Title: The effect of Appendectomy on the Clinical Course of Ulcerative Colitis - The ACCURE Trial; UK arm
Funder: Department of Health and Social Care

Abstract: Background and aims There is increasing evidence that the appendix can affect the level of inflammatory activity in Ulcerative Colitis (UC) and that its removal (appendicectomy) can result in an improved disease course. Research suggests that dysbiosis within the appendix results in immune dysregulation and chronic colonic mucosal inflammation. Our randomised external pilot study confirmed appendicectomy to be both an attractive treatment option to patients and clinicians, and safe with minimal morbidity. The proposed study will support a UK arm of the ongoing Dutch ACCURE Study, to both aid recruitment rate and increase the statistical power of that study from 80% to 90%. It will therefore provide a more robust and timely answer regarding the clinical effectiveness of therapeutic appendicectomy in UC. Clinical Hypothesis Appendicectomy will result in an improved clinical course in UC compared to standard medical therapy. Patients undergoing the intervention will experience an increased chance of maintaining remission and an associated improvement in overall symptoms. Mechanistic Hypothesis Dysbiosis in the appendix is associated with dysregulated production of short chain fatty acids (SCFA), leading to aberrant immune activation and persistent/reactivated colonic inflammation. This effect can be suppressed by the removal of the appendix. Quantification of faecal short chain fatty acid concentration may be able to predict response to appendicectomy in UC and so stratify patients for prophylactic surgery. Design Observer-blinded multicentre randomised controlled trial [UK arm]. Embedded mechanistic evaluation to stratify responders. Population Adults with an established diagnosis of UC and a disease flare in the preceding 12 months requiring medical therapy. Intervention 50:50 randomisation to control arm or laparoscopic appendicectomy performed by a named consultant general surgeon on an elective (planned) theatre list, using a standardised 3-port technique. Endpoints Primary: The one year cumulative UC relapse rate, defined both clinically and endoscopically as Mayo-score =5 with endoscopy subscore of 2 or 3. Secondary: Number of relapses per patient in the first year after randomisation Time to first relapse Health related quality of life Treatment costs Number of colectomies. During longer term follow up beyond one year, disease activity including number of relapses and number of colectomies will be measured. Sample size The Dutch ACCURE trial is powered on a clinically relevant reduction in relapse rate from an expected 40% in the control group to 20% in the intervention group. At an alpha of 5%, 164 patients are needed to detect such a difference at 80% power. Allowing for a 10% attrition, our Dutch collaborators intend to randomise 182 patients. To increase the power from 80% to 90% requires an additional 60 patients (including 10% attrition). We therefore propose to recruit 90 patients in the UK, to both power up the trial and help complete main recruitment. Statistical analysis Analyses will be performed by our Dutch collaborators on an ITT basis, according to their pre-specified SAP (see protocol). Duration 30 months total: 0-2 Set-up and approvals 3-14 Staggered opening of 10 sites and recruitment over a 12 month period. Recruitment rate once open predicted to average at 1.5 pts/month/site. 15-26 Follow-up 27-30 Data collation, conglomeration, analysis and report writing

Lay abstract: Aim: To establish whether a minor operation to remove the appendix (appendicectomy) improves symptoms in patients suffering from Ulcerative Colitis (UC), and explore how this treatment might work. Background: Ulcerative Colitis (UC) is a chronic inflammatory condition of the large bowel affecting around 150,000 people in the UK, of whom over 40% experience a relapse annually causing pain and diarrhoea. Reducing relapses and thus improving quality of life are priorities for patients. Previous research suggests that the appendix affects the development and activity of UC. We undertook a pilot study of appendicectomy in 53 patients and found this to be both safe and attractive to patients and their doctors. Some of those who underwent appendicectomy reported feeling better, with fewer flare-ups over the following year. However, our study was not designed to be large enough to prove any definite benefit. Design and methods: Patients with relapsing UC will be invited to participate in this trial. We replicate a study currently being carried out in The Netherlands, using the same design and study procedures. This will allow us to combine our findings with the Dutch group in one large analysis, thereby obtaining a more robust result and in a more timely fashion. As such, patients may potentially benefit sooner from this intervention if we prove it to be effective. This UK arm will recruit 90 patients currently in disease remission and randomise them to receive either standardised medical treatment or standardised medical treatment plus a laparoscopic (keyhole) appendicectomy operation as a day-case procedure. All patients will then be followed up for one-year with information about disease activity, medication use and HRQOL obtained. Health resource usage and health-related quality of life (HRQOL) information will also be obtained. Patient and public involvement: In addition to interviewing patients with UC during our feasibility trial, a UC patient and an experienced lay advocate are co-applicants and will sit on the trial management team. Dissemination: If appendicectomy can be shown to improve symptoms in UC, widespread uptake is anticipated. Understanding the mechanism by which appendicectomy alters the disease course could both enhance our understanding of the causes of UC and unlock new treatment pathways for sufferers of this chronic disease.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL