- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03555188
TReatment of Irritable Bowel Syndrome With Diarrhoea Using Titrated ONdansetron Trial (TRITON)
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 Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Catherine Olivier
- Phone Number: 0113 343 9477
- Email: triton@leeds.ac.uk
Study Contact Backup
- Name: Suzanne Hartley
- Phone Number: 0113 343 9477
- Email: triton@leeds.ac.uk
Study Locations
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Barnsley, United Kingdom
- Barnsley Hospital NHS Foundation Trust
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Birmingham, United Kingdom
- Sandwell and West Birmingham Hospitals NHS Trust
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Durham, United Kingdom
- County Durham and Darlington NHS Foundation Trust
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Edinburgh, United Kingdom
- Westen General Hosptal, Edinburgh
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Leeds, United Kingdom
- Leeds Teaching Hospitals NHS Trust
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London, United Kingdom
- University College London Hospitals NHS Foundation Trust
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London, United Kingdom
- London North West NHS Foundation Trust
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London, United Kingdom
- Queen Mary, University of London
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Manchester, United Kingdom
- University Hospital of South Manchester
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Manchester, United Kingdom
- Salford Royal Hospital
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Middlesbrough, United Kingdom
- SouthTees Hospitals NHS FoundationTrust
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Nottingham, United Kingdom
- Nottingham University Hospitals NHS Trust
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Sheffield, United Kingdom
- Royal Hallamshire Hospital
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Stoke, United Kingdom
- University Hospitals of North Midlands NHS Trust
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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>>.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Ondansetron
Taken orally 4mg-24mg daily for 12 weeks.
Dose to be amended throughout according to symptoms.
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Ondansetron is a highly selective receptor antagonist (5-HT3RA)
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Placebo Comparator: Placebo
Taken orally 4mg-24mg daily for 12 weeks.
Dose to be amended throughout according to symptoms.
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Ondansetron is a highly selective receptor antagonist (5-HT3RA)
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Weekly responder for abdominal pain and stool consistency
Time Frame: 12 weeks
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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.
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12 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Stool Frequency
Time Frame: 12 weeks
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For the endpoint analysis, the mean number of stools per day over the last month (weeks 9-12) will be used.
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12 weeks
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Stool Consistency
Time Frame: 12 weeks
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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)
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12 weeks
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Urgency of defecation
Time Frame: 12 weeks
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The mean daily urgency score over last month (weeks 9-12)
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12 weeks
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Satisfactory relief of IBS symptoms
Time Frame: 12 weeks c
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Defined as satisfactory relief of IBS symptoms for at least 6 out of 12 weeks
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12 weeks c
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Functional dyspepsia
Time Frame: 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).
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SF-LDQ questionnaire at week 0 and week 12
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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).
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IBS Symptom Severity Scale
Time Frame: This information is collected at baseline (week 0) and again after treatment (week 12).
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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.
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This information is collected at baseline (week 0) and again after treatment (week 12).
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Rescue Medication
Time Frame: 12 weeks
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The total number of days taken loperamide throughout the 12 weeks
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12 weeks
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Abdominal pain score
Time Frame: 12 weeks
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The mean daily pain score over the last month (weeks 9-12)
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12 weeks
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Hospital Anxiety and Depression Scale
Time Frame: This information is collected at baseline (week 0) and again after treatment (week 12).
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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.
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This information is collected at baseline (week 0) and again after treatment (week 12).
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Stool frequency post treatment
Time Frame: 4 weeks
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The mean number of stools per day for 1 months after treatment (weeks 13-16)
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4 weeks
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Stool consistency post treatment
Time Frame: 4 weeks
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The mean daily stool consistency over 1 month (weeks 13-16) .
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4 weeks
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Urgency of defecation post treatment
Time Frame: 4 weeks
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The mean daily urgency score over 1 month post treatment (weeks 13-16).
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4 weeks
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Abdominal pain post treatment
Time Frame: 4 weeks
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The mean daily pain score over 1 month (weeks 13-16)
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4 weeks
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IBS Quality of life summary score
Time Frame: 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).
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IBS-QOL questionnaire at 0 and 12 weeks
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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).
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Colonic transit
Time Frame: 12 weeks
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Colonic Transit study to determine if ondansetron slows colonic transit.
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12 weeks
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Ondansetron and cyclical retrograde propagated contractions in the sigmoid colon
Time Frame: 12 weeks
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High resolution colonic manometry at baseline and week 12
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12 weeks
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Ondansetron and rectal compliance/pressure thresholds for pain/urgency.
Time Frame: 12 weeks
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Barostat assessment at baseline and week 12
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12 weeks
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Does ondansetron reduce total faecal bile acids and total tryptase and does the reduction correlate with changes in urgency?
Time Frame: 12 weeks
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Stool samples collected at baseline and week 12
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12 weeks
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Do polymorphisms in the TPH-1 gene predict response to ondansetron and does this alter 5-HT or TPH1-mRNA
Time Frame: 12 weeks
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Bloods and biopsies taken at baseline and week 12
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12 weeks
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Chair: Robin Spiller, University of Nottingham
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- Disease
- Signs and Symptoms, Digestive
- Gastrointestinal Diseases
- Colonic Diseases, Functional
- Colonic Diseases
- Intestinal Diseases
- Syndrome
- Irritable Bowel Syndrome
- Diarrhea
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Autonomic Agents
- Peripheral Nervous System Agents
- Antiemetics
- Gastrointestinal Agents
- Dermatologic Agents
- Serotonin Agents
- Serotonin Antagonists
- Serotonin 5-HT3 Receptor Antagonists
- Antipruritics
- Ondansetron
Other Study ID Numbers
- 15/74/01
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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