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.
Background: Irritable bowel syndrome with diarrhoea is characterised by frequent, loose, or watery bowel movements with marked reduction of quality of life. A previous small study suggested ondansetron benefits patients with irritable bowel syndrome with diarrhoea.
Methods: A clinical trial aiming to recruit 400 patients meeting established criteria for irritable bowel syndrome with diarrhoea from 18 centres throughout the UK. Patients received either ondansetron or placebo for 12 weeks but neither the investigator and nor patient could tell which they were receiving. They recorded their worst abdominal pain, stool frequency and consistency daily. The main end point was the proportion of patients meeting a standard recommended by the U.S. Food and Drug Administration (FDA). Being called a “FDA responder” meant they showed reductions to both pain and days with loose bowel movements. Other less important end points included pain intensity, stool consistency and frequency. We also measured the time for content to pass through the gut (whole gut transit time).
Results: The study closed early due to slow recruitment with 80 patients randomised. There were 40.5% of responders in the ondansetron group and 27.9% in the placebo group; however, due to low numbers these differences could be due to chance. Ondansetron produced a significant improvement in average stool consistency in the final month of treatment. Ondansetron slowed whole gut transit time which increased from baseline to 12 weeks by a mean of 3.8 hours, while it fell 2.2 hours on placebo, a difference unlikely to be due to chance.
Conclusion: These results are consistent with previous studies showing that ondansetron improves stool consistency and slows transit. However, because the numbers recruited were smaller than planned, the apparent improvement in “FDA responder” rate could have been due to chance. A further larger trial is needed to confirm the benefit of ondansetron which should be done in primary care where most patients are to be found.
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