Title: A randomised, placebo controlled trial to determine the efficacy and mode of action of ondansetron in the treatment of irritable bowel syndrome with diarrhoea
Funder: Department of Health and Social Care

Abstract: BACKGROUND: Irritable bowel syndrome (IBS) affects around 10% of the population accounting for 1.8 million consultations/year in England and Wales. Around 1/3 meet criteria for IBS with diarrhoea (IBS-D). Alosetron, a 5-hydroxytryptamine-3(5-HT3) receptor antagonist (5HT3RA), proven to be effective for IBS-D, was withdrawn owing to adverse effects(6). Ondansetron, also a 5-HT3RA, is a widely used anti-nauseant which our pilot data shows is highly effective in IBS-D, slowing transit and reducing urgency. The mechanism of action is, however, unclear since 5HT3RAs stimulate colonic contractions(10) which would normally exacerbate diarrhoea. Furthermore it is unclear why the dose requirement varies so widely. AIMS: To explore the effects & underlying mechanisms whereby Ondansetron improves symptoms of IBS-D. DESIGN: Double-blind, placebo-controlled, multi-centre (12 sites), parallel-group RCT, with embedded mechanistic studies within selected specialist centres POPULATION: Patients meeting modified Rome IV criteria for IBS-D in whom alternative diagnoses have been excluded. Symptoms will be confirmed during a screening phase using a daily symptom diary. INTERVENTION: O4-24 mgs daily will be compared to an identical appearing placebo. Dose titration will be used to avoid constipation which occurs in 1/4 patients if a standard dose is used. ASSESSMENTS: Prior to starting treatment and in the final week of treatment patients will provide blood and stool samples and in selected centres also undergo studies of colonic motility, compliance and sensitivity. All centres will perform whole gut transit studies before and during the last week of the 12-week treatment period. OUTCOMES: PRIMARY CLINCAL: being a weekly responder for both pain intensity and stool consistency for >=6 out of 12 weeks (FDA recommended endpoint) Secondary outcomes: stool consistency (Bristol Stool Form Score), stool frequency, faecal urgency, scores on the Gastrointestinal Symptoms Rating Scale Questionnaire for IBS (GSRS-IBS)(2), use of loperamide rescue. MECHANISTIC: Using high resolution colonic manometry (2 centres, n=40) we will test the hypothesis that Ondansetron slows transit by increasing cyclical retrograde contractions in the left colon. Ondansetron’s impact on colonic transit will be assessed using radio-opaque markers and abdominal X-ray at 4 days (n=400). We will also assess whether it increases rectal compliance/sensitivity (4 centres, n=80) and correlate this with reduction in faecal urgency. SAMPLE SIZE: 400 participants recruited from 12-13 UK sites over 24 months provides 90% power at 5% significance to detect a 15% absolute difference between randomised groups in the 12 week primary outcome, assuming 17% control rate and 15% attrition STATISTICAL ANALYSIS: Intention to treat; reported according to CONSORT. Primary analysis will compare the proportion of patients achieving FDA response (pain & consistency) at 12 weeks between groups using a logistic regression model. STUDY DURATION: 44 months SIGNIFICANCE: Improved understanding of how 5-HT3RAs work in IBS-D will allow Ondansetron to be used throughout the world.

Lay abstract: Irritable bowel syndrome (IBS) is an extremely common condition found in around 10% of the population. People with IBS experience recurrent abdominal pain and an erratic bowel habit, which can markedly reduce their quality of life. Around 1/3 have diarrhoea as their main complaint, so- called IBS with diarrhoea (IBS-D). Key symptoms are frequent, loose, or watery stools and great urgency when needing to open their bowels. Previous evidence suggests such patients may have an excess of a chemical called serotonin (5-hydroxytryptamine [5-HT)) in their intestine which acts on a receptor (a part of the cell surface that responds to drugs), the 5-HT3 receptor (5-HT3R) to stimulate movement through the bowel (transit) and secretion. A drug which blocked the 5-HT3R (a 5-HT3R antagonists [5-HT3RA]), alosetron, was very effective in controlling IBS-D symptoms but unfortunately it had to be withdrawn owing to side effects. Ondansetron is an older 5-HT3RA, which has an excellent safety record, used over many years to treat nausea. We have encouraging pilot data from a recent trial in IBS-D which showed that Ondansetron slows transit and reduces the need for urgent defaecation, which is such a debilitating feature of this condition. We now wish to find out how it works. One study suggested alosetron actually increased motility. Recent improvements in the methods of studying motility suggest some motility patterns actually slow down bowel movement, so we will look to see if Ondansetron stimulates these. Alosetron allows the rectum to relax more when distended, a phenomenon called accommodation. We will examine whether the improvement in accommodation is related to the reduction in urgency. Another important change caused by slowing transit is to allow colonic bacteria to break down substances secreted by the digestive system, like bile acids and digestive enzymes, which otherwise sensitize the rectum to distension. We will measure total bile acid concentrations and the amount of pancreatic enzyme, tryptase, in the stools to see if these are important in determining urgency. Assessing the importance of these factors is best done as part of a trial in which we treat patients with a 5-HT3RA or a placebo (a substance without any effect, given to control for patients expectations of benefit) and compare the change in symptoms with the change in each factor, since then we can control for other unknown factors. Patients entering the trial will be fully evaluated to make sure they do not have another condition causing their symptoms. We will make our initial assessments and then enter our patients into a trial in which they are randomly given either Ondansetron or placebo for 12 weeks while recording symptoms. Neither the patient nor the study team will know which treatment they get until the end of the trial to avoid any bias. We will repeat our measurements in the 12th week to see the effect of the drug compared to placebo. The study will improve our ability to predict who will respond to Ondansetron and exactly how it works so newer better drugs can be developed for this common but poorly understood condition

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL