An Open Label Randomised Trial to Assess the Efficacy of Post-Operative Ferric Maltol Vs Standard Care for Anaemia Following Colorectal Cancer Surgery
Phase: PHASE3
Conditions: Cancer Colon
Sponsor: The Royal Wolverhampton Hospitals NHS Trust

SHORT TITLE/ACRONYM PICoC Study – 
Perioperative Iron for Colorectal Cancer 
 
                   EudraCT number - 2021-006004-32 
 
Version 0.6 27/10/2023 
 
 
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An Open Label Randomised Trial to Assess the Efficacy of 
Post-Operative Ferric Maltol Vs Standard Care for Anaemia 
Following Colorectal Cancer Surgery 
 
Perioperative Iron for Colorectal Cancer (PICoC Study) 
 
 
 
This protocol has regard for the HRA guidance and order of content 
 
 
 
 
PROTOCOL VERSION NUMBER AND DATE:   
0.6  27th October 2023 
 
 
SPONSOR:   
 
 
 
The Royal Wolverhampton NHS Trust 
 
 

SHORT TITLE/ACRONYM PICoC Study – 
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FULL/LONG TITLE OF THE TRIAL 
An Open Label Randomised Trial to Assess the Efficacy of Post-Operative Ferric 
Maltol Vs Standard Care for Anaemia Following Colorectal Cancer Surgery 
 
SHORT TRIAL TITLE / ACRONYM 
Perioperative Iron for Colorectal Cancer (PICoC Study) 
 
 
PROTOCOL VERSION NUMBER AND DATE – V0.6 27th October 2023 
 
RESEARCH REFERENCE NUMBERS 
 
IRAS Number: 
1003910 
EudraCT Number: 
 
2021-006004-32 
ISRCTN Number / Clinical 
trials.gov Number: 
 
Clinical Trials- NCT05177484  
ISRCTN submission number 40928 
SPONSORS Number: 
2021GAS120 
FUNDERS Number: 
IIS-2020-UK-131 
 
 
 

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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the Chief Investigator agrees to conduct the trial in compliance with the approved protocol 
and will adhere to the principles outlined in the Medicines for Human Use (Clinical Trials) 
Regulations 2004 (SI 2004/1031), amended regulations (SI 2006/1928) and any subsequent 
amendments of the clinical trial regulations, GCP guidelines, the Sponsor’s (and any other 
relevant) SOPs, and other regulatory requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be 
used for any other purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor 
I also confirm that I will make the findings of the trial publicly available through publication or 
other dissemination tools without any unnecessary delay and that an honest accurate and 
transparent account of the trial will be given; and that any discrepancies and serious 
breaches of GCP from the trial as planned in this protocol will be explained. 
 
For and on behalf of the Trial Sponsor: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
Chief Investigator: 
Signature: 
...................................................................................................... 
 
Date: 
....../....../...... 
Name: (please print): 
...................................................................................................... 
 
 
 
(Optional) 
Statistician: 
 
 
Signature: 
...................................................................................................... 
 
 
Name: (please print): 
......................................................................................................
 
 
 
 
 
 
 
 
 

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 KEY TRIAL CONTACTS 
 
Chief Investigator - 1 
Professor. Matthew James Brookes 
Consultant Gastroenterologist and Honorary Senior 
Lecturer, Gastroenterology Department, Royal 
Wolverhampton Hospital NHS Trust 
Chief Investigator - 2 
Miss Nuha Yassin 
Consultant Colorectal Surgeon 
University Hospitals Birmingham NHS Foundation 
Trust 
Headquarters 
Queen Elizabeth Hospital Birmingham 
Mindelsohn Way, Edgbaston 
Birmingham 
West Midlands 
B15 2GW 
Trial Co-ordinator/ Clinical 
Research Fellow  
Dr Alexandra Marley  
 
Sponsor 
The Royal Wolverhampton NHS Trust, New Cross 
Hospital, Wolverhampton Rd, Heath Town, 
Wolverhampton WV10 0QP 
Funder(s) 
Norgine Pharmaceuticals Ltd. 
Key Protocol Contributors 
Mr. Edward Alexander Dickson 
Clinical Research Fellow, Academic Department of 
Surgery and Biomedical Research Unit, University of 
Nottingham, Queen’s Medical Centre, Nottingham 
NG7 2UH 
 
Mr. Austin George Acheson 
Associate Professor in Academic Colorectal Surgery 
Department of Surgery, Queen’s Medical Centre, 
Nottingham NG7 2UH 
 
 
Additional Trial Steering 
Committee Members 
Statistical support: Dr Niall Galbraith  
Patient Representative: Miss Sue Blackwell 

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Lead Scientist: Dr Hafid Omar 
 
 
 
SIGNATURE PAGE 
3 
KEY TRIAL CONTACTS 
4 
I. LIST OF ABBREVIATIONS 
6 
II. TRIAL SUMMARY 
8 
III. FUNDING AND SUPPORT IN KIND 
9 
IV. ROLE OF TRIAL SPONSOR AND FUNDER 
9 
V. KEY WORDS: 
9 
VI. TRIAL FLOW CHART 
10 
1 
BACKGROUND 
11 
2 
RATIONALE 
12 
3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
13 
4 
TRIAL DESIGN 
15 
5 
TRIAL SETTING 
17 
6 
PARTICIPANT ELIGIBILITY CRITERIA 
17 
7 
TRIAL PROCEDURES 
18 
8 
TRIAL TREATMENTS 
26 
9 
PHARMACOVIGILANCE 
29 

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10 STATISTICS AND DATA ANALYSIS 
35 
11 DATA MANAGEMENT 
37 
12  MONITORING, AUDIT & INSPECTION 
38 
13 ETHICAL AND REGULATORY CONSIDERATIONS 
39 
14  DISSEMINIATION POLICY 
42 
15 REFERENCES 
42 
16.  APPENDICIES 
44 
 
i. LIST OF ABBREVIATIONS 
Define all unusual or ‘technical’ terms related to the trial.  Add or delete as appropriate to 
your trial.  Maintain alphabetical order for ease of reference. 
AE 
Adverse Event 
AR 
Adverse Reaction 
ARBT 
Allogenic Red Blood Cell Transfusion 
CA 
Competent Authority 
CI 
Chief Investigator 
CPA 
Clinical Pathology Accreditation 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP  
Clinical Trial of Investigational Medicinal Product  
CTU 
Clinical Trials Unit  
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
European Commission 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
GCP 
Good Clinical Practice 

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GMP 
Good Manufacturing Practice  
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of 
technical requirements for registration of 
pharmaceuticals for human use. 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File (This forms part of the TMF) 
ISRCTN 
International Standard Randomised Controlled Trials 
 
Number 
MA 
Marketing Authorisation 
MDT 
Multidisciplinary Team 
MHRA 
Medicines and Healthcare products Regulatory 
Agency 
MS 
Member State 
NHS R&D 
National Health Service Research & Development   
NIMP 
Non-Investigational Medicinal Product 
NICE 
National Institute for Clinical Excellence 
PI 
Principal Investigator 
PIC 
Participant Identification Centre 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person  
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SSI 
Site Specific Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
 
 

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ii. TRIAL SUMMARY 
Trial Title 
An Open Label Randomised Trial to Assess the Efficacy of Post-Operative 
Ferric Maltol Vs Standard Care for Anaemia Following Colorectal Cancer 
Surgery 
Short title 
PICoC Trial – Perioperative Iron in Colorectal Cancer 
Clinical Phase  
Feasibility  
Trial Design 
Open label randomised controlled trial 
Trial Participants 
Anaemic patients with colorectal adenocarcinoma undergoing surgery 
Planned Sample Size 
40 participants 
Treatment duration 
12 weeks from completion of surgery 
Follow up duration 
12 weeks 
Planned Trial Period 
24 months 
 
Objectives 
Outcome Measures 
Primary 
 
Feasibility measures 
 
• 
Eligible patients from screening 
• 
Study exclusion 
• 
Acceptability of recruitment 
• 
Study retention 
Secondary 
 
1. To compare change in blood 
indices between intervention and 
control groups. 
2. To compare quality of life between 
groups. 
3. To compare post-operative 
complications, survival and length 
of stay between intervention and 
control groups. 
4. To compare allogenic red blood 
cell transfusion use between 
groups. 
5. Tolerability of ferric maltol. 
1. Change in haemoglobin and 
haematinic markers 
2. Quality of life as determined by 
the SF36, EQ-5D and FACT-An 
questionnaires 
3. Post-operative morbidity and 
mortality and length of stay  
4. Post-operative allogenic blood 
transfusion. 
5. Side-effects and reactions to 
ferric maltol 
IMP 
Ferric Maltol (Feraccru) 
Dose, Route of 
Administration 
Oral tablets, 30mg dose twice daily. 

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iii. FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
(Names and contact details of ALL 
organisations providing funding and/or 
support in kind for this trial) 
FINANCIAL AND NON 
FINANCIALSUPPORT GIVEN 
Norgine Ltd 
An unrestricted open commercial grant to 
fully support trial delivery and consumables 
 
 
 
 
 
 
iv. ROLE OF TRIAL SPONSOR AND FUNDER 
The Royal Wolverhampton NHS Trust is the sponsor of this study and assumes overall 
responsibility for the initiation, and management of the study. 
Funding and drug supply for the study (Ferric iron) has been provided by Norgine 
Pharmaceuticals Ltd. 
 
Protocol contributors 
The study design, conduct, data analysis and interpretation, manuscript writing, and result 
dissemination will be the responsibility of the research team, overseen by the sponsor.  
The protocol will be reviewed by Norgine Ltd. prior to ethics submission but they will not be 
involved in the study conduct, data analysis or interpretation 
 
v. KEY WORDS: 
Anaemia, Colorectal Cancer, Ferric maltol, Iron, Peri-
operative 
 
 
 

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vi. TRIAL FLOW CHART 
 
 
 

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1 
BACKGROUND 
 
Colorectal cancer is associated with iron deficiency anaemia in 40-60% of cases (Leichtle, 
Mouawad et al. 2011). This anaemia can lead to poorer post-operative outcomes such as 
higher complication rates, increased length of stay and reduced survival (Muñoz, Acheson et 
al. 2018). There has been a recent shift towards the correction of preoperative anaemia in 
order to optimize perioperative outcomes. However, despite improvements in preoperative 
haemoglobin there exists a group of patients who develop worsening or recurrent anaemia 
in the post-operative period. Without intervention up to 90% of patients in the immediate 
postoperative period may develop anaemia (Shander, Knight et al. 2004). This is not 
unexpected given the peri‐operative blood loss; poor nutritional intake in the postoperative 
period; and the frequent blood sampling for laboratory tests. Our data from previous trials 
has demonstrated that despite preoperative intravenous iron therapy 75% of patients remain 
anaemic at the time of their colorectal cancer operation (Keeler, Simpson et al. 2017). In 
addition, our unpublished data has found that around 1/3 of patients treated with 
preoperative iron therapy develop a recurrence of their anaemia in the first year 
postoperatively. Studies have identified that traditional oral ferrous iron supplementation is 
largely ineffective (Bisbe et al. 2014) for the treatment of postoperative anaemia. However, a 
newer oral iron preparation - ferric maltol (Ferracru) has been found to be better tolerated 
and more efficacious than ferrous iron (Schmidt, Ahmad et al. 2016, Oppong, Lovato et al. 
2018). This study aims to evaluate whether the use of iron supplementation in the form of 
Feraccru could lead to a more sustained or improved a response in haemoglobin if given 
after a colorectal cancer operation. Improving this postoperative anaemia may have 
important implications for clinician and patient reported outcomes. The Perioperative Iron in 
Colorectal Cancer (PICoC) trial will run as a feasibility study to assess the proposed design, 
recruitability and outcome measures. Anaemic colorectal cancer patients treated with 

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preoperative intravenous iron will be randomised in an open label design to receive a course 
of Ferric maltol (intervention group) or standard care (control group) postoperatively. 
Secondary outcome measures will focus on a comparison of change in blood indices, quality 
of life, allogenic red blood transfusion rates and postoperative complications between 
groups. Follow up will continue until the first postoperative outpatient visit at approximately 
12 weeks following discharge. 
 
2 
RATIONALE  
 
The PICoC study aims to investigate whether oral ferric maltol given postoperatively offers 
an improvement in patient and clinician reported outcomes compared to standard care. If 
postoperative anaemia can be improved this could lead to fewer complication rates, better 
quality of life and a shorter length of stay in colorectal cancer patients after operation. 
Traditionally oral ferrous (Fe2+) iron preparations, such as ferrous fumarate or ferrous 
sulphate have been used to treat iron deficiency anaemia. However, these forms of iron 
supplementation can damage the gut mucosa by the process of oxidative stress leading to 
symptoms of abdominal pain, nausea, constipation or diarrhoea. 
Ferric maltol is a novel oral iron therapy which has shown promise as an effective treatment 
for iron deficiency anaemia in conditions such as inflammatory bowel disease (Gasche, 
Ahmad et al. 2014). After oral ingestion of ferric maltol, ferric iron reaches the intestinal 
mucosa as a complex, allowing more efficient absorption of ferric iron by the gut compared 
to ferrous iron (Levey, Barrand et al. 1988), even at a low dose. This is also thought to lead 
to a more favourable side effect profile with patients (Schmidt, Ahmad et al. 2016, Oppong, 
Lovato et al. 2018) 
Current standard care involves monitoring for signs of worsening anaemia in the 
postoperative period with the option of transfusing allogenic blood (ARBT) if the clinical need 

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arises. Existing NICE guidance advises a haemoglobin threshold of 70g/L to trigger ARBT. 
This leaves a large number of postoperative anaemic patients without an effective treatment 
leading to higher complication rates, increased length of stay. In addition, where transfusions 
are used they carry a small but significant risk of infection, immune reaction as well as a high 
cost. Studies have also drawn links between ARBT and cancer recurrence (Amato and 
Pescatori 2006, Acheson, Brookes et al. 2012). 
Owing to the change in stool colour with oral iron supplementation it is not possible to blind 
patients to the study group allocation and therefore the intervention will be compared to 
standard care rather than placebo. 
3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
3.1 
Primary objective 
 
To determine the feasibility of a phase IV open label, controlled multi-centre randomised trial 
of oral ferric maltol versus standard care postoperatively for colorectal cancer patients who 
have been treated with preoperative intravenous iron for anaemia. Feasibility measures will 
include: 
• 
Eligible patients from screening 
• 
Study exclusion 
• 
Acceptability of recruitment 
• 
Study retention 
 
3.2 
Secondary objectives 
 
• 
To investigate whether the use of ferric maltol could improve the postoperative quality of 
life of patients after colorectal cancer surgery compared to standard care. 

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• 
To calculate the change in postoperative haemoglobin and haematinics in response to 
ferric maltol compared to standard care. 
• 
To compare postoperative allogenic red blood cell transfusion rates in patients receiving 
ferric maltol or standard care 
• 
To review the tolerability of ferric maltol for the treatment of postoperative colorectal 
cancer patients 
• 
To compare length of stay and complication rates in patients receiving ferric maltol or 
standard care postoperatively. 
• 
To assess for immunological and metabolomic peri-operative differences between 
patients receiving ferric maltol preparations and standard care. 
 
3.3 
Outcome measures/endpoints 
 
3.3.1 Primary endpoint/outcome 
 
Study feasibility will be the primary endpoint. No a priori criteria will be used to determine 
study feasibility. We will use the data generated by PICoC to determine the sample size and 
outcome measures of a definitive trial 
 
3.3.2 Secondary endpoints/outcomes 
 
1. Levels of haemoglobin and haematinic markers (full blood count, ferritin, iron, transferrin, 
and transferrin saturation). Immunological and metabolomic markers will also be 
assessed. These will be measured at a point preoperatively before intravenous iron 
treatment, on the day of surgery and at defined time points postoperatively during the 
administration of oral ferric maltol or during standard care 
2. Side-effects and reactions to ferric maltol administration 
3. Peri- and post-operative morbidity and mortality 
4. Post-operative complications 

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5. Post-operative length of stay  
6. Post-operative allogenic blood transfusion. 
7. Quality of life as determined by the SF36, EQ-5D and FACT-An questionnaires. 
 
4 
TRIAL DESIGN 
 
This study will be a single centre, open labelled, randomised controlled trial comparing the 
effect of postoperative oral ferric maltol (intervention group) to standard care (control group), 
in patients with colorectal adenocarcinoma who have received pre-operative intravenous 
iron for anaemia. Each patient will be expected to participate for a period of 10 to 20 weeks, 
depending on the time between their diagnosis and the planned operation date. The 
participant will be recruited after the cancer MDT meeting confirming the diagnosis of 
colorectal adenocarcinoma and the ensuring that the patient is suitable for operative 
management. All study procedures will be undertaken at the time of existing hospital 
appointments where possible. 
Recruitment will take place following the explanation of the cancer diagnosis by the clinical 
team. The patients will be asked by a member of the clinical or research team to state 
whether they consent to being approached by the research team for further information 
regarding the study. If they agree, a face-to-face conversation or a phone call to the patient 
will be arranged to discuss the research. A letter of invitation to participate in the trial 
(accompanied by a patient information leaflet) will then be given or posted to the patients. 
The patient will be given adequate time to consider participation in the study and they will be 
given the opportunity to ask any questions they may have. Patients who are eligible will then 
be invited to consent to the study.  
After consenting to participate baseline data including demographics, past medical history 
and existing medications will be noted. Patients will be asked to complete the 3 quality of life 
questionnaires and they will have their blood taken including a full blood count, haematinics 

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(including iron, ferritin, transferrin and transferrin saturation) urea and electrolytes, liver 
function tests and erythropoietin. If the patients have consented to the optional sample sub-
study, the patients may be asked to give other samples of faeces, urine, saliva or sweat. 
Following this visit the patient will receive their preoperative intravenous iron infusion as is 
standard care. If they are taking any existing oral iron supplementation they will be asked to 
stop this treatment prior to receiving their preoperative intravenous iron. Once the surgical 
procedure has been performed, tissue samples from the resected bowel may be obtained for 
analysis. 
The participant is next reviewed when they are admitted on the morning of the operation. 
Blood tests and the quality of life questionnaires will be repeated. 
Preoperatively patients will undergo randomisation to one of the two study arms.  After 
operation the participants haemoglobin will be checked on day 2 of their recovery. If, at this 
point, postoperative anaemia is confirmed they will enter into their study arm. The 
intervention group will commence a course of oral ferric maltol provided oral intake has 
recommenced and the control group will receive standard care. All patients will have blood 
tests checked again at day 3 and day 5 postoperatively if they remain as an inpatient. If they 
are found to be anaemic on either of these two blood tests they will, at this stage, enter their 
allocated treatment pathway. If a patient shows no evidence of anaemia on either day 2, 3 or 
5 blood tests they will be withdrawn from the study. If the patients have consented to the 
optional sample sub-study, the patients may be asked to give other samples of faeces, 
urine, saliva or sweat at days 2, 3 or 5 along with the blood tests. Patients will continue 
treatment according to their randomisation allocation until 12 weeks after the operation, at 
which point the patient attends a routine surgical outpatient follow-up clinic. During the 
outpatient visit the participants will undergo their final blood and optional sample sub-study  
testing (if consented) as well as questionnaire completion. 

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The participants may only be required to attend the hospital for one extra visit to consent 
and where possible this will be arranged to coincide with existing appointments. The study is 
designed such that all other procedures are carried out when the participant attends for their 
routine visits as per the normal clinical pathway.  
 
 
5 
TRIAL SETTING 
 
The trial will initially run as a single center study in order to assess reproducibility and 
feasibility across different sites. The main host center will be The Royal Wolverhampton 
NHS Trust.  
6 
PARTICIPANT ELIGIBILITY CRITERIA 
 
 
6.1 
Inclusion criteria 
 
• 
Participant is willing and able to give informed consent for participation in the study. 
• 
Male or Female, aged 18+ years. 
• 
Diagnosed with histologically or radiologically diagnosed colorectal adenocarcinoma. 
• 
Anaemic at point of diagnosis of colorectal adenocarcinoma (Defined as haemoglobin 
10g/L below WHO criteria: 120g/L for males and 110g/L for females, to account for a 10% 
fluctuation in Hb)  
• 
Undergoing surgery for colorectal cancer with curative intent. 
• 
Date of planned surgery is ≥ 14 days from date of planned initiation of recruitment.  
• 
Able (in the investigators opinion) and willing to comply with all study requirements. 
• 
Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified 
of participation in the study. 
 
6.2 
Exclusion criteria 
 
• 
Patients with mental health issues or learning disabilities resulting in their inability to 
consent to the study 

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• 
Patients who do not have a histological diagnosis of colorectal adenocarcinoma 
• 
Female participants who are pregnant, lactating or planning a pregnancy during the 
course of the study. 
• 
Patients with evidence of iron overload or disturbances in utilisation of iron as stated in 
the product SPC. 
• 
Previous gastric, small bowel or colorectal surgery (where ≥50% of stomach or terminal 
ileum has been resected) 
• 
Chemotherapeutic treatment within the last 4 weeks. 
• 
Known previous anaemia not attributable to colorectal carcinoma (i.e. anaemia in patients 
with well established, inflammatory disorders) 
• 
Known haematological disease. 
• 
Features necessitating urgent surgery (e.g. obstructive symptoms). 
• 
Previous allergy to intravenous or oral iron or related iron products. 
• 
Patients who are unable to consent. 
• 
Any other significant disease or disorder which, in the opinion of the Investigator, may 
either put the participants at risk because of participation in the study, or may influence 
the result of the study, or the participant’s ability to participate in the study. 
• 
Participants who have participated in another research study involving an investigational 
product in the past 12 weeks 
• 
Confirmed liver or lung metastases 
 
7 
TRIAL PROCEDURES  
 
7.1 
Recruitment 
 
Identification of suitable subjects will occur via the surgical outpatient clinics and the 
colorectal cancer MDT meetings. This will be conducted by the clinical team, nurse 
specialists, research nurses and the clinical research fellow. Recruitment will take place 
following explanation of the cancer diagnosis and treatment plan by the clinical team. The 
patient will be aware of the diagnosis and the plan for surgery at the point of attendance. 
The patient will also be aware that they are anaemic. 
Initially the patient will be approached by a member of the clinical team. Following this the 
research team will explain the trial to the patient and provide them with a patient information 

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sheet. Alternatively, the patient may be sent the information sheet in the post by any of the 
relevant clinical or research teams. Following explanation of the trial the patient will be given 
adequate time to deliberate the information and ask questions. If the patient wishes to join 
the trial at that point, they will be invited to sign the informed consent form. Patients will be 
offered participation in the optional sample sub-study. After valid informed consent is given, 
the study procedures will commence at this visit and baseline assessments will be 
undertaken. The additional visits for intervention and follow up will then be planned.  
 
7.1.1 Participant identification 
 
All patients who attend the surgical outpatient clinic for a two-week wait appointment or who 
are found to have an abnormal lesion on lower gastrointestinal endoscopy or who are 
discussed at the colorectal cancer MDT will be screened for eligibility. As part of standard 
clinical practice all patients will have their haemoglobin level checked to determine if they 
are anaemic. Patients who are found to have an abnormal lesion will be discussed at the 
weekly colorectal cancer MDT meeting. Patients who are anaemic and who are diagnosed 
to have adenocarcinoma within the lower gastrointestinal tract will be identified at the MDT 
meeting. The research team will liaise with the colorectal nurse specialists who attend the 
MDT meetings. After the MDT meeting a patient will be called to clinic to inform them of the 
diagnosis, outcome and any plan for surgical management. In certain cases this clinic visit 
may be replaced by a phone call from a colorectal nurse specialists. 
Once the patients have been informed of their diagnosis and the management plan, a 
member of the clinical or research team will introduce the trial to the patient and 
subsequently the first discussion with the research team will take place. Eligibility will be 
confirmed by a medical practitioner. 
 
7.1.2 Screening 
 

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Screening will be undertaken using the results of existing investigations carried out as part of 
the normal colorectal cancer pathway as stated above. If a potentially eligible patient is 
identified by the screening process but is found to not have had a recent haemoglobin level 
checked within one month, then the research team will identify and refer this patient to the 
clinical team. The patient can then be advised to have their blood retested at their GP 
practice, or be provided with a blood form to undergo the testing in the hospital setting. This 
blood testing is part of standard pre-treatment clinical practice. 
 
7.1.3 Payment  
 
No payments or incentives will be given to study participants 
 
7.2 
Consent 
 
A named member of the clinical or research team, who are on the study’s delegation log, will 
take consent from the participant once they have ascertained that the patient fits the 
eligibility and inclusion criteria. 
It will be clearly stated that the participant is free to withdraw from the study or the optional 
sample sub-study at any time for any reason without prejudice to future care, and with no 
obligation to give the reason for withdrawal. The participant will be allowed as much time as 
wished to consider the information, and the opportunity to question the Investigator, their GP 
or other independent parties to decide whether they will participate in the study.  Written 
informed consent will then be obtained by means of participant dated signature and dated 
signature of the person who presented and obtained the informed consent. The person who 
obtained the consent will have been authorised to do so by the Chief/Principal Investigator. 
A copy of the signed informed consent will be given to the participants.  The original signed 
form will be retained at the study site. A copy of the signed informed consent will be placed 
in the participant’s medical notes.  
 

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7.3 
The Randomisation scheme 
 
Randomisation will be undertaken via an online platform in a 1:1 fashion to either the control 
group (standard care) or the intervention group (postoperative ferric maltol). The study will 
be an open label design and participants will be informed of their group allocation after their 
operation. Randomisation alerts with allocation details will be emailed to the CI, research 
fellow, research nurses and the pharmacy team. 
 
7.4 
Blinding 
 
Patient and investigator will not be blinded to the study treatment allocation due to the 
change in stool colour with oral iron intake. It is not possible to simulate this change with a 
placebo “dummy” drug for the control group.  
 
7.5 
Baseline data 
 
Following the consent process the following baseline data will be recorded 
• 
Demographics 
 Date of birth, gender, race, smoking status, alcohol intake, height and weight 
• 
Medical History 
History of any disease or surgical interventions including the relevant dates 
• 
Concomitant medication & drug allergies 
Dose, route, start date (and end date of medication if medication was stopped within 
the six weeks prior to recruitment) 
Start and end date of any iron supplements 
Compliance to medication 
• 
Laboratory tests 
Haematologic markers: Full blood count, iron, ferritin, transferrin, transferrin 
saturation, erythropoietin 
Inflammatory markers: C-reactive protein levels  

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Female participants of child-bearing age will undergo a urine pregnancy test, as is 
routine with patients undergoing surgery  
 
• 
Optional samples for sub-study 
Urine, stool, saliva and sweat samples may be taken for analyses  
 
• 
Questionnaires 
Quality of life score (using SF36, EQ-5D and FACT-An questionnaires) 
 
• 
Grip strength may be recorded 
 
 
7.7 
Trial assessments 
 
Following the consent process and baseline data collection the patient will attend for their 
preoperative iron infusion, as is routine care. They will then undergo the following trial 
assessments: 
Day of Surgery (on the morning of their operation.):  
• 
A brief interview will take place at the surgical pre-operative assessment ward 
to ascertain if the patient had any questions or if they experienced any side-effects in 
the intervening time. Any pre-operative blood transfusion will be noted. Information 
will be documented in the CRF.  
• 
Blood will be drawn for the following tests: Full blood count, C reactive 
protein, iron, ferritin, transferrin, transferrin saturation, and erythropoietin. 
• 
Optional sub-study urine, stool, saliva and sweat samples may be taken for analyses  
• 
Grip strength may be recorded 

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• 
The participant will be requested to complete Quality of Life (QoL) 
questionnaires SF36, EQ-5D and FACT- An questionnaires.  
Postoperatively they will be randomised to either the intervention group or the control 
group and the following assessments will be undertaken 
Day 2 postoperatively. 
• 
Information regarding the peri-operative period, intraoperative blood loss and any 
transfusion requirements will be documented in the CRF. 
• 
Blood will be drawn for the following tests: Full blood count, erythropoietin, C-reactive 
protein, iron, ferritin, transferrin, transferrin saturation. 
• 
Optional sub-study urine, stool, saliva and sweat samples may be taken for analyses 
• 
Grip strength may be recorded 
• 
At this point the Haemoglobin will be used to confirm postoperative anaemia (Hb 
<130g/L men, <120g/L women) allowing patients to commence their allocated 
treatment pathway according to randomisation.  
Day 3 postoperatively. 
• 
Blood will be drawn for the following tests: Full blood count, erythropoietin, C 
reactive protein, iron, ferritin, transferrin, transferrin saturation. 
• 
Optional sub-study urine, stool, saliva and sweat samples may be taken for analyses  
• 
Grip strength may be recorded 
Day 5 postoperatively (if remains an inpatient). 
• 
Blood will be drawn for the following tests: Full blood count. 
• 
Optional sub-study urine, stool, saliva and sweat samples may be taken for 
analyses 
• 
Grip strength may be recorded 

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Entry into postoperative treatment pathway 
 If a patient is found to be not anaemic on day 2 postoperatively (Hb ≥130g/L men, ≥120g/L 
women) they will complete screening and remain in the study but will not enter their 
allocated treatment pathway (i.e ferric maltol or standard care). If they remain anaemic on 
day 3 or day 5 blood tests they will, at this stage, enter their allocated treatment pathway. If 
patients have a normal haemoglobin on days 2, 3 or 5 they will be withdrawn from the study.  
 
Outpatient Follow Up 
Finally, after discharge the patient will be seen in their first outpatient clinic at 8-12 weeks 
postoperatively. Where follow up occurs earlier, for example, due to the clinician’s normal 
practice or due to a complication, then the usual 8-12 week outpatient visit will still be used. 
At this visit the following assessments will be undertaken 
• 
Information regarding postoperative complications, the length of hospital stay and 
readmissions to hospital will be documented in the CRF 
• 
Any postoperative transfusion requirements will be documented in the CRF. 
• 
Blood will be drawn for the following tests: Full blood count, erythropoietin, C-reactive 
protein, iron, ferritin, transferrin, transferrin saturation 
• 
Optional sub-study urine, stool, saliva and sweat samples may be taken for analyses 
• 
Grip strength may be recorded 
• 
The participant will be requested to complete Quality of Life questionnaires: SF36, 
EQ-5D and FACT- An questionnaires.  
 
7.8 
Withdrawal criteria 
  
There will be intention-to-treat analyses carried out. Analysis of all participants who have 
been randomised will be undertaken regardless of withdrawal. The reason for withdrawal will 

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be recorded in the CRF.  Each participant has the right to withdraw study at any time. A 
participant will be withdrawn from the study if any of the following occurs: 
• 
Absence of anaemia on postoperative days 2, 3 and 5. 
• 
Pregnancy 
• 
Ineligibility (either arising during the study or retrospective having been inadvertently 
overlooked at screening) 
• 
Significant protocol deviation as defined by the CI 
• 
An adverse event which requires discontinuation of the study medication or results in 
inability to continue to comply with study procedures 
• 
Disease progression which requires discontinuation of the study medication or results in 
inability to continue to comply with study procedures 
• 
Patients who do not undergo an operation as a result of a change in fitness for surgery 
will be excluded. 
• 
Consent withdrawn. 
• 
Lost to follow up 
 
7.9 
Collection, storage and analysis of clinical samples 
 
All blood samples will be taken and delivered immediately for process in a CPA NHS 
laboratory at the individual study site. Processing of blood samples will follow the NHS 
laboratory protocols in keeping with Good Laboratory Practice. If consented for the optional 
sample sub-study, samples will be stored within the research secure repository within the 
trust in keeping with standard research protocols.  
Please refer to the laboratory manual for details of sample collection, storage and 
destruction protocols.  
Sampling methods include: 
Faecal and blood samples will be collected at base line and days 2, 3, 5 and 12 
postoperatively. Surgical resections will be collected at time of surgery.  
1. Faecal samples will be collected in universal tubes 2-3 tubes per patient and put on ice 
until transferred to -80 freezer. 
2. Serum will be prepared from the blood samples as follows: 

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Collect blood in a sterile 15 ml test tube or a plastic vacutainer containing no anticoagulants. 
Incubate tubes in an upright position at room temperature for 30-45 minutes (no longer than 
60 minutes). This will allow enough time for the blood to clot. 
If using vacutainers with clot activators such as the BD Vacutainer Plus Plastic Serum Tube 
(red top), invert carefully 5 times before incubation. 
Centrifuge tubes at 1500 x g for 10 minutes with the break OFF. 
Use Pasteur pipette to carefully transfer equal amount of the supernatant into two cryotubes 
without disturbing the cloudy cell layer below the supernatant (10 ml of whole blood 
produces 4-6 ml of serum).   
Immediately store tubes in -80 freezer. 
Serum samples will be tested for chemokines and inflammatory markers by Multiplex 
immune assays. 
 
3. Surgical resections will be collected in 2ml tubes on ice (preferably liquid nitrogen or dry 
ice) and immediately frozen in -80 freezer. 
Tissue resections will be used to determine the expression of immune cells and their 
activation markers as well as proliferation and apoptotic markers using immunofluorescence 
microscopy.  Resections will also be used to study the microbiome using 16s-rRNA gene 
sequencing and taxonomic analysis to determine changes in probiotic and pathogenic 
bacterial populations. 
 
4. Paraffin embedded sections will be collected from the pathology archives at a later date.  
Paraffin embedded sections may also be used to determine the expression of inflammatory 
markers using immunohistochemistry.   
 
 
7.10 End of trial 
 
The end of trial will be defined as the date of the last study visit of the last patient undergoing 
the trial. The sponsor will notify the MHRA of the end of the trial within 90 days of its 
completion. 
 
8 
TRIAL TREATMENTS 
 
8.1 
Name and description of the medicinal product 
 

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The study intervention treatment is oral ferric maltol (Feraccru®). The recommended dose is 
one 30mg capsule twice daily, morning and evening, on an empty stomach. Feraccru is 
indicated in adults for the treatment of iron deficiency. No dose adjustment is needed in 
elderly patients or patients with renal impairment (eGFR ≥15 ml/min/1.73 m2). The control 
group will receive standard care only. Any treatments will be at the discretion of the patient’s 
usual clinical team. The study treatments will be randomly allocated in a 1:1 fashion but 
there will be no blinding of the treatment 
 
8.2 
Regulatory status of the drug 
 
The marketing authorisation holder for Feraccru is Norgine B.V. Amsterdam, Netherlands 
(MA number EU/1/15/1075/001) 
8.3 
Product Characteristics 
 
The Summary of Product Characteristics will be used to inform the clinical management of 
ferric maltol. Accessed via https://www.medicines.org.uk/emc/product/2083/smpc. 
 
8.4 
Drug storage and supply 
  
The drug will be stored in Trials Pharmacies at each study site. At all sites the drug will be 
stored in a temperature-controlled room below 25oC. The study drug will be donated by 
Norgine Ltd. 
 
8.5 
Dosage schedules 
 
Participants in the intervention arm will take one 30mg capsule twice daily, morning and 
evening, on an empty stomach. Treatment will commence as soon as postoperative anaemia is 
confirmed on day 2, 3 or 5 blood tests provided oral intake has been resumed and will continue 
until the first routine outpatient visit. If a dose is missed the subject will be allowed to take their 
missed dose within 6 hours of the correct time. If there is any interruption to treatment, for 

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example due to vomiting or illness, the patient will be asked to recommence treatment as soon 
as they are deemed safe to do so by a medical practitioner. 
 
8.6 
Known drug reactions and interaction with other therapies 
 
Oral iron is known to reduce the absorption of penicillamine, bisphosphonates, ciprofloxacin, 
entacapone, levodopa, levofloxacin, levothyroxine (thyroxine) moxifloxacin, mycophenolate, 
norfloxacin and ofloxacin. If applicable, these medicinal products will be given at least 2 
hours apart from Feraccru. Absorption of both iron and antibiotic may be reduced if oral iron 
is given with tetracycline. Administration of Feraccru and tetracyclines will be separated by 2 
to 3 hours. Absorption of oral iron may also be reduced by calcium and magnesium salts 
(such as magnesium trisilicate). Administration of Feraccru with such compounds will be 
separated by at least 2 hours. 
 
8.7 
Concomitant medication 
 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care. Any medication, other 
than the study medication, taken during the trial will be recorded in the CRF. Participants 
who are on existing oral iron supplementation at time of recruitment to the trial will stop 
taking this as prescribed for the duration of the study and after discussion with the patient. 
 
8.8 
Assessment of compliance with treatment 
  
Participants will self-administer the oral ferric maltose tablets. Patients will be asked to 
declare their compliance with the study drug during the final follow up study visit. If there is a 
high level of non-compliance (<70%), the patient will be included in the trial under the 
intention-to-treat-analysis. The reasons for non-compliance will be documented in the CRF. 
 

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9 
PHARMACOVIGILANCE 
 
9.1 
Definitions 
 
9.1.1 Adverse Event (AE) 
 
An AE or adverse experience is: 
Any untoward medical occurrence in a patient or clinical investigation in participants 
administered a medicinal product, which does not necessarily have to have a causal 
relationship with this treatment (the study medication). 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of the study 
medication, whether or not considered related to the study medication. 
 
9.1.2 Adverse Reaction (AR) 
 
All untoward and unintended responses to a medicinal product related to any dose. 
The phrase "responses to medicinal products" means that a causal relationship between a 
study medication and an AE is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out. All cases judged by either the reporting medically qualified professional or the 
sponsor as having a reasonable suspected causal relationship to the study medication qualify 
as adverse reactions. 
 
 
9.1.3 Severe Adverse Events 
 
To ensure no confusion or misunderstanding of the difference between the terms "serious" and 
"severe", which are not synonymous, the following note of clarification is provided: 
The term "severe" is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This is not the same as "serious," which 

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is based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a participant's life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
 
9.1.4 Serious Adverse Event or Serious Adverse Reaction 
 
A serious adverse event or reaction is any untoward medical occurrence that at any dose: 
 
• 
Results in death, 
 
• 
Is life-threatening, 
  
 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 
• 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation, 
 
• 
Results in persistent or significant disability/incapacity, or 
 
• 
Is a congenital anomaly/birth defect. 
 
• 
Other important medical events* 
 
*Other events that may not result in death, are not life threatening, or do not require 
hospitalisation, may be considered a serious adverse event when, based upon appropriate 
medical judgement, the event may jeopardise the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
9.1.5 Expected Serious Adverse Events/Reactions 
 
Serious adverse events that could be expected during the course of the study according to the 
SmPC include vomiting, hematemesis, gastrointestinal perforation, abdominal pain and 
dysphagia which could be related to the progression of the disease. Adverse events may also 
be anticipated in relation to any postoperative chemotherapy used. These would include 
anaemia, neutropenia (and consequences of sepsis), thrombocytopenia (and consequences or 

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coagulopathy), rashes, photosensitivity, taste/hearing disturbance, hair loss, discoloured urine, 
diarrhoea, oral ulceration and renal failure. These adverse events will be recorded in the CRF 
as significant clinical events. 
Events which are not deemed secondary to the underlying cancer will be reported to the 
sponsor as a Serious Adverse Event within 24 hours of the Investigator becoming aware of the 
event. 
 
 
9.1.6 Suspected Unexpected Serious Adverse Reactions 
 
A serious adverse reaction, the nature or severity of which is not consistent with the applicable 
product information as stated in the reference safety information in the SmPC that follows: 
Common symptoms: “Abdominal pain (including upper abdomen), Flatulence, Constipation, 
Abdominal discomfort/ distension, Diarrhoea, Discoloured faeces, Nausea” 
 
9.2 
Recording and reporting of SAEs, SARs AND SUSARs  
 
All AEs occurring during the study observed by the investigator or reported by the participant, 
whether or not attributed to study medication, will be recorded on the CRF. These adverse 
events will be recorded in the CRF. All SAEs assigned by the PI or delegate (or following 
central review) as both suspected to be related to IMP-treatment and unexpected will be 
classified as SUSARs and will be subject to expedited reporting to the Medicines and 
Healthcare Products Regulatory Agency (MHRA). The sponsor will inform the MHRA, the REC 
and Marketing Authorisation Holder (if not the sponsor) of SUSARs within the required 
expedited reporting timescales. All related AEs that result in a participant’s withdrawal from the 
study or are present at the end of the study, will be followed up until a satisfactory resolution 
occurs. 
 
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to require the participant’s removal from treatment. A participant may also voluntarily withdraw 
from treatment due to what he or she perceives as an intolerable AE. If either of these occurs, 
the participant will undergo an end of study assessment and be given appropriate care under 
medical supervision until symptoms cease or the condition becomes stable. 
 
The severity of events will be assessed according to the Common Terminology Criteria for 
Adverse Events (CTCEA V 5.0) the following scale:  
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
• 
Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age 
appropriate instrumental ADL.  
• 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL.  
• 
Grade 4 Life-threatening consequences; urgent intervention indicated.  
• 
Grade 5 Death related to AE 
 
The relationship of AEs to the study medication will be assessed by a medically qualified 
investigator. Any pregnancy occurring during the clinical study and the outcome of the 
pregnancy, will be recorded and followed up for congenital abnormality or birth defect. 
 
9.3 
Responsibilities 
 
 Principal Investigator (PI):  
Checking for AEs and ARs when participants attend for treatment / follow-up. 
1. Using medical judgement in assigning seriousness, causality and whether the 
event/reaction was anticipated using the Reference Safety Information 
approved for the trial. 
2. Ensuring that all SAEs are recorded and reported to the sponsor within 24 
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as soon as available. Ensuring that SAEs are chased with the sponsor if a 
record of receipt is not received within 2 working days of initial reporting.  
3. Ensuring that AEs and ARs are recorded and reported to the sponsor in line 
with the requirements of the protocol.  
 
 
 
Chief Investigator (CI) / delegate or independent clinical reviewer: 
1. Clinical oversight of the safety of patients participating in the trial, including an 
ongoing review of the risk / benefit. 
2. Using medical judgement in assigning the SAEs seriousness, causality and 
whether the event was anticipated (in line with the Reference Safety 
Information) where it has not been possible to obtain local medical 
assessment. 
3. Immediate review of all SUSARs.  
4. Review of specific SAEs and SARs in accordance with the trial risk 
assessment and protocol as detailed in the Trial Monitoring Plan. 
5. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body 
System coding to all SAEs and SARs. 
6. Preparing the clinical sections and final sign off of the Development Safety 
Update Report (DSUR). 
Sponsor: (NB where relevant these can be delegated to CI) 
1. Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs 
according to the trial protocol onto a database.  

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2. Reporting safety information to the CI, delegate or independent clinical 
reviewer for the ongoing assessment of the risk / benefit according to the Trial 
Monitoring Plan. 
3. Reporting safety information to the independent oversight committees 
identified for the trial (Data Monitoring Committee (DMC) and / or Trial Steering 
Committee (TSC)) according to the Trial Monitoring Plan. 
4. Expedited reporting of SUSARs to the Competent Authority (MHRA in UK) and 
REC within required timelines. 
5. Notifying Investigators of SUSARs that occur within the trial. 
6. Checking for (annually) and notifying PIs of updates to the Reference Safety 
Information for the trial. 
7. Preparing standard tables and other relevant information for the DSUR in 
collaboration with the CI and ensuring timely submission to the MHRA and 
REC. 
 
Trial Steering Committee (TSC):  
In accordance with the Trial Terms of Reference for the TSC, periodically reviewing 
safety data and liaising with the DMC regarding safety issues. 
 
Data Monitoring Committee (DMC) 
In accordance with the Trial Terms of Reference for the DMC, periodically reviewing 
overall safety data to determine patterns and trends of events, or to identify safety 
issues, which would not be apparent on an individual case basis. Mr Graham 
Williams, Consultant Colorectal Surgeon, will lead the DMC. 
 

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9.4 
Notification of Deaths 
 
All deaths will be reported to the sponsor irrespective of whether the death is related to 
disease progression, the IMP, or an unrelated event. This report will be issued within 24 
hours of the study team being notified of the death. 
 
Reporting urgent safety measures 
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event 
no later than 3 days from the date the measures are taken, give written notice to the MHRA 
and the relevant REC of the measures taken and the circumstances giving rise to those 
measures. 
 
9.5 Development safety update reports 
 
The CI will provide DSURs once a year throughout the clinical trial, or as necessary, to the 
Competent Authority (MHRA in the UK), where relevant the Research Ethics Committee and 
the sponsor.  The report will be submitted within 60 days of the Developmental International 
Birth Date (DIBD) of the trial each year until the trial is declared ended 
 
10 STATISTICS AND DATA ANALYSIS 
 
10.1 Sample size calculation 
 
No sample size calculation will be performed for this feasibility study. We will recruit a total of 40 
patients to this trial (20 per arm), based on literature and guidance that 30 or more patients 
would be sufficient to estimate a parameter (Lancaster, Dodd et al. 2004) 
 
10.2 Statistical analysis plan 
 
As this is a feasibility study, a descriptive analysis will be performed on the data. 
Numbers and percentages will be presented for categorical data, mean and 
standard deviations for normally distributed continuous data, and median and inter-

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quartile ranges for skewed data. Change in the outcome measures for the secondary 
objectives will also be presented between the intervention and control groups. 
Further, data will also be used to help determine an adequate sample size for a 
larger study, and also prediction of a likely duration that recruitment will be needed 
for this to take place. The level of statistical significance to be used is p<0.05. 
 
10.3.2 Primary outcome analysis 
 
The primary objective will be assessed using feasibility outcomes measures. This will include 
the number of eligible patients (pre-screening eligibility), willingness to be recruited to study 
(acceptability), willingness to be randomised (acceptability/concordance), study exclusion 
(screen failure rates), withdrawal of patients (non-concordance), compliance with the 
randomised treatment, study retention (retention rates), number of patients recruited over a 
given time (recruitment rate), and completion of outcome measures. 
 
10.3.3 Secondary outcome analysis 
 
Outcomes for the secondary objectives include evaluation of transfusion rates, change in 
blood indices and change, quality of life. The median change in transfusion rates and 
haemoglobin will be reported. Quality of life will be reported as change from baseline and 
assessed for minimal clinically important difference. 
 
10.4 Interim analysis and criteria for the premature termination of the trial 
 
The trial will be terminated if there is an unacceptable number of SUSARs or SARs. Any interim 
data analysis will be performed at the request of the DMC. 
 
10.5 Procedure to account for missing or spurious data 
  
All attempts will be made to avoid and to recover any missing data. In the event of missing 
data being unrecoverable, a repeat sample may be taken in the case of a blood test. If this is 

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not possible (e.g. due to interventions being commenced), the participant will be excluded 
from the trial. Any unused or spurious data will be recorded in the CRF in the section for 
additional information. 
  
11 
DATA MANAGEMENT 
 
 
11.1 Data collection tools and source document identification 
 
Source documents will include the hospital records, drug charts, fluid balance 
charts, blood test reports and computer record of any blood transfusion. In this 
study, the CRF will be used as the source document for any correspondence with 
the patient, height, weight and blood pressure measurements. 
All 
study 
documentation will have the official letterhead of the centre on correspondence. 
All documents will be stored safely in confidential conditions. On all study-specific 
documents, other than the signed consent, the participant will be referred to by the 
study participant number/code, not by name. 
 
11.2 Data handling and record keeping 
 
All study data will be entered onto the CRF and subsequently entered onto a 
password protected database that will be saved on an NHS computer. A password 
protected back-up copy of the database will be saved on the Chief Investigator’s 
computer. The participants will be identified by a study specific participants number 
and/or code in any database. The name and any other identifying detail will NOT 
be included in any study data electronic file. 
 
11.3 Access to Data 
 

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Direct access to data will be granted to authorised representatives from the Sponsor, host 
institution and the regulatory authorities to permit trial-related monitoring, audits and 
inspections- in line with participant consent. 
 
11.4 Archiving 
 
As soon as practicably possible after the completion of the study the Sponsor will give 
permission to the Investigator site to archive their essential documentation. The site will be 
required to archive their documentation for at 5 years after completion of the study, and no 
study documentation will be destroyed without prior written agreement between the Sponsor 
and the Investigator. Should the Investigator wish to assign the study records to another 
party or move them to another location written agreement must be obtained from the 
sponsor. Likewise, the sponsor will archive its study documentation for 5 years. All 
documents will be stored in such a way that they can be accessed at a later date. 
Consideration will be given to security and environmental risks. 
 
 
12  
MONITORING, AUDIT & INSPECTION 
 
The research sponsor will ensure that arrangements and systems are in place for the 
management and monitoring of research. The arrangements for monitoring and auditing the 
conduct of the study will reflect the allocation of responsibilities set out in the Research 
Governance Framework. As this is a CTIMP, sponsors and investigators will fulfil statutory 
obligations relating to pharmacovigilance under Part 5 of the Medicines for Human Use 
(Clinical Trials) Regulations 2004. A Trial Monitoring plan will be developed and agreed by 
the Sponsor. This will be informed by a Trial Risk Assessment which will consider the safety 
or physical or mental integrity of the trial participants and the scientific value of the research 
(including the potential risk associated with the implementation of the intervention and 

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recruitment which can, if not monitored and mitigated, affect the integrity and smooth 
running of this trial). This monitoring plan will detail the timing and content of reports to 
monitor trial conduct and implementation and adherence with the Consolidated Standards of 
Reporting Trials (CONSORT). This monitoring plan may also include site monitoring. 
 
13 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
13.1 Research Ethics Committee (REC) review & reports 
 
The Investigators will ensure that this study is conducted in full conformity with the 
current revision of the Declaration of Helsinki (last amended October 2000, with 
additional footnotes added 2002 and 2004). The Investigator will ensure that this 
study is conducted in full conformity with relevant regulations and with the ICH 
Guidelines for Good Clinical Practice (CPMP/ICH/135/95) July 1996.The protocol, 
informed consent form, participant information sheet and any proposed advertising 
material will be submitted to the HRA, an appropriate Research Ethics 
Committee (REC), regulatory authorities (MHRA in the UK), and host institution(s) for 
written approval. The Investigator will submit and, where necessary, obtain approval 
from the above parties for all substantial amendments to the original approved 
documents. 
 
13.2 Regulatory Compliance 
  
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from the MHRA 
and Favourable REC opinion. The protocol and trial conduct will comply with the Medicines for 
Human Use (Clinical Trials) Regulations 2004 and any relevant amendments 
Before any site can enrol patients into the study, the Chief Investigator/Principal Investigator 
or designee will ensure that appropriate approvals from participating organisations are in 

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place. For any amendment to the study, the Chief Investigator or designee, in agreement 
with the sponsor will submit information to the appropriate body in order for them to issue 
approval for the amendment. The Chief Investigator or designee will work with sites (R&D 
departments at NHS sites as well as the study delivery team) so they can put the necessary 
arrangements in place to implement the amendment to confirm their support for the study as 
amended. 
 
13.3 Protocol compliance 
  
Protocol non-compliances will be defined as departures from the approved protocol. 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK 
regulations on Clinical Trials and must not be used e.g. it is not acceptable to enrol a 
participant if they do not meet the eligibility criteria or restrictions specified in the trial 
protocol. Accidental protocol deviations will be adequately documented on the relevant 
protocol deviation form and reported to the Chief Investigator and Sponsor immediately. 
Deviations from the protocol which are found to frequently recur are not acceptable, will 
require immediate action and could potentially be classified as a serious breach. 
 
 
13.4 Notification of Serious Breaches to GCP and/or the protocol 
  
A “serious breach” is a breach which is likely to effect to a significant degree – 
a. the safety or physical or mental integrity of the participants of the trial; or 
b. the scientific value of the trial 
In the event of a serious breach the sponsor will be notified immediately of any case where 
the above definition applies during the trial conduct phase. In addition, the sponsor will notify 
the licensing authority in writing of any serious breach of 

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(a) the conditions and principles of GCP in connection with that trial; or  
(b) the protocol relating to that trial, as amended from time to time, within 7 days 
of becoming aware of that breach 
 
13.5 Data protection and patient confidentiality 
  
The trial staff will ensure that the participants’ anonymity is maintained. The 
participants will be identified only by initials and a participants ID number on the 
CRF and any electronic database. All documents will be stored securely and only 
accessible by trial staff and authorised personnel. The study will comply with the 
Data Protection Act 2018 which requires data to be anonymised as soon as it is 
practical to do so. 
 
 
13.6 Indemnity 
 
This is an NHS-sponsored research study. For NHS sponsored research HSG (96)48 
reference no. 2 refers. If there is negligent harm during the clinical trial when the NHS body 
owes a duty of care to the person harmed, NHS Indemnity covers NHS staff, medical 
academic staff with honorary contracts, and those conducting the study. NHS Indemnity 
does not offer no-fault compensation and is unable to agree in advance to pay 
compensation for non-negligent harm.  
 
13.7 Amendments  
 
A request for a substantial amendment to the CTA or the documents that supported the original 
application for the CTA, will be submitted via a valid notice of amendment to the licencing 
authority (MHRA) for consideration. To request a substantial amendment to the REC 
application or the supporting documents, a valid notice of amendment will be submitted to the 
REC for consideration. The MHRA and/or the REC will provide a response regarding the 

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Perioperative Iron for Colorectal Cancer 
 
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amendment within 35 days of receipt of the notice. The sponsor and study team will make the 
decision to amend the protocol and will decide whether an amendment is substantial or non-
substantial. Any amendments will be tracked to identify the most recent protocol version. 
 
13.8 Access to the final trial dataset 
 
Direct access will be granted to authorised representatives from the sponsor, host institution 
and the regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
14  
DISSEMINIATION POLICY 
 
The results will be published in a scientific journal that is peer-reviewed and the 
paper will be reviewed and approved by all the investigators prior to submission 
for publication.  
 
15 
REFERENCES 
 
Acheson, A. G., M. J. Brookes and D. R. Spahn (2012). "Effects of allogeneic red blood cell 
transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a 
systematic review and meta-analysis." Ann Surg 256(2): 235-244. 
 
Amato, A. and M. Pescatori (2006). "Perioperative blood transfusions and recurrence of 
colorectal cancer." Cochrane Database of Systematic Reviews(1). 
 
Bisbe E, Moltó L, Arroyo R, Muniesa JM, Tejero M. Randomized trial comparing ferric 
carboxymaltose vs oral ferrous glycine sulphate for postoperative anaemia after total knee 
arthroplasty. Br J Anaesth. 2014;113(3):402-409. 
 
Gasche, C., T. Ahmad, Z. Tulassay, D. C. Baumgart, B. Bokemeyer, C. Büning, S. Howaldt 
and A. Stallmach (2014). "Ferric Maltol Is Effective in Correcting Iron Deficiency Anemia in 
Patients with Inflammatory Bowel Disease: Results from a Phase-3 Clinical Trial Program." 
Inflammatory Bowel Diseases 21(3): 579-588. 
 
Keeler, B. D., J. A. Simpson, O. Ng, H. Padmanabhan, M. J. Brookes and A. G. Acheson 
(2017). "Randomized clinical trial of preoperative oral versus intravenous iron in anaemic 
patients with colorectal cancer." Br J Surg 104(3): 214-221. 
 

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Lancaster, G. A., S. Dodd and P. R. Williamson (2004). "Design and analysis of pilot studies: 
recommendations for good practice." J Eval Clin Pract 10(2): 307-312. 
 
Leichtle, S. W., N. J. Mouawad, R. Lampman, B. Singal and R. K. Cleary (2011). "Does 
Preoperative Anemia Adversely Affect Colon and Rectal Surgery Outcomes?" Journal of the 
American College of Surgeons 212(2): 187-194. 
 
Levey, J. A., M. A. Barrand, B. A. Callingham and R. C. Hider (1988). "Characteristics of 
iron(III) uptake by isolated fragments of rat small intestine in the presence of the 
hydroxypyrones, maltol and ethyl maltol." Biochem Pharmacol 37(10): 2051-2057. 
 
Muñoz, M., A. G. Acheson, E. Bisbe, A. Butcher, S. Gómez-Ramírez, A. A. Khalafallah, H. 
Kehlet, S. Kietaibl, G. M. Liumbruno, P. Meybohm, R. Rao Baikady, A. Shander, C. So-
Osman, D. R. Spahn and A. A. Klein (2018). "An international consensus statement on the 
management of postoperative anaemia after major surgical procedures." Anaesthesia 
73(11): 1418-1431. 
 
Shander, A., K. Knight, R. Thurer, J. Adamson and R. Spence (2004). "Prevalence and 
outcomes of anemia in surgery: a systematic review of the literature." The American Journal 
of Medicine 116(7, Supplement 1): 58-69. 
 
 
 

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16.  APPENDICIES 
 
16.1  Appendix 1 – Schedule of Procedures 
 
Procedures 
Screening Baseline Treatment Phase 
Follow Up 
 
Visit 1 
Visit 2 
Visit 3    
Day of 
surgery    
Visit 4 
Day2 
Visit 5 
Day 3 
Visit 6 
Day 5 
Vist 7 
8-12 weeks 
Screening 
X 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Concomitant medications 
 
X 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
 
Randomisation 
 
 
X 
 
 
 
 
Dispensing of trial drugs 
 
 
 
(X) 
(X) 
(X) 
 
Blood Sample 
 
X 
X 
X 
X 
X 
X 
Urine Sample* 
 
X 
X 
X 
X 
X 
X 
Tumour Sample 
 
 
X 
 
 
 
 
Paraffin embedded 
sections 
 
 
 
 
 
 
X at a later 
date 
Faeces/stool sample* 
 
X 
X 
X 
X 
X 
X 
Saliva sample* 
 
X 
X 
X 
X 
X 
X 
Sweat sample* 
 
X 
X 
X 
X 
X 
X 
QoL questionnaire 
completion 
 
X 
X 
 
 
 
X 
Grip Strength 
 
 
X 
X 
X 
X 
X 
Adverse event 
assessments  
 
X 
X 
X 
X 
X 
X 
CRF Data collection 
 
X 
X 
X 
X 
X 
X 
Physician’s Withdrawal 
Checklist 
 
X 
X 
X 
X 
X 
X 
*If consented for sample sub-study. 
 

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16.2 
Appendix 2 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
n/a 
 
 
 
 
 
Protocol amendments must be submitted to the Sponsor for approval prior to submission to 
the REC committee or MHRA. 
 
16.3 Appendix 3 - Study Questionnaires 
 
Provided separately