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    Clinical Trial Results:
    A randomized controlled trial to evaluate the short-term efficacy and long-term health economic impact of a dietary intervention compared to pharmacotherapy with a musculotropic spasmolytic agent for newly diagnosed or newly treated irritable bowel syndrome in primary care.

    Summary
    EudraCT number
    2017-003258-18
    Trial protocol
    BE  
    Global end of trial date
    03 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Mar 2021
    First version publication date
    14 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DOMINO
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04270487
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UZLeuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Florencia Carbone, University Hospital Leuven, 0032 16345190, florencia.carbone@uzleuven.be
    Scientific contact
    Florencia Carbone, University Hospital Leuven, 0032 16345190, florencia.carbone@uzleuven.be
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary outcome is the improvement in IBS-Symptom Severity Score after 8 weeks of otilonium bromide compared to dietary intervention, with a 50-point drop being the established cut-off used in clinical trials. Based on our clinical experience and the available clinical data, we hypothesize that the dietary intervention will be superior to treatment with otilonium bromide 40 mg t.i.d. in improving IBS-SSS.
    Protection of trial subjects
    study participants were followed up by their GP. Study participants who had not yet finished the study during the Covid-19-pandemic were able to perform V3 and V4 by telephone.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jul 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 472
    Worldwide total number of subjects
    472
    EEA total number of subjects
    472
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    432
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    IBS patients were recruited by GPs in primary care

    Pre-assignment
    Screening details
    Patients were eligible if they were newly diagnosed with IBS or newly to be treated for IBS. The diagnostic gold standard, in line with clinical practice, was the clinician’s diagnostic judgment. Also, patients who did not receive treatment with OB over the preceding 3 months, and who did not rece

    Period 1
    Period 1 title
    overall study period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    patients were randomized to the diet or medication arm

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    lowering FODMAP diet
    Arm description
    The dietary arm in the study is the FODMAP lowering diet, also partially based on the dietary recommendations from the NICE and the British Dietetic Association. The diet was provided to the patients as a mobile phone application. The app included, among other tools, instructions to follow the diet, indications on what foods to avoid, to decrease ingestion or to use as alternatives. The possibility to acquire the diet on paper format was possible if the patient did not own a smart phone or tablet or if he had fail to download it.
    Arm type
    lowering FODMAP diet

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Otilonium Bromide
    Arm description
    The medication arm in the study will use Otilonium Bromide (40 mg t.i.d.) which is a well-established and well-tolerated treatment modality. In accordance with the pragmatic design of this trial, patients received the medication prescribed by the GP and were requested to buy it at the pharmacy.
    Arm type
    Active comparator

    Investigational medicinal product name
    Otilonium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The medication arm in the study will use Otilonium Bromide (40 mg t.i.d.). Patients randomized to the Otilonium Bromide arm, will take OB during 8 weeks (treatment phase). After the 8 week treatment phase they can continue the intake of OB during the follow up phase (16 weeks) or they can stop the intake of OB after the 8 week treatment phase and start another treatment during the FU phase (but they were not allowed to start a diet)

    Number of subjects in period 1 [1]
    lowering FODMAP diet Otilonium Bromide
    Started
    227
    232
    end of treatment phase (8 weeks)
    219
    219
    Completed
    198
    193
    Not completed
    29
    39
         Physician decision
    -
    2
         Lack of efficacy
    9
    11
         concurrent disease
    1
    4
         Consent withdrawn by subject
    17
    20
         Lost to follow-up
    2
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 472 included patients, 459 patients were randomized. 13 patients withdrew consent before randomization.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall study period
    Reporting group description
    459 patients were randomized

    Reporting group values
    overall study period Total
    Number of subjects
    459 459
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    423 423
        From 65-84 years
    36 36
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.9 ± 14.7 -
    Gender categorical
    Units: Subjects
        Female
    343 343
        Male
    116 116

    End points

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    End points reporting groups
    Reporting group title
    lowering FODMAP diet
    Reporting group description
    The dietary arm in the study is the FODMAP lowering diet, also partially based on the dietary recommendations from the NICE and the British Dietetic Association. The diet was provided to the patients as a mobile phone application. The app included, among other tools, instructions to follow the diet, indications on what foods to avoid, to decrease ingestion or to use as alternatives. The possibility to acquire the diet on paper format was possible if the patient did not own a smart phone or tablet or if he had fail to download it.

    Reporting group title
    Otilonium Bromide
    Reporting group description
    The medication arm in the study will use Otilonium Bromide (40 mg t.i.d.) which is a well-established and well-tolerated treatment modality. In accordance with the pragmatic design of this trial, patients received the medication prescribed by the GP and were requested to buy it at the pharmacy.

    Primary: treatment responder rate after 8 weeks

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    End point title
    treatment responder rate after 8 weeks
    End point description
    IBS – symptom severity score scale (IBS-SSS) questionnaire: To assess the severity of IBS. The maximum achievable score is 500. Mild, moderate and severe cases were indicated by scores of 75 to 175, 175 to 300 and >300 respectively. Controls scored below 75 and patients scoring in this range can be considered to be in remission.
    End point type
    Primary
    End point timeframe
    The primary outcome variable of the trial was treatment responder rate after 8 weeks. A responsive patient was defined as a patient with at least 50-point drop from baseline on the IBS IBS-SSS.
    End point values
    lowering FODMAP diet Otilonium Bromide
    Number of subjects analysed
    222
    231
    Units: %
        number (not applicable)
    71.1
    61.3
    Statistical analysis title
    Responder rate (low FODMAP diet vs OB)
    Statistical analysis description
    The primary outcome variable of the trial was treatment responder rate after 8 weeks. A responsive patient was defined as a patient with at least 50-point drop from baseline on the IBS-SSS.
    Comparison groups
    lowering FODMAP diet v Otilonium Bromide
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.03
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [1] - All analyses were conducted on an intention-to-treat (ITT) basis. For this analysis, the responder status was determined for all patients and the proportion of responders was compared between treatment arms using mixed effect logistic regression (MELR) which is effectively a mixed-model logistic regression in which treatment group is treated as a fixed effect and general practice as a random effect.

    Secondary: Change in IBS-SSS (end - start)

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    End point title
    Change in IBS-SSS (end - start)
    End point description
    Treatment efficacy calculated using the change in IBS-symptom severity score scale (IBS-SSS). The IBS-SSS is used to assess the severity of IBS. The maximum achievable score is 500. Mild, moderate and severe cases were indicated by scores of 75 to 175, 175 to 300 and >300 respectively. Controls scored below 75 and patients scoring in this range can be considered to be in remission.
    End point type
    Secondary
    End point timeframe
    Treatment efficacy after 8 weeks of treatment (low FODMAP diet vs Otilonium Bromide) The change score for IBS-SSS was calculated as change from baseline to end of treatment phase.
    End point values
    lowering FODMAP diet Otilonium Bromide
    Number of subjects analysed
    222
    231
    Units: score
        arithmetic mean (standard deviation)
    -97.9 ± 8.6
    -77.4 ± 8.4
    Statistical analysis title
    Change in IBS symptom severity score
    Statistical analysis description
    The change score for IBS-SSS and all specified quantitative outcomes was calculated as change from baseline to end of therapy. Comparison of treatment groups employed linear regression with change score as the outcome variable and a single dummy-coded independent variable representing treatment group membership as the independent variable.
    Comparison groups
    lowering FODMAP diet v Otilonium Bromide
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Regression, Linear
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    from signing the informed consent form until 30 days after the final study visit
    Adverse event reporting additional description
    The DOMINO trial was considered a low risk trial. Information regarding adverse events (AE) and serious adverse events (SAE) for the study treatments was indicated to GPs but collection of these data specific for this trial was not requested. Only serious adverse reactions (SAR) clearly related to OB were to be registered in the eCRF by the GP.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20
    Frequency threshold for reporting non-serious adverse events: 1%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The DOMINO trial was considered a low risk trial. For this reason, information regarding adverse events (AE) for the study treatments was indicated to GPs but collection of these data specific for this trial was not requested. It was the GP’s responsibility to determine all AEs and SAEs and manage them in the patient's medical record in accordance with standard clinical practice guidelines, and this for up to 30 days after the end of the trial.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2018
    protocol versie 6 (04/04/2018); ICF versie 3 (04/04/2018) (Nl + Fr); eCRF: automatische e-mailnotificaties naar patiënten (Nl + Fr); Toevoeging van de lijst met 80 huisartsen-onderzoekers **
    17 Jul 2018
    protocol versie 7 (11/06/2018); ICF versie 4 (11/06/2018) (Nl + Fr)
    18 Oct 2018
    Toevoeging van de lijst met 21 huisartsen-onderzoekers
    05 Mar 2019
    Toevoeging van 6 bijkomende huisartsen-onderzoekers ** Toevoeging van GDPR informatieformulier voor patiënten (Nl + Fr)

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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