Anna Sandell 19 July 2012 AGENDA 1. 1. GENERAL RAL STUDY I Y - PowerPoint PPT Presentation

Anna Sandell 19 July 2012

AGENDA 1. 1. GENERAL RAL STUDY I Y INFO FORM RMATION 2. 2. STUDY Y OUTLI LINE AN AND D OBJE BJECT CTIVE VES 3. 3. PROTOCO COL L OUTLIN LINE 4. 4. INVE VESTIGATIONAL AL MEDI DICI CINAL AL PRODU DUCT CT 5. 5. STUDY Y SCH CHEDU DULE LED VI D VISITS & P & PROCE CEDU DURE RES 6. 6. CO CONSENT & RAN & RANDO DOMISATION 7. 7. BI BIOLOGICAL CAL SAM AMPLE LES 8. 8. AD ADVE VERS RSE EVE VENT RE REPORTING 9. 9. PROHIBI BITED D MEDI DICA CATIONS 10. 10. EMERGENCY U CY UNBLI BLINDI DING 11. 11. WI WITHDRA DRAWAL WAL OF P F PAR ARTICI CIPAN ANTS 12. 12. STUDY Y MAN ANAGEMENT EXP XPECT CTATIONS

GENERAL STUDY INFORMATION CHI HIEF EF IN INVESTIGA ESTIGATOR: OR: • Professor Mark Hull, Molecular Gastroenterology, University of Leeds FUNDE FUNDER: • • Efficacy and Mechanism Evaluation programme (EME) • Very competitive and rigorous process – Approx £1million SPONSOR: SPONSO • • University of Leeds CO CO-ORD ORDIN INATI TING NG CENTRE: ENTRE: • • Nottingham Clinical Trials Unit • Anna Sandell Trial Manager • Ellie Harrison Trial Administrator • Statistics • Data Entry • Data Management

STUDY OUTLINE AND OBJECTIVES OU OUTLI TLINE: NE: PHASE 3, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED 2X2 FACTORIAL TRIAL PR PRIM IMARY OBJEC OBJECTIVE TIVE To determine whether the naturally-occurring omega -3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) prevents colorectal adenomas, either alone or in combination with aspirin SEC SECON ONDARY OBJEC OBJECTIVE TIVE 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 1 o en endp dpoint oint – nu numbe mber of r of pa patients tients with ith a a po polyp(s) yp(s) 2 o o en endp dpoints oints – polyp number, ‘advanced’ lesions, location, AEs

PROTOCOL OUTLINE IN INCLUSI USION ON: 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 EX EXCLUSI USION ON CRITERIA ITERIA: : 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 . EX EXCL CLUS USION ON CR CRITE TERIA RIA : : 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 PRODUCT GAS ASTRO-RE RESISTAN ANT E EPA-FF FFA A 2G 2G D DAI AILY Y (taken as 2 x 500mg capsules BD) ENTERI RIC-CO COATED D AS ASPIRI RIN 300M 300MG D DAI AILY Y (taken as 1 x 300mg tablet OD) PLA LACE CEBO BO FO FOR R EPA-FF FFA A (taken as 2 x capsules BD) PLA LACE CEBO BO FO FOR R AS ASPIRI RIN (taken as 1 x tablet OD) NB all trial medication must be taken with food and everyone is blinded to the treatment allocation DU DURA RATION OF T F TRI RIAL AL MEDI DICA CATION: 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 & PROCEDURES Co Colon lonoscopy – up to 4 weeks before V1

STUDY SCHEDULED VISITS & PROCEDURES V1 1 (ba (basel seline ine total 1 total 1-1.5 1.5 hr) hr) - consent, randomisation, FFQ, blood and urine

CONSENT 3 O 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 AN ANY Y STUDY RE Y RELA LATED P D PROCE CEDU DURE RE 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 INS NSTR TRUC UCTIONS TIONS AR ARE A E AT T TH THE E FRONT ONT OF OF EVE EVERY CA Y CASE SE RE RECO CORD RD FOR 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 Food Frequency Questionnaire (to measure how 2 x 6 ml blood sample Urine sample much omega 3 is consumed from the diet)

STUDY SCHEDULED VISITS & PROCEDURES V2 2 ph phon one e ca call ll (week (week 2) 2) – AEs, trial meds, con meds (15 min) V3 3 pho phone ne call call (w (week eek 12) 12) – AEs, trial meds, con meds (15 min)

STUDY SCHEDULED VISITS & PROCEDURES V4 4 6 6 mon month ou th out-pa patient vi tient visi sit t (week (week 25 25) – trial medication return & dispensing , AEs, bloods & urine (1 hr)

STUDY SCHEDULED VISITS & PROCEDURES 38) – AEs, trial meds, con meds (15 min) +/- V5 5 ph phon one e ca call ll (week (week 38 V5a 5a ph phon one e ca call ll (week (week 38 38) – AEs, trial meds, con meds (15 min)

STUDY FLOW DIAGRAM

STUDY SCHEDULED VISITS & PROCEDURES V6 6 exit xit co colono lonoscop scopy y (week (week 50 50 or or up up to 62) to 62) – trial med return, AEs, bloods & urine, rectal biopsies (1.5hr)

STUDY SCHEDULED VISITS & PROCEDURES V7 7 fina final l vi visi sit t (week (week 52 52 or or up up to to 64 64) ) - adenoma details and FFQ ( 25 min) NB see protocol and CRF for time window allowances for each visit

BIOLOGICAL SAMPLES – WHY? To under o underst stand and ho how w EP EPA and as A and aspiri pirin w n wor ork, alone and in k, alone and in • combina combination tion To identify a biomar o identify a biomarker(s) er(s) tha that pr t predicts edicts w whether hether EP EPA A • and/or and/or aspir aspirin w in wor orks ks (to (towar ards ds per personalis sonalised ed chemopr hemoprevention) ention) To deter o determine w mine whether hether the the pa patient tient genoty genotype pe pr predicts edicts • ef efficac ficacy of y of EP EPA and as A and aspiri pirin, n, alone or in combina alone or in combination tion

LIQUID CHROMATOGRAPHY- TANDEM MASS SPECTROMETRY