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
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EudraCT number |
2015-001138-10 |
Trial protocol |
PL CZ RO |
Global end of trial date |
08 Apr 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Apr 2020
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First version publication date |
24 Apr 2020
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
F-FR-00250-105
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02704091 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Ipsen Pharma SAS
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Sponsor organisation address |
65 quai Georges Gorse, Boulogne-Billancourt, France, 92100
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Public contact |
Medical Director, Ipsen Pharma SAS, clinical.trials@ipsen.com
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Scientific contact |
Medical Director, Ipsen Pharma SAS, clinical.trials@ipsen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Apr 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Apr 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 Mar 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Tunisia: 188
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Country: Number of subjects enrolled |
Czech Republic: 187
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Country: Number of subjects enrolled |
Poland: 179
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Country: Number of subjects enrolled |
Egypt: 126
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Country: Number of subjects enrolled |
Algeria: 121
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Country: Number of subjects enrolled |
Lebanon: 52
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Worldwide total number of subjects |
853
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EEA total number of subjects |
366
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
804
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From 65 to 84 years |
45
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85 years and over |
4
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Recruitment
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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
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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
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Investigator, Assessor, Carer, Data analyst, Subject, Monitor | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Smecta®
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Diosmectite consisted of powder for suspension for oral use. Each sachet contained 3 grams diosmectite as active substance.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Oral use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Diosmectite
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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
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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). | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Diosmectite
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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
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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). |
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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).
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End point type |
Primary
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End point timeframe |
From randomisation (Day 1) up to Day 9
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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%).
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Comparison groups |
Diosmectite v Placebo
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Number of subjects included in analysis |
853
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.2524 | ||||||||||||
Method |
Wilcoxon-Gehan test | ||||||||||||
Confidence interval |
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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. |
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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).
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End point type |
Secondary
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End point timeframe |
From randomisation (Day 1) up to Day 9
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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.
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Comparison groups |
Diosmectite v Placebo
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Number of subjects included in analysis |
852
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.3511 | ||||||||||||
Method |
Gehan-Wilcoxon test | ||||||||||||
Confidence interval |
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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).
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End point type |
Secondary
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End point timeframe |
From randomisation (Day 1) up to Day 9
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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.
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Comparison groups |
Diosmectite v Placebo
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Number of subjects included in analysis |
852
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.7285 | ||||||||||||
Method |
Gehan-Wilcoxon test | ||||||||||||
Confidence interval |
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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).
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End point type |
Secondary
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End point timeframe |
From randomisation (Day 1) up to Day 9
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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.
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Comparison groups |
Diosmectite v Placebo
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Number of subjects included in analysis |
853
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1807 | ||||||||||||
Method |
Gehan-Wilcoxon test | ||||||||||||
Confidence interval |
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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).
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End point type |
Secondary
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End point timeframe |
From randomisation (Day 1) up to Day 9
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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.
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Comparison groups |
Diosmectite v Placebo
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Number of subjects included in analysis |
825
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.4294 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Least Squares (LS) Mean Difference | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-0.04
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.15 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
upper limit |
0.07 |
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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).
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End point type |
Secondary
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End point timeframe |
From randomisation (Day 1) up to Day 9
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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.
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Comparison groups |
Diosmectite v Placebo
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Number of subjects included in analysis |
825
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.0465 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-0.12
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.24 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
upper limit |
0 |
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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.
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End point type |
Secondary
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End point timeframe |
From randomisation (Day 1) up to Day 9
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
From randomisation (Day 1) up to Day 9
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No statistical analyses for this end point |
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Adverse events information
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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.
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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.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
Diosmectite
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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
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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). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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07 Jan 2019 |
- Update of targeted countries for participant's recruitment;
- Prolongation of study duration;
- Update of exclusion criteria #21. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |