Open studies

Working with the NIHR Bioresource, we are proposing to develop a centralised national recallable bioresource of 25,000 patients with Crohn’s disease or ulcerative colitis (collectively inflammatory bowel disease / IBD) to support scientific and clinical IBD research. Key features of IBD Bioresource:1. DNA and serum + clinical and genetic data from 25,000 IBD patients recruited UKwide stored in a central biorepository funded by NIHR Bioresource 2. 1000 newly diagnosed IBD patients. Detailed samples unconfounded by treatment or surgery, plus followup samples + clinical data 3. Recallability run by the NIHR Bioresource office, allowing patients stratified by clinical subtype or carriage of specific IBD genetic risk variants to be recruited for stratified ‘stage 2′ scientific studies or clinical trials (each stage 2 study would require separate funding and new consent for each subject).IBD affects 4 per 1000 Europeans, peaking in young adults. Despite intensive medical therapies ~50% of patients require major surgery +/colostomy for treatment failure or complications. There is a pressing need to understand the causes of IBD and develop better treatments.Since 2007 we and others have identified >160 distinct genetic risk factors for IBD. The next steps require additional sequencing for rare variants and functional analysis, to understand how associated variants disturb cell function to cause IBD; and translation of this knowledge for clinical benefit. These require access to a large Bioresource of patients of known or ascertainable genotype, to obtain fresh samples for analysis or to recruit patients to stratified clinical trials.’Recallability’ is a key novel feature for our disease area. The ethical framework for this has been established by the NIHR Cambridge Bioresource which since 2007 has run a programme of ‘recallability-by-genotype’ for healthy individuals. Our IBD Bioresource will be part of the NIHR Bioresource, and will extend recallable functionality to IBD allowing translation of recent genetic advances.

Full title: Investigation of the Genetic and Molecular Pathogenesis of Primary Biliary Cirrhosis

Summary: The PBC Genetics Study is a national effort to establish a PBC DNA collection consisting of DNA samples from approximately 5000 patients with PBC. The DNA collection has already been used for a genome-wide association study (GWAS) of PBC. The next major analysis will be a genome wide association study of response to Ursodeoxycholic acid (UDCA).

Full title: Predicting serious drug side effects in gastroenterology
These studies will investigate the genetics of 7 rare adverse reactions from drugs commonly used in gastroenterology (and other diseases).

1)Demyelination complicating anti-TNF therapy in Inflammatory bowel disease and other inflammatory disorders.

2)Proton Pump inhibitor induced interstitial nephritis.

3)Thiopurine induced pancreatitis in Inflammatory bowel disease.

4)Thiopurine induced myelosuppression in Inflammatory bowel disease.

5) Thiopurine induced liver injury in inflammatory bowel disease

6) Sulfasalazine induced neutropenia in IBD and rheumatoid Arthritis.

7) Thiopurine Hypersensitivity Reaction

8) Immunogenicity to Biologic Drugs in Inflammatory Bowel Disease (IMGEN)

9) Anti-TNF induced adverse skin reaction (ANTS)

The studies aim is to identify genetic markers that predict these side affects, so that these drugs can be avoided, or monitoring intensified, in genetically high risk patients. A simple, cheap,diagnostic test will be developed using this data which can be rapidly adopted into medium & large sized hospitals.
The secondary objectives are:

(a) to understand the mechanisms underlying drug side effects

(b) through a knowledge of the mechanisms, to learn about particular functional chemical groups which predispose to toxicity, & thereby facilitate more rational drug design.

(c) to develop a network of interested UK clinicians for further pharmacogenetic research projects.
The study is supported by the International serious adverse events consortium, CORE (British Gastroenterology and the international IBD genetics consortium.

A UK Collaborative Study to Determine the Genetic Basis of Primary Sclerosing Cholangitis.

Full title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Week Study to Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis

Summary: This study evaluates the effectiveness and safety of etrasimod in subjects with ulcerative colitis (UC) with moderately to severely active ulcerative colitis. Each subject will be enrolled in the study for approximately 18 weeks, including 28 days of screening (medical tests and results review to assess suitability), 12 weeks of treatment (induction), and 2 weeks of follow-up. Subjects will be randomly selected (like flipping a coin) to receive either once daily etrasimod (active drug) or placebo (control without drug). Neither the subject nor the research team know which treatment the subject is receiving.

The primary objective is to assess the potential effectiveness of etrasimod on clinical remission in subjects with moderately to severely active ulcerative colitis after 12 weeks of treatment.

The study will be conducted in approximately 330 participants worldwide.

Health Status, examined disease:
Ulcerative Colitis

Active drug: etrasimod (oral tablet)
Etrasimod: once daily, for 12 weeks.
Placebo comparator: Placebo (oral tablet)
Matching placebo: once daily

Key Inclusion and Exclusion criteria:
• Males, females and adolescents aged 16-80 years.
• Diagnosed with UC equal or more than 3 months prior to screening
• Active UC confirmed by endoscopy and histology
• Severe extensive colitis.
• Diagnosis of Crohn’s Disease.
• Diagnosis of microscopic colitis, ischemic colitis, or infectious colitis.

Full title: An Open-Label Extension Study of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis

Summary: An Open-Label Extension Study of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis

Full title: The NAFLD BioResource, part of the NIHR BioResource – A Research Study to Characterise Novel Clinical and Genetic Phenotypes, and Understand the Natural History of Non-Alcoholic Fatty Liver Disease (NAFLD)

Summary: NAFLD (Non-alcoholic Fatty Liver Disease), defined as the accumulation of excess fat in the liver, is now the commonest cause of liver disease in Western countries and affects approximately 30-40% of the UK population. Data suggest that NAFLD progresses to NASH (Non-alcoholic steatohepatitis) in about 20% of cases of which 20–25% may progress on to more advanced stages of hepatic fibrosis and cirrhosis, although predicting which individual patients will progress to develop advanced fibrosis is challenging.

Weight loss, as part of lifestyle change, is the only recommended intervention, with a > 10% loss associated with an improvement in fibrosis. As attaining and sustaining weight loss is difficult there have also been concerted efforts to develop pharmacological therapies for patients with NASH. A major challenge has been slow recruitment to clinical trials due to the lack of recallable databases. Patient factors including genotyping/phenotyping will play an ever-more significant role in optimising the choice of pharmacotherapy for patients.

Working with the NIHR Bioresource, we are proposing to develop a centralised national recallable BioResource up to 7500 patients with NAFLD to support scientific and clinical NAFLD research.

1) To characterise novel clinical and genetic phenotypes across NAFLD
2) To investigate impact and interaction of co-morbidities across NAFLD
3) To understand the natural history of NAFLD in the UK

4) To collect and store blood (for DNA extraction, plasma, serum and other biological components storage) as well as clinical and health and lifestyle data from up to 7,500 participants who have been diagnosed with NAFLD
5) Create a resource of recallable volunteers to help with future research, by obtaining consent from participants that they agree to be approached in the future and invited to further studies.

Studies in follow up

Closed to recruitment – in follow up.

IBD Cancer and Serious Infection in Europe – The purpose of this research is to gain more information about some of the long-term benefits and also some of the health risks potentially associated with certain treatments for Inflammatory Bowel Diseases (IBD) which consists of colitis and Crohns disease These treatments include: 5-ASA (such as mesalazine), steroids, azathioprine/ Mercaptupurine, Methotrexate and the newer biologic treatments (such as Adalimumb, Infliximab, or vedolizumab).

The long term risks of some of these therapies are not fully understood. For example, although considered to be extremely low risk, the exact risk of some very rare infections and some rare tumours such as lymphoma are not fully known and this study will help in quantifying this risk accurately This research will also gain information on the long-term benefits and the potential of these treatments to modify IBD as well as collecting data on Benefit-Risk and cost issues (such as direct, indirect and cost benefits).

Closed to recrutiment – in follow up.

A Long-Term Non-Interventional Registry to Assess Safety and Effectiveness of HUMIRAr (Adalimumab) in Patients with Moderately to Severely Active Ulcerative Colitis (UC).