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    Clinical Trial Results:
    Bacillus clausii in Preventing Antibiotic-associated Diarrhea among Filipino Infants and Children: A Multi-center, Randomized, Open-label Clinical Trial of Efficacy and Safety

    Summary
    EudraCT number
    		 2014-004629-42
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    05 Oct 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2016
    First version publication date
    27 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENTER_L_01125
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00447161
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi-aventis Philippines Inc.
    Sponsor organisation address
    3rd Floor, Feliza Building, 108 V.A. Rufino Street, Legaspi Village , Makati City, Philippines, 1229
    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
    06 Feb 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of the probiotic Bacillus clausii in preventing antibiotic-associated diarrhea among hospitalized immunocompetent Filipino infant and children.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of pediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jul 2006
    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
    Philippines: 323
    Worldwide total number of subjects
    323
    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)
    103
    Children (2-11 years)
    210
    Adolescents (12-17 years)
    10
    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 2 sites in the Philippines. A total of 323 subjects were screened between 17 July 2006 and 15 August 2007.

    Pre-assignment
    Screening details
    		 All 323 subjects were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bacillus clausii
    Arm description
    		 Bacillus clausii for 7 to 21 days along with antibiotic therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bacillus clausii
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Vial containing 2 billion spores twice daily.

    Arm title
    		 No intervention-control
    Arm description
    		 Subjects received antibiotic therapy only.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Bacillus clausii No intervention-control
    Started
    162
    161
    Completed
    161
    161
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bacillus clausii
    Reporting group description
    		 Bacillus clausii for 7 to 21 days along with antibiotic therapy.

    Reporting group title
    No intervention-control
    Reporting group description
    		 Subjects received antibiotic therapy only.

    Reporting group values
    		 Bacillus clausii No intervention-control Total
    Number of subjects
    		 162 161 323
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 48 55 103
        Children (2-11 years)
    		 109 100 209
        Adolescents (12-17 years)
    		 4 6 10
        Not available
    		 1 0 1
    Gender categorical
    Units: Subjects
        Female
    		 66 67 133
        Male
    		 96 94 190
    Source of infection
    Units: Subjects
        Respiratory
    		 120 119 239
        Genito-urinary
    		 15 11 26
        Skin & soft tissue
    		 26 31 57
        Not available
    		 1 0 1
    Antibiotic exposure
    Units: Subjects
        Penicillins
    		 69 82 151
        Cephalosporin
    		 60 52 112
        Coamoxyclav/Ampicillin-Sulbactam
    		 12 13 25
        Combination/Sequential
    		 21 14 35

    End points

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    End points reporting groups
    Reporting group title
    Bacillus clausii
    Reporting group description
    		 Bacillus clausii for 7 to 21 days along with antibiotic therapy.

    Reporting group title
    No intervention-control
    Reporting group description
    		 Subjects received antibiotic therapy only.

    Primary: Number of Antibiotic-Associated Diarrhea Events

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    End point title
    		 Number of Antibiotic-Associated Diarrhea Events
    End point description
    Antibiotic-associated diarrhea is defined as diarrhea that occurs in association with the administration of antibiotics. Analysis was performed on all randomized and treated subjects.
    End point type
    Primary
    End point timeframe
    Day 0 to 6 weeks post treatment (maximum 9 weeks)
    End point values
    		 Bacillus clausii No intervention-control
    Number of subjects analysed
    162
    161
    Units: events
    3
    7
    Statistical analysis title
    		 Bacillus clausii vs No intervention-control
    Statistical analysis description
    Relative risk was calculated from cumulative incidence ratios, and two-tailed 95% test-based confidence intervals.
    Comparison groups
    Bacillus clausii v No intervention-control
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 Chi-squared
    Parameter type
    		 Relative risk
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 1.62

    Secondary: Number of Antibiotic Associated Diarrhea Events Per Day

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    End point title
    		 Number of Antibiotic Associated Diarrhea Events Per Day
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0 to 6 weeks post treatment (maximum 9 weeks)
    End point values
    		 Bacillus clausii No intervention-control
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: events
    Notes
    [1] - Data was not analysed for this outcome measure.
    [2] - Data was not analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Number of Gastrointestinal Related Symptoms

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    End point title
    		 Number of Gastrointestinal Related Symptoms
    End point description
    Gastrointestinal related symptoms included nausea, vomiting and abdominal pain. Analysis was performed on all randomized and treated subjects.
    End point type
    Secondary
    End point timeframe
    Day 0 to 6 weeks post treatment (maximum 9 weeks)
    End point values
    		 Bacillus clausii No intervention-control
    Number of subjects analysed
    162
    161
    Units: events
        Nausea
    1
    1
        Vomiting
    7
    4
        Abdominal pain
    3
    2
    No statistical analyses for this end point

    Secondary: Duration of Hospital Stay

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    End point title
    		 Duration of Hospital Stay
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0 to 6 weeks post treatment (maximum 9 weeks)
    End point values
    		 Bacillus clausii No intervention-control
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: week
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [3] - Data was not analysed for this outcome measure.
    [4] - Data was not analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clostridium difficile Associated Diarrhea

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    End point title
    		 Number of Subjects With Clostridium difficile Associated Diarrhea
    End point description
    Analysis was performed on 10 subjects who developed diarrhea.
    End point type
    Secondary
    End point timeframe
    Day 0 to 6 weeks post treatment (maximum 9 weeks)
    End point values
    		 Bacillus clausii No intervention-control
    Number of subjects analysed
    3
    7
    Units: subjects
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 9) regardless of seriousness or relationship to investigational product. Analysis was performed on all randomized and treated subjects.
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (from first dose of study medication up to 14 days after the last dose of study medication).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Not applicable
    Dictionary version
    0.0
    Reporting groups
    Reporting group title
    Bacillus clausii
    Reporting group description
    		 Bacillus clausii for 7 to 21 days along with antibiotic therapy.

    Reporting group title
    No intervention-control
    Reporting group description
    		 Subjects received antibiotic therapy only.

    Serious adverse events
    		 Bacillus clausii No intervention-control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 161 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Bacillus clausii No intervention-control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 161 (0.00%)
    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: Safety was very good and no adverse events related to Bacillus clausii were reported.

    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.
    Age for 1 subject was missing and in subjects enrolled per age group field of Trial Information section this subject is reported under “Children (2-11 years)” to avoid validation error. Actual age distribution is provided in baseline characteristics.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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