Treatment of irritable bowel syndrome with diarrhoea using titrated ondansetron (TRITON): study protocol for a randomised controlled trial

David Gunn,John Mclaughlin,Lesley A Houghton ,Rachael Kearns,Amanda Farrin,Adam D Farmer ,Alexander C Ford,Tom Morris,Maura Corsetti,Maria Eugenicos,Mark Scott,Peter J Whorwell ,Ayesha Akbar,Rabia Lalani,Phil G Dinning ,Ron Fried ,Anton Emmanuel,David S Sanders ,Ivana Holloway,Kapil Kapur,Yan Yiannakou,Catherine Olivier ,Qasim Aziz,Nigel Trudgill,Robin C Spiller

doi:10.1186/s13063-019-3562-6

Abstract

BackgroundIrritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D.MethodsThis trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants (n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis.The primary endpoint is the proportion of “responders” in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed.Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity (n = 80) using the barostat, and/or high-resolution colonic manometry (n = 40) to assess motor patterns in the left colon and the impact of ondansetron.DiscussionThe TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron’s mechanisms of action we hope to better identify patients with IBS-D who are likely to respond.Trial registrationISRCTN, ISRCTN17508514, Registered on 2 October 2017.

Highlights

Irritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population
One key effect we found, seen with other 5HT3 receptor antagonists (5HT3RA) [7], was a marked reduction in urgency, which may be important in improving quality of life in patients with IBS-D [8]
Potential mechanisms of action of 5HT3 receptor antagonists The 5HT3RAs slow colonic transit, an effect we found marked in the left colon and the rectosigmoid region of patients with IBS-D, but the underlying mechanism was unclear [6]

Summary

Introduction

Irritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D It has, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D. Loose, or watery stools with associated urgency, which can severely limit socialising, travelling, and eating out This can lead to a marked reduction in quality of life and loss of work productivity. When patients with IBS are asked to rank symptoms in order of importance, erratic bowel habit is rated first, followed by abdominal pain and, for those with diarrhoea, urgency [1] This can often be associated with incontinence, which is socially debilitating, but often under-reported [2]

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