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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-Controlled, Parallel Group, Multicenter, Comparative Study to Assess the Efficacy and Safety of Spores of Enterogermina in Combination with Oral Rehydration Therapy (ORT) and Zinc Versus Placebo in Combination with ORT and Zinc Administered for 5 Days in the Treatment of Acute Diarrhea in Children.

    Summary
    EudraCT number
    		 2016-005165-31
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    24 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2020
    First version publication date
    07 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS14914
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1189-8467
    Other trial identifiers
    		 Study name: KIDDIE
    Sponsors
    Sponsor organisation name
    Sanofi-aventis Recherche & Développement
    Sponsor organisation address
    1, Avenue Pierre Brossolette, Chilly Mazarin, France, 91385
    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
    11 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of Bacillus clausii probiotic strain (Enterogermina) in combination with oral rehydration therapy (ORT) and Zinc compared to placebo in combination with ORT and Zinc, for a period of 5 days in Indian children with acute diarrhea.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric subjects. The parent(s) or guardian(s) were fully informed and consented of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. The consent form for the parent(s)/guardian(s) was provided. Repeated invasive procedures were minimised. 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 minimise distress and discomfort.
    Background therapy
    		 ORT and Zinc were administered as non-investigational medicinal products.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Dec 2018
    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: 457
    Worldwide total number of subjects
    457
    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)
    234
    Children (2-11 years)
    223
    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 9 active centers in India between 08 December 2018 and 19 March 2020.

    Pre-assignment
    Screening details
    		 A total of 464 subjects were screened in this study, of which 7 subjects were screening failure. Screening failure was mainly due to inclusion criteria not met. A total of 457 subjects were randomised to receive either placebo and Enterogermina in a 1:1 ratio, of which 454 subjects were treated in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to Enterogermina 2 times in a day: one in the morning and one in the evening for a period of 5 days (Days 1 to 5) along with ORT for 5 days and zinc 20 milligrams (mg) once a day for up to 14 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as 2 mini bottles per day, one in the morning, one in the evening for a period of 5 days in combination with ORT and zinc. If the first dose was administered in the morning of Day 1, the last dose (i.e., tenth dose) was administered in the evening of Day 5. If the first dose was administered in the evening of Day 1, the tenth dose was administered in the morning of Day 6. Placebo could be taken with or without food or drink.

    Arm title
    		 Enterogermina
    Arm description
    		 Subjects received Enterogermina 2 times in a day: one in the morning and one in the evening for a period of 5 days (Days 1 to 5) along with ORT for 5 days and zinc 20 mg once a day for up to 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enterogermina
    Investigational medicinal product code
    SSR29263
    Other name
    Bacillus clausii
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Enterogermina (4 billion spores of polyantibiotic-resistant B. clausii per day) was administered as 2 mini bottles per day, one in the morning, one in the evening for a period of 5 days in combination with ORT and zinc. If the first dose was administered in the morning of Day 1, the last dose (ie, tenth dose) was administered in the evening of Day 5. If the first dose was administered in the evening of Day 1, the tenth dose was administered in the morning of Day 6. Enterogermina could be taken with or without food or drink.

    Number of subjects in period 1
    		Placebo Enterogermina
    Started
    228
    229
    Treated
    227
    227
    Completed
    222
    223
    Not completed
    6
    6
         Randomised and not treated
    1
    2
         Subject’s parent or legal guardian decision
    1
    2
         Adverse event
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to Enterogermina 2 times in a day: one in the morning and one in the evening for a period of 5 days (Days 1 to 5) along with ORT for 5 days and zinc 20 milligrams (mg) once a day for up to 14 days.

    Reporting group title
    Enterogermina
    Reporting group description
    		 Subjects received Enterogermina 2 times in a day: one in the morning and one in the evening for a period of 5 days (Days 1 to 5) along with ORT for 5 days and zinc 20 mg once a day for up to 14 days.

    Reporting group values
    		 Placebo Enterogermina Total
    Number of subjects
    		 228 229 457
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 2.0 ( 1.1 ) 2.0 ( 1.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 116 116 232
        Male
    		 112 113 225
    Duration of current diarrhea episode
    Units: hours
        arithmetic mean (standard deviation)
    		 29.3 ( 8.7 ) 31.1 ( 9.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to Enterogermina 2 times in a day: one in the morning and one in the evening for a period of 5 days (Days 1 to 5) along with ORT for 5 days and zinc 20 milligrams (mg) once a day for up to 14 days.

    Reporting group title
    Enterogermina
    Reporting group description
    		 Subjects received Enterogermina 2 times in a day: one in the morning and one in the evening for a period of 5 days (Days 1 to 5) along with ORT for 5 days and zinc 20 mg once a day for up to 14 days.

    Primary: Duration of Diarrhea in Children With Acute Diarrhea

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    End point title
    		 Duration of Diarrhea in Children With Acute Diarrhea
    End point description
    The duration of acute diarrhea (in hours), was counted from the date/time of randomisation up to diarrhea recovery. Diarrhea recovery was defined as the first normal stool as recorded according to Bristol scores. A score <5 was described as normalisation of stool. Analysis was performed by Kaplan-Meier estimates. The 95% Confidence Interval (CI) was calculated using the log-log transformation. Analysis was performed on Intent-to-treat (ITT) population which included all randomised subjects analysed according to the treatment group allocated by randomisation.
    End point type
    Primary
    End point timeframe
    From the time of randomisation up to recovery (maximum duration: 5 days)
    End point values
    		 Placebo Enterogermina
    Number of subjects analysed
    228
    229
    Units: hours
        median (confidence interval 95%)
    42.13 (39.80 to 43.87)
    42.83 (40.90 to 44.90)
    Statistical analysis title
    		 Enterogermina group versus Placebo group
    Statistical analysis description
    The stratified log-rank test included the following factors: age (less than 2 years; greater than or equal to 2 years) viral status (viral; non-viral) and breast feeding status (Yes; No; Mixed). Hazard ratio and corresponding 95% CI were provided using a Cox proportional hazard model which included the same factors as in the stratified log-rank test.
    Comparison groups
    Placebo v Enterogermina
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6968 [1]
    Method
    		 Stratified Log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.13
    Notes
    [1] - Threshold for significance at 0.05 level.

    Secondary: Frequency of Stools per Visit

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    End point title
    		 Frequency of Stools per Visit
    End point description
    Percentage frequency of stool per day: 0 times, 1 time, 2 times, 3 times, and more than 3 times was reported in the end-point. Analysis was performed on ITT population. Here "n"= subjects with available data for each specified categories.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Day 5
    End point values
    		 Placebo Enterogermina
    Number of subjects analysed
    228
    229
    Units: percentage of stools
    number (not applicable)
        Day 1: 0 times (n=228,229)
    0.9
    0.4
        Day 1: 1 time (n=228,229)
    0.9
    0.9
        Day 1: 2 times (n=228,229)
    12.3
    16.2
        Day 1: 3 times (n=228,229)
    15.4
    16.2
        Day 1: More than 3 times (n=228,229)
    70.6
    66.4
        Day 2: 0 times (n=227,228)
    0.4
    0.9
        Day 2: 1 time (n=227,228)
    10.6
    8.3
        Day 2: 2 times (n=227,228)
    20.3
    21.5
        Day 2: 3 times (n=227,228)
    25.1
    29.8
        Day 2: More than 3 times (n=227,228)
    43.6
    39.5
        Day 3: 0 times (n=226,225)
    1.8
    1.3
        Day 3: 1 time (n=226,225)
    33.2
    35.1
        Day 3: 2 times (n=226,225)
    27.4
    31.1
        Day 3: 3 times (n=226,225)
    19.5
    13.8
        Day 3: More than 3 times (n=226,225)
    18.1
    18.7
        Day 4: 0 times (n=214, 211)
    0.9
    0.9
        Day 4: 1 time (n=214, 211)
    51.9
    53.1
        Day 4: 2 times (n=214, 211)
    26.6
    26.1
        Day 4: 3 times (n=214, 211)
    11.2
    10.0
        Day 4: More than 3 times (n=214, 211)
    9.3
    10.0
        Day 5: 0 times (n=201, 200)
    1.0
    1.0
        Day 5: 1 time (n=201, 200)
    60.2
    67.5
        Day 5: 2 times (n=201, 200)
    25.4
    20.5
        Day 5: 3 times (n=201, 200)
    7.5
    5.0
        Day 5: More than 3 times (n=201, 200)
    6.0
    6.0
    No statistical analyses for this end point

    Secondary: Dehydration Status Evaluated by Investigator Using World Health Organization (WHO) Classification

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    End point title
    		 Dehydration Status Evaluated by Investigator Using World Health Organization (WHO) Classification
    End point description
    Dehydration status evaluated as per WHO classification at each day was categorised as: no dehydration, some dehydration, and severe dehydration. Dehydration status was evaluated before each IMP intake during the hospitalisation. Analysis was performed on ITT population. Here "n"= subjects with available data for each specified categories.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Day 5
    End point values
    		 Placebo Enterogermina
    Number of subjects analysed
    228
    229
    Units: subjects
    number (not applicable)
        Day 1: No dehydration (n=225,224)
    0
    0
        Day 1: Some dehydration (n=225,224)
    225
    224
        Day 1: Severe dehydration (n=225,224)
    0
    0
        Day 2: No dehydration (n=224,225)
    65
    57
        Day 2: Some dehydration (n=224,225)
    158
    168
        Day 2: Severe dehydration (n=224,225)
    1
    0
        Day 3: No dehydration (n=144,151)
    77
    89
        Day 3: Some dehydration (n=144,151)
    67
    62
        Day 3: Severe dehydration (n=144,151)
    0
    0
        Day 4: No dehydration (n=78,93)
    58
    66
        Day 4: Some dehydration (n=78,93)
    20
    27
        Day 4: Severe dehydration (n=78,93)
    0
    0
        Day 5: No dehydration (n=50,59)
    43
    44
        Day 5: Some dehydration (n=50,59)
    7
    15
        Day 5: Severe dehydration (n=50,59)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE)

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE)
    End point description
    Adverse events (AEs) were any untoward medical occurrence in a patient or clinical study subject, administered a pharmaceutical product and which does not necessarily have to have a causal relationship with treatment. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (defined as date/time from first dose of study drug to the date/time of the last dose of study drug taken + 24 hours). SAE were defined as any untoward medical occurrence that, at any dose: a) resulted in death; b) was life-threatening; c) required inpatient hospitalisation or prolongation of existing hospitalisation; d) resulted in persistent disability/incapacity e) was a congenital anomaly/birth defect. Analysis was performed on safety population which included all randomized subjects who received at least one dose or part of a dose of the double-blind Investigational Medicinal Product.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Day 6
    End point values
    		 Placebo Enterogermina
    Number of subjects analysed
    227
    227
    Units: subjects
    number (not applicable)
        Any TEAE
    28
    22
        Any treatment emergent SAE
    0
    0
        Any TEAE leading to death
    0
    0
        Any TEAE leading to treatment discontinuation
    3
    2
    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 randomisation up to end of study (Day 6) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are TEAEs that developed/worsened during ‘TEAE period’(defined as the date/time from the first dose of study drug to the date/time of the last dose of the study drug taken + 24 hours) i.e. up to Day 6. Analysis was performed on safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to Enterogermina 2 times in a day: one in the morning and one in the evening for a period of 5 days (Days 1 to 5) along with ORT for 5 days and zinc 20 mg once a day for up to 14 days.

    Reporting group title
    Enterogermina
    Reporting group description
    		 Subjects received Enterogermina 2 times in a day: one in the morning and one in the evening for a period of 5 days (Days 1 to 5) along with ORT for 5 days and zinc 20 mg once a day for up to 14 days.

    Serious adverse events
    		 Placebo Enterogermina
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 227 (0.00%)
    0 / 227 (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
    		 Placebo Enterogermina
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 227 (12.33%)
    22 / 227 (9.69%)
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 227 (0.44%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 227 (2.64%)
    5 / 227 (2.20%)
         occurrences all number
    6
    5
    Eye disorders
    Periorbital Swelling
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 227 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 227 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 227 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    6 / 227 (2.64%)
    6 / 227 (2.64%)
         occurrences all number
    6
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 227 (0.88%)
    0 / 227 (0.00%)
         occurrences all number
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 227 (0.88%)
    1 / 227 (0.44%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 227 (0.44%)
         occurrences all number
    0
    1
    Rash Erythematous
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 227 (0.44%)
         occurrences all number
    0
    1
    Infections and infestations
    Dysentery
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 227 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 227 (1.32%)
    5 / 227 (2.20%)
         occurrences all number
    3
    5
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 227 (1.32%)
    1 / 227 (0.44%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 227 (0.88%)
    2 / 227 (0.88%)
         occurrences all number
    2
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 227 (0.88%)
         occurrences all number
    0
    2
    Lactose Intolerance
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 227 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jan 2018
    Following changes were made: this study was considered as a phase III instead of a phase IV study; removed the provision of the interim analysis; included objective parameters of efficacy.
    19 Jun 2018
    Following changes were made: changed the indication from acute diarrhea to acute moderate diarrhea.
    02 Jul 2019
    Following changes were made: Due to the RIDA QUICK rotavirus/adenovirus combi test no longer being available in India, it was replaced by another test kit for determination of rotavirus and/or adenovirus in stool samples. The instructions for the new test were added to the study manual; deleted from Appendix D the instructions for rotavirus/adenovirus test kit and add the test kit instructions to the study manual, so to avoid a protocol amendment in case of further virus test kit change.

    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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