A randomised, placebo controlled trial to determine the efficacy and mode of action of ondansetron in the treatment of irritable bowel syndrome with diarrhoea

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 Alosetron, a 5-hydroxytryptamine-3(5-HT3) receptor antagonist (5HT3RA), proven to be effective for IBS-D, was withdrawn owing to adverse effects(6).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.