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1-140 READY, STEADY GO….Claire Bewshea Exeter IBD and Pharmacogenetic Research Manager

Exeter IBD and Pharmacogenetics Research Group

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Inflammatory Bowel Disease Background Carrie Grant Treatment

Studies 5ASA PRED 4PANTS

Did you Know ? Thanks

Exeter IBD and Pharmacogenetics Research Group

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Inflammatory Bowel Disease (IBD)

Exeter IBD and Pharmacogenetics Research Group

• 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?

4Exeter IBD and Pharmacogenetics Research Group

"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 state in 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

Carrie Grant – CD diagnosed 1988.

Exeter IBD and Pharmacogenetics Research Group 5

Treatment for IBD

There is no current cure.

Aims of treatment 1. Reduce symptoms – inducing remission 2. 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 complicationsand to 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

• Advertised the study asking for volunteers.

• MHRA – yellow card.

• Presented at gastroenterology and nephrology conferences

• Approached the International IBD genetics consortium

5ASA - What did we do?

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

• 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 !

Current Pants Status

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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.

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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.