Title: A programme of Cochrane systematic reviews to investigate optimal treatment strategies using emerging pharmacological interventions, dietary therapies and interventions to manage pain in Inflammatory Bowel Disease
Funder: Department of Health and Social Care

Abstract: Background IBD is a group of inflammatory conditions of the gut. The disease most commonly presents as the conditions CD UC. CD and UC are chronic lifelong conditions with no cure and are characterised by periods of remission and relapse. Therefore, treatments aim to induce remission, maintain remission and reduce associated symptoms of the disease. Gastrointestinal symptoms, such as abdominal pain, urgency, diarrhoea and bleeding, can be accompanied by pain and tiredness. Although the mortality rate is low, the conditions have a substantial impact on a patient’s ability to lead a normal life and can still be life threatening. In the UK, there are estimated to be around 240,000 patients with these conditions (Royal College of Physicians 2016). Based on recent data (Gosh 2015), the cost for direct gastrointestinal care of IBD patients within the NHS can be estimated at £1 billion per annum. With 1 in 250 people affected, IBD therefore has a significant social and economic impact on society. IBD is a condition that also presents a considerable burden to children, with approximately 5 in 100,000 new cases in under 16 year olds per annum and current data suggesting that this number is increasing (Hope 2012). There are broadly three classes of treatment that are commonly used to induce and maintain remission in IBD: antinflammatory agents, immunospressive agents and biologic therapies. Recent research has investigated the potential of dietary interventions, modification of the gut microbiota using probiotics and antibiotic therapies. Therapies to treat anaemia have also attracted much research. The three primary classes of drugs for induction and maintenance of remission all have the potential to be efficacious with different side effect profiles. However, National Institute for Health and Care Excellence (NICE) guidance has limited advice regarding such emerging therapies (NICE 2013, 2016) and therefore an up-to-date synthesis of the evidence base is required to inform practice and future national and international guidance, such as those from NICE. The James Lind Alliance (JLA) priority setting partnership (PSP) enables the establishment of shared interests of patients, carers and clinicians. As a result, questions that they all consider important but that have not been addressed previously, are highlighted (JLA 2016). Last year, the JLA completed a PSP Top 10 for inflammatory bowel disease (JLA 2015). This Top 10 describes key areas for future research, with substantial areas of clinical management considered, including strategies to induce remission, maintain remission and enhance quality of life for sufferers. The final draft topic list was one of the key items discussed within the user group panels and clinical professionals’ panel consultations: PSP Question 1: Optimal treatment strategies What is the optimal treatment strategy considering efficacy, safety and cost-effectiveness (immunomodulators, biologics, surgery, combinations) in IBD management: selecting the right patient group, right stage of disease, and assessing potential for withdrawal? Review title: 1. Interventions to maintain post-surgical remission in Crohn’s disease PSP Question 3: Diet to achieve normal daily activity and symptom control What role does diet have in the management of mildly active or quiescent ulcerative colitis or Crohn’s Disease to achieve normal daily activities and symptom control? Review titles: 2. Dietary therapy for maintenance of remission in Crohn’s 3. Dietary therapy for induction of remission in Crohn’s PSP question 4: Effective pain management in IBD How can pain be most effectively managed in people with IBD? Review titles: 4. Interventions for the management of pain in ulcerative colitis 5. Interventions for the management of pain in Crohn’s disease PSP question 7: Optimal diet therapy to achieve or support mucosal healing What is the optimal dietary therapy (liquid enteral diet and/or reintroduction diet) and duration to achieve mucosal healing in active IBD and/or remission either as a primary or adjunctive treatment? Is there a difference between adults and children? Review titles: 6. Enteral nutritional therapy for induction of remission in Crohn's disease 7. Enteral nutrition for maintenance of remission in Crohn's disease PSP question 8: Fatigue in IBD What is the association between IBD and fatigue and how should it be managed? Review titles: 8. Interventions for treating iron deficiency anaemia in CD 9. Interventions for treating iron deficiency anaemia in UC PSP question 10: Does influencing the gut microbiota influence the course of IBD? Review titles: 10. Antibiotics for induction and maintenance of remission in CD 11. Antibiotics for induction of remission in acute flare up of UC 12. Probiotics for maintenance of remission in CD 13. Probiotics for induction of remission in UC 14. Probiotics for maintenance of remission in UC Methods For the comparison of interventions through direct and indirect evidence, we will use network meta-analysis. We will use standard methodological procedures expected by Cochrane for reviews and adhere to ‘MECIR’ standards for the conduct and reporting of systematic reviews. All protocols for each review title will undergo extensive editorial and peer review before commencing the full systematic reviews. Details of areas of complex methodology are also included, with explanation as to when and why these methods will be deployed. We will identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress), using several sources. We will search electronic databases PubMed, MEDLINE, EMBASE and CENTRAL, using searches designed by the Cochrane IBD group's information specialist. Other specialist databases including LILACS, CINAHL and ongoing trials registers will be searched as appropriate. Abstracts from major international meetings from the last two years will be included to ensure new studies are captured (Digestive disease week, Advances in IBD, UEGW). Also, we will contact individuals with an interest in the field and check reference lists of relevant publications. All electronic databases will be searched from inception to the current date, although for reviews being upated searches may be restricted to relevant dates. No language restrictions will be imposed on the searches, with support offered by the modern languages department to translate any foreign language papers. All searches will be conducted by an experienced information specialist. We will store search results electronically using EndNote reference management software and upload into Covidence for managing study selection and extraction of data. This allows literature review databases to be made available to all personnel working on the review, facilitating handling and importing of references into RevMan. EndNote allows efficient retrieval of manuscripts of research papers arising from the reviews (pdfs). Each review will be published in the Cochrane library. To facilate rapid dissemination, completed reviews may be sent for presentation at international scientific meetings prior to full editorial review and publication. We will work with relevant groups to offer more focussed presentations at such events to ensure detailed dissemination, such as workshops and user group panels at international meetings (e.g. Digestive Disease Week, BSG / BSPGHAN annual meetings, Advances in IBD Crohn’s and Colitis Foundation meeting). Before publication, the steering group will oversee the production of a structured dissemination strategy, for each review to ensure rapid uptake and impact on NHS practice. Author teams, in association with the Cochrane IBD group editorial team, will complete a dissemination strategy prior to publication of each review. The process to be followed involves dissemination through three key routes and will begin when groups of reviews are completed: 1) Through UK clinical networks Each completed review will be considered by the steering group to ascertain if there are key implications for practice or research. If this is the case, the BSG and BSGHAN guideline and research committees will be contacted. Additionally, NICE will be contacted and the findings presented. This will allow the guideline development teams to consider if an update is needed prior to the planned date for such activity. 2) Through UK Patient and service use groups Regardless of whether changes to practice or not are indicated, our core service user and patient group will be convened for each review and with the help of the facilitator, the results discussed. This will be in light of the steering group findings and highlight if any changes to practice are indicated. These will be disseminated through Crohn’s and Colitis UK and CCFA, once peer reviewed by their own internal service user teams. 3) Through Cochrane IBD group activities The IBD group has well established approaches to ensure international dissemination and utility of their works. These are in addition to the core Cochrane activities of publication, blog summaries and Cochrane network contacts. Key to these activities are the publication of short form reviews to international networks, co-publication agreements with key high impact journals in the field and finally a Cochrane symposia at the world’s largest gastroenterology conference annually that presents key new findings in IBD.

Lay abstract: What is Inflammatory Bowel Disease (IBD)? IBD is a long-term inflammatory disorder that can involve any part of the gastrointestinal tract. The disease most commonly presents as the conditions Crohn’s disease (CD) and ulcerative colitis (UC). It can affect people of any age. When people have active IBD they experience symptoms such as abdominal pain, diarrhoea, nausea, sometimes dramatic weight loss, joint pain and bleeding in their stools. When symptoms disappear, people are considered to be in remission. These symptoms are related to inflammation and ulceration of the bowel. Active IBD can be treated by medical therapy (e.g. drugs such as steroids, immunosuppressives or biologics) or by surgery to remove the diseased portions of the intestine. The goal of therapy in IBD is to induce remission and maintain remission for as long as possible Why are the treatments being investigated? CD and UC are chronic lifelong conditions with no cure and are characterised by periods of remission and relapse. This is different from many other illnesses, which have a definitive treatment and often a goal of cure. There is a portfolio of treatment options and use of these treatment options varies from patient to patient, based on many factors. Additionally, there is lots of ongoing research across the globe into new and existing therapies. Therefore, we need a complete and systematic review of the evidence that exists around each of the treatments including their costs. This review needs to be presented in a way that is accessible to patients and professionals. This project will produce 14 systematic reviews of different IBD treatments. A systematic review is a literature review that finds all evidence on a topic and critically analyzes these studies. How will the project work? The core team is based at the University of Central Lancashire (UCLAN). The team consists of a Chief Investigator (Dr Morris Gordon) and methodologist (Prof Andrew Clegg) based at UCLAN with significant experience in the field and three researchers hired for the project. They are supported by a wider team with IBD experience, systematic review experience, health economics and the UCLAN service user group COMENSUS. The team will complete the reviews in blocks of 3 or 4 over 6 months intervals, to ensure full completion of reviews before the next ones begin and to make sure that output to clinicians and users is ongoing throughout the project. How will the results impact patients and the NHS? Despite much research on all treatments being considered in this project and their widespread use, the highest quality review of evidence is lacking. Through an ongoing process of feedback, the results will be promptly relayed to the national societies for Gastroenterology in the UK, International societies and to IBD patient groups. Additionally, we will liaise with the National Institute for Health and Care Excellence and other similar agencies internationally to ensure the work is recognised and as stakeholders our team can contribute to updates of guidance. This research will ensure that decision making is based on the best evidence available and clinicians and patients in partnership can make informed choices as to their IBD treatment options.

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY;6.7 PHYSICAL
Health categories: ORAL AND GASTROINTESTINAL