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    Clinical Trial Results:
    Evaluation of The Effects of Enterogermina, 2 Billion Bacillus clausii Spores, on The Intestinal Flora of Children Antibiotic-Treated for Bacterial Upper Respiratory Tract Infections: Open, Pilot Study

    Summary
    EudraCT number
    		 2006-002482-39
    Trial protocol
    		 IT  
    Global end of trial date
    28 Dec 2007

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

    Trial information

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    Trial identification
    Sponsor protocol code
    PM_L_0199
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00424905
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi S.pA
    Sponsor organisation address
    Viale Bodio 37/b, Milan, Italy, 20158
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, 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
    30 Apr 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of Bacillus clausii (Enterogermina®) on fecal microbial flora (using polymerase chain reaction-denaturing gradient gel electrophoresis [PCR-DGGE] method) in antibiotic-treated children with complicated acute otitis media or beta-hemolytic streptococcal pharyngo-tonsillitis.
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 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
    Italy: 58
    Worldwide total number of subjects
    58
    EEA total number of subjects
    58
    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)
    9
    Children (2-11 years)
    49
    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 1 centre in Italy between 15 December 2006 and 28 December 2007.

    Pre-assignment
    Screening details
    		 A total of 60 subjects were randomized of which no data was collected from 2 subjects due to informed consent issues and hence, overall 58 subjects were included in the analysis.

    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 + Amoxicillin
    Arm description
    		 Bacillus clausii along with amoxicillin for 5-10 days, then alone for 7 additional days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spores of polyantibiotic-resistant 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 of polyantibiotic resistant Bacillus clausii twice daily.

    Investigational medicinal product name
    Amoxicillin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Amoxicillin 50 milligram per kilogram per day (mg/kg/day) divided in 3 daily doses.

    Arm title
    		 Amoxicillin
    Arm description
    		 Amoxicillin for 5-10 days.
    Arm type
    		 Untreated Control Arm

    Investigational medicinal product name
    Amoxicillin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Amoxicillin 50 mg/kg/day divided in 3 daily doses.

    Number of subjects in period 1
    		Bacillus clausii + Amoxicillin Amoxicillin
    Started
    30
    28
    Treated
    29
    26
    Completed
    22
    21
    Not completed
    8
    7
         Randomized but not treated
    1
    2
         Adverse event
    1
    2
         Unspecified
    2
    2
         Impossible to collect 1st faecal sample correctly
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bacillus clausii + Amoxicillin
    Reporting group description
    		 Bacillus clausii along with amoxicillin for 5-10 days, then alone for 7 additional days.

    Reporting group title
    Amoxicillin
    Reporting group description
    		 Amoxicillin for 5-10 days.

    Reporting group values
    		 Bacillus clausii + Amoxicillin Amoxicillin Total
    Number of subjects
    		 30 28 58
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 5 4 9
        Children (2-11 years)
    		 25 24 49
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 40 ± 18.88 42.1 ± 18.94 -
    Gender categorical
    Units: Subjects
        Female
    		 11 18 29
        Male
    		 19 10 29
    Race
    Units: Subjects
        Caucasian
    		 29 23 52
        Asian
    		 0 1 1
        Black
    		 0 1 1
        Hispanic
    		 1 0 1
        Other
    		 0 3 3
    Primary Diagnosis
    Units: Subjects
        Complicated Acute Otitis Media
    		 19 19 38
        Beta-Hemolytic Streptococcal Pharyngo-Tonsillitis
    		 11 9 20

    End points

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    End points reporting groups
    Reporting group title
    Bacillus clausii + Amoxicillin
    Reporting group description
    		 Bacillus clausii along with amoxicillin for 5-10 days, then alone for 7 additional days.

    Reporting group title
    Amoxicillin
    Reporting group description
    		 Amoxicillin for 5-10 days.

    Primary: Change of Microbial Composition of Fecal Bacterial Flora: Number of Responders

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    End point title
    		 Change of Microbial Composition of Fecal Bacterial Flora: Number of Responders
    End point description
    Analysis of bacterial flora was performed by Polymerase Chain Reaction Denaturing Gradient Gel Electrophoresis (PCR-DGGE). Statistical analysis was performed on similarity coefficient on the basis of Dice algorithm. A subject was classified as responder if the similarity coefficient (similarity of bacterial groups between samples obtained at baseline and Day 13 to 18) was greater than or equal to (>=) 80%. Analysis was carried out on intent-to-treat (ITT) population which included all randomized and treated subjects with a baseline and post-baseline sample.
    End point type
    Primary
    End point timeframe
    Baseline, Day 13 to 18
    End point values
    		 Bacillus clausii + Amoxicillin Amoxicillin
    Number of subjects analysed
    19
    21
    Units: subjects
    6
    6
    Statistical analysis title
    		 Bacillus clausii + Amoxicillin vs Amoxicillin
    Statistical analysis description
    The proportion of responders was compared between the two treatment arms.
    Comparison groups
    Bacillus clausii + Amoxicillin v Amoxicillin
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.836
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 4.47

    Primary: Changes of Microbial Composition of Fecal Bacterial Flora: Mean Similarity Coefficient

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    End point title
    		 Changes of Microbial Composition of Fecal Bacterial Flora: Mean Similarity Coefficient
    End point description
    Analysis was carried out on ITT population.
    End point type
    Primary
    End point timeframe
    Baseline, Day 13 to 18
    End point values
    		 Bacillus clausii + Amoxicillin Amoxicillin
    Number of subjects analysed
    19
    21
    Units: percentage of similarity
        arithmetic mean (standard error)
    74.4 ± 2.6
    72.4 ± 2.5
    Statistical analysis title
    		 Bacillus clausii + Amoxicillin vs Amoxicillin
    Statistical analysis description
    Similarity coefficient was analysed as continuous variable by means of Analysis of Variance (ANOVA).
    Comparison groups
    Bacillus clausii + Amoxicillin v Amoxicillin
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.578
    Method
    		 ANOVA
    Parameter type
    		 Mean difference
    Point estimate
    2.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.31
         upper limit
    		 9.38

    Secondary: Change From Baseline in Body Weight

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    End point title
    		 Change From Baseline in Body Weight
    End point description
    Analysis was carried out on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 13 to 18
    End point values
    		 Bacillus clausii + Amoxicillin Amoxicillin
    Number of subjects analysed
    18
    19
    Units: kilogram(s)
        arithmetic mean (standard error)
    0.22 ± 0.16
    -0.09 ± 0.15
    No statistical analyses for this end point

    Secondary: Abdominal Symptoms

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    End point title
    		 Abdominal Symptoms
    End point description
    Abdominal symptoms such as discomfort, bloating, straining, stool frequency and consistency, reported daily on subject's diary in terms of a point rating scale or presence/absence. Analysis was carried out on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 13 to 18
    End point values
    		 Bacillus clausii + Amoxicillin Amoxicillin
    Number of subjects analysed
    19
    21
    Units: subjects
        Abdominal Discomfort – Day 1
    5
    3
        Abdominal Discomfort – Last measure
    1
    0
        Abdominal Bloating – Day 1
    5
    4
        Abdominal Bloating – Last Measure
    1
    0
        Abdominal Staining – Day 1
    1
    0
        Abdominal Staining – Last Measure
    1
    2
        Stool Episodes > 1 Per Day – Day 1
    3
    7
        Stool Episodes > 1 Per Day – Last Measure
    3
    3
        Abnormal Stool Consistency – Day 1
    9
    6
        Abnormal Stool Consistency – Last Measure
    2
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Bacillus clausii Spores Count

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    End point title
    		 Number of Subjects With Bacillus clausii Spores Count
    End point description
    Analysis was carried out on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 13 to 18
    End point values
    		 Bacillus clausii + Amoxicillin Amoxicillin
    Number of subjects analysed
    19
    21
    Units: subjects
        Day 1
    4
    1
        Last Measure
    17
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects with Gastrointestinal Intestinal (GI) Symptoms

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    End point title
    		 Number of Subjects with Gastrointestinal Intestinal (GI) Symptoms
    End point description
    Analysis was carried out on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 13 to 18
    End point values
    		 Bacillus clausii + Amoxicillin Amoxicillin
    Number of subjects analysed
    19
    21
    Units: subjects
    0
    0
    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 (13 - 18 days) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (12 - 17 days). Analysis was carried out on safety population which included all randomized and treated subjects.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Amoxicillin
    Reporting group description
    		 Amoxicillin for 5 - 10 days.

    Reporting group title
    Bacillus clausii + Amoxicillin
    Reporting group description
    		 Bacillus clausii along with amoxicillin for 5­-10 days, then alone for 7 additional days.

    Serious adverse events
    		 Amoxicillin Bacillus clausii + Amoxicillin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Drug Toxicity
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Amoxicillin Bacillus clausii + Amoxicillin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 26 (46.15%)
    9 / 29 (31.03%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 26 (23.08%)
    7 / 29 (24.14%)
         occurrences all number
    6
    8
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 26 (3.85%)
    3 / 29 (10.34%)
         occurrences all number
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0

    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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