Treatment of Irritable Bowel Syndrome with diarrhoea using Titrated Ondansetron (TRITON): study protocol for a randomised control trial

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

Abstract

Background – Irritable 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 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.

Methods – This trial is a phase III, parallel group randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. 400 participants meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and social media to receive either ondansetron (dose titrated up to 24mg 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 to 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.

Discussion – The 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.

Citation

Gunn, D., Fried, R., Lalani, R., Farrin, A., Holloway, I., Morris, T., Olivier, C., Kearns, R., Corsetti, M., Mark Scott, S., Farmer, A., Emmanuel, A., Whorwell, P., Yiannakou, Y., Sanders, D., Mclaughlin, J., Kapur, K., Eugenicos, M., Akbar, A., Trudgill, N., …Spiller, R. (2019). Treatment of Irritable Bowel Syndrome with diarrhoea using Titrated Ondansetron (TRITON): study protocol for a randomised control trial. Trials, 20, Article 517. https://doi.org/10.1186/s13063-019-3562-6

• Journal Article Type: Article
• Acceptance Date: Jul 8, 2019
• Online Publication Date: Aug 20, 2019
• Publication Date: Aug 20, 2019
• Deposit Date: Jul 22, 2019
• Publicly Available Date: Aug 20, 2019
• Journal: Trials
• Electronic ISSN: 1745-6215
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 20
• Article Number: 517
• DOI: https://doi.org/10.1186/s13063-019-3562-6
• Keywords: Barostat; Diarrhoea; Irritable bowel syndrome; High-resolution manometry; Ondansetron
• Public URL: https://nottingham-repository.worktribe.com/output/2329899
• Publisher URL: https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3562-6
• Additional Information: Received: 8 March 2019; Accepted: 8 July 2019; First Online: 20 August 2019; : Informed consent will be obtained from participants prior to entry into the trial. The trial has been submitted to and approved by Yorkshire & The Humber – Leeds West Research Ethics Committee (ref 17/YH/0262), the Medicines & Healthcare products Regulatory Agency (EudraCT: 2017–000533-31), the Health Research Authority (HRA) (IRAS project ID 219133) and local R&D departments for each participating site prior to entering patients into the trial.; : No data on individual persons are used in the manuscript.; : RS has received research funding from Lesaffre and Ironwood. He has also acted on advisory boards for Allergan, Commonwealth Diagnostics International, Danone, Ipsen, and Yuhan, and received speakers’ fees from Menarini. MS has received speakers’ fees and honoraria from Medical Measurement Systems (MMS)/Laborie.
• Contract Date: Aug 20, 2019