A Randomised Placebo-controlled Phase III Trial of the Effect of the Omega-3 Fatty Acid Eicosapentaenoic Acid (EPA) on Colorectal Cancer Recurrence and Survival After Surgery for Resectable Liver Metastases
Phase: PHASE3
Conditions: Liver Metastasis, Colon Cancer
Sponsor: Mark A Hull, PhD FRCP

 
EMT2 version 9.0, 27th July 2022 
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EMT2:  
EPA for Metastasis Trial 2 
A randomised placebo-controlled phase III trial of the effect of the omega-3 fatty acid 
eicosapentaenoic acid (EPA) on colorectal cancer recurrence and survival after surgery for 
resectable liver metastases 
 
 
ClinicalTrials.gov: NCT032428477 
EudraCT Number: 2016-000628-24 
 
 
 
Sponsor:  
  University of Leeds  
 
Sponsor id:   
MO16/053 
 
IRAS id: 
 
199321 
 
Funded by:  
  Yorkshire Cancer Research  
 
 
 
Chief Investigator:  Professor Mark Hull 
 
 
 
Professor of Molecular Gastroenterology 
 
 
 
Leeds Institute of Biomedical & Clinical Sciences 
 
 
 
Wellcome Trust Brenner Building 
 
 
 
St James’s University Hospital 
 
 
 
Leeds, LS9 7TF 
 
 
 
Tel: 0113 343 8650 
 
 
 
Email: m.a.hull@leeds.ac.uk 
 
 
 
The Sponsor and Clinical Trials Research Unit (CTRU) accept no responsibility for the 
accuracy of content reproduced from this protocol and incorporated into additional 
documentation developed by collaborating or third party organisations. 
 
 
 
 

 
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1. Key Contacts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General enquiries 
emt2@leeds.ac.uk 
Chief Investigator 
Professor Mark Hull 
Professor of Molecular Gastroenterology,  
University of Leeds  
Honorary Consultant Gastroenterologist,  
Leeds Teaching Hospitals NHS Trust 
 
 
Tel: 0113 343 8650 
Email: m.a.hull@leeds.ac.uk  
CTRU Scientific Lead/Safety statistician 
Dr David Cairns 
Associate Professor of Statistics in Late-phase Clinical Trials 
Clinical Trials Research Unit  
University of Leeds 
 
 
Tel: 0113 343 1712  
Email: D.A.Cairns@leeds.ac.uk   
CTRU Trial Statistician 
Ms Pei Loo Ow 
Medical Statistician 
Clinical Trials Research Unit 
University of Leeds 
 
 
Tel: 0113 343 5476 
Email: P.L.Ow@leeds.ac.uk 
CTRU Delivery Lead 
Miss Alexandra Smith 
Head of Trial Management 
Clinical Trials Research Unit 
University of Leeds 
 
 
Tel: 0113 343 2657 
Email: a.f.smith@leeds.ac.uk 
 
CTRU Clinical Advisor 
Dr Fiona Collinson 
Deputy Director (Cancer) Leeds Institute of Clinical Trials 
Research 
Clinical Trials Research Unit 
University of Leeds 
 
Tel: 0113 343 9126 
Email: f.j.collinson@leeds.ac.uk 
 
General Enquiries:  
Email: emt2@leeds.ac.uk    
 
Registration/Randomisation: Tel: 0113 343 2290 
 
                                                   https://lictr.leeds.ac.uk/webrand/ 
 
Pharmacovigilance: Tel: 0113 343 1486 
                                   Fax: 0113 343 0686 
 
Emergency Unblinding : Tel: 0113 343 4930 
(during office hours) 

 
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Trial and Data Management (for queries regarding trial site set up, regulatory and governance 
queries, eligibility, treatment, CRF and data query completion, safety reporting and randomisation 
processes) 
Mrs Sharon Ruddock 
Senior Trial Co-ordinator 
Clinical Trials Research Unit 
University of Leeds 
 
 
Tel: 0113 343  7903 
Email: s.p.ruddock@leeds.ac.uk  
Mrs Simone Ryan 
Trial Coordinator/Data Manager 
Clinical Trials Research Unit 
University of Leeds 
 
Tel: 0113 343  2812 
Email: S.Ryan@leeds.ac.uk 
Health Economics 
 
Dr Peter Hall 
Visiting Associate Professor of Health Economics 
Academic Unit of Health Economics 
University of Leeds 
 
Tel: 0131 651 8510 
Email: p.s.hall@ed.ac.uk 
Laboratory studies 
Professor Paul Loadman 
Professor of Cancer Pharmacology 
Institute of Cancer Therapeutics 
University of Bradford 
 
Tel: 01274 233228 
Fax: 01274 233234 
Email: 
p.m.loadman@bradford.ac.uk 
Ms Amanda Race 
Research Assistant 
Institute of Cancer Therapeutics 
University of Bradford 
 
Tel: 01274 235841  
Email: a.d.race@bradford.ac.uk 
Dr Tim Brend 
Biobanking Coordinator 
Leeds Institute of Medical Research 
St James’s University Hospital 
University of Leeds  
Tel: 0113 343 8509 
E-mail: T. Brend@leeds.ac.uk 
Safety Reporting  
Tel: 0113 343 1486 
Fax: 0113 343 0686 
 
Registration/Randomisation/Replenishment/Replacement 
Direct line for 24 hour registration/ 
randomisation/replenishment: 
0113 343 2290  
or by the web 
https://lictr.leeds.ac.uk/webrand/ 
 
Emergency Unblinding  
(during office hours only) 
Tel: 0113 343 4930 
 
 
 

 
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2. Contents 
1. 
Key Contacts .................................................................................................................................... 2 
2. 
Contents .......................................................................................................................................... 4 
3. 
Trial Summary ................................................................................................................................. 8 
4. 
Trial Schema .................................................................................................................................. 11 
5. 
Abbreviations and Glossary .......................................................................................................... 13 
6. 
Background ................................................................................................................................... 15 
6.1 
Colorectal cancer and liver metastasis ................................................................................. 15 
6.2 
Omega-3 fatty acids .............................................................................................................. 15 
6.2.1 Evidence that EPA has anti-CRC activity .............................................................................. 17 
6.2.2 
Mechanisms of the anti-neoplastic activity of O3FAs................................................... 18 
6.2.3 
Interaction of EPA with other CRC treatment modalities ............................................. 19 
6.3 
O3FAs and cancer cachexia ................................................................................................... 19 
6.4 
Safety and tolerability of EPA treatment .............................................................................. 19 
6.5 
The IMP in EMT2 ................................................................................................................... 20 
6.6 
Rationale for the trial ............................................................................................................ 22 
7. 
Aims and Objectives ...................................................................................................................... 22 
7.1 
Aims....................................................................................................................................... 22 
7.2 
Primary Objective.................................................................................................................. 22 
7.3 
Secondary Objectives ............................................................................................................ 23 
7.4 
Exploratory Objectives .......................................................................................................... 23 
8. 
Design ............................................................................................................................................ 23 
9. 
Eligibility ........................................................................................................................................ 24 
9.1 
Inclusion criteria .................................................................................................................... 24 
9.2 
Exclusion criteria ................................................................................................................... 24 
9.3 
Resection of primary colorectal cancer ................................................................................ 25 
9.4 
Chemotherapy prior to liver resection ................................................................................. 25 
9.5 
Prior and concurrent participation in other clinical trials ..................................................... 26 
9.6 
Biospecimen collection to investigate the prebiotic effect of EPA treatment for CRCLM ... 26 
10. Recruitment Process ..................................................................................................................... 27 
10.1 
Recruitment Setting .............................................................................................................. 27 
10.2 
Eligibility Screening ............................................................................................................... 27 
10.3 
Informed Consent and Eligibility ........................................................................................... 27 
10.3.1 
Initial Information and Initial Approach ........................................................................ 28 
10.3.2 
Consent Process ............................................................................................................ 28 
10.3.3 
Loss of capacity following informed consent ................................................................ 29 

 
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10.3.4 
Eligibility Process ........................................................................................................... 29 
10.4 
Registration and Randomisation ........................................................................................... 30 
10.4.1 
Timing of Registration and Randomisation ................................................................... 30 
10.4.2 
Treatment Allocation .................................................................................................... 30 
10.4.3 
Registration and Randomisation Process ..................................................................... 31 
10.4.4 
Post Randomisation Actions ......................................................................................... 32 
11. Trial Medicinal Product Management .......................................................................................... 33 
11.1 
Supply and distribution ......................................................................................................... 34 
11.2 
Prescribing and participant supply management ................................................................. 34 
11.3 
Dispensing ............................................................................................................................. 35 
11.4 
Storage .................................................................................................................................. 36 
11.5 
Reconciliation ........................................................................................................................ 36 
12. Treatment ..................................................................................................................................... 37 
12.1 
Treatment Details ................................................................................................................. 37 
12.2 
Treatment Regimen .............................................................................................................. 37 
12.2.1 
Treatment breaks .......................................................................................................... 37 
12.2.2 
Concomitant medication............................................................................................... 38 
12.2.3 
Known Toxicities ........................................................................................................... 39 
12.2.4 
Dose reduction .............................................................................................................. 40 
12.2.5 
Treatment Compliance ................................................................................................. 42 
12.3 
Blinding ................................................................................................................................. 42 
12.3.1 
Emergency Unblinding .................................................................................................. 43 
12.4 
Withdrawals .......................................................................................................................... 45 
13. Assessments, Samples and Data Collection .................................................................................. 45 
13.1 
Assessment of eligibility and randomisation ........................................................................ 45 
13.2 
Visit 1: Baseline Assessment and Data Collection ................................................................ 46 
13.3 
Research nurse telephone calls (every 2 weeks between visits 1 and 2) ............................. 47 
13.4 
Visit 2: CRCLM surgery, Treatment Assessments and Data Collection ................................. 47 
13.5 
Visit 3: Treatment Assessments and Data Collection ........................................................... 49 
13.6 
Visits 4-6: Treatment Assessments and Data Collection ...................................................... 50 
13.7 
Visits 7-9: Treatment Assessments and Data Collection ...................................................... 52 
13.8 
Visit 10/Exit Visit: Treatment Assessments and Data Collection .......................................... 53 
13.9 
60 days post-treatment telephone call ................................................................................. 54 
13.10 End of Trial Treatment .......................................................................................................... 55 
13.11 Disease Progression .............................................................................................................. 55 
13.12 Quality of Life ........................................................................................................................ 56 
13.13 Health Economics .................................................................................................................. 56 
13.14 Cachexia CT measurements .................................................................................................. 56 

 
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13.15 Red Blood Cell Fatty Acid Analysis ........................................................................................ 57 
13.16 Adverse Events and Serious Adverse Events ........................................................................ 58 
13.17 Pregnancies ........................................................................................................................... 59 
13.18 Deaths ................................................................................................................................... 59 
13.19 Protocol Deviations and Violations ....................................................................................... 59 
13.20 End of Trial ............................................................................................................................ 59 
13.21 Trial Data and Documentation held at sites ......................................................................... 60 
13.22 Case Report Forms (CRFs) ..................................................................................................... 60 
13.23 Safety Monitoring Plan ......................................................................................................... 60 
14. Pharmacovigilance ........................................................................................................................ 60 
14.1 
General Definitions ............................................................................................................... 60 
14.2 
Operational Definitions ......................................................................................................... 62 
14.2.1 
Adverse Events (AEs) / Adverse Reactions (ARs) .......................................................... 62 
14.2.2 
Serious Adverse Events (SAEs) / Serious Adverse Reactions (SARs) ............................. 62 
14.2.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ...................................... 63 
14.3 
Reporting Requirements ....................................................................................................... 64 
14.3.1 
Reporting of Adverse Events (AEs) ................................................................................ 65 
14.3.2 
Reporting of Adverse Reactions (ARs) .......................................................................... 65 
14.3.3 
Reporting of Serious Adverse Events (SAEs) ................................................................. 65 
14.3.4 
Expedited Reporting of Serious Adverse Reactions (SARs) and Suspected Unexpected 
Serious Adverse Reactions (SUSARs) ............................................................................................ 66 
14.4 
Responsibilities ..................................................................................................................... 66 
14.4.1 
Principal Investigator: ................................................................................................... 66 
14.4.2 
Chief Investigator (CI) / delegate: ................................................................................. 66 
14.4.3 
CTRU: ............................................................................................................................. 67 
14.4.4 
Trial Steering Committee (TSC): .................................................................................... 68 
14.4.5 
Data Monitoring & Ethics Committee (DMEC): ............................................................ 68 
15. Participant-reported measures ..................................................................................................... 68 
16. Economic Evaluation ..................................................................................................................... 68 
17. Endpoints ...................................................................................................................................... 69 
17.1.1 
Primary Endpoint .......................................................................................................... 69 
17.1.2 
Secondary Endpoints .................................................................................................... 70 
17.1.3 
Exploratory Endpoints ................................................................................................... 70 
18. Statistical Considerations .............................................................................................................. 70 
18.1 
Sample size and planned recruitment rates ......................................................................... 70 
18.1.1 
Sample size .................................................................................................................... 70 
18.1.2 
Planned Recruitment Rate ............................................................................................ 72 
19. Statistical Analysis ......................................................................................................................... 72 

 
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19.1 
General Considerations ......................................................................................................... 72 
19.2 
Analysis populations ............................................................................................................. 72 
19.3 
Frequency of analysis ............................................................................................................ 73 
19.4 
Primary endpoint analysis ..................................................................................................... 73 
19.5 
Secondary endpoint analysis ................................................................................................ 73 
19.6 
Subgroup Analyses ................................................................................................................ 74 
19.7 
Exploratory endpoint analysis ............................................................................................... 74 
20. Trial Monitoring ............................................................................................................................ 75 
20.1 
Data Monitoring and Ethics Committee (DMEC) .................................................................. 75 
20.2 
Data Monitoring .................................................................................................................... 75 
20.3 
Clinical Governance Issues .................................................................................................... 76 
21. Quality Assurance, Ethical and Regulatory Considerations .......................................................... 76 
21.1 
Quality Assurance ................................................................................................................. 76 
21.2 
Serious Breaches ................................................................................................................... 76 
21.3 
Ethical considerations ........................................................................................................... 76 
22. Confidentiality ............................................................................................................................... 77 
23. Archiving ....................................................................................................................................... 78 
24. Statement of indemnity ................................................................................................................ 78 
25. Study Organisational Structure ..................................................................................................... 78 
25.1 
Individuals and Individual Organisations .............................................................................. 78 
25.2 
Oversight and Trial Monitoring Groups ................................................................................ 79 
26. Publication Policy .......................................................................................................................... 79 
27. References .................................................................................................................................... 81 
28. Appendix A: Schedule of Events ................................................................................................... 86 
29. Appendix B: Pharmacovigilance Reporting Flowchart .................................................................. 88 
30. Appendix C: Safety Monitoring Plan ............................................................................................. 89 
31. Appendix D: Response Evaluation Criteria in Solid Tumours (RECIST) ......................................... 90 
32. Appendix E: Summary of Product Characteristics ........................................................................ 90 
 
 
 
 
 
 

 
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3. Trial Summary 
 
Title 
A randomised placebo-controlled phase III trial of the effect of the 
omega-3 fatty acid eicosapentaenoic acid (EPA) on colorectal 
cancer recurrence and survival after surgery for resectable liver 
metastases 
Acronym 
EMT2 
Background 
Despite significant advances in diagnosis and treatment of 
colorectal cancer (CRC), it remains the second most common 
cause of cancer-related death in the UK. The majority of deaths 
from CRC are related to distant metastasis, predominantly to the 
liver. Overall 5-year survival following liver resection and adjuvant 
chemotherapy for colorectal cancer liver metastases (CRCLM) is, 
at best, 40-60%. Despite surgery with curative intent, up to 60% of 
patients develop recurrence within 2 years of surgery. A 
randomised controlled trial (RCT) of the omega-3 fatty acid (O3FA) 
eicosapentaenoic acid (EPA) addressing anti-neoplastic activity 
demonstrated that treatment with EPA 2g daily for 6 months was 
associated with a significant reduction in rectal adenoma size and 
multiplicity compared with placebo.  There is pre-clinical evidence 
that O3FAs reduce existing CRC tumour growth in rodent models 
of metastasis. The EMT study was a Phase II RCT of EPA 2 g daily 
in patients (n=88) undergoing liver resection surgery for CRCLM. 
Although there was no difference in the primary endpoint (tumour 
proliferation index), metastases from the EPA arm had a lower 
vascularity score (suggesting possible anti-angiogenic activity) than 
placebo-treated tumours. Although EPA (or placebo) treatment was 
limited to the pre-operative period, overall survival (OS) and 
disease-free survival (DFS) were specified as exploratory end-
points on the basis that oral dosing with EPA before liver surgery 
would provide tissue EPA exposure in the immediate peri-operative 
period with prolonged bioavailability in the post-operative period 
due to the slow tissue ‘washout’ kinetics of EPA. Survival analysis 
demonstrated that the median DFS in the EPA group was 22.6 
months compared with 14.7 months in the placebo group. Any DFS 
benefit was explained by a reduction in CRC recurrence from 12 
months after surgery onwards. 
Design 
A randomised, double-blind, placebo-controlled, multi-centre, 
phase III trial of the omega-3 fatty acid (O3FA) eicosapentaenoic 
acid (EPA) as the ethyl ester (icosapent ethyl [IPE; Vascepa® or 
Vazkepa®]) in patients undergoing liver resection surgery for 
colorectal cancer liver metastasis (CRCLM) with curative intent. 
Objectives 
Primary 
• To determine whether icosapent ethyl (IPE) treatment 
improves Progression-Free Survival (PFS) 
 
 

 
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Secondary 
• To determine whether IPE treatment improves overall 
survival (OS) (key secondary objective) 
• To confirm the safety and tolerability profile of IPE before and 
after surgery, including during cancer chemotherapy  
• To determine whether IPE treatment improves quality of life 
(QoL) after CRCLM surgery  
• To perform a health economic analysis of IPE treatment 
starting before and continuing after CRCLM surgery 
• To determine whether IPE treatment has an effect on the 
diagnosis of new primary cancers (excluding DCIS, cervical 
carcinoma in situ, superficial bladder carcinoma where 
treatment consisted of resection only and non-melanoma 
skin cancer where treatment consisted of resection or 
radiotherapy only) 
Exploratory 
• To determine whether baseline, pre-operative and/or 6 month 
post-operative red blood cell EPA content predicts disease-
related outcomes 
• To determine whether IPE treatment maintains muscle mass 
in CRCLM patients and whether there is any association 
between changes in muscle mass and disease-related 
outcomes 
 
Endpoints 
Primary endpoint:  
• Progression Free Survival (PFS) during a minimum of 2 
years follow up. 
Secondary endpoints: 
• Overall Survival (OS) 
• Safety and tolerability profile of IPE including during 
chemotherapy 
• Participant-reported quality of life after CRCLM surgery 
• Cost-effectiveness of IPE treatment  
• New primary cancers (excluding DCIS, cervical carcinoma in 
situ, superficial bladder carcinoma where treatment consisted 
of resection only and non-melanoma skin cancer where 
treatment consisted of resection or radiotherapy only) 
Exploratory endpoints: 
• Red blood cell EPA content 
• Muscle mass in CRCLM patients measured by abdominal CT 
scan 
Population 
Adult individuals listed for CRCLM resection with curative intent. 
Randomisation 
Randomisation (1:1) to receive either IPE capsules or placebo 
capsules.  

 
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Dose 
4 capsules per day containing IPE (equivalent to 4 g EPA-ethyl 
ester [EE] daily) or 4 placebo capsules per day 
Duration 
Participants will start treatment before CRCLM surgery and will 
continue to receive treatment for a minimum of 2 years and a 
maximum of 4 years post-liver resection. Participants are followed 
up for 60 days beyond the end of treatment and then by case 
record review annually to collect primary outcome and overall 
survival data. 
Evaluation of 
outcome 
measures 
Participants are clinically assessed 6 months post-operatively (from 
liver resection) and at 6-monthly intervals thereafter for disease 
progression/recurrence.  
QoL outcomes are assessed using the EQ-5D, EORTC QLQ-C30 
and QLQ-LMC21 supplementary module questionnaires.  
Health economic outcomes are assessed using a modified UK 
Cancer Costs Questionnaire Version 2.0 and data collected at each 
trial visit and telephone call. 
Adverse events will be documented during study treatment and 
follow-up. 
Measurement of the red blood cell fatty acid content will be 
performed by liquid chromatography-tandem mass spectrometry 
(LC-MS/MS) measurement of individual fatty acid (FA) species. 
Changes in lean body mass will be measured longitudinally from 
routine CT abdomen images based on muscle area at the L3 
vertebral level. 
 
 
 
 
 
 

 
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4. Trial Schema 
 
 
 
 
 
 
 

 
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5. Abbreviations and Glossary 
 
Abbreviation 
Definition 
AA 
Arachidonic acid 
AE 
Adverse Event 
ALA 
Alpha-linolenic acid 
AR 
Adverse Reaction 
CI 
Chief Investigator 
COX 
Cyclooxygenase enzymes 
CRC 
Colorectal cancer 
CRCLM 
Colorectal cancer liver metastasis 
CRF 
Case Report Form 
CT 
Computerised tomography 
CTRU 
Clinical Trials Research Unit 
DCIS 
Ductal carcinoma in situ 
DHA 
Docosahexaenoic acid 
DFS 
Disease-free survival 
DMEC 
Data Monitoring and Ethics Committee 
DPA 
Docosapentaenoic acid 
EDTA 
Ethylenediaminetetraacetic acid 
EPA 
Eicosapentaenoic acid 
EPA-EE 
Eicosapentaenoic acid ethyl ester 
EPA-FFA 
Eicosapentaenoic acid free fatty acid 
EPA-TG 
Eicosapentaenoic acid triglyceride 
GCP 
Good clinical practice 
HR 
Hazard ratio 
IB 
Investigator brochure 
ICT 
Institute of Cancer Therapeutics 
IMP 
Investigational medicinal product 
IPE 
Icosapent ethyl 
ITT 
Intention to treat 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
MDT 
Multi-disciplinary team 

 
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MHRA 
Medicines and Healthcare products Regulatory Agency 
NOAC 
New oral anticoagulant 
O3FA 
Omega-3 fatty acid 
O6FA 
Omega-6 fatty acid 
OS 
Overall survival 
PFS 
Progression-free survival 
PG 
Prostaglandin 
PI 
Principal Investigator 
PIS/ICF 
Participant Information Sheet and Informed Consent 
Form 
QALY 
Quality adjusted life year 
RCT 
Randomised controlled trial 
RN 
Research nurse 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TG 
triglyceride 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
 
 
 
Term 
Definition 
Kit-code 
Unique numerical identifier used to identify the IMP boxes without 
revealing the treatment allocation. 
Replenishment 
A repeat allocation of trial IMP via the CTRU 24-hr automated 
system. 
Replacement 
A repeat allocation of trial IMP via the 24-hr automated system 
which takes place at an unscheduled time point. 
Safety Statistician 
An independent CTRU statistician responsible for undertaking tasks 
that require knowledge of the treatment allocation. 
Authorised Unblind 
Individual (AUI) 
A member of CTRU staff who is permitted to have knowledge of 
treatment allocation but is not part of the trial team or the safety 
statistician. The individual is authorised to perform tasks and 
processes where knowledge of treatment allocation is required. This 
ensures the blind is not compromised for the blinded members of the 
team. A trial may have multiple people designated as AUI. 
 
 

 
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6. Background 
 
6.1 
Colorectal cancer and liver metastasis   
Despite huge advances in diagnosis and treatment of colorectal cancer (CRC), it remains the 
second most common cause of cancer-related death with 15,903 deaths from CRC in the UK 
in 20141.  
Despite significant improvements in survival from CRC, overall five-year survival for CRC is 
still only 59%1. The majority of deaths from CRC are related to distant metastasis 
(predominantly to the liver)2. Approximately half of all CRC patients will develop liver 
metastasis (CRCLM), median survival from which, without treatment, is only 6 months 
(increasing to >24 months with systemic chemotherapy)2.  
Liver metastases are surgically resectable in 10-20% of cases and this provides the only 
prospect of cure (20% long-term [>10 year] disease-free survival)2-3. Overall 5-year survival 
following liver resection and adjuvant chemotherapy for CRCLM is, at best, 40-60%2. The use 
of oxaliplatin-based chemotherapy (oxaliplatin/5-fluorouracil or oxaliplatin/capecitabine) has 
become integral to management of resectable CRCLM2. However, timing of chemotherapy for 
resectable disease remains controversial with some cases receiving neoadjuvant (pre-
operative) chemotherapy rather than post-operative adjuvant chemotherapy4. Some patients 
with unresectable CRCLM also undergo a trial of chemotherapy aiming to ‘downsize’ their 
disease prior to a final decision regarding resectability2,4. Despite surgery with curative intent, 
up to 60% of patients develop recurrence within 2 years of surgery3. Approximately 20% of 
these are eligible for second or ‘re-do’ hepatectomy, with similar post-operative outcomes to 
the first resection5, but the remainder have incurable disease, which is invariably fatal. 
6.2 
Omega-3 fatty acids 
Omega-3 polyunsaturated fatty acids (O3FAs) are naturally occurring lipids consisting of a 
variable length carbon chain with a methyl group at one (the omega []) end and a carboxylic 
acid group at the other (alpha) end6. They contain more than one C-C double bond, one of 
which is located at the third C atom (3) from the omega end. The dominant long-chain (≥13 
carbons) O3FAs in nature are C18:33 (where X:Y denotes the carbon chain-length:number 
of C-C double bonds) alpha-linolenic acid (ALA), C20:53 eicosapentaenoic acid (EPA) and 
C22:63 docosahexaenoic acid (DHA)6. The majority of O3FAs reside naturally in a 
triglyceride (TG) form in the phospholipid bilayer of all cells. EPA and DHA have physiological 
(structural and signalling) activity as integral components of the cell plasma membrane in 
humans but ALA is believed to be inactive. ALA is found in significant quantities in seed oils, 
plants and vegetables. However, ALA is a poor substrate for human elongase and desaturase 
enzymes meaning that the dominant dietary source of EPA and DHA is restricted to cold-water 
oily fish such as salmon, mackerel and herring7. A 100 g portion of oily fish contains 
approximately 1 g O3FAs8. In contrast, omega-6 fatty acids (O6FAs) such as C18:26 linoleic 
acid are ubiquitous in vegetable oils used widely in the ‘western’ diet, leading to a 
preponderance of C20:46 arachidonic acid (AA) over O3FAs in human cell membranes7-8.        

 
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O3FAs are widely available as nutritional supplements, either as a complex mixture of 
naturally-occurring variable chain-length O3FAs (predominantly EPA and DHA) in fish oil (250-
300 mg/g) or more commonly as a soft-gelatin capsule formulation, in which EPA alone, or in 
combination with DHA, is concentrated (to >300 mg/g)7. O3FAs can be presented in the TG 
form, as the ethyl ester (EE), or as the free fatty acid (FFA)9.  
Pancreatic lipase stimulated by food (especially fat) intake hydrolyses O3FA-TGs producing 
O3FA FFAs, which are absorbed by small intestinal enterocytes before re-esterification to the 
TG form for chylomicron transport to the liver and eventual systemic distribution leading to 
incorporation into all plasma cell membranes9. Omega-3 fatty acid EEs require hydrolysis by 
carboxyl-ester lipase (also known as bile salt-dependent lipase) in order to generate FFAs for 
enterocyte uptake9. Presence of pancreatic lipase and carboxyl-ester lipase in the intestinal 
lumen is critically dependent on stimulation of pancreatic secretion by food intake. Food fat 
content has been demonstrated to affect O3FA tissue incorporation after short-term 
administration of EEs10.     
Systemic O3FA bioavailability is most accurately and reliably measured in clinical studies by 
quantification of red blood cell (RBC) O3FA levels11. Oral dosing studies have determined that 
O3FA tissue incorporation approaches steady-state levels at two weeks after starting 
supplements, reaching a peak between 4-6 weeks, and that ‘washout’ to basal levels can take 
as long as 3 months12. Recently, whole blood O3FA testing from dried finger-prick blood 
samples has emerged as an alternative to venepuncture needed for RBC isolation13. 
Preliminary data suggest a strong correlation between whole blood and RBC O3FA levels after 
O3FA supplementation13. 
There have been few direct comparisons of bioavailability of EPA given as the FFA, TG and 
EE. Most studies have been short-term (< 2 weeks) and measured plasma/serum TG levels, 
which are of uncertain relevance to tissue omega-3 fatty acid incorporation9 In the studies of 
El Boustani et al.14-20 and Lawson and Hughes1517, 1619, plasma TG levels were higher after FFA 
administration than TG ingestion, when omega-3 PUFAs were given with a low-fat meal. 
Interestingly, in the longer study of Dyerberg et al.17, plasma TG levels after TG administration 
were in slight excess of those after FFA ingestion. 
 
One comparison of tissue (RBC) EPA incorporation after longer-term mixed omega-3 PUFA 
administration as the –TG, -EE or krill oil (4 weeks) reported no significant difference between 
formulations with equivalent EPA and DHA content18ref. In another long-term (6 months) 
comparison of mixed EPA/DHA administration in TG and EE forms in hyperlipidaemic subjects, 
TG treatment resulted in a significantly greater % RBC content of EPA than the EE group19.  
 
Overall, the available data suggest little difference between bioavailability of the EPA-TG, EPA-
EE and EPA-FFA forms of EPA, when EPA alone or an omega-3 PUFA mix is given with food9. 
By contrast, bioavailability of the EE form of EPA is more variable and more dependent on 
simultaneous food intake in short-term studies9. However, differences in ‘bioavailability’ of 
different formulations of mixed omega-3 PUFAs during long-term (weeks-months) dosing are 
insignificant and other factors (eg. compliance, other host factors) are likely to be more 
important than the type of omega-3 PUFA used.      
 

 
EMT2 version 9.0, 27th July 2022 
17 
 
Compliance (in turn, affected by tolerability of any given O3FA formulation) is likely to play an 
important role in tissue O3FA exposure but has not been studied formally. It is likely that 
variable compliance contributes to the significant intra-patient (coefficient of variation [CV] 
~5%) and inter-patient variability (CV~10%) in O3FA levels (measured by red blood cell 
membrane content) recognised during medium-term (weeks) supplementation9,20-22.  
 
Similar TG-lowering effects of mixed EPA/DHA preparations in humans have been 
consistently observed for O3FAs in the TG, EE and FFA form suggesting that the chemical 
form of EPA does not affect clinical effectiveness during long-term dosing 22-23. Moreover, 
O3FAs, either EPA alone or as an EPA-DHA mix, have demonstrated similar efficacy as the 
TG, EE or FFA in several rodent CRC models (see 6.2.1)6. 
     
6.2.1   Evidence that EPA has anti-CRC activity 
Evidence that O3FAs have anti-CRC activity has been summarised elsewhere6. In brief, a 
large body of human observational studies has not demonstrated a relationship between 
dietary O3FA intake and CRC risk, perhaps because of methodological limitations of dietary 
measurement and/or modest dietary O3FA intake in most study cohorts6. By contrast, a strong 
and consistent signal that O3FAs have anti-CRC activity has emerged from rodent models of 
colorectal carcinogenesis6. The majority of pre-clinical studies have tested O3FA mixtures 
including both EPA and DHA. The limited number of studies investigating the anti-CRC activity 
of either EPA or DHA alone has demonstrated equivalence6. Pre-clinical evidence that O3FAs 
have anti-CRC activity has led to a number of colorectal mucosal biomarker studies which 
reported that oral dosing with an EPA/DHA mixture or EPA alone (1-4g per day) was 
associated with reduced epithelial cell proliferation and increased apoptosis6.  
Clinical studies looking at the chemoprevention efficacy of O3FAs have to date been restricted 
to EPA with no studies of pure DHA preparations. Importantly, EPA is considered to be the 
‘universal donor’ such that C20:53 EPA can be metabolised to C22:63 DHA in humans via 
C22:53 docosapentaenoic acid (DPA), which is reflected by increased DHA tissue content 
following EPA supplementation24. The first Phase III RCT of EPA addressing anti-neoplastic 
activity demonstrated that treatment with 99% EPA-FFA 2g daily for 6 months was associated 
with a significant reduction in rectal adenoma size (29.8%) and multiplicity (22.4%) compared 
with placebo24. This preliminary observation prompted an adenomatous polyp prevention trial 
of EPA (using both 99% FFA 2 g and 90% TG 2870 mg daily [also equivalent to 2 g FFA]) and 
aspirin 300 mg daily in ‘high risk’ individuals (n=709) undergoing colonoscopic surveillance in 
the English Bowel Cancer Screening Programme, results of which are expected in 201725. 
There is also pre-clinical evidence that O3FAs reduce existing CRC tumour growth in rodent 
models of metastasis6. It has been demonstrated that dietary supplementation with EPA-FFA 
(producing similar tissue EPA incorporation to that seen in clinical studies24) abrogated mouse 
MC-26 CRC cell liver metastasis after intra-splenic injection in Balb/c mice26. These 
experimental observations prompted a Phase II RCT of EPA-FFA 2 g daily in patients (n=88) 
undergoing liver resection surgery for CRCLM (the EPA for Metastasis Trial [EMT] study)27. 

 
EMT2 version 9.0, 27th July 2022 
18 
 
The primary end-point of the EMT study was the histological CRC cell proliferation index, but 
safety and tolerability were key secondary endpoints. Due to the ‘window of opportunity’ trial 
design, EPA-FFA or placebo treatment was restricted to the pre-operative period (median EPA 
treatment duration 30 days). As expected, EPA treatment was associated with higher intra-
tumoral EPA levels27. Although there was no difference in the primary endpoint (tumour 
proliferative index), metastases from the EPA arm had a lower vascularity score, suggesting 
possible anti-angiogenic activity, than placebo-treated tumours27. Adverse events in patients 
with CRCLM awaiting surgery were limited to mild GI upset, with withdrawal because of 
symptoms occurring in only two cases27. Importantly, there was no excess intra-operative or 
post-operative bleeding risk associated with EPA treatment in keeping with a lack of any 
clinically significant effect of EPA on bleeding events27. 
Although EPA (or placebo) treatment was limited to the pre-operative period, overall survival 
(OS) and disease-free survival (DFS) were specified as exploratory end-points on the basis 
that oral dosing with EPA before liver surgery would provide tissue EPA exposure in the 
immediate peri-operative period with prolonged bioavailability in the post-operative period due 
to the slow tissue ‘washout’ kinetics of EPA12. Survival analysis demonstrated that the median 
DFS in the EPA-FFA group was 22.6 months compared with 14.7 months in the placebo group. 
Any DFS benefit was explained by a reduction in CRC recurrence from 12 months after surgery 
onwards27. A Cox multivariate analysis revealed that EPA treatment was associated with 
improved DFS (hazard ratio [HR] 0.35 [95% confidence interval 0.15-0.79]). EPA use also 
conferred OS benefit with 7 CRC-related deaths in 41 evaluable CRCLM patients who received 
EPA-FFA compared with 14 deaths in 42 placebo group patients (HR 0.40 [95% confidence 
interval 0.16-1.0])27.  
The two previous adequately powered RCTs of perioperative chemotherapy in patients 
undergoing CRCLM resection, including the most recent New EPOC trial, both used PFS as 
the primary endpoint28-29. These trials are not directly comparable to the EMT study due to 
differences in the study populations related to trial exclusion criteria and historical differences 
in hepatobiliary surgical practice27. However, the median PFS in these trials28-29 and smaller 
preceding studies30 is slightly longer (approximately 21 months versus 15 months) than the 
median PFS in the placebo arm of the EMT study27. Two-year OS in the EMT study was 71.5% 
compared with 78-79% OS in the control arm of the two most recent trials 28-29, perhaps related 
to not having preoperative chemotherapy as an exclusion criterion, and wider inclusion criteria 
in the latter trials. 
6.2.2  Mechanisms of the anti-neoplastic activity of O3FAs 
The mechanistic basis of the anti-CRC activity of O3FAs has not been fully elucidated. Multiple 
mechanisms of action almost certainly contribute to the anti-neoplastic activity31. For example, 
EPA (but to a much lesser extent DHA) is a substrate for the cyclooxygenase (COX) enzymes, 
which drive colorectal carcinogenesis6. EPA effectively inhibits COX-1 but leads to synthesis 
of 3-series prostaglandins (PGs) by COX-2 at the expense of pro-tumorigenic 2-series PGs 
such as PGE226,31-32. Alternatively, EPA and DHA alter membrane fluidity, which may inhibit 

 
EMT2 version 9.0, 27th July 2022 
19 
 
pro-tumorigenic signalling through cell surface receptors such as the epidermal growth factor 
receptor31. More recently, O3FAs have been characterised as ligands for specific fatty acid G 
protein-coupled receptors such as GPR12031. The lipophilic, membrane-bound nature of the 
O3FAs and the above putative mechanisms of action are compatible with extended ‘washout’ 
after cessation of therapy and suggest that prolonged anti-CRC activity is plausible even after 
limited short-term treatment. 
6.2.3.  Interaction of EPA with other CRC treatment modalities 
There is preliminary evidence that concurrent O3FA therapy may improve the efficacy of 
platinum-based chemotherapy of lung cancer36 and further evidence that O3FAs may protect 
against muscle loss and improve quality of life in cancer chemotherapy patients37.  There has 
been no large, randomised study of the effect of O3FA supplementation on chemotherapy 
outcomes in CRC patients except for two uncontrolled case series that support improved 
tolerability and nutritional parameters during both FOLFOX and FOLFIRI regimens38-39.     
Acetyl-salicylic acid (aspirin) may also have anti-CRCLM activity40. Adjuvant aspirin therapy in 
patients who have undergone primary CRC surgery is currently being tested in the Add-aspirin 
trial41. Aspirin (like EPA) inhibits COX-1 (by irreversible acetylation) and alters enzymatic 
activity of COX-2, leading to reduced prostaglandin production42. Therefore, a valid hypothesis 
is that aspirin and EPA may have additive anti-CRC activity.     
 
6.3 
O3FAs and cancer cachexia 
Although recent systematic reviews of a small number of studies in other cancers, particularly 
pancreas, have not demonstrated a clear signal, it has been hypothesised that O3FAs may 
abrogate cancer cachexia (the clinical syndrome of weight loss, muscle atrophy, loss of 
appetite, fatigue and weakness) perhaps by anti-inflammatory properties43. One explanation 
for the different effect of EPA on OS and DFS observed during the first 18 months post-surgical 
follow-up in the EMT study is that EPA could reduce cancer-related cachexia. Therefore, a 
valid hypothesis is that EPA treatment abrogates the reduction in muscle mass (termed 
sarcopaenia) that is an integral feature of the cancer-related cachexia syndrome. This can be 
tested by measuring lean body mass longitudinally using routine CT abdomen images using 
the method of Baracos (based on muscle area at the L3 vertebral level), in parallel with 
assessment of patient-reported symptoms44.   
 
6.4 
Safety and tolerability of EPA treatment 
Vast experience of O3FAs in a cardiology setting and from the informal ‘over-the-counter’ 
nutritional supplement market has confirmed that long-term O3FA supplementation is safe, 
with a restricted set of mild side-effects generally pertaining to the gastrointestinal tract such 
as dyspepsia, eructation and diarrhoea (all ≤10%)45. Total daily doses of O3FAs up to 4g are 

 
EMT2 version 9.0, 27th July 2022 
20 
 
considered safe45. In practice, no excess bleeding risk has been observed in large-scale 
randomised controlled trials (RCTs) of doses of mixed O3FAs and pure EPA up to 2 g daily, 
including the EMT trial in CRCLM patients27, despite some ex vivo evidence for anti-platelet 
activity of O3FAs46. Previous studies of O3FA use in cardiology patients taking anti-platelet 
and anti-coagulant drugs have not demonstrated any excess of bleeding events45,47. The 
Summary of Product Characteristics (SmPC) for the mixed O3FA preparation, which is 
licensed in the UK (Omacor®), advises that it has been used in conjunction with warfarin 
without haemorrhagic complications but advises that the prothrombin time should be checked 
if there is co-prescription with warfarin. The FFA and TG formulations, which have been used 
in current and previous RCTs in patients with, and at risk of, CRC have not raised any safety 
concerns24,27. In particular, there was no excess of peri-operative bleeding events in the group 
that received EPA prior to liver surgery compared with placebo in the EMT trial27. 
 
6.5 
The IMP in EMT2   
Icosapent ethyl (IPE) or Vazkepa®, also known as AMR101 or Vascepa® in the USA, (Amarin 
Pharmaceuticals Inc.), is approved by the Medicines and Healthcare Products Regulatory 
Agency (MHRA), European Medicines Agency (EMA) and US Federal Drug Administration 
(FDA) for prevention of cardiovascular events in individuals with established cardiovascular 
disease, or diabetes and at least one other cardiovascular risk factor, who are already taking 
a statin and have elevated blood triglyceride levels at a dose of 4  g per day. It is available as 
1 g (998 mg) EPA-EE in soft gelatin capsules. Therefore, each capsule contains the equivalent 
of 914 mg EPA-FFA. Dosing is recommended with meals. Pharmacokinetic studies have 
demonstrated a dose-response relationship with the plasma and red blood cell EPA level 
attained (and changes in other red blood cell O3FAs), with IPE 4 g/day providing a significant 
increase in plasma and red blood cell EPA level after 12 weeks therapy compared with 2 
g/day48. Plasma EPA levels (expressed as the % total fatty acids) in patients with 
hypertriglyceridaemia after 12 weeks treatment with 2 g/day and 4 g/day were 1.9% and 3.4-
3.6% respectively48-49. An 8-week study in healthy volunteers of EPA FFA 2 g daily (used in 
EMT27 and seAFOod25 trials) resulted in plasma EPA levels of 4.6%50. Treatment with EPA 
FFA 2 g daily for a shorter period (median 30 days) in the EMT trial (which may not have 
generated steady-state O3FA levels) was associated with a similar % increase in red blood 
cell EPA content (240%)27 to that seen with IPE 2 g/day for 12 weeks (300%; cf. 500% with 4 
g/day)48. In a Japanese trial of 1800 mg EPA-EE per day for 5 years, the % change from 
baseline of serum EPA (as the % of total fatty acids) was only 126%51. Therefore, the available 
evidence suggests that dosing with 4 g/day IPE will produce EPA bioavailability most similar 
to that obtained with EPA-FFA and EPA-TG in previous CRC trials52 with the caveats that there 
has been no direct comparison between different EPA formulations in CRC patients and that 

 
EMT2 version 9.0, 27th July 2022 
21 
 
differences in methodology for measurement and reporting of plasma, serum and red blood 
cell EPA content mean that direct comparisons should be carried out cautiously. 
 
Short-term studies have demonstrated no difference in bioavailability between single and split 
(BD) IPE dosing at 2 g/day53. Therefore, the dose of IPE used in the EMT2 trial (4 g/day) is 
recommended as a twice daily 2 g (2 x 1g capsules) dose. 
 
A large (n=8179) randomised trial of IPE 4 g/day for prevention of cardiovascular disease 
with median follow-up of 4.9 years (REDUCE-IT; NCT01492361) reported that overall rates 
of adverse events and serious adverse events in the IPE group were not significantly 
different from placebo users54. Atrial fibrillation or atrial flutter occurred in 5.8% of subjects 
receiving IPE in REDUCE-IT compared with 4.5% in subjects receiving placebo54. Atrial 
fibrillation or atrial flutter requiring hospitalisation for 24 hours or more occurred in 3% of 
subjects treated with IPE compared with 2% in subjects receiving placebo. Atrial fibrillation 
and atrial flutter were reported more frequently in subjects with a previous history of atrial 
fibrillation or atrial flutter receiving IPE than in those receiving placebo (12.5% vs 6.3%)54. A 
recent meta-analysis of five RCTs of O3FA supplementation on cardiovascular outcomes, 
which included data on incidence of atrial fibrillation, reported an overall 37% increase in risk 
of atrial fibrillation in O3FA users compared with the placebo arm, regardless of dose or 
formulation of the O3FAs55. 
 
Bleeding occurred in 11.8% of subjects receiving IPE in REDUCE-IT compared with 9.9% in 
subjects receiving placebo54. Serious bleeding events were reported more frequently in 
subjects receiving IPE than in those receiving placebo when administered in combination with 
concomitant antithrombotic medication (3.4% vs 2.6%) but occurred at the same rate (0.2%) 
in subjects not taking concomitant anticoagulant/antiplatelet medication54. The bleeding events 
most frequently observed with IPE in the REDUCE-IT trial were gastrointestinal bleeding 
(3.1%), contusion (2.5%), haematuria (1.9%), and epistaxis (1.5%). 
 
EPA-EE has been licensed in Japan since the 1990’s as Epadel (Mochida Pharmaceutical 
Co.), at a 1800 mg dose (capsule or sachet), and, more recently (2013), in an OTC form 
(Epadel T). This product has been the subject of the large (n=18645) JELIS trial56, in which 
GI adverse events were reported in 3.8% (placebo 1.7%). 
 
 
 

 
EMT2 version 9.0, 27th July 2022 
22 
 
6.6 
Rationale for the trial 
 
Despite optimal multidisciplinary team management of patients with CRCLM using liver 
resection surgery and systemic chemotherapy, metastatic CRC of the liver remains a 
significant cause of cancer-related death with long-term survival occurring in a small minority 
of patients and with overall 5 year survival being typically only 40-60%. Therefore, there 
remains a need for safe, well-tolerated treatment that will improve outcomes for patients with 
CRCLM. 
 
The EMT study suggested that short-term pre-operative treatment with EPA might provide 
long-term OS and DFS benefit in patients undergoing liver resection surgery for CRCLM. 
EMT2 will determine definitively whether prolonged EPA treatment, starting before surgery 
and continuing afterwards, reduces cancer progression, and secondarily whether there is an 
OS benefit, in CRCLM patients. For the EMT2 trial, PFS will be used as the primary endpoint 
on the basis that 1) participants will have clinically evident metastatic CRC at randomisation 
prior to liver surgery and 2) other major RCTs of outcomes after CRCLM surgery have 
employed PFS as the primary outcome measure. In addition, OS will be the key secondary 
outcome measure in order to explore any effect on OS after CRC progression during the 
intervention period (see Section 7.3). 
 
7. Aims and Objectives 
EMT2 is a randomised placebo-controlled, double-blind trial of EPA-EE (IPE) for CRCLM 
patients. 
7.1 
Aims 
 
The trial aims to determine whether oral IPE therapy started before CRCLM surgery and 
continued for a minimum of 2 years post liver resection lengthens progression-free survival 
(PFS) in patients undergoing liver resection surgery for CRCLM with curative intent. 
 
7.2 
Primary Objective 
 
• 
To determine whether IPE treatment improves progression-free survival (PFS) in 
CRCLM patients. 
 
 

 
EMT2 version 9.0, 27th July 2022 
23 
 
7.3 
Secondary Objectives 
 
• 
To determine whether IPE treatment improves overall survival (OS). 
• 
To confirm the safety and tolerability profile of IPE before and after surgery, including 
during chemotherapy. 
• 
To determine whether IPE treatment improves participant reported quality of life after 
CRCLM surgery.  
• 
To perform a health economic analysis of IPE treatment. 
• 
To determine whether IPE treatment has an effect on the diagnosis of new primary 
cancers (excluding DCIS, cervical carcinoma in situ, superficial bladder carcinoma where 
treatment consisted of resection only and non-melanoma skin cancer where treatment 
consisted of resection or radiotherapy only). 
 
7.4 
Exploratory Objectives 
 
• 
To determine whether baseline, pre-operative and/or 6 month post-operative red blood 
cell EPA content predicts disease-related outcomes. 
• 
To determine whether IPE treatment maintains muscle mass in CRCLM patients and 
whether there is any association between changes in muscle mass and disease related 
outcomes. 
8. Design 
 
The EMT2 study is a prospective randomised, double-blind, placebo-controlled, multi-centre, 
parallel-group, superiority phase III trial of the omega-3 fatty acid (O3FA) eicosapentaenoic 
acid (EPA) in patients undergoing liver resection surgery with curative intent for colorectal 
cancer liver metastases (CRCLM). 
Eligible participants will be randomised on an equal basis to receive 4 x 1 g capsules per day 
of either icosapent ethyl (IPE; equivalent to 4 g of EPA-EE or 3656 mg EPA-FFA) taken as 2 
capsules twice daily with food or 4 placebo (containing light mineral oil instead of IPE) capsules 
taken in an identical fashion. 
The trial is designed to investigate whether EPA (IPE) treatment will result in an improvement 
in PFS (see section 17.1 for definition). 
EMT2 is a double-blind trial design in which participants and site personnel will be blinded to 
the treatment allocation to minimise the possible introduction of bias. 

 
EMT2 version 9.0, 27th July 2022 
24 
 
All participants will be followed up for a minimum of 2 years until the last participant recruited 
reaches 2 years post liver resection (Please refer to Section 13 on Assessments/samples/data 
collection for more details on the follow-up schedule). 
There is also the option for EMT2 participants to join a sub-study funded by The US National 
Institutes of Health called Prebiotic effect of eicosapentaenoic acid treatment for colorectal 
cancer liver metastases, in which biospecimens (stool, urine, blood, and tumour tissue) will be 
collected before and after EPA or placebo treatment (refer to the Biospecimen Collection 
protocol). 
9. Eligibility 
 
Eligibility waivers to inclusion and exclusion criteria are not permitted. 
9.1 
Inclusion criteria 
• 
Aged ≥18 years  
• 
Able to provide written informed consent 
• 
Histological diagnosis of CRC with evidence of liver metastases 
• 
Planned liver resection surgery for CRCLM with curative intent, including repeat ‘re-do’ 
CRCLM liver surgery (a second independent resection for a separate CRC liver 
recurrence)  
• 
Intention to receive IMP treatment prior to CRCLM surgery 
 
9.2 
Exclusion criteria 
• 
Previous CRCLM surgery for the management of the current metastatic disease1  
• 
Incurable extra-hepatic metastases 
• 
Current (in the last 2 months) or planned regular (>3 doses per week) use of O3FA-
containing drugs or supplements, including Vazkepa®, Omacor®, fish oil and cod-liver 
oil supplements 
• 
Fish/seafood allergy 
• 
Diagnosis of hereditary fructose intolerance 
• 
Soya or peanut allergy 
• 
Inability to comply with trial treatment and follow-up schedule  
 
1 Patients who have previously undergone CRCLM surgery and who present with new CRC liver disease in 
planned two-staged surgery are ineligible. 

 
EMT2 version 9.0, 27th July 2022 
25 
 
• 
Known bleeding tendency/condition (e.g. von Willebrand disease) 
• 
A previous malignancy within the last 5 years other than: 
− 
colorectal cancer   
− 
non-melanoma skin cancer where treatment consisted of resection only or 
radiotherapy 
− 
ductal carcinoma in situ (DCIS) where treatment consisted of resection only 
− 
cervical carcinoma in situ where treatment consisted of resection only 
− 
superficial bladder carcinoma where treatment consisted of resection only 
• 
A previous malignancy where the patient has been disease-free for ≤5 years 
• 
Pregnant or breastfeeding women or women of childbearing potential not willing to use 
effective contraceptive measures2. Women of childbearing potential are defined as 
fertile, following menarche and until becoming post-menopausal, unless permanently 
sterile. 
• 
Men defined as fertile (post-pubescent and not permanently sterile by vasectomy or 
bilateral orchidectomy) and not willing to use effective contraceptive measures3 if 
appropriate.  
 
9.3 
Resection of primary colorectal cancer 
It is expected that some patients may present with primary colorectal cancer and liver 
metastases concurrently. These patients are eligible for trial participation providing that both 
the primary colorectal cancer and the liver metastases are considered able to be resected 
curatively. Eligibility of participants should be confirmed at the point at which liver resection is 
definitely scheduled regardless of the primary CRC management. 
 
9.4 
Chemotherapy prior to liver resection 
It is expected that some patients may require chemotherapy prior to liver resection surgery.  
Depending on the patient presentation, this may include chemotherapy for treatment of the 
primary colorectal cancer prior to resection of the liver metastases (for patients with a 
synchronous presentation) or ‘downsizing’ chemotherapy for liver metastases that are 
borderline operable.  
 
2 Acceptable contraception is defined as one of the following: combined (oestrogen and progesterone 
containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), 
progesterone only hormonal contraception associated with inhibition of ovulation (oral, injectable, 
implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, 
vasectomised partner, practicing true abstinence (when this is in line with the preferred and usual lifestyle of 
the participant) 
3 Acceptable contraception is defined as: condom, consider contraception for non-pregnant partner during 
treatment until the end of systemic exposure in the male participant plus a 90 day period 

 
EMT2 version 9.0, 27th July 2022 
26 
 
Please note that it is necessary to determine the purpose of chemotherapy treatment prior to 
liver resection as ‘downsizing’ chemotherapy for borderline operable liver metastases is a 
stratification factor and must be confirmed prior to randomisation. Prior chemotherapy at any 
time-point is not an exclusion criterion for EMT2. However, patients must have completed 
chemotherapy and have an MDT recommendation for CRCLM resection with curative intent 
in order to be eligible for EMT2 participation. 
Details of the chemotherapy treatment regimens will be recorded.  
 
9.5 
Prior and concurrent participation in other clinical trials 
The eligibility of participants who have participated in other previous or concurrent trials will be 
determined on a case by case basis and must be discussed with the CTRU, Sponsor and the 
respective trial team prior to randomisation. 
Co-enrolment with participants in the colorectal cohort of the Add-Aspirin trial (EudraCT 2013-
004 398-28, Sponsor University College London) will be permitted providing that the respective 
eligibility criteria of each trial are fulfilled41. Add-Aspirin aims to assess whether regular aspirin 
use after standard therapy prevents recurrence and prolongs survival in participants with non-
metastatic common solid tumours including CRC41. Add-Aspirin participants with CRC who go 
on to develop CRCLM may be eligible for EMT2 if liver resection with curative intent is 
considered appropriate. EMT2 participants are also permitted to participate in the Add-Aspirin 
study following CRCLM surgery if the participant fulfils the eligibility criteria defined by the 
current Add-Aspirin protocol; information on Add-Aspirin trial participation should be provided 
on the EMT2 Follow-Up CRF. This pragmatic trial design facilitates the assessment of the 
efficacy of EPA in participants who use aspirin which may become standard practice in the 
future. This approach also minimises any potential negative effects on recruitment due to 
competing trials in the same patient population. 
 
9.6 
Biospecimen collection to investigate the prebiotic effect 
of EPA treatment for CRCLM 
Once an individual has provided written informed consent to participate in EMT2, the 
participant may be given the opportunity to take part in a sub-study, which involves collection 
of stool, urine, blood and tumour tissue at three timepoints (visit 1-3), or more, during the EMT2 
trial (See Biospecimen Collection protocol). Alternatively, existing EMT2 participants can be 
given the opportunity to provide a single stool and urine specimen at any point at or after visit 
3 (see Biospecimen Collection protocol).   
 
 

 
EMT2 version 9.0, 27th July 2022 
27 
 
10. 
Recruitment Process 
 
10.1 
Recruitment Setting 
Participants will be recruited from multiple research sites in England. Research sites will be 
required to have obtained management approval and undertake a site initiation meeting with 
the CTRU prior to the start of recruitment into the trial. 
 
10.2 
Eligibility Screening 
Participating research sites will be required to complete a paper Screening Form for all those 
patients presenting to the hepatobiliary multi-disciplinary team (MDT) for consideration for liver 
resection surgery for CRCLM.  
Documented reasons for ineligibility or patient declining participation will be closely monitored 
by the CTRU as part of a regular review of recruitment progress. Screening forms should be 
returned to CTRU on a monthly basis. Anonymised information will be collected including: 
- 
Age 
- 
Gender 
- 
Date screened 
- 
‘Downsizing chemotherapy (yes or no) 
- 
Known extra hepatic CRC metastases with curative treatment planned (yes or no) 
- 
Current regular aspirin use (yes to current use, no current use or Add-aspirin trial 
participant still receiving IMP) 
- 
Reason not eligible for trial participation or 
- 
Eligible but declined and reason for this or 
- 
Other reason for non-randomisation 
 
10.3 
Informed Consent and Eligibility 
The Principal Investigator (PI) will retain overall responsibility for the informed consent of 
participants at their site and must ensure that any person delegated responsibility to participate 
in the informed consent process is duly authorised, trained and competent to participate 
according to the current ethically approved protocol, principles of Good Clinical Practice (GCP) 
and Declaration of Helsinki 1996. Informed consent must be obtained by a clinician authorised 
by the PI on a delegation log prior to the participant undergoing procedures that are specifically 
for the purposes of the study and are not standard routine care at the participating site. 
Assenting participants will be broadly assessed for eligibility during the screening process 
based on their medical history according to the inclusion and exclusion criteria. 
The right of a patient to refuse participation without giving reasons will be respected. The 
participant must remain free to withdraw at any time from the study without giving reasons and 
without prejudicing his/her further treatment and will be provided with a contact point where 

 
EMT2 version 9.0, 27th July 2022 
28 
 
he/she may obtain further information about the trial. Where a participant is required to re-
consent or new information is required to be provided to a participant, it is the responsibility of 
the PI to ensure this is done in a timely manner and according to any timelines requested by 
the CTRU. 
10.3.1 Initial Information and Initial Approach 
Potential participants will be identified through the hepatobiliary MDT at the time of the decision 
to offer CRCLM surgery to that individual. Potential participants who require a primary CRC 
resection or ‘downsizing’ chemotherapy for liver metastases prior to CRCLM surgery should 
be reviewed for CRCLM surgery by the MDT again following primary CRC surgery/ 
‘downsizing’ chemotherapy of CRCLM and assessed regarding eligibility for trial participation 
at that point.  
Potential participants will be approached about the trial at the outpatient appointment, at which 
CRCLM surgery is discussed and will be provided with the full Participant Information Sheet 
and Informed Consent Form (PIS/ICF) at this time. 
 
10.3.2 Consent Process 
Potential participants will be given sufficient time (e.g. 1-2 hours or as considered sufficient by 
the individual) to independently consider the verbal and written trial information provided. 
Potential participants may be invited to provide their informed consent for the study at the time 
of the initial approach. This approach may be beneficial when patients have travelled a 
significant distance for tertiary-level clinical management and may not accept a dedicated 
research visit soon after the outpatient clinic appointment.  A member of the site trial team may 
contact a potential participant by telephone and send the PIS/ICF in advance of the outpatient 
clinic visit in order to introduce the concept of the EMT2 Trial and research in general, 
particularly if there is likely to be a short period of time between the clinic assessment and 
likely CRCLM surgery.   
However, if any potential participant requires more time to consider trial participation, this will 
be accommodated through an additional visit for consent and randomisation, with provision to 
take the PIS/ICF home for subsequent telephone contact by a research nurse. If the potential 
participant is interested in taking part in the study, the research nurse will arrange a dedicated 
clinic visit for the purpose of consent, randomisation and dispensing of treatment. 
Assenting potential participants will be invited to provide written informed consent. The PI or 
any other clinician who has received Good Clinical Practice (GCP) training and is authorised 
on the trial delegation log is permitted to take informed consent for trial participation. The right 
of the participant to refuse consent without giving reasons will be respected. Further, the 
participant will be told that they are free to withdraw from the trial at any time without giving 
reasons and without prejudicing any further treatment. 

 
EMT2 version 9.0, 27th July 2022 
29 
 
A record of the consent process detailing the date of consent and all those present will be kept 
in the participants’ medical notes. The original consent form(s) will be filed in the Investigator 
Site File, a copy of the consent form(s) will be given to the participant and a copy of the consent 
form(s) will be returned to the Clinical Trials Research Unit (CTRU), at the University of Leeds 
and another copy will be filed in the hospital notes (as per local practice). 
After informed consent has been obtained for the EMT2 trial, the participant will be given the 
opportunity to decide whether to join the Biospecimen Collection sub-study by reading the 
separate PIS for this study. Informed consent and inclusion in the sub-study is independent of 
EMT2 participation (refer to study specific documentation). 
Prior to or at Visit 10 (end of the Intervention Phase), participants will be approached to provide 
their written informed consent to continue into the extended follow-up phase.  
 
10.3.3 Loss of capacity following informed consent 
Where valid informed consent is obtained from the participant and the participant subsequently 
becomes unable to provide ongoing informed consent by virtue of physical or mental 
incapacity, the consent previously given when capable remains legally valid. 
Participants who lose mental capacity after informed consent has been obtained will continue 
trial treatment if considered appropriate by the PI and the participant’s carer/family with the 
participant’s best interests foremost in the decision-making process. Ongoing collection of 
safety and follow-up data will continue via the clinical care team for inclusion in the trial analysis 
in order to preserve the integrity of the trial’s intention to treat analysis and fulfil regulatory 
requirements specifically for pharmacovigilance purposes. 
 
10.3.4. Eligibility Process 
The MDT will assess eligibility for CRCLM liver resection using a recent CT scan to confirm 
that the CRCLM are resectable with curative intent. A trial clinician listed on the EMT2 
Authorised Personnel Log will confirm suitability for surgery and eligibility for EMT2 but in the 
majority of cases, patients suitable for surgery are eligible for participation in the study. 
Women of childbearing potential will have a pregnancy test following consent and prior to 
randomisation. Women found to be pregnant will not be randomised into the trial but will be 
registered and assigned a trial number for monitoring purposes.  
A CT scan of the thorax/abdomen/pelvis will be used to confirm that the participant is eligible 
for curative CRCLM resection and may be collected retrospectively as part of the sarcopaenia 
analysis (see Section 13.15). 

 
EMT2 version 9.0, 27th July 2022 
30 
 
All EMT2 participants are eligible for the Biospecimen Collection sub-study if the NHS research 
site is taking part in the Biospecimen Collection sub-study. 
 
10.4 
Registration and Randomisation 
 
 
 
10.4.1  Timing of Registration and Randomisation 
Recruitment of some participants into the EMT2 trial requires a trial-specific investigation to 
confirm eligibility. Women of childbearing potential will require a pregnancy test prior to 
randomisation. Therefore, recruitment is a two-step process with all participants providing 
written 
informed 
consent 
for 
entry 
into 
the 
trial 
before 
the 
CTRU 
24-hour 
registration/randomisation system is accessed.  
Those participants who are not women of childbearing potential will be registered and 
randomised into the trial during the same telephone call/web session. 
Those participants who are women of childbearing potential will be registered into the trial and 
will require a pregnancy test. Those participants who are confirmed not to be pregnant can 
then be randomised into the trial. Those participants who are confirmed to be pregnant must 
be registered into the trial but will not be randomised. 
Informed written consent for entry into the trial must be obtained prior to registration. Following 
confirmation of written informed consent and eligibility, participants will be registered and 
randomised into the trial by an authorised member of staff at the trial site. All participants who 
consent to the trial must be registered. Where possible, the date for surgery should be booked 
prior to randomisation. Randomisation should take place as soon as possible after consent is 
obtained and eligibility confirmed, and will be prior to the day of CRCLM surgery.  
 
 10.4.2 Treatment Allocation 
Participants will be randomised on a 1:1 basis to receive either IPE 4 g daily or placebo and 
will be allocated a trial number and a unique kit-code to identify which box of capsules (active 
[IPE]or placebo) will be dispensed. The participant’s randomisation allocation will not be 
disclosed in order to maintain the blinding of the trial. 
A computer-generated minimisation programme that incorporates a random element will be 
used to ensure that treatment groups are well balanced for the following participant 
characteristics, details of which will be required for randomisation: 
• 
’Downsizing’ chemotherapy prior to liver resection* (yes or no) 
• 
Known extrahepatic CRC metastases with curative treatment planned (yes or no) 
• 
Current regular (intention to use daily) aspirin use: 

 
EMT2 version 9.0, 27th July 2022 
31 
 
− 
yes to current regular aspirin use 
− 
no to current regular aspirin use 
− 
Add-aspirin trial participant still taking IMP (placebo or aspirin, double-blind 
trial so treatment allocation not required to be known at EMT2 
randomisation) 
• 
Randomising Centre 
• 
Time between randomisation date and date of planned liver resection surgery (<2 
weeks or ≥2 weeks) 
*For definition see Section 9.4 
 
10.4.3 Registration and Randomisation Process 
Registration and randomisation will be performed centrally using the CTRU automated 24-
hour telephone/web randomisation service. Authorisation codes and PINs, provided by the 
CTRU, will be required to access the randomisation system. Only authorised members of staff 
at the trial sites will be able to access the randomisation system.  
Participants will be registered into the trial and issued a trial number. Women of childbearing 
potential will be required to take a pregnancy test prior to randomisation. Participants who are 
not women of childbearing potential may proceed directly to randomisation during the same 
telephone call/web session. 
The following information will be required in order for the participant to be registered and 
randomised. The person performing the registration/randomisation should have all details to 
hand: 
• 
Name and code (assigned by the CTRU) of trial site  
• 
Name of person performing the registration/randomisation 
• 
Patient initials, and date of birth 
• 
Confirmation of eligibility  
• 
Confirmation of whether the participant is a woman of childbearing potential 
• 
Confirmation of written informed consent 
• 
Stratification factors (see section 0) 
• 
Planned operation date 
 

 
EMT2 version 9.0, 27th July 2022 
32 
 
 
Direct line for 24-hour registration/randomisation 
0113 343 2290 
Website for registration/randomisation: 
https://lictr.leeds.ac.uk/webrand/ 
 
Please ensure that the Eligibility Checklist and Randomisation CRFs have been 
completed before starting the registration/randomisation process 
 
At the end of the registration process a unique EMT2 trial participant identifier will be assigned. 
At the end of the randomisation process a unique kit-code will be provided which identifies the 
box of capsules that needs to be dispensed by pharmacy. The participant’s randomisation 
allocation will not be disclosed in order to maintain the blinding of the trial.  
 
10.4.4  Post Randomisation Actions 
Two Confirmation of Randomisation notifications, detailing the participant details and the kit-
code they have been allocated, will be sent to site by email: one to the nominated contact in 
the local research team and another to pharmacy. These notifications are generated and sent 
automatically from the CTRU. In the event of a system failure, the kit-code may need to be 
provided to the pharmacy directly by the member of site staff randomising the participant (this 
information will be provided as part of the randomisation procedure). Confirmation of 
randomisation will also be automatically sent to the local PI. 
10.4.4.1  Pharmacy 
The kit-code provided will inform pharmacy which box of capsules needs to be dispensed to 
the 
participant. 
Upon 
receipt 
of 
the 
Confirmation 
of 
Randomisation/Replenishment/Replacement notification the pharmacy will dispense the box 
with the required kit-code and will subsequently confirm to CTRU the kit-code of the box 
dispensed by peeling off the relevant section of the label containing the kit-code confirmation, 
attaching this to the Confirmation of Randomisation/Replenishment/Replacement received 
and returning this back to CTRU immediately by fax or by sending a scanned copy via secure 
email. The participant’s trial number and initials should be recorded on the IMP box and on the 
corresponding codebreak envelope. The codebreak envelopes will be held securely by 
pharmacy in order to be available for any necessary emergency unblindings (see Section 0). 
 
10.4.4.2  Research Team 
At the end of the randomisation procedure, the trial participant identifier and kit-code must be 
added to the Randomisation CRF and all participant details must be added to the main 

 
EMT2 version 9.0, 27th July 2022 
33 
 
Participant ID Log. Once received by the research team, the Confirmation of Randomisation 
is filed in the EMT2 Investigator Site File. 
 
11. 
Trial Medicinal Product Management 
Please refer to the EMT2 Pharmacy and Investigational Medicinal Product (IMP) Study Site 
Operating Procedure (SSOP) for full details of the trial IMP management requirements.  
Within the trial the following are classed as IMPs: 
Eicosapentaenoic acid ethyl ester (EPA-EE [IPE]) 
• Composition: soft, amber to light yellow, oblong gelatin capsules, one capsule contains 
1g (998 mg) pure EPA-EE equivalent to 914 mg EPA-FFA 
• Supplied by Amarin Pharma Inc. 
Placebo  
• 
Composition: soft, amber to light yellow, oblong gelatin capsules containing 1 g light 
mineral oil57 
• 
Supplied by Amarin Pharma Inc. 
Capsule excipients for both active and placebo capsules are sorbitol (83 mg per capsule) 
and maltitol (30 mg per capsule). Therefore, patients with hereditary fructose intolerance are 
not eligible for the EMT2 trial. 
 
The IMP also contains soya lecithin. The MHRA has deemed that patients who have a 
known allergy to soya or peanut should not use IPE (Vazkepa®) capsules. Therefore, known 
allergy to soya or peanut is an exclusion criterion for recruitment to EMT2. 
 
The capsule coating contains gelatin of animal origin and therefore is not suitable for 
vegetarians.      
For handling guidance of both EPA-EE (IPE) and placebo, please refer to the SmPC for IPE 
(icosapent ethyl) (Vazkepa®). The guidelines in this protocol are in line with manufacturers’ 
recommendations at the time of writing, but SmPCs are updated from time to time. Up-to-
date SPCs are posted on the MHRA website (https://products.mhra.gov.uk/product/) 
[Appendix E].  
In order to maintain the blinding of the trial, both the IPE and placebo capsules look identical 
and are identically packaged and labelled in bottles with the same study-specific label in 
accordance with Directive 2001/20/EC and the Medicines for Human Use (Clinical Trials) 
Regulations 2004 (as amended).  IMP boxes will be identified only by a unique kit-code 
assigned at random. 

 
EMT2 version 9.0, 27th July 2022 
34 
 
 
11.1 
Supply and distribution  
Stockport Pharmaceuticals at Stockport NHS Foundation Trust will act as the trial’s Central 
Pharmacy and holds a Manufacturer’s Authorisation for Investigational Medicinal Products 
(IMP). 
The trial IPE capsules and placebo capsules are obtained from Amarin Pharma Inc. 
(Bedminster, New Jersey, USA).  IMP will be imported from the USA by Fisher Clinical 
Services (Horsham, UK) and will then be sent to the Central Pharmacy where the bottles and 
boxes will be labelled and packaged for trial purposes.  
Labelled trial IMP boxes will be stored by Stockport Pharmaceuticals and distributed to 
participating centres on request by CTRU. CTRU will manage a record of IMP at participating 
centres and order replacement stock as required. 
Management of IMP supply will be carried out by CTRU using a kit logistics application which 
is linked to the 24-hour randomisation system. The kit logistics application will allocate kit-code 
labelled IMP boxes, as assigned by the safety statistician, at randomisation and at each trial 
visit. An authorised member of the trial team will use the 24-hour telephone/web randomisation 
system to obtain a kit code for the IMP to be dispensed to a participant at each visit as required; 
this is known as replenishment. Should a participant require a dispensing before a scheduled 
replenishment visit or delivery (for example if they lose the capsules) an authorised member 
of the trial team will access the 24-hour telephone/web randomisation system to obtain a kit 
code to be dispensed. This is known as replacement. 
Blinded management of the kit logistics application will be conducted by the Senior Trial Co-
ordinator. Management of the kit-code lists uploaded to the kit logistics application will be 
conducted unblinded by the CTRU Safety Statistician. In addition to the automated system, 
there will be a back-up kit-code list for each site which will also be maintained by the CTRU 
Safety Statistician. The CTRU Safety Statistician will be responsible for maintaining all kit-
code lists and all lists will be securely password-protected when treatment information is 
contained within the list.  
Trial IMPs (IPE and placebo) will be provided to sites free of charge for use in this clinical trial. 
 
11.2 
Prescribing and participant supply management 
Each box contains seven bottles of IMP capsules (130 capsules in each bottle) and is sufficient 
for approximately 7 months of trial treatment (to allow for a standard 6 month treatment period 
and incorporating a +/- 2 week window around the visit date). One box of IMP capsules will be 
dispensed to participants at the start of treatment (visit 1) and at visit 3/trial telephone call 
onwards. It is expected that the entire box of IMP capsules dispensed at visit 1 will not have 
been used by visit 2.  However, a repeat dispensing of IMP should be dispensed at visit 2 if 

 
EMT2 version 9.0, 27th July 2022 
35 
 
surgery is >2 weeks after randomisation to cover a possible trial treatment period in excess of 
7 months between visit 1 and visit 3.  
Participants will be asked to bring in their IMP boxes at each trial visit or report the number of 
capsules remaining at a trial telephone call so that the participant’s IMP can be checked by 
the research nurse with regards to the amount of IMP remaining and the expiry date. If the 
participant requires a further supply of IMP to ensure that there is sufficient IMP to continue 
treatment until the next trial visit (i.e. a 7 month supply), an additional box will be dispensed.  
The expiry date of the capsules will be printed on the bottle and box labels, the IMP bottles 
and the IMP box and the participant will be responsible for checking on an ongoing basis that 
the capsules being used have not expired. The participant will be provided with a Participant 
Drug Tracking Card which will list the visit/telephone call numbers, visit date/telephone call 
dates, kit-codes and expiry dates of all IMP boxes dispensed to the participant to aid in tracking 
which IMP box to use. Participants will be asked to return any expired IMP supply to clinic 
when attending trial visits.  For participants undertaking telephone clinic follow-up due to 
distance from the trial site hospital, participants will be asked to store all unused/expired IMP 
until it is collected at the end of the trial. 
Since IMP will be dispensed at each visit, it is expected that the participant may eventually 
accumulate sufficient IMP to last until the next trial visit and a dispensing will not be required. 
It is the responsibility of the prescribing healthcare professional to determine whether the 
participant has sufficient IMP with an appropriate expiry date (i.e. a 7 month supply) to miss a 
dispensing episode. 
 
11.3 
Dispensing 
The relevant site pharmacist will be notified by the CTRU of all randomisations, replenishments 
and replacements at that site, either by fax or secure email; each Confirmation of 
Randomisation/Replenishment/Replacement notification will detail the participant trial ID 
number, date of birth, initials and the kit-code assigned to that participant. In order to maintain 
the blinding of the trial the pharmacist will not be informed of the participant’s treatment 
allocation.  
Each box of trial IMP, identifiable only by the unique kit-code, will have a corresponding 
code-break envelope. Each time a box is dispensed, the participant identifiers must be 
added to the trial IMP box label and also to the corresponding code-break envelope by 
the dispensing pharmacist. This code-break envelope will then be held securely within 
the site pharmacy for access required in the event of unblinding (see Section 12.3). 
At each dispensing the participant will receive one trial IMP box, containing seven bottles (130 
capsules per bottle, providing 910 capsules per box), of either IPE or placebo.  

 
EMT2 version 9.0, 27th July 2022 
36 
 
Participants will take 4 capsules per day with food. A suggested schedule is 2 capsules taken 
in the morning with food and 2 capsules in the evening with food but participants are able to 
vary the timing to once daily with food according to preference and ease of use. 
Dispensing must be performed by an authorised member of site staff as delegated on the trial 
Pharmacy Authorised Personnel Log. All dispensed trial IMP must be recorded on the trial 
Accountability and Dispensing Log. 
Courier delivery of IMP is permissible for participants who are unable to return to collect IMP 
from the dispensing hospital after Visit 2 due to the excessive distance between home and 
hospital.  The IMP delivery will be arranged by a member of the site staff, who will be 
responsible for arranging a courier and confirming successful delivery to the participant.  
Courier account and contact details will be provided by CTRU.  Receipt of the IMP by the 
participant should be documented in the participant’s clinical notes.   
11.4 
Storage 
Trial IMPs will be stored in pharmacy at room temperature. If the pharmacy storage 
temperature exceeds 25°C please quarantine stock and contact CTRU. 
The supply of trial IMPs (IPE and placebo) must not be used for any purpose other than 
that outlined in this protocol and should be clearly ring-fenced from standard hospital 
stock. 
 
11.5 
Reconciliation   
Receipt of IMP at participating centres and trial stock dispensed to participants must be 
recorded on the EMT2 Accountability and Dispensing Logs. These completed logs will be 
returned to CTRU upon request to facilitate central IMP reconciliation. 
Participants should return any unused trial IMP stock to the participating centre and the 
pharmacy should record these returns. The returned capsules should be counted, recorded 
and the record returned to CTRU prior to local destruction as per standard operating 
procedures. For participants receiving a courier delivery of IMP, unused capsules will be 
collected and returned to the dispensing pharmacy at Visit 10/Exit visit or sooner if the 
participant stops treatment or withdraws from trial treatment and follow up. 
Code-break envelopes for any un-dispensed trial IMP will be returned to CTRU during 
reconciliation for each trial IMP batch. Code-break envelopes for dispensed trial IMP will be 
collected after all participants have completed the 60-day post-treatment period at the 
completion of trial treatment. Code-break envelopes will be checked by the CTRU for potential 
unreported unblinding (i.e. opened or damaged envelopes). 
 

 
EMT2 version 9.0, 27th July 2022 
37 
 
12. 
Treatment  
The following section of the protocol describes treatment for participants with IPE or placebo. 
The local Investigator, the site pharmacist, other members of the site staff involved with the 
trial, and the participants themselves, will remain blinded to the treatment allocation (except 
when emergency unblinding is required). 
 
12.1 
Treatment Details 
Participants will be randomised to receive either IPE or placebo capsules for a minimum of 2 
years and a maximum of 4 years post liver resection. Participants will be resupplied with IMP 
at each trial visit, as required. Since IMP will be dispensed at each visit/telephone call, it is 
expected that the participant may eventually accumulate sufficient IMP to last until the next 
trial visit and a dispensing will not be required. It is the responsibility of the prescribing 
healthcare professional to determine whether the participant has sufficient IMP with an 
appropriate expiry date to miss a dispensing visit. 
When dispensing IMP at trial visits/telephone calls, authorised members of staff at the 
participating centre will access the CTRU 24-hour service which will inform the site of the kit-
code for the box to be dispensed. Pharmacy will receive a fax or email to inform them of which 
kit-code labelled box to dispense. 
 
12.2 
Treatment Regimen  
Participants will be randomised to receive either 4 x 1g capsules of IPE or 4 identical placebo 
capsules daily.  Participants should take their capsules with food. 
The trial treatment should be taken daily from the date of randomisation until the participant 
has completed study treatment (maximum of four years treatment post liver resection).  
Trial treatment will continue following diagnosis of disease progression or diagnosis of 
a new primary cancer as there is still potential for EPA treatment to improve outcomes of any 
new or recurrent cancer. 
 
12.2.1 Treatment breaks 
While it is preferred that participants continue their trial medication daily, it may be necessary 
for participants to take one or more treatment breaks during follow-up. Examples of possible 
reasons for a treatment break include in-patient hospital stays (eg. for CRCLM surgery) if nil 
by mouth is specified or during chemotherapy treatment or other concurrent treatment that 
results in a persistent adverse reaction (AR) or difficulty taking IMP.  

 
EMT2 version 9.0, 27th July 2022 
38 
 
In the event of a persistent AR, a dose reduction (see Section 12.2.4) should be tried prior to 
a treatment break. Details of any dose reduction or break in treatment should be recorded on 
the Treatment CRF, including the duration and reason. 
 
12.2.2  Concomitant medication 
It is expected that a proportion of participants will require chemotherapy following CRCLM 
surgery. It is not considered necessary for trial treatment to be discontinued during 
chemotherapy. However, should the participant experience adverse events (AEs) during 
chemotherapy that might be exacerbated by EPA use and these do not resolve with the IPE 
dose–reduction algorithm (see Figure 1 in Section 0), the participant may take a temporary 
treatment break from trial treatment. Details of this treatment break should be recorded on the 
Treatment CRF. 
Details of any concomitant medication, including details of all over-the-counter medications, 
should be recorded on the Treatment CRF. 
Over-the-counter or prescribed nutritional supplements containing any O3FA eg. Seven 
Seas® or prescribed O3FAs (Vazkepa, Omacor) are prohibited while participants are 
receiving trial treatment and are an exclusion criterion for the trial. Therefore, any participants 
consistently using over-the-counter O3FA preparations or requiring treatment with a 
prescription O3FA for hypertriglyceridaemia or for vascular prophylaxis will be withdrawn from 
trial treatment and the site will complete the Protocol Violation CRF and forward this to CTRU 
as soon as possible. The participant will continue to be followed up as normal. 
As participants are not informed of their treatment allocation, it is possible that any concomitant 
O3FA supplementation could add to their treatment dose which is not advised in the interest 
of participant safety. In addition, persistent use of over-the-counter O3FAs may compromise 
the trial results should participants in the placebo arm receive O3FAs, as this will result in 
‘contamination’ of the control group. 
Participants should be reminded at each trial visit/telephone call that it is not permitted 
for O3FA supplements to be taken during trial participation. 
Concomitant use of aspirin and/or any other anti-platelet agent is allowed with usual 
management of anti-platelet agent use around interventional procedures being followed. 
Similarly, concomitant warfarin use is allowed with usual careful monitoring of anticoagulation 
control. In the absence of any data on any adverse interaction between O3FAs and new oral 
anticoagulants (NOACs) such as rivaroxaban and dabigatran, concomitant use of NOACs is 
allowed. In the REDUCE-IT trial of 8179 individuals with cardiovascular disease or risk factors 
(approximately 10% taking concomitant anticoagulation, with or without an antiplatelet agent), 
serious bleeding events were reported more frequently in subjects receiving IPE 4 g daily 
(3.4%) than in those receiving placebo (2.6%) when administered in combination with 

 
EMT2 version 9.0, 27th July 2022 
39 
 
concomitant antithrombotic medication, but occurred at the same rate (0.2%) in subjects not 
taking concomitant anticoagulant/antiplatelet medication54.    
12.2.3.  Known Toxicities 
As this is a blinded trial, adverse events should be assessed for a causal relationship 
assuming the participant has been receiving active IPE. 
The active IMP (IPE  4 g per day; Vazkepa®) is licensed for use in the UK for reduction of the 
risk of cardiovascular events in adults, who have elevated triglyceride levels despite statin 
treatment and have established cardiovascular disease, or diabetes and at least one other 
cardiovascular risk factor. The safety profile and adverse reactions associated with IPE 4 g 
per day, which are described in the Summary of Product Characteristics (SmPC) for IPE 
approved by the MHRA, are based largely on the REDUCE-IT trial of 8179 individuals with a 
median age of 64 years, male sex 71% and white race 90%54. These characteristics are similar 
to the proposed EMT2 trial population, who have CRC and are likely to have fewer 
cardiovascular risk factors. Therefore, the SmPC will be used as the Reference Safety 
Information (RSI) for IPE (see link). 
 
The most frequently reported adverse reactions associated with IPE are bleeding (11.8%), 
peripheral oedema (7.8%), atrial fibrillation (5.8%), constipation (5.4%), musculoskeletal pain 
(4.3%), gout (4.3%) and rash (3.0%). A list of adverse reactions and frequencies is available 
in the IPE SmPC. 
Bleeding occurred in 11.8% of subjects receiving IPE in the REDUCE-IT trial compared with 
9.9% in subjects receiving placebo. Serious bleeding events were reported more frequently in 
subjects receiving IPE than in those receiving placebo when administered in combination with 
concomitant antithrombotic medication (3.4% vs. 2.6%), but occurred at the same rate (0.2%) 
in subjects not taking concomitant anticoagulant/antiplatelet medication. The bleeding events 
most frequently observed with IPE were gastrointestinal bleeding (3.1%), contusion (2.5%), 
haematuria (1.9%), and epistaxis (1.5%). 
Atrial fibrillation or atrial flutter occurred in 5.8% of subjects receiving IPE in the REDUCE-IT 
trial compared with 4.5% in subjects receiving placebo54. Atrial fibrillation or atrial flutter 
requiring hospitalisation for 24 hours or more occurred in 3% of subjects treated with IPE 
compared with 2% in subjects receiving placebo. Atrial fibrillation and atrial flutter were 
reported more frequently in subjects with a previous history of atrial fibrillation or atrial flutter 
receiving IPE than in those receiving placebo (12.5% vs. 6.3%). An increased risk of atrial 
fibrillation in cardiovascular outcomes RCTs has subsequently been reported for other O3FA 
formulations, including mixed EPA and DHA formulations55.  
Constipation occurred in 5.4% of subjects receiving IPE in the REDUCE-IT trial compared with 
3.6% of subjects receiving placebo54. Serious constipation was less common for IPE (0.1%) 
and placebo (0.2%). The relative incidence of constipation in this study may have been 

 
EMT2 version 9.0, 27th July 2022 
40 
 
confounded by a residual laxative effect of the placebo, which comprised a subtherapeutic 
dose of light mineral oil (4 mL), which is the same placebo content used in EMT257. 
12.2.4.  Dose reduction  
Participants should be advised to contact the relevant research nurse between the 6-monthly 
clinic visits/telephone calls in the event of a persistent AE that may require capsule dose 
reduction. 
In the event that the participant experiences AEs that the treating clinician suspects to be 
related to trial treatment, the clinician should review the participant’s treatment regimen (eg. 
have the capsules been taken with food?). 
If the AE persists, the dose of trial treatment should be temporarily reduced as per the dose 
reduction algorithm in Figure 1 below. Dose reduction should be recorded in the medical notes 
and on the Treatment CRF. 
If a participant is undergoing a course of chemotherapy and a dose reduction has stopped the 
symptoms of an AE, the dose should not be increased back to full dose until the course of 
chemotherapy has completed.  
If a participant is undergoing a course of chemotherapy and has stopped taking trial capsules 
due to an AE (i.e. is on a treatment break), the participant should resume on the reduced dose 
once the course of chemotherapy has completed with a view to increasing the capsule dose 
to 4 capsules daily, in due course. A decision to permanently stop trial treatment should not 
be made during chemotherapy if possible. 
If a participant is still experiencing symptoms of the AE following a dose reduction, is not 
undergoing a course of chemotherapy and no other factors are considered to be contributory, 
a permanent halt to trial treatment should be considered. If a participant does permanently 
stop trial treatment, a Withdrawal CRF should be completed and returned to CTRU within 24 
hours. The participant should continue to attend trial visits or take a trial specific telephone call 
as per the trial visit schedule. 
 

 
EMT2 version 9.0, 27th July 2022 
41 
 
Figure 1: Dose reduction algorithm 
 

 
EMT2 version 9.0, 27th July 2022 
42 
 
12.2.5.  Treatment Compliance 
Treatment compliance will be assessed by questions at each trial visit/telephone call to 
determine if the participant has had any delayed, missed or modified doses. This information 
will be recorded on the appropriate Follow-up Form. Any unused expired capsules will be 
collected from the participants by the research team at the next trial visit or at the end of the 
trial for those participants undertaking telephone clinic follow up and returned to pharmacy for 
drug reconciliation and local destruction (see Section 11.5 above for further details). 
The fatty acid analysis on visit 2 and 3 samples compared with baseline visit 1 (see 
Section13.16) will act as a marker of compliance to IPE and also allows the assessment of 
whether the placebo arm has been ‘contaminated’ by possible participant supplementation 
with over-the-counter O3FA. 
 
12.3 
Blinding 
The Principal Investigator, participating centre staff, pharmacy staff, participants and the 
CTRU staff involved in the day to day activities of the trial will be blinded to the treatment 
allocation of each participant. 
Participants will not be informed of their trial allocation until the final analysis has been 
completed and the results of the study are published. At this time the CTRU will provide each 
site with a list of treatment allocations for participants recruited at that site. Participants cannot 
request their trial allocations until this time. 
The following controls will be employed to maintain the double blind status of the trial: 
• 
The IPE and placebo capsules and bottles will be identical in appearance and have the 
same labelling. 
• 
Boxes will be identified by a unique kit code assigned at random. The CTRU Safety 
Statistician (an independent CTRU statistician responsible for carrying out tasks requiring 
access to unblinded information) will be responsible for maintaining this list, which will be 
securely password protected when treatment information is contained within the list. 
• 
The Investigator and other members of the site staff involved with the trial and the 
participants themselves will remain blinded to the treatment allocation (except where 
emergency unblinding is necessitated). 
The following outlines how unblinding will be kept to a minimum for tasks to be conducted 
unblinded at the CTRU: 

 
EMT2 version 9.0, 27th July 2022 
43 
 
• 
Management of kit-codes on the kit logistics application which is linked to the 24-hour 
randomisation system will be conducted by the CTRU Safety Statistician in addition to 
maintaining the back-up kit-code lists for each centre. 
• 
Any unblinded interim reports provided to the Data Monitoring and Ethics Committee 
(DMEC) will be provided by the CTRU Safety Statistician and the reports will be securely 
password-protected. 
• 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be unblinded by the 
CTRU Safety Statistician. If the event requires expedited reporting, the Safety Statistician 
will pass the SUSAR to the trial Data Manager who will be responsible for electronic 
SUSAR reporting to the Medicine and Healthcare Regulatory Agency (MHRA) and the 
ethics committee. Unblinded records of SUSARs reported will be maintained by the Safety 
Statistician. 
Code break procedures are outlined below and described in detail in the Emergency 
Unblinding SSOP provided in the Investigator Site File and Pharmacy Site File. 
 
12.3.1 
Emergency Unblinding 
Whilst the safety of participants in the trial must always take priority, maintenance of the blind 
is crucial to the integrity of the trial. Investigators should only break the blind when information 
about the participant‘s trial treatment is clearly necessary for the appropriate medical 
management of the participant and where stopping the blinded medication is not sufficient.  
Unblinding may be requested on the grounds of safety by the Chief Investigator (CI), local PI 
or treating physician. It is anticipated that requests for unblinding will most likely originate from 
a participant, carer (or friend/family member) or personal physician (e.g. GP) at the time of an 
adverse event or planned change in non-trial related drug therapy. Requests for unblinding 
will first be handled by the local PI or delegate who will explore the reason for the request and 
evaluate the importance of knowledge of treatment assignment for participant safety. In the 
event of a Serious Adverse Event (SAE), all participants should be treated as though they are 
receiving the active medication. Refer to protocol Section 14 (Pharmacovigilance). 
Should an alternative to unblinding not be identified, and if unblinding is required to optimise 
medical management of the participant, investigators should follow the emergency unblinding 
process.  
Emergency unblinding is provided by the CTRU during Office Hours and the 
participating site pharmacy at all other times, thereby covering each 24-hour period. It 
is encouraged that requests for Emergency unblinding should be made directly with 
CTRU wherever possible. 

 
EMT2 version 9.0, 27th July 2022 
44 
 
During Office Hours (9:00 to 17:00 Monday to Friday excluding public/bank holidays, the period 
between Christmas Eve and New Year, Thursday afternoon before Good Friday and all 
Tuesdays following a bank holiday except for Mayday and New Year’s Day), Investigators 
should telephone CTRU who will carry out the unblinding procedure.  
Outside of Office Hours, or where the Investigator is unable to contact CTRU, emergency 
unblinding may also be undertaken by contacting the local/assigned pharmacy department at 
the respective participating centre who will also hold code-break envelopes. Code-Break 
envelopes for unblindings will be provided to pharmacy at the time of IMP delivery and each 
envelope will be linked to a specific box of capsules using a unique kit-code. 
 
 
   
 
 
The following information will be needed to perform an emergency unblinding:   
• 
Participant details, including trial ID number, initials and date of birth  
• 
Name of trial research site and site code  
• 
Name of person making the request for a code-break  
• 
Reason for requesting a code-break  
• 
Confirmation of whether the PI authorised the request  
 
Following the emergency unblinding of a participant, CTRU will fax or send via secure email a 
confirmation of emergency unblinding to the requester and the local PI. The details of the 
emergency unblinding should be recorded on the EMT2 Unblinding Log provided by CTRU.  
Outside of Office Hours, or where the Investigator or treating physician is unable to contact 
CTRU, emergency unblinding must be performed by the local pharmacy department. The 
responsible pharmacist on duty will complete the Unblind Request CRF, retrieve the code-
break information and reveal the treatment allocation to the person requesting the unblind. 
The pharmacist must return (by fax or secure email) the completed Unblind Request CRF to 
the CTRU within 24 hours of the unblinding request.  
Following an emergency unblinding the participant should stop trial treatment and be treated 
in line with local hospital policy. The participant will continue to be followed-up as per the trial 
protocol. 
Further information on emergency unblinding can be found in the Emergency Unblinding 
SSOP located within the Investigator Site File and Pharmacy Site File. 
Direct line for CTRU emergency unblinding: 0113 343 4930 

 
EMT2 version 9.0, 27th July 2022 
45 
 
12.4 
Withdrawals 
In line with usual clinical care, cessation or alteration of regimens at any time will be at the 
discretion of attending clinicians or the participants themselves. All participants withdrawn from 
treatment or prescribed alternative treatment will still attend for follow-up assessments unless 
unwilling to do so and CRFs will continue to be completed. 
The Withdrawal CRF should be completed and faxed or sent via secure email to the CTRU 
within 24 hours of the research team becoming aware.  
Treatment breaks are permitted if necessary (see Section 12.2.1). Participants should not be 
recorded as withdrawn from trial treatment until it is clear that they will not be resuming trial 
treatment. 
The PI or delegate should make every effort to ensure that the specific wishes of any 
participant who wishes to withdraw consent for further involvement in the trial are defined and 
documented using the Withdrawal CRF in order that the correct processes are followed by the 
CTRU and site following the withdrawal of consent.  
It should be made clear to any participant specifically withdrawing consent for further 
data collection that data pertaining to safety will continue to be collected for regulatory 
reporting purposes and will be included in any safety analysis. In addition it is 
suggested that the participant is made aware of the fact that if any significant new 
information becomes available in regard to the treatment they have received in the trial 
it may be necessary to contact them in the future. 
In the event that the liver metastases are not able to be removed surgically, trial treatment and 
follow-up should continue as per protocol (see section 13.4). 
 
13. 
Assessments, Samples and Data Collection 
Data will be collected using paper CRFs, the electronic templates for which will be provided 
by the CTRU and upon completion should be returned to the CTRU at the University of Leeds. 
Participating hospitals will be expected to maintain a file of essential trial documentation 
(Investigator Site File), which will be provided by the CTRU, and keep copies of all completed 
CRFs for the trial in the Investigator Site File. 
 
The timings of interventions and assessments required for the EMT2 trial are summarised in 
Appendix A: Schedule of Events. 
 
13.1 
Assessment of eligibility and randomisation 
Potential participants will be identified through the hepatobiliary MDT at the time of the decision 
to offer CRCLM surgery to that individual. The MDT will review the most recent CT of the 

 
EMT2 version 9.0, 27th July 2022 
46 
 
thorax, abdomen and pelvis and determine eligibility for CRCLM surgery. This CT scan may 
be collected retrospectively as part of the sarcopaenia analysis. 
If the patient is eligible for CRCLM surgery, the surgeon will assess eligibility (medical review 
including medical history, assessment of management of the underlying disease, pregnancy 
and concomitant medication use) for trial participation at the surgical outpatient visit at which 
CRCLM surgery is discussed with the patient.  The trial site team may telephone the potential 
participant in order to introduce the trial in general terms and then send a PIS/ICF in advance 
of an outpatient clinic appointment, especially if the time between outpatient review of eligibility 
for surgery and the date of CRCLM surgery is limited. 
Participants must be screened and have given written informed consent before any trial 
specific procedures are performed and the participant is randomised. 
For patients who do not go on to be registered, details should be added to the Screening Log 
(see Section 10.2). All patients who consent to trial participation must be registered. 
If, following randomisation, a participant is found to be in breach of the eligibility criteria the 
Protocol Violations CRF should be completed and returned (by fax or secure email) to CTRU 
immediately. 
 
13.2 
Visit 1: Baseline Assessment and Data Collection 
Trial specific assessments must take place following consent and randomisation, except for 
the baseline Quality of Life questionnaires which must be done following consent but should 
wherever possible be done before meeting with the clinician/randomisation. 
Once randomised into the study, the participant will be assessed by a member of the research 
team and the following baseline assessments will be carried out: 
• 
Participant self-reported assessments: the EQ-5D, EORTC QLQ-C30 and QLQ-
LMC21 Quality of Life questionnaires and a health economics questionnaire will be 
administered to the participant in a Participant Questionnaire Visit 1 Pack.  
• 
Participants should be provided with a Participant Diary Booklet to record information 
over the next visit period. The information collected in the booklet will be the information 
to be collected in the health economics questionnaire and details on compliance and 
adverse events. The booklet is intended to act as a reminder to the participant and 
must not be handed in to clinic or returned to the CTRU. 
• 
Weight in kilograms (in light indoor clothing and without shoes). 
• 
Blood sample for red blood cell fatty acid analysis (for Sheffield Teaching Hospitals 
NHS Foundation Trust and Leeds Teaching Hospitals NHS Trust only). A blood 
sample should be collected in two EDTA-coated Vacuette® tubes and agitated 

 
EMT2 version 9.0, 27th July 2022 
47 
 
immediately to prevent clotting. The blood components should be separated within 30 
minutes of taking the blood sample (see Section 13.16). If not processed immediately, 
store the two tubes in the fridge at 4°C for up to 30 minutes. 
• 
One box of IMP will be dispensed. 
• 
A CT scan should be organised for 6 months following the anticipated date of CRCLM 
surgery, once known. For participants undergoing a two-stage resection, the CT scan 
should be planned for 6 months following the completion of the second resection. 
• 
An invitation to join the Biospecimen Collection sub-study should be extended to the 
participant using the dedicated PISICF (see Biospecimen Collection protocol). 
• 
If written informed consent for the Biospecimen Collection sub-study is obtained, 
sample collection packs should be provided and a blood sample taken (if consent 
given) according to the Biospecimen Collection protocol.  
 
13.3 
Research nurse telephone calls (every 2 weeks between 
visits 1 and 2) 
Participants will be contacted every 2 weeks +/-3 days by a research nurse between 
randomisation and CRCLM surgery. If the research nurse is unable to contact the participant 
every reasonable effort will be made to contact the participant as soon as possible. The 
research nurse will contact the participant by telephone to perform the following assessments: 
• 
Toxicity assessment: collection of any adverse events which may have occurred over 
the last two weeks.  
• 
Details of hospital resource activity (e.g. hospital inpatient stays, outpatient clinics 
attending, accident and emergency attendances). 
• 
Treatment compliance: the participant will be asked if they have missed any treatment 
doses in the last two weeks and for what reason.  
• 
Details of concomitant medications including over-the-counter O3FA supplements 
since visit 1 or since the last research nurse telephone call. Participants should be 
reminded that over-the-counter O3FA supplements are prohibited. 
 
13.4 
Visit 2: CRCLM surgery, Treatment Assessments and 
Data Collection 
Participants will have a trial visit during admission on the first day of the hospital inpatient stay 
for CRCLM surgery. The CRCLM surgery should be <6 weeks from post randomisation. 
The following assessments will be carried out: 

 
EMT2 version 9.0, 27th July 2022 
48 
 
• 
Toxicity assessment: collection of any adverse events which may have occurred since 
the last research nurse telephone call. 
• 
Details of hospital resource activity (e.g. hospital inpatient stays, outpatient clinics 
attending, accident and emergency attendances). 
• 
Participant self-reported assessments: a health economics questionnaire will be 
administered to the participant in a Participant Questionnaire Visit 2 Pack. It is 
preferable that this is administered to the participant before surgery but if this is not 
possible within the timeframe pre-surgery, the Visit 2 Pack may be completed during 
the inpatient stay.  
• 
Participants should be provided with a Participant Diary Booklet to record information 
over the next visit period. The information collected in the booklet will be the information 
to be collected in the health economics questionnaire and details on compliance and 
adverse events. The booklet is intended to act as a reminder to the participant and 
must not be handed in to clinic or returned to the CTRU. 
 
• 
Weight in kilograms (in light indoor clothing and without shoes). This may be taken 
from the pre-operative assessment in the clinical records. 
 
• 
Blood sample for red blood cell fatty acid analysis (for Sheffield Teaching Hospitals 
NHS Foundation Trust and Leeds Teaching Hospitals NHS Trust only). Please note 
that it is preferable that the blood sample is obtained prior to surgery, ideally on 
admission to hospital. A blood sample should be collected in two EDTA-coated 
Vacuette® tubes and agitated immediately to prevent clotting. The blood components 
should be separated within 30 minutes of taking the blood sample (see Section 13.16). 
If not processed immediately, store the two tubes in the fridge at 4°C for up to 30 
minutes. 
 
• 
See Biospecimen Collection protocol if participant is in this sub-study. 
• 
Treatment compliance: the participant will be asked if they have missed any treatment 
doses since the last research nurse telephone call and for what reason.  
• 
Details of concomitant medications including over-the-counter O3FA supplements 
since the last research nurse telephone call. Participants should be reminded that over-
the-counter O3FA supplements are prohibited. 
• 
The IMP dispensed at visit 1 should be checked regarding the expiry date and the 
participant should be advised to use the IMP box currently in use before opening the 
IMP box dispensed at visit 2. 
• 
One box of IMP should be dispensed if necessary.   

 
EMT2 version 9.0, 27th July 2022 
49 
 
• 
In the event that the liver metastases are not able to be removed surgically and 
macroscopic disease remains, a CT scan should be arranged as soon as 
possible in order to measure the existing disease. Trial treatment and follow-up 
should continue as per protocol. 
 
 
13.5 
Visit 3: Treatment Assessments and Data Collection 
Participants will have a trial visit 6 months +/- 2 weeks after the date of CRCLM surgery. For 
those participants having adjuvant chemotherapy the CT scan may be during the 
chemotherapy treatment period to ensure that the trial visit at 6 months +/- 2 weeks can be 
adhered to. For all participants the following assessments will be carried out: 
• 
Clinical evaluation to assess for disease progression and new primary cancer, as per 
local standard practice. 
• 
Toxicity assessment: collection of any adverse events which may have occurred since 
the last trial visit. 
• 
Details of hospital resource activity (e.g. hospital inpatient stays, outpatient clinics 
attending, accident and emergency attendances). 
• 
Participant self-reported assessments: the EQ-5D, EORTC QLQ-C30 and QLQ-
LMC21 Quality of Life questionnaires and a health economics questionnaire will be 
administered to the participant in a Participant Questionnaire Visit 3-10 Pack. 
Questionnaires should be completed by participants at the time of clinical assessment, 
but before discussion of the outcome of any medical assessments or blood tests 
wherever possible. 
• 
Participants should be provided with a Participant Diary Booklet to record information 
over the next visit period. The information collected in the booklet will be the information 
to be collected in the health economics questionnaire and details on compliance and 
adverse events. The booklet is intended to act as a reminder to the participant and 
must not be handed in to clinic or returned to the CTRU. 
• 
Weight in kilograms (in light indoor clothing and without shoes). 
• 
CT scan of thorax, abdomen and pelvis. 
• 
Treatment compliance: the participant will be asked if they have missed any treatment 
doses since the last trial visit and for what reason.  
• 
Details of concomitant medications including over-the-counter O3FA supplements 
since the last trial visit. Participants should be reminded that over-the-counter O3FA 
supplements are prohibited. 

 
EMT2 version 9.0, 27th July 2022 
50 
 
• 
Blood sample for red blood cell fatty acid analysis (for Sheffield Teaching Hospitals 
NHS Foundation Trust and Leeds Teaching Hospitals NHS Trust only). A blood sample 
should be collected in two EDTA-coated Vacuette® tubes and agitated immediately to 
prevent clotting. The blood components should be separated within 30 minutes of 
taking the blood sample (see Section13.16). If not processed immediately, store the 
two tubes in the fridge at 4°C for up to 30 minutes. 
• 
See Biospecimen Collection protocol if participant is already in this sub-study. 
• 
If the EMT2 participant has not already taken part in the Biospecimen Collection, an 
invitation to join the Biospecimen Collection sub-study to provide a single stool and 
urine sample should be extended to the participant using the dedicated post-surgery 
PIS/ICF (see Biospecimen Collection protocol). 
• 
If new written informed consent for the Biospecimen Collection sub-study is obtained, 
a sample collection pack should be provided according to the Biospecimen Collection 
protocol. 
• 
One box of IMP will be dispensed. 
• 
The IMP dispensed at visit 2 should be checked regarding the expiry date and the 
participant should be advised to use the IMP box currently in use before opening the 
IMP box dispensed at visit 3.  
 
For Visit 3 and all subsequent trial visits, follow-up can be on a remote basis by telephone 
interview, QoL questionnaires posted and courier delivery of IMP, if participants are unable to 
attend the recruiting hospital for repeat visits.  Clinical evaluation, toxicity assessment, 
compliance and concomitant medication assessment, as well as determination of hospital 
resource activity, will be performed by telephone.  Self-reported weight will be obtained.  IMP 
will be delivered to the participant’s postal address (see Section 11.3). CT scanning will be 
performed by the local Oncology team as per usual surveillance guidelines.  Participants 
randomised in Leeds and Sheffield, but undergoing remote follow-up, will not be expected to 
provide blood samples for Visit 3. 
 
13.6 
Visits 4-6: Treatment Assessments and Data Collection 
Participants will have a trial visit at 12, 18 and 24 months (+/- 2 weeks) after the date of CRCLM 
surgery. The following assessments will be carried out at each visit: 
• 
Clinical evaluation to assess for disease progression and new primary cancer, as per 
local standard practice. 
• 
Toxicity assessment: collection of any adverse events which may have occurred since 
the last trial visit. 

 
EMT2 version 9.0, 27th July 2022 
51 
 
• 
Details of hospital resource activity (e.g. hospital inpatient stays, outpatient clinics 
attending, accident and emergency attendances). 
• 
Participant self-reported assessments: the EQ-5D, EORTC QLQ-C30 and QLQ-
LMC21 Quality of Life questionnaires and a health economics questionnaire will be 
administered to the participant in a Participant Questionnaire Visit 3-10 Pack. 
Questionnaires should be completed by participants at the time of clinical/telephone 
assessment, but before discussion of the outcome of any medical assessments or 
blood tests wherever possible. 
• 
Participants should be provided with a Participant Diary Booklet to record information 
over the next visit period. The information collected in the booklet will be the information 
to be collected in the health economics questionnaire and details on compliance and 
adverse events. The booklet is intended to act as a reminder to the participant and 
must not be handed in to clinic or returned to the CTRU. 
• 
Weight in kilograms (in light indoor clothing and without shoes). 
• 
CT scan of thorax, abdomen and pelvis. 
• 
Treatment compliance: the participant will be asked if they have missed any treatment 
doses since the last trial visit and for what reason.  
• 
Details of concomitant medications including over-the-counter O3FA supplements in 
since the last trial visit. Participants should be reminded that over-the-counter O3FA 
supplements are prohibited. 
• 
One box of IMP will be dispensed. 
• 
The IMP dispensed at the previous visit should be checked regarding the expiry date 
and the participant should be advised to use the IMP box currently in use before 
opening the IMP box dispensed at this visit/telephone call. 
• 
See Biospecimen Collection protocol if participant is already in this sub-study. A 
sample collection pack may need handing /posting to the participant at visit 5. 
• 
If the EMT2 participant has not already taken part in the Biospecimen Collection, an 
invitation to join the Biospecimen Collection sub-study to provide a single stool and 
urine sample should be extended to the participant using the dedicated post-surgery 
PIS/ICF (see Biospecimen Collection protocol). 
• 
If new written informed consent for the Biospecimen Collection sub-study is obtained, 
a sample collection pack should be provided according to the Biospecimen Collection 
protocol.  
 

 
EMT2 version 9.0, 27th July 2022 
52 
 
See Section 13.5 for details of remote follow-up for Visits 4-6. 
 
13.7 
Visits 7-9: Treatment Assessments and Data Collection 
Participants should have a trial visit at 30, 36 and 42 months (+/- 2 weeks) after the date of 
CRCLM surgery. The following assessments will be carried out at each visit: 
• 
Clinical evaluation to assess for disease progression and new primary cancer, as per 
local standard practice. 
• 
Toxicity assessment: collection of any adverse events which may have occurred since 
the last trial visit. 
• 
Details of hospital resource activity (e.g. hospital inpatient stays, outpatient clinics 
attending, accident and emergency attendances). 
• 
Participant self-reported assessments: the EQ-5D, EORTC QLQ-C30 and QLQ-
LMC21 Quality of Life questionnaires and a health economics questionnaire will be 
administered to the participant in a Participant Questionnaire Visit 3-10 Pack. 
Questionnaires should be completed by participants at the time of clinical assessment, 
but before discussion of the outcome of any medical assessments or blood tests 
wherever possible. 
• 
Participants should be provided with a Participant Diary Booklet to record information 
over the next visit period. The information collected in the booklet will be the information 
to be collected in the health economics questionnaire and details on compliance and 
adverse events. The booklet is intended to act as a reminder to the participant and 
must not be handed in to clinic or returned to the CTRU. 
• 
Weight in kilograms (in light indoor clothing and without shoes). 
• 
CT scan of thorax, abdomen and pelvis at visit 8 only: CT scans are carried out on an 
annual basis after 2 years post CRCLM surgery. 
• 
Treatment compliance: the participant will be asked if they have missed any treatment 
doses since the last trial visit and for what reason.  
• 
Details of concomitant medications including over-the-counter O3FA supplements 
since the last trial visit. Participants should be reminded that over-the-counter O3FA 
supplements are prohibited. 
• 
One box of IMP will be dispensed. 

 
EMT2 version 9.0, 27th July 2022 
53 
 
• 
The IMP dispensed at the previous visit should be checked regarding the expiry date 
and the participant should be advised to use the IMP box currently in use before 
opening the IMP box dispensed at the most recent visit. 
• 
See Biospecimen Collection protocol if participant is already in this sub-study. A 
sample collection pack may need handing /posting to the participant at visit 7. 
• 
If the EMT2 participant has not already taken part in the Biospecimen Collection, an 
invitation to join the Biospecimen Collection sub-study to provide a single stool and 
urine sample should be extended to the participant using the dedicated post-surgery 
PIS/ICF (see Biospecimen Collection protocol). 
• 
If new written informed consent for the Biospecimen Collection sub-study is obtained, 
a sample collection pack should be provided according to the Biospecimen Collection 
protocol.   
 
See Section 13.5 for details of remote follow-up for Visits 7-9. 
 
13.8 
Visit 
10/End 
of 
Interventional 
Phase: 
Treatment 
Assessments and Data Collection 
Prior to or at Visit 10, all participants (whether they have continued on IMP or not) should be 
contacted to discuss the possibility of joining the extended follow-up phase of EMT2 and obtain 
written informed consent to continue into the extended follow-up phase. 
Participants will have the visit 10 no later than 48 months (+/- 2 months) after liver resection 
surgery.  
The following assessments will be carried out at the visit: 
• 
Clinical evaluation to assess for disease progression and new primary cancer, as per 
local standard practice. 
• 
Toxicity assessment: collection of any adverse events which may have occurred 
since the last trial visit. 
• 
Details of hospital resource activity (e.g. hospital inpatient stays, outpatient clinics 
attending, accident and emergency attendances). 
• 
Participant self-reported assessments: the EQ-5D, EORTC QLQ-C30 and QLQ-
LMC21 Quality of Life questionnaires and a health economics questionnaire will be 
administered to the participant in a Participant Questionnaire Visit 3-10 Pack. 
Questionnaires should be completed by participants at the time of clinical 
assessment, but before discussion of the outcome of any medical assessments or 
blood tests wherever possible.  

 
EMT2 version 9.0, 27th July 2022 
54 
 
• 
Weight in kilograms (in light indoor clothing and without shoes). 
• 
CT scan of thorax, abdomen and pelvis. 
• 
Treatment compliance: the participant will be asked if they have missed any 
treatment doses since the last trial visit and for what reason.  
• 
Details of concomitant medications including over-the-counter O3FA supplements 
since the last trial visit. 
• 
The IMP dispensed at any previous visit should be returned to pharmacy.  For those 
who have undergone remote follow-up, arrangements will be made for the trial 
courier to collect all unused IMP. 
• 
See Biospecimen Collection protocol if participant is in this sub-study. A sample 
collection pack may need handing /posting to the participant at visit 10.   
 
Participants who have completed the intervention phase (whether still taking IMP or not) and 
have provided separate written informed consent for extended follow-up will continue into the 
extended follow-up phase.   
The extended follow-up phase of the trial consists of annual case record review at 60, 72 and 
up to a maximum 84 months after the intervention phase ended and will finish two years after 
the last participant is randomised to the EMT2 trial. 
 
13.9 
60 days post-treatment telephone call 
Participants will be contacted 60 days after the participant’s visit 10 if the participant was still 
taking IMP at visit 10. The research nurse will contact the participant by telephone to perform 
the following assessments: 
• 
Toxicity assessment: collection of any adverse events which may have occurred over 
the last 60 days. 
• 
Details of any ‘over-the-counter’ O3FA supplement use since the last trial visit. 
 
13.10  
 Extended follow up phase 
The participant’s clinical records should be reviewed at 60 and 72 months after the date of 
CRCLM surgery/randomisation for participants who have consented to extended follow-up to 
collect any evidence of disease progression or a new primary cancer. 
 

 
EMT2 version 9.0, 27th July 2022 
55 
 
13.11  End of follow up phase/Trial  
The participant’s clinical records should be reviewed at 84 months after the date of CRCLM 
surgery/randomisation for participants who have consented to extended follow-up in order to 
collect any evidence of disease progression or a new primary cancer.  This will be the last 
assessment for participants reaching this time point. 
 
13.12  Disease Progression 
The date of clinical progression is defined as the date of the CT scan or the relevant 
assessment at which disease progression or new recurrence is identified. This can be clinical 
progression or, for RECIST evaluable disease, radiological progression by RECIST principles.  
In the event that the liver or extra-hepatic metastases are found to be unable to be resected 
following randomisation (macroscopic disease remaining), a CT scan to determine the existing 
disease should be carried out as soon as possible following surgery. This scan will act as a 
baseline for assessment of progression and should be reported in accordance with RECIST 
v1.158 (see Appendix D). Subsequent scans to monitor disease progression should also be 
reported in accordance with RECIST v1.1. 
Up to 5 target lesions should be defined. Disease progression is defined as:  
• 
Appearance of one or more new lesions 
• 
A minimum 20% increase in the sum of diameters of target lesions. In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. 
• 
Clear, unequivocal progression of non-target lesions (which may be measurable or 
non-measurable) 
In the event that a participant is found to have positive microscopic margins following liver 
resection (microscopic disease) an immediate CT scan is not required as this disease is not 
evaluable according to RECIST. Disease progression is defined as the appearance of CRC 
metastases by CT scan of the thorax/abdomen/pelvis.  
Disease progression in the extra-hepatic metastases will be assessed using the CT scan of 
the thorax/abdomen/pelvis if appropriate. Other clinical evaluations will be carried out to 
monitor extra-hepatic metastases as required and as per local standard practice. 
In a small number of cases, participants may have clear clinical symptoms of disease 
progression without confirmatory imaging. In this circumstance, clinical deterioration that is 
unambiguously due to CRC progression should be reported as a progression event and the 
date of clinical assessment should be recorded as the date of clinical progression.  

 
EMT2 version 9.0, 27th July 2022 
56 
 
 
13.13  Quality of Life 
For all participants, Quality of Life (QoL) questionnaires will be completed at visit 1, visit 3 and 
at all clinic visits thereafter. The QoL questionnaires include the EQ-5D, EORTC QLQ-C30 
and QLQ-LMC21 questionnaires. 
 
13.12.1. Timing and administration of Quality of Life questionnaires 
Participants will be asked to complete the Quality of Life questionnaires prior to receiving their 
first box of capsules and wherever possible prior to meeting with the clinician at the clinic visit 
(or prior to randomisation at visit 1). The Visit 1 Questionnaire Pack should be given to 
participants after consent has been obtained and eligibility has been confirmed. All 
questionnaires will be provided in clinic or by post. 
Questionnaires should be completed by participants at the time of clinical assessment, but 
before discussion of the outcome of any medical assessments or blood tests wherever 
possible. Participants will be asked to seal the questionnaires in pre-supplied envelopes prior 
to being given to research staff. Research staff will then send the sealed envelopes to the 
CTRU for entry into the database. 
 
13.14  Health Economics 
For all participants, a health economics questionnaire will be completed at all clinic visits. 
 
13.15  Cachexia CT measurements 
Changes in lean body mass will be measured longitudinally from the routine CT abdomen 
images from participants in Leeds and Sheffield using the method of Baracos (based on 
muscle area at the L3 vertebral level44). The routine CT scans will be obtained at baseline 
(confirmation of eligibility), visit 3 and visit 4. The CT scan images will be requested at the end 
of the interventional phase, depending on the availability of funding for measurement of this 
exploratory endpoint. These measurements could easily be extended to cover longer periods 
of follow-up or expanded to include participants at other sites if funding is available. 
It is the responsibility of the participating centre to obliterate all personal identifiable data prior 
to sending the CT scan to the CTRU/central reviewer. The trial number, date of birth and initials 
will be used to identify the participant.  
 

 
EMT2 version 9.0, 27th July 2022 
57 
 
13.16  Red Blood Cell Fatty Acid Analysis 
Blood samples taken at visits 1, 2 and 3 will be collected from participants recruited at two of 
the participating centres: Sheffield Teaching Hospitals NHS Foundation Trust and Leeds 
Teaching Hospitals NHS Trust. These samples will be analysed to measure the red blood cell 
fatty acid content which determines the absolute and relative content of the major O3FAs 
including EPA, as well as the EPA/AA and EPA+DHA/AA ratio52.  
The fatty acid analysis on the baseline samples (see Section 13.2) will enable the investigation 
of whether O3FA status predicts subsequent therapeutic response to IPE. The absolute and 
differential O3FA levels at visits 2 and 3 will also act as a marker of compliance to IPE and 
allows the assessment of whether the placebo arm has been ‘contaminated’ by possible 
participant supplementation with over-the-counter O3FA. 
At visits 1-3, whole blood will be collected in EDTA tubes for centrifugation and isolation of 
plasma and red blood cells. Both fractions will be stored locally at -30°C before courier 
transport of the complete sample sets to the Institute of Cancer Therapeutics (ICT), University 
of Bradford which will act as the central biobank. Lipid extraction from red blood cells followed 
by derivatisation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
measurement of individual fatty acid (FA) species will be performed as described in the EMT2 
Lab Manual52. 
The red blood cell fatty acid analysis will be carried out centrally at the Institute of Cancer 
Therapeutics (ICT), University of Bradford. 
The fatty acid analysis will be carried out on blood samples from all participants recruited at 
Sheffield Teaching Hospitals NHS Foundation Trust and Leeds Teaching Hospitals NHS Trust 
only. 
At visits 1-3, whole blood will be collected for centrifugation and isolation of plasma and red 
blood cells. Blood samples will be obtained using the BD Vacutainer® system, following local 
Trust practice. Two purple cap K2EDTA 6ml tubes will be filled to capacity. Tubes should be 
agitated immediately to prevent clotting.   
The blood components should be separated within 30 minutes of taking the blood sample. If 
not processed immediately, the two K2EDTA Vacutainer tubes should be stored in the fridge 
at 4°C for up to 30 minutes. 
Separation of blood components will be achieved by centrifugation of the sample in K2EDTA 
Vacutainers in a centrifuge, preferably refrigerated.  
Full details on the separation of the blood components are provided in the EMT2 Lab Manual. 
All separated fractions will be stored locally at -30°C before courier transport of the complete 
sample sets to the ICT, Bradford every three months. Lipid extraction from red blood cells 

 
EMT2 version 9.0, 27th July 2022 
58 
 
followed by derivatisation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
measurement of individual FA species will be performed as described in the EMT2 Lab 
Manual. 
The fatty acid-analysis may be carried out at intervals during the two years of recruitment in 
order to assess treatment compliance and/or ‘contamination’ by ‘over-the-counter’ O3FA use.  
Any blood samples remaining following analysis for trial purposes will be stored at the Institute 
of Cancer Therapeutics at the University of Bradford and may provide a resource for future 
studies in colorectal cancer. Ethical approval will be obtained for any future studies involving 
EMT2 data or samples and the Institute of Cancer Therapeutics at the University of Bradford 
has been granted a main HTA licence (12191). Participants will not be identified in the results 
of future studies. 
It is the responsibility of the participating centre to ensure that samples are appropriately 
labelled in accordance with the trial procedures to conform with the 1998 Data Protection Act. 
Blood samples collected from participants as part of this study will be transported, stored, 
accessed and processed in accordance with national legislation relating to the use and storage 
of human tissue for research purposes and such activities shall at least meet the requirements 
as set out in the 2004 Human Tissue Act. 
13.17  Biospecimen Collection, storage and transport 
Please see the Biospecimen Collection protocol for details of sample collection and transport. 
The use of a barcode identifier linked to the EMT2 trial participant number and date of the 
sample means that all samples will be stored, transported and analysed in an anonymised but 
linked manner. 
  
13.18 Adverse Events and Serious Adverse Events 
Adverse Events (AEs) and Adverse Reactions (ARs) will be collected at all trial clinic visits and 
by 2-weekly telephone calls between visit 1 and visit 2 and at 60 days post visit 10/exit visit. 
AEs and ARs will be collected on the CRFs. These should be reported via the standard data 
management routes and expedited reporting is not required. 
Serious Adverse Events (SAEs), Serious Adverse Reactions (SARs) and Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected from randomisation until 
60 days after the last trial IMP was taken.  
For all SAEs, SARs and SUSARs occurring in the trial, an SAE or SAR Report CRF must be 
completed and faxed or sent via secure email to the CTRU within 24 hours of the site 
becoming aware of the event (see Pharmacovigilance Section 14). 
Please see Appendix B for details on the Pharmacovigilance reporting procedures. 

 
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13.19  Pregnancies 
Although non-clinical studies have demonstrated no reproductive or developmental toxicity 
relating to EPA supplementation, there have been no formal studies on the effect of EPA on 
human reproductive or developmental toxicity. Therefore women of childbearing age and men 
with partners of childbearing potential must use effective contraceptive measures for the 
duration of trial treatment and for 60 days following permanent cessation of trial treatment. 
All pregnancies and suspected pregnancies (in a trial participant or their partner) occurring 
from the date of randomisation to the telephone call at 60 days after the end of trial treatment 
must be reported to the CTRU by completing the Notification of Pregnancy CRF which must 
be faxed or sent via secure email to the CTRU within 7 days of the site becoming aware of 
the pregnancy.  
All trial participants who become pregnant during trial participation must discontinue trial 
treatment immediately. 
The CTRU will report all pregnancies occurring during trial treatment to the Sponsor and all 
pregnancies will be followed-up until the outcome is known. 
 
13.20  Deaths 
All deaths occurring from the date of randomisation to the telephone call 60 days after the end 
of trial treatment must be recorded on the Notification of Death CRF and faxed or sent via 
secure email to the CTRU within 24 hours of the site becoming aware of the death. 
Deaths occurring more than 60 days after the end of trial treatment but during trial follow-up 
must also be recorded on the Notification of Death CRF but may be returned as per standard 
data management processes.  
 
13.21  Protocol Deviations and Violations 
The CTRU undertake to adopt all reasonable measures to record data in accordance with the 
protocol. Under practical working conditions, however, some minor variations may occur due 
to circumstances beyond the control of the CTRU. All such deviations will be documented in 
the study records, together with the reason for their occurrence; where appropriate, deviations 
will be detailed in the published report.  
 
13.22  End of follow up phase and End of Trial  
The end of the intervention and follow-up phases of the trial is defined as the date when the 
last participant recruited has reached 2 years post-surgery or randomisation (if that individual 

 
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was randomised but didn’t undergo surgery).  The end of the EMT2 trial will occur at the date 
of the collection of the last participant’s last data item. 
13.23  Trial Data and Documentation held at sites 
Participating sites must maintain essential trial documentation in an Investigator Site File and 
a Pharmacy Site File, which will be provided by the CTRU. It is the responsibility of the site 
staff to ensure these files are properly maintained during the trial and archived according to 
the Sponsor requirements at the end of the trial (see Section 23 on archiving).  
 
13.24  Case Report Forms (CRFs) 
Data will be recorded by site research staff on trial-specific paper CRFs. The originals will be 
submitted by post to the CTRU within two weeks of the data being collected, and 
photocopies of the completed CRFs will be held at site. A number of CRFs require expedited 
reporting to the CTRU: 
• 
Within 24 hours of the research team becoming aware: SAE and SAR CRFs, Death 
CRFs, Withdrawal CRFs (to the CTRU) 
• 
Within 7 days of the research team becoming aware: Notification of Pregnancy (to the 
CTRU) 
Only the participant’s trial number, date of birth and initials will be added to the CRFs. 
Participating centre staff are responsible for ensuring the CRFs returned to CTRU do 
not contain any other personal identifiable data (with the exception of the participant’s 
NHS number which will be recorded at baseline). Following receipt of the completed CRFs, 
the CTRU will contact sites to resolve any missing or discrepant data. 
It is the responsibility of the site to ensure all photocopies of the completed CRFs are 
appropriately maintained at site during the trial (including any amendments) and archived 
according to the Sponsor requirements at the end of the trial (see Section 23 on archiving). 
 
13.25  Safety Monitoring Plan 
 
See Appendix C. 
 
14. 
Pharmacovigilance 
14.1 
General Definitions 
‘Adverse Event’ (AE) – any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment.  

 
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61 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporarily associated with the use of a 
medicinal product, whether or not considered to be related to the medicinal product. 
 
‘Adverse Reaction’ (AR) – all untoward and unintended responses to an investigational 
medicinal product related to any dose administered. This definition implies a reasonable 
possibility of a causal relationship which is supported by facts, evidence or arguments to 
suggest a causal relationship. This definition includes medication errors and uses outside what 
is foreseen in the protocol (i.e. if an AR occurs as a result of a medication error and including 
misuse and abuse of the product). 
 
‘Serious Adverse Event’ (SAE) – any untoward medical occurrence or effect that at any dose: 
- 
results in death, 
- 
is life-threatening, 
- 
requires hospitalisation or prolongation of existing hospitalisation, 
- 
results in persistent or significant disability or incapacity, 
- 
is a congenital anomaly or birth defect, 
- 
jeopardised the subject or required intervention to prevent one of the above. 
These characteristics/consequences have to be considered at the time of the event. For 
example, regarding a life-threatening event, this refers to an event in which the subject was at 
risk of death at the time of event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. Medical and scientific judgement must be exercised in 
deciding whether an event is ’serious’ in accordance with these criteria.   
‘Serious Adverse Reaction’ (SAR) – reference is made to the criterion of ‘Seriousness’ above 
in relation to SAE. Where an SAE is deemed to have been related to any IMP used in this trial 
the event is termed as a serious adverse reaction (Any suspected transmission via a medicinal 
product of an infectious agent is also considered a serious adverse reaction.) 
‘Suspected Unexpected Serious Adverse Reaction’ (SUSAR) – means an adverse 
reaction, the nature and severity of which is not consistent with the applicable product 
information: 
- 
in the case of a product with a marketing authorisation, in the summary of product 
characteristics for that product, 
- 
in the case of any other investigational medicinal product, in the investigator’s 
brochure relating to the trial in question. 

 
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62 
 
The term ‘severity’ is used here to describe the intensity of a specific event. This has to be 
distinguished from the term ‘serious’. Reports which add significant information on the 
specificity, increase of occurrence, or severity of a known, already documented serious 
adverse reaction constitute unexpected events. 
  
14.2 
Operational Definitions  
Adverse events will be collected for all participants and will be evaluated for intensity and 
causal relationship with the trial medication or other factors according to the National Cancer 
Institute (NCI) CTCAE V4.0 (NCI-CTCAE). A copy is provided in the EMT2 Investigator Site 
File and may also be obtained at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Published date: May 28, 2009 
 
14.2.1  Adverse Events (AEs) / Adverse Reactions (ARs) 
For general definitions of AEs and ARs, please see section 14.1 above. As this is a blinded 
trial, AEs should be assessed for expectedness and causal relationship assuming that the 
participant has been receiving IPE 4 g daily.  
 
14.2.2  Serious Adverse Events (SAEs) / Serious Adverse Reactions (SARs) 
When determining whether an SAE or SAR is expected or not, reference will be made to the  
Reference Safety Information (Section 4.8) which is the SmPC for IPE (Vazkepa®) used in the 
EMT2 trial and supplied by CTRU.  See Appendix E for the link to an online version of the 
SmPC.   
Participants may receive chemotherapy during trial participation if considered appropriate by 
the treating clinician. Chemotherapy will be prescribed as per local standard practice and is 
not a trial intervention. It is not considered necessary for trial treatment to be discontinued 
during chemotherapy. In the event that the participant experiences an SAE during 
chemotherapy treatment, it should be assessed whether the event is related to chemotherapy 
or IPE. If the event is related to chemotherapy, it should be assessed whether the event could 
possibly have been exacerbated by IPE. Please refer to Appendix B for the Pharmacovigilance 
Reporting Flowchart. 
 
14.2.2.1 
Events not to be classed as SAEs / SARs 
The following events will not be classed as SAEs / SARs within this trial and will therefore not 
be subject to expedited reporting:  

 
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63 
 
Hospitalisation for: 
• 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition; 
• 
Treatment which was elective or pre-planned, for a pre-existing condition not 
associated with any deterioration in condition, e.g. pre-planned hip replacement 
operation which does not lead to further complications; 
• 
Any admission to hospital or other institution for general care where there was no 
deterioration in condition; 
• 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious as given above and not resulting in hospital admission. 
 
14.2.2.2   Events classed as expected SAEs / SARs 
Any events which will be classed as expected SAEs / SARs within this trial are given in the 
Reference Safety Information (Section 4.8) which is the SmPC for IPE (Vazkepa®).  Such 
events will not be reportable as SUSARs on the trial, unless the severity of the event is 
considered to be unexpected. The current version of the SmPC for IPE (link) must be referred 
to. 
All events should be reviewed for relatedness by the Principal Investigator, or another 
medically qualified member of the research team authorised on the EMT2 Authorised 
Personnel Log. The CI will review all SARs on behalf of the Sponsor in order to determine 
expectedness. 
 
14.2.2.3  Suspected Unexpected Serious Adverse Reactions (SUSARs) 
For general definitions of SAEs and SARs, please see Section 0 above. A Suspected 
Unexpected Serious Adverse Reaction (SUSAR) is a serious adverse drug reaction which also 
demonstrates the following characteristic of being unexpected:  
Unexpected – An adverse event, the nature OR severity of which is NOT consistent 
with the RSI in the SmPC for IPE.   
SUSARs will be subject to expedited reporting to the Medicines and Healthcare and products 
Regulatory Authority (MHRA) and Research Ethics Committee. 
As this is a blinded trial, serious adverse events should be assessed for expectedness and 
causal relationship assuming that the participant has been receiving IPE.  
Events associated with placebo will usually not satisfy the criteria for a SUSAR and therefore 
expedited reporting. However, where SARs are thought to be associated with placebo (e.g. 

 
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64 
 
reaction due to excipient or impurity), the CTRU will forward such cases to the CI for review 
of causality and expectedness on behalf of the Sponsor and, if appropriate, onward report to 
the MHRA and REC. Routinely breaking the blind could compromise the integrity of the trial. 
For this reason, blind-breaking will only take place where information about the participant’s 
trial treatment is clearly necessary for the appropriate medical management of the 
participant. In all cases the Investigator would be expected to provide an evaluation on the 
causality of SAEs as though the participant was receiving the active medication.  
 
14.3 
Reporting Requirements 
All SAEs/SARs/SUSARs occurring from the time of randomisation until the 60 days post 
cessation of trial treatment must be recorded on the SAE Form or the SAR Form.   
For each SAE or SAR/SUSAR the following information will be collected: 
• Full details in medical terms and case description 
• event duration (start and end dates, if applicable) 
• action taken 
• outcome 
• seriousness criteria 
• causality (i.e. relatedness to trial drug), in the opinion of the investigator 
• whether the event would be considered expected or unexpected 
• Principal Investigator signature (or another clinically qualified member of the 
medical team authorised in the EMT2 Authorised Personnel Log) 
For SARs and SUSARs additional information will be collected on concomitant medications, 
relevant medical history, diagnostic tests and treatment for the event. 
All events must be reviewed and assessed (for seriousness and causality) by the Principal 
Investigator, or another medically qualified member of the research team authorised in the 
EMT2 Authorised Personnel Log. If an authorised medic is not available on the day the site 
team become aware of the event, initial reports without causality must still be faxed or sent via 
secure email to the CTRU within 24 hours of the site becoming aware, and must be followed-
up by medical assessment as soon as possible thereafter.  
SARs must be recorded on the SAR Form and faxed or sent via secure email to CTRU within 
24 hours of the research staff becoming aware of the event. 
Subsequently, follow-up reports (detailing changes in condition or other follow-up information) 
must be reported to CTRU within 24 hours of the information becoming available. Events will 
be followed up until the event is resolved or a final outcome has been reached. 

 
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SAEs must be recorded on the SAE Form and reported to the CTRU within 24 hours of the 
trial team becoming aware of the event. SAE data will be reviewed as collated data and will 
be reviewed for trends by the Chief Investigator at quarterly intervals (in a blinded manner) 
and by the Data Monitoring and Ethics Committee at six monthly intervals (in an unblinded 
manner).   
It is expected that SAEs, SARs and SUSARs may be identified by the centre at which the 
participant is receiving chemotherapy (for those participants receiving chemotherapy as per 
standard practice) which may be different to the randomising centre. It is the responsibility of 
the chemotherapy team to report events fulfilling the seriousness criteria to the trial team at 
the randomising centre. An authorised clinician on the trial team is responsible for assessing 
whether the event is related to trial treatment. If the event is considered to be serious, it is the 
responsibility of the trial team to report the event to the CTRU within 24 hours of becoming 
aware of the event.  
 
14.3.1  Reporting of Adverse Events (AEs)  
All AEs occurring from randomisation up to 60 days after the end of trial treatment must 
be recorded on the appropriate CRF. These are not subject to expedited reporting to CTRU. 
 
14.3.2  Reporting of Adverse Reactions (ARs) 
All ARs occurring from randomisation up to 60 days after the end of trial treatment must 
be recorded on the appropriate CRF, which will be posted to CTRU within 2 weeks of the 
assessment. These are not subject to expedited reporting to CTRU. 
  
14.3.3  Reporting of Serious Adverse Events (SAEs)  
All SAEs occurring from randomisation up to 60 days after the end of trial treatment (see 
Section 0 above for definition) must be recorded on the SAE CRF and sent to the CTRU within 
24 hours.  
Please ensure that only one event is reported on each SAE CRF (details of multiple symptoms 
should be listed if they relate to the same event).  
Once all resulting queries have been resolved, the original wet-ink CRF will be posted to the 
CTRU and a copy retained at site. 
 

 
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66 
 
14.3.4 Expedited Reporting of Serious Adverse Reactions (SARs) and 
Suspected Unexpected Serious Adverse Reactions 
(SUSARs) 
All SARs and SUSARs occurring from randomisation up to 60 days after the end of trial 
treatment (see Section 0 above for definition) must be recorded on the SAR CRF and faxed 
or sent via secure email to the CTRU within 24 hours of the local research team site staff 
becoming aware of the event (this includes participants who have withdrawn consent for data 
collection, see Section 12.4). Any SARs or SUSARs which the site team become aware of 
after this point must still be reported to CTRU. 
Once all resulting queries have been resolved, the original wet-ink CRF will be posted to the 
CTRU and a copy retained at site.  
Please ensure that only one event is reported on each SAR CRF (details of multiple symptoms 
should be listed if they relate to the same event).  
 
14.4 
Responsibilities 
 
14.4.1  Principal Investigator: 
1. 
Checking for AEs and ARs when participants attend for treatment / follow-up. 
2. 
Using medical judgement in assigning seriousness and causality using the 
EMT2 IPE Investigator Brochure approved for the trial. 
3. 
Ensuring that all SAEs, SARs and SUSARs are recorded and reported to the 
CTRU within 24 hours of becoming aware of the event and provide further 
follow-up information as soon as available. Ensuring that SAEs, SARs and 
SUSARs are chased with CTRU if a record of receipt is not received within 2 
working days of initial reporting.  
4. 
Ensuring that AEs and ARs are recorded and reported to the CTRU in line with 
the requirements of the protocol.  
 
14.2  Chief Investigator (CI) / delegate: 
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 
seriousness, 
causality 
and 
expectedness of SAEs where it has not been possible to obtain local medical 
assessment. 

 
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3. Immediate review of all events assessed as SARs in order to determine 
expectedness. In the event of disagreement between local assessment and the 
Chief Investigator (CI), local assessment will not be downgraded but the CI 
may add comments prior to reporting to MHRA and REC. 
4. Review of specific SAEs 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). 
7. Conduct of the Biospecimen Collection sub-study. 
 
14.4.3 CTRU:  
1. Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs 
according to the trial protocol onto a MACRO database.  
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 committee identified 
for the trial (Data Monitoring & Ethics Committee (DMEC) and Trial Steering 
Committee (TSC)) according to the Trial Monitoring Plan. 
4. Expedited reporting of SUSARs to the MHRA, REC and Sponsor within 
required timelines. 
5. Notifying Investigators of SUSARs that occur within the trial. 
6. The unblinding of a participant for the purpose of expedited SUSAR reporting. 
7. Checking for (annually) and notifying Principal Investigators of updates to the 
Reference Safety Information for the trial. 
8. Preparing standard tables and other relevant information for the DSUR in 
collaboration with the CI and ensuring timely submission to the MHRA and 
REC.  
9. Notify Amarin Pharma Inc of any SUSARs occurring in trial participants using 
the CTRU SUSAR CRF. Initials and date of birth will be removed from the CRF 
before sending to Amarin. Participants will be identified by trial number only. 
 

 
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14.4.4  Trial Steering Committee (TSC):  
In accordance with the Trial Terms of Reference for the TSC, periodically reviewing 
safety data and liaising with the DMEC regarding safety issues. 
 
14.4.5  Data Monitoring & Ethics Committee (DMEC):  
In accordance with the Trial Terms of Reference for the DMEC, periodically 
reviewing unblinded overall safety data to determine patterns and trends of events, 
or to identify safety issues, which would not be apparent on an individual basis. 
 
15. 
Participant-reported measures  
Quality of life will be assessed by participants' self-reported symptoms and functioning using 
validated instruments completed by participants at visits 1, 3 and all clinic visits thereafter. All 
instruments are self-administered to avoid interviewer bias. The three QoL questionnaires and 
the health economics questionnaire to be used in this study are described below. 
The EQ-5D is a well validated, multi-purpose, standard health-related QoL evaluation 
questionnaire, which will be used to assess generic QoL. It provides a simple descriptive profile 
and a single index value for health status. 
The EORTC QLQ-C30 is a well validated questionnaire developed to assess the quality of life 
of cancer patients. This information relates to the previous 1-week time period. It is 
supplemented by disease-specific modules and the colorectal liver metastases module QLQ-
LMC21 will also be used in the study. The majority of this information relates to the previous 
1-week time period, with information relating to the effect of the disease or treatment on the 
participants’ sex-life relating to the previous 4-week time period. 
A participant self-reported questionnaire will be administered at Visit 10/Exit Visit to determine 
the participant’s opinion of their trial treatment allocation at the end of the treatment period. 
This questionnaire will be used to evaluate the effectiveness of the blinding measures used 
throughout the trial. 
 
16. 
Economic Evaluation 
The aim of the economic evaluation is to provide an estimate of the cost-effectiveness of IPE 
in comparison with placebo. The economic evaluation also aims to identify important drivers 
of cost differences between the trial arms, the likely magnitude of cost differences and the 
likely magnitude of differences in health status to assist in the design of subsequent research 
and economic modelling in this area. The economic analysis will be conducted by the 

 
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Academic Unit of Health Economics, University of Leeds, under the supervision of the lead 
Health Economist. The timeframe for the health economics analysis will be 4 months from 
receipt of the final dataset. 
Health economic data will be collected at each trial visit using patient questionnaires and 
clinical records transcribed onto trial case report forms and by a Hospital Episode Statistics 
data download at the time of analysis. The scope will include secondary care costs, primary 
care and community NHS costs, patient out-of-pocket expenses and wider societal costs59. 
The calculation of Quality Adjusted Life Years (QALYs) will rely on the EuroQoL EQ-5D-5L 
questionnaire in order to weight survival for quality of life. The incremental cost effectiveness 
ratio will be calculated between trial arms. Outcomes will comprise: (i) cost per disease 
recurrence prevented at 2 years, and (ii) the cost per QALY at 2 years, both reported alongside 
the trial primary endpoint59.  
CRFs will, where possible, collect data in a manner consistent with activity types used by the 
NHS Reference Costs, from which unit costs will be assigned to secondary care activity. Other 
national sources of NHS unit costs such as the Commercial Medicines Unit Electronic 
Medicines Information Tool and the PSSRU Unit Costs of Health and Social care will be used 
to assign non-secondary care unit costs. A second analysis, performed as a sensitivity 
analysis, will use secondary care activity costed from linked Hospital Episode Statistics using 
the Department of Health HRG grouper software once this becomes available for 2 years 
follow-up for all patients 
The non-parametric bootstrap method will be used to produce a within-trial probabilistic 
sensitivity analysis of the incremental cost effectiveness ratio. The impact of missing data will 
be examined using imputation methods. In addition to presenting the expected incremental 
cost effectiveness ratio, the scatterplot on the cost effectiveness plane the cost effectiveness 
acceptability curve and the expected value of perfect information will also be reported. The 
value based price of IPE will be calculated. Subgroup analysis will be conducted for trial 
stratification factors and any other factors described in the Statistical Analysis Plan. 
 
17. 
Endpoints 
 
17.1 
Primary Endpoint 
The primary endpoint is progression free survival (PFS) during a minimum of 2 years follow 
up. PFS is defined as the time from randomisation to death (from any cause), first documented 
evidence of disease progression (as defined in Section 13.12), new recurrence or clinical 
deterioration unequivocally due to disease progression58. 
 

 
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17.2 
Secondary Endpoints 
The secondary endpoints are: 
• 
Overall Survival (OS), defined as the time from randomisation to death, from any 
cause (key secondary endpoint) 
• 
Safety and tolerability of IPE before and after surgery, including during chemotherapy 
• 
Patient reported quality of life, measured using the EQ-5D, EORTC QLQ-C30 and 
QLQ-LMC21 questionnaires 
• 
Cost-effectiveness of IPE 
• 
New primary cancers (excluding DCIS, cervical carcinoma in situ, superficial bladder 
carcinoma where treatment consisted of resection only and non-melanoma skin 
cancer where treatment consisted of resection or radiotherapy only) 
 
17.3 
Exploratory Endpoints 
The exploratory endpoints are: 
• 
Red blood cell membrane EPA content, measured at baseline, surgery and 6 months 
after surgery (only patients from Leeds and Sheffield) 
• 
Change in lean body mass measured by CT scanning during follow up as assessed 
by the L3 skeletal muscle index score 
18. 
Statistical Considerations 
 
18.1 
Sample size and planned recruitment rates 
 
 
18.1.1  Sample size  
At study outset it was specified that a sample size of 448 participants (giving 247 events) would 
be required to detect a HR of 0.7 for PFS in favour of EPA (the treatment arm) with a power 
of 80% at the 5% (2-sided) level of significance. This assumes the control arm has a median 
PFS of 21 months and the treatment arm has a median PFS of 30 months. It also assumed a 
24 month recruitment period and a minimum 24 months follow up, and allowed for 10% 
dropout.  
In advance of protocol version 9.0, in light of the slower than expected recruitment rate and 
based on the recommendation of the independent DMEC and TSC, a minimum sample size 
of 388 was specified. This minimum sample size takes into account a revised 67 month 

 
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71 
 
recruitment period and the minimum 24 month follow-up. It was determined by considering the 
effect of the extended study duration and the opportunity to observe the required events in 
fewer patients observed for greater time. This revised minimum sample size also allows for 
the observed higher rate of 15% dropout related to the COVID-19 pandemic and other protocol 
compliance issues. All other design parameters remain unchanged, including the given 
number of events required to trigger analysis (247 events). 
The HR for PFS in the Phase II EMT study27 was 0.694, but the EPA arm, by chance, recruited 
a higher proportion of patients with poor prognostic features, and a multivariate analysis 
including these factors actually yielded a HR of 0.35 (95% confidence interval: 0.15-0.79) 
lending credence to the assumed more conservative HR of 0.7 chosen for this larger phase III 
study, given that the magnitude of benefit observed in phase II studies is often greater than 
that observed in the phase III counterpart. 
The EMT study tested EPA-FFA 2g daily27. Although the EMT2 study will evaluate IPE 4 g 
daily, we assume similar efficacy of EPA given as IPE, compared with EPA-FFA, for the 
purposes of the trial power calculation. 
The power calculation for the main secondary endpoint of OS uses a simulation approach 
based on an established mathematical model60 that assumes a plateau in the time to event 
curves at around 4-5 years. Assuming 80% OS at 2 years in the control arm 28-29, and a 
difference between the treatment arms of 10% in the actuarial OS rate at 2 years (equivalent 
to a hazard ratio of 0.47 similar to that observed in the EMT study27), 448 patients (80 events) 
yields approximately 91% power to detect such a difference, and 78% power to detect a lesser 
HR of 0.55. This calculation again assumes 24 months recruitment and a minimum 24 months 
follow-up, a 5% (2-sided) significance level and a 10% dropout rate.  Although this is an 
optimistic scenario, it is based on the EMT trial results27, which suggested that it is entirely 
possible that EPA produces benefits both before and after progression, and this (secondary) 
endpoint encompasses that possibility. We note that OS is likely to be, if anything, slightly less 
than 80% at 2 years, from experience in the phase II EMT trial, which would increase the 
power under these assumptions. 
In terms of the exploratory change in lean body mass endpoint, assuming a mean L3 skeletal 
muscle index score of the order of 50 cm2/m2, and a standard deviation of the order of 10 in 
this score61 then it would be possible to detect a relatively small mean difference between the 
treatment arms of 5 in the L3 skeletal muscle index (e.g. from 50 to 45) with 128 patients (64 
in each arm) tested at the 12-month post-surgical follow-up with 80% power and using a 5% 
(2-sided) significance level. Therefore, this analysis is currently restricted to participants in 
Leeds and Sheffield. This high power with a small sample size is possible because we are 
looking at differences in a continuous variable, which yields higher sensitivity to changes on 
smaller numbers of patients.   
 

 
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18.1.2  Planned Recruitment Rate 
We proposed to recruit into this trial from eight sites incorporating the large UK hepatobiliary 
units offering ‘high-volume’ tertiary level CRCLM management. For a two-year recruitment 
period, the combined annual CRCLM resection rate of 890 patients (roughly 40% of the 
national workload) allows for a realistic 25% randomisation rate in order to recruit to time and 
target (224 per year). In the EMT study, only 4 of 203 (2%) CRCLM patients screened for 
eligibility refused to participate27. Although the excellent acceptability of the EMT study was 
aided by the dedicated study Research Fellow and single site-nature of the trial, we expect 
that the number of screened individuals who decline to participate will be low based on the 
preliminary data from the EMT study, combined with the excellent safety and tolerability profile 
of IPE. Given the relatively low number of exclusion criteria, we believe that a 25% recruitment 
rate allowing recruitment to time and target is realistic and obtainable despite the possibility of 
some placebo avoidance behaviour based on the phase II trial data28. 
In advance of protocol version 9.0, the recruitment rate in light of the COVID-19 pandemic, 
and the subsequent recovery was evaluated. Based on reasonable recruitment rate 
projections and the revised minimum sample size describe above, we anticipate that 
recruitment will extend to 67 months rather than the originally planned 24 months. This 
duration has been agreed with study funder and the independent DMEC and TSC. 
 
 
 
19. 
Statistical Analysis 
 
19.1 
General Considerations  
 
Statistical analysis is the responsibility of the CTRU Trial Statistician under the supervision of 
the Supervising Statistician, except for the health economic analysis which is the responsibility 
of the health economic TMG member. A full statistical analysis plan will be written before any 
analyses are undertaken and in accordance with CTRU standard operating procedures. 
 
19.2 
Analysis populations 
Analyses will be conducted on the intention to treat (ITT) basis where participants will be 
included according to which treatment they were randomised to receive, apart from the 
safety/tolerability endpoint which will be based on the safety population. The safety population 
will consist of all patients who take at least one dose of any trial treatment; analyses based on 
the safety population will summarise participants according to treatment received. All 
hypothesis tests will be two-sided and will use a 5% significance level. 

 
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Sensitivity analyses may be performed for each endpoint, for example to take into account 
differing assumptions about missing data if there is a significant number of missing data, and 
will be detailed in the full statistical analysis plan. 
 
19.3 
Frequency of analysis 
A DMEC will be set up to independently review data on safety and recruitment. Interim reports 
will be presented to the DMEC in strict confidence, on at least yearly intervals. This committee, 
in light of the interim data and of any advice or evidence they wish to request, will advise the 
TSC if there is proof beyond reasonable doubt that one treatment is better. No formal interim 
analyses are planned hence no statistical testing will take place until final analysis. 
We do not propose interim futility or early stopping (for superiority) analyses. Given the 
relatively short recruitment and follow-up periods in this trial, and the absence of a plausible 
reason to believe that outcomes would be worse in the EPA arm, we are highly unlikely to 
have observed sufficient events to stop for futility at 2½ years because of limited overall follow-
up. Similarly, the relative paucity of events expected halfway through the four-year 
interventional period (i.e. at the end of recruitment) means that there would have to be a huge 
implausible difference in PFS in favour of EPA in order to stop for superiority. 
The final analysis will take place after the last patient recruited has been followed up for 24 
months or the number of events required has been reached, whichever occurs first. 
19.4 
Primary endpoint analysis  
The primary endpoint is progression free survival (PFS) (see section 17 for definition). 
PFS will be analysed using the 95% confidence interval of the hazard ratio; the 95% 
confidence interval of the difference in median PFS will also be presented to aid interpretation. 
Kaplan-Meier survival curves will be calculated for PFS. Patients without a PFS event at the 
time of analysis will be censored at the time they were last known to be alive and progression-
free. Differences in PFS between the treatment groups will be compared using multivariate 
modelling (for example, an extended Cox model if appropriate) to adjust for the minimisation 
factors of ‘downsizing’ chemotherapy, extrahepatic CRC metastases, randomising centre, and 
time between randomisation and surgery and also regular aspirin use during follow-up which 
will be included as a time dependent covariate. A sensitivity analysis will also be conducted to 
examine the effects of other potential effect modifiers in addition to the minimisation factors. 
The primary analysis will be the multivariate analysis which adjusts for the minimisation factors 
and regular aspirin use during follow-up. Treatment HRs and corresponding 95% confidence 
intervals will be obtained from the multivariate models. 
19.5 
Secondary endpoint analysis 
Kaplan-Meier survival curves will be calculated for Overall Survival (OS). Participants without 
an OS event at the time of analysis will be censored at the time they were last known to be 
alive. Differences in OS between the treatment groups will be compared using multivariate 

 
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modelling (for example, an extended Cox model if appropriate) to adjust for the minimisation 
factors and regular aspirin use during follow-up, which will be included as a time dependent 
covariate, and subsequent analyses will be conducted to examine the effects of other potential 
effect modifiers in addition to the minimisation factors. Treatment HRs and corresponding 95% 
confidence intervals will be obtained from the multivariate models. 
Safety analyses will summarise the AE, AR, SAE, SAR and SUSAR rates per participant, by 
treatment received and overall. Suspected relationship to IPE will be presented along with 
other causality, outcome and event duration. 
QoL will be measured using the general EQ-5D and cancer specific EORTC QLQ-C30 and 
QLQ-LMC21 questionnaires. These will be analysed using random effects (multi-level) models 
to account for the hierarchical nature of repeated measures data and the models will include 
adjustments for baseline QoL, the minimisation factors and regular aspirin use during follow-
up, which will be included as a time dependent covariate, with subsequent sensitivity analyses 
to adjust for any other potential effect modifiers in addition to the minimisation factors. The 
nature of any missing data will be investigated and if it is suspected that data are not missing 
at random alternative analyses will be carried out to allow for the nature of the missing data. 
The number and timing of new primary cancers will be summarised descriptively by 
treatment group. 
19.6 
Subgroup Analyses 
A subgroup analysis comparing the outcomes for patients that receive ≥2 weeks of IMP prior 
surgery and patients that receive <2 weeks of EPA will be performed. Further subgroup 
analyses will be performed to investigate the effect of aspirin and EPA and the effect of EPA 
on the MSI status of the primary colorectal cancer on PFS. 
19.7 
Exploratory endpoint analysis 
Red blood cell membrane EPA content will be measured at baseline, at surgery and 6 months 
after surgery in all participants from Leeds and Sheffield52. The effect of red blood cell 
membrane EPA content on disease-related outcomes (PFS and OS) will be analysed using 
an extended Cox model (if appropriate) which will adjust for the minimisation factors and 
regular aspirin use during follow-up, which will be included as a time dependent covariate and 
will also include red blood cell membrane EPA content as a time dependent covariate. 
Subsequent sensitivity analyses will be conducted to adjust for any other potential effect 
modifiers in addition to the minimisation factors. 
Lean body mass will be measured longitudinally from the routine CT abdomen images using 
the method of Baracos (based on muscle area at the L3 vertebral level)44. The difference in 
muscle mass between the EPA and placebo treatment groups will be analysed using a random 
effects (multi-level) model to account for the hierarchical nature of the repeated measures 
data. The model will be adjusted for the baseline muscle mass, minimisation factors and 

 
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regular aspirin use during follow-up, which will be included as a time dependent covariate, with 
a subsequent sensitivity analysis to adjust for any other potential effect modifiers in addition 
to the minimisation factors.  A possible association between changes in muscle mass and 
disease related outcomes (PFS and OS) will be analysed using an extended Cox model (if 
appropriate) which will adjust for the minimisation factors and regular aspirin use during follow-
up, which will be included as a time dependent covariate, and will also include lean body mass 
as a time dependent covariate. A subsequent sensitivity analysis will be carried out to adjust 
for any other potential effect modifiers as well as the minimisation factors. 
Weight will also be analysed as a measure of cachexia. The difference in weight of patients 
between the treatment arms will be analysed using a random effects (multi-level) model to 
account for the hierarchical nature of the repeated measures data and will be adjusted for 
baseline weight, the minimisation factors and regular aspirin use during follow-up, which will 
be included as a time dependent covariate. A sensitivity analysis will also be carried out to 
adjust for other potential effect modifiers as well as the minimisation factors.  
Analysis of the biospecimens collected during the sub-study ‘The prebiotic effect of EPA 
treatment for CRCLM’ are detailed in Appendix A of the Biospecimen Collection protocol. 
Laboratory work will take place in Leeds Institute of Medical Research and ICT, University of 
Bradford, as well as Massachusetts General Hospital and Harvard School of Public Health in 
Boston, USA.  
20. 
Trial Monitoring 
20.1 
Data Monitoring and Ethics Committee (DMEC)  
A Trial Monitoring Plan will be developed and agreed by the Trial Management Group (TMG) 
and Trial Steering Committee (TSC) based on the trial risk assessment; this may include on 
site monitoring. 
The independent DMEC will review the safety and ethics of the study.  Detailed unblinded 
reports will be prepared by the CTRU for the DMEC at approximately 6 monthly intervals. The 
DMEC will be provided with detailed unblinded reports containing the information agreed in 
the data monitoring analysis plan.  
Any unblinded interim reports provided to the DMEC will be provided by the CTRU Safety 
Statistician for consideration in a closed session and the reports will be securely password-
protected. 
20.2 
Data Monitoring 
Data will be monitored for quality and completeness by the CTRU. Missing data will be chased 
until it is received, confirmed as not available, or the trial is at analysis. However, missing data 
items will not be chased from participants (although missing questionnaires sometimes are).  
The CTRU will reserve the right to intermittently conduct source data verification exercises on 
a sample of participants, which will be carried out by staff from the CTRU. Source data 

 
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verification will involve direct access to patient notes at the participating hospital sites and the 
ongoing central collection of copies of consent forms and other relevant investigation reports.  
 
20.3 
Clinical Governance Issues 
To ensure responsibility and accountability for the overall quality of care received by 
participants during the study period, clinical governance issues pertaining to all aspects of 
routine management will be brought to the attention of the TSC and, where applicable, to 
individual NHS Trusts. 
 
21. 
Quality Assurance, Ethical and Regulatory 
Considerations 
 
21.1 
Quality Assurance  
The trial will be conducted in accordance with the principles of GCP in clinical trials, as 
applicable under UK regulations, the NHS Research Governance Framework (RGF), and 
through adherence to CTRU Standard Operating Procedures (SOPs). 
 
21.2 
Serious Breaches 
The CTRU and Sponsor have systems in place to ensure that serious breaches of GCP or the 
trial protocol are picked up and reported. Investigators are required to promptly notify the 
CTRU of a serious breach (as defined by Regulation 29A of the Medicines for Human Use 
(Clinical Trials) Regulations 2004 and amendments) that they become aware of. 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 subjects of the trial; or  
b) the scientific value of the trial 
For further information, the Investigator should contact the Senior Trial Co-ordinator at the 
CTRU. 
 
21.3 
Ethical considerations  
The trial will be performed in accordance with the recommendations guiding physicians in 
biomedical research involving human subjects adopted by the 18th World Medical Assembly, 
Helsinki, Finland, 1964, amended at the 52nd World Medical Association General Assembly, 
Edinburgh, Scotland, 1996.  Informed written consent will be obtained from the participants 

 
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prior to randomisation into the trial.  The right of a patient to refuse participation without giving 
reasons must be respected.  The participant must remain free to withdraw at any time from 
the trial without giving reasons and without prejudicing his/her further treatment.  The trial will 
be submitted to and approved by a main REC and the appropriate Site Specific Assessor for 
each participating centre prior to entering participants into the trial.  The CTRU will provide the 
main REC with a copy of the final protocol, participant information sheets, consent forms and 
all other relevant trial documentation.  
22. 
Confidentiality  
All information collected during the course of the trial will be kept strictly confidential. 
Information will be held securely on paper and electronically at the CTRU. The CTRU will 
comply with all aspects of the 1998 Data Protection Act and operationally this will include: 
• 
consent from participants to record personal details including name, date of birth and  
hospital ID 
• 
appropriate storage, restricted access and disposal arrangements for participant personal 
and clinical details 
• 
consent from participants for access to their medical records by responsible individuals 
from the research staff or from regulatory authorities, where it is relevant to trial 
participation 
• 
consent from participants for the data collected for the trial to be used to evaluate safety 
and develop new research. 
• 
data collection forms that are transferred to or from the CTRU will be coded with a trial 
number and will include two participant identifiers, usually the participant’s initials and date 
of birth. 
• 
where central monitoring of source documents by CTRU (or copies of source documents) 
is required (such as scans or local blood results), the participant’s name must be 
obliterated by site before sending. 
• 
where anonymisation of documentation is required, sites are responsible for ensuring only 
the instructed identifiers are present before sending to CTRU. 
If a participant withdraws consent from further trial treatment or from further collection of data, 
their data and samples will remain on file and will be included in the final trial analysis. 
The trial staff at the participating sites will be responsible for ensuring that any data / 
documentation sent to the CTRU is appropriately anonymised as per instructions given by 
CTRU in accordance with the trial procedures to conform with the 1998 Data Protection Act. 

 
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23. 
Archiving  
At the end of the trial, data will be securely archived in line with the Sponsor’s procedures for 
a minimum of 15 years. Data held by the CTRU will be archived in the Sponsor archive facility 
and site data and documents will be archived at the participating sites.  Following authorisation 
from the Sponsor, arrangements for confidential destruction will then be made.  
 
24. 
Statement of indemnity 
 
The University of Leeds will be liable for negligent harm caused to participants treated in the 
UK that is caused by the design of the study.   
The NHS has a duty of care to patients treated in the UK, whether or not the patient is taking 
part in a clinical study, and the NHS remains liable for harm to UK patients due to clinical 
negligence under this duty of care. 
25. 
Study Organisational Structure 
 
25.1 
Individuals and Individual Organisations 
Chief Investigator (CI) – The CI is involved in the design, conduct, co-ordination and 
management of the trial. The CI will have overall responsibility for the design and set-up of the 
trial, the investigational drug supply and pharmacovigilance within the trial.  
Trial Sponsor – The Sponsor is responsible for trial initiation management and financing of 
the trial as defined by Directive 2001/20/EC. These responsibilities are delegated to the CTRU 
as detailed in the trial contract. 
Clinical Trials Research Unit – The CTRU will have responsibility for conduct of the trial as 
delegated by the Sponsor in accordance with relevant GCP standards and CTRU SOPs. The 
CTRU will provide set-up and monitoring of trial conduct to CTRU SOPs, and the GCP 
Conditions and Principles as detailed in the UK Medicines for Human Use (Clinical Trials) 
Regulations 2006 including, randomisation design and service, database development and 
provision, protocol development, CRF design, trial design, source data verification, monitoring 
schedule and statistical analysis for the trial. In addition the CTRU will support main REC, Site 
Specific Assessment and NHS Permissions submissions and clinical set-up, ongoing 
management including training, monitoring reports and promotion of the trial. The CTRU will 
be responsible for the day-to-day running of the trial including trial administration, database 
administrative functions, data management, safety reporting and all statistical analyses. 

 
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Academic Unit of Health Economics, University of Leeds – The Academic Unit of Health 
Economics will conduct the economic analysis, under the supervision of the lead Health 
Economist. 
Central pharmacy – Stockport Pharmaceuticals, Stepping Hill Hospital, Poplar Grove, 
Stockport. The central pharmacy is responsible for the labelling, packaging and distribution of 
trial IMP.  
Central laboratory - Institute of Cancer Therapeutics, University of Bradford. The central 
laboratory is responsible for the red blood cell fatty acid analysis. 
 
25.2 
Oversight and Trial Monitoring Groups 
Trial Management Group (TMG) – The TMG, comprising the CI, CTRU team, other key 
external members of staff involved in the trial and a nursing representative will be assigned 
responsibility for the clinical set-up, on-going management, promotion of the trial, and for the 
interpretation and publishing of the results. Specifically the TMG will be responsible for (i) 
protocol completion, (ii) CRF development, (iii) obtaining approval from the main REC and 
supporting applications for Site Specific Assessments, (iv) submitting a CTA application and 
obtaining approval from the MHRA, (v) completing cost estimates and project initiation, (vi) 
nominating members and facilitating the TSC and DMEC, (vii) reporting of serious adverse 
events, (viii) monitoring of screening, recruitment, treatment and follow-up procedures, (ix) 
auditing consent procedures, data collection, trial end-point validation and database 
development. 
Trial Steering Committee (TSC) – The TSC will provide overall supervision of the trial, in 
particular trial progress, adherence to protocol, participant safety and consideration of new 
information.  It will include an Independent Chair, not less than two other independent members 
and a consumer representative. The CI and other members of the TMG may attend the TSC 
meetings and present and report progress. The Committee will meet annually as a minimum. 
Data Monitoring and Ethics Committee (DMEC) – The DMEC will include independent 
membership and will review the safety and ethics of the trial by reviewing interim data during 
recruitment and follow-up and will report to the TSC. The Committee will meet annually as a 
minimum. 
26. 
Publication Policy 
The trial will be registered with an authorised registry, according to the International Committee 
of Medical Journal Editors (ICMJE) Guidelines, prior to the start of recruitment.  
The success of the trial depends upon the collaboration of all participants. For this reason, 
credit for the main results will be given to all those who have collaborated in the trial, through 
authorship and contributorship. Uniform requirements for authorship for manuscripts submitted 

 
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to medical journals will guide authorship decisions. These state that authorship credit should 
be based only on substantial contribution to:  
• 
conception and design, or acquisition of data, or analysis and interpretation of data, 
• 
drafting the article or revising it critically for important intellectual content, 
• 
and final approval of the version to be published, 
• 
and that all these conditions must be met (www.icmje.org). 
In light of this, the Chief Investigator, and relevant senior CTRU staff will be named as authors 
in any publication. In addition, all collaborators will be listed as contributors for the main trial 
publication, giving details of roles in planning, conducting and reporting the trial. 
To maintain the scientific integrity of the trial, data will not be released prior to the first 
publication of the analysis of the primary endpoint, either for trial publication or oral 
presentation purposes, without the permission of the Trial Steering Committee and Yorkshire 
Cancer Research. This includes data from the Biospecimen Collection study that include any 
clinical trial endpoints. In addition, individual collaborators must not publish data concerning 
their participants which is directly relevant to the questions posed in the trial until the first 
publication of the analysis of the primary endpoint. 
 
 
 

 
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52. Watson H, Cockbain AJ, Spencer J, et al. Measurement of red blood cell 
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28. 
Appendix A: Schedule of Events 
Events 
Standard practice surgery 
eligibility checks 
Visit 1 (0 months) 
2 weekly telephone 
calls****** 
Visit 2: Surgery        
(<6 weeks post 
randomisation) 
Visit 3 (6 months)* 
Visit 4 (12 months) 
Visit 5 (18 months) 
Visit 6 (24 months) 
Visit 7 (30 months) 
Visit 8 (36 months) 
Visit 9 (42 months) 
Visit 10 (48 months)/End 
of Intervention phase 
60days post treatment 
end (phone call) 
Extended follow up phase 
(60, 72 & 84 months) 
Clinical 
Procedures/  
Assessments 
CT 
thorax/abdomen/pelvis 
x 
  
  
** 
x 
x 
x 
x 
  
x 
  
x 
  
 
Weight 
  
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
 
Blood sample*** 
  
x 
  
x 
x 
  
  
  
  
  
  
  
  
 
CRCLM surgery 
  
  
  
x 
  
  
  
  
  
  
  
  
  
 
AE assessment 
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Concomitant 
medications 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
 
Pregnancy test**** 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Compliance monitoring 
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
 
Biospecimen collection 
(optional)***** 
 
x 
 
X****** 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Trial 
interventions 
Randomisation 
  
x 
  
  
  
  
  
  
  
  
  
  
  
 
IMP dispensing 
  
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
  
  
 
Participant 
Completed 
Questionnaires 
Participant 
Questionnaire Visit 1 
Pack 
  
x 
  
  
  
  
  
  
  
  
  
  
  
 
Participant 
Questionnaire Visit 2 
Pack 
  
  
  
x 
  
  
  
  
  
  
  
  
  
 
Participant 
Questionnaire Visit 3-
10 Pack 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
  
 
Data Collection through CRFs 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 

 
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*For Visit 3 and subsequent trial assessments, there is the possibility of remote (telephone) follow up in which case body weight is self-reported, 
blood sampling is not required and IMP is sent via courier to the participant’s postal address. 
**In the event that macroscopic disease remains following liver resection and curative treatment is not possible, a CT scan should be carried out 
as soon as possible to measure the extent of the existing disease.  
*** Blood sample collection at Sheffield Teaching Hospitals NHS Foundation Trust and Leeds Teaching Hospitals NHS Trust. 
**** For women of child-bearing potential: following consent, the participant must be registered before the pregnancy test is performed as this is 
a trial specific test. The participant cannot be randomised until a negative test has been obtained. 
***** See separate Biospecimen Collection protocol. 
****** Only if CRCLM surgery is ≥2 weeks from randomisation. 

 
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29. 
Appendix B: Pharmacovigilance Reporting 
Flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Yes 
 
 
 
            No 
     
 
 
 
 
 
 
 
 
 
 
 
Serious Adverse Event (SAE) – any untoward medical occurrence 
or effect that: 
-
results in death 
-
is life-threatening 
-
requires hospitalisation or prolongation of existing 
hospitalisation 
-
results in persistent or significant disability or incapacity 
-
is a congenital anomaly or birth defect 
-
jeopardised the subject or required intervention to 
prevent one of the above 
Event 
considered to 
be related to 
IPE 
Event 
considered to 
be related to 
chemotherapy 
and not 
exacerbated 
by IPE
Event considered to be a 
reaction to IPE and is 
expected 
 
Report as a Serious 
Adverse Reaction (SAR) 
Fax to CTRU  
within 24 hours  
using SAE CRF 
 
Report as a 
Serious 
Adverse Event 
(SAE) 
Fax to CTRU 
within 24 hours 
using the SAE 
CRF 
Event 
considered to 
be related to 
chemotherapy 
and 
exacerbated 
by IPE
Event 
considered to 
be related to 
chemotherapy, 
possible/unsure 
the event has 
been 
exacerbated by 
IPE 
Event 
considered not 
to be related 
to 
chemotherapy 
or IPE 
 
Report as a 
Serious 
Adverse Event 
(SAE) 
 
Fax to CTRU 
within 24 hours 
using the SAE 
CRF 
 
Participant not currently 
receiving chemotherapy 
and not received 
chemotherapy in the 
previous 8 weeks
Participant currently receiving chemotherapy or 
received chemotherapy in the previous 8 weeks* 
Event is: 
- a death or 
hospitalisation 
due to disease 
progression 
- hospitalisation 
for 
chemotherapy 
administration, 
palliative care or 
elective 
surgery 
 
Report as a 
Serious 
Adverse Event 
(SAE) 
 
Fax to CTRU 
within 24 hours 
using the SAE 
CRF  
 
Assess for causality assuming that the participant has received IPE 
Event considered to be a 
reaction to IPE and is not 
expected 
 
Report as a Serious 
Unexpected Adverse 
Reaction (SUSAR) 
Fax to CTRU  
within 24 hours  
using SUSAR  CRF 
Is the event considered to be a reaction to IPE and is 
expected? 

 
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30. 
Appendix C: Safety Monitoring Plan 
 
Study Title: EMT2 
Risks associated with trial interventions 
 LOW ≡ Comparable to the risk of standard medical care 
 MODERATE ≡ Somewhat higher than the risk of standard medical care 
 HIGH ≡ Markedly higher than the risk of standard medical care 
 
Justification:  Briefly justify the risk category selected and your conclusions below  (where the table is 
completed in detail the detail need not be repeated, however a summary should be given): 
 
This trial involves the use of familiar drugs in line with standard practice.  
 
What are the key risks related to 
therapeutic interventions you plan to 
monitor in this trial? 
How will these risks be minimised? 
IMP/Interventi
on  
Body system/Hazard 
Activity 
Frequency 
Comments 
IPE 
 
 
 
 
Upper and lower 
gastrointestinal 
symptoms 
Recommend that the 
capsules are taken with 
food. 
Twice daily 
Dose reduction 
algorithm 
(section 12.2.4) 
to be used in the 
event that 
symptoms do not 
resolve. This 
includes the 
option for a 
temporary 
treatment break 
during 
chemotherapy. 
A data monitoring and ethics committee (DMEC) will be convened who will periodically (at least 
annually) review unblinded safety information.  The DMEC will in light of these reports, have the 
authority to recommend trial closure to the Trial Steering Committee (TSC) should they have 
concerns over the safety or ethics of the trial.  The TSC have the authority to recommend closure of 
the trial to the sponsor at any time. 
Participant data will be entered onto a validated database and monitored for completeness and 
quality by the CTRU.  Missing data will be chased until it is received, confirmed as not available, or 
the trial is at analysis.  A validation check program will be incorporated into the database to verify 
the data, and discrepancy reports will be generated for resolution by the local investigator.  Priority 
validations will be incorporated into the validation program to ensure that any discrepancies related 
to participant rights or the safety of participants are expedited to participating centres for 
resolution. 
 
 
 
 

 
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31. 
Appendix D: Response Evaluation Criteria 
in Solid Tumours (RECIST) 
 
 
In the case of macroscopic disease (liver and extra-hepatic metastases) remaining following 
surgical resection response to treatment will be assessed based on RECIST v1.158.  A copy 
of the revised RECIST guideline is provided in the Investigator Site File and may also be 
obtained at: 
 
http://www.eortc.be/recist/  
 
Published date: January 200958.  
 
 
32. 
Appendix E: Summary of Product 
Characteristics for Icosapent Ethyl 
 
An uptodate copy of the Summary of Product Characteristics for Icosapent Ethyl (Vakepa) is 
available by following the web link below: 
 
https://products.mhra.gov.uk/product/?product=VAZKEPA%20998%20MG%20SOFT%20CA
PSULES