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1-140 ready, steady Go….

1-140 ready, steady Go…. Claire Bewshea Exeter IBD and Pharmacogenetic Research Manager. Inflammatory Bowel Disease Background Carrie Grant Treatment Studies 5ASA PRED 4 PANTS Did you Know ? Thanks. Inflammatory Bowel Disease (IBD). Chronic inflammation of the gut

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1-140 ready, steady Go….

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  1. 1-140 ready, steady Go…. Claire Bewshea Exeter IBD and Pharmacogenetic Research Manager Exeter IBD and Pharmacogenetics Research Group

  2. Inflammatory Bowel Disease Background Carrie Grant Treatment Studies 5ASA PRED 4 PANTS Did you Know ? Thanks Exeter IBD and Pharmacogenetics Research Group

  3. Inflammatory Bowel Disease (IBD) • Chronic inflammation of the gut • 2 diseases: Crohn’s and Colitis • Symptoms: stomach ache, recurring or bloody diarrhoea, weight loss and extreme tiredness • Effect 1:250 un the UK • Causes is not known • Genetics? , Environmental? Exeter IBD and Pharmacogenetics Research Group

  4. Carrie Grant – CD diagnosed 1988. • "A couple of years ago I didn't eat for 90 days. Some sufferers can go for months without symptoms but I suffer constantly from stomach ache and diarrhoea. • “My bowel was in a terrible statein May 1989 I had to have bowel surgery” …. eight inches of her large bowel was removed. • “I’m just grateful for every day when I'm not in too much pain. • “My Life with Crohn’s disease “ www.nhs.uk Exeter IBD and Pharmacogenetics Research Group

  5. Treatment for IBD • There is no current cure. • Aims of treatment • Reduce symptoms – inducing remission • Maintaining remission. • Aminosalicylates - 5ASA , Sulphasalazine or Mesalazine • Cortisteroids– cheap. • Immunosuppressents-Azathiopurine or mercaptoprine • Anti-TNF – Inflixamab and adalimumab • Surgery Exeter IBD and Pharmacogenetics Research Group

  6. Pilot study - 5ASA induced Nephrotoxicity in IBD • Aim –to describe the clinical features of this rare complicationsandto find a genetic marker that would predict people who would be susceptible to getting this side effect. • Started March 2011 • Retrospective • Simple study design • Consent • One off Blood sample taken and clinical data from medical notes. • 1. First site opened in Exeter – but the aim was to recruit 200 patients! Exeter IBD and Pharmacogenetics Research Group

  7. Challenges: Patients? • Small budget 60 K per annum covered only coordinators salary, DNA extraction and consumables. • Very rare side affect, some historical – 20 years ago. • Small recruitment at sites, 1-2. • Finding patients. • No budget for patient recruitment! What had we let ourselves in for……. Exeter IBD and Pharmacogenetics Research Group

  8. 5ASA - What did we do? • Advertised the study asking for volunteers. • MHRA – yellow card. • Presented at gastroenterology and nephrology conferences • Approached the International IBD genetics consortium Exeter IBD and Pharmacogenetics Research Group

  9. 5ASA continued Doctors . • Further challenges recruiting sites who had not participated in research • Gastroenterology was a low priority and not well researched. • Very small team. • Legal proceeding with disgruntled patients. • 5ASA used a non commercial agreement Exeter IBD and Pharmacogenetics Research Group

  10. 5ASA Success . • In June 2013 • Exceeded our target and recruited 212 patients , samples sent to the Broad for GWAS. • 140 sites opened ( 1 or more patient recruited from 88 NHS hospitals) • October 2014 • Manuscript submitted to Gastroenterology. • Incidence is low and morbidity is high with 13% of patients requiring renal replacement and 70% of patients failing to return to a normal creatinine . • Interstitial nephritis cohort - Significant association in the class II MHC region that predisposes patient s to development of nephrotoxicity . Exeter IBD and Pharmacogenetics Research Group

  11. PRED 4 started March 2012. • Study Arms: • Thiopurine induced leucopenia • Thiopurine induced pancreatitis • PPI induced nephrotoxicity • Anti –TNF induced demyelination • PRED 6? Jan 2014 • Thiopurine induced liver injury • Sulfasalasine induced neutropenia • PRED 7 ? Oct/Nov 2014 • Thiopurine induced Flu Like syndrome. Exeter IBD and Pharmacogenetics Research Group

  12. PRED 4 study • 1200 over 140 sites. • No n CTA or MTA - quick approval over the infrastructure we built from 5ASA. • Sites set up now with research to complete the SSI, localised documents. • Success - September 2014 • Thiopurine induced pancreatitis published in Nature Genetics • Identified an association with a common variant in the Class II HLA region. • October/November 2014. • GWAS on the TIM arm, open the thiopurine induced flu syndrome. Exeter IBD and Pharmacogenetics Research Group

  13. Personalising Anti-TNF therapy in Crohns disease - PANTS • Observational, prospective study over 3 years • Aim : investigate PNR, LOR and withdrawal to anti-TNF in CD • Simple study design • No processing of samples at site, no requirement for MTA or non commercial agreement • NIHR adoption • Recruit 1200 • Collaboration with Industry, NHS and academia. Exeter IBD and Pharmacogenetics Research Group

  14. Current Pants Status • Recruited 750 patients • Real time CRP, calprotectin (drug and anti body levels)* • Sophisticated web capture tool and sample management database • Anti TNF drug and anti body assay – clinical service • Calprotectin service. • Extension study incorporating a withdrawal studyExpanding team ! Exeter IBD and Pharmacogenetics Research Group

  15. Exeter IBD and Pharmacogenetics Research Group

  16. Exeter IBD and Pharmacogenetics Research Group • Did you know ………Between the members of 3 (currently 2! ) • 255 site files (600 research staff) • 150 emails daily • 2300 patients recruited across all studies • 7 budgets to manage • 15 recruitment faxes daily • 40 sites boxes (inc 800 Labelled envelopes , 900 tubes etc) weekly. Exeter IBD and Pharmacogenetics Research Group

  17. Thank you! Exeter CRF Royal Devon and Exeter NHS Trust – R&D and Blood sciences. University of Exeter Medical school NIHR CORE CCUK IBD Patients and the 140 NHS sites that have worked with us. Exeter IBD and Pharmacogenetics Research Group

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