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Anna Sandell 19 July 2012

AGENDA

1. GENERAL STUDY INFORMATION

2. STUDY OUTLINE AND OBJECTIVES

3. PROTOCOL OUTLINE

4. INVESTIGATIONAL MEDICINAL PRODUCT

5. STUDY SCHEDULED VISITS & PROCEDURES

6. CONSENT & RANDOMISATION

7. BIOLOGICAL SAMPLES

8. ADVERSE EVENT REPORTING

9. PROHIBITED MEDICATIONS

10.EMERGENCY UNBLINDING

11.WITHDRAWAL OF PARTICIPANTS

12.STUDY MANAGEMENT EXPECTATIONS

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

STUDY OUTLINE AND OBJECTIVESOUTLINE:

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

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

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

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

INVESTIGATIONAL MEDICINAL PRODUCTGASTRO-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

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)

PHARMACY & DISPENSING

And 3 packs of these at each dispensing

(Aspirin 300mg E/C or Placebo 62 tablets

per container)

STUDY SCHEDULED VISITS & PROCEDURESColonoscopy – up to 4 weeks before V1

STUDY SCHEDULED VISITS & PROCEDURESV1 (baseline total 1-1.5 hr)

- consent, randomisation, FFQ, blood and urine

CONSENT

3 OPTIONS:

1) SSP or Research Nurse takes Informed Consent

2) SSP or Research Nurse takes Informed Consent but PI counter-signature is required

3) 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

RANDOMISATION

INSTRUCTIONS ARE AT THE FRONT OF EVERY CASE RECORD FORM

• Web-based system

• Accessed from any computer with internet access

• https://ctu4.nottingham.ac.uk/0921/login.asp

• 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

RANDOMISATION

RANDOMISATION

RANDOMISATION

PRESCRIPTION

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

STUDY SCHEDULED VISITS & PROCEDURES

Urine sample 2 x 6 ml blood sample

Food Frequency Questionnaire

(to measure how much omega 3 is consumed from the diet)

STUDY SCHEDULED VISITS & PROCEDURESV2 phone call (week 2) – AEs, trial meds, con meds (15 min)

V3 phone call (week 12)– AEs, trial meds, con meds (15 min)

STUDY SCHEDULED VISITS & PROCEDURESV4 6 month out-patient visit (week 25)– trial medication return &

dispensing , AEs, bloods & urine (1 hr)

STUDY SCHEDULED VISITS & PROCEDURESV5 phone call (week 38)– AEs, trial meds, con meds (15 min) +/-V5a phone call (week 38)– AEs, trial meds, con meds (15 min)

STUDYFLOW DIAGRAM

STUDY SCHEDULED VISITS & PROCEDURESV6 exit colonoscopy (week 50 or up to 62)– trial med return, AEs,

bloods & urine, rectal biopsies (1.5hr)

STUDY SCHEDULED VISITS & PROCEDURESV7 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

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

LIQUID CHROMATOGRAPHY- TANDEM MASS SPECTROMETRY

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

BIOLOGICAL SAMPLES - URINE

Urine (3 times – start, middle, end)

Measuring lipid metabolites including stable PGE2 metabolite

BIOLOGICAL SAMPLES – RECTAL BX

Rectal biopsies (exit colonoscopy only)

Fixed adenoma tissue blocks (at end of trial)

Rectal biopsies – measuring:1) EPA incorporation2) Mucosal lipid levels eg. PGE2, lipoxins, RvE1

Immunhistochemistry for:1) COX-22) Cell receptors for eg. RvE1 (ChemR23)

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

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

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.

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

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

 https://ctu4.nottingham.ac.uk/0921_unblind/login.asp

If need arises for non-emergency unblinding then must be discussed with the CI

EMERGENCY ONLY:

Local hospital Pharmacy to unblind using unblinding web-based system

 https://ctu4.nottingham.ac.uk/0921_unblind/login.asp

If need arises for non-emergency unblinding then must be discussed with the CI

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

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

FLOW CHART OF EPA/PLACEBO CAPSULE REDUCTION

YES

YES

ONE twice a

day

TWO twice a

day

NO

Adverse Events?Has participant had any of the

following persistent

symptoms which has lead to

consideration of stopping IMP?

• nausea•abdo

pain/dyspepsia• diarrhoea

Are capsules and

tablets taken with food?

Give advice about taking

IMP with meals

NO

What number

of capsules

is participa

nt taking?

Reduce to ONE twice a day until

next visit/call

Consider stopping

capsules but continue

tablets and call Trial Manager

ONE twice a

day

TWO twice a

day

What number

of capsules

is participa

nt taking?Continue

to take TWO

capsules twice a

day

Increase back to TWO twice a day with food

(see note below)

Telephone check up within 2 weeks

YES

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

Consider stopping

tablets and call Trial Manager

No capsules

INVESTIGATOR SITE FILEEach 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

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 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

• 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

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

PROGRESS TO DATE (1)• BCSP CENTRES ALREADY OPENED TO RECRUITMENT:

• 14 CENTRES• 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

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

PROGRESS TO DATE (3)• BCSP CENTRES TO BE OPENED TO RECRUITMENT SHORTLY:

• 14 CENTRES• 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

PROGRESS TO DATE (4)

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