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    Clinical Trial Results:
    Efficacy of diosmectite (Smecta®) in the symptomatic treatment of acute diarrhoea in adults. A multicentre, randomised, double-blind, placebo-controlled, parallel groups study

    Summary
    EudraCT number
    		 2015-001138-10
    Trial protocol
    		 PL   CZ   RO  
    Global end of trial date
    08 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Apr 2020
    First version publication date
    24 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    F-FR-00250-105
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02704091
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ipsen Pharma SAS
    Sponsor organisation address
    65 quai Georges Gorse, Boulogne-Billancourt, France, 92100
    Public contact
    Medical Director, Ipsen Pharma SAS, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen Pharma SAS, clinical.trials@ipsen.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate that diosmectite efficacy (administered as 2 sachets three times a day [TID]) is superior to placebo regarding the time to recovery of an acute diarrhoea episode presumed of infectious origin in adult participants.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, in accordance with the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Consolidated Guideline on Good Clinical Practice, in compliance with Independent Ethics Committees/Institutional Review Boards and informed consent regulations, and adhered to all local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Mar 2016
    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
    Tunisia: 188
    Country: Number of subjects enrolled
    Czech Republic: 187
    Country: Number of subjects enrolled
    Poland: 179
    Country: Number of subjects enrolled
    Egypt: 126
    Country: Number of subjects enrolled
    Algeria: 121
    Country: Number of subjects enrolled
    Lebanon: 52
    Worldwide total number of subjects
    853
    EEA total number of subjects
    366
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    804
    From 65 to 84 years
    45
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study enrolled adult participants with a recent episode of acute diarrhoea presumed of infectious origin, defined as the passage of 3 or more unformed (loose or watery) stools per day without alarm symptoms within the first 48 hours. Participants were randomised at 62 study centres in Algeria, Czech Republic, Egypt, Lebanon, Poland and Tunisia.

    Pre-assignment
    Screening details
    		 858 participants were randomised, of which 853 were included in the analysis and 5 were excluded due to invalid consent. Only participants included in the analysis are presented in the subject disposition. Participants received a diary evaluation booklet (DEB) to record each stool plus consistency on a daily basis from inclusion until end of 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, Assessor, Carer, Data analyst, Subject, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Diosmectite
    Arm description
    		 Participants received diosmectite as 2 sachets, TID (2 sachets in the morning, 2 sachets at mid-day, and 2 sachets in the evening). Each sachet was taken in half a glass of water. The mandatory treatment period was from Day 1 to Day 4 or Day 5 (with a minimum of 24 sachets taken within 4 or 5 days). Treatment could continue from Day 5 up to Day 8 or 9 (with a maximum of 48 sachets taken within 8 or 9 days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diosmectite
    Investigational medicinal product code
    Other name
    Smecta®
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Diosmectite consisted of powder for suspension for oral use. Each sachet contained 3 grams diosmectite as active substance.

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo as 2 sachets, TID (2 sachets in the morning, 2 sachets at mid-day, and 2 sachets in the evening). Each sachet was taken in half a glass of water. The mandatory treatment period was from Day 1 to Day 4 or Day 5 (with a minimum of 24 sachets taken within 4 or 5 days). Treatment could continue from Day 5 up to Day 8 or 9 (with a maximum of 48 sachets taken within 8 or 9 days).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo consisted of powder for suspension for oral use similar to the investigational product without the active substance. The placebo was presented in sachets.

    Number of subjects in period 1
    		Diosmectite Placebo
    Started
    430
    423
    Completed
    402
    400
    Not completed
    28
    23
         Adverse event, non-fatal
    4
    3
         Unspecified
    2
    8
         Lost to follow-up
    13
    5
         Consent withdrawn
    4
    4
         Protocol deviation
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Diosmectite
    Reporting group description
    		 Participants received diosmectite as 2 sachets, TID (2 sachets in the morning, 2 sachets at mid-day, and 2 sachets in the evening). Each sachet was taken in half a glass of water. The mandatory treatment period was from Day 1 to Day 4 or Day 5 (with a minimum of 24 sachets taken within 4 or 5 days). Treatment could continue from Day 5 up to Day 8 or 9 (with a maximum of 48 sachets taken within 8 or 9 days).

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo as 2 sachets, TID (2 sachets in the morning, 2 sachets at mid-day, and 2 sachets in the evening). Each sachet was taken in half a glass of water. The mandatory treatment period was from Day 1 to Day 4 or Day 5 (with a minimum of 24 sachets taken within 4 or 5 days). Treatment could continue from Day 5 up to Day 8 or 9 (with a maximum of 48 sachets taken within 8 or 9 days).

    Reporting group values
    		 Diosmectite Placebo Total
    Number of subjects
    		 430 423
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.7 ( 14.5 ) 38.6 ( 14.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 232 241 473
        Male
    		 198 182 380

    End points

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    End points reporting groups
    Reporting group title
    Diosmectite
    Reporting group description
    		 Participants received diosmectite as 2 sachets, TID (2 sachets in the morning, 2 sachets at mid-day, and 2 sachets in the evening). Each sachet was taken in half a glass of water. The mandatory treatment period was from Day 1 to Day 4 or Day 5 (with a minimum of 24 sachets taken within 4 or 5 days). Treatment could continue from Day 5 up to Day 8 or 9 (with a maximum of 48 sachets taken within 8 or 9 days).

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo as 2 sachets, TID (2 sachets in the morning, 2 sachets at mid-day, and 2 sachets in the evening). Each sachet was taken in half a glass of water. The mandatory treatment period was from Day 1 to Day 4 or Day 5 (with a minimum of 24 sachets taken within 4 or 5 days). Treatment could continue from Day 5 up to Day 8 or 9 (with a maximum of 48 sachets taken within 8 or 9 days).

    Primary: Time to Recovery

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    End point title
    		 Time to Recovery
    End point description
    Time to recovery was defined as the time from the first study treatment intake recorded in the electronic case report form (eCRF) to the first formed stool followed by a non-watery stool, recorded in the DEB. Results are presented as median time to recovery, calculated using the Kaplan-Meier technique. The Intention-To-Treat (ITT) population included all randomised participants (with the exception of those excluded from the analysis), analysed according to the arm to which they were randomised. Participants prematurely withdrawn without recovery or ending the study without recovery were censored (not responders) at the date/time of their last stool as recorded in the DEB. Participants who had not filled in the DEB (i.e. no post-baseline evaluation of stools) were censored at the date/time of their first study treatment intake (or the randomisation date/time if not administered).
    End point type
    Primary
    End point timeframe
    From randomisation (Day 1) up to Day 9
    End point values
    		 Diosmectite Placebo
    Number of subjects analysed
    430
    423
    Units: Hours
        median (confidence interval 95%)
    66.0 (53.7 to 71.0)
    68.6 (57.5 to 77.8)
    Statistical analysis title
    		 Difference Between Treatment Groups
    Statistical analysis description
    The primary analysis tested the equality of time to recovery between the 2 treatment groups, applying the 2-sided Gehan-Wilcoxon test (α=5%).
    Comparison groups
    Diosmectite v Placebo
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.2524
    Method
    		 Wilcoxon-Gehan test
    Confidence interval
    Notes
    [1] - The following Null-hypothesis was tested: H0: λA(t) = λB (t) versus H1: λA(t) ≠ λB (t), where λ(t) represents the hazard at time t, A=diosmectite and B=placebo.

    Secondary: Time From Diarrhoea Onset to Recovery

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    End point title
    		 Time From Diarrhoea Onset to Recovery
    End point description
    The event of diarrhoea onset (i.e. loose or watery stool) was recorded in the eCRF and the event of recovery (i.e. first formed stool followed by a non-watery stool) was recorded in the DEB. Results are presented as median time from diarrhoea onset to recovery, calculated using the Kaplan-Meier technique. The ITT population included all randomised participants (with the exception of those excluded from the analysis), analysed according to the arm to which they were randomised. Participants prematurely withdrawn without recovery or ending the study without recovery were censored (not responders) at the date/time of their last stool as recorded in the DEB. Participants who had not filled in the DEB (i.e. no post-baseline evaluation of stools) were censored at the date/time of their first study treatment intake (or the randomisation date/time if not administered).
    End point type
    Secondary
    End point timeframe
    From randomisation (Day 1) up to Day 9
    End point values
    		 Diosmectite Placebo
    Number of subjects analysed
    429
    423
    Units: Hours
        median (confidence interval 95%)
    91.0 (82.5 to 107.0)
    92.2 (84.2 to 102.8)
    Statistical analysis title
    		 Difference Between Treatment Groups
    Statistical analysis description
    Comparison between the 2 treatment groups for time from diarrhoea onset to recovery, analysed using the Gehan-Wilcoxon test.
    Comparison groups
    Diosmectite v Placebo
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3511
    Method
    		 Gehan-Wilcoxon test
    Confidence interval

    Secondary: Time From Diarrhoea Onset to First Formed Stool

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    End point title
    		 Time From Diarrhoea Onset to First Formed Stool
    End point description
    The event of diarrhoea onset (i.e. loose or watery stool) was recorded in the eCRF and the event of first formed stool was recorded in the DEB. Results are presented as median time from diarrhoea onset to first formed stool, calculated using the Kaplan-Meier technique. The ITT population included all randomised participants (with the exception of those excluded from the analysis), analysed according to the arm to which they were randomised. Participants prematurely withdrawn with no formed stool or ending the study with no formed stool were censored at the date/time of their last stool as recorded in the DEB. Participants who had not filled in the DEB (i.e. no post-baseline evaluation of stools) were censored at the date/time of their first study treatment intake (or the randomisation date/time if not administered).
    End point type
    Secondary
    End point timeframe
    From randomisation (Day 1) up to Day 9
    End point values
    		 Diosmectite Placebo
    Number of subjects analysed
    429
    423
    Units: Hours
        median (full range (min-max))
    84.3 (77.5 to 94.2)
    84.6 (79.8 to 91.0)
    Statistical analysis title
    		 Difference Between Treatment Groups
    Statistical analysis description
    Comparison between the 2 treatment groups for time from diarrhoea onset to first formed stool, analysed using the Gehan-Wilcoxon test.
    Comparison groups
    Diosmectite v Placebo
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7285
    Method
    		 Gehan-Wilcoxon test
    Confidence interval

    Secondary: Time From the First Study Treatment Intake to the Last Watery Stool

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    End point title
    		 Time From the First Study Treatment Intake to the Last Watery Stool
    End point description
    The event of first study treatment intake was recorded in the eCRF and the event of last watery stool was recorded in the DEB. Results are presented as median time from first study treatment intake to last watery stool, calculated using the Kaplan-Meier technique. The ITT population included all randomised participants (with the exception of those excluded from the analysis), analysed according to the arm to which they were randomised. Participants prematurely withdrawn with no watery stool or ending the study with no watery stool were censored at the date/time of their last stool as recorded in the DEB. Participants who had not filled in the DEB (i.e. no post-baseline evaluation of stools) were censored at the date/time of their first study treatment intake (or the randomisation date/time if not administered).
    End point type
    Secondary
    End point timeframe
    From randomisation (Day 1) up to Day 9
    End point values
    		 Diosmectite Placebo
    Number of subjects analysed
    430
    423
    Units: Hours
        median (confidence interval 95%)
    56.2 (44.6 to 66.2)
    60.0 (52.8 to 68.8)
    Statistical analysis title
    		 Difference between Treatment Groups
    Statistical analysis description
    Comparison between the 2 treatment groups for time from first study treatment intake to last watery stool, analysed using the Gehan-Wilcoxon test.
    Comparison groups
    Diosmectite v Placebo
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1807
    Method
    		 Gehan-Wilcoxon test
    Confidence interval

    Secondary: Number of Stools, Per 12-Hour Period

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    End point title
    		 Number of Stools, Per 12-Hour Period
    End point description
    Number of stools, per 12-hour period, was recorded in the DEB. The ITT population included all randomised participants (with the exception of those excluded from the analysis), analysed according to the arm to which they were randomised. n = number of participants with data available for analysis for each specified time point. Note: median number of stools in the diosmectite arm at time point 204-216 hours was not calculated since zero participants were available for analysis (denoted by 999999).
    End point type
    Secondary
    End point timeframe
    From randomisation (Day 1) up to Day 9
    End point values
    		 Diosmectite Placebo
    Number of subjects analysed
    413
    412
    Units: Stools
    median (full range (min-max))
        0 - 12 hours (n=413, 412)
    3.0 (0 to 11)
    3.0 (0 to 14)
        12 - 24 hours (n=407, 411)
    2.0 (0 to 7)
    2.0 (0 to 7)
        24 - 36 hours (n=402, 407)
    1.0 (0 to 8)
    2.0 (0 to 19)
        36 - 48 hours (n=396, 400)
    1.0 (0 to 7)
    1.0 (0 to 6)
        48 - 60 hours (n=386, 391)
    1.0 (0 to 7)
    1.0 (0 to 9)
        60 - 72 hours (n=373, 383)
    1.0 (0 to 6)
    1.0 (0 to 7)
        72 - 84 hours (n=320, 329)
    1.0 (0 to 12)
    1.0 (0 to 7)
        84 - 96 hours (n=269, 264)
    1.0 (0 to 6)
    1.0 (0 to 7)
        96 - 108 hours (n=191, 174)
    1.0 (0 to 5)
    1.0 (0 to 7)
        108 - 120 hours (n=151, 143)
    1.0 (0 to 5)
    1.0 (0 to 6)
        120 - 132 hours (n=109, 120)
    1.0 (0 to 4)
    1.0 (0 to 6)
        132 - 144 hours (n=95, 109)
    1.0 (0 to 6)
    1.0 (0 to 4)
        144 - 156 hours (n=75, 100)
    1.0 (0 to 4)
    1.0 (0 to 6)
        156 - 168 hours (n=57, 80)
    1.0 (0 to 4)
    1.0 (0 to 5)
        168 - 180 hours (n=42, 60)
    1.0 (0 to 5)
    1.0 (0 to 4)
        180 - 192 hours (n=32, 44)
    1.0 (0 to 5)
    1.0 (0 to 5)
        192 - 204 hours (n=17, 16)
    1.0 (1 to 4)
    1.0 (0 to 4)
        204 - 216 hours (n=0, 1)
    999999 (999999 to 999999)
    1.0 (1 to 1)
    Statistical analysis title
    		 Difference Between Treatment Groups Overall
    Statistical analysis description
    Comparison between the 2 treatment groups for number of stools for the overall time period, based on an analysis of covariance (ANCOVA) method for repeated measurements. The model included the number of stools 24 hours before randomisation (baseline) as covariate, treatment, time point (12-hour period), the treatment by time point interaction as fixed effects and participant as random effect.
    Comparison groups
    Diosmectite v Placebo
    Number of subjects included in analysis
    825
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4294
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.07

    Secondary: Number of Watery Stools, Per 12-Hour Period

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    End point title
    		 Number of Watery Stools, Per 12-Hour Period
    End point description
    Number of watery stools, per 12-hour period, was recorded in the DEB. The ITT population included all randomised participants (with the exception of those excluded from the analysis), analysed according to the arm to which they were randomised. n = number of participants with data available for analysis for each specified time point. Note: median number of watery stools in the diosmectite arm at time point 204-216 hours was not calculated since zero participants were available for analysis (denoted by 999999).
    End point type
    Secondary
    End point timeframe
    From randomisation (Day 1) up to Day 9
    End point values
    		 Diosmectite Placebo
    Number of subjects analysed
    413
    412
    Units: Stools
    median (full range (min-max))
        0 - 12 hours (n=413, 412)
    3.0 (0 to 11)
    3.0 (0 to 14)
        12 - 24 hours (n=407, 411)
    1.0 (0 to 7)
    1.0 (0 to 7)
        24 - 36 hours (n=402, 407)
    0.0 (0 to 8)
    1.0 (0 to 19)
        36 - 48 hours (n=396, 400)
    0.0 (0 to 7)
    0.0 (0 to 6)
        48 - 60 hours (n=386, 391)
    0.0 (0 to 7)
    0.0 (0 to 9)
        60 - 72 hours (n=373, 383)
    0.0 (0 to 6)
    0.0 (0 to 7)
        72 - 84 hours (n=320, 329)
    0.0 (0 to 10)
    0.0 (0 to 7)
        84 - 96 hours (n=269, 264)
    0.0 (0 to 6)
    0.0 (0 to 7)
        96 - 108 hours (n=191, 174)
    0.0 (0 to 5)
    0.0 (0 to 7)
        108 - 120 hours (n=151,143)
    0.0 (0 to 5)
    0.0 (0 to 6)
        120 - 132 hours (n=109, 120)
    0.0 (0 to 4)
    0.0 (0 to 5)
        132 - 144 hours (n=95, 109)
    0.0 (0 to 6)
    0.0 (0 to 4)
        144 - 156 hours (n=75, 100)
    0.0 (0 to 3)
    0.0 (0 to 5)
        156 - 168 hours (n=57, 80)
    0.0 (0 to 4)
    0.0 (0 to 5)
        168 - 180 hours (n=42, 60)
    0.0 (0 to 5)
    0.0 (0 to 4)
        180 - 192 hours (n=32, 44)
    0.0 (0 to 5)
    0.0 (0 to 5)
        192 - 204 hours (n=17, 16)
    0.0 (0 to 4)
    0.0 (0 to 3)
        204 - 216 hours (n=0, 1)
    999999 (999999 to 999999)
    0.0 (0 to 0)
    Statistical analysis title
    		 Difference Between Treatment Groups Overall
    Statistical analysis description
    Comparison between the 2 treatment groups for number of watery stools for the overall time period, based on an ANCOVA method for repeated measurements. The model included the number of watery stools 24 hours before randomisation (baseline) as covariate, treatment, time point (12-hour period), the treatment by time point interaction as fixed effects and participant as random effect.
    Comparison groups
    Diosmectite v Placebo
    Number of subjects included in analysis
    825
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0465
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0

    Secondary: Percentage of Participants With Associated Symptoms, Per 12-Hour Period

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    End point title
    		 Percentage of Participants With Associated Symptoms, Per 12-Hour Period
    End point description
    Percentage of participants with associated symptoms (at least 1 symptom of nausea, vomiting, abdominal pain or anal irritation) per 12-hour period is presented. Nausea, vomiting, abdominal pain and anal irritation were recorded in the DEB. The ITT population included all randomised participants (with the exception of those excluded from the analysis), analysed according to the arm to which they were randomised. n = number of participants with data available for analysis for each specified time point.
    End point type
    Secondary
    End point timeframe
    From randomisation (Day 1) up to Day 9
    End point values
    		 Diosmectite Placebo
    Number of subjects analysed
    430
    423
    Units: Percentage of participants
    number (not applicable)
        0 - 12 hours (n=400, 390)
    76.3
    76.4
        12 - 24 hours (n=395, 395)
    67.1
    64.6
        24 - 36 hours (n=402, 397)
    56.2
    54.2
        36 - 48 hours (n=395, 395)
    44.8
    45.6
        48 - 60 hours (n=392, 395)
    34.9
    35.4
        60 - 72 hours (n=376, 379)
    28.7
    28.8
        72 - 84 hours (n=370, 381)
    24.3
    22.0
        84 - 96 hours (n=329, 345)
    21.6
    20.6
        96 - 108 hours (n=228, 242)
    20.6
    24.0
        108 - 120 hours (n=177, 173)
    18.6
    24.9
        120 - 132 hours (n=136, 136)
    18.4
    27.9
        132 - 144 hours (n=103, 117)
    12.6
    21.4
        144 - 156 hours (n=86, 104)
    10.5
    19.2
        156 - 168 hours (n=71, 87)
    8.5
    16.1
        168 - 180 hours (n=58, 76)
    8.6
    11.8
        180 - 192 hours (n=49, 61)
    8.2
    9.8
        192 - 204 hours (n=31, 38)
    9.7
    10.5
        204 - 216 hours (n=17, 20)
    5.9
    0.0
    No statistical analyses for this end point

    Secondary: Abdominal Pain Intensity Scores, Per 12-Hour Period

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    End point title
    		 Abdominal Pain Intensity Scores, Per 12-Hour Period
    End point description
    Abdominal pain intensity per 12-hour period was recorded in the DEB. Abdominal pain intensity was rated with a 5-point ordinal scale: 0 = absent, 1= mild, 2 =moderate, 3 = severe, 4= very severe. Higher scores indicate a worse outcome. The median abdominal pain intensity score for each 12-hour period is presented. The ITT population included all randomised participants (with the exception of those excluded from the analysis), analysed according to the arm to which they were randomised. n = number of participants with data available for analysis for each specified time point.
    End point type
    Secondary
    End point timeframe
    From randomisation (Day 1) up to Day 9
    End point values
    		 Diosmectite Placebo
    Number of subjects analysed
    430
    423
    Units: Scores on a scale
    median (full range (min-max))
        0 - 12 hours (n=384, 377)
    1.0 (0 to 4)
    1.0 (0 to 4)
        12 - 24 hours (n=382, 379)
    1.0 (0 to 4)
    1.0 (0 to 4)
        24 - 36 hours (n=393, 386)
    0.0 (0 to 4)
    0.0 (0 to 4)
        36 - 48 hours (n=382, 380)
    0.0 (0 to 4)
    0.0 (0 to 4)
        48 - 60 hours (n=381, 380)
    0.0 (0 to 4)
    0.0 (0 to 4)
        60 - 72 hours (n=368, 366)
    0.0 (0 to 4)
    0.0 (0 to 4)
        72 - 84 hours (n=362, 369)
    0.0 (0 to 4)
    0.0 (0 to 4)
        84 - 96 hours (n=319, 336)
    0.0 (0 to 4)
    0.0 (0 to 4)
        96 - 108 hours (n=220, 233)
    0.0 (0 to 3)
    0.0 (0 to 4)
        108 - 120 hours (n=171, 171)
    0.0 (0 to 3)
    0.0 (0 to 4)
        120 - 132 hours (n=133, 133)
    0.0 (0 to 4)
    0.0 (0 to 4)
        132 - 144 hours (n=101, 113)
    0.0 (0 to 2)
    0.0 (0 to 4)
        144 - 156 hours (n=86, 104)
    0.0 (0 to 3)
    0.0 (0 to 4)
        156 - 168 hours (n=67, 86)
    0.0 (0 to 3)
    0.0 (0 to 4)
        168 - 180 hours (n=55, 75)
    0.0 (0 to 3)
    0.0 (0 to 4)
        180 - 192 hours (n=45, 60)
    0.0 (0 to 2)
    0.0 (0 to 4)
        192 - 204 hours (n=29, 38)
    0.0 (0 to 4)
    0.0 (0 to 4)
        204 - 216 hours (n=17, 20)
    0.0 (0 to 1)
    0.0 (0 to 0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events were collected from Day 1 until 7 days after the end of the study treatment, up to 16 days.
    Adverse event reporting additional description
    The safety population included all randomised participants who received at least 1 dose of study treatment (except for those excluded from the analysis). Participants were analysed according to the actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Diosmectite
    Reporting group description
    		 Participants received diosmectite as 2 sachets, TID (2 sachets in the morning, 2 sachets at mid-day, and 2 sachets in the evening). Each sachet was taken in half a glass of water. The mandatory treatment period was from Day 1 to Day 4 or Day 5 (with a minimum of 24 sachets taken within 4 or 5 days). Treatment could continue from Day 5 up to Day 8 or 9 (with a maximum of 48 sachets taken within 8 or 9 days).

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo as 2 sachets, TID (2 sachets in the morning, 2 sachets at mid-day, and 2 sachets in the evening). Each sachet was taken in half a glass of water. The mandatory treatment period was from Day 1 to Day 4 or Day 5 (with a minimum of 24 sachets taken within 4 or 5 days). Treatment could continue from Day 5 up to Day 8 or 9 (with a maximum of 48 sachets taken within 8 or 9 days).

    Serious adverse events
    		 Diosmectite Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 430 (0.23%)
    1 / 421 (0.24%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         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: 0%
    Non-serious adverse events
    		 Diosmectite Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 430 (6.74%)
    32 / 421 (7.60%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 430 (0.70%)
    7 / 421 (1.66%)
         occurrences all number
    3
    7
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 430 (2.09%)
    9 / 421 (2.14%)
         occurrences all number
    9
    9
    Anorectal discomfort
         subjects affected / exposed
    5 / 430 (1.16%)
    3 / 421 (0.71%)
         occurrences all number
    5
    3
    Constipation
         subjects affected / exposed
    2 / 430 (0.47%)
    3 / 421 (0.71%)
         occurrences all number
    2
    3
    Nausea
         subjects affected / exposed
    1 / 430 (0.23%)
    3 / 421 (0.71%)
         occurrences all number
    1
    4
    Proctalgia
         subjects affected / exposed
    2 / 430 (0.47%)
    0 / 421 (0.00%)
         occurrences all number
    2
    0
    Anal pruritus
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences all number
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 430 (0.23%)
    2 / 421 (0.48%)
         occurrences all number
    1
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 430 (0.23%)
    1 / 421 (0.24%)
         occurrences all number
    1
    1
    Cough
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Acrophobia
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 430 (0.47%)
    0 / 421 (0.00%)
         occurrences all number
    2
    0
    Arthralgia
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences all number
    1
    0
    Spinal pain
         subjects affected / exposed
    0 / 430 (0.00%)
    2 / 421 (0.48%)
         occurrences all number
    0
    2
    Muscle spasms
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences all number
    1
    0
    Arthritis salmonella
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences all number
    0
    1
    Urethritis
         subjects affected / exposed
    0 / 430 (0.00%)
    1 / 421 (0.24%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 430 (0.23%)
    0 / 421 (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
    10 Mar 2016
    - Rewording of an inclusion criteria to fit better with the clinical presentation of a recent acute diarrhoea episode; - At the request of Czech Republic Ethical Committee and Health Authorities: change or addition of some selection criteria and of criteria for withdrawal and poststudy follow up; standardisation of dietary measures.
    07 Jan 2019
    - Update of targeted countries for participant's recruitment; - Prolongation of study duration; - Update of exclusion criteria #21.

    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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