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TReatment of Irritable Bowel Syndrome With Diarrhoea Using Titrated ONdansetron Trial (TRITON)

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ClinicalTrials.gov Identifier: NCT03555188
Recruitment Status : Recruiting
First Posted : June 13, 2018
Last Update Posted : June 13, 2018
Sponsor:
Collaborators:
Barnsley Hospital NHS Foundation Trust
Barts & The London NHS Trust
County Durham and Darlington NHS Foundation Trust
Flinders University
The Leeds Teaching Hospitals NHS Trust
London North West Healthcare NHS Trust
NHS Lothian
Queen Mary University of London
Sandwell & West Birmingham Hospitals NHS Trust
Sheffield Teaching Hospitals NHS Foundation Trust
University College London Hospitals
University Hospitals of North Midlands NHS Trust
Manchester University NHS Foundation Trust
University of Manchester
National Institute for Health Research, United Kingdom
Information provided by (Responsible Party):
University of Leeds

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.

Condition or disease Intervention/treatment Phase
IBS - Irritable Bowel Syndrome Drug: Ondansetron Phase 3

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 5HT3RA's 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: TRITON is a parallel group, randomised, double-blinded, placebo controlled trial, to determine the superiority of Ondansetron.
Masking: Double (Participant, Investigator)
Masking Description: This is a double-blinded study.
Primary Purpose: Treatment
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
Actual Study Start Date : March 29, 2018
Estimated Primary Completion Date : February 1, 2020
Estimated Study Completion Date : February 28, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diarrhea

Arm Intervention/treatment
Experimental: Ondansetron
Taken orally 4mg-24mg daily for 12 weeks. Dose to be amended throughout according to symptoms.
Drug: Ondansetron
Ondansetron is a highly selective receptor antagonist (5-HT3RA)

Placebo Comparator: Placebo
Taken orally 4mg-24mg daily for 12 weeks. Dose to be amended throughout according to symptoms.
Drug: Ondansetron
Ondansetron is a highly selective receptor antagonist (5-HT3RA)




Primary Outcome Measures :
  1. Weekly responder for abdominal pain and stool consistency [ Time Frame: 12 weeks ]
    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.


Secondary Outcome Measures :
  1. Stool Frequency [ Time Frame: 12 weeks ]
    For the endpoint analysis, the mean number of stools per day over the last month (weeks 9-12) will be used.

  2. Stool Consistency [ Time Frame: 12 weeks ]
    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)

  3. Urgency of defecation [ Time Frame: 12 weeks ]
    The mean daily urgency score over last month (weeks 9-12)

  4. Satisfactory relief of IBS symptoms [ Time Frame: 12 weeks c ]
    Defined as satisfactory relief of IBS symptoms for at least 6 out of 12 weeks

  5. 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). ]
    SF-LDQ questionnaire at week 0 and week 12

  6. IBS Symptom Severity Scale [ Time Frame: This information is collected at baseline (week 0) and again after treatment (week 12). ]
    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.

  7. Rescue Medication [ Time Frame: 12 weeks ]
    The total number of days taken loperamide throughout the 12 weeks

  8. Abdominal pain score [ Time Frame: 12 weeks ]
    The mean daily pain score over the last month (weeks 9-12)

  9. Hospital Anxiety and Depression Scale [ Time Frame: This information is collected at baseline (week 0) and again after treatment (week 12). ]
    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.

  10. Quality of life [ 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). ]
    IBS-QOL questionnaire at 0 and 12 weeks

  11. Stool frequency post treatment [ Time Frame: 4 weeks ]
    The mean number of stools per day for 1 months after treatment (weeks 13-16)

  12. Stool consistency post treatment [ Time Frame: 4 weeks ]
    The mean daily stool consistency over 1 month (weeks 13-16) .

  13. Urgency of defecation post treatment [ Time Frame: 4 weeks ]
    The mean daily urgency score over 1 month post treatment (weeks 13-16).

  14. Abdominal pain post treatment [ Time Frame: 4 weeks ]
    The mean daily pain score over 1 month (weeks 13-16)


Other Outcome Measures:
  1. Colonic transit [ Time Frame: 12 weeks ]
    Colonic Transit study to determine if ondansetron slows colonic transit.

  2. Ondansetron and cyclical retrograde propagated contractions in the sigmoid colon [ Time Frame: 12 weeks ]
    High resolution colonic manometry at baseline and week 12

  3. Ondansetron and rectal compliance/pressure thresholds for pain/urgency. [ Time Frame: 12 weeks ]
    Barostat assessment at baseline and week 12

  4. Does ondansetron reduce total faecal bile acids and total tryptase and does the reduction correlate with changes in urgency? [ Time Frame: 12 weeks ]
    Stool samples collected at baseline and week 12

  5. Do polymorphisms in the TPH-1 gene predict response to ondansetron and does this alter 5-HT or TPH1-mRNA [ Time Frame: 12 weeks ]
    Bloods and biopsies taken at baseline and week 12



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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% or C4 results of <19 ng/ml), Note: Cholecystectomy will not be an exclusion criteria if bile acid diarrhoea has been excluded
    3. Lactose malabsorption.
    4. Coeliac disease (tTG or duodenal biopsy)
  6. All patients 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, 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 >= 30 on a 0 to 100 point scale.
  9. Any stools with a consistency of 6 or 7 on the Bristol Stool Form score (BSFS) for 2 -6 day per week.

Exclusion Criteria:

  1. Gastrectomy
  2. Intestinal resection
  3. Other known organic GI diseases (e.g. Inflammatory bowel disease - Crohns disease, Ulcerative colitis.)
  4. Inability to stop anti-diarrhoeal drugs for the duration of the study.
  5. QTc interval >=420msec. 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.
  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. Patients taking SSRIs or tricyclic antidepressants are not excluded if on a stable dose for at least 3 months and with no plan to change the dose during the study.
  11. Patients currently taking any of the restricted medications.*

    * Restricted medications - Apomorphine, Tramadol & medications likely to alter bowel habit (in the opinion of the investigator).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 only stools of consistency 7 on the Bristol Stool Form score (BSFS) for 7 days a week.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03555188


Contacts
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Contact: Catherine Olivier 0113 343 9477 triton@leeds.ac.uk
Contact: Suzanne Hartley 0113 343 9477 triton@leeds.ac.uk

Locations
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United Kingdom
Barnsley Hospital NHS Foundation Trust Not yet recruiting
Barnsley, United Kingdom
Principal Investigator: Kapil Kapur         
Sandwell and West Birmingham Hospitals NHS Trust Recruiting
Birmingham, United Kingdom
Principal Investigator: Nigel Trudgill         
County Durham and Darlington NHS Foundation Trust Not yet recruiting
Durham, United Kingdom
Principal Investigator: Yan Yiannakou         
Westen General Hosptal, Edinburgh Not yet recruiting
Edinburgh, United Kingdom
Principal Investigator: Maria Euegnicos         
Leeds Teaching Hospitals NHS Trust Not yet recruiting
Leeds, United Kingdom
Principal Investigator: Alexander Ford         
London North West NHS Foundation Trust Not yet recruiting
London, United Kingdom
Principal Investigator: Ayesha Akbar         
Queen Mary, University of London Not yet recruiting
London, United Kingdom
Principal Investigator: Qasim Aziz         
University College London Hospitals NHS Foundation Trust Not yet recruiting
London, United Kingdom
Principal Investigator: Anton Emmanuel         
Salford Royal Hospital Not yet recruiting
Manchester, United Kingdom
Principal Investigator: John McLaughlin         
University Hospital of South Manchester Not yet recruiting
Manchester, United Kingdom
Principal Investigator: Peter Whorwell         
Nottingham University Hospitals NHS Trust Not yet recruiting
Nottingham, United Kingdom
Principal Investigator: Maura Corsetti         
Royal Hallamshire Hospital Recruiting
Sheffield, United Kingdom
Principal Investigator: David Sanders         
University Hospitals of North Midlands NHS Trust Recruiting
Stoke, United Kingdom
Principal Investigator: Adam Farmer         
Sponsors and Collaborators
University of Leeds
Barnsley Hospital NHS Foundation Trust
Barts & The London NHS Trust
County Durham and Darlington NHS Foundation Trust
Flinders University
The Leeds Teaching Hospitals NHS Trust
London North West Healthcare NHS Trust
NHS Lothian
Queen Mary University of London
Sandwell & West Birmingham Hospitals NHS Trust
Sheffield Teaching Hospitals NHS Foundation Trust
University College London Hospitals
University Hospitals of North Midlands NHS Trust
Manchester University NHS Foundation Trust
University of Manchester
National Institute for Health Research, United Kingdom
Investigators
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Study Chair: Robin Spiller University of Nottingham

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Responsible Party: University of Leeds
ClinicalTrials.gov Identifier: NCT03555188     History of Changes
Other Study ID Numbers: 15/74/01
First Posted: June 13, 2018    Key Record Dates
Last Update Posted: June 13, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of Leeds:
Diarrhoea

Additional relevant MeSH terms:
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Syndrome
Diarrhea
Irritable Bowel Syndrome
Disease
Pathologic Processes
Signs and Symptoms, Digestive
Signs and Symptoms
Colonic Diseases, Functional
Colonic Diseases
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Ondansetron
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Antipruritics
Dermatologic Agents
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Anti-Anxiety Agents