Ondansetron for irritable bowel syndrome with diarrhoea: randomised controlled trial
Authors: Gunn David , Topan Rabia , Fried Ron , Holloway Ivana , Brindle Richard , Hartley Suzanne , Barnard Lorna , Corsetti Maura , Scott S Mark , Farmer Adam , Akbar Ayesha , Eugenicos Maria , Trudgill Nigel , Kapur Kapil , McLaughlin John , Sanders David S , Ramadas Arvind , Whorwell Peter , Houghton Lesley , Dinning Phil G , Aziz Qasim , Ford Alexander C , Farrin Amanda , Spiller Robin 
Published: November 2023

Background
Irritable bowel syndrome with diarrhoea is characterised by frequent, loose or watery stools with associated urgency, resulting in marked reduction of quality of life. Ondansetron, a 5-hydroxytryptamine-3 receptor antagonist, has been shown to benefit patients with irritable bowel syndrome with diarrhoea.

Objective
To evaluate the effect of ondansetron in irritable bowel syndrome with diarrhoea.

Design
Phase III, parallel-group, randomised, double-blind, multicentre, placebo-controlled trial in 400 patients, with embedded mechanistic studies.

Setting
Hospital, primary care and community.

Participants
Eighty participants meeting Rome IV criteria for irritable bowel syndrome with diarrhoea.

Intervention
Ondansetron 4 mg (dose titrated up to two tablets three times a day) or matched placebo for 12 weeks.

Main outcome measures
Clinical – Primary patient-reported end point was % ‘Food and Drug Administration-defined responders’ over 12 weeks. Secondary end points were worst abdominal pain intensity, worst urgency, stool consistency, stool frequency, anxiety, depression and dyspepsia at 12 and 16 weeks.

Main outcome measures
Mechanistic – Whole gut transit time, faecal water, protease (FP), bile acids and assessment of rectal sensitivity using a barostat.

Results
Clinical – The study closed early due to slow recruitment. Between 1 January 2018 and 11 May 2020, 80 patients were recruited and randomised (20% of target), 37 to ondansetron, 43 to placebo. Discontinuations (4 ondansetron; 2 placebo) meant 75 completed the 12-week trial treatment. There were four protocol violations. In the intention-to-treat analysis, 15 (40.5%) on ondansetron were primary end-point responders (95% CI 24.7% to 56.4%), and 12 (27.9%) on placebo (95% CI 14.5% to 41.3%), p = 0.19, adjusted OR 1.93 (0.73, 5.11). Pain intensity reduction occurred in 17 (46.0%) on ondansetron (95% CI 29.9% to 62.0%) and 16 (37.2%) on placebo (95% CI 22.8% to 51.7%), p = 0.32. Improvement in stool consistency occurred in 25 (67.6%) on ondansetron (95% CI 52.5% to 82.7%) and 22 (51.2%) on placebo (95% CI 36.2% to 66.1%), p = 0.07. Use of rescue medication, loperamide, was lower on ondansetron [7 (18.9%) vs. 17 (39.5%)]. Average stool consistency in the final month of treatment reduced significantly more on ondansetron, adjusted mean difference –0.5 [standard error (SE) 0.25, 95% CI (–1.0 to –0.02), p = 0.042]. Ondansetron improved dyspepsia score (SFLDQ), adjusted mean difference –3.2 points [SE 1.43, 95% CI (–6.1 to –0.4), p = 0.028]. There were no serious adverse events.
Mechanistic – mean (SD). Ondansetron increased whole gut transit time between baseline and week 12 by 3.8 (9.1) hours on ondansetron, significantly more than on placebo –2.2 (10.3), p = 0.01. Mean volume to reach urgency threshold using the barostat increased on ondansetron by 84 (61) ml and 38 (48) ml on placebo, n = 8, p = 0.26. Ondansetron did not significantly alter protease, faecal water or bile acids. Changes in referral pathways substantially reduced referrals, impairing recruitment, which meant the study was underpowered.

Conclusion
Our results are consistent with previous studies and confirmed ondansetron improves stool consistency and urgency but showed minor effect on pain. We plan to undertake a simplified version of this trial overcoming the changed referral pathways by recruiting in primary care, using software linked to primary care records to identify and randomise patients with irritable bowel syndrome with diarrhoea to ondansetron or placebo and remotely follow their progress; thus minimising barriers to recruitment.

Trial registration
This trial is registered as ISRCTN17508514.

Funding
This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 9. See the NIHR Journals Library website for further project information.