will have: 
(1) made substantial contributions to conception or design or acquisition of data, or analysis 
and interpretation of data; AND 

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(2) participated in drafting the article or revising it critically for important intellectual 
content; AND 
(3) approved the final version to be published. 
 
Each author will meet all of these conditions and all individuals meeting these criteria will be 
authors. Acquisition of funding, collection of data, or general supervision of the research 
group does not justify authorship. Each author will have participated sufficiently in the work 
to take public responsibility for appropriate portions of the content. 
 
17. Study support 
The study is sponsored by Shield Therapeutics PLC, the manufacturer of Feraccru®. Shield 
Therapeutics PLC have commissioned pH Associates Ltd to develop materials for and co- 
ordinate the conduct of the study, including protocol development, ethical and local 
approval, retrospective data collection, analysis and presentation of the results. pH 
Associates is an independent consultancy specialising in the evaluation of healthcare 
services and interventions in the NHS through observational research, with a focus on the 
design and implementation of 'Real World Data' projects in order to understand current  
NHS practices. 

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4. Stein J, Hartmann F, Dignass AU. Diagnosis and management of iron deficiency anemia 
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Churchill Livingstone; 2001. 
 
14. Goddard AF, James MW, McIntyre AS, Scott BB. Guidelines for the management of iron 
deficiency anaemia. Gut. 2011 Oct;60(10):1309–16. 

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15. Smith A. Prescribing iron. Prescribers’ J. 1997;37:82–7.