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    Clinical Trial Results:
    Bacillus Clausii in the Treatment of Acute Community-acquired Diarrhea Among Latin American Children (cadiLAc)

    Summary
    EudraCT number
    2016-003444-37
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    07 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Nov 2016
    First version publication date
    19 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENTERR06929
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02169817
    WHO universal trial number (UTN)
    U1111-1149-1704
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly, Mazarin, France, 91380
    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
    14 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the effectiveness of treatment with Bacillus clausii probiotic strain (Enterogermina) in combination with oral rehydration therapy (ORT) for a period of 5 days, in the duration of acute community-acquired diarrhea in Latin American children.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric 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 minimised.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Jul 2014
    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
    Guatemala: 71
    Country: Number of subjects enrolled
    Argentina: 50
    Country: Number of subjects enrolled
    Peru: 50
    Country: Number of subjects enrolled
    Brazil: 188
    Country: Number of subjects enrolled
    Colombia: 110
    Country: Number of subjects enrolled
    Mexico: 158
    Worldwide total number of subjects
    627
    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)
    338
    Children (2-11 years)
    289
    Adolescents (12-17 years)
    0
    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 30 centers in 6 countries. A total of 642 subjects were screened between 18 July 2014 and 30 December 2015.

    Pre-assignment
    Screening details
    A total 642 subjects were screened, and 627 subjects were treated.

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

    Arms
    Arm title
    Bacillus clausii + ORT
    Arm description
    Bacillus clausii along with oral rehydration therapy (ORT) was given for 5 days.
    Arm type
    Experimental

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

    Investigational medicinal product name
    ORT
    Investigational medicinal product code
    Other name
    Enterolyte®
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    ORT (low osmolarity formulation) according to the Investigator's recommendation.

    Number of subjects in period 1
    Bacillus clausii + ORT
    Started
    627
    Completed
    605
    Not completed
    22
         Adverse events
    2
         Missed doses due to personal reasons
    9
         Consent withdrawn by subject
    2
         Overdosing
    1
         Lost to follow-up
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    Bacillus clausii along with ORT was given for 5 days.

    Reporting group values
    Overall Study Total
    Number of subjects
    627 627
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    2.2 ± 1.3 -
    Gender categorical
    Units: Subjects
        Female
    259 259
        Male
    368 368

    End points

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    End points reporting groups
    Reporting group title
    Bacillus clausii + ORT
    Reporting group description
    Bacillus clausii along with oral rehydration therapy (ORT) was given for 5 days.

    Primary: Duration of Diarrhea

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    End point title
    Duration of Diarrhea [1]
    End point description
    Duration of diarrhea, as counted from the first intake of the investigation product up to the first appearance of a loose stool followed by two consecutive normal stools. Analysis was performed on per-protocol (PP) population included all eligible subjects (not screen failure subjects) with no major protocol deviations.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 5
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was not a comparative study (no inference was planned). Primary endpoint was provided only in terms of descriptive statistics.
    End point values
    Bacillus clausii + ORT
    Number of subjects analysed
    598
    Units: hours
        arithmetic mean (standard deviation)
    82.9 ± 40.1
    No statistical analyses for this end point

    Secondary: Mean Number of Stools per Day

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    End point title
    Mean Number of Stools per Day
    End point description
    Analysis was performed on PP population.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 5
    End point values
    Bacillus clausii + ORT
    Number of subjects analysed
    600
    Units: stool episodes
    arithmetic mean (standard deviation)
        Baseline
    5.6 ± 2.1
        Day 1
    3.5 ± 2.1
        Day 2
    3.4 ± 2
        Day 3
    2.6 ± 1.8
        Day 4
    2.2 ± 1.6
        Day 5
    1.8 ± 1.5
    No statistical analyses for this end point

    Secondary: Consistency of Stools

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    End point title
    Consistency of Stools
    End point description
    Analysis was performed on PP population.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 5
    End point values
    Bacillus clausii + ORT
    Number of subjects analysed
    600
    Units: stool episodes
    arithmetic mean (standard deviation)
        Day 1: Normal
    0.1 ± 0.4
        Day 1: Loose
    1 ± 1.5
        Day 1: Watery
    2.4 ± 2.4
        Day 2: Normal
    0.2 ± 0.6
        Day 2: Loose
    1.4 ± 1.5
        Day 2: Watery
    1.8 ± 2.2
        Day 3: Normal
    0.4 ± 0.8
        Day 3: Loose
    1.4 ± 1.4
        Day 3: Watery
    0.8 ± 1.6
        Day 4: Normal
    0.7 ± 1
        Day 4: Loose
    1 ± 1.3
        Day 4: Watery
    0.4 ± 1.3
        Day 5: Normal
    0.9 ± 1
        Day 5: Loose
    0.6 ± 1.1
        Day 5: Watery
    0.2 ± 1
    No statistical analyses for this end point

    Secondary: Number of Vomiting Episodes per Day

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    End point title
    Number of Vomiting Episodes per Day
    End point description
    Analysis was performed on PP population. Here, "n" signifies the subjects with data available at specified time point.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 5
    End point values
    Bacillus clausii + ORT
    Number of subjects analysed
    600
    Units: vomiting episodes
    arithmetic mean (standard deviation)
        Baseline (n=599)
    0.9 ± 1.7
        Day 1 (n=600)
    0.3 ± 0.7
        Day 2 (n=600)
    0.2 ± 0.5
        Day 3 (n=600)
    0.1 ± 0.4
        Day 4 (n=600)
    0 ± 0.3
        Day 5 (n=599)
    0 ± 0.3
    No statistical analyses for this end point

    Secondary: Parent / Legal Guardian's Assessment of Children's Overall Acceptance of Enterogermina

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    End point title
    Parent / Legal Guardian's Assessment of Children's Overall Acceptance of Enterogermina
    End point description
    Children’s acceptance of enterogermina was recorded by their parents/legal guardian on a diary as: Excellent, good, fair, poor. Acceptance was assessed separately after both Dose 1 and Dose 2. Total percentage of subjects (assessed after dose 1 and dose 2) were reported. Analysis was performed on PP population.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 5
    End point values
    Bacillus clausii + ORT
    Number of subjects analysed
    600
    Units: percentage of subjects
    number (not applicable)
        Excellent
    73
        Good
    20.4
        Fair
    5.1
        Poor
    1.5
    No statistical analyses for this end point

    Secondary: Parent / Legal Guardian's Assessment of Children's Overall General State

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    End point title
    Parent / Legal Guardian's Assessment of Children's Overall General State
    End point description
    Children’s general state was recorded by their parents/legal guardian on a diary as: Good, fair and poor. Analysis was performed on PP population.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 5
    End point values
    Bacillus clausii + ORT
    Number of subjects analysed
    600
    Units: percentage of subjects
    number (not applicable)
        Day 1: Good
    34
        Day 1: Fair
    51.8
        Day 1: Poor
    14.2
        Day 2: Good
    49.7
        Day 2: Fair
    43.3
        Day 2: Poor
    7
        Day 3: Good
    69.5
        Day 3: Fair
    28.3
        Day 3: Poor
    2.2
        Day 4: Good
    82.8
        Day 4: Fair
    15.5
        Day 4: Poor
    1.7
        Day 5: Good
    91.7
        Day 5: Fair
    7.8
        Day 5: Poor
    0.5
    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 informed consent form up to final visit (between Day 6 and Day 10) regardless of seriousness or relationship to investigational product. Analysis was done on safety population.
    Adverse event reporting additional description
    Reported AE are treatment-emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (first day of initial dose of study drug, up to the last visit).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Bacillus clausii + ORT
    Reporting group description
    Bacillus clausii along with ORT was given for 5 days.

    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: No non-serious adverse events (equal or greater than threshold of 5%) were observed in any subjects during the study.
    Serious adverse events
    Bacillus clausii + ORT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 627 (0.16%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 627 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Bacillus clausii + ORT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 627 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2014
    Change in exclusion criteria to clarify the permission of probiotics and prebiotics in dairy food (such as yoghurt, cheese, milk) prior to study.

    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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