TReatment of Irritable Bowel Syndrome With Diarrhoea Using Titrated ONdansetron Trial

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomised, Placebo Controlled Trial to Determine the Efficacy and Mode of Action of Ondansetron in the Treatment of Irritable Bowel Syndrome With Diarrhoea

Conditions
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IBS - Irritable Bowel Syndrome

Intervention / Treatment
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* Drug: Ondansetron


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written (signed and dated) informed consent. Considered fit for study participation. Meeting Rome IV criteria for IBS-D Aged ≥ 18 years Undergone standardised workup to exclude the following alternative diagnoses: Microscopic colitis (colonoscopy or flexible sigmoidoscopy), 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) Lactose malabsorption. Coeliac disease (tTG or duodenal biopsy) 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). For women of child bearing potential, a negative pregnancy test should be performed within 72 hours of confirmation of eligibility. Weekly average worst pain score >= X on a 0 to 100 point scale <<redacted to prevent patient bias>>. 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: Gastrectomy Intestinal resection Other known organic GI diseases (e.g. Inflammatory bowel disease - Crohns disease, Ulcerative colitis.) 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 QTc interval ≥450msec for men and ≥470msec for women. Assessed within the last 3 months by a 12-lead ECG. Previous chronic use of ondansetron or contraindications to it (rare as per BNF) 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. Women who are pregnant or breastfeeding 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. 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). 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. Patients with stools of consistency X on the Bristol Stool Form score (BSFS) for X days a week <<redacted to prevent patient bias>>.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: TRITON is a parallel group, randomised, double-blinded, placebo controlled trial, to determine the superiority of Ondansetron.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ondansetron<br>Taken orally 4mg-24mg daily for 12 weeks. Dose to be amended throughout according to symptoms. | Drug: Ondansetron<br>* Ondansetron is a highly selective receptor antagonist (5-HT3RA)<br>|
| Placebo Comparator: Placebo<br>Taken orally 4mg-24mg daily for 12 weeks. Dose to be amended throughout according to symptoms. | Drug: Ondansetron<br>* Ondansetron is a highly selective receptor antagonist (5-HT3RA)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weekly responder for abdominal pain and stool consistency | Measured at 12 weeks post randomisation and defined, as recommended by the FDA, as patient being a weekly responder for BOTH pain intensity AND stool consistency for at least 6 weeks in the 12 week treatment period. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stool Frequency | For the endpoint analysis, the mean number of stools per day over the last month (weeks 9-12) will be used. | 12 weeks | 
| Stool Consistency | Defined as number of days per week with at least 1 loose stool and the average stool consistency over the last month (weeks 9-12) | 12 weeks | 
| Urgency of defecation | The mean daily urgency score over last month (weeks 9-12) | 12 weeks | 
| Satisfactory relief of IBS symptoms | Defined as satisfactory relief of IBS symptoms for at least 6 out of 12 weeks | 12 weeks c | 
| Functional dyspepsia | SF-LDQ questionnaire at week 0 and week 12 | 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). | 
| IBS Symptom Severity Scale | Irritable Bowel Syndrome Symptom Severity Scale questionnaire which asks patients about their IBS symptoms such as abdominal pain etc. The patients will provide yes/no answer or a score on a 0-100 scale with 0 being the minimum amount and 100 being define as quite severe/definitely. | This information is collected at baseline (week 0) and again after treatment (week 12). | 
| Rescue Medication | The total number of days taken loperamide throughout the 12 weeks | 12 weeks | 
| Abdominal pain score | The mean daily pain score over the last month (weeks 9-12) | 12 weeks | 
| Hospital Anxiety and Depression Scale | Hospital Anxiety and Depression Scale questionnaire. This information is collected via a questionnaire which asks the patient about their general overall feelings. It asks a variety of question and the patient is to tick the box beside the reply that is closest to how they feel. Each question has 1 of 4 potential replies (feelings) that vary depending on the nature of the question. | This information is collected at baseline (week 0) and again after treatment (week 12). | 
| IBS Quality of life summary score | IBS-QOL questionnaire at 0 and 12 weeks | 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). | 
| Stool frequency post treatment | The mean number of stools per day for 1 months after treatment (weeks 13-16) | 4 weeks | 
| Stool consistency post treatment | The mean daily stool consistency over 1 month (weeks 13-16) . | 4 weeks | 
| Urgency of defecation post treatment | The mean daily urgency score over 1 month post treatment (weeks 13-16). | 4 weeks | 
| Abdominal pain post treatment | The mean daily pain score over 1 month (weeks 13-16) | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diarrhoea