Condition category
Digestive System
Date applied
11/09/2017
Date assigned
02/10/2017
Last edited
02/10/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Irritable bowel syndrome (IBS) with diarrhoea (IBS-D) is a common condition characterised by recurrent abdominal pain with frequent, loose stools passed with urgency. Such patients may have an excess of serotonin (5-hydroxytryptamine [5-HT)) in their intestine which stimulates movement through the bowel (transit) and secretion. Ondansetron is a drug which blocks the 5-HT receptor, which is used to treat nausea, and has an excellent safety record. A pilot study has known that that Ondansetron slows transit and improves IBS-D symptoms so there is a need to find out how this works. Bowel contractions can be measured using a new high resolution system and bowel relaxation by assessing pressure during rectal distension with a balloon to determine whether these changes are related to improved symptoms. Total bile acid concentrations and the amount of pancreatic enzyme can be measured, tryptase, in the stools as these may sensitise the rectum causing urgency. The response to ondansetron may depend upon genetic factors so the variation in the gene controlling the rate of 5HT production needs to be assessed. The aim of this study is to treat patients with Ondansetron or a placebo (a dummy tablet without any effect) and compare the change in symptoms.

Who can participate?
Adults aged 18 and older with IBS

What does the study involve?
Participants are allocated to one of two groups. Those in the first group receive the medication Ondansetron taken by mouth for 12 weeks. Those in the second group receive a placebo (a dummy tablet without any effect). Participants are contacted by researchers to discuss any symptoms. Participants are measured in the 12th week to see the effect of the drug compared to placebo.

What are the possible benefits and risks of participating?
Participants may benefit from a reduction in their symptoms if ondansetron is effective. There are risks such as constipation. Ondansetron is currently licenced for the management of nausea and vomiting post-operatively or following treatment with cancer. In this setting it is used in a much higher dose (32mg) and is administered intravenously. Within its current licenced use, ondansetron has been associated with prolongation of the QT interval. This effect is not anticipated in the TRITON study giving that patients will be administered a much lower dose (4-8mg) orally. However as safeguard, those with a prolonged QT or taking drugs known to prolong this will be excluded from the study. Ischaemic colitis has been associated with other, similar drugs and therefore those with Ischaemic colitis are excluded from the study. Additionally, if participants develop rectal bleeding whilst on study, they will be recommended to have a sigmoidoscopy. It is likely that bleeding will stem from the anal canal associated with trauma from frequent defecation.

Where is the study run from?
University of Leeds (UK)

When is the study starting and how long is it expected to run for?
February 2017 to September 2020

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Ms Cat Lowe
triton@leeds.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Ms Cat Lowe

ORCID ID

Contact details

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom
+44 1133 439241
triton@leeds.ac.uk

Additional identifiers

EudraCT number

2017-000533-31

ClinicalTrials.gov number

Protocol/serial number

33831

Study information

Scientific title

TReatment of Irritable bowel syndrome using Titrated ONdansetron Trial

Acronym

TRITON

Study hypothesis

The overall aim of the study is to investigate the effectiveness and mechanism of action of ondansetron, a 5HT3RA, in patients with IBS-D, as assessed by stool frequency, consistency, urgency and abdominal pain.

Ethics approval

Yorkshire & The Humber - Leeds West Research Ethics Committee, provision opinion received 24/08/2017, ref: 17/YH/0262

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Gastroenterology, Primary sub-specialty: Gastroenterology; UKCRC code/ Disease: Oral and Gastrointestinal/ Other diseases of intestines

Intervention

Participation attend an initial visit where they are registered for the study. Patients are asked to complete a two-week daily paper diary recording:
1. Stool frequency
2. Stool consistency for each stool using the Bristol stool form scale (BSFS)
3. Worst abdominal pain experienced that day (on a scale of 0-100, where 0 is no pain and 100 is worst imaginable pain)
4. Worst bowel movement urgency (on a scale of 0-100, where 0 is no urgency and 100 is worst imaginable urgency)
5. If they have used loperamide that day.
The completed pages of the patient diaries will be collected at each visit by the local study team. This information is used to confirm eligibility at the randomisation visit.

In addition the CTRU will send each patient two text messages to the mobile phone number provided every day. The first will ask if they have passed a stool which has had a consistency 6 or 7 on the BSFS and the patient will need to text back 1 for yes and 0 for no. The second will ask what their worst abdominal pain score was that day, from a scale of 0-100 (where 0 is no pain and 100 is worst imaginable pain) and the patient will need to text back the score from 0-100.

The study nurse will discuss this process with the patients and if it is highlighted that this will be a problem, the patient will complete only the paper diary. The mobile number provided will be verified prior to use. The patient may withdraw from receiving text messages upon request.

Completed diaries will be brought to visit two Eligibility confirmation.

Participants attend a third visit where they are randomised. Participants are randomised on a 1:1 basis to receive either ondansetron or placebo. Participants are randomised based on stratification factors to ensure the treatment groups are well-balanced. Details of which are required at randomisation include the site name, colonic monometry assessment carried out and barostat assessment carried out. This is a double blinded trial and therefore neither the patient nor those responsible for their care (treating team and research team) will know the allocation. Patients are given the opportunity to find out what treatment arm they are allocated to at the end of the study period. Upon randomisation, participants are allocated either 4mg Ondansetron or placebo and instructed to start their treatment on one capsule a day. Depending on the response, participants are asked to increase the dose in 4 mg steps every two days to a maximum of 8 mg three times a day. Treatment lasts for 12 weeks and the follow up visit occurs four weeks from the last dose of trial treatment.

Patients are asked to continue to record the following information until visit 6 (Follow-Up visit)
Daily:
1. Stool frequency
2. Stool consistency for each stool - using the Bristol stool form scale (BSFS);
3. Worst abdominal pain experienced that day - on a scale of 0-100, where 0 is no pain and 100 is worst imaginable pain.
4. Worst bowel movement urgency - on a scale of 0-100, where 0 is no urgency and 100 is worst imaginable urgency.
5. Number of trial medication capsules taken.
6. If they have used loperamide that day.

Weekly they record if they feel they have had satisfactory relief from their symptoms that week.

The completed pages of the patient diaries will be collected in at each visit by the local study team.

Text Messaging
Patients will continue to receive two text messages to their mobile phone every day for the next 6 weeks unless they have withdrawn from this aspect. The first will ask if they have passed a stool which has had a consistency 6 or 7 on the BSFS and the patient will need to text back 1 for yes and 0 for no. The second will ask what their worst abdominal pain score was that day, from a scale of 0-100 (where 0 is no pain and 100 is worst imaginable pain) and the patient will need to text back the score from 0-100.

During the first two week patients will be contacted every 2 days the site team to discuss symptoms. The dose will then be titrated as required.

Intervention type

Other

Phase

Phase III

Drug names

Primary outcome measures

FDA defined responder rate (in relation to abnormal defecation and abdominal pain) is measured using weekly responder for Abdominal Pain Intensity and Stool consistency scales at week six and 12.

Secondary outcome measures

1. Treatment effect of ondansetron in relation to:
1.1. Stool frequency (number of stools passed per day) is measured using patients diaries daily from baseline and week 12
1.2. Stool consistency (number of days per week with at least 1 loose stool) and average stool consistency (from weeks 9-12) is measured using patient diaries and the Bristol Stool Form Score (BSFS) daily from baseline and week 12
1.3. Urgency of defecation is measured using patient diaries daily from baseline and week 12
1.4. Satisfactory relief of IBS symptoms is measured using patient diaries weekly from baseline and week 12
1.5. Functional dyspepsia score is measured using the short-form Leeds dyspepsia questionnaire (SF-LDQ) at baseline and week 12
1.6. IBS severity is measured using the IBS Symptom Severity Scale (IBS-SSS) questionnaire at baseline and week 12
1.7. Use of rescue medication is measured using patient diaries daily from baseline and week 12
1.8. Abdominal pain score is measured using the patient diaries daily from baseline and week 12
2. Assessing the patient’s mood over 12 weeks following treatment with Ondansetron by:
2.1 Measuring Aanxiety and depression scores are measured using the Hospital Anxiety and Depressison Scale (HADS) at baseline and week 12
2.2. Measuring the Qquality of life is measured using the IBS-QOL summary score at baseline and 12 weeks
3. Longer term effects of ondansetron after 12 weeks of treatment (off-treatment):
3.1. Stool frequency longer term is measured using patient diaries daily from weeks 13-16
3.2. Stool consistency is measured using daily patient diaries from weeks 13 to 16
3.3. Urgency of defaecation is measured using daily patient diaries from weeks 13 to 16
3.4. Abdominal pain is measured using daily patient diaries from weeks 13 to 16

Overall trial start date

01/02/2017

Overall trial end date

30/09/2020

Reason abandoned

Eligibility

Participant inclusion criteria

1. Written (signed and dated) informed consent
2. Considered fit for study participation
3. Meeting Rome IV criteria (Appendix 1) for IBS-D
4. Aged ≥ 18 years
5. Undergone standardised workup to exclude the following alternative diagnoses
5.1. Microscopic colitis (colonoscopy or flexible sigmoidoscopy)
5.2. 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)
5.3. Lactose malabsorption
5.4. 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 days per week*
* Inclusion criteria 8 & 9 will be assessed after the patient has completed the 14 day daily stool and pain diary and returned the results at visit 2

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 400; UK Sample Size: 400

Participant exclusion criteria

1. Gastrectomy
2. Intestinal resection
3. Other known organic GI diseases (e.g. Inflammatory bowel disease – Crohns disease, Ulcerative colitis, coeliac disease)
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 (unless at a stable dose for at least 3 months)
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 a stool of 6 or 7 on Bristol Stool Form score (BSFS) for 7 days a week

Recruitment start date

01/01/2018

Recruitment end date

31/10/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Nottingham University Hospitals NHS Trust Headquarters
QMC Campus Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

St James’s University Hospital
Leeds Teaching Hospitals NHS Trust Beckett Street West Yorkshire
Leeds
LS9 7TF
United Kingdom

Trial participating centre

The Royal London Hospital
Barts and the London NHS Trust Trust Offices White Chapel
London
E1 1BB
United Kingdom

Trial participating centre

St Mary’s Hospital
Imperial College Healthcare NHS Trust Praed Street
London
W2 1NY
United Kingdom

Trial participating centre

University College London Hospital NHS Foundation Trust
250 Euston Road
London
NW1 2PG
United Kingdom

Trial participating centre

Wythenshawe Hospital
University Hospital of South Manchester NHS Foundation Trust Southmoor Road Wythenshawe
Manchester
M23 9LT
United Kingdom

Trial participating centre

Salford Royal NHS Foundation Trust
Salford Royal Stott Lane
Manchester
M6 8HD
United Kingdom

Trial participating centre

Darlington Memorial Hospital
County Durham and Darlington NHS Foundation Trust Hollyhurst Road Darlington Country
Durham
DL3 6HX
United Kingdom

Trial participating centre

City Hospital
Sandwell and West Birmingham Hospitals NHS Trust Dudley Road West Midlands
Birmingham
B18 7QH
United Kingdom

Trial participating centre

Barnsley Hospital NHS Foundation Trust
Gawber Road South Yorkshire
Barnsley
S75 2EP
United Kingdom

Trial participating centre

North Staffordshire Royal Infirmary
University Hospital of North Staffordshire NHS Trust Princes Road Staffordshire
Stoke-on-Trent
ST4 7LN
United Kingdom

Trial participating centre

Western General Hospital
Crewe Road South
Edinburgh
EH4 2XU
United Kingdom

Sponsor information

Organisation

Nottingham University Hospitals NHS Trust

Sponsor details

Trust Headquarters
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

30/09/2021

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes