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    Summary
    EudraCT Number:2017-000533-31
    Sponsor's Protocol Code Number:17GA001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-07-18
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2017-000533-31
    A.3Full title of the trial
    TReatment of Irritable bowel syndrome using Titrated ONdansetron Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ondansetron for the treatment of IBS with diarrhoea: predicting the responder.
    A.3.2Name or abbreviated title of the trial where available
    TRITON Trial v1.0
    A.4.1Sponsor's protocol code number17GA001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNottingham University Hospitals NHS Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNIHR - Efficacy and Mechanism Evaluation Programme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Leeds
    B.5.2Functional name of contact pointLorna Barnard
    B.5.3 Address:
    B.5.3.1Street AddressCTRU, University of Leeds
    B.5.3.2Town/ cityLeeds
    B.5.3.3Post codeLS2 9JT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01133430555
    B.5.6E-mailTRITON@leeds.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameOndansetron
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Irritable Bowel Syndrome with Diarrhoea
    E.1.1.1Medical condition in easily understood language
    Irritable Bowel Syndrome with Diarrhoea
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10060845
    E.1.2Term Diarrhea predominant irritable bowel syndrome
    E.1.2System Organ Class 100000004856
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10060849
    E.1.2Term Diarrhoea predominant irritable bowel syndrome
    E.1.2System Organ Class 100000004856
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Does 12 weeks treatment with Ondansetron improve symptoms on pain and loose stools in patients with irritable bowel syndrome with diarrhoea compared to placebo?
    E.2.2Secondary objectives of the trial
    What effect can be seen with Ondansetron on stool frequency, consistency, urgency of defecation, satisfactory relief of IBS symptoms and use of rescue medication and abdominal pain over 12 weeks of treatment?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must fulfil all of the following criteria.
    1. Written (signed and dated) informed consent.
    2. Considered fit for study participation.
    3. Meeting Rome IV criteria for IBS-D (see Appendices)
    4. Aged ≥ 18 years
    5. Undergone standardised workup to exclude the following alternative diagnoses
    a) Microscopic colitis (colonoscopy or flexible sigmoidoscopy), within previous 2 years
    b) 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
    c) Lactose malabsorption (In the opinion of the patient’s clinician. Suggested but not mandated methods to exclude lactose malabsorption as an alternative diagnosis include hydrogen breath test/milk challenge or failure to respond to lactose free diet).
    d) 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 ≥ 30 points 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 pre-treatment daily stool and pain diary and returned the results at visit 2.
    E.4Principal exclusion criteria
    Patients must not fulfil any of the following criteria:
    1. Gastrectomy
    2. Intestinal resection
    3. Other known organic GI diseases (e.g. inflammatory bowel disease – Crohn’s 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 (see section 8.7)
    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, laboratory blood values 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 only stools of consistency 7 on the Bristol Stool Form score (BSFS) for 7 days a week. ^^
    ^^ Exclusion criterion 12 will be assessed after the patient has completed the 14 day pre-treatment daily stool and pain diary and returned at visit 2.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be defined, as recommended by the FDA, as a patient being a weekly responder for BOTH pain intensity AND stool consistency for at least 6 weeks in the 12 week follow-up period. Weekly responder status is defined as follows:

    1. Weekly responder for Abdominal Pain Intensity:
    • At least 30% decrease from baseline in weekly average of worst daily abdominal pain score (abdominal pain score measured on a 0 to 100 point scale in past 24 hours)

    2. Weekly responder for Stool Consistency:
    • A decrease of at least 50% in the number of days per week with at least one loose stool consistency (BSFS = 6 or 7) compared with baseline.

    To achieve success in the primary endpoint, a patient must be a weekly responder for both pain and for consistency during the same 6 weeks within the 12 week follow-up period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be measured at 12 weeks post randomisation.
    E.5.2Secondary end point(s)
    What is the estimated treatment effect of ondansetron in relation to stool frequency, consistency, urgency of defecation, satisfactory relief of IBS symptoms and use of rescue medication and abdominal pain over 12 weeks of treatment?

    1. Stool frequency will be defined as number of stools per day up to 12 weeks post randomisation using patient’s diary.

    For the endpoint analysis, the mean number of stools per day over the last month (weeks 9-12) will be used.

    2.
    a. Stool consistency will be defined as number of days per week with at least 1 loose stool
    b. Average stool consistency over the last month (weeks 9-12)

    Consistency will be assessed daily by Bristol Stool Form Score (BSFS) and a loose stool is defined as BSFS >5.

    For the endpoint analyses, the mean number of days per week with at least 1 loose stool over last month (weeks 9-12) and the mean daily stool consistency over the last month (weeks 9-12) will be used.


    3. Urgency of defecation (on a scale 0-100)

    For the endpoint analyses, the mean daily urgency score over last month (weeks 9-12) will be used.


    4. Satisfactory relief of IBS symptoms will be defined as moderate or significant relief of IBS symptoms for at least 6 out of 12 weeks

    For the endpoint analyses, the proportion of patients with satisfactory relief of symptoms will be used.


    5. Score of functional dyspepsia Questionnaire

    For the endpoint analyses, the functional dyspepsia score at 12 weeks will be used.

    6. Score of IBS Symptom Severity Scale Questionnaire for IBS (IBS-SSS)
    For the endpoint analyses, the IBS-SSS score at 12 weeks will be used.

    7. Use of rescue medication will be defined as use of loperamide and assessed by total number of days having to take loperamide over 12 weeks.

    8. Abdominal pain score (on a scale 0-100)

    For the endpoint analyses, the mean daily pain score over last month (weeks 9-12) will be used.

    Does the treatment with Ondansetron improve patient’s mood over 12 weeks of treatment?

    9. Hospital Anxiety and Depression Scale (HADS) score

    For the endpoint analyses, the HADS score at 12 weeks will be used.

    10. IBS-QOL Questionnaire

    For the endpoint analyses, the IBS-QOL summary score at 12 weeks will be used.

    What is longer term (one month) effect of ondansetron after 12 weeks of treatment (off-treatment)?

    11. Stool Frequency

    12. Stool consistency

    13. Urgency of defaecation

    14. Abdominal pain

    The clinical definitions for endpoints 11-14 are the same as definitions for secondary endpoints 1, 2, 3 and 8 respectively.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Endpoint 1, 2, 3 & 8 will be measured over weeks 9-12 post randomisation

    Endpoint 4 will be measured weekly over weeks 0-12 post randomisation

    Endpoints 5, 6, 7, 9 & 10 will be measured at 12 weeks post randomisation

    Endpoints 11-14 are collected from 13-16 weeks post randomisation
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned13
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of trial is defined as the last patient last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 390
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state400
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 400
    F.4.2.2In the whole clinical trial 400
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Following study completion, participating patients will be discharged to standard care and will be treated according to local practice.

    Ondansetron is a marketed drug and as such generic forms are available to be prescribed by local sites outside this trial, though this would need to be under consultant supervision as it is not currently licensed for IBS .
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-08-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-09-10
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