Clinical trial NCT03555188: TReatment of Irritable Bowel Syndrome With Diarrhoea Using Titrated ONdansetron Trial
Official title: A Randomised, Placebo Controlled Trial to Determine the Efficacy and Mode of Action of Ondansetron in the Treatment of Irritable Bowel Syndrome With Diarrhoea
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: IBS - Irritable Bowel Syndrome
Keywords: Diarrhoea
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: Barnsley Hospital NHS Foundation Trust
name: Barts & The London NHS Trust
name: County Durham and Darlington NHS Foundation Trust
name: Flinders University
name: The Leeds Teaching Hospitals NHS Trust
name: London North West Healthcare NHS Trust
name: NHS Lothian
name: Queen Mary University of London
name: Sandwell & West Birmingham Hospitals NHS Trust
name: Sheffield Teaching Hospitals NHS Foundation Trust
name: University College London Hospitals
name: University Hospitals of North Midlands NHS Trust
name: Manchester University NHS Foundation Trust
name: University of Manchester
name: National Institute for Health Research, United Kingdom
First posted: 2018-06-13
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: TRITON is a parallel group, randomised, double-blinded, placebo controlled trial, to determine the superiority of Ondansetron.
Primary purpose: TREATMENT

Brief summary: A placebo controlled study to determine the efficacy and mode of action of ondansetron in the treatment of irritable bowel syndrome with diarrhoea.

Detailed description: Irritable bowel syndrome (IBS) affects around 10% of the population and accounts for 1.8 million consultations/year in primary care in England and Wales (0.6 million patients). Around one third of patients meet the criteria for IBS with diarrhoea (IBS-D) and despite its high prevalence, there is no satisfactory treatment at present. Loperamide is currently used to reduce bowel frequency, however it does not improve symptoms such abdominal pain.

Other symptoms of IBS-D include frequent, loose, or watery stools with associated urgency, which can severely limit socialising, travelling, and eating out, resulting in a reduced quality of life and work productivity.

The primary aim of the study is to determine the effectiveness and safety of the use of ondansetron in patients with the symptoms of IBS-D including urgency, looseness of stool, frequency of defecation and abdominal discomfort. Ondansetron belongs to a class of drug known as 5HT3RAs and a recent meta-analysis shows that 5HT3RAs is an effective treatment for IBS-D, improving stool consistency and reducing frequency and urgency of defecation.

400 patients with IBS-D will be randomised on a 1:1 basis to receive either Ondansetron or Placebo. Both treatments will be administered in oral doses of between 4-24mg daily for 12 weeks. Dose titration will be undertaken in the first two weeks of the study to avoid constipation.

The primary outcome of response will be assessed at 12 weeks post randomisation using patient reported data on daily stool frequency and abdominal pain.

If ondansetron is effective in the trial, it could easily be widely adopted since it is an inexpensive, safe, and generic drug. By providing an effective treatment, it could not only reduce patient symptoms, but also reduce costs of repeated referral and investigation.

Eligibility criteria: Inclusion Criteria:

1. Written (signed and dated) informed consent.
2. Considered fit for study participation.
3. Meeting Rome IV criteria for IBS-D
4. Aged ≥ 18 years
5. Undergone standardised workup to exclude the following alternative diagnoses:

   1. Microscopic colitis (colonoscopy or flexible sigmoidoscopy),
   2. Bile acid diarrhoea (SeHCAT results of \> 10%, C4 results of \<19 ng/ml or failed 1 week trial of a bile acid binding agent \[colestyramine 4g t.d.s. , colesevelam 625mg t.d.s. or equivalent\]) within previous 5 years, Note: Cholecystectomy will not be an exclusion criteria if bile acid diarrhoea has been excluded. Patients with SeHCAT values of 5-10% will be eligible if they fail to respond to a 1 week trial of bile acid binding agent (see above)
   3. Lactose malabsorption.
   4. Coeliac disease (tTG or duodenal biopsy)
6. Patients of child bearing potential or with partners of child bearing potential must agree to use methods of medically acceptable forms of contraception during the study and for 90 days after completion of study drug, (e.g. implants, injectable, combined oral contraceptives, barrier methods, true abstinence (when this is in line with the preferred and usual lifestyle of the patient) or vasectomised partners).
7. For women of child bearing potential, a negative pregnancy test should be performed within 72 hours of confirmation of eligibility.
8. Weekly average worst pain score \>= X on a 0 to 100 point scale \<\<redacted to prevent patient bias\>\>.
9. Any stools with a consistency of X on the Bristol Stool Form score (BSFS) for X day per week\<\<redacted to prevent patient bias\>\>.

Exclusion Criteria:

1. Gastrectomy
2. Intestinal resection
3. Other known organic GI diseases (e.g. Inflammatory bowel disease - Crohns disease, Ulcerative colitis.)
4. Unable or unwilling to stop restricted medication including regular loperamide, antispasmodics (e.g. buscopan, mebeverine, peppermint oil, alverine citrate), eluxadoline, tricyclic antidepressant doses \>30mg/day or other drugs likely in the opinion of the investigator to alter bowel habit. These medicines should be discontinued for a 7 day washout period prior to registration. Note: Intermittent loperamide will be permitted but only as rescue medication
5. QTc interval ≥450msec for men and ≥470msec for women. Assessed within the last 3 months by a 12-lead ECG.
6. Previous chronic use of ondansetron or contraindications to it (rare as per BNF)
7. Pulse, Blood pressure, FBC or LFTs outside the normal ranges according to the site's local definition of normal. Assessed within the last 3 months.Note: Minor rises in ALT (\<2 x upper limit of normal) will be acceptable but the patient's GP will be informed if they remain elevated at end of the study.
8. Women who are pregnant or breastfeeding
9. Patients currently participating or who have been in an IMP trial in the previous three months where the use of the IMP may cause issues with the assessment of causality in this study.
10. Currently taking SSRIs or tricyclic antidepressants (unless at a stable dose for at least 3 months and with no plan to change the dose during the study).
11. Currently taking and unwilling or unable to stop any of the prohibited medications.\*

    \*Prohibited medications - Apomorphine \& tramadol which interact with ondansetron. Caution should be taken with patients on QT prolonging drugs and cardio toxic drugs. These patients should be reviewed by the PI to determine if they are suitable for the study.
12. Patients with stools of consistency X on the Bristol Stool Form score (BSFS) for X days a week \<\<redacted to prevent patient bias\>\>.

Primary outcomes:
measure: Weekly responder for abdominal pain and stool consistency
timeFrame: 12 weeks
Secondary outcomes:
measure: Stool Frequency
timeFrame: 12 weeks
measure: Stool Consistency
timeFrame: 12 weeks
measure: Urgency of defecation
timeFrame: 12 weeks
measure: Satisfactory relief of IBS symptoms
timeFrame: 12 weeks c
measure: Functional dyspepsia
timeFrame: This information is collected via a questionnaire which asks the patient about any symptoms associated with IBS that they may be experiencing. This information is collected at baseline (week 0) and again after treatment (week 12).
measure: IBS Symptom Severity Scale
timeFrame: This information is collected at baseline (week 0) and again after treatment (week 12).
measure: Rescue Medication
timeFrame: 12 weeks
measure: Abdominal pain score
timeFrame: 12 weeks
measure: Hospital Anxiety and Depression Scale
timeFrame: This information is collected at baseline (week 0) and again after treatment (week 12).
measure: IBS Quality of life summary score
timeFrame: This information is collected via a questionnaire which asks the patient about the quality of their life. This information is collected at baseline (week 0) and again after treatment (week 12).
measure: Stool frequency post treatment
timeFrame: 4 weeks
measure: Stool consistency post treatment
timeFrame: 4 weeks
measure: Urgency of defecation post treatment
timeFrame: 4 weeks
measure: Abdominal pain post treatment
timeFrame: 4 weeks
Other outcomes:
measure: Colonic transit
timeFrame: 12 weeks
measure: Ondansetron and cyclical retrograde propagated contractions in the sigmoid colon
timeFrame: 12 weeks
measure: Ondansetron and rectal compliance/pressure thresholds for pain/urgency.
timeFrame: 12 weeks
measure: Does ondansetron reduce total faecal bile acids and total tryptase and does the reduction correlate with changes in urgency?
timeFrame: 12 weeks
measure: Do polymorphisms in the TPH-1 gene predict response to ondansetron and does this alter 5-HT or TPH1-mRNA
timeFrame: 12 weeks
Locations:
city: Barnsley
country: United Kingdom
facility: Barnsley Hospital NHS Foundation Trust
city: Birmingham
country: United Kingdom
facility: Sandwell and West Birmingham Hospitals NHS Trust
city: Durham
country: United Kingdom
facility: County Durham and Darlington NHS Foundation Trust
city: Edinburgh
country: United Kingdom
facility: Westen General Hosptal, Edinburgh
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: London North West NHS Foundation Trust
city: London
country: United Kingdom
facility: Queen Mary, University of London
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Salford Royal Hospital
city: Manchester
country: United Kingdom
facility: University Hospital of South Manchester
city: Middlesbrough
country: United Kingdom
facility: SouthTees Hospitals NHS FoundationTrust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Stoke
country: United Kingdom
facility: University Hospitals of North Midlands NHS Trust
Study officials:
affiliation: University of Nottingham
name: Robin Spiller
role: STUDY_CHAIR
References:
citation: Gunn D, Topan R, Barnard L, Fried R, Holloway I, Brindle R, Corsetti M, Scott M, Farmer A, Kapur K, Sanders D, Eugenicos M, Trudgill N, Whorwell P, Mclaughlin J, Akbar A, Houghton L, Dinning PG, Aziz Q, Ford AC, Farrin AJ, Spiller R. Randomised, placebo-controlled trial and meta-analysis show benefit of ondansetron for irritable bowel syndrome with diarrhoea: The TRITON trial. Aliment Pharmacol Ther. 2023 Jun;57(11):1258-1271. doi: 10.1111/apt.17426. Epub 2023 Mar 3.