Gayle Scott, Research Nurse. WGH Edinburgh. Randomised controlled trial of 6- Mercaptopurine versus placebo to prevent recurrence of Crohn s disease following surgical resection. Lead Site: Western General Hospital, Edinburgh. Chief Investigator: Professor Jack Satsangi Investigators: Dr Ian Arnott, Professor Malcolm Dunlop, Mr David Bartolo and Ms Mhairi Collie. 1
The Problem Crohn s disease is incurable. 80% of patients with Crohn s disease will require intestinal resection. Recurrence is common: 20-25% need second op at 5 years No clear evidence that surgical technique or medical therapy reduces recurrence. Background In August 2006 the Medical Research Council awarded TOPPIC a 1.9m grant Aug 06 May 07 Ethics, MHRA and R&D approvals Recruitment of key personnel Drug and placebo sourced (not funded by MRC) Packaging and distribution arranged Trial Steering Committee and Data Monitoring Committee established E-CRF developed 2
Does 6-MP prevent or delay post-operative recurrence of Crohn s Disease? We now plan to recruit 234 patients across the UK. Recruitment phase 3 years, with follow-up for 3 years This is the first truly double blind placebo controlled trial of a thiopurine in post operative Crohn s disease Primary Outcome/Endpoint Clinical recurrence of Crohn s disease (defined by a CDAI value of greater than 150 together with a 100 point rise in the CDAI score from baseline) together with the need for anti-inflammatory rescue therapy or primary surgical intervention 3
Secondary Objectives 1. Does 6MP prevent or delay endoscopic evidence of recurrence? 2. Can faecal calprotectin be used as a noninvasive marker of disease recurrence? 3. Do drug metabolite levels relate to clinical efficacy of 6MP? 4. Can we predict postoperative recurrence using clinical, genetic or serological data? Recruitment Recruitment began in 5 centres (Edinburgh, Glasgow x2, Aberdeen, Dundee) in May 2008 The ability to recruit 234 patients was based on pathology reports from recruiting centres Assumed only 60% of eligible patients participated Recruitment so far has been disappointing 67 randomised patients 19 patients in screening phase Actually 30% of eligible patients participated 4
Why is Recruitment Slow? Potential explanations include Therapies are changing? Patients wary of placebo? Incomplete ascertainment? 5
URGENT Study now being driven by Steering Group/MRC therefore need for urgent improvement in recruitment figures More money, more sites more time? 6
ENGLISH SITES ACTIVELY RECRUITING: Royal Devon and Exeter (Dr Tariq Ahmed), Torbay District General (Dr Cathryn Edwards), Royal Liverpool Hospital (Dr Keith Leiper), Manchester Royal Infirmary (Dr Simon Campbell), Salford Royal (Dr Simon Lal), Bristol Royal Infirmary (Dr Tom Creed), University Hospital of Coventry (Dr Chuka Nwokolo), UCLH (Dr Stuart Bloom), Oxford Radcliffe (Dr Simon Travis). ENGLISH SITES AWAITING REGULATORY APPROVAL: Royal Free (Dr Charles Murray), Barts (Dr James Lindsay) Leicester (Dr Barrie Rathbone), Norwich (Dr Ian Beales), Swansea (Dr Linzi Thomas), Stockton on Tees (Dr Matt Rutter), Southampton (Dr Fraser Cummings), Plymouth (Dr Stephen Lewis), Durham/Darlington (Dr Anjan Dhar), Hull (Dr Shaji Sebastian), Leeds (Dr John Hamlin), Shrewsbury (Dr Mark Smith), New Cross Wolverhampton (Dr Matt Brookes), North Staffordshire Uni Hospital (Dr Sandip Sen), Nottingham (Professor Chris Hawkey), Sheffield (Dr Alan Lobo), St Mark s (Dr Naila Arebi), Rotherham (Pierre Willemse) and Birmingham (Dr Jason Goh). Inclusion Criteria At least 16 years of age (18 in England) Established diagnosis i of Crohn s disease confirmed at recent resection Ileocolonic or small bowel resection within 3 months No more than 100cm of fixed small bowel resected in total. Previous resection is acceptable Able to start oral nutrition within the first 2 post-op weeks Normal or Carrier TPMT Able to provide written informed consent prior to screening and to comply with the requirements of the study protocol. Off antibiotics 2 weeks prior to randomisation. 7
Exclusion Criteria 1. Pregnancy at baseline or breast feeding 2. A known hypersensitivity or intolerance to 6MP 3. Pancreatitis associated with Azathioprine 4. Receiving an experimental treatment for Crohn s disease in the 4 weeks prior to study entry 5. Known to require further surgery at study entry i.e. for the removal of an abscess developing from the primary surgery 6. Stricturoplasty procedure alone (Stricturoplasty and resection procedure together will not be considered an exclusion) 7. Presence of stoma 8. Significant haematological, renal or hepatic dysfunction or clinically important lung disease, i.e. LFTs >x2 upper limit of normal, Hb 10, WBC <3.5, Neutrophils <1.5, Platelets <100x106/l Exclusion Cont.. 9. Systemic infection including hepatitis B, hepatitis C, HIV and active TB 10. A diagnosis of indeterminate colitis or ulcerative colitis 11. A history of illicit drug or alcohol abuse in the 1 year prior to study entry 12. History of cancer excluding basal cell carcinoma treated more than 5 years previously and insitu tumours 13. Presence of a medical or psychiatric condition, disease or laboratory abnormality that in the opinion of the PI may place the subject at unacceptable risk during the study 14. Deficient for TPMT 15. Evidence of untreated post-op infection e.g. C.diff, UTI or chest infection. If these have been appropriately treated in the opinion of the PI, and inclusion criteria 8 is met, (off antibiotics for 2 weeks prior to randomisation) this will not be considered an exclusion. 8
Design Patients will be randomised to either 6MP (1-1.5mgs/kg) or placebo 4-6 weeks after discharge Will receive either 6MP or placebo for 3 years 13 separate visits during the 3 years (156 weeks) Colonoscopy after 1 and 3 years Recruitment Dedicated Nurse at each site Close links with MDT including pathologists Suitable resection contact nurse Visits will all be managed by nurse/medical Team 9
Contact: Gayle Scott: 0131 5373858 or 07850256670 gayle.scott@ed.ac.uk ac 10