Award Title: Management of diarrhoea in patients with stable ulcerative colitis: multi-arm multi-stage trial of low FODMAP diet, amitriptyline, ondansetron, or loperamide (MODULATE)
Funder: Department of Health and Social Care

Abstract: Aims of the research:_x000D_
We want to find out whether treatments used for diarrhoea in people with irritable bowel syndrome (IBS) can help people with stable ulcerative colitis (UC) and diarrhoea, with no sign of active bowel inflammation._x000D_
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Background to the research:_x000D_
About 1 in 5 people with UC report ongoing diarrhoea, even when there is no sign of bowel inflammation. These symptoms can be difficult to treat because, when there is no inflammation, simply using more powerful drugs does not seem to improve them. They also cause discomfort and distress, reducing peoples’ quality of life, and impacting on their psychological health and mood._x000D_
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This is a similar situation to people living with IBS, who often experience troublesome diarrhoea that reduces quality of life. In IBS, a low FODMAP diet improves diarrhoea, because some poorly absorbed sugars (FODMAPs) increase small intestinal water content. Drugs like ondansetron (an anti-sickness drug), amitriptyline (an old-fashioned anti-depressant drug), or loperamide (an anti-diarrhoeal drug) can also be effective in IBS with diarrhoea. This is because they change bowel activity, and can relieve tummy pain. These treatments may therefore help people with UC with diarrhoea who have no active bowel inflammation, but we are unsure as there are no large studies._x000D_
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Design and methods used:_x000D_
Doctors will invite people with UC who have diarrhoea, and who do not currently have active bowel inflammation, to take part. We will check people are suitable with a questionnaire, a camera test of the lower bowel, and blood and stool tests at their local hospital._x000D_
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All participants will be provided with standard first-line dietary advice. People will also be given one of the following: a low FODMAP diet; ondansetron; amitriptyline; loperamide; or no additional treatment. A computer will randomly decide who gets which one. People will be asked to follow the diet or take the tablets for 6 months, in addition to their doctor’s usual treatment for UC. People will be aware which treatment they get._x000D_
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We will follow people up at 8 wks and 6 mths. We will ask people to fill out questionnaires about symptoms, quality of life, and mood, and provide blood and stool again at 6 mths. We will record side effects during treatment, and adherence to each treatment. We will look at how many flare-ups people experience, whether usual treatment for UC has been changed, and whether surgery has been required.  As we need almost 500 people, the study will take place in 26 UK hospitals._x000D_
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Patient and public involvement:_x000D_
We have involved patients in the development of this application. Specifically, we have a co-applicant with experience of UC, and support from Crohn’s and Colitis UK. We will continue to collaborate closely with patients and families if the study is funded._x000D_
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The team:_x000D_
We are a team of doctors, researchers, and patients. Together we have a special interest in UC, long-term conditions, medically unexplained symptoms, and carrying out similar research studies. The research will be run by a clinical trials research unit with experience in carrying out large scale studies._x000D_
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Dissemination:_x000D_
We will publish the results in academic journals and present them at conferences. We will feed back to all doctors and dietitians involved in the study. We will hold a public involvement workshop towards the end of the study to discuss how to share findings with our study participants and the public in an accessible way.

Lay Abstract: Design: Pragmatic, seamless, phase 2/3, open, parallel group, MAMS RCT, with internal pilot._x000D_
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Setting: 26 secondary care centres._x000D_
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Target population: Adults with stable UC and at least moderate discomfort from diarrhoea on GSRS, despite optimal medical therapy._x000D_
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Inclusion criteria: >/=18 years; stable UC (Mayo score </=1 at sigmoidoscopy, CRP <5mg/L, and FC <250mcg/g)._x000D_
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Exclusion criteria: Previous or planned gastrointestinal (GI) surgery; active UC (Mayo score >1, CRP >/=5mg/L, or FC >/=250mcg/g); steroids within the last 2 mths; coeliac disease; previous colorectal cancer or dysplasia; allergy/contraindication to, or previous failed trial of, study interventions; pregnancy/breastfeeding._x000D_
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Health technology being assessed: Phase 2: Control (standard first-line dietary advice); low FODMAP diet; ondansetron; amitriptyline; loperamide (all drugs titrated)._x000D_
Phase 3: Control; up to 2 interventions with greatest evidence of efficacy in phase 2._x000D_
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Patients allocated 1:1:1:1:2 in phase 2, (larger group = control) (4). In phase 3, this is reversed to 2:1 or 2:2:1, with final ratio 5:8 or 5:5:7. Allocation via minimisation with random element, minimised on centre, degree of discomfort from diarrhoea, and extent of UC._x000D_
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Measurement of outcomes: Via self-completed questionnaires._x000D_
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Phase 2 primary (8 wks): Improvement in diarrhoea, via GSRS (minor discomfort or less);_x000D_
Phase 3 primary (6 mths): Disease-specific quality of life via IBD-Q._x000D_
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Secondary (8 wks and 6 mths)_x000D_
Adverse events and safety;_x000D_
Symptoms: Improvement in discomfort from loose stools, diarrhoea, urgency, abdominal pain;_x000D_
Disease activity: Escalation of medical therapy, need for surgery, FC, CRP;_x000D_
Mood: HADS;_x000D_
Adherence._x000D_
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Sample size: Phase 2: 66 patients per intervention arm and 132 control give 90% power to detect an absolute difference of 17% (50% intervention, 33% control) in proportion achieving improvement in diarrhoea, with a 1-sided 20% significance level, assuming 10% lost to follow-up._x000D_
Phase 3: with 2 (1) interventions carried forward: additional 38 (20) per intervention arm; 19 (10) control, give 90% power to detect a 16-point difference in IBD-Q, with 2-sided 2.5% (5%) significance, assuming an extra 10% lost to follow-up, and SD of 32 (5, 6). Total patients: 491 (426)._x000D_
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Analysis: ITT, as per CONSORT._x000D_
Phase 2: Multivariable logistic regression fitted to achieving improvement in diarrhoea at 8 wks, with adjustment for stratification factors. Progression to phase 3 based on achieving reduction in diarrhoea, as well as safety and adherence. At most, 2 interventions progress._x000D_
Phase 3:  The primary analysis compares mean IBD-Q scores between groups using a linear regression model adjusting for stratification variables and baseline IBD-Q. Multiple imputation for missing data._x000D_
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Internal pilot: Progression criteria assessed at 4-6 mths (recruitment) and after a further 6 mths (adherence and follow-up). Patient outcomes included in the final analysis._x000D_
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Difference between current and planned care pathways: Low FODMAP diet or pharmacological therapy added to current optimal UC treatment. All patients receive standard dietary advice sheet._x000D_
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Project timetable:_x000D_
45 mths:_x000D_
9-mth set-up;_x000D_
25-mth recruitment;_x000D_
6-mth follow-up;_x000D_
5-mth analysis, write up, dissemination._x000D_
Recruitment rate: 14 pts/mth during pilot, then 20-30 pts/mth, from 26 centres._x000D_
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Expertise in team: Gastroenterology, dietetics, psychiatry, statistics, trial design/delivery, PPI.

Research Activity Codes: 6.1 PHARMACEUTICALS;6.7 PHYSICAL
Health Categories: ORAL AND GASTROINTESTINAL