1. seAFOod initiation MEETING
THE SEAFOOD (SYSTEMATIC EVALUATION OF ASPIRIN AND FISH OIL)POLYP PREVENTION TRIAL
Anna Sandell 19 July 2012

2. agenda GENERAL STUDY INFORMATION STUDY OUTLINE AND OBJECTIVES
PROTOCOL OUTLINE
INVESTIGATIONAL MEDICINAL PRODUCT
STUDY SCHEDULED VISITS & PROCEDURES
CONSENT & RANDOMISATION
BIOLOGICAL SAMPLES
ADVERSE EVENT REPORTING
PROHIBITED MEDICATIONS
EMERGENCY UNBLINDING
WITHDRAWAL OF PARTICIPANTS
STUDY MANAGEMENT EXPECTATIONS

3. GENERAL STUDY INFORMATION
CHIEF INVESTIGATOR:
Professor Mark Hull, Molecular Gastroenterology, University of Leeds
FUNDER:
Efficacy and Mechanism Evaluation programme (EME)
Very competitive and rigorous process – Approx £1million
SPONSOR:
University of Leeds
CO-ORDINATING CENTRE:
Nottingham Clinical Trials Unit
Anna Sandell Trial Manager
Ellie Harrison Trial Administrator
Statistics
Data Entry
Data Management

4. STUDY OUTLINE AND OBJECTIVES
OUTLINE: PHASE 3, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED 2X2 FACTORIAL TRIAL PRIMARY OBJECTIVE To determine whether the naturally-occurring omega -3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) prevents colorectal adenomas, either alone or in combination with aspirin SECONDARY OBJECTIVE To assess the tolerability and safety of EPA in the free fatty acid form (EPA-FFA) alone, and in combination with aspirin, in elderly (60-75) years participants 1o endpoint – number of patients with a polyp(s) 2o endpoints – polyp number, ‘advanced’ lesions, location, AEs

5. PROTOCOL OUTLINE
INCLUSION:
60-73 Yrs BCSP Patients
Classified as High Risk at the first complete screening Colonoscopy within past 4 weeks
nb high risk = 5 or more small adenomas or 3 or more adenomas with at least one being ≥10mm diameter

6. PROTOCOL OUTLINE
EXCLUSION CRITERIA: main ones listed here (see protocol for extensive list) Need for more than one repeat colonoscopy or flexible sigmoidoscopy within a 3 month window Malignant change in an adenoma requiring colorectal cancer MDT management Regular (>3 doses/week) prescribed or OTC aspirin or prescribed or OTC non-aspirin NSAID use – not prepared to stop OTC use Aspirin intolerance, hypersensitivity including aspirin-sensitive asthma Active peptic ulcer disease within past 3 months or any previous peptic ulcer (not on PPI treatment) NB if taking PPI then they are eligible Fish or seafood allergy Current or planned regular(>3 doses/week) use of fish oil supplements - not prepared to stop OTC use

7. PROTOCOL OUTLINE cont.
EXCLUSION CRITERIA: main ones listed here (see protocol for extensive list)
Known clinical diagnosis or gene carrier of a hereditary CRC predisposition,(Familial Adenomatous Polyposis) or Hereditary Non Polyposis Colorectal Cancer
Previous or newly diagnosed Inflammatory Bowel Disease or colorectal resection
Known bleeding diathesis or concomitant warfarin therapy or any other anti- coagulant or anti-platelet therapy
Severe liver impairment (anyone who is known to have or is likely to have a coagulopathy (INR>/=1.5) from liver impairment)
Severe renal failure (creatinine clearance <10ml/min)
Current Methotrexate use at a weekly dose of 15 mg or more
Participating in another interventional clinical trial
Failure to give Informed Consent

8. INVESTIGATIONAL MEDICINAL PRODUCT
GASTRO-RESISTANT EPA-FFA 2G DAILY (taken as 2 x 500mg capsules BD) ENTERIC-COATED ASPIRIN 300MG DAILY (taken as 1 x 300mg tablet OD) PLACEBO FOR EPA-FFA (taken as 2 x capsules BD) PLACEBO FOR ASPIRIN (taken as 1 x tablet OD) NB all trial medication must be taken with food and everyone is blinded to the treatment allocation DURATION OF TRIAL MEDICATION: Start next morning following dispensing of trial medication at v1 Take every day until day before surveillance colonoscopy NB If participant has any planned invasive medical procedure then they must stop taken the trial medication for 10 days before the planned procedure and re-start 4 days after the procedure

9. PHARMACY & DISPENSING
Dispensing is at week 0 and week 25 (visit 4) and week 50 (visit 5a) if required
Each participant has 5 packs of these at each dispensing
(EPA-FFA 500mg or Placebo capsules 150 capsules per container)

10. PHARMACY & DISPENSING
And 3 packs of these at each dispensing (Aspirin 300mg E/C or Placebo 62 tablets per container)

11. STUDY SCHEDULED VISITS & PROCEDURES
Colonoscopy – up to 4 weeks before V1

12. STUDY SCHEDULED VISITS & PROCEDURES
V1 (baseline total hr) - consent, randomisation, FFQ, blood and urine

13. CONSENT 3 OPTIONS: SSP or Research Nurse takes Informed Consent
SSP or Research Nurse takes Informed Consent but PI counter-signature is required
PI only can take Informed Consent
ALWAYS ENSURE YOU HAVE THE PARTICIPANT’S CONSENT PRIOR
TO ANY STUDY RELATED PROCEDURE
NB - ensure that you find out your Trust requirements prior to recruitment start
- ensure that the PI has delegated the responsibility for Informed Consent to you and this is recorded on the delegation log prior to recruitment start

14. RANDOMISATION INSTRUCTIONS ARE AT THE FRONT OF EVERY CASE RECORD FORM
Web-based system
Accessed from any computer with internet access
Easy to use
Will provide Participant ID following confirmation of participant details (pt initials, gender, DOB) – use this ID for all study documentation
Will generate prescription – print off, obtain prescriber’s signature, take to pharmacy
Keep your username and password safe for log-in (audit trial)
New members of staff need to request username and password – via Trial Manager
If you cannot access the randomisation database – call Trial Manager

15. RANDOMISATION

16. randomisation

17. randomisation

18. prescription

19. PHARMACY & DISPENSING Prescription
generated from the web-based randomisation system and completed by the prescribing physician
Note: EPA-FFA is a fish oil and allergy to fish oil is part of the exclusion criteria.
It defines which container numbers should be dispensed for the participant.
The container numbers specified will have been delivered to your hospital
Give participant seAFOod bag to carry Trial Medication supplies
participant will receive a total of 8 items (boxes/tubs)
Inform participant to start the trial med next morning and always take with food
Trial med to be stored at room temp at / below 25 deg C

20. STUDY SCHEDULED VISITS & PROCEDURES
Food Frequency Questionnaire
(to measure how much omega 3 is consumed from the diet)
2 x 6 ml blood sample
Urine sample

21. STUDY SCHEDULED VISITS & PROCEDURES
V2 phone call (week 2) – AEs, trial meds, con meds (15 min)
V3 phone call (week 12)– AEs, trial meds, con meds (15 min)

22. STUDY SCHEDULED VISITS & PROCEDURES
V4 6 month out-patient visit (week 25)– trial medication return & dispensing , AEs, bloods & urine (1 hr)

23. STUDY SCHEDULED VISITS & PROCEDURES
V5 phone call (week 38)– AEs, trial meds, con meds (15 min) +/-
V5a phone call (week 38)– AEs, trial meds, con meds (15 min)

24. STUDY FLOW DIAGRAM

25. STUDY SCHEDULED VISITS & PROCEDURES
V6 exit colonoscopy (week 50 or up to 62)– trial med return, AEs, bloods & urine, rectal biopsies (1.5hr)

26. STUDY SCHEDULED VISITS & PROCEDURES
V7 final visit (week 52 or up to 64) - adenoma details and FFQ ( 25 min)
NB see protocol and CRF for time window allowances for each visit

27. BIOLOGICAL SAMPLES – why?
To understand how EPA and aspirin work, alone and in combination
To identify a biomarker(s) that predicts whether EPA and/or aspirin works (towards personalised chemoprevention)
To determine whether the patient genotype predicts efficacy of EPA and aspirin, alone or in combination

28. Liquid chromatography- tandem mass spectrometry

29. BIOLOGICAL SAMPLES - blood
Blood (3 times – start, middle, end)
Blood handling
Centrifuge (own lab or supplied equipment)
Plasma (to measure lipid biomarkers)
White blood cells (to obtain DNA)
Red blood cells (to measure EPA levels)
Lipids are labile so rapid cooling and freezing is preferred

30. BIOLOGICAL SAMPLES - URINE
Urine (3 times – start, middle, end)
Measuring lipid metabolites including stable PGE2 metabolite

31. BIOLOGICAL SAMPLES – RECTAL BX
Rectal biopsies (exit colonoscopy only) Fixed adenoma tissue blocks (at end of trial)
Rectal biopsies – measuring:
1) EPA incorporation
2) Mucosal lipid levels eg. PGE2, lipoxins, RvE1
Immunhistochemistry for:
1) COX-2
2) Cell receptors for eg. RvE1 (ChemR23)

32. BIOLOGICAL SAMPLES LAB MANUAL Instructions on processing and storage
30 mins from obtaining samples to freezer (allowing for site-specific factors)
Unique id labels in Investigator Site File section 7
Collection of samples every 3-4 months by CitySprint courier
Samples long term storage in Bradford lCT (Institute of Cancer Therapeutics)
CONSUMABLES PROVIDED
Blood tubes, aliquots, cryo rack, marker pen, Pathoseal bags, gloves
1st shipment to supply 10 participants

33. ADVERSE EVENT REPORTING
Always ask participant about Adverse Events at every phone call and clinic visit
Record all on the AE log and update log at every phone call and clinic visit
If AE fulfils SERIOUS criteria, complete SAE form immediately:
Participant has died from the event
Event is life-threatening if no immediate treatment given
Event has prolonged an existing hospital admission or resulted in a new hospital admission
Event has resulted in persistent or significant disability/incapacity
Event has resulted in a congenital anomaly or a birth defect (following either parent taking trial medication)
Medical or surgical intervention required to prevent one of the outcomes above
Medically significant – does not fulfil any of the criteria above but in the opinion of PI, requires reporting

34. ADVERSE EVENT REPORTING
PI or delegate must complete SAE form immediately
PI MUST SIGN and complete PI sections
if PI unavailable for next 24 hrs, complete as much as possible and call Trial Manager
Call Trial Manager to notify of an SAE
Fax completed SAE form as soon as completed (within 24 hrs of notification of SAE)
NB enquire specifically about dyspepsia, nausea, abdominal pain,halitosis, diarrhoea, bleeding episodes (including haematemesis/melaena) and diagnosis of stroke at each follow-up visit and telephone call
For the purpose of this Trial pre-planned elective hospital submissions will not be classed as a SAE.

35. prohibited medications
PROHIBITED MEDS
Warfarin or any other anti-coagulant or anti-platelet therapy (any dose),
Regular (>3x per week on an ongoing basis) prescribed or OTC aspirin,
Regular (>3x per week on an ongoing basis) prescribed or OTC non-steroidal anti- inflammatory drug (NSAID),
Ongoing or planned use of fish oil supplements
Methotrexate use at a weekly dose of 15 mg or more.
NB: 1) Participants should be advised to avoid taking any aspirin-containing over-the-counter
analgesia and to take an alternative (such as paracetamol) when pain relief is
necessary.
2) “regular” = use on a continuing basis over a period of time in consecutive weeks

36. EMERGENCY UNBLINDING
“For the majority of cases, unblinding will not be required because there is no antidote to the investigational treatments, and the medical care and usually the management of the patient would not be any different even if the treatment group assignment of the patient were known.” PROTOCOL
EMERGENCY ONLY:
Local hospital Pharmacy to unblind using unblinding web-based system  
If need arises for non-emergency unblinding then must be discussed with the CI

37. Withdrawal of participants
Participants can only be withdrawn from the trial completely if :
Participant withdraws consent
Participant lost to follow-up
Participant had more than 1 repeat colorectal endoscopy
Investigator’s opinion due to an Adverse Event
Participants who stop trial medication will still be followed- up until end of trial
Participants who are unblinded to their treatment allocation will stop the trial medication but will still be followed up until the end of the trial
AN END OF TRIAL CRF SHOULD ALWAYS BE COMPLETED

38. Trial medication side effects ?
Main side effects are: diarrhoea, nausea, dyspepsia, abdominal pain 1) Always check participant taking trial medication with food 2) Trial med can be reduced if AEs causing participants distress Capsules can be reduced to 1 capsule BD (increase after 1 -2 weeks) Aspirin can only be stopped not modified

39. Flow chart of EPA/placebo capsule reduction
Adverse Events?
Has participant had any of the following persistent symptoms which has lead to consideration of stopping IMP?
nausea
abdo pain/dyspepsia
diarrhoea
What number of capsules is participant taking?
Are capsules and tablets taken with food?
TWO twice a day NO
YES NO
YES
Give advice about taking IMP with meals
Continue to take TWO capsules twice a day
ONE twice a day
YES
What number of capsules is participant taking?
Increase back to TWO twice a day with food
(see note below)
TWO twice a day
ONE twice a day
Reduce to ONE twice a day until next visit/call
Consider stopping capsules but continue tablets and call Trial Manager
No capsules
Telephone check up within 2 weeks
Consider stopping tablets and call Trial Manager
Note:- participant should only be encouraged to increase back to TWO capsules twice a day on ONE occasion during the trial. If a participant has increased the number of capsules with return of symptoms then he/she should remain on ONE capsule twice a day

40. Investigator site file
Each Site will be provided today with a:
Site file
Pharmacy File (remains in pharmacy)
The Site File Contains all trial records kept at the site:
Protocol, Summary of Product Characteristics (SmPC), IMPD, IB
REC approved study documents
Main REC & local R&D approval
MHRA approval
Delegation of Responsibility Log
Signed consent forms
Subject ID / Screening logs
Adverse Event Reporting
Investigator/study personnel CVs and GCP certificates
Investigator Meeting & Initiation Visit Reports
Trial Report
Monitoring Records
It is the Sites responsibility to maintain the ISF

41. Study management CENTRE expectations
Each BCSP Centre has a target of recruiting a total of 60 participants over 2 yrs
can be divided between the separate sites within the BCSP
If poor recruitment within 6 months - ? Close site and open a new site
All personnel who will be working on seAFOod need to have a GCP certificate and have been trained either at this SIV or by PI/SSP
All patients who are classified as “high-risk” must be entered onto the screening log regardless of whether they are eligible or not.
Crucial for reports and trial management that this data is captured
Screening logs to be faxed through to Ellie every 2 weeks (wednesdays)
reminders will be sent
All personnel need to be recorded on the delegation log with their duties recorded
A copy of this must be sent to CTU and hospital pharmacy every time there is an alteration

42. Study management expectations
All CRFs to be posted to the Clinical Trials Unit within 1 week of completion
All data captured within the CRF must also be noted either on the BCSP database or within the patient’s medical records
Participant’s medical records must have an entry to say that consent has been given for entry to seAFOod trial
Any invoices for participant travel expenses (up to £10 – must have receipts) or admin costs be submitted to myself CTU with receipts

43. PROGRESS TO DATE (1) BCSP CENTRES ALREADY OPENED TO RECRUITMENT:
TEES SC
NORTH OF TYNE SC
SOUTH OF TYNE SC
DERBYSHIRE SC
NORWICH SC
CALDERDALE, KIRKLEES AND WAKEFIELD SC
COUNTY DURHAM AND DARLINGTON SC
HARROGATE, LEEDS AND YORK SC
BRADFORD AND AIREDALE SC
HULL SC
CUMBRIA AND WESTMORELAND SC
NOTTINGHAM SC
LEICS, NORTHANTS AND RUTLAND SC
COVENTY AND WARWICKSHIRE SC
DORSET SC

44. We need YOU! PROGRESS TO DATE (2) STUDY RECRUITMENT START DATE:
Recruitment open Nov 2011
Currently recruited 52 participants
Leading recruiting site = Glenfield and Kettering
Total 853 participants required
2 year recruitment period

45. PROGRESS TO DATE (3) BCSP CENTRES TO BE OPENED TO RECRUITMENT SHORTLY:
SURREY SC
WEST HERTS SC
EAST AND NORTH HERTS SC
CORNWALL SC
SOUTH DEVON SC
BRISTOL AND WESTON SC
SOMERSET SC
SOUTH EAST LONDON SC
WOLVERHAMPTON SC
LANCASHIRE SC
PETERBOROUGH AND HUNTINGDON SC
UNIVERSITY COLLEGE HOSPITAL LONDON SC
SOUTH ESSEX SC
NORTH ESSEX SC
BOLTON SC

46. Progress to date (4)

47. SEAFOOD WEBSITE