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    Clinical Trial Results:
    Randomized, Placebo-controlled, Clinical Trial to Evaluate the Efficacy of Probiotic Bacillus Clausii in the Treatment of Pediatric Patients With Irritable Bowel Syndrome

    Summary
    EudraCT number
    2018-004519-31
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    25 Nov 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Jun 2021
    First version publication date
    10 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENTERL08784
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study name: BaclauSII
    Sponsors
    Sponsor organisation name
    Sanofi Aventis de México SA de CV
    Sponsor organisation address
    Av. Universidad 1738 Coyoacán Centro CDMX, Z.P., Mexico, 04000
    Public contact
    Trial Transparency Team, Sanofi Aventis Recherche & Developpement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Aventis Recherche & Developpement, Contact-US@sanofi.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the proportion of subjects with clinical improvement of symptoms (assessed with Global Assessment Questions) between Bacillus clausii versus placebo groups, both added to conventional treatment, at Week 8, in 6 to less than (<) 18-year-old subjects with irritable bowel syndrome (IBS).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Mar 2019
    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
    Mexico: 259
    Worldwide total number of subjects
    259
    EEA total number of subjects
    0
    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)
    154
    Adolescents (12-17 years)
    105
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at multiple sites in Mexico. A total of 311 subjects were screened from 11-Mar-2019 to 10-Jul-2020, of which 52 subjects were non-randomised.

    Pre-assignment
    Screening details
    A total of 259 subjects were randomised and treated in this study.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bacillus clausii
    Arm description
    Subjects received Bacillus clausii spores once daily (QD) for 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Enterogermina®
    Investigational medicinal product code
    Other name
    Bacillus clausii spores
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral suspension of Bacillus clausii at total daily dose of 4 billion colony forming units (CFU) per day, divided in 5 millilitres (mL) per vial of 2 billion CFU, QD every morning prior to meal.

    Arm title
    Placebo
    Arm description
    Subjects received placebo matched to Bacillus clausii QD for 8 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral suspension of match placebo to Bacillus clausii vials QD every morning prior to meal.

    Number of subjects in period 1
    Bacillus clausii Placebo
    Started
    129
    130
    Completed
    124
    129
    Not completed
    5
    1
         Protocol violation
    1
    1
         Subject withdrawn informed consent form
    3
    -
         Other-misunderstood discontinuation criteria
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bacillus clausii
    Reporting group description
    Subjects received Bacillus clausii spores once daily (QD) for 8 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matched to Bacillus clausii QD for 8 weeks.

    Reporting group values
    Bacillus clausii Placebo Total
    Number of subjects
    129 130 259
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.93 ± 3.30 11.19 ± 3.12 -
    Gender categorical
    Units: Subjects
        Female
    76 81 157
        Male
    53 49 102

    End points

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    End points reporting groups
    Reporting group title
    Bacillus clausii
    Reporting group description
    Subjects received Bacillus clausii spores once daily (QD) for 8 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matched to Bacillus clausii QD for 8 weeks.

    Primary: Percentage of Subjects With Clinical Improvement of Symptoms at Week 8 (Global Assessment): Intention-to-treat (ITT) Population

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    End point title
    Percentage of Subjects With Clinical Improvement of Symptoms at Week 8 (Global Assessment): Intention-to-treat (ITT) Population
    End point description
    Response rates was defined as subjects with clinical improvement of symptoms in the global assessment questions: a) ‘How well did the medication relieve your symptoms?’, where satisfaction with treatment was rated as ‘Excellent’ or ‘Good’; and b) ‘Overall how do you feel your problem is?', where symptom relief was rated as ‘Better’. Treatment responders was defined as subjects having satisfaction with treatment and symptoms relief at Week 8. Analysis was performed on ITT population that included all randomised subjects, analyzed according to the treatment group allocated by randomization.
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    Bacillus clausii Placebo
    Number of subjects analysed
    129
    130
    Units: percentage of subjects
        number (not applicable)
    73.6
    78.5
    Statistical analysis title
    Bacillus clausii versus Placebo
    Comparison groups
    Bacillus clausii v Placebo
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8182
    Method
    Chi-square test
    Parameter type
    Difference in percentage
    Point estimate
    -4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.5
         upper limit
    3.9

    Primary: Percentage of Subjects With Clinical Improvement of Symptoms at Week 8 (Global Assessment): Per-protocol (PP) Population

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    End point title
    Percentage of Subjects With Clinical Improvement of Symptoms at Week 8 (Global Assessment): Per-protocol (PP) Population
    End point description
    Response rates was defined as subjects with clinical improvement of symptoms in the global assessment questions: a) ‘How well did the medication relieve your symptoms?’, where satisfaction with treatment was rated as ‘Excellent’ or ‘Good’ ; and b) ‘Overall how do you feel your problem is?', where symptom relief was rated as ‘Better’. Treatment responders was defined as subjects having satisfaction with treatment and symptoms relief at Week 8. Analysis was performed on PP population that included all subjects who completed the study without major protocol deviations (may include errors in the allocation of the Investigational Medicinal Product (IMP), the use of treatments not allowed by protocol, poor adherence to treatment (compliance <20%), or lost to follow-up).
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    Bacillus clausii Placebo
    Number of subjects analysed
    75
    71
    Units: percentage of subjects
        number (not applicable)
    80.0
    78.9
    Statistical analysis title
    Bacillus clausii versus Placebo
    Comparison groups
    Bacillus clausii v Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4332
    Method
    Chi-square test
    Parameter type
    Difference in percentage
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.9
         upper limit
    12.1

    Secondary: Percentage of Subjects With Clinical Improvement of Symptoms at Week 4 (Global Assessment)

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    End point title
    Percentage of Subjects With Clinical Improvement of Symptoms at Week 4 (Global Assessment)
    End point description
    Subjects with clinical improvement of symptoms was assessed using global assessment questions: a) ‘How well did the medication relieve your symptoms?’, where satisfaction with treatment was rated as ‘Excellent’ or ‘Good’ ; and b) ‘Overall how do you feel your problem is?', where symptom relief was rated as ‘Better’. Treatment responders was defined as subjects having satisfaction with treatment and symptoms relief at Week 4. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Bacillus clausii Placebo
    Number of subjects analysed
    129
    130
    Units: percentage of subjects
        number (not applicable)
    72.4
    76.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Improvement of Symptoms at Week 4 and Week 8: Assessed by Subject’s Global Assessment of Relief in Children (SGARC)

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    End point title
    Percentage of Subjects With Clinical Improvement of Symptoms at Week 4 and Week 8: Assessed by Subject’s Global Assessment of Relief in Children (SGARC)
    End point description
    Clinical Improvement of symptoms by SGARC was assessed by asking a question from subject/caregiver: “Consider how your child felt this past week in regard to his or her IBS; especially the overall well-being, symptoms of stomach discomfort, pain, and altered bowel habits. Compared with the way he or she usually felt before entering the study, how do you rate the relief of symptoms during the last week?” Subject/Caregiver responded on a scale ranging from 0-4, where: 0=Complete relief; 1=Considerable relief; 2=Somewhat relieved; 3=Unchanged and 4=Worse, where higher scores indicated worse outcomes. Responders to the treatment were defined as subjects with a complete relief or a considerable relief. Analysis was performed on ITT population. Here, "number of subjects analysed" signifies number of subjects evaluable for this endpoint and "n" signifies number of subjects with available data for specified category for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Weeks 4 and 8
    End point values
    Bacillus clausii Placebo
    Number of subjects analysed
    129
    130
    Units: percentage of subjects
    number (not applicable)
        Week 4 (n=127,129)
    61.4
    70.3
        Week 8 (n=126,129)
    76.0
    85.3
    No statistical analyses for this end point

    Secondary: Percentage of Days With Bloating Episodes

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    End point title
    Percentage of Days With Bloating Episodes
    End point description
    Abdominal distention/bloating was assessed by 3-point likert scale that consisted of single question, i.e., “Compared to the way you felt before entering the study, have your abdominal distention/bloating symptoms over past 4 weeks been”. Subject/Caregiver responded on scale that ranged from 1 to 3, where 1=Better; 2=Same; and 3=Worse, where higher scores indicated worst outcomes. Percentage of days with bloating episodes was calculated as: percentage of days with bloating at Visit i = total number of days with bloating episodes (between Visit i and Visit i-1)/total number of days between Visit i and Visit i-1 *100; where number of visit: i = 2 (Week 4), 3 (Week 8), 4 (Week 16); expressed in terms of mean and standard deviation in this endpoint. Analysis was performed on ITT population. Here, "number of subjects analysed" signifies number of subjects evaluable for this endpoint and "n" signifies number of subjects with available data for specified category for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8 and 16
    End point values
    Bacillus clausii Placebo
    Number of subjects analysed
    129
    130
    Units: percentage of days
    arithmetic mean (standard deviation)
        Week 4 (n=127,128)
    22.25 ± 26.17
    22.15 ± 21.07
        Week 8 (n=123,129)
    18.41 ± 28.42
    15.91 ± 23.21
        Week 16 (n=109,117)
    12.71 ± 19.85
    15.46 ± 23.18
    No statistical analyses for this end point

    Secondary: Mean Number of Abdominal Pain Episodes Per Day

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    End point title
    Mean Number of Abdominal Pain Episodes Per Day
    End point description
    Mean number of abdominal pain episodes (according to the subject diary information) by day was calculated using formula: mean number of abdominal pain per day at Visit i = sum of all number of abdominal pain episodes (between Visit i and Visit i-1)/total number of days (between Visit i and Visit i-1), where number of Visit i = 2 (Week 4), 3 (Week 8), 4 (Week 16). Analysis was performed on ITT population. Here, "number of subjects analysed" signifies number of subjects evaluable for this endpoint and "n" signifies number of subjects with available data for specified category for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8 and 16
    End point values
    Bacillus clausii Placebo
    Number of subjects analysed
    129
    130
    Units: abdominal pain episodes per day
    arithmetic mean (standard deviation)
        Week 4 (n=123,121)
    0.47 ± 0.74
    0.55 ± 0.66
        Week 8 (n=113,115)
    0.29 ± 0.45
    0.29 ± 0.58
        Week 16 (n=99,107)
    0.33 ± 0.75
    0.31 ± 0.50
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were collected from the time from the IMP administration up to 1 day after last IMP administration regardless of seriousness or relationship to IMP.
    Adverse event reporting additional description
    Reported adverse events (AE) were treatment-emergent AE that developed or worsened during treatment-emergent period (time from the IMP administration up to 1 day after last IMP administration). Analysis was performed on safety population that included subjects who had actually received at least 1 dose or part of a dose of IMP.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Bacillus clausii
    Reporting group description
    Subjects received Bacillus clausii spores QD for 8 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matched to Bacillus clausii QD for 8 weeks.

    Serious adverse events
    Bacillus clausii Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Bacillus clausii Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 129 (13.18%)
    20 / 130 (15.38%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 129 (8.53%)
    14 / 130 (10.77%)
         occurrences all number
    14
    16
    Infections and infestations
    Influenza
         subjects affected / exposed
    7 / 129 (5.43%)
    7 / 130 (5.38%)
         occurrences all number
    7
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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