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    Clinical Trial Results:
    A Phase III, Controlled, Open-Label, Randomized, Parallel Group, Multicentric, Comparative Study to Assess the Efficacy and Safety of Oral Rehydration Therapy (ORT) in Combination With Spores of Bacillus clausii (Enterogermina™) Versus ORT Alone, Administered For 5 Days in the Treatment of Acute Diarrhea in Children

    Summary
    EudraCT number
    		 2014-004636-19
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    26 Dec 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    25 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENTER_L_01486
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00457353
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi India Limited
    Sponsor organisation address
    Sanofi House, CTS No.117-B, L&T Business Park, Saki Vihar Road, Powai, Mumbai, India, 400072
    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
    29 Feb 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Dec 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of treatment with oral rehydration therapy (ORT) in combination with Bacillus clausii probiotic strain (Enterogermina™) as compared to treatment with ORT alone, for a period of 5 days, in reducing the duration of acute diarrhea in Indian 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
    02 Mar 2007
    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
    India: 264
    Worldwide total number of subjects
    264
    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)
    1
    Infants and toddlers (28 days-23 months)
    185
    Children (2-11 years)
    78
    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 6 centers in India. A total of 487 subjects were screened between 02 March 2007 and 18 December 2007.

    Pre-assignment
    Screening details
    		 Of 487 screened subjects, 264 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
    		 ORT + Bacillus clausii
    Arm description
    		 Oral Rehydration Therapy (ORT) along with Bacillus clausii for 5 days.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    ORS
    Investigational medicinal product code
    Other name
    ELECTRAL®
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    ORS (based on World Health Organization formula) according to the Investigator's recommendation.

    Arm title
    		 Oral Rehydration Therapy
    Arm description
    		 ORS alone for 5 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ORS
    Investigational medicinal product code
    Other name
    ELECTRAL®
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    ORS preparations administered according to the Investigator's recommendation.

    Number of subjects in period 1
    		ORT + Bacillus clausii Oral Rehydration Therapy
    Started
    132
    132
    Completed
    130
    127
    Not completed
    2
    5
         Adverse event
    -
    1
         Subject moved
    1
    -
         Lost to follow-up
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ORT + Bacillus clausii
    Reporting group description
    		 Oral Rehydration Therapy (ORT) along with Bacillus clausii for 5 days.

    Reporting group title
    Oral Rehydration Therapy
    Reporting group description
    		 ORS alone for 5 days.

    Reporting group values
    		 ORT + Bacillus clausii Oral Rehydration Therapy Total
    Number of subjects
    		 132 132 264
    Age categorical
    Units: Subjects
        Newborns (0-27 days)
    		 1 0 1
        Infants and toddlers (28 days-23 months)
    		 95 90 185
        Children (2-11 years)
    		 36 42 78
    Gender categorical
    Units: Subjects
        Female
    		 57 60 117
        Male
    		 75 72 147

    End points

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    End points reporting groups
    Reporting group title
    ORT + Bacillus clausii
    Reporting group description
    		 Oral Rehydration Therapy (ORT) along with Bacillus clausii for 5 days.

    Reporting group title
    Oral Rehydration Therapy
    Reporting group description
    		 ORS alone for 5 days.

    Primary: Duration of Diarrhea

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    End point title
    		 Duration of Diarrhea
    End point description
    Duration of diarrhea, as counted from the first intake of the investigational product up to the first appearance of a loose stool followed by two consecutive normal stools. Analysis was performed on safety population included all randomized and treated subjects.
    End point type
    Primary
    End point timeframe
    From D1 to end of treatment visit (Day 6)
    End point values
    		 ORT + Bacillus clausii Oral Rehydration Therapy
    Number of subjects analysed
    129
    126
    Units: hours
        arithmetic mean (standard deviation)
    48.6 ( 38.2 )
    56.1 ( 40 )
    Statistical analysis title
    		 ORT + Bacillus clausii vs ORT
    Statistical analysis description
    Analysis was performed by a log-rank test (Kaplan-Meier survival analysis).
    Comparison groups
    Oral Rehydration Therapy v ORT + Bacillus clausii
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 Logrank
    Confidence interval

    Secondary: Number of Stools Per Day

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    End point title
    		 Number of Stools Per Day
    End point description
    Analysis was performed on safety population. Number of subjects analysed = subjects with data available at each day.
    End point type
    Secondary
    End point timeframe
    On each day (D1 to D6)
    End point values
    		 ORT + Bacillus clausii Oral Rehydration Therapy
    Number of subjects analysed
    111
    101
    Units: stool episodes
        arithmetic mean (standard deviation)
    7.4 ( 6.5 )
    8.6 ( 6.5 )
    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 safety population.
    End point type
    Secondary
    End point timeframe
    On each day (D1 to D6)
    End point values
    		 ORT + Bacillus clausii Oral Rehydration Therapy
    Number of subjects analysed
    129
    126
    Units: subjects
        Day 1: Watery
    57
    52
        Day 1: Loose
    61
    64
        Day 2: Watery
    31
    34
        Day 2: Loose
    66
    62
        Day 3: Watery
    14
    18
        Day 3: Loose
    53
    63
        Day 4: Watery
    4
    6
        Day 4: Loose
    35
    44
        Day 5: Watery
    3
    5
        Day 5: Loose
    25
    26
        Day 6: Watery
    3
    2
        Day 6: Loose
    14
    18
    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 safety population. Here, "n" signifies the subjects with data available at specified time point.
    End point type
    Secondary
    End point timeframe
    On each day (D1 to D6)
    End point values
    		 ORT + Bacillus clausii Oral Rehydration Therapy
    Number of subjects analysed
    129
    126
    Units: vomiting episodes
    arithmetic mean (standard deviation)
        Day 1 (n=129, 126)
    0.4 ( 0.9 )
    0.4 ( 1 )
        Day 2 (n=129, 126)
    0.3 ( 0.8 )
    0.3 ( 0.8 )
        Day 3 (n=129, 126)
    0.2 ( 0.7 )
    0.2 ( 0.8 )
        Day 4 (n=129, 126)
    0.1 ( 0.6 )
    0.2 ( 0.6 )
        Day 5 (n=129, 126)
    0.1 ( 0.4 )
    0.1 ( 0.7 )
        Day 6 (n=107, 100)
    0.1 ( 0.4 )
    0.1 ( 0.6 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (visit 2) regardless of seriousness or relationship to investigational product. Analysis was performed on safety population.
    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 up to 12 days after last dose).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    ORT + Bacillus clausii
    Reporting group description
    		 ORT along with Bacillus clausii for 5 days.

    Reporting group title
    Oral Rehydration Therapy
    Reporting group description
    		 ORS alone for 5 days.

    Serious adverse events
    		 ORT + Bacillus clausii Oral Rehydration Therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 126 (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
    		 ORT + Bacillus clausii Oral Rehydration Therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 129 (23.26%)
    27 / 126 (21.43%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 129 (5.43%)
    6 / 126 (4.76%)
         occurrences all number
    7
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 129 (3.10%)
    7 / 126 (5.56%)
         occurrences all number
    4
    8
    Vomiting
         subjects affected / exposed
    20 / 129 (15.50%)
    20 / 126 (15.87%)
         occurrences all number
    21
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2007
    1. Method of ORS prepartion was changed. 2. As per part of the standard therapy in both the arms, Zinc supplements were given to all subjects in the dose of 20 mg/day for 14 days.
    27 Nov 2007
    The sample size was recalculated. The sample size with a drop out rate of 5% was determined to be 264 subjects.

    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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