Clinical trial NCT02704091
Conditions: Acute Diarrhoea
Sponsor: Ipsen
Start date: 2016-03-17; Completion date: 2019-04-08
Enrollment: 858 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to demonstrate that diosmectite efficacy is superior to placebo regarding time to recovery of an acute diarrhoea episode presumed of infectious origin in adult subjects.

Detailed description:

Arms: arm 1: 2 sachets, three times a day (TID), during 5 to 9 days arm 2: 2 sachets of placebo, TID, during 5 to 9 days
Interventions: intervention 1: Smecta intervention 2: Smecta placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
IPSEN GROUP 
F-FR-00250-105 
 
CONFIDENTIAL 
 
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PROTOCOL TITLE: EFFICACY OF DIOSMECTITE (SMECTA®) IN THE 
SYMPTOMATIC TREATMENT OF ACUTE DIARRHOEA IN ADULTS. A 
MULTICENTRE, RANDOMISED, DOUBLE BLIND, PLACEBO-CONTROLLED, 
PARALLEL GROUPS STUDY 
 
STUDY PROTOCOL 
 
STUDY number: F-FR-00250-105 
 
(Diosmectite- BN 00250) 
EudraCT number: n° 2015-001138-10 
 
Final Version (with Amendment No. 4): 07 January 2019 
 
 
Sponsor’s Medically Responsible Person: 
Study Sponsor: 
 
Ipsen Pharma SAS 
  
65 quai Georges Gorse 
Ipsen Pharma SAS 
92100 Boulogne-Billancourt, France 
65 quai Georges Gorse 
Tel: 
 
92100 Boulogne-Billancourt, France 
Fax: 
 
Tel: 
 
 
Fax: 
 
 
 
Monitoring Office: and/or CRO  
Co-ordinating Investigator: 
 
 
 
Délégation à la Recherche 
Ipsen Pharma SAS 
Centre Hospitalier Régional Universitaire  
65 quai Georges Gorse 
de Lille 
92100 Boulogne-Billancourt, France 
2, avenue Oscar Lambret,  
Tel: 
 
59037 Lille, France Cedex 
Fax: 
 
Tel: 
 
 
Fax: 
 
Pharmacovigilance/Emergency Contact: 
 Ipsen Innovation,  
ZI de Courtaboeuf - 5 avenue du Canada - 91940 Les Ulis - France 
Tel: 
  
Tel: 
 – 
 
For SAEs reporting: 
Fax: 
 
Email: 
 
 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation. 
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INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol F-FR-00250-105 entitled Efficacy of the 
diosmectite (Smecta®) in the symptomatic treatment of acute diarrhoea in adults. A 
multicentre, randomised, double blind, placebo-controlled, parallel groups study. I 
am aware of my responsibilities as an investigator under the guidelines of Good 
Clinical Practice (GCP), local regulations (as applicable) and the study protocol. I 
agree to conduct the study according to these guidelines and to appropriately direct 
and assist the staff under my control, who will be involved in the study. 
 
NAME: [ ] 
TITLE: 
INVESTIGATOR 
SIGNATURE: 
 
 
 
 
DATE: 
OFFICE: [ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
Sponsor's Representative Signature: 
NAME: 
 
 
TITLE: 
 
 
SIGNATURE: 
 
 
DATE: 
OFFICE: Ipsen Pharma SAS 
 
Medical Department 
 
65 quai Georges Gorse  
 
92100 Boulogne-Billancourt, France 
 
Tel: 
 
 
Fax: 
 
PPD
PPD
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COORDINATING INVESTIGATOR’S AGREEMENT 
 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol F-FR-00250-105 entitled Efficacy of the 
diosmectite (Smecta®) in the symptomatic treatment of acute diarrhoea in adults. A 
multicentre, randomised, double blind, placebo-controlled, parallel groups study. I 
am aware of my responsibilities as a coordinating investigator under the guidelines 
of Good Clinical Practice (GCP), local regulations (as applicable) and the study 
protocol. I agree to conduct the study according to these guidelines and to 
appropriately direct and assist the staff under my control, who will be involved in 
the study. 
 
NAME: 
 
TITLE: 
COORDINATING 
SIGNATURE: 
 
INVESTIGATOR 
 
 
DATE: 
OFFICE: Délégation à la Recherche 
 
Centre Hospitalier Régional Universitaire de Lille 
 
2, avenue Oscar Lambret 
 
59037 Lille 
 
France Cedex 
 
PPD


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SUMMARY OF CHANGES 
The current version of the protocol was released on 07 January 2019 and includes 
Amendment 4. The corresponding amendment form was prepared and is provided in 
Appendix 6 (Table 1). 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
25 January 2016 
Appendix 4 
2 
10 March 2016 
Appendix 5 
3 
08 August 2017 
Appendix 6 
4 
07 January 2019 
Appendix 7 
 


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SYNOPSIS 
 
NAME OF SPONSOR/COMPANY: IPSEN PHARMA SAS 
Name of finished product: SMECTA® 
Name of active ingredient(s): Diosmectite- BN 00250 
 
Title of study: EFFICACY OF DIOSMECTITE (SMECTA) IN THE SYMPTOMATIC 
TREATMENT OF ACUTE DIARRHOEA IN ADULTS. 
A MULTICENTRE, RANDOMISED, DOUBLE BLIND, PLACEBO-CONTROLLED, PARALLEL 
GROUPS STUDY. 
Study number: F-FR-00250-105 
Number of planned centres: 90 centres in 6 countries, including Algeria, Czech Republic, 
Poland, Tunisia, Lebanon and Egypt. 
Planned study period: 
December 2015 to September 2019 
Phase of development: 
Phase IV  
Objectives: 
Primary:  
• 
To demonstrate that diosmectite efficacy is superior to placebo regarding 
time to recovery of an acute diarrhoea episode presumed of infectious 
origin in adult subjects. 
Secondary:  
• 
To demonstrate that diosmectite efficacy is superior to placebo regarding 
other efficacy criteria. 
• 
To assess the clinical tolerance of diosmectite versus placebo. 
Methodology:  
The study is a multicentre, prospective, double blind, placebo-controlled randomised 
comparative study. Efficacy and safety of diosmectite (administered at a dose and treatment 
regimen in line with the Diosmectite Beaufour Summary of Product Characteristics (SmPC) 
approved in France (the daily dosage can be doubled at the beginning of treatment for acute 
episode), i.e. 2 sachets containing 3 g of diosmectite each, three times a day (TID), a 
minimum of 24 sachets to be taken in 4 or 5 days and with a maximum of 48 sachets to be 
taken in 8 or 9 days) will be evaluated  in adult subjects with a recent episode of acute 
diarrhoea presumed of infectious origin.  
Therapeutic schema: 
Two sachets (TID): 6 sachets per day (active or placebo): 
• 
From Day 1 to Day 4 or Day 5:  
- 
Mandatory treatment period = 24 sachets. 
• 
From Day 5 to Day 8 or Day 9: 
- 
If one formed stool is followed by a nonwatery stool, i.e. recovery, the 
treatment is stopped. 
- 
In any case, treatment stops after a maximum of 48 sachets have been 
taken  


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At Visit 1, subjects will be blindly randomised to one of the two treatment groups (either 
active or placebo according to the randomisation list). Each randomised subject will receive 
a treatment box containing 48 sachets. 
The treatment can be stopped after 4 days in case of 1 formed stool followed by a 
nonwatery stool. At Visit 2 (Day 5 or Day 6), a physical examination will be performed and 
safety will be assessed.  
In case the subject has not recovered from diarrhoea at Visit 2, he/she will prolong the 
treatment with a maximum of 48 sachets up to Day 8 or Day 9 at the latest. For these 
subjects only, a third visit (Visit 3; Day 9 or Day 10) is planned.  
Number of subjects planned:  
A total of 726 assessable subjects are planned to be included in the study. 
As it is assumed 5% subjects withdrawn without recovery and a maximum of 10% 
nonevaluable subjects, 854 subjects (427 per treatment group) will have to be randomised 
in order to achieve an 80% power. 
Diagnosis and criteria for inclusion: 
Inclusion criteria: 
(1) 
Provision of written informed consent prior to any study related 
procedures, 
(2) 
male or female subject (outpatient) legally considered as an adult (age of 
majority). In Czech Republic the upper limit of age will be 70 years 
inclusive. 
(3) 
subject has a diagnosis of acute diarrhoea presumed of infectious origin, 
defined as:  
- 
the passage of 3 or more unformed loose or watery stools (rated  
 
according to the Bristol scale) per day without associated alarm  
 
symptoms*  
- 
having started within 48 hours before Visit 1 (first study  
drug 
intake time).  
(4) 
subject has, usually, normal bowel habits (Rome III criteria)** ,  i.e. at least 
3 stools per week and no more than 3 stools per day, 
(5) 
subject must be willing and able to comply with study restrictions and 
willing to return to the clinic for the follow up evaluation(s) as specified in 
the protocol. 
*Symptoms considered as alarm symptoms are identified in the exclusion criteria (1) 
** Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. 
Functional Bowel Disorders. Gastroenterology 2006;131:1480–91. 
 
Exclusion criteria: 
Exclusion criteria related to acute diarrhoea episode: 
(1) 
At least one of the following alarm symptoms*  
• 
Bloody diarrhoea*, 
• 
pus in the stools*, 
• 
fever 38.0°C*, 


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• 
moderate or severe dehydration according to World Health 
Organisation 
(WHO) 
definition, 
requiring 
intravenous 
(IV) 
rehydration*, 
• 
repeated vomiting*, 
• 
persistent abdominal pain* 
*These symptoms are considered as alarm symptoms 
(2) 
other episode of acute watery diarrhoea within the previous 30 days, 
(3) 
persistent diarrhoea, defined as acutely starting episode of diarrhoea lasting 
more than 14 days, 
(4) 
history of chronic diarrhoea (Rome III criteria); i.e. 3 or more loose or 
watery stools per day for at least 12 weeks, consecutive or not, in the 
preceding 12 months, 
(5) 
traveller’s diarrhoea defined as a diarrhoeal episode due to contamination 
experienced by subjects having travelled in at risk countries, or coming 
from abroad and experiencing locally an acute diarrhoea episode, occurring 
usually within the first 2 weeks of the stay in a foreign environment.  
Exclusion criteria related to drugs: 
(6) 
Diarrhoea suspected to be induced by drug, for example: 
• 
antibiotic therapy, including Clostridium difficile-induced diarrhoea, 
within 1 week before entry in the study, 
• 
laxative agent, 
• 
thyroid hormone (at a nonstabilised dosing), 
• 
colchicine intake, etc…  
(7) 
anti-diarrhoeal agent intake during the last month,  
(8) 
any subject requiring repeated intake of a drug with a narrow therapeutic 
margin (for example, digoxin, theophylline, etc…), 
(9) 
history of hypersensitivity to diosmectite or its excipients or placebo 
components, 
(10) subject likely to require treatment during the study with drugs that are not 
permitted by the study protocol (for example, antibiotic agent, anti-
diarrhoeal agent, antiemetic drug, antispasmodic drug), 
(11) use of any investigational medication within the last 30 days before 
entering this study,  
(12) subject who previously entered in a clinical study within the past 30 days.  
 
Other Digestive Exclusion criteria: 
(13) History of gastric or intestinal resection, vagotomy, 
(14) known digestive malabsorption disease, including coeliac disease 
(15) known lactose intolerance, 
(16) any suspicion of abdominal surgery need, 
(17) known inflammatory bowel disease. 
 
Other Exclusion criteria: 
(18) Known Human immunodeficiency virus (HIV) positive status, 


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(19) known or suspected immunosuppression, 
(20) known severe renal or hepatic insufficiency, 
(21) Uncontrolled diabetes of all types and non insulin dependant diabetes 
during first 6 months of medical treatment and other known endocrine 
disease, 
(22) history of, or known current, problems with alcohol abuse and/or known 
drug addiction (cocaine, heroin, hashish…), 
(23) previous enrolment in this study,  
(24) any mental condition rendering the subject unable to understand the nature, 
scope and possible consequences of the study, and/or evidence of an 
uncooperative attitude. 
(25) Pregnant or lactating women 
Test product, dose, mode of administration: 
The test product consists of sachet of powder for suspension for oral use containing 3 g of 
diosmectite. 
 
Diosmectite will be presented in sachets according to the following composition: 
• 
active substance: 
- diosmectite: 3 g 
• 
other components: 
- vanillin, saccharin sodium and glucose monohydrate. 
Each sachet will be mixed with water prior to administration 
The regimen below will be 2 sachets TID: 
• 
2 sachets in the morning, 
• 
2 sachets at mid-day, 
• 
2 sachets in the evening.  
Duration of treatment: 
This study will consist of an inclusion visit, i.e. Visit 1 (the subject will be randomised and 
start treatment that day) and a 4- to 9-day day dosing period. Subjects are expected to take 
the study treatment in this study with a minimum of 24 sachets to be taken in 4 days or 5 
days and with a maximum of 48 sachets to be taken in 8 or 9 days.  Visit 2 will be on Day 5 
or Day 6 and Visit 3 will be on Day 9 or Day 10. 
The subject’s participation in the study will be considered to have ended when the subject 
will have recovered from diarrhoea, defined as one formed stool followed by a nonwatery 
stool and when the last follow-up visit is performed. 
The overall duration of the study for each subject will be 5 to 6 days (if subject has 
recovered by Visit 2) or 9 to 10 days (duration of study treatment can be from 4 to 9 days). 
Reference therapy, dose and mode of administration:  
Placebo: 
Placebo will be presented in sachets according to the following composition: 
• 
titan dioxide, Spray dried liquid glucose, vanillin, saccharin sodium, glucose 
monohydrate, 


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• 
caramel colouring E 150 B. 
 
The regimen will be the same as for the active treatment. 
Criteria for evaluation: 
Efficacy: 
Primary endpoint and evaluation: time to recovery, defined as the time (hours, minutes) 
from the 1st study treatment intake to the first formed stool (this formed stool must have 
been followed by a nonwatery stool). Consistency will be rated according to the Bristol 
scale. 
Secondary endpoints and evaluations: 
(a) 
abdominal pain intensity (rated with a 5-point ordinal scale: 0 = absent, 1= 
mild, 2 =moderate, 3 = severe, 4= very severe) per 12-hour period, 
(b) 
time (hours, minutes) from diarrhoea onset to recovery defined as first 
formed stool followed by a nonwatery stool 
(c) 
time (hours, minutes) from first watery stool to the first formed stool 
(d) 
time (hours, minutes) from the 1st study treatment intake to the last watery 
stool, 
(e) 
number of stools, per 12-hour period, 
(f) 
number of watery stools, per 12-hour period,  
(g) 
Percentage of subjects with associated symptoms such as nausea, vomiting, 
abdominal pain and anal irritation, per 12-hour period. 
 
Safety: 
Occurrence of adverse events (AEs) reported by the subject from the time that the subject 
gives informed consent until 7 days after the end of the study treatment. Vital signs (blood 
pressure, heart rate in sitting position, respiratory rate, body temperature and body weight) 
measurement at each visit, physical examination findings and measurements, at each visit, 
body height (at Visit 1 only), concomitant medication usage throughout the study. 
 
Microbiological Tests: 
A fresh stool will be collected as soon as possible after inclusion for microbiological 
laboratory testing (for virology, bacteriology and parasitology testing) in order to determine 
the microbiological status of this acute diarrhoea episode , i.e. the absence/presence of the 
following faecal pathogens: 
 
Virology testing 
• 
rotavirus, 
• 
adenovirus, 
• 
norovirus, 
Bacteriology and parasitology testing 
• 
enteropathogenic and enterotoxigenic Escherichia coli (E. coli), 
• 
staphylococcus aureus, 


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• 
shigella, 
• 
salmonella, 
• 
campylobacter, 
• 
yersinia enterocolitica, 
• 
amoeibiasis (entamoeba histolytica), 
• 
giardia/lamblia. 
 
Statistical Methods: 
Sample size rationale: 
Assuming a median time to recovery of 55 hours in the active group and 70 hours in the 
placebo group (corresponding to a difference of 15 hours as evidenced in the Khediri et al 
study [Gastroenterology Research and Practice, Volume 2011, Article ID 783196, 
http://dx.doi.org/10.1155/2011/783196]), 363 subjects per treatment group (726 in total) 
will be required in order to detect such a difference using a two-sided Gehan-Wilcoxon test 
at a significance level of 5% and a power of 80%.  
It is assumed a maximum of 5% of subjects prematurely withdrawn without recovery and a 
maximum of 10% of nonevaluable subjects (because of poor/incomplete diary completion). 
Accordingly, 854 subjects (427 per treatment group) will be required in order to achieve an 
80% power.  
 
Planned Statistical analyses: 
Populations: 
Following study populations will be defined: 
• 
Intent to treat (ITT) population: all randomised subjects analysed according to the 
arm to which they were randomised.  
• 
Safety population: all randomised subjects with at least one dose of study 
medication analysed according to the actual treatment received.  
• 
Modified Intent to treat (mITT) population: all randomised subjects who received at 
least one dose of study medication and have at least one efficacy assessment for the 
primary endpoint***. Subjects will be analysed according to the arm to which they 
were randomised. 
• 
Per protocol (PP) population: all subjects in the mITT population for whom no 
major protocol violations/deviations occurred. 
***The efficacy assessment will be based on the Diary evaluation booklet (DEB), therefore subjects who 
have not filled in the DEB will be excluded from the efficacy analysis. 
 
All efficacy endpoints and subject demographics will be evaluated in the ITT population. 
Treatment administration/compliance and safety will be analysed in the Safety population. 
Supportive analysis using mITT and PP population will be carried out. 
 
Primary endpoint: 
The primary endpoint (time from the 1st treatment dose intake (T0) to recovery defined as 
first formed stool followed by a nonwatery stool, in hours) will be analysed using a time to 
event analysis (Kaplan-Meyer method) and the comparison between the two treatment 
groups will be done using Gehan-Wilcoxon test, as the efficacy of the active product is 


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expected quickly after study intake. In this analysis, subjects prematurely withdrawn or 
ending the study without recovery will be censored. 
Estimated medians and quartiles will be provided with their 95% confidence intervals (CIs), 
leading to a comparison of the time between groups where 25, 50 and 75% of the subjects 
have recovered.  
Descriptive statistics for efficacy evaluation may be provided by country, season, 
absence/presence of faecal pathogens. 
 
Secondary endpoints: 
The secondary endpoints related to time to event (efficacy variables b, c and d) will be 
analysed using the same methodology as for the primary efficacy endpoint. 
Regarding the secondary endpoints based on number of stools per 12-hour period, a 
repeated measurement model of number of stools during the post baseline period will be 
fitted using the analysis of covariance (ANCOVA) method if data warrant. The model will 
include as fixed effects number of stools 24 hours before randomisation (baseline), 
treatment, time point (12-hour period) and the treatment by time point interaction effect. 
The same analysis will be performed for number of watery stools.  
Regarding the efficacy endpoints related to binary data, a general linear mixed model will 
be fitted if data warrant in order to evaluate the treatment effect at each 12-hour period, 
according to the same methodology as described above. 
 
Safety endpoints: 
AEs per treatment group will be described for the Safety population. 
AEs will be coded according to Medical Dictionary for Regulatory Activities (MedDRA) 
and AE listings will be presented by subject, system organ class and preferred term. 
Incidence of all reported AEs/treatment emergent AEs (TEAEs) and SAEs will be tabulated 
by treatment group and overall. In addition, summary tables will be presented by maximum 
intensity, drug relationship and AEs/TEAEs associated with premature withdrawal of study 
medication. 
Concomitant medication will be coded by using WHO Drug Dictionary and will be 
summarised by treatment group and overall with the number and percentage of subjects 
receiving concomitant medication by drug class and preferred drug name. 
Summary statistics (mean, median, SD and range as appropriate) by treatment group and 
overall will be presented for vital signs (blood pressure, heart rate in sitting position, 
respiratory rate, body temperature, body weight), at each assessment with change from 
baseline.  
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 16 
1 
BACKGROUND INFORMATION ............................................................................ 18 
1.1 
Introduction ................................................................................................................... 18 
1.2 
Name and Description of Investigational Medicinal Product ................................... 19 
1.3 
Findings from Nonclinical and Clinical Studies ......................................................... 19 
1.4 
Known and Potential Risks and Benefits to Human Subjects .................................. 20 
1.5 
Selection of Investigational Medicinal Products and Dosages .................................. 21 
1.6 
Compliance Statement .................................................................................................. 21 
1.7 
Population to Be Studied .............................................................................................. 21 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 22 
2.1 
Purpose of the Study ..................................................................................................... 22 
2.2 
Study Objectives ........................................................................................................... 22 
3 
STUDY DESIGN ........................................................................................................... 23 
3.1 
General Design and Study Schema ............................................................................. 23 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 23 
3.2.1 
Primary Efficacy Endpoint and Evaluation .............................................. 23 
3.2.2 
Secondary Efficacy Endpoints and Evaluations ........................................ 24 
3.2.3 
Safety Endpoints and Evaluations ............................................................. 24 
3.3 
Randomisation and Blinding ....................................................................................... 24 
3.4 
Study Treatments and Dosage ..................................................................................... 25 
3.5 
Study Duration .............................................................................................................. 26 
3.6 
Stopping Rules and Discontinuation Criteria ............................................................ 26 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability ......... 26 
3.7.1 
Investigational Medicinal Product Storage and Security .......................... 26 
3.7.2 
Investigational Medicinal Product Preparation ........................................ 26 
3.7.3 
Investigational Medicinal Product Accountability .................................... 26 
3.8 
Maintenance of Randomisation and Blinding ............................................................ 27 
3.9 
Source Data Recorded on the Case Report Form ...................................................... 27 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 29 
4.1 
Inclusion Criteria .......................................................................................................... 29 
4.2 
Exclusion Criteria ......................................................................................................... 29 
4.3 
Subject Withdrawal Criteria and Procedures ........................................................... 30 
5 
STUDY PROCEDURES .............................................................................................. 32 
5.1 
Study Schedule .............................................................................................................. 32 
5.2 
Study Visits .................................................................................................................... 35 
5.2.1 
Visit 1 (Procedures for Enrolment, Day 1) ................................................ 35 
5.2.2 
Visit 2 (follow-up or End of study, Day 5 or Day 6) .................................. 36 


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5.2.3 
Visit 3 (End of study if patient is not recovered at Visit 2, Day 9 or Day 
10) ................................................................................................................ 36 
5.2.4 
Early Withdrawal Visit ................................................................................ 36 
5.2.5 
Diary Evaluation Booklet (DEB) ............................................................... 37 
6 
TREATMENT OF SUBJECTS ................................................................................... 38 
6.1 
Study Drugs Administered ........................................................................................... 38 
6.1.1 
Diosmectite .................................................................................................. 38 
6.1.2 
Placebo ........................................................................................................ 38 
6.2 
Concomitant Medication/Therapy .............................................................................. 38 
6.3 
Procedures for Monitoring Subject Compliance ....................................................... 39 
7 
ASSESSMENT OF EFFICACY .................................................................................. 40 
7.1 
Primary Efficacy Endpoint and Evaluation ............................................................... 40 
7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 40 
7.3 
Microbiological Tests .................................................................................................... 40 
7.4 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 41 
8 
ASSESSMENT OF SAFETY ....................................................................................... 41 
8.1 
Adverse Events .............................................................................................................. 41 
8.1.1 
Definition of an Adverse Event .................................................................. 41 
8.1.2 
Categorisation of Adverse Events ............................................................... 42 
8.1.2.1 
Intensity Classification ................................................................................. 42 
8.1.2.2 
Causality Classification ............................................................................... 42 
8.1.2.3 
Assessment of Expectedness ......................................................................... 42 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 42 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 42 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 42 
8.1.3 
Recording and Follow up of Adverse Events ............................................. 43 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 43 
8.1.5 
Pregnancy .................................................................................................... 44 
8.1.6 
Deaths .......................................................................................................... 45 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 45 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 45 
8.2 
Physical Examination ................................................................................................... 45 
8.3 
Vital Signs ...................................................................................................................... 45 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 46 
10 
STATISTICS ................................................................................................................. 47 
10.1 Analyses Populations .................................................................................................... 47 
10.1.1 
Populations Analysed .................................................................................. 47 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 47 
10.2 Sample Size Determination .......................................................................................... 47 


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10.3 Significance Testing and Estimations ......................................................................... 48 
10.4 Statistical/Analytical Methods ..................................................................................... 48 
10.4.1 
Demographic and Other Baseline Characteristics .................................... 48 
10.4.2 
Homogeneity of Treatment Groups ............................................................ 48 
10.4.3 
Subject Disposition and Withdrawals ......................................................... 48 
10.4.4 
Pharmacokinetic Data ................................................................................ 48 
10.4.5 
Efficacy Evaluation ..................................................................................... 48 
10.4.6 
Adjustment for Country/Centre Effect ....................................................... 50 
10.4.7 
Safety Evaluation ........................................................................................ 50 
10.5 Subgroup Analyses ....................................................................................................... 50 
10.6 Interim Analyses ........................................................................................................... 50 
11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 51 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 52 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................... 52 
12.1.1 
Protocol Amendments ................................................................................. 52 
12.1.2 
Protocol Deviations, Violations, and Exceptions ....................................... 52 
12.2 Information to Study Personnel .................................................................................. 52 
12.3 Study Monitoring .......................................................................................................... 53 
12.4 Audit and Inspection .................................................................................................... 53 
12.5 Data Quality Assurance ................................................................................................ 53 
13 
ETHICS ......................................................................................................................... 54 
13.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 54 
13.2 Informed Consent ......................................................................................................... 54 
13.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 55 
13.4 Confidentiality Regarding Study Subjects ................................................................. 55 
14 
DATA HANDLING AND RECORD KEEPING ....................................................... 56 
14.1 Data Recording of Study Data ..................................................................................... 56 
14.2 Data Management ......................................................................................................... 56 
14.3 Record Archiving and Retention ................................................................................. 57 
15 
FINANCING AND INSURANCE ............................................................................... 58 
15.1 Contractual and Financial Details ............................................................................... 58 
15.2 Insurance, Indemnity and Compensation .................................................................. 58 
16 
REPORTING AND PUBLICATIONS OF RESULTS ............................................. 59 
16.1 Publication Policy ......................................................................................................... 59 
16.2 Clinical Study Report ................................................................................................... 59 
17 
REFERENCES .............................................................................................................. 60 
 


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LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Study Schedule ..................................................................................................... 32 
Table 3 
Chart for Bristol scale ......................................................................................... 34 
 
LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................................ 33 
 


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LIST OF ABBREVIATIONS 
 
ABBREVIATION 
Wording Definition  
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical (ATC) 
CA 
Competent Authorities 
CFR 
Code of Federal Regulations (United States of America) 
CI 
Confidence interval 
CRO 
Contract research organisation 
CSR 
Clinical study report 
DEB 
Diary evaluation booklet 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
ESPGHAN 
European Society for Paediatric Gastroenterology, 
Hepatology and Nutrition 
ESPID 
European Society for Paediatric Infectious Diseases 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
IEC 
Independent ethics committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional review board 
ITT 
Intent to treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to treat 
ORS 
Oral rehydration salts 
PI 
Package Insert 
PP 
Per protocol 
PDD 
Protocol deviation document 


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SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System® 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment emergent adverse event 
TFL 
Tables, figures and listings 
TID 
Three times a day 
TMF 
Trial master file 
US 
United States 
WHO 
World Health Organization 
UNICEF 
United Nations Children’s fund 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Diarrhoea is one of the most frequent conditions around the world. Its acute form is 
among the leading causes of morbidity and mortality in developing countries 
accounting for 5 to 8 million deaths per year in infants and children [1]. In Western 
countries, acute diarrhoea is not a life-threatening disease but is one of the most 
common diagnoses in general practice. The annual rate of diarrhoea illness among 
adults in Western Europe and the United States (US) averages about one episode per 
person per year [1, 2, 3]. The affection is usually self-limited but symptoms can be 
disturbing and incapacitating. It is commonly recognised that its symptoms lead to 
substantial costs for the society as it is estimated that half of the episodes are related 
to missed workdays [4]. Diarrhoea may be acute or chronic, and appropriate therapy 
depends on proper diagnosis. Prevention and treatment of dehydration is the 
cornerstone of patient management for acute diarrhoea, particularly in young 
children and the elderly. However, reducing diarrhoea duration and relief of 
associated symptoms (abdominal pain, cramps from intermittent spasm, distension 
from gas produced by fermentation, discomfort due to the number of bowel 
movements and associated irritation of the perianal region) are also important 
treatment goals.  
The recommended therapeutic regimen is to provide oral rehydration solutions 
(ORS) and to continue food intake. Although ORS effectively mitigates 
dehydration, it has no effect on the duration, severity, or frequency of diarrhoeal 
episodes. Adjuvant therapy with micronutrients, probiotics, or anti-diarrhoeal agents 
may thus be useful [5]. Diosmectite has demonstrated eƥcacy in the treatment of 
acute watery diarrhoea in children. The European Society for Paediatric 
Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society 
for Paediatric Infectious Diseases (ESPID) treatment guidelines consider the use of 
racecadotril, diosmectite, or probiotics as possible adjunctive therapy to ORS. Only 
racecadotril and diosmectite reduce stool output, but no treatment has yet been 
shown to reduce hospitalisation rate or mortality. Appropriate management with 
validated treatments may help reduce the health and economic burden of acute 
diarrhoea in children worldwide [5], and acute gastroenteritis is best managed using 
a few simple, well-defined medical interventions [6]. 
Currently, there is no international consensus for the treatment of acute diarrhoea in 
adults as opposed to children where treatment with diosmectite or racecadotril is 
recommended (ESPGHAN and ESPID treatment guidelines). 
A total of six randomised comparative studies have evaluated the efficacy of 
diosmectite in the treatment of acute diarrhoea in adults. The clinical development 
programme of diosmectite for the symptomatic treatment of diarrhoea has taken 
place over 2 periods. In the early period (up to 2000), the number of patients 
enrolled was usually small and the methodological quality limited.  
In the later period (since 2000), one study initiated by Ipsen [7], has been conducted 
in accordance with contemporary clinical trial methodology and guidelines for the 
assessment of anti-diarrhoeal agents and conformed to a rigorous randomised, 
placebo-controlled, blinded design. This study, considered as pivotal, performed in 
Tunisia in 2005-2006, was a placebo-controlled study in 346 patients using time to 
recovery from diarrhoea as the primary outcome measure. This study showed a 


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significant benefit of diosmectite versus placebo which was of clinical relevance. 
However, the study conducted in Tunisia is the only placebo-controlled study that 
has been conducted for the indication of acute diarrhoea in adults. 
 
 
 
1.2 
Name and Description of Investigational Medicinal Product 
The investigational medicinal product (IMP) is the Diosmectite BEAUFOUR 
product approved in France, which differs only from SMECTA®, a diosmectite 
marketed in more than 73 countries, by the aroma (respectively vanilla versus 
orange and vanilla) known by the main product trade name SMECTA® (French 
approved name) and licenced in more than 73 countries. The investigational 
medicinal product is further referred to in this protocol as diosmectite. References to 
SMECTA® are made in this protocol as Diosmectite BEAUFOUR and SMECTA® 
are considered as similar products. Diosmectite is also known as intergrade smectite 
of beidellitic nature or beidellitic montmorillonite. Diosmectite is a gastrointestinal 
adsorbent mucostabiliser according to the Anatomical Therapeutic Chemical (ATC) 
classification index form. The active substance of diosmectite is dioctahedral 
smectite, a naturally-occurring double silicate of aluminium and magnesium 
belonging to the group of dioctahedral smectites.  
Diosmectite is composed of units made of two silica tetrahedral sheets 
encompassing a central alumina octahedral one. Iron, magnesium and calcium may 
replace aluminium in the alumina octahedral layer, originating negative charges 
inside the sheets. The ionic deficiency is balanced by exchangeable cations between 
the layers [8]. According to the lamellar structure and the ionic properties, 
diosmectite exhibits a high adsorption to the gastrointestinal mucus. Diosmectite 
binds in a noncovalent manner with the mucosal glycoproteins and increases the 
rheological properties of the mucus. As a consequence, the mucus provides a stable 
layer over the luminal surface, reinforcing the mucus barrier to chemical agents and 
micro-organisms [9]. 
A more detailed description of the product is given in Section 3.4. 
1.3 
Findings from Nonclinical and Clinical Studies 
Diosmectite and mineral clays with adsorptive properties have been extensively 
used orally in human medicine. Silicate clays are also used as a bulking or 
opacifying agent, absorbent, emulsion stabiliser, viscosity increasing agent and 
colorant in many cosmetic or noncosmetic products [10]. 
Given the mineral nature, the size of the structure and the close adherence to the 
mucus gel, absorption through the gastrointestinal tract is not expected. Primary 
pharmacodynamic studies were conducted to investigate the local mode of action of 
diosmectite. The objectives of these studies were to characterise the binding of 
diosmectite to mucosal glycoproteins and the protector effect on gastrointestinal 
cells. 
The toxicological profile has been established during the development of 
diosmectite. Oral administration was used in nonclinical studies since it is the 
intended route for clinical administration. Acute studies were conducted in rats and 
mice and repeated dose studies were conducted in rats and dogs. In vivo 
genotoxicity studies were conducted in rats and mice.  
Further details may be found in the current investigator’s brochure (IB). 
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1.4 
Known and Potential Risks and Benefits to Human Subjects 
Data on the safety of diosmectite have been collected from clinical studies involving 
over 3000 subjects and from over 30 years of postmarketing experience. 
Diosmectite appears to be well tolerated and the absence of any obvious systemic 
treatment related side effects can be explained by the fact that systemic exposure to 
this medication is negligible. The most frequently described side effect of 
diosmectite is constipation, which is usually of mild to moderate severity and 
transient. However, cases of severe constipation and aggravation of pre-existing 
constipation have been reported very infrequently from spontaneous reporting. 
Hypersensitivity reactions have also been documented in subjects treated with 
diosmectite through spontaneous reporting. Both constipation and hypersensitivity 
reactions are listed events for diosmectite. 
The benefits of diosmectite in the treatment of acute diarrhoea in adults have been 
demonstrated in a large placebo-controlled randomised clinical trial [7]. In this 
study, the median duration of diarrhoea was reduced by 15 hours in subjects treated 
with diosmectite compared with the placebo group. A reduction in the duration of 
diarrhoea of 15 hours (22%), allowing a more rapid return to normal activity was 
considered as highly clinically relevant. The amplitude of the treatment effect was 
comparable to that previously reported with loperamide, a reference anti-diarrhoeal 
medication, and direct comparative trials have not demonstrated any inferiority of 
diosmectite with respect to loperamide. With regard to improvement in associated 
symptoms, another relevant benefit in this indication, the placebo-controlled study 
did not demonstrate a significant treatment effect, although it was not designed or 
necessarily powered for this variable. 
With respect to risk for the subjects, the safety profile of diosmectite is acceptable in 
the target indications. At last an acute diarrhoea episode in adults without 
concomitant alarm symptoms, according to the selection criteria, is usually self-
resolving and not life-threatening. All subjects should receive recommended 
hydration and diet advice according to WHO guidelines [11]. 
The benefit to risk ratio for diosmectite in the treatment of acute diarrhoea in adults 
can thus be considered favourable for the recruited subjects, therefore the potential 
uncertainties and risks for the subjects included in this new study should be very 
low. 
 
 
 The 
sample size calculation was based upon the assumption that the duration of the 
diarrhoea episode would be shorter than 8 days for the majority of the subjects (it 
was planned 7 days in the previous study) with few expected late censures. The 
definition of recovery (i.e. one formed stool followed by a nonwatery stool); was 
selected to guarantee the clinical relevance of the primary criterion as it was 
confirmed by the evaluation of the results of the Tunisian study by expert clinical 
gastroenterologists and from Health Authorities. However, this is much more 
constraining compared to trials performed in the early period up to 2000, which 
defined recovery as the first nonliquid stool.  
Additional information regarding risks and benefits to human subjects may be found 
in the IB. 
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1.5 
Selection of Investigational Medicinal Products and Dosages 
In this multicentre, prospective, double blind, placebo-controlled randomised 
comparative study, diosmectite or placebo will be administered at a dosing of 2 
sachets three times a day (TID) with a minimum of 24 sachets to be taken in 4 or 5 
days and with a maximum of 48 sachets to be taken in 8 or 9 days in adult subjects 
with a recent episode of acute diarrhoea presumed of infectious origin. The dose and 
treatment regimen are in line with diosmectite Summary of Product Characteristics 
(SmPC) (the daily dosage can be doubled at the beginning of treatment for acute 
episode), rehydration, and special diet. The mandatory amount of sachets to be 
taken is 24 sachets within 4 or 5 days, then up to recovery (one formed stool, 
followed by a nonwatery stool). The treatment will be stopped after 8 or 9 days 
treatment at the latest. 
A more detailed description of administration procedures is given in Section 6.1.  
1.6 
Compliance Statement 
The study will be conducted in compliance with independent ethics 
committees/institutional review boards (IECs/IRBs), informed consent regulations, 
the Declaration of Helsinki and International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) Guidelines. Any episode of noncompliance will be 
documented. 
In addition, the study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable 
opinion 
from 
the 
IEC/IRB 
for 
the 
study 
protocol/amendment(s), written informed consent form, any consent form updates, 
subject emergency study contact cards, subject recruitment procedures (for 
example, advertisements), any written information to be provided to subjects and a 
statement from the IEC/IRB that they comply with GCP requirements. The IEC/IRB 
approval must identify the protocol version as well as the documents reviewed. 
1.7 
Population to Be Studied 
The study will enrol subjects (outpatients) legally considered as adults (age of 
majority) 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 
within the first 48 hours. 


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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
Oral Rehydration Salts are not routinely needed in healthy adults suffering from 
acute diarrhoea, although rehydration through increased intake of normal beverages 
is recommended. No specific recommendations for clinical trials in acute infectious 
diarrhoea in adults have been published since those produced by the Food and Drug 
Administration (FDA), which date from 1977 [12]. Since acute diarrhoea in adults is 
generally self-limiting and rarely life-threatening or associated with critical 
dehydration, rapid resolution of the diarrhoeal episode is the treatment goal. For this 
reason, duration of the diarrhoeal episode rather than stool output is the standard 
outcome variable for studies in adults. Since the risk of dehydration is low, ORS are 
not normally necessary, and experimental medications can be evaluated as the 
primary treatment against placebo. 
Diosmectite has been demonstrated to have several pharmacological properties 
which act clearly in the field of acute watery diarrhoea pathophysiology. A total of 6 
randomised comparative studies have evaluated the efficacy of diosmectite in the 
treatment of acute diarrhoea in adults.  
One pivotal study initiated by Ipsen [7], was conducted for the assessment of anti-
diarrhoeal agents and conformed to a rigorous randomised, placebo-controlled, 
blinded design. This study showed a significant benefit of diosmectite versus 
placebo, which was of clinical relevance.  
 
 
 
 
There is no international consensus for the treatment by an antidiarrheal agent, in 
adult suffering from mild to moderate acute diarrhoea in adults. In addition placebo-
treated subjects are not at risk in the study, owing to the fact that the disease is self-
limiting and because patients with alarm symptoms will be excluded from the study. 
In the absence of alarm symptoms, there is no need for an antimicrobial agent 
(antibiotic). 
 
 
 
. 
2.2 
Study Objectives 
The primary objective of the study is to demonstrate that diosmectite efficacy is 
superior to placebo regarding the time to recovery of an acute diarrhoea episode 
presumed of infectious origin in adult subjects. 
 
The secondary objectives of the study are as follows: 
• 
To demonstrate that diosmectite efficacy is superior to placebo regarding 
other efficacy criteria. 
• 
To assess the clinical tolerance of diosmectite versus placebo  
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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
The study is a multicentre, prospective, double blind, placebo-controlled 
randomised comparative study.  Efficacy and safety of diosmectite (administered at 
a dose and treatment regimen in line with diosmectite Summary of Product 
Characteristics (SmPC) for France (the daily dosage can be doubled at the beginning 
of treatment for acute episode), i.e. 2 sachets TID with a minimum of 24 sachets to 
be taken in 4 or 5 days and with a maximum of 48 sachets to be taken in 8 or 9 
days) will be evaluated in adult subjects with a recent episode of acute diarrhoea 
presumed of infectious origin.  
 
 
 
 
In the previous phase IV study, the calculation of the number of subjects was based 
on a delta hours of 24 hours (difference of median time to recovery between the 
active group and the placebo group), while the delta actually found was 15 hours 
which was considered as clinically relevant.  
The duration of the study treatment in this current study for each subject will be 
from 4 to 9 days. 
At Visit 1, subjects will be randomised to 1 of the 2 treatment groups. Physical 
examination will be performed and a stool sample will be collected for 
microbiological examination. The treatment schema will consist of 2 sachets TID a 
day (i.e. in the morning, mid-day, and in the evening) with a minimum of 24 sachets 
taken within 4 or 5 days. The treatment will start at the investigator’s office.  
Subjects will receive a paper diary (diary evaluation booklet (DEB)) to be 
completed to record each stool and its consistency on a daily basis from inclusion 
until the end of the study. Symptoms such as nausea, vomiting, abdominal pain and 
anal irritation and study treatment intake will also be recorded. The patient will be 
contacted by the investigator or by a dedicated person of the investigator team on a 
daily basis to verify that the DEB is completed by the patient. 
The treatment can be stopped in case of recovery according to the protocol 
definition after intake of 24 sachets within 4 or 5 days. At Visit 2 (Day 5 or Day 6), 
a physical examination will be performed and safety will be assessed.  
In case the subject has not recovered from diarrhoea at Visit 2, he/she will prolong 
the treatment with a maximum of 48 sachets taken up to Day 8 or Day 9 at the 
latest. For these subjects only, a third visit (Visit 3; Day 9 or Day 10) is planned to 
perform a physical examination and assess safety. 
3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Efficacy Endpoint and Evaluation 
The primary efficacy endpoint is the time to recovery, defined as time from the 1st 
study treatment intake recorded in the electronic case report form (eCRF) to the first 
formed stool followed by a nonwatery stool, recorded in the DEB. 
Consistency will be rated according to the Bristol scale [13]. 
 
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3.2.2 
Secondary Efficacy Endpoints and Evaluations 
The secondary endpoints are the following: 
(a) 
abdominal pain intensity (rated with a 5-point ordinal scale: 0 = absent, 1= 
mild, 2 =moderate, 3 = severe, 4= very severe) per 12-hour period, recorded 
in the DEB 
(b) 
time (hours, minutes) from diarrhoea onset to recovery defined as first formed 
stool followed by a nonwatery stool, recorded in the DEB 
(c) 
time (hours, minutes) from first watery stool to the first formed stool, 
recorded in the DEB 
(d) 
time (hours, minutes) from the 1st study treatment intake recorded in the 
eCRF to the last watery stool recorded in the DEB, 
(e) 
number of stools, per 12-hour period, recorded in the DEB 
(f) 
number of watery stools, per 12-hour period, recorded in the DEB 
(g) 
percentage of subjects with associated symptoms such as nausea, vomiting, 
abdominal pain and anal irritation, per 12-hour period, recorded in the DEB*. 
 
*Nausea, vomiting, abdominal pain and anal irritation, per 12-hour period will be 
recorded in the DEB. The percentage of subjects will not be recorded in the DEB. 
3.2.3 
Safety Endpoints and Evaluations 
The safety and tolerability of diosmectite will be assessed throughout the study by 
evaluating adverse events (AEs) recorded from subject from the time that the 
subject gives informed consent until 7 days after the end of the study treatment, vital 
signs measurements, and physical examination results, and concomitant medication 
usage. 
3.3 
Randomisation and Blinding 
The secondary packaging is similar allowing the blinded conditions of the study to 
be maintained. Subjects and investigators will remain blinded to treatment 
assignment during the study. 
 
The sponsor’s randomisation manager who is a statistician independent from the 
study will prepare the master list of randomisation numbers for this study. It will be 
produced in blocks, in a balanced 1:1 ratio. After eligibility is confirmed, at Visit 1 
(Day 1), subjects will be assigned a randomisation number and to the associated 
treatment arm, in sequential order within each centre. 
 
Each subject will be treated with the treatment pack allocated to this randomisation 
number. 
The investigator will under no circumstances change the randomisation number and 
the treatment arm allocated to the subject. 
Recruitment will stop once 854 subjects have been randomised. Randomised 
subjects who terminate their study participation for any reason before starting the 
treatment will retain their randomisation number (the randomisation number will not 
be reused). The next subject is given the next randomisation number.  
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The sponsor’s randomisation manager will keep the master list. A copy of this list 
will be confidentially supplied to the Unit in charge of drug packaging. The master 
list and the copy supplied to the Unit in charge of drug packaging will be kept 
confidential in a secure location. Access to the randomisation list must be restricted 
until authorisation is given to release it for final analysis. 
3.4 
Study Treatments and Dosage 
IMP (active and placebo sachets) is not to be taken at the same time as other 
authorised drugs. A 2-hour period is recommended before or after diosmectite 
intake to avoid any potential interaction (adsorption) issue with other medication. 
The test product, IMP, consists of a powder for suspension for oral use. The subject 
will take 2 sachets TID (in the morning, at mid-day, and in the evening). The first 
intake of IMP will be during the first visit. If the first visit occurs in the afternoon, 
only 4 sachets will be taken at Day 1, if the first visit occurs in the evening, only 2 
sachets will be taken at Day 1. The morning intake can be until 11am, the mid-day 
intake until 6pm, the evening intake after 6pm However, the patient will have to 
take at least 24 sachets before Visit 2 at Day 5 or Day 6. 
A more detailed description of administration procedures for diosmectite is given in 
Section 6.1.1.  
The comparator will be a placebo, consisting of a powder for suspension for oral use 
similar to the investigational product without the active substance. 
A more detailed description of administration procedures for placebo is given in 
Section 6.1.2. 
The IMP will be packaged and delivered to the investigational sites/central or 
interim storage. A sufficient quantity of IMP will be supplied as well as an 
acknowledgement of receipt form. Code break envelopes will also be supplied.  
The sponsor’s representative will receive a Certificate of Analysis for which batch 
of IMP has been used under their study, and the Certificate of Compliance which 
reflects the product release statement.  
The core label texts for all packaging units will be translated or adjusted, to be in 
compliance with applicable regulatory requirements, national laws in force and in 
accordance with the local languages. A description of the core text of the IMP labels 
is displayed below: 
• 
name, address and telephone number of the sponsor, contract research 
organisation (CRO) or investigator (the main contact for information on the 
product, clinical study and emergency unblinding,  
• 
study number, 
• 
pharmaceutical dosage form, 
• 
route of administration, 
• 
quantity of dose units, 
• 
batch number, 
• 
randomisation number, 
• 
“For clinical study use only”, 
• 
storage conditions, 
• 
expiry date, 
• 
patient Number (this information will be completed by the investigator). 
The label content will be adjusted to the different regulatory requirement of each 
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The investigator, or designee, will only dispense IMPs to subjects included in this 
study. Each subject will only be given the IMP carrying his/her number. The 
dispensing for each subject will be documented in the eCRF. 
3.5 
Study Duration 
This study will consist of an inclusion visit, i.e. Visit 1 (the subject will be 
randomised and start treatment that day) and a 4- to 9- day dosing period. In this 
study, subjects are expected to take the study treatment with a minimum of 24 
sachets to be taken in 4 days to 5 days and with a maximum of 48 sachets to be 
taken in 8 or 9 days. Visit 2 will be on Day 5 or Day 6 and Visit 3 will be on Day 9 
or Day 10. 
The subject’s participation in the study will be considered to have ended when the 
subject will have recovered from diarrhoea, defined as one formed stool followed by 
a nonwatery stool and when the last follow-up visit is performed. 
The study will be considered to have started when the first subject has been 
enrolled/ provided signed informed consent.  
3.6 
Stopping Rules and Discontinuation Criteria 
There are no formal rules for early termination of this study. During the conduct of 
the study, serious adverse events (SAEs) will be reviewed (see Section 8.1.4) as 
they are reported from the study centre to identify safety concerns. The study may 
be terminated by the sponsor at any time. 
A subject may discontinue participation in the study at any time for any reason (for 
example, lack of efficacy, withdrawal of consent, AE). The investigator and/or 
sponsor can withdraw a subject from the study at any time for any reason (for 
example, protocol violation or deviation as defined in Section 12.1.2, 
noncompliance with the protocol conditions or AE). 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability 
3.7.1 
Investigational Medicinal Product Storage and Security 
The investigator, or an approved representative (for example, pharmacist), will 
ensure that all IMP and any other study related material is stored in a secured area, 
under recommended temperature monitored storage conditions, in accordance with 
applicable regulatory requirements. 
3.7.2 
Investigational Medicinal Product Preparation 
The investigator, or an approved representative (for example, pharmacist), will 
ensure that all IMP is dispensed by qualified staff members. 
3.7.3 
Investigational Medicinal Product Accountability 
All IMP and any other study related material is to be accounted for on the IMP 
accountability log provided by the sponsor. It is essential that all used and unused 
supplies are retained for verification (by the sponsor or sponsor’s representative). 
The investigator should ensure adequate records are maintained in the IMP 
accountability log. 
The destruction of used and unused IMP (active or placebo) should be carried out 
only after any discrepancies have been investigated and satisfactorily explained and 
the reconciliation has been accepted. The study treatment will be destroyed either at 
site or in the interim storage facility or in a dedicated company that has agreement 


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for the destruction of IMP. In case it is not possible to destroy the IMP in the 
country, the IMP will be sent back to the sponsor for destruction. 
3.8 
Maintenance of Randomisation and Blinding 
Two sets of individual sealed code break envelopes will be prepared by the 
sponsor’s randomisation manager to enable emergency code break procedures for 
individual subjects without compromising the blind of the study. One set will be 
provided to the investigational site and one set will be provided to the Central 
Department of Pharmacovigilance at the sponsor. 
Code break envelopes will only be opened in cases of medical emergency when 
treatment is dependent on knowledge of the IMP received. In the event of an SAE or 
unexpected AE, which requires the identification of the study treatment group, the 
investigator should first contact the Pharmacovigilance Representative outlined in 
the protocol. The investigator should then review the case status and all pertinent 
information 
with 
the 
representative 
from 
the 
Central 
Department 
of 
Pharmacovigilance who will consult with the Therapeutic Area Drug Safety 
physician prior to any code break. 
Once it has been determined that knowledge of the treatment code is necessary, the 
investigator will ascertain the subject’s identification number and randomisation 
number, and then break the blind for the subject concerned. The investigator will 
then sign date and provide reason for the code break on the Emergency Code break 
form, and on the code break envelope. Moreover, the investigator is   allowed to 
unblind the trial randomisation code in case of emergency endangering a subject 
without prior consultation with the sponsor. 
Monitors should routinely check the integrity of the envelopes that are stored at the 
study site. They must collect envelopes from the study site prior to study close out 
and ensure that they are all intact. If envelope(s) have been opened at the site or by 
the sponsor’s representative, the monitor must ensure a written explanation is 
clearly documented (opener’s name, dated signature and reason for opening) on the 
visit status page of the eCRF. 
Confirmation of the integrity of all code break envelopes at study completion must 
be documented in the Trial master file (TMF). All sets of the sealed individual 
subject envelopes must be kept in the TMF in the co-ordinating office at study 
completion for proof of integrity. 
3.9 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 Code of Federal 
Regulations (CFR) Part 11. As required by GCP, the sponsor assigned monitor will 
verify, by direct reference to the source documents, that the data required by the 
protocol are accurately reported on the eCRF.  
The source documents must, as a minimum, contain a statement that the subject is 
included in a clinical study, the date that informed consent was obtained prior to 
participation in the study, the identity of the study, diagnosis and eligibility criteria, 
visit dates (with subject status), IMP administration, and any AEs and associated 
concomitant medication. 
As required by ICH GCP Section 6.4.9, if some items are recorded directly on the 
eCRF and are considered as source data, the identification of these data must be 
documented and agreed between the investigator and the sponsor. 
Definition for source data and source documents are given below: 


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• 
Source Data: All original records and certified copies of original records of 
clinical findings, observations, or other activities necessary for the 
reconstruction and evaluation of the study. Source data are contained in 
source documents (original records or certified copies). 
• 
Source Documents: Original documents, data and records (for example, 
hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x rays, subject files, and records kept 
at the pharmacy, at the laboratories and at medicotechnical departments 
involved in the clinical study). 
The subject must have consented to their medical records being viewed by the 
sponsor’s authorised personnel, and by local, and possibly foreign, Competent 
Authorities (CAs). This information is included in the informed consent. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
All subjects must fulfil all of following criteria to be included in the study: 
(1) 
Provision of written informed consent prior to any study related procedures, 
(2) 
male or female subject (outpatient) legally considered as an adult (age of 
majority). In Czech Republic the upper limit of age will be 70 years inclusive. 
(3) 
subject has a diagnosis of acute diarrhoea presumed of infectious origin, 
defined as:  
 
- 
the passage of 3 or more unformed loose or watery stools (rated 
 
 
according to the Bristol scale) per day without associated alarm 
 
 
symptoms*  
 
- 
having started within 48 hours before Visit 1 
(first study 
drug intake time).  
(4) 
subject has, usually, normal bowel habits, (Rome III criteria) ** , i.e. at least 
3 stools per week and no more than 3 stools per day, 
(5) 
subject must be willing and able to comply with study restrictions and willing 
to return to the clinic for the follow up evaluation(s) as specified in the 
protocol. 
*Symptoms considered as alarm symptoms are identified in the exclusion criteria (1) 
**Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. 
Functional Bowel Disorders. Gastroenterology 2006; 131:1480–91. 
 
4.2 
Exclusion Criteria 
Subjects will not be included in the study if they meet: 
• 
Exclusion criteria related to the acute diarrhoea episode: 
(1) 
At least one of the following alarm symptoms*  
• 
bloody diarrhoea*, 
• 
pus in the stools*, 
• 
fever 38.0°C*, 
• 
moderate or severe dehydration according to World Health Organisation 
(WHO) definition, requiring intravenous (IV) rehydration*, 
• 
repeated vomiting* 
• 
persistent abdominal pain* 
*These symptoms are considered as alarm symptoms 
(2) 
other episode of acute watery diarrhoea within the previous 30 days, 
(3) 
persistent diarrhoea, defined as acutely starting episode of diarrhoea lasting 
more than 14 days, 
(4) 
history of chronic diarrhoea (Rome III criteria); i.e. 3 or more loose or watery 
stools per day for at least 12 weeks, consecutive or not, in the preceding 12 
months, 
(5) 
traveller’s diarrhoea defined as a diarrhoeal episode due to contamination 
experienced by subjects having travelled in at risk countries, or coming from 
abroad and experiencing locally an acute diarrhoea episode, occurring usually 
within the first 2 weeks of the stay in a foreign environment.  
 


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• 
Exclusion criteria related to drugs: 
(6) 
Diarrhoea suspected to be induced by drug for example: 
• 
antibiotic therapy, including Clostridium difficile-induced diarrhoea, 
within 1 week before entry in the study, 
• 
laxative agent 
• 
thyroid hormone (at a nonstabilised dosing), 
• 
colchicine intake, etc… (See Appendix 1) 
(7) 
anti-diarrhoeal agent intake during the last month,  
(8) 
any subject requiring repeated intake of a drug with a narrow therapeutic 
margin (for example, digoxin, theophylline, etc…) (See Appendix 2), 
(9) 
history of hypersensitivity to diosmectite or its excipients or placebo 
components, 
(10) subject likely to require treatment during the study with drugs that are not 
permitted by the study protocol (for example, antibiotic agent, anti-diarrhoeal 
agent, antiemetic drug, antispasmodic drug), 
(11) use of any investigational medication within the last 30 days before entering 
this study,  
(12) subject who previously entered in a clinical study within the past 30 days.  
 
• 
Other digestive exclusion criteria: 
(13) History of gastric or intestinal resection, vagotomy, 
(14) known digestive malabsorption disease, including coeliac disease 
(15) known lactose intolerance, 
(16) any suspicion of abdominal surgery need, 
(17) known inflammatory bowel disease. 
• 
Other exclusion criteria: 
(18) Known Human immunodeficiency virus (HIV) positive status, 
(19) known or suspected immunosuppression, 
(20) known severe renal or hepatic insufficiency, 
(21) Uncontrolled diabetes of all types and non insulin dependant diabetes during 
first 6 months of medical treatment and other known endocrine disease, 
(22) history of, or known current, problems with alcohol abuse and/or known drug 
addiction (cocaine, heroin, hashish…), 
(23) previous enrolment in this study,  
(24) any mental condition rendering the subject unable to understand the nature, 
scope and possible consequences of the study, and/or evidence of an 
uncooperative attitude, 
(25) Pregnant or lactating women. 
 
4.3 
Subject Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable 
country’s acceptance), each subject is free to withdraw from the study at any time 
and for any reason. The investigator and/or subject will be asked to perform/attend a 
final visit at any time in case of withdrawal, whatever the reason. The investigator 
also has the right to withdraw a subject from the study in the event of concurrent 
illness, AEs, or other reasons concerning the health or well-being of the subject, or 
in the case of lack of cooperation. In addition, a subject may be withdrawn from the 


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study as described in Section 3.6. Should a subject decide to withdraw from the 
study after administration of IMP, or should the investigator decide to withdraw the 
subject, all efforts will be made to complete and report the observations up to the 
time of withdrawal as thoroughly as possible. A complete final evaluation at the 
time of the subject’s withdrawal should be made (see Section 5.2.4) and an 
explanation given of why the subject is withdrawing or being withdrawn from the 
study. 
The reason for and date of withdrawal from the study must be recorded on the 
eCRF. If a subject withdraws consent, every attempt will be made to determine the 
reason. If the reason for withdrawal is an AE or a clinically significant laboratory 
test abnormality, monitoring will continue until the event has resolved or stabilised, 
until the subject is referred to the care of a local health care professional, or until a 
determination of a cause unrelated to the IMP or study procedure is made. The 
specific AE or test result(s) must be recorded on the eCRF. All evaluations should 
be performed, according to the protocol, on the last day the subject receives IMP, or 
as soon as possible thereafter. 


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5 
STUDY PROCEDURES 
5.1 
Study Schedule 
Table 2 
Study Schedule 
Visit (Day) 
Visit 1 
Visit 2 (Day 5 
or 6) 
Visit 3 (Day 
9 or 10) 
Early withdrawal 
Informed Consent 
X 
 
 
 
Demographic Data 
X 
 
 
 
History of current acute 
diarrhoea episode 
X 
 
 
 
Medical 
and 
surgical 
history 
X 
 
 
 
Prior and concomitant 
medications for acute 
diarrhoea episode 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
Eligibility criteria 
X 
 
 
 
Randomisation 
X 
 
 
 
Study 
drug 
administration 
X[a] 
X[b] 
X[c] 
X 
Patient 
diary 
(DEB) 
delivery/verification/coll
ection 
X 
X 
X 
X 
Visit status 
X 
X 
X 
X 
Concomitant/surgical 
procedures 
 
X 
X 
X 
Adverse events 
X 
X 
X[d] 
X 
Prior and Concomitant 
Medications/ Non drug 
Therapies 
excluding 
those taken for acute 
diarrhoea episode 
X[e] 
X 
X 
X 
Faecal 
sampling 
and 
results for microbiology 
analysis 
X[f] 
 
X[g] 
 
 
Faecal virological results 
 
X 
 
 
a 
The first treatment must be taken during Visit 1. It will be taken in the morning, mid-day or in the 
evening depending on the time of Visit 1. The morning intake can be until 11am, the mid-day intake 
until 6pm, the evening intake can be after 6pm.  
b 
a minimum of 24 sachets should be taken within 4 or 5 days 
c 
a maximum of 48 sachets should be taken within 8 or 9 days 
d 
reported by the subject until 7 days after the end of the study treatment 
e 
taken within 30 days preceding Visit 1 
f 
A fresh stool will be collected as soon as possible after inclusion 
g 
faecal results will be recorded at Visit 2 


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A summary of the study design is presented in Figure 1. 
Figure 1 Study Design 
 
 


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A summary of the chart for the Bristol scale is presented in Table 3. 
Table 3 
Chart for Bristol scale 
Bristol Scale 
Subject Inclusion 
Subject Recovery 
(first formed stool followed by a nonwatery stool) 
Type 
Diarrhoea (Loose or watery 
stool) 
First formed stool 
Nonwatery stool 
1 
 
X 
X 
2 
X 
X 
3 
X 
X 
4 
X 
X 
5 
 
X 
6 
X 
 
7 
X 
 


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5.2 
Study Visits 
5.2.1 
Visit 1 (Procedures for Enrolment, Day 1) 
A signed and dated informed consent form will be obtained before screening 
procedures. Evaluations obtained as part of routine medical care and performed 
during the screening period may be used in place of the study specific evaluations. 
Subjects will acknowledge and agree to the possible use of this information for the 
study by giving informed consent. 
After informed consent is obtained, at enrolment, subjects will be allocated a subject 
number. All enrolled subjects must be identifiable throughout the study. The 
investigator will maintain a list of subject numbers and names to enable records to 
be found at a later date if required. 
 
Enrolment (Visit 1) will take place within 48 hours after onset of diarrhoea. The 
following assessments will be performed: 
• 
eligibility check (inclusion/exclusion criteria), 
• 
demographic data (date of birth/age and sex will be collected according to 
individual country requirements), 
• 
medical and surgical history, including ongoing medical conditions 
• 
history of the current acute diarrhoea episode including: 
- date and time (hours, minutes) of first watery stool, 
- number of stools including number of watery stools and for each 12h period 
during the last 24 hours, 
- presence of other associated symptoms for the last 24 hours: nausea, 
vomiting, abdominal pain, anal irritation. 
• 
physical examination, 
• 
vital signs (blood pressure and heart rate in sitting position, respiratory rate, 
body temperature, body height and weight), 
• 
one faecal sampling for microbiological examination to be collected as soon 
as possible after inclusion,  
• 
prior and concomitant medications/non-drug therapies (excluding those taken 
for acute diarrhoea episode) taken within 30 days preceding the 
enrolment/inclusion visit, 
• 
prior and concomitant medications for acute diarrhoea episode 
Following confirmation of eligibility for the study, subjects will be given a 
randomisation/treatment allocation number and allocated to receive either 
diosmectite or placebo as specified in Section 6.1. 
• 
collection of AEs, 
• 
study treatment unit will be delivered to the subject according to the 
randomisation procedure, 
• 
visit Status will be recorded 
• 
start of treatment at the centre: time of first intake of study treatment  (data to 
be recorded in the eCRF). 
• 
the DEB and information for use will be delivered to the subject. Refer to 
Section 5.2.5 for details to be recorded in DEB 


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Next visit will be performed after at least 24 sachets have been taken (i.e. 4 or 5 
days after the first visit (i.e. Day 5 or Day 6)). 
 
Under no circumstances will subjects be enrolled more than once. 
Each investigator will also maintain a record of all subjects enrolled into the study 
(i.e. who signed the informed consent form). Records up to the time of premature 
termination should be completed. In the event that the subject was not receiving 
IMP, the primary reason will be recorded. 
5.2.2 
Visit 2 (follow-up or End of study, Day 5 or Day 6) 
The following procedures will be performed: 
• 
Adverse events will be reported by subject since the last visit and will be 
collected.  
• 
The Investigator will check in the DEB if clinical data were appropriately 
recorded and if the study drug was appropriately used. 
• 
Any change in the concomitant medication and/or surgical procedures since 
Visit 1 will be checked and recorded in the eCRF.  
• 
A physical examination and body weight measurement will be performed. 
• 
Vital signs (blood pressure, heart rate in sitting position, respiratory rate, 
body temperature and body weight) will be checked. 
• 
Faecal microbiological results will be recorded 
• 
Visit Status will be recorded 
In case of recovery, the study treatment will be stopped. A last visit (Visit 3) will be 
planned at Day 9 or 10 for subjects who did not recover by Visit 2 
5.2.3 
Visit 3 (End of study if patient is not recovered at Visit 2, Day 9 or Day 10) 
• 
Adverse events will be reported by subjects since the last visit and will be 
collected until 7 days after the last treatment intake. 
• 
Any change in the concomitant medication and/or surgical procedures since 
Visit 2 will be checked and recorded in the DEB. 
• 
A physical examination and body weight measurement will be performed. 
• 
Vital signs (blood pressure, heart rate in sitting position, respiratory rate body 
temperature and body weight) will be checked. 
• 
The Investigator will check in the DEB if clinical data were appropriately 
recorded and if the study drug was appropriately used. A copy of the DEB 
will be kept in the subject’s file and the original will be sent to the Sponsor 
(Data Management). 
• 
Visit Status will be recorded 
Treatments units with used and unused sachets will be kept by the investigator. 
5.2.4 
Early Withdrawal Visit 
• 
Adverse events will be reported by subjects since the last visit and will be 
collected until 7 days after the last treatment intake. 
• 
Any change in the concomitant medication and/or surgical procedures since 
the previous visit will be checked and recorded in the DEB. 
• 
A physical examination and body weight measurement will be performed. 
• 
Vital signs (blood pressure, heart rate in sitting position, respiratory rate, 
body temperature and body weight) will be checked. 


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• 
The Investigator will check in the DEB if clinical data were appropriately 
recorded and if the study drug was appropriately used. A copy of the DEB 
will be kept in the subject’s file and the original will be sent to the Sponsor 
(Data Management). 
In case of either: 
- impaired general health condition 
- and/or moderate or severe dehydration 
- and/or fever above 38°C 
- and/or pus or blood in the stool 
- and /or positive microbiological finding for Entamoeba histolytica or 
Giardia/Lamblia or Shigella in stool, the subject will be withdrawn from the study 
and an effective rehydration therapy and/or an anti-parasitic or antibiotic treatment 
will be immediately given accordingly. 
If the subject is discontinued from the study (i.e., ceases participation in the study 
prior to completion of the protocol), the reason will be recorded in the eCRF. 
Withdrawal due to AEs (see Section 8.1.2) should be distinguished from other 
conditions for withdrawal. The investigator will record the reason for study 
discontinuation, provide or arrange for appropriate follow up (if required) for such 
subjects, and document the course of the subject’s condition.  
In all cases, the investigator must ensure the subject receives appropriate medical 
treatment (i.e. need for IV rehydration, and/or antiparasitic, and/or antibiotic 
therapy) and follow up to determine the final outcome if the period of the trial is 
over. 
5.2.5 
Diary Evaluation Booklet (DEB) 
The primary endpoints will be recorded in the DEB. The subject will be asked to 
record in the DEB each day, including at Day 1, the following data until the next 
visit: date, time of onset and consistency of stools (according to the Bristol scale; 
see Appendix 3, presence of symptoms such as nausea, vomiting, abdominal pain, 
anal irritation, and study drug consumption (number of sachets taken each day). See 
also Section 7.4. 
 


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6 
TREATMENT OF SUBJECTS 
6.1 
Study Drugs Administered 
At enrolment, subjects will be allocated a subject number. Following confirmation 
of eligibility for the study, subjects will be allocated to either diosmectite or 
placebo. 
The regimen below will be 2 sachets* TID: 
• 
2 sachets in the morning, 
• 
2 sachets at mid-day, 
• 
2 sachets in the evening. 
*Each sachet to be taken in half a glass of water 
Subjects will receive a box that contains 48 sachets of study medication. 
A minimum of 24 sachets is to be taken within 4 or 5 days and then until recovery 
(with a maximum of 48 sachets taken within 8 or 9 days). The acute diarrhoea 
episode will be considered to have resolved after the subject has passed one formed 
stool followed by a nonwatery stool. 
• 
From Day 1 to Day 4 or Day 5:  
- 
mandatory treatment period = 24 sachets 
• 
From Day 5 to Day 8 or Day 9:  
- 
if one formed stool is followed by a nonwatery stool, i.e. recovery, the 
treatment is stopped, 
- 
in any case, treatment stops after a maximum of 48 sachets have been 
taken 
Each randomised subject will receive a numbered box. The box labels will comprise 
a detachable part on which the box number and protocol number will be written.  
At Visit 1, when the study drug box is given to the subject, the investigator will 
stick the detachable part of the label on a study treatment log. 
6.1.1 
Diosmectite 
Diosmectite consists of sachet of powder for suspension for oral use. 
Diosmectite will be presented in sachets according to the following composition: 
• 
active substance: 
- 
diosmectite: 3 g 
• 
other components: 
- 
vanillin, saccharin sodium and glucose monohydrate 
Each sachet will be mixed with water prior to administration 
6.1.2 
Placebo 
Placebo will be presented in sachets according to the following composition: 
• 
titan dioxide, spray dried liquid glucose, vanillin, saccharin sodium, glucose 
monohydrate, 
• 
caramel colouring E 150 B. 
6.2 
Concomitant Medication/Therapy 
Any prior or concomitant therapy or medication given to a subject within 30 days 
before IMP administration or during IMP administration will be indicated on the 
eCRF. Dose and generic name or tradename will be indicated. 
The following concomitant medications are not permitted during this study: 
• 
Antibiotics 


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• 
Anti-diarrheal agents 
• 
Antiemetic drugs 
• 
Antispasmodic drugs 
All forbidden concomitant medication are listed in Appendix 1 and Appendix 2. 
 
The following hydration and dietary advices will be provided if the subject does not 
have signs of dehydration: 
• have frequent water intake and small meals, throughout the day: 
- intake mixed low fiber foods such as eggs (white mainly), white meats, beef, fish, 
cheese, white rice, potatoes, white bread, pasta, semolina, tapioca, cassava,... 
• avoid canned fruit juices, beverages with sorbitol, alcohol, coffee, tea, or other 
caffeinated beverages, fatty foods, fried meats or fish, high fibre-rich foods such as  
oily seeds (e.g. almonds, peanuts, etc.), fruits, beans, lentils, chickpeas, raw 
vegetables.  
 
In case of mild dehydration, food intake could be started after correction of 
dehydration, using Oral Rehydration Salts (ORS) therapy according to World 
Health 
Organisation 
(WHO)/United 
Nations 
Children’s 
Fund 
(UNICEF) 
recommendation (Clinical management of acute diarrhoea WHO/UNICEF joint 
statement 2004).  
6.3 
Procedures for Monitoring Subject Compliance 
The investigator will be responsible for monitoring subject compliance. The subject 
can be withdrawn from the study at any time if the investigator or the sponsor 
determines that he/she is not in compliance with the study protocol. 
Details of compliance, deviations from the scheduled amount of IMP intake 
regarded as major protocol violations will be detailed in the statistical analysis plan 
(SAP). 
Where a subject is consistently noncompliant with IMP intake they should be 
discontinued from IMP/withdrawn from the study. Please refer to Section 4.3 for the 
criteria for discontinuing the subject from IMP. 


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7 
ASSESSMENT OF EFFICACY 
For the treatment schedule in this study, refer to the schedule in Table 2. For 
characteristics of subject recovery, refer to Table 3. 
7.1 
Primary Efficacy Endpoint and Evaluation 
The primary endpoint will be the time to recovery (hours) defined as the time 
(hours, minutes) from the 1st study treatment intake recorded in the eCRF to the 
first formed stool recorded in the DEB (this formed stool must have been followed 
by a nonwatery stool). Consistency will be rated according to the Bristol scale [13]. 
See Appendix 3 for the Bristol scale. 
7.2 
Secondary Efficacy Endpoints and Evaluations 
The secondary endpoints are: 
• 
abdominal pain intensity (rated with a 5-point ordinal scale: 0 = absent, 1= 
mild, 2 =moderate, 3 = severe, 4= very severe) per 12-hour period, 
• 
time (hours, minutes) from diarrhoea onset to recovery defined as 1st formed 
stool followed by a nonwatery stool, 
• 
time (hours, minutes) from first watery stool to the first formed stool, 
• 
time (hours, minutes) from the 1st study treatment intake to the last watery 
stool, 
• 
number of stools, per 12-hour period, 
• 
number of watery stools, per 12-hour period, 
• 
percentage of subjects with associated symptoms such as nausea, vomiting, 
abdominal pain, and anal irritation, per 12-hour period.  
7.3 
Microbiological Tests 
A fresh stool will be collected as soon as possible after inclusion for microbiological 
laboratory testing (for virology, bacteriology and parasitology testing) in order to 
determine the microbiological status of this acute diarrhoea episode , i.e. the 
absence/presence of the following faecal pathogens: 
 
Virology testing 
• 
rotavirus, 
• 
adenovirus, 
• 
norovirus, 
Bacteriology and parasitology testing 
• 
enteropathogenic and Enterotoxigenic Escherichia Coli (E. coli), 
• 
staphylococcus aureus, 
• 
shigella, 
• 
salmonella, 
• 
campylobacter, 
• 
yersinia enterocolitica, 
• 
amoeibiasis (entamoeba histolytica), 
• 
giardia / lamblia. 
 
Details of the methodology and technical specifications will be provided in the 
laboratory manual located in the Investigator Site File and in the TMF. 


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Laboratory test results provided by the lab will be recorded in the laboratory results 
section of the eCRF by the investigator at Visit 2. 
7.4 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data 
The subject will be asked to complete, each day from Day 1 (day of Visit 1) to the 
end of the treatment visit (Visit 2 (Day 5 or Day 6) or Visit 3(Day 8 or Day 9)), the 
DEB with the following information: 
• 
Stools: 
- 
date and time to onset, 
- 
consistency rated as either watery, loose, formed or hard (according to 
the Bristol scale; see Appendix 3), 
• 
Presence or not of an episode for each 12-hour period: 
- 
nausea, 
- 
vomiting, 
- 
abdominal pain 
- 
anal irritation. 
• 
abdominal pain intensity (rated with a 5-point ordinal scale: 0 = absent, 1= 
mild, 2 =moderate, 3 = severe, 4= very severe)  
• 
Study drug consumption (number of sachets per day) 
Methods for assessing efficacy data are described above in Section 7.1 and Section 
7.2. Timing of efficacy assessments are discussed in Section 5. Procedures for 
recording efficacy data are discussed in Section 14.1, and methods of analysis are 
discussed in Section 10.4.5. 
8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed 
consent and throughout the study until 7 days after the end of study treatment (see 
Section 3.5 for a definition of the study duration) and will be elicited by direct, non-
leading questioning or by spontaneous reports. Further details for AE reporting can 
be found in Section 8.1.2. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. 
An undesirable medical condition can be symptoms (for example, nausea, chest 
pain), signs (for example, tachycardia, enlarged liver) or the abnormal results of an 
investigation (for example, laboratory findings). In clinical studies an AE can 
include an undesirable medical condition occurring at any time, including run in or 
washout periods, even if no IMP has been administered.  
This definition includes events occurring from the time of the subject giving 
informed consent until the end of the study (as defined in Section 3.5). 
Signs and symptoms should not be reported as AEs/SAEs if they are clearly related 
to a relapse or an expected change or progression of the baseline diarrhoea. 
These signs and symptoms should only be reported as AEs/SAEs (depending on the 
investigator’s judgement) if they are: 
• 
Judged by the investigator to be unusually severe or accelerated diarrhoea, or 


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• 
If the investigator considers the deterioration of diarrhoea signs and 
symptoms to be caused directly by the IMP. 
If there is any uncertainty about an AE being due solely to the diarrhoea under 
study, it should be reported as an AE/SAE as appropriate. 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
AEs will be classified as mild, moderate or severe according to the following 
criteria: 
• 
Mild: symptoms do not alter the subject’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but 
are not hazardous, uncomfortable or embarrassing to the subject 
• 
Severe: symptoms definitely hazardous to well-being, significant impairment 
of function or incapacitation. 
8.1.2.2 
Causality Classification 
The relationship of an AE to IMP administration will be classified according to the 
following: 
• 
Related: reports including good reasons and sufficient information (for 
example, plausible time sequence, dose response relationship, pharmacology, 
positive dechallenge and/or rechallenge) to assume a causal relationship with 
IMP administration in the sense that it is plausible, conceivable or likely. 
• 
Not related: reports including good reasons and sufficient information (for 
example, implausible time sequence and/or attributable to concurrent disease 
or other drugs) to rule out a causal relationship with IMP administration. 
8.1.2.3 
Assessment of Expectedness 
The expectedness of an AE shall be determined by the sponsor according to the IB 
for an unapproved IMP, or the SmPC or Package Insert (PI) for an authorised 
medicinal product that is being used according to the terms and conditions of the 
marketing authorisation. If the IMP has marketing authorisations in several 
countries with different SmPCs or PIs, one will be selected as the reference 
document for assessing expectedness. 
The reference document for assessing expectedness of AEs/event in this study will 
be the current IB. 
8.1.2.4 
Laboratory Test Abnormalities 
Not applicable. 
8.1.2.5 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the investigator, in physical 
examination findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the investigator as clinically significant that 
result in a change in IMP dosage or administration schedule, or in discontinuation of 
the IMP, or require intervention or diagnostic evaluation to assess the risk to the 
subject, should be recorded as AEs.  


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8.1.3 
Recording and Follow up of Adverse Events 
At each visit, the subject should be asked a nonleading question such as: “How have 
you felt since starting after the last assessment?” 
All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to IMP, will be recorded on the AE page(s) of the CRF/eCRF. Events 
involving drug reactions, accidents, illnesses with onset during the treatment phase 
of the study, or exacerbation’s of pre-existing illnesses should be recorded. 
Any AEs already recorded and designated as ‘continuing’ should be reviewed at 
each subsequent assessment. 
For all AEs, the investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as a SAE requiring immediate notification to the sponsor or its 
designated representative. For all AEs, sufficient information should be obtained by 
the investigator to determine the causality of the AE (i.e. IMP or other illness). The 
investigator is required to assess causality and record that assessment on the 
CRF/eCRF. Follow up of the AE, after the date of IMP discontinuation, is required 
if the AE or its sequelae persist. Follow up is required until the event or its sequelae 
resolve or stabilise at a level acceptable to the investigator and the sponsor’s clinical 
monitor or his/her designated representative. 
8.1.4 
Reporting of Serious Adverse Events 
All SAEs (as defined below) regardless of treatment group or suspected relationship 
to IMP must be reported immediately (within 24 hours of the investigator’s 
knowledge of the event) to the pharmacovigilance contact specified at the beginning 
of this protocol. If the immediate report is submitted by telephone, this must be 
followed by detailed written reports using the SAE report form. 
A SAE is any AE that: 
(1) 
Results in death. 
(2) 
Is life-threatening, that is any event that places the subject at immediate risk 
of death from the event as it occurred. It does not include an event that, had it 
occurred in a more severe form, might have caused death. 
(3) 
Results in inpatient hospitalisation or prolongation of existing hospitalisation, 
excluding admission for social or administrative reasons (see further). 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a 
substantial disruption of a person’s ability to conduct normal life functions. 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who 
received the IMP. 
(6) 
Is an important medical event that may not result in death, be life threatening, 
or require hospitalisation when, based upon appropriate medical judgement, 
may jeopardise the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not 
result in in-patient hospitalisation, or the development of drug dependency or 
drug abuse. 
In addition to the above criteria, any additional AE that the sponsor or an 
investigator considers serious should be immediately reported to the sponsor and 
included in the corporate SAEs database system. 


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• 
Hospitalisation is defined as any in-patient admission (even if less than 
24 hours). For chronic or long term in-patients, in-patient admission also 
includes transfer within the hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original 
reason for the initial admission, as determined by the investigator or 
treating physician. For protocol-specified hospitalisation in clinical studies, 
prolongation is defined as any extension beyond the length of stay described 
in the protocol. Prolongation in the absence of a precipitating, treatment 
emergent, clinical AE (i.e. not associated with the development of a new AE 
or worsening of a pre-existing condition) may meet criteria for “seriousness” 
but is not an adverse experience and thus is not subject to immediate 
reporting to the sponsor.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the 
subject’s screening documentation. Hospitalisation for a preplanned or 
elective treatment/surgical procedure should not be reported as an SAE unless 
there are complications or sequelae which meet the criteria for seriousness 
described above. 
Any SAE must be reported immediately (within 24 hours), independent of the 
circumstances or suspected cause, if it occurs or comes to the attention of the 
investigator at any time during the study period. 
Any AE/SAE with a suspected causal relationship to IMP administration occurring 
at any other time after completion of the study must be promptly reported. 
The following information is the minimum that must be provided to the sponsor 
pharmacovigilance contact within 24 hours for each SAE: 
• 
Study number 
• 
Centre number 
• 
Subject number 
• 
AE 
• 
Investigator's name and contact details 
The additional information included in the SAE form must be provided to the 
sponsor or representative as soon as it is available. The investigator should always 
provide an assessment of causality for each event reported to the sponsor. Upon 
receipt of the initial report, the sponsor will ask for the investigator's causality 
assessment if it was not provided with the initial report. 
The investigator should report a diagnosis or a syndrome rather than individual 
signs or symptoms. The investigator should also try to separate a primary AE 
considered as the foremost untoward medical occurrence from secondary AEs 
which occurred as complications. 
8.1.5 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP 
has interfered with a contraceptive method. If pregnancy occurs during the study, 
the outcome of the pregnancy will then need to be collected poststudy and it may be 
necessary to discontinue administration of the IMP.  
Information regarding pregnancies must be collected on the adverse event page of 
the eCRF and reported to the sponsor as an SAE. The sponsor will request further 


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information from the investigator as to the course and outcome of the pregnancy 
using the Standard Pregnancy Outcome Report Form. 
8.1.6 
Deaths 
All AEs resulting in death either during the study period or within 7 days after the 
last dose of IMP, must be reported as an SAE within 24 hours of the investigator’s 
knowledge of the event.  
The convention for recording death is as follows:  
• 
adverse event term: lead cause of death, 
• 
outcome: fatal. 
 
The only exception is if the cause of death is unknown (i.e. sudden or unexplained 
death), in which case the AE term may be “death” or “sudden death”. 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the IMP (see 
Section 4.3). 
If the IMP is discontinued due to a SAE, it must be reported immediately to the 
sponsor’s designated representative (see Section 8.1.4). 
In all cases, the investigator must ensure the subject receives appropriate medical 
follow up (see Section 8.1.3). 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports of 
Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring during the 
study to the CA, IECs and other investigators concerned by the IMP. Reporting will 
be done in accordance with the applicable regulatory requirements. 
8.2 
Physical Examination 
Physical examinations, including body weight, will be conducted at Baseline 
(Visit 1), at Visit 2 and at Visit 3 if applicable. Body height will be measured at 
Baseline. 
Any clinically significant physical examination findings (abnormalities) observed 
during the study will be reported as AEs. Any physical examination findings 
(abnormalities) persisting at the end of the study will be followed by the investigator 
until resolution or until reaching a clinically stable endpoint. 
8.3 
Vital Signs 
Blood pressure and heart rate will be assessed with an automated device so that 
measurements are independent of the observer. Blood pressure and heart rate will be 
recorded after five minutes rest in sitting position. Absolute values and change from 
Baseline will be analysed. 
Respiratory rate, body temperature, body height (only at visit 1) and body weight 
will be recorded. 


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9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
Pharmacokinetics is not applicable to this study and pharmacodynamics is not 
assessed in this study. 


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10 
STATISTICS 
10.1 
Analyses Populations 
The following population will be used during statistical analyses: 
a) 
Intent to treat (ITT) population: all randomised subjects analysed 
according to the arm to which they were randomised. 
b) 
Safety population: all randomised subjects with at least one dose of study 
medication analysed according to the actual treatment received 
c) 
Modified Intent to treat (mITT) population: all randomised subjects who 
received at least one dose of study medication and have at least one efficacy 
assessment for the primary endpoint*. Subjects will be analysed according to 
the arm to which they were randomised. 
d) 
Per protocol (PP) population: all subjects in the mITT population for whom 
no major protocol violations/deviations occurred. 
*The efficacy assessment will be based on the DEB; therefore subjects who have 
not filled in the DEB will be excluded from the efficacy analysis 
10.1.1 
Populations Analysed 
The primary analysis based on the primary efficacy endpoints will be evaluated 
based on the ITT population. In addition, analysis will be performed on mITT and 
PP population as secondary. 
Secondary efficacy endpoints as well as demographics characteristics will be 
performed on the ITT population. In addition, analysis will be performed on the PP 
population as secondary.  
The analyses of safety data will be performed on the Safety population. 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses 
Any major protocol deviation will be described in the Protocol Deviation Document 
(PDD) and its impact on inclusion in each analysis population (mITT, PP and Safety 
populations) for any subject will be specified. The final list of protocol deviations 
impacting the mITT and/or PP population will be finalized at latest during the blind 
data review meeting held prior to database lock, before any unblinding of treatment 
groups. The list of major protocol deviations impacting inclusion in the PP 
population will be reviewed during the blind data review meeting held prior to 
database lock and before the unblinding of the treatment groups. The list will be 
updated to include any additional major protocol deviations impacting inclusion in 
the PP population. 
10.2 
Sample Size Determination 
Assuming a median time to recovery of 55 hours in the active group and 70 hours in 
the placebo group (corresponding to a difference of 15 hours as evidenced in the 
Khediri et al study [7], 363 evaluable subjects per treatment group (726 in total) will 
be required in order to detect such a difference using a two-sided Gehan- Wilcoxon 
test at a significance level of 5% and a power of 80%.  
It is assumed a maximum of 5% subjects prematurely withdrawn without recovery 
and a maximum of 10% nonevaluable subjects (because of poor/incomplete diary 
(DEB) completion). 
Accordingly, 854 subjects (427 per treatment group) have to be randomized in order 
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10.3 
Significance Testing and Estimations 
All statistical tests will be performed two-sided with a type I error rate set at (5%). 
For any efficacy endpoints, the 95% confidence interval (CI) of the difference 
between treatment groups will be calculated when appropriate. 
10.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the 
sponsor’s Biometry Department. 
A SAP describing the planned statistical analysis in detail with tables, figures and 
listings (TFLs) templates will be developed as a separate document. 
The SAP will detail the rules and conventions used to compute the derived analysis 
variables and to handle missing data 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® 
(version 9.2 or higher). 
Descriptive statistics will be presented as follows: 
• 
continuous variables: number of observations, number of missing values 
mean, standard deviation (SD), median, percentiles, minimum and maximum, 
• 
dichotomous or categorical variables: frequency and percentage of each of the 
categories. 
No adjustments for multiple testing are planned. 
All study data will be at least presented in listings. 
10.4.1 
Demographic and Other Baseline Characteristics 
In order to ensure balance of treatment groups, descriptive summary statistics (n, 
mean, SD, median, minimum, maximum) or frequency counts of demographic and 
baseline data (medical history, concomitant disease (ongoing medical history, prior 
medications, baseline symptoms, presence/absence of faecal pathogens), season of 
randomisation (summer/winter season), etc…) will be presented by treatment group 
and overall for the ITT population. 
10.4.2 
Homogeneity of Treatment Groups 
Descriptive statistics for demographic and other baseline characteristics will be 
tabulated for each treatment groups, 95% CIs may be calculated for baseline 
characteristics. 
10.4.3 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in populations will 
be tabulated by country. The reasons for subject exclusions from each of the 
populations will also be tabulated. In addition, the numbers of subjects who were 
randomised, discontinued and completed will be tabulated by treatment group. 
Primary reasons for discontinuation of study treatment will be tabulated. 
10.4.4 
Pharmacokinetic Data 
No pharmacokinetic data analysis will be performed. 
10.4.5 
Efficacy Evaluation 
The primary analysis of efficacy data will be performed on the ITT population. 
Additionally, for the main efficacy variable, a supportive analysis using mITT and 
PP populations will be carried out. 


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The primary endpoint (time from the first study treatment intake (T0)) to recovery 
defined as 1st formed stool followed by a nonwatery stool (in hours), will be 
analysed using a time to event methodology.  
Time to event data will be analysed by using survival methods. The results will be 
presented both in summary tables and graphically in Kaplan-Meier plots and the 
estimated medians and quartiles will be provided. 
The comparison between the 2 groups of treatment will be performed using Gehan-
 Wilcoxon test. Subject prematurely withdrawn or ending the study without 
recovery will be censored (not responder). 
Sensitivity analyses will be conducted to further explore the primary efficacy 
endpoint adjusting by country. 
A cox model [14] will be used to assess the impact of other factors like season of 
randomisation, absence/presence of faecal pathogens on the treatment effect.  
 
The analysis regarding secondary efficacy endpoints will be performed on the ITT 
population; supportive analysis using PP population will be carried out. 
The secondary efficacy variables are: 
a) 
Abdominal pain intensity per 12-hour period. 
b) 
Time (hours, minutes) from diarrhoea onset to recovery defined as 1st formed 
stool followed by a nonwatery stool. 
c) 
Time (hours) from first watery stool to the first formed stool. 
d) 
Time (hours) from the 1st study treatment intake to the last watery stool. 
e) 
Number of stools, per 12-hour period. 
f) 
Number of watery stools, per 12-hour period. 
g) 
Percentage of subjects with associated symptoms such as nausea, vomiting, 
abdominal pain and anal irritation, per 12-hour period. 
Missing data of secondary efficacy variables will not be replaced.  
The secondary endpoints related to time to event (efficacy variables b, c and d) will 
be analysed using the same methodology as for the primary efficacy endpoint. 
Regarding the secondary endpoints based on number of stools per 12-hour period, a 
repeated measurement model of number of stools during the post baseline period 
will be fitted using the analysis of covariance (ANCOVA) method if data warrant. 
The model will include as fixed effects number of stools 24 hours before 
randomisation (baseline), treatment, time point (12-hour period) and the treatment 
by time point interaction effect. The residual variance-covariance pattern will be 
fitted using an unstructured matrix. In addition a cumulative number of stools per 
12-hour period will be presented graphically. 
The same analysis will be performed for number of watery stools. The model will 
include, as fixed effects, number of watery stools 24 hours before randomisation, 
treatment, time point (12-hour interval) and the treatment by time point interaction 
effect. 
Regarding the efficacy endpoints related to binary data, a general linear mixed 
model will be fitted if data warrant in order to evaluate the treatment effect at each 
12-hour period, according to the same methodology as described above.  
In addition point estimate will be tabulated by treatment group and overall with their 
corresponding two-sided 95% CIs and when appropriate in terms of mean, SD, 
median and interquartile as well as the range.  
More details will be given in the SAP.  


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10.4.6 
Adjustment for Country/Centre Effect 
Adjustment for country effect will be planned for the analysis of primary efficacy 
by using country as covariates in the cox model. 
10.4.7 
Safety Evaluation 
Safety evaluation will be performed in the Safety population.  
All safety data will be included in the subject data listings. Analyses and summary 
tables will be based upon the Safety population. 
AEs will be coded according to Medical Dictionary for Regulatory Activities 
(MedDRA; current version at time of database lock) and will be classified by 
MedDRA preferred term and system organ class. AE listings will be presented by 
subject, system organ class and preferred term. 
Incidence of all reported AEs/treatment emergent AEs (TEAEs) and SAEs will be 
tabulated by treatment group and overall. In addition, summary tables will be 
presented by maximum intensity, drug relationship and AEs/TEAEs associated with 
premature withdrawal of study medication. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving the first dose of IMP, or  
• 
it was present prior to receiving the first dose of IMP but the intensity 
increased during the active phase of the study, or  
• 
it was present prior to receiving the first dose of IMP, the intensity is the 
same but the drug relationship became related during the active phase of the 
study.  
Treatment emergent AEs will be flagged (*) in the AEs listings. 
Concomitant medication will be coded by using WHO Drug Dictionary and will be 
summarised by treatment group and overall with the number and percentage of 
subjects receiving concomitant medication by drug class and preferred drug name. 
Summary statistics (mean, median, SD and range as appropriate) by treatment group 
and overall will be presented for vital signs (blood pressure, heart rate in sitting 
position, respiratory rate, body weight at each assessment with change from 
Baseline. 
10.5 
Subgroup Analyses 
Descriptive statistics for efficacy evaluation may be provided by country, season, 
absence/presence and type of faecal pathogens. 
Descriptive statistics for safety evaluation will be provided within each category of 
the following variables: 
• 
country, 
• 
season, 
• 
absence/presence and type of faecal pathogens. 
Details of the above will be specified in the SAP. 
10.6 
Interim Analyses 
No interim analysis will be performed. 


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11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
Authorised personnel from external CAs and sponsor authorised Quality Assurance 
personnel may carry out inspections and audits. The purpose of an audit is to ensure 
that ethical, regulatory and quality requirements are fulfilled in all studies performed 
by the sponsor. 
Auditors and inspectors must have direct access to study documents and site 
facilities as specified in Section 12.4, and to any other locations used for the purpose 
of the study in question (for example, laboratories). 
In the event of the site being notified directly of a regulatory inspection, the 
investigator must notify the sponsor’s representative as soon as possible, to assist 
with preparations for the inspection. 


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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Protocol Amendments and Protocol Deviations and Violations 
12.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the 
prior written approval or favourable opinion of a written amendment by the 
IEC/IRB and local Regulatory Authority, except when necessary to eliminate 
immediate safety concerns to the subjects or when the change involves only 
logistics or administration. The principal investigator and the sponsor will sign the 
protocol amendment. 
12.1.2 
Protocol Deviations, Violations, and Exceptions 
A protocol deviation is nonadherence to protocol specific study procedures or 
schedules that does not involve inclusion/exclusion criteria, primary objective 
evaluation criteria, and/or GCP guidelines. Deviations are considered minor and do 
not impact the study. 
A protocol violation is any significant divergence from the protocol, 
i.e. nonadherence on the part of the subject, the investigator, or the sponsor to 
protocol specific inclusion/exclusion criteria, primary objective evaluation criteria, 
and/or GCP guidelines. Protocol violations will be identified and recorded, by study 
centre personnel, on the eCRF. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific 
entry criteria to allow subjects to enter a study. If under extraordinary circumstances 
such action is considered ethically, medically, and scientifically justified for a 
particular subject, prior approval from the sponsor and the responsible IRB/IEC, in 
accordance with the Standard Operating Procedure (SOP), is required before the 
subject will be allowed to enter the study. If investigative centre personnel learn that 
a subject who did not meet protocol eligibility criteria was entered in a study (a 
protocol violation), they must immediately inform the sponsor. Such subjects will 
be discontinued from the study, except in an exceptional instance following review 
and written approval by the sponsor and the responsible IRB/IEC, according to the 
applicable SOP. 
12.2 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff 
members involved in the study or in any element of subject management, both 
before starting any study procedures and during the course of the study (for 
example, when new staff become involved). The investigator must assure that all 
study staff members are qualified by education, experience, and training to perform 
their specific responsibilities. These study staff members must be listed on the study 
centre authorisation form, which includes a clear description of each staff member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, 
including the investigator, and for ensuring their compliance with the protocol. 
Additional information will be made available during the study when new staff 
become involved in the study and as otherwise agreed upon with either the 
investigator or the study monitor. 


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12.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring this data to verify that the rights and well-
being of subjects are protected, that study data are accurate (complete and verifiable 
to source data) and that the study is conducted in compliance with the protocol, 
GCP and regulatory requirements. 
Sponsor assigned monitors will conduct regular site visits. The investigator will 
allow direct access to all relevant files (for all subjects) and clinical study supplies 
(dispensing and storage areas) for the purpose of verifying entries made in the 
eCRF, and assist with the monitor’s activities, if requested. Adequate time and 
space for monitoring visits should be made available by the investigator. 
The site must complete the eCRFs according to the sponsor monitoring manual, of 
the subject’s visit and on an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits. The central study 
monitor at the sponsor will use functions of the Electronic Data Capture (EDC) 
system to address any queries raised while reviewing the data entered by the study 
site personnel in a timely manner. 
Whenever a subject name is revealed on a document required by the sponsor (for 
example, laboratory print outs) the name must be blacked out permanently by the 
site personnel, leaving the initials visible, and annotated with the subject number as 
identification. 
12.4 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality 
Assurance personnel may carry out inspections and audits (see Section 11). 
12.5 
Data Quality Assurance 
Monitored eCRFs transferred from the investigational site to the assigned Data 
Management group will be reviewed (secondary monitoring) for completeness, 
consistency, legibility and protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require 
additional electronic manual queries to be raised to the investigator by the monitor for 
clarification/correction. The investigator must ensure that queries are dealt with 
promptly. All data changes and clarifications can be viewed in the audit trail function 
of the eCRF. 


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13 
ETHICS 
13.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent 
regulations, the Declaration of Helsinki and ICH GCP Guidelines (Section 1.6). 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB and local Regulatory Authority for 
the study protocol/amendment(s), written informed consent form, any consent form 
updates, subject emergency study contact cards, subject recruitment procedures (for 
example, advertisements), any written information to be provided to subjects and a 
statement from the IEC/IRB that they comply with GCP requirements. The IEC/IRB 
and local Regulatory Authority approval must identify the protocol version as well 
as the documents reviewed. 
After IEC/IRB and local Regulatory Authority approval, changes will require a 
formal amendment. Once the study has started, amendments should be made only in 
exceptional circumstances. Changes that do not affect subject safety or data integrity 
are classified as administrative changes and generally do not require ethical 
approval. If ethically or substantially relevant aspects are concerned, the IEC/IRB 
and/or local Regulatory Authority must be informed accordingly and, if necessary, 
approval sought prior to implementation. Ethical approval on administrative 
changes will be obtained if required by local/site IEC/IRB. 
13.2 
Informed Consent 
Prior to study entry, the investigator, or a person designated by the investigator, will 
explain the nature, purpose, benefits and risks of participation in the study to each 
subject, subject’s legally acceptable representative or impartial witness. Written 
informed consent must be obtained prior to the subject entering the study (before 
initiation of any study-related procedure and administration of the IMP). Sufficient 
time will be allowed to discuss any questions raised by the subject. 
The sponsor will provide a sample informed consent form. The final version 
controlled form must be agreed to by the sponsor and the IEC/IRB and must contain 
all elements included in the sample form, in language readily understood by the 
subject. Each subject’s original consent form, personally signed and dated by the 
subject or by the subject’s legally acceptable representative, and by the person who 
conducted the informed consent discussion, will be retained by the investigator. The 
investigator will supply subjects with a copy of their signed informed consent. 
The consent form may need to be revised during the study should important new 
information become available that may be relevant to the safety of the subject or as 
a result of protocol amendments. In this instance approval should always be given 
by the IEC/IRB. It is the investigator’s responsibility to ensure that all subjects 
subsequently entered into the study and those currently in the study sign the 
amended form. This is documented in the same way as previously described. 
Subjects who have completed the study should be informed of any new information 
that may impact on their welfare/well-being. 
The investigator should, with the consent of the subject, inform the subject’s 
primary physician about their participation in the clinical study. 


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13.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s Regulatory Affairs group will ensure 
all legal regulatory aspects are covered, and obtain approval of the appropriate 
regulatory bodies, prior to study initiation in regions where an approval is required. 
13.4 
Confidentiality Regarding Study Subjects 
The investigator must assure that the privacy of the subjects, including their 
personal identity and all personal medical information, will be maintained at all 
times. In eCRFs and other documents or image material submitted to the sponsor, 
subjects will be identified not by their names, but by an identification code (for 
example, initials and identification number). 
Personal medical information may be reviewed for the purpose of verifying data 
recorded on the eCRF. This review may be conducted by the study monitor, 
properly authorised persons on behalf of the sponsor, the quality assurance unit, or 
regulatory authorities. Personal medical information will always be treated as 
confidential. 


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14 
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Recording of Study Data 
In compliance with GCP, the medical records/medical notes, etc, should be clearly 
marked and permit easy identification of a subject’s participation in the specified 
clinical study. 
The investigator must record all data relating to protocol procedures, IMP 
administration, laboratory data, safety data and efficacy ratings on the CRFs/eCRFs 
provided for the study. The investigator, by completing the signature log, may 
formally designate authority to complete CRFs/eCRFs to appropriately qualified 
staff having certified user access to the eCRF. Subject completed diaries and 
questionnaires will be printed or electronic. 
The investigator must, as a minimum, provide an electronic signature (e-signature) 
to each case report book to attest to the accuracy and completeness of all the data. If 
any changes are made to the eCRF, after a form has been locked and electronically 
signed, the investigator will be required to perform an additional e-signature 
authorising agreement with any new information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is 
always required. In the eCRF, the audit trail function will allow the changes made to 
be viewed on each item entered. 
14.2 
Data Management 
EDC will be utilised for collecting subject data. Each site is required to have a 
computer and internet connection available for site entry of clinical data. All entries 
in the eCRF will be done under the electronic signature of the person performing the 
action. This electronic signature consists of an individual and confidential username 
and password combination. It is declared to be the legally binding equivalent of the 
handwritten signature. Only sponsor authorised users will have access to the eCRF as 
appropriate to their study responsibilities. Users must have successfully undergone 
software application training prior to entering data into the eCRF. 
Data management will be conducted either by a CRO, directed by the sponsor’s data 
management department or by the sponsor’s data management department. All data 
management procedures will be completed in accordance with the sponsor and the 
contracted CRO SOPs. Prior to data being received in-house at the assigned CRO, it 
will be monitored at the investigator site, (for further details please see Section 12.3 
Monitoring Procedures). The eCRF data and other data documentation retrieved from 
the investigator site(s) will be tracked by the CRO and the monitor. 
The sponsor will ensure that an appropriate eCRF is developed to capture the data 
accurately, and suitable queries are raised to resolve any missing or inconsistent data. 
The investigator will receive their data, from the clinical study, in an electronic format 
(PDF files) which will be an exact copy of the eCRF, and will include the full audit 
trail, for archiving purposes and future reference. 
Any queries generated during the data management process will also be tracked by the 
contracted data management CRO/will be raised within the EDC system. It is the 
central study monitor’s responsibility to ensure that all queries are resolved by the 
relevant parties. 


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The sponsor will also ensure that SAE data collected in the eCRF are consistent 
with information provided to the sponsor’s pharmacovigilance department (and vice 
versa).  
The coding of an AE, medical history and concomitant medication terms will be 
performed by a CRO, directed by the sponsor’s Biometry Group, and reviewed and 
approved by the sponsor. Concomitant medications will be coded using WHODRUG 
and AEs/medical history terms will be coded using MedDRA. 
14.3 
Record Archiving and Retention 
During the pre-study and initiation visits, the monitor must ensure the archiving 
facilities are adequate and archiving/retention responsibilities of the investigator 
have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or planned 
marketing applications in an ICH region (that is at least 15 years or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the 
product. However, these documents should be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the 
sponsor. The investigator should take measures to prevent accidental or premature 
destruction of these documents. The final archiving arrangements will be confirmed by 
the monitor when closing out the site. The sponsor will inform the investigator, in 
writing, as to when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her 
responsibility for maintenance and retention of study documents, the sponsor must 
be notified (preferably in writing) so that adequate provision can be made for their 
future maintenance and retention. 


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15 
FINANCING AND INSURANCE 
15.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and 
the sponsor will sign a clinical study agreement prior to the start of the study, outlining 
overall sponsor and investigator responsibilities in relation to the study. Financial 
remuneration will cover the cost per included subject, based on the calculated costs of 
performing the study assessments in accordance with the protocol, and the specified 
terms of payment will be described in the contract. The contract should describe 
whether costs for pharmacy, laboratory and other protocol required services are being 
paid directly or indirectly. 
Financial Disclosure Statements will need to be completed for each investigator 
according to the local transparency requirement and legal guidelines and, if applicable, 
to the new European Transparency Initiative led by the EFPIA. 
15.2 
Insurance, Indemnity and Compensation 
The sponsor will provide Product Liability insurance for all subjects included in the 
clinical study. Where required, a hospital specific indemnity agreement will be used. 


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16 
REPORTING AND PUBLICATIONS OF RESULTS 
16.1 
Publication Policy 
The sponsor encourages acknowledgement of all individuals/organisations involved 
in the funding or conduct of the study, including medical writers or statisticians 
subject to the consent of each individual and entity concerned, including 
acknowledgement of the sponsor. 
The results of this study may be published or communicated to scientific meetings 
by the investigators involved in the study. For multicentre studies, a plan for 
scientific publication and presentation of the results may be agreed and 
implemented by the study investigators or a Steering Committee. The sponsor 
requires that reasonable opportunity be given to review the content and conclusions 
of any abstract, presentation, or paper before the material is submitted for 
publication or communicated. This condition also applies to any amendments that 
are subsequently requested by referees or journal editors. The sponsor will 
undertake to comment on the draft documents within the time period agreed in the 
contractual arrangements, including clinical trial agreements, governing the 
relationship between the sponsor and authors (or the author’s institution). Requested 
amendments will be incorporated by the author, provided they do not alter the 
scientific value of the material. 
If patentability would be adversely affected by publication, this will be delayed until 
(i) a patent application is filed for the content of the publication in accordance with 
applicable provisions of the clinical trial agreement concerned, (ii) the sponsor 
consents to the publication, or (iii) the time period as may be agreed in the 
contractual arrangements, including clinical trial agreements, governing the 
relationship between the sponsor and authors (or authors’ institution) after receipt of 
the proposed publication by the sponsor, whichever of (i), (ii) or (iii) occurs first. 
The author undertakes to reasonably consider the sponsor's request for delay to the 
proposed publication should the sponsor reasonably deem premature to publish the 
results obtained at the then stage of the study. 
16.2 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH guideline on 
structure and contents of CSRs. A final CSR will be prepared where any subject has 
signed informed consent, regardless of whether the study is completed or prematurely 
terminated. Where appropriate an abbreviated report may be prepared. The CSR will 
be in compliance with any applicable regulatory requirements, national laws in force 
and will be in English. 


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17 
REFERENCES 
1. 
Garthwright W., Archer D., Kvenberg J. Estimates of incidence and cost of 
intestinal infectious diseases in the United States; Public Health Rep. 
1988;103: 107-15. 
2. 
Guerrant RL, Hugues JM, Lima NL, Crane J. Diarrhoea in developed and 
developing countries, magnitude, special settings and etiologies. Rev of Infect 
Dis 1990; 12 suppl I: s41-50. 
3. 
Thielman NM, Guerrant RL Acute infectious Diarrhoea N Engl J Med. 
2004;350: 38-47 
4. 
Avenclano P, Matson D., Long J., et al Costs associated with office visits for 
diarrhoea in infants and toddllers. Pediatric. Infect. Dis. J. 1993; 12: 897-902. 
5. 
Faure C. Role of Antidiarrhoeal Drugs as Adjunctive Therapies for Acute 
Diarrhoea in Children. Int J Pediat. 2013;2013:612403 
6. 
Guarino A1, Ashkenazi S, Gendrel D, Lo Vecchio A, Shamir R, Szajewska 
H. European Society for Pediatric Gastroenterology, Hepatology, and 
Nutrition/European Society for Pediatric Infectious Diseases evidence-based 
guidelines for the management of acute gastroenteritis in children in Europe: 
update 2014. J Pediatr Gastroenterol Nutr. 2014 Jul;59(1):132-52. 
7. 
Khediri F, Mrad AI, Azzouz M, Doughi H, Najjar T, Mathiex-Fortunet H, 
Garnier P, Cortot A (2011). Efficacy of diosmectite (Smecta®) in the 
Treatment of Acute Watery Diarrhoea in Adults: A Multicentre, Randomised, 
Double-Blind, Placebo-Controlled, Parallel Group Study. Gastroenterol Res 
Pract;783:196 
8. 
Grim RE: Applied clay mineralogy. Mc Graw Hill, London .1968;51-125 
9. 
Allen A, Leonard A: Mucus structure. Gastroenterol Clin Biol. 1985; 9(12 Pt 
2):9-12. 
10. 
Elmore AR: Final report on the safety assessment of aluminum silicate, 
calcium silicate, magnesium aluminum silicate, magnesium silicate, 
magnesium trisilicate, sodium magnesium silicate, zirconium silicate, 
attapulgite, bentonite, Fuller's earth, hectorite, kaolin, lithium magnesium 
silicate, lithium magnesium sodium silicate, montmorillonite, pyrophyllite, 
and zeolite. Int J Toxicol. 2003; 22 Suppl 1:37-102. 
11. 
World Health Organization (2005), The treatment of diarrhoea. A manual for 
physicians and other senior health workers. In:WHO, Geneva. 
12. 
US Food and Drugs Administration (1977) Guidelines for the clinical 
evaluation of anti-diarrhoeal drugs. In:FDA, Rockville, USA. 
13. 
Heaton KW. Stool form scale as a useful guide to intestinal transit time. 
Scand J Gastroenterol. 1997;32(9):920-4. 
14. 
Cox DR. Regression models and life tables J Roy Statist Soc B. 1972;34:187-
220 


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LIST OF APPENDICES 
Appendix 1 List of drugs prohibited at the time of study entry and leading to 
exclusion ................................................................................................................... 62 
Appendix 2 Narrow Therapeutic Index (NTI) drugs ................................................ 66 
Appendix 3 Bristol Stool Chart ................................................................................ 68 
Appendix 4 Amendment No. 1 ................................................................................. 70 
Appendix 5 Amendment No. 2 ................................................................................. 75 
Appendix 6 Amendment No. 3 ................................................................................. 84 
Appendix 7 Amendment No. 4 ................................................................................. 87 
 


IPSEN GROUP 
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Appendix 1 List of drugs prohibited at the time of study entry and leading to 
exclusion 


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Main drugs known to induce diarrhoea within the first days following the first intake (non-
exhaustive list): 
 
• 
alpha-glucosidase inhibitors: eg Acarbose 
• 
biguanides: eg Metformin 
• 
biliary acids (cheno-deoxycholic acid) 
• 
bisphophonates 
• 
prostaglandins  
• 
protease inhibitors (for HIV) 
• 
selective serotonin uptake inhibitors 
• 
thyroid hormones (at a non-stabilised dosing) 
• 
auranofin (gold salts) 
• 
bepridil 
• 
calcitonin 
• 
captopril 
• 
colchicin 
• 
diacerein 
• 
didanosin  
• 
digoxin 
• 
leflunomid 
• 
methyldopa 
• 
olsalazin 
• 
orlistat 
• 
propranolol 
• 
quinidin 
• 
ticlopidine 
 
Any antiemetic drugs: 
• 
Dopamine antagonists: 
- 
domperidone (Motilium) 
- 
olanzapine (Zyprexa) 
- 
droperidol, haloperidol, chlorpromazine, prochlorperazine 
- 
alizapride 
- 
prochlorperazine  
- 
metoclopramide   
• 
Antihistamines (H1 histamine receptor antagonists): 
- 
cyclizine 
- 
diphenhydramine  
- 
dimenhydrinate  
- 
doxylamine 
- 
meclizine  
- 
mirtazapine  
- 
promethazine  
- 
hydroxyzine  
• 
5-HT3 receptor antagonists 


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• 
NK1 receptor antagonist: 
• 
cannabinoids   
 
Any anti-diarrhoeal drugs:  
• 
Any strains of probiotic drugs approved for acute diarrhoea therapeutic management 
• 
Antisecretory drugs: 
- 
racecadotril 
• 
Motility-modifying drugs: 
- 
Opiates:  
- 
loperamide  
- 
diphenoxylate  
- 
diphenoxylate with atropine 
- 
paregoric tincture of opium 
- 
codeine 
• 
Antimicrobial agents  
- 
nifuroxazide type 
- 
rilbroquinol & tiliquinol 
• 
Adsorbents 
- 
Any therapeutic clays:  
- 
smectite, diosmectite, 
- 
attapulgite 
• 
Other mucosal protectants and adsorbents 
- 
kaolin-pectin formulations 
- 
methylenic Lactoproteins  
- 
gelatin tannate 
- 
activated charcoal 
- 
bismuth subsalicylate 
- 
others 
• 
Any other anti-diarrhoeal agents 
 


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Any Antibiotic Agents: 
• 
penicillins : penicillin G, penicillin-VK, methicillin, nafcillin, oxacillin, ampicillin, 
amoxicillin, amoxicillin + clavulanic acid 
• 
cephalosporins : cephalothin, cefazolin, cephapririn, cephalexin, cefacor, cefotetan, 
ceftriaxone, cefpirome, cefepime 
• 
fluroquinolones : ciprofloxacin, levofloxacin, norfloxacin, moxifloxacin 
• 
aminoglycosides  gentamicin, tobramycin, amikacin, kanamycin, neomycin, 
• 
macrolides: erythromycin, azithromycin, clarithromycin, clindamycin, dirithromycin 
• 
carbapenems: ertapenem, imienem, meropenem 
• 
monobactams:: aztreonam    
• 
other: vancomycin, rifampicine, doxycycline, linezolid, tetracycline, trimethoprim, 
sulfamethoxazole, co-trimoxazole, metronidazole, tinidazole. 
 
Any antispasmodic drugs such as: 
• 
Dicycloverine hydrochloride 
• 
Papaverine chlorhydrate 
• 
Pinaverium bromure  
• 
Mebeverine chlorhydrate 
• 
Phloroglucinol  
• 
Trimebutine maleate 
• 
Dihexyverine chlorhydrate 
• 
Clidinium bromure 
• 
Alverine citrate 
 


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Appendix 2 Narrow Therapeutic Index (NTI) drugs 
 


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Listing and Definition of Narrow Therapeutic Index or Range (NTI) Drugs 
 
NOTE: This was a sample list of drugs published by the FDA in 1988. Refer to 
official definition or contact specific drug manufacturer for accurate 
determination if a drug has a narrow therapeutic index or range. 
 
Aminophylline 
Carbamazepine 
Clindamycin 
Clonidine 
Digoxin* 
Disopyramide 
Dyphylline 
Guanethidine 
Isoetharine mesylate 
Isoproterenol 
Levoxyine* 
Lithium Carbonate 
Metaporterenol 
Minoxidil 
Oxytriphylline 
Phenytoin 
Prazosin 
Primidone 
Procainamide 
Quinidine gluconate 
Theophylline 
Valproic Acid 
Valproate sodium syrup 
 
*Also Pre 1938 Drug 
Warfarin sodium 
 
OFFICIAL DEFINITION: Under Section 320.33(c) of Code of 
Federal Register 21, the US FDA defines a drug product as having a 
narrow therapeutic ratio as follows: 
(a) 
there is less than a 2-fold difference in median lethal dose and 
median effective dose values, or 
(b) 
there is less than 2-fold difference in the minimum toxic concentrations and 
minimum effective concentrations in the blood, and 
(c) 
safe and effective use of the drug products require careful titration and Patient 
monitoring. 
 


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Appendix 3 Bristol Stool Chart 
 


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• 
Types 1–2 indicate hard stool, 
• 
Types 3 and 4 are the ideal stools (especially the latter), as they are easy to 
defecate while not containing any excess liquid, 
• 
Types 5, 6 and 7 tend towards diarrhoea. 
The subjects will be included if stool consistency is watery (Type 7) and/ or loose 
(Type 6) (See chart for Bristol scale below) (Acute diarrhoea episode is defined as 
the passage of 3 or more unformed (loose or watery) stools per day).  
The subject will be considered to have recovered if the subject records a stool with a 
formed consistency corresponding to Type 1 to Type 4 (inclusive), followed by a 
nonwatery stool corresponding to Type 1 to 5 (inclusive) (See chart for Bristol scale 
below) (Time to recovery = Time (hours, minutes)) from the 1st study treatment 
intake to the first formed stool (this formed stool must have been followed by a 
nonwatery stool). 
Chart for Bristol scale 
Bristol Scale 
Subject Inclusion 
Subject Recovery 
(first formed stool followed by a nonwatery stool) 
Type 
Diarrhoea (Loose or watery 
stool) 
First formed stool 
Nonwatery stool 
1 
 
X 
X 
2 
X 
X 
3 
X 
X 
4 
X 
X 
5 
 
X 
6 
X 
 
7 
X 
 

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IPSEN GROUP 
F-FR-00250-105 
 
CONFIDENTIAL 
 
SAP Final Version: 15 July 2019 
1/50 
CONFIDENTIAL  
 
STATISTICAL AND ANALYSIS PLAN 
 
EFFICACY OF DIOSMECTITE (SMECTA®) IN THE SYMPTOMATIC 
TREATMENT OF ACUTE DIARRHOEA IN ADULTS. A MULTICENTRE, 
RANDOMISED, DOUBLE BLIND, PLACEBO CONTROLLED, PARALLEL 
GROUPS STUDY 
 
PROTOCOL VERSION AND DATE:  
FINAL VERSION (AMENDMENT NO. 3): 08 AUGUST 2017 
 
SAP Version 
Date 
Final Version  
15 July 2019 


IPSEN GROUP 
F-FR-00250-105 
 
CONFIDENTIAL 
 
SAP Final Version: 15 July 2019 
2/50 
CONFIDENTIAL  
 
 
STUDY NUMBER: 
F-FR-00250-105 
EUDRACT NUMBER 
2015-001138-10 
PROTOCOL TITLE: 
EFFICACY OF DIOSMECTITE (SMECTA®) IN 
THE SYMPTOMATIC TREATMENT OF ACUTE 
DIARRHOEA IN ADULTS. A MULTICENTRE, 
RANDOMISED, DOUBLE BLIND, PLACEBO-
CONTROLLED, PARALLEL GROUPS STUDY 
SAP VERSION: 
Final Version  
SAP DATE: 
15 July 2019 
 
Further to your review and agreement to the Statistical and Analysis Plan version 
indicated above, please sign to indicate approval for your area of responsibility: 
 
RESPONSIBILITY 
NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Clinical Statistics 
Manager or designee 
 
 
IPSEN Innovation 
65, quai Georges Gorse 
92 650 Boulogne Billancourt, 
FRANCE 
 
 
Clinical Study Co-
ordinator 
 
 
IPSEN Innovation 
65, quai Georges Gorse 
92 650 Boulogne Billancourt, 
FRANCE 
 
 
Vice President 
Medical 
Development 
  
 
Ipsen Pharma SAS  
65, quai Georges Gorse 
92 650 Boulogne Billancourt, 
FRANCE 
 
 
PPD
PPD
PPD


IPSEN GROUP 
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CONFIDENTIAL 
 
SAP Final Version: 15 July 2019 
3/50 
CONFIDENTIAL  
 
 
 
RESPONSIBILITY 
NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Study statistician 
 
  
BIOTRIAL 
Rue Jean-Louis Bertrand 
35000 Rennes FRANCE 
 
 
Manager statistician 
 
 
BIOTRIAL 
Rue Jean-Louis Bertrand 
35000 Rennes FRANCE 
 
 
 
IMPORTANT: This completed record (with additional sheets, where required), confirms the 
above-mentioned Statistical and Analysis Plan version became the Final Statistical and 
Analysis Plan 
 
PPD
PPD


IPSEN GROUP 
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CONFIDENTIAL 
 
SAP Final Version: 15 July 2019 
4/50 
CONFIDENTIAL  
 
 
History of Changes 
Old Version Number Date Old Version Date New Version Reason for Change 
Page 
Section 
Was 
Is 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
INFORMATION TAKEN FROM THE PROTOCOL ............................................. 10 
1.1 
Study objectives ............................................................................................................. 10 
1.1.1 
Primary objective ......................................................................................... 10 
1.1.2 
Secondary objectives ................................................................................... 10 
1.2 
Study design ................................................................................................................... 10 
1.2.1 
Study population .......................................................................................... 11 
1.2.2 
Study exposure ............................................................................................. 11 
1.3 
Methods and procedures .............................................................................................. 11 
1.3.1 
Subject identification and allocation to study treatment ........................... 11 
1.3.2 
Subjects assessments ................................................................................... 12 
1.3.2.1 
Efficacy assessments .................................................................................... 12 
1.3.2.2 
Safety assessments ........................................................................................ 12 
1.3.2.3 
Other assessments ........................................................................................ 13 
1.3.2.4 
Withdrawal/discontinuation ......................................................................... 13 
1.3.3 
Schedule of assessments .............................................................................. 15 
1.3.4 
Planned sample size .................................................................................... 15 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................... 16 
2.1 
Efficacy ........................................................................................................................... 16 
2.1.1 
Intention-To-Treat population (ITT) .......................................................... 16 
2.1.2 
Modified Intention-To-Treat population (mITT) ....................................... 16 
2.1.3 
Per Protocol population (PP) ...................................................................... 16 
2.2 
Safety .............................................................................................................................. 16 
2.3 
Other populations ......................................................................................................... 16 
2.3.1 
Screened population .................................................................................... 16 
2.4 
Pharmacokinetics .......................................................................................................... 16 
2.5 
Primary population ....................................................................................................... 16 
3 
STATISTICAL METHODS ........................................................................................ 17 
3.1 
Statistical analysis strategy........................................................................................... 17 
3.1.1 
Primary efficacy endpoint(s) ....................................................................... 17 
3.1.2 
Secondary efficacy endpoint(s) ................................................................... 17 
3.1.3 
Safety endpoint(s) ........................................................................................ 17 
3.1.4 
Multiplicity ................................................................................................... 17 
3.1.5 
Significance testing and estimation ............................................................ 18 
3.2 
Analysis methods ........................................................................................................... 18 
3.2.1 
Efficacy ........................................................................................................ 18 
3.2.1.1 
Primary efficacy analysis ............................................................................. 18 


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3.2.1.2 
Secondary efficacy analysis ......................................................................... 23 
3.2.2 
Safety ............................................................................................................ 25 
3.2.2.1 
Adverse events .............................................................................................. 26 
3.2.2.2 
Laboratory data ........................................................................................... 27 
3.2.2.3 
Vital signs ..................................................................................................... 27 
3.2.2.4 
ECG .............................................................................................................. 27 
3.2.2.5 
Other assessments (as applicable) ............................................................... 27 
3.2.3 
Missing data and outliers ............................................................................ 27 
3.2.3.1 
Missing data ................................................................................................. 27 
3.2.3.2 
Missing or incomplete dates ......................................................................... 27 
3.2.3.3 
Outliers ......................................................................................................... 28 
3.2.4 
Subject disposition ....................................................................................... 29 
3.2.5 
Withdrawals ................................................................................................. 29 
3.2.6 
Demographic and baseline characteristics ................................................. 29 
3.2.6.1 
Demographics data ...................................................................................... 29 
3.2.6.2 
Other Baseline characteristics ..................................................................... 30 
3.2.7 
Medical and surgical history, Non-Drug therapies, concomitant 
surgical procedures ..................................................................................... 30 
3.2.8 
Subject compliance ...................................................................................... 31 
3.2.9 
Prior and concomitant therapies ................................................................ 31 
3.2.10 
Pharmacokinetics & antibodies (if applicable) .......................................... 32 
3.2.11 
Pharmacodynamics (if applicable) ............................................................. 32 
3.2.12 
Derived data ................................................................................................. 32 
3.2.13 
Visit windows (optional) .............................................................................. 37 
3.2.14 
Rules and data formats ............................................................................... 37 
3.2.15 
Pooling of Centres ....................................................................................... 38 
3.2.16 
Interim analysis ........................................................................................... 38 
3.2.17 
Role of independent data monitoring committee (DMC)/interim data 
review committee [if applicable] ................................................................. 38 
3.2.18 
Covariates and analysis of subgroups ........................................................ 38 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 40 
4.1 
Hardware ....................................................................................................................... 40 
4.2 
Software ......................................................................................................................... 40 
4.3 
Validation programs ..................................................................................................... 40 
4.4 
Restitution of the programs.......................................................................................... 40 
5 
CHANGES FROM PROTOCOL ................................................................................ 40 
6 
REFERENCES .............................................................................................................. 41 
7 
DATA PRESENTATION ............................................................................................. 41 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE: 
Adverse Event 
ANCOVA: 
Analysis of Covariance 
am 
ante meridiem 
ATC: 
Anatomic Therapeutic Class 
BMI 
Body Mass Index 
Bpm 
Beats per minutes 
CRF: 
Case Report Form 
CRO: 
Contract Research Organisation 
DEB 
Diary Evaluation Booklet 
e: 
Electronic 
ICH: 
International Conference on Harmonisation  
IMP: 
Investigational Medicinal Product 
ITT: 
Intention-To-Treat 
KM: 
Kaplan-Meier 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
Modified Intention-to-Treat 
PDD 
Protocol Deviations Document 
pm 
Post meridiem 
PP: 
Per Protocol 
PT: 
Preferred Term 
QC: 
Quality Control 
SAE: 
Serious Adverse Event 
SAP: 
Statistical and Analysis Plan  
SAS®: 
Statistical Analysis System® 
SEM: 
Standard Error of the Mean 
SmPC 
Summary of Product Characteristics 
SOC: 
System Organ Class 


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SOP: 
Standard Operating Procedure 
TEAE: 
Treatment Emergent Adverse Event 
TID 
Three times a day 
WHO-DD: 
World Health Organization – Drug dictionary 


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1 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1 
Study objectives 
1.1.1 
Primary objective 
The primary objective of the study is to demonstrate that diosmectite efficacy is 
superior to placebo regarding the time to recovery of an acute diarrhoea episode 
presumed of infectious origin in adult subjects. 
1.1.2 
Secondary objectives 
The secondary objectives of the study are as follows: 
• 
To demonstrate that diosmectite efficacy is superior to placebo regarding 
other efficacy criteria. 
• 
To assess the clinical tolerance of diosmectite versus placebo 
1.2 
Study design 
The study is a multicentre, prospective, double blind, placebo-controlled 
randomised comparative study. Efficacy and safety of diosmectite (administered at a 
dose and treatment regimen in line with diosmectite Summary of Product 
Characteristics (SmPC) for France (the daily dosage can be doubled at the beginning 
of treatment for acute episode)) will be evaluated in adult subjects with a recent 
episode of acute diarrhoea presumed of infectious origin. 
At Visit 1, subjects will be randomised to 1 of the 2 treatment groups (either 
diosmectite or placebo). Physical examination will be performed and a stool sample 
will be collected for microbiological examination. The treatment schema will 
consist of 2 sachets TID a day (i.e. in the morning, mid-day, and in the evening) 
with a minimum of 24 sachets taken within 4 or 5 days.  
The treatment will start at the investigator’s office. Subjects will receive a paper 
diary (diary evaluation booklet (DEB)) to be completed to record each stool and its 
consistency on a daily basis from inclusion until the end of the study. Symptoms 
such as nausea, vomiting, abdominal pain and anal irritation and study treatment 
intake will also be recorded. The subject will be contacted by the investigator or by 
a dedicated person of the investigator team on a daily basis to verify that the DEB is 
completed by the subject. The treatment can be stopped in case of recovery 
according to the protocol definition after intake of 24 sachets within 4 or 5 days. At 
Visit 2 (Day 5 or Day 6), a physical examination will be performed and safety will 
be assessed. 
In case the subject has not recovered from diarrhoea at Visit 2, he/she will prolong 
the treatment with a maximum of 48 sachets taken up to Day 8 or Day 9 at the 
latest. For these subjects only, a third visit (Visit 3; Day 9 or Day 10) is planned to 
perform a physical examination and assess safety.  


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Figure 1: Study Design 
 
 
1.2.1 
Study population 
854 subjects will be randomised to one of the two treatment groups (either active or 
placebo) at a ratio of 1:1 (i.e. 427 per treatment group). It is planned to recruit 
subjects in 90 centres in 7 countries, including Algeria, Czech Republic, Egypt, 
Lebanon, Poland, Romania and Tunisia. 
1.2.2 
Study exposure 
The overall duration of the study will be approximately 34 months: 
• 
Expected recruitment duration: 34 months. 
• 
Expected subject participation duration: the overall duration of the study 
for each subject will be 5 to 6 days (if subject has recovered by Visit 2) or 
9 to 10 days (duration of study treatment can be from 4 to 9 days). 
1.3 
Methods and procedures 
1.3.1 
Subject identification and allocation to study treatment 
After informed consent is obtained, at enrolment, subjects will be allocated a subject 
number. All enrolled subjects must be identifiable throughout the study. The 
investigator will maintain a list of subject numbers and names to enable records to 
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Following confirmation of eligibility for the study, subjects will be allocated to 
either diosmectite or placebo. The investigator will under no circumstances change 
the randomisation number and the treatment arm allocated to the subject. 
1.3.2 
Subjects assessments 
1.3.2.1 
Efficacy assessments 
The Diary Evaluation Booklet (DEB): 
The primary endpoint will be recorded in the DEB. The subject will be asked to 
record in the DEB each day, including at Day 1, the following data until the next 
visit: date, time of onset and consistency of stools (according to the Bristol scale), 
presence of symptoms such as nausea, vomiting, abdominal pain, anal irritation, and 
study drug consumption (number of sachets taken each day).  
The Bristol scale: 
The Bristol stool scale is designed to classify the form of human faeces into seven 
categories as follows: 
• 
Types 1–2 indicate hard stool, 
• 
Types 3 and 4 are the ideal stools (especially the latter), as they are easy to 
defecate while not containing any excess liquid, 
• 
Types 5, 6 and 7 tend towards diarrhoea. 
The subject will be considered to have recovered if the subject records a stool with a 
formed consistency corresponding to Type 1 to Type 4 (inclusive), followed by a 
nonwatery stool corresponding to Type 1 to 5 (inclusive).  
Abdominal Pain intensity: 
Abdominal pain intensity, using a 5-point ordinal scale, will be recorded by the 
subject in the DEB, per 12-hour period. In case of absence of abdominal pain, 
subject will tick "no" and in case of presence, subject will tick yes and then level of 
pain be rated as follows: 1= mild, 2 =moderate, 3 = severe, 4= very severe. 
Presence of associated diarrhoea symptoms:  
Associated symptoms such as nausea, vomiting, abdominal pain and anal irritation, 
will be recorded by the subject (by ticking yes or no), per 12-hour period (except on 
Day 1, depending on whether first two sachets were taken before or after noon), in 
the DEB.  
1.3.2.2 
Safety assessments 
Adverse Events (AEs) 
AEs will be monitored from the time that the subject gives informed consent and 
throughout the study until 7 days after the end of study treatment 
Physical Examination  
Physical examinations, including body weight (kg) and body height (cm), will be 
conducted at Baseline (Visit 1), at Visit 2 and at Visit 3 if applicable. Height will be 
measured at Baseline only. 
Any clinically significant physical examination findings (abnormalities) observed 
during the study will be reported as AEs. Any physical examination findings 


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(abnormalities) persisting at the end of the study will be followed by the investigator 
until resolution or until reaching a clinically stable endpoint. 
Vital Signs  
Blood pressure (mmHG) and heart rate (bpm) will be recorded after five minutes 
rest in sitting position at baseline (Visit 1) and each post-baseline visit, as well as 
body temperature (in °C using an oral/rectal/axillary/auricular/forehead/temporal 
thermometer). 
1.3.2.3 
Other assessments 
Demographic data (date of birth and sex), medical and surgical history, including 
ongoing medical conditions, prior medications for acute diarrhoea episode as well as 
other prior medications will be collected at first visit.  
A history of current acute diarrhoea episode will also be recorded, including: 
• 
Date and time (hours, minutes) of first unformed loose or watery stool,  
• 
Number of stools including number of unformed loose or watery stools, 
for each 12h period during the last 24 hours, 
• 
Presence of other associated symptoms for the last 24 hours: nausea, 
vomiting, abdominal pain, anal irritation. 
One faecal sampling for microbiological examination will be collected as soon as 
possible after inclusion for microbiological laboratory testing (for virology, 
bacteriology and parasitology testing) in order to determine the microbiological 
status of this acute diarrhoea episode , i.e. the absence/presence of the following 
faecal pathogens: 
Virology testing: 
• 
Rotavirus, 
• 
Adenovirus, 
• 
Norovirus. 
Bacteriology and parasitology testing: 
• 
Enteropathogenic and Enterotoxigenic Escherichia Coli (E. coli), 
• 
Staphylococcus aureus, 
• 
Shigella, 
• 
Salmonella, 
• 
Campylobacter, 
• 
Yersinia enterocolitica, 
• 
Amoeibiasis (entamoeba histolytica), 
• 
Giardia / lamblia. 
1.3.2.4 
Withdrawal/discontinuation 
In case of either: 
• 
impaired general health condition 
• 
and/or moderate or severe dehydration 
• 
and/or fever above 38°C 


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• 
and/or pus or blood in the stool 
• 
and /or positive microbiological finding for Entamoeba histolytica or 
Giardia/Lamblia or Shigella in stool,  
the subject will be withdrawn from the study and an effective rehydration therapy 
and/or an anti-parasitic or antibiotic treatment will be immediately given 
accordingly. 
If the subject is discontinued from the study (i.e. ceases participation in the study 
prior to completion of the protocol), the reason will be recorded in the eCRF. 
Withdrawal due to AEs should be distinguished from other conditions for 
withdrawal. The investigator will record the reason for study discontinuation, 
provide or arrange for appropriate follow up (if required) for such subjects, and 
document the course of the subject’s condition. In all cases, the investigator must 
ensure the subject receives appropriate medical treatment (i.e. need for IV 
rehydration, and/or antiparasitic, and/or antibiotic therapy) and follow up to 
determine the final outcome if the period of the trial is over. 


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1.3.3 
Schedule of assessments 
Table 1 
Schedule of Assessments 
 
1.3.4 
Planned sample size 
Assuming a median time to recovery of 55 hours in the active group and 70 hours in 
the placebo group (corresponding to a difference of 15 hours as evidenced in the 
Khediri et al study [1]), 363 evaluable subjects per treatment group (726 in total) 
will be required in order to detect such a difference using a two-sided Gehan-
Wilcoxon test at a significance level of 5% and a power of 80%. 
It is assumed a maximum of 5% of subjects prematurely withdrawn without 
recovery and a maximum of 10% of non-evaluable subjects (because of 
poor/incomplete diary completion). Accordingly, 854 subjects (427 per treatment 
group) will be required in order to achieve an 80% power. 


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2 
SUBJECT POPULATIONS (ANALYSIS SETS) 
2.1 
Efficacy 
2.1.1 
Intention-To-Treat population (ITT) 
The ITT population will be defined as all randomised subjects analysed according 
to the arm to which they were randomised. 
2.1.2 
Modified Intention-To-Treat population (mITT) 
The mITT population will be defined as all randomised subjects who received at 
least one dose of study medication and have at least one efficacy assessment for the 
primary endpoint*. Subjects will be analysed according to the arm to which they 
were randomised. 
*The efficacy assessment will be based on the DEB. Therefore subjects with DEB 
where primary endpoint cannot be derived will be excluded from the efficacy 
analysis. Any exclusion from efficacy analysis should be discussed and finalized 
during the Data Review Meeting.  
2.1.3 
Per Protocol population (PP) 
The Per Protocol population will be defined as all subjects in the mITT population 
for whom no major protocol violations/deviations occurred. 
Criteria for exclusion from the Per Protocol population should be provided in the 
Protocol Deviation Plan and detailed in the Protocol deviations Specifications  
The list of major protocol deviations impacting inclusion in the PP population will 
be reviewed during the blind data review meeting held prior to database lock and 
before the unblinding of the treatment groups. The list will be updated to include 
any additional major protocol deviations impacting inclusion in the PP population. 
2.2 
Safety 
The safety population will be defined as all randomised subjects with at least one 
dose of study medication analysed according to the actual treatment received. 
2.3 
Other populations 
2.3.1 
Screened population 
The screened population will be defined as all subjects enrolled who provided their 
written informed consent.  
2.4 
Pharmacokinetics 
Not applicable.  
2.5 
Primary population 
The primary analysis based on the primary efficacy endpoint will be evaluated 
based on the ITT population. In addition, analysis will be performed on mITT and 
PP population as secondary. 
Secondary efficacy endpoints as well as demographics characteristics will be 
performed on the ITT population. In addition, if at least 10% of the subjects in the 
ITT set are excluded from the PP set, analysis will be performed on the PP 
population as secondary. 
The analyses of safety data will be performed on the Safety population. 


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3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with ICH E9 guidelines and 
will be based on the pooled data from the individual study sites, unless otherwise 
stated. 
BIOTRIAL will perform the statistical analysis of this study under the supervision 
of the Medical affairs Biometry department of IPSEN.  
3.1.1 
Primary efficacy endpoint(s) 
The primary efficacy endpoint is the time to recovery, defined as time from the 1st 
study treatment intake recorded in the electronic case report form (eCRF) to the first 
formed stool followed by a nonwatery stool, recorded in the DEB. 
Consistency will be rated according to the Bristol scale.  
3.1.2 
Secondary efficacy endpoint(s) 
The secondary endpoints are the following: 
(a) 
Abdominal pain intensity (rated with a 5-point ordinal scale: 0 = absent, 
1= mild, 2 =moderate, 3 = severe, 4= very severe) per 12-hour period, 
recorded in the DEB 
(b) 
Time (hours, minutes) from diarrhoea onset per eCRF to recovery defined 
as first formed stool followed by a nonwatery stool, recorded in the DEB 
(c) 
Time (hours, minutes) from diarrhoea onset recorded in the eCRF to the 
first formed stool, recorded in the DEB 
(d) 
Time (hours, minutes) from the 1st study treatment intake recorded in the 
eCRF to the last watery stool recorded in the DEB, 
(e) 
Number of stools, per 12-hour period, recorded in the DEB 
(f) 
Number of watery stools, per 12-hour period, recorded in the DEB 
(g) 
Percentage of subjects with associated symptoms such as nausea, 
vomiting, abdominal pain and anal irritation, per 12-hour period, recorded 
in the DEB*. 
*Nausea, vomiting, abdominal pain and anal irritation, per 12-hour period will be 
recorded in the DEB. The percentage of subjects will not be recorded in the DEB. 
3.1.3 
Safety endpoint(s) 
The safety and tolerability of diosmectite will be assessed throughout the study by 
evaluating adverse events (AEs) recorded from subject from the time that the 
subject gives informed consent until 7 days after the end of the study treatment, 
vital signs measurements, and physical examination results, and concomitant 
medication usage. 
3.1.4 
Multiplicity 
No adjustments for multiple testing are planned. Only primary analysis of the 
primary endpoint (ITT population) will be considered confirmatory. 


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3.1.5 
Significance testing and estimation 
All statistical tests will be performed two-sided with a type I error rate set at (5%). 
For any efficacy endpoints, the 95% confidence interval (CI) of the difference 
between treatment groups will be calculated when appropriate. 
3.2 
Analysis methods 
3.2.1 
Efficacy 
3.2.1.1 
Primary efficacy analysis 
(a) 
Main analysis 
The primary analysis of efficacy data will be performed on the ITT population.  
The primary endpoint (time from the first study treatment intake (T0)) to recovery 
defined as 1st formed stool followed by a nonwatery stool (in hours), will be 
analysed using a time to event methodology.  
Any stool recorded before dosing should not be taken into account in the analysis.  
The time to recovery will be given in hours and will be analyzed using the Kaplan 
Meier (KM) survival analysis method (see SAS syntax hereafter). The median 
recovery time, first and third quartiles with their 95% CIs will be estimated for each 
treatment group using KM product-limit estimation. In addition, KM cumulative 
estimators will be computed for recovery rates at 12, 24, 36, 48, 60, 72, 84, 96 hours 
and estimates for every 12 hours thereafter as applicable. 
Results will be also presented graphically in Kaplan-Meier plots.   
The primary analysis will test the equality of time to recovery between the two 
treatment groups, applying the two-sided Gehan-Wilcoxon test (α =5%) based on 
the ITT set. 
The following Null-hypothesis is 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. 
 
 
 
 
Subjects prematurely withdrawn without recovery or ending the study without 
recovery will be censored (not responder) at their last date/time of stools as recorded 
in the DEB.  
Special cases of censoring: subjects who have not filled in the DEB (i.e. no post 
baseline evaluation regarding "stool number" and "consistency" according to Bristol 
scale) will be censored at the date and time of their first study drug intake (or the 
randomisation date time if not administered).  
A frequency table of reasons of censoring will be displayed by treatment group.  
Rules for handling incomplete dates and times recorded on the DEB are described in 
section 3.2.3.2. 
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(b) 
Secondary analysis 
Additionally, for the main efficacy variable, a supportive analysis using mITT and 
PP populations will be carried out. 
(c) 
Sensitivity analysis – Adjustment by Country 
Sensitivity analyses will be conducted to further explore the primary efficacy 
endpoint adjusting by country, on the ITT set, using the SAS syntax below:  
 
 
 
 
Subgroup analysis: 
• 
Kaplan Meier estimates will be displayed graphically by country if the sample 
size of each country is sufficient (at least 15 subjects for each country per 
treatment group).  
• 
Kaplan Meier estimates (median and 95%CI) will also be presented in tables by 
treatment group as well as the Hazard Ratio (HR) (including 95%CI) of 
diosmectite over placebo calculated by means of Cox hazard model (see SAS 
syntax below): 
 
 
 
 
  
• 
Hazard ratios including 95% CIs of all subgroups will be presented in a forest 
plot.  
These analyses will be purely explorative and no adjustment for multiplicity will be 
performed.  
(d) 
Sensitivity analyses – patients with positive parasitology testing. 
Patients with positive parasitology testing (i.e. with amoeibiasis or giardia/lamblia) 
could have gastro- enteritis corresponding to the protocol inclusion criteria and 
therefore be included in the study, considering the investigator is not aware of these 
pathologies. Since diosmectite is known to have no efficacy on the diarrhoea linked 
with amoeibiasis or giardia/lamblia, these patients will have to be handled 
differently for the analysis. 
• 
If there are few patients with positive parasitology testing (<30): a sensibility 
analysis excluding these patients will be performed. Therefore, the same analysis 
as primary analysis will be performed on the subgroup of patients without these 
pathologies, based on ITT population. 
• 
If the number of patients with positive parasitology testing is important (>=30): 
the Kaplan-Meier analysis will be adjusted with the parasitology factor (same 
analysis as for country adjustment described in paragraph (c)). Additionally, the 
analysis will be performed for each subgroup. 
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(e) 
Sensitivity analyses – patients with positive bacteriology testing. 
The same sensibility analysis will be performed for patients with a positive 
bacteriology testing (i.e. with Enteropathogenic or enterotoxigenic E. Coli, 
Staphylococcus aureus, Shigella, Salmonella, Campylobacter or Yersinia 
enterocolitica). 
(f) 
Sensitivity analysis – recovered patients without recovery confirmation. 
For patients whose last stool is a formed stool without any other subsequent stool to 
allow the confirmation of the recovery will be considered having recovered. This 
new endpoint will be analysed using the same methodology as for the primary 
efficacy endpoint on the ITT set.  
(g) 
Baseline prognostic factors  
The same subgroup analysis will be performed for the following baseline variables: 
Season of randomisation, Absence/Presence of faecal pathogens (virology, 
bacteriology and parasitology testing), Time since diarrhoea onset. 
Cox analyses to assess the impact of baseline prognostic factors 
A multivariate analysis of the time-to-recovery will be performed in order to take 
into account prognostic factors. A Cox proportional hazards model [2] will be 
performed to estimate the HR and its two-sided 95% CI. 
The factors included in this analysis will include but will not be limited to (see 
section 3.2.18 for the parameterization): 
Table 2 
Prognostics factors for the Cox model analysis  
Covariate 
Categories 
Time since diarrhoea onset 
≤ median (reference) 
> median 
Number of watery stools during the 
last 24 hours prior inclusion 
Not applicable. 
Country  
Algeria, Czech Republic, Egypt, Lebanon, Poland, Tunisia 
(largest country to be used as reference) 
Season of randomisation 
Winter (reference), Summer. 
Absence/presence of faecal 
pathogens for Virology testing 
Positive (Rotavirus or Adenovirus or Norovirus) (reference), 
Negative (None) 
Not done/missing 
Absence/presence of faecal 
pathogens for Bacteriology testing 
Positive (Enteropathogenic or enterotoxigenic E. Coli or 
Staphylococcus aureus or Shigella or Salmonella or 
Campylobacter or Yersinia enterocolitica) (reference)  
Negative (None) 
Not done/missing 
Absence/presence of faecal 
pathogens for Parasitology testing 
Positive (aemibiasis or Giardia/lamblia) (reference),  
Negative (None) 
Not done/missing. 
Since it is an exploratory search, other covariates may be added. 
Step1:  
Each of the potential factors associated with recovery listed in Table 2 together with 
the treatment variable will be tested in separate Cox proportional hazards models. 
Any factors found to be significant at p≤0.20 (via the Wald chi-square test statistic) 


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will be considered to be potentially important. The association between each 
covariate and treatment will be further explored by presenting separate KM plots for 
each level of the covariate. 
For this selection, the following SAS® code will be used: 
 
  
 
 
Step2:  
In a second step, each pre-selected parameter will be tested with the other retained 
parameters at the 0.001 level to confirm that there is no strong link between them. 
For continuous variables the Pearson correlation will be tested. For a mix of 
categorical and continuous variables Spearman’s correlation coefficient will be used 
and for categorical variables a Chi2 test will be used. If the independence is not met 
for two parameters (p < 0.001) or r ≥0.5, the choice will be done according to 
clinical and statistical relevance. 
Step3:  
All selected parameters will be entered into a multivariate Cox model. The stepwise 
variable selection method in the SAS® procedure PHREG will be performed with 
p=0.20 to enter variables in the model, and p=0.15 to remove variables from the 
model, to select the best model, in addition to the treatment variable which will be 
included in the model. 
Tied events will be handled with the Exact method:  
 
  
  
  
 
  
 
  
 
 
The interaction of each remaining term in the multivariate model with treatment will 
also be investigated. This will be done by adding interaction terms to the model. If 
there is evidence of any interaction with treatment (according to the p-value of the 
likelihood ratio test statistic obtained with TYPE3(LR) option of MODEL 
statement), the significant interaction terms (at p≤0.10) will be maintained in the 
model.  
The maximum likelihood estimates of model coefficients (with associated standard 
error, degrees of freedom, Wald Chi-square statistic and p-value) will be presented 
for the final model along with the hazard ratios and 95% confidence intervals. 
A single vertical bar graph will be presented showing the hazard ratios and 95% CIs 
(in favour of diosmectite or Placebo) from the separate individual models (i.e., each 
model containing a single covariate along with terms for treatment).  
The hazard ratio and 95% CI from the overall final multivariate model will also be 
included in the above mentioned figure. For any covariate where the treatment by 
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covariate interaction is significant in the final multivariate model, the hazard ratio 
for treatment within each level of the covariate will be shown. 
Then, the assumptions of proportional hazards (PH) will be examined both 
graphically and statistically. 
The graphical methods used will be: 
• 
Plot ln(-ln(S(t))) versus t or ln(t) and look for parallelism 
• 
Plot Observed and predicted S(t) and look for close fit. 
• 
Use the PH graph by using the ASSESS option of the PHREG procedure 
of SAS®. ASSESS statement in SAS® includes plot of randomly 
generated residual processes to allow for graphic assessment of the 
observed residuals in terms of what is “too large”: i.e. the path from the 
actual data is compared to the randomly-generated paths under PH. 
The following SAS® code will be used with the final model retained: 
 
 
 
  
The second method to check the proportional hazards assumption will be using the 
time-dependent covariates, i.e. time*covariate interactions will be added to the 
model. 
The following SAS® code will be used  
 
  
 
 
 
 
 
 
The form of the interaction that will give the more efficient estimates (ex: TIME or 
log (TIME) must be chosen. With log(TIME), TRTPt=TRTP*log(TIME). 
If the added interaction is not statistically significant at the level of 0.10, this 
indicates that proportional hazard assumption is satisfied. 
On the contrary, if the interaction is statistically significant, it means that the effect 
of the given covariate is not constant over time, so PH assumption is violated. To 
solve this problem (i.e. to model the non-PH), the interaction will be left in the 
model.  
If PH fails for a covariate VARXi, previously checked covariates will be re-check 
after adjusting for the non-PH of VARXi. 
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The second method used to handle non-PH will be to enter the covariate VARXi as 
a stratification variable in the model to have the estimation for each level of the 
covariate: 
 
 
 
 
Therefore, the model with interaction and stratified model will be run, and the 
model with best fit statistics will be chosen. 
Finally the estimation of the best model (selected with the stepwise procedure) will 
be presented, as well as the best model adjusted for non-PH, if applicable. 
All the SAS outputs produced during the analyses and the model checking 
procedures will be included in the statistical appendix (see section 4.3).  
3.2.1.2 
Secondary efficacy analysis 
The analysis regarding secondary efficacy endpoints will be performed on the ITT 
population. Supportive analysis using PP population will be carried out if more than 
10% of subjects are excluded from ITT set. 
Rules for handling incomplete dates and times recorded on the DEB are described in 
section 3.2.3.2.  
(a) 
Abdominal pain intensity per 12-hour period 
Intensity of abdominal pain per 12-hour period will be summarized by treatment 
group (an absence of pain will be considered as value zero).  
Considering the ordinal nature of the outcome, difference between diosmectite and 
placebo will be studied by fitting a cumulative logit model assuming an ordered 
multinomial response distribution. The model will include treatment group as fixed 
effects and a random intercept effect. Contrasts between diosmectite and placebo 
will be given in term of odds ratios (modelling the probabilities to obtain higher 
scores of pain intensity). The model will be performed for each time point (12-hour 
period) separately (see SAS Syntax below).  
 
 
  
 
 
 
 
  
 
(b) 
Time from diarrhoea onset to recovery 
This endpoint is a time to event endpoint which will be analysed using the same 
methodology as for the primary efficacy endpoint. The date and time of diarrhoea 
onset will be the start date and time of diarrhoea onset as recorded from the “History 
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of current acute diarrhoea episode” eCRF section. Subjects will be censored using 
the same rules as defined for the primary endpoint.  
(c) 
Time from diarrhoea onset to the first formed stool. 
This endpoint is a time to event endpoint which will be analysed using the same 
methodology as for the primary efficacy endpoint. 
(d) 
Time from the 1st study treatment intake to the last watery stool. 
This endpoint is a time to event endpoint which will be analysed using the same 
methodology as for the primary efficacy endpoint. 
(e) 
Number of stools, per 12-hour period. 
Number of stools per 12-hour period (0-12h, 12-24h, 24-36h…) will be computed 
by summing the number of stools as recorded in the DEB by the subject using the 
time (24-hour clock) of visit to restrooms. The number of stools per 12-hour period 
will then summarized by treatment group. From first to last intake, if no stool is 
reported in the diary at a specific time interval, the number of stools at the 
considered 12-hour period will be considered as zero.  
Any stool with a missing evaluation consistency should be counted in the total 
number of stools per 12-hour period (if time of stool is not missing).  
Any stool with a missing time, with a consistency evaluation and which is 
embedded within the same time interval will be counted in the number of stools for 
the considered time interval. The number of stools per 12-hour period during the 
post baseline period will be analysed with an analysis of covariance (ANCOVA) 
method with repeated measurements. The model will include number of stools 24 
hours before randomisation (baseline) as covariate, treatment, time point (12-hour 
period until visit 3), the treatment by time point interaction as fixed effects and 
subject as random effect. The residual variance-covariance pattern will be fitted 
using an unstructured matrix (see SAS Syntax below). Adjusted means, 95% CIs 
and corresponding p-values of differences between diosmectite and placebo, derived 
from the model, will be displayed globally and for each time point. 
 
 
 
 
 
 
 
 
 
 
 
If the model fails to converge, only time intervals with a sufficient number of 
patients could be included in the model.  
In the event of gross violations from the normality assumptions (identified using the 
shape of the distribution and QQ plots of change from baseline overall and by visit) 
or from the covariance model assumptions or in case of convergence criterion fails 
to be reached, a non-parametric analysis will be used instead (Mann-Wilcoxon-
Mann-Whitney test (see SAS syntax below)) at each time point separately. 
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proc npar1way noprint data =<DATA>; 
by ATPT; 
class TRTP; 
 
var AVAL; 
 
 
In addition the cumulative number of stools per 12-hour period will be presented 
graphically using barcharts of means (± SEM) on observed values at each time point 
by treatment group.  
(f) 
Number of watery stools, per 12-hour period. 
The same analysis as described above will be performed for number of watery 
stools (corresponding to type 6 or 7). The model will include, as fixed effects, 
number of watery stools 24 hours before randomisation, treatment, time point (12-
hour interval) and the treatment by time point interaction effect. 
(g) 
Percentage of subjects with associated symptoms such as nausea, vomiting, 
abdominal pain and anal irritation, per 12-hour period. 
The proportion of subjects with at least one associated symptom will be displayed 
per treatment group and per 12-hour period, using data retrieved from the DEB for 
post baseline values and using data retrieved from the eCRF for baseline value 
(Presence of associated symptoms during the last 24 hours from the “History of 
current acute diarrhoea episode” page). Same results will be displayed for each 
symptom separately: nausea, vomiting, abdominal pain and anal irritation. To assess 
the treatment effect at each 12-hour period on associated symptoms overall and on 
each symptom separately, a non-linear mixed model will be used including 
treatment and status of subjects at baseline (With or without associated symptoms), 
time-point and treatment by time-point interaction as fixed effects and number of 
watery stools during 24h prior inclusion as covariate (see SAS Syntax below).  
 
 
 
 
 
  
 
In addition the percentage of subjects (with at least associated symptom and for 
each symptom separately) per 12-hour period will be presented graphically using 
barcharts at each time point by treatment group.  
3.2.2 
Safety 
All safety data will be included in the data listings and summary tables will be based 
on the safety population. 
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3.2.2.1 
Adverse events 
Adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 22.0.  
Listings will be presented and sorted by treatment group, subject id, start time of 
AEs, primary system organ class, preferred term and verbatim text for all adverse 
events recorded during the study.  
Listings of serious adverse events (SAE), adverse events leading to withdrawal and 
listings of deaths will also be presented. 
Adverse events will be monitored from the time that the subject gives informed 
consent and throughout the study until 7 days after the end of study treatment. A 
TEAE is defined as any AE that occurs during the active phase of the study (i.e. 
from the first study drug intake until 48h after last study drug intake) and if: 
• 
it was not present prior to receiving the first dose of IMP, or 
• 
it was present prior to receiving the first dose of IMP but the intensity 
increased during the active phase of the study, or 
• 
it was present prior to receiving the first dose of IMP, the intensity is the 
same but the drug relationship became related during the active phase of 
the study. 
Treatment Emergent Adverse Events (TEAE) will be flagged (*) in the adverse 
events listing and will be summarised. 
Related adverse events are those events with causality missing or related.  
An overall summary table of all AEs with the number and percentage of subjects 
with at least one: 
- 
AE, 
- 
TEAE, 
- 
TEAE by intensity, 
- 
TEAE by causality, 
- 
TEAE by intensity and causality, 
- 
SAE, 
- 
TEAE leading to premature withdrawal of study. 
Note: In the event of multiple adverse events (corresponding to different PTs) being 
reported by the same subject, each subject is counted for each intensity level, each 
causality level or each intensity and causality combined level. That means that the 
total of subjects for all levels of intensity / causality might be higher than the overall 
number of subjects with at least one AE. 
Incidence of all reported AEs, TEAEs, SAEs and non-serious AES (classified by 
primary System Organ Class (SOC) and Preferred Term (PT)) will be tabulated by 
treatment group. In addition, summary tables will be presented by maximum 
intensity, drug relationship and TEAEs/SAEs associated with premature withdrawal 
of study. 
Note: In the event of multiple occurrence of a same AE (same Preferred Term) by 
the same subject, the maximum intensity (severe > missing > moderate > mild) and 
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Note: In case of missing data for relationship/intensity, the AE (PT) will be 
presented with the most severe category (related and/or severe) when crossing 
intensity and relationship. 
3.2.2.2 
Laboratory data 
Not applicable.  
3.2.2.3 
Vital signs 
Vital signs will be listed at each assessment by treatment group and subject. Any 
unscheduled vital signs will be flagged [U] in the listing. 
Baseline values (values at first visit) will be defined as the last vital signs 
measurement collected prior to the first dose of study drug. 
Summary statistics by treatment group will be presented (blood pressure, heart rate 
in sitting position, body temperature and body weight) at each scheduled assessment 
for actual values and changes from baseline. 
3.2.2.4 
ECG 
Not applicable. 
3.2.2.5 
Other assessments (as applicable) 
Any new or worsening clinically significant abnormal physical examination results 
should be recorded on the Adverse Event eCRF page and will be part of the AE 
analysis.  
3.2.3 
Missing data and outliers 
3.2.3.1 
Missing data 
If there is a significant number of missing values for a subject (or if there is 
confirmed data appearing spurious), a decision will be made following consultation 
with the sponsor regarding the handling of these data in summaries, prior to 
breaking the blind. 
Any repeat or additional assessments performed will be included in the individual 
subject data listings. 
3.2.3.2 
Missing or incomplete dates 
Missing date and/or time related to stools in patients diaries for time-to-event 
analyses (time to recovery, time to first formed stool, time to last watery stool, time 
to recovery without confirmation): 
Rules of imputation for events: in case of time information is missing but 
information on date and on stool consistency are available, the time will be imputed:  
- 
to 23:59 if there is no other subsequent stools the same day, 
- 
to time of the next stool the same day minus 1 minute otherwise. 
Rules of imputation for censoring: in case of time information is missing but 
information on date and on stool consistency are available, the time will be imputed:  
- 
to the half of the interval (i.e. to (24:00 - time of last stool) / 2) if there is 
at least one non-missing time the last day 
- 
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Missing first administration time for time-to-event analyses:  
If time of first administration is missing for a subject, it will be imputed with the 
date/time of the first stool after randomization as recorded in the diary. If date/time 
of randomization is also missing, time of first intake will be imputed with the time 
of the first stool of the diary.  
Other:  
In all listings, missing or incomplete dates should be left as they have been 
recorded. However, for calculation / sorting / assignation based on dates, the 
following methods will be used: 
(1) 
The most conservative approach will be systematically considered (i.e. if 
the onset date of an AE/concomitant medication is missing / incomplete, it 
is assumed to have occurred during the study treatment phase (i.e. a TEAE 
for AEs) except if the partial onset date or other data [stop date, …] 
indicates differently). 
(2) 
A missing/incomplete date of medical history or disease diagnosis will be 
assumed to have occurred before any study treatment. 
(3) 
If a partial date and the associated information do not allow to state about 
the assignation to a group / category, all the possible groups / categories 
will be considered (i.e.: an AE could be assigned to several possible doses 
at event onset according to its partial onset date and stop date. Particularly 
an AE with missing start date will be assigned to each dose received 
before its end date. Similarly a medication with partial start and stop dates 
could be considered as prior and concomitant treatment). 
(4) 
Where this is possible, the derivations based on a partial date will be 
presented as superior inequalities (i.e.: for an AE started in FEB2004 after 
the administration performed on 31JAN2004, the days since last dose will 
be “≥2”, similarly the duration of ongoing AEs or medication will 
be“≥xx” according to the start and last visit dates). 
3.2.3.3 
Outliers 
Any outlier identified prior to unblinding which is impossible/unplausable will be 
excluded from the analysis. For other identified outliers, the impact should be 
assessed by performing the statistical analysis with the actual values and at least one 
other analysis eliminating or reducing the outlier effect. 
If any outliers are identified after unblinding the statistical analysis should be 
performed with the actual values and at least one other analysis eliminating or 
reducing the outlier effect. 
A search of outliers/missing values by BIOTRIAL should be performed before the 
unblinding and actions with the sponsor should be defined. This will be done for 
variables used for the primary and secondary analysis. A specific focus will be on 
the DEB data and especially on the dates and times of each recorded stool (missing 
values and chronological order) and their consistencies including summaries of 
number of stools overall and according to Bristol scale). The date/time of first 
watery stool (i.e. diarrhoea onset) recorded on the eCRF will also be examined (if 
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hours period (baseline data). A detection of abnormal values for raw and changes 
from baseline on vital signs data will also be performed.  
3.2.4 
Subject disposition 
A listing of dates of assessments (relative day) and their study exposure will be 
presented by subject for each treatment group. A summary table will present the 
extent of subject exposure in the study for each treatment group. 
The numbers and percentages of subjects in each of the ITT, mITT, PP and safety 
populations will be tabulated by country. The reasons for subject exclusions from 
each of the populations will also be tabulated. In addition, the numbers of subjects 
who were randomized, treated, discontinued and completed will be tabulated by 
treatment group. Primary reasons for discontinuation of study will be tabulated. 
All the protocol deviations identified prior to unblinding will be listed by subject 
for each treatment group. 
3.2.5 
Withdrawals 
Discontinued subjects will be listed and a summary table of the number and 
percentage of subjects who withdrew from the study and the reasons for withdrawal 
will be presented by treatment group. 
3.2.6 
Demographic and baseline characteristics 
Baseline value will be defined as the value measured at first visit and if missing, the 
last evaluable value before the first administration of study drug if any.  
All demographic and baseline characteristics will be listed by treatment group and 
subject. 
Summary statistics will be provided for demographic and baseline characteristics by 
treatment group, for the ITT population. 
3.2.6.1 
Demographics data 
Demographic characteristics will be summarized using the following information: 
• 
Age (years): summary statistics. 
• 
Gender: number (%) of subjects for Male/Female. 
• 
Country: number (%) for Algeria, Czech Republic, Egypt, Lebanon, Poland, 
and Tunisia. 
• 
Body Height (cm): summary statistics. 
• 
Body Weight (kg): summary statistics. 
• 
BMI (kg/m2): summary statistics and number (%) for the following categories: 
Underweight (< 18.5 kg/m2), Normal or Healthy Weight ([18.5 – 25.0[ kg/m2), 
Overweight ([25.0 – 30.0[ kg/m2) and Obese (≥ 30.0 kg/m2). 
• 
Seasons of randomisation (according to date of randomisation): number (%) of 
subjects in each category: winter and summer.  
• 
Virology, Bacteriology and Parasitology testing: number (%) of subjects for 
Positive/Negative/Not done or Missing.  
• 
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3.2.6.2 
Other Baseline characteristics 
o History of disease: diarrhoea episode characteristics will be summarized using 
the following information from the “History of current acute diarrhoea episode” 
eCRF page: 
o Duration since diarrhoea diagnosis (hours): summary statistics  
o Time since diarrhoea onset: number (%) in categories [0-12H[; [12-
24H[; [24-36H[; [36-48H[; ≥48H. 
o Number of stools during the last 24 hours: summary statistics on overall 
and for: 
 Stools/unformed loose or watery stools of the first 12 hours-
period  
 Stools/ unformed loose or watery stools of the second 12 hours-
period  
o Presence of associated symptoms during the last 24 hours: number (%) 
of subjects in each category Nausea (Yes/No), Vomiting (Yes/No), 
Abdominal pain (Yes/No), Anal irritation (Yes/No).  
o Results of virology/microbiology for stool examination:  
o Results of Virology testing with number (%) of subjects in each 
category: Rotavirus, Adenovirus, Norovirus, None, Missing. 
o Results of Bacteriology and parasitology testing with number (%) of 
subjects in each category:  
 Bacteriology subgroups: Enteropathogenic and enterotoxigenic E. 
Coli, 
Staphylococcus 
aureus, 
Shigella, 
Salmonella, 
Campylobacter, Yersinia enterocolitica, None, Missing. 
 Parasitology subgroups: Aemibiasis (entamoeba histolytica), 
Giardia/lamblia, None, Missing. 
o Additionally, above frequency tables will be provided with number (%) 
of patients with a positive result to: 
 Virology and parasitology, 
 Virology and bacteriology, 
 Parasitology and bacteriology, 
 Virology, bacteriology and parasitology. 
3.2.7 
Medical and surgical history, Non-Drug therapies, concomitant surgical 
procedures 
Medical and surgical history will be coded using MedDRA Version 22.0 as well as 
Prior and Concomitant Non-Drug therapies and Concomitant Surgical Procedures. 
Listings will present the preferred term and verbatim text. The listings will be sorted 
by treatment group, subject, primary system organ class, preferred term and 
verbatim text.  
Frequency tables of the number and percentage of subjects will be provided by 
primary system organ class and preferred term for each treatment group for:  


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• 
Prior medical and surgical history: separately for prior and ongoing 
conditions 
• 
Concomitant non-drug therapy 
• 
Concomitant surgery. 
Prior non-drug therapies will only be listed.  
In the event of multiple incidences of the same primary system organ class 
/preferred term being reported by the same subject, the subject will be counted once 
for that primary system organ class/preferred term. 
These summaries will be produced on the safety population. 
3.2.8 
Subject compliance 
Data collected from both “Study Treatment Administration (on site)” eCRF section 
and “Study drug intake” part of the DEB will be presented in individual listings with 
information such as date of intake, time of intake when taken on site and number of 
sachets taken by the subject. Listings will be ordered by treatment group, subject 
and visit, for all subjects of the Safety set.  
Study drug exposure (days) will be summarized on the safety population. 
Summary statistics on number of sachets taken during the mandatory period (from 
Day1 to Day4/Day5), until recovery and until end of study will be displayed by 
treatment group. 
Compliance will be expressed in percentage as the total sachets taken based on the 
expected total sachets to be taken and will be calculated during the mandatory 
treatment period for all subjects, until the recovery for subjects with recovery and 
until the end of study for subjects with no recovery (see section 3.2.12). Compliance 
will be categorized as < 80% (Under compliance), 80-120% (Compliance) and > 
120% (Over compliance) and will be summarized in percentage and in class overall, 
on the safety population.  
3.2.9 
Prior and concomitant therapies 
Two types of medications will be analysed:  
• 
General medications: using the information retrieved from the “Prior and 
Concomitant Medications (Excluding current acute diarrhoea episode)” eCRF 
section. 
• 
Medications related to current diarrhoea episode: using the information 
retrieved from the “Prior and Concomitant Medications for the current acute 
diarrhoea episode” eCRF page. 
Prior medications are defined as the medications taken within 30 days preceding 
visit 1 and stopped prior to the first study drug intake.  
Concomitant medications are defined as medications that have been taken during 
the treatment period regardless the start or stop date. For any partial date, if it is not 
clear when the medication started or ended but shows a possibility that it has been 
taken during the treatment period then it will be considered as a concomitant 
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All therapies will be coded using the latest version of WHO-Drug Dictionary. The 
therapeutic class will correspond to the second level of ATC code, that is, 
corresponding to the first 3 figures (see section 3.2.12-Derived data). 
Listings will be presented for the therapeutic class, preferred term and verbatim text. 
The listings will be sorted by treatment group, subject, chronological start date, 
therapeutic class, preferred name and verbatim name.  
Frequency tables of the number and percentage of subjects in the safety population 
for each treatment group and on overall, by therapeutic class and preferred name 
will be provided:  
• 
for general prior and concomitant therapies, 
• 
for prior and concomitant therapies for acute diarrhoea.  
3.2.10 
Pharmacokinetics & antibodies (if applicable) 
Not applicable. 
3.2.11 
Pharmacodynamics (if applicable) 
Not applicable. 
3.2.12 
Derived data 
The derived data are variables which are calculated from the raw data in the eCRF 
or DEB data and not included in the database.  
Efficacy derived variables: 
Primary endpoint: 
• 
Time to recovery = Time (hours, minutes) from the 1st study treatment 
intake to the first formed stool (this formed stool must have been followed 
by a nonwatery stool): 
(Date/time of Recovery or last date/time of stool (if censored) – date/time 
of 1st treatment intake). 
The subject will be considered to have recovered if the subject records a 
stool with a formed consistency corresponding to Type 1 to Type 4 
(inclusive), followed by a nonwatery stool corresponding to Type 1 to 5 
(inclusive). Dates and times will be retrieved from the DEB filled in by the 
subject. Imputations rules in case of partial time variables are described in 
section 3.2.3.2. Stools without consistency evaluation will not be taken 
into account for the determination of recovery.  
Rules of censoring are described in the table below: 
Event 
Decision 
Date of event or censoring to consider 
for the analysis 
Recovery 
Not censored 
Date/time of first form stool followed 
by a nonwatery stool 
No recovery and 
subject completed the 
study 
Censored 
Date/time of last stool 
No recovery and 
subject prematurely 
withdrawn the study 
Censored 
Date/time of last stool 


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Event 
Decision 
Date of event or censoring to consider 
for the analysis 
No recovery and no 
post-baseline 
evaluation of stools 
Censored 
Date/time of first IMP intake (if 
administered) 
Date/time of randomisation (if not 
administered) 
Secondary endpoints: 
• 
Time from diarrhoea onset to recovery (hours) will be calculated as 
follows: 
(Date/time of Recovery or last date/time of stool (if censored) – date/time 
of diarrhoea onset). 
The date and time of diarrhoea onset will be the start date/time of first 
unformed loose or watery stool as recorded in the “History of current 
acute diarrhoea episode” eCRF page.  
Rules of censoring are the same as described for primary endpoint.  
• 
Time from diarrhoea onset to the first formed stool (hours) will be 
calculated as follows: 
(Date/time of 1st formed stool or last date/time of stool (if no formed stool) 
– date/time of diarrhoea onset). 
The date of 1st formed stool will be the earliest date of stools with a 
formed consistency corresponding to type 1 to 4, whatever the 
consistencies of the next stools. 
Rules of censoring are described in the table below: 
Event 
Decision 
Date of event or censoring to consider 
for the analysis 
Formed stool 
Not censored 
Earliest Date/time of formed stool  
No formed stool and 
subject completed the 
study 
Censored 
Date/time of last stool 
No formed stool and 
subject prematurely 
withdrawn the study 
Censored 
Date/time of last stool 
No formed stool and 
no post-baseline 
evaluation of stools 
Censored 
Date/time of first IMP intake (if 
administered) 
Date/time of randomisation (if not 
administered) 
 
Time from the first study treatment intake to the last watery stool (hours) 
will be calculated as follows: 
(Date/time of last watery stool or last date/time of stool (if censored) – 
date/time of 1st treatment intake). 
The date of last watery stool will be the latest date of stools recorded by 
the subject, with a consistency corresponding to type 6 or 7.  
Rules of censoring are described in the table below: 
Event 
Decision 
Date of event or censoring to consider 
for the analysis 
Watery stool 
Not censored 
Date/time of last watery stool  


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Event 
Decision 
Date of event or censoring to consider 
for the analysis 
No watery stool and 
subject completed the 
study 
Censored 
Date/time of last stool 
No watery stool and 
subject prematurely 
withdrawn the study 
Censored 
Date/time of last stool 
No watery stool  and 
no post-baseline 
evaluation of stools 
Censored 
Date/time of first IMP intake (if 
administered) 
Date/time of randomisation (if not 
administered) 
 
12-hour period (for analysis of number of stools and number of watery 
stools): is defined as the number of hours between the date/time of stool 
recorded in the DEB and the date/time of first IMP intake and will be 
expressed in time intervals of 12 hours ([0-12h[, [12-24h[, [24-36h[….).  
Other derived variables 
The following derived data will be calculated and included in the listings: 
 
Study day 
Study day based on the 1st treatment intake will be calculated as following:  
If the date was on or after treatment intake then 
 
Study day = Date - date of study treatment intake + 1 
If the date was before treatment intake then 
 
Study day = Date - date of study treatment intake. 
 
Study exposure (days) 
Study exposure (days) will be calculated as follows: 
Exposure (days) = (Date of Last Study Visit – Date of Informed Consent + 1). 
 
Study Drug Exposure (days) 
Drug exposure (days) = (last sachet intake date – first sachet intake date + 1). 
 
Compliance (%) 
Compliance of study medication will be calculated as follows: 
Compliance (%) = (Total sachets taken / Expected total sachets) x 100. 
(a) 
During the mandatory treatment period:  
Expected total sachets = 24 therefore,  
Compliance = (Total sachets taken from Day1 to Day4 or Day5) / 24.  
The number of sachets taken by the patient during the mandatory period will be 
derived according to the time of day at which the subjects has taken the first of 
two sachets on day 1: in the morning if the first two sachets have been taken 
before 11:00 a.m. (<11:00 a.m.), the afternoon if taken between 11:00 a.m. and 
6:00 p.m. ([11:00 a.m.; 6:00 p.m.]) and the evening if taken after 6:00 p.m. 
(>6:00 p.m). Patients with a missing time of first administration will be 
considered to have taken their first two sachets in the morning (i.e. before 
11:00 a.m.).  
(b) 
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Expected total sachets will be calculated using date and time of recovery 
according to diary: 
Expected total sachets = (Date of confirmation of Recovery – Date of 1st sachet 
intake +1) * 6(1) (2). 
(1): the expected number of sachets for each day is theoretically 6 sachets. For 
the day of recovery, according to the time of last nonwatery stool which 
immediately follows the recovery (confirmation of recovery), the theoretical 
number of sachets will be: 0 sachet if time of the last nonwatery stool is before 
07:00 a.m. (<7:00 a.m) (i.e. the subject is considered to have taken no sachet 
the day of recovery), 2 sachets if time of last nonwatery stool is between 7:00 
a.m. and 12:00 p.m. ([7:00 a.m.;12:00 p.m.[), 4 sachets if time of last 
nonwatery stool is between 12:00 p.m. and 7:00 p.m. ([12:00 p.m.;7:00 p.m.] 
and 6 sachets if time is over 7:00 p.m. (>7:00 p.m).  
In case of missing data, the time of confirmation of recovery will be imputed as 
follows: 
- 
if the day of confirmation is the same as the day of recovery, time of 
confirmation will be imputed by the time of recovery +1 minute 
- 
if the day of confirmation is not the same, date and time of confirmation 
will be imputed by the day of confirmation and  time to 00:01 a.m. 
(2): the number of expected sachets to be taken on the first day of intake will 
depend on the time of the first intake. If the first sachets were taken after noon 
by the subject, 2 sachets will be subtracted from the total expected number of 
sachets for that subject at day 1.  
If the recovery occurs the day corresponding to the first IMP intake, the total 
expected sachets will be the minimum between the theoretical number of 
sachets estimated using the time of recovery as described in (1) and using the 
time of the first IMP as described in (2). 
The number of sachets taken by the subject the day of the recovery will be 
calculated using the time of the confirmation of the recovery only if the 
number of sachets taken that day is more or equal 6: the subject is considered 
to have taken 0 sachet if this time is before 7:00 a.m. (<7:00 a.m), 2 sachets is 
this time is between 7:00 a.m. and 12:00 p.m. ([7:00 a.m.;12:00 p.m.[) and 4 
sachets if this time is between 12:00 p.m. and 7:00 p.m. ([12:00 p.m.;7:00 
p.m.]. If subject took less than 6 sachets the day of the recovery, the number of 
sachets taken by the subject is equal to the number of sachets as declared in the 
diary.  
(c) 
Until the end of study for subjects without recovery: 
For the calculation of the compliance, the expected total sachets will be based 
according to the last visit date of the subject: 
For the first day, the number of expected total sachets taken will depend on the 
time of day at which the subject has taken the first two sachets (cf. rules 
described in paragraph a). For the subsequent days, the theoretical number of 
sachets will be 6 by diary day until the last day of the diary, plus:  
- 
2 sachets if the subject declared to have taken any sachet the last day in 
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- 
the number of sachets taken by the subject that day if the subject took at 
least one sachet the last day. 
In case of premature withdrawal, if date of collection or date of withdrawal is 
completed, then the expected total sachets to be taken by the subject will be 
based on the last available date in the diary.  
If patient ended the study on the day of first administration then the expected 
total sachets will be the minimum between expected sachets according to the 
time of first administration as described in (a) and the number of sachets taken 
by the patient that day.  
The number of sachets recorded in the DEB on Day 1 (“Study Drug intake” section) 
includes the first 2 sachets taken on site. 
Compliances for patients without diary or with no information on their diary 
regarding the number of sachets will not be calculated. 
 
Change from baseline 
Change from baseline at a given visit will be calculated as a difference from 
baseline (assessment at the first visit). 
 
Therapeutic Class 
The therapeutic class will correspond to the first 3 figures of the ATC code. The 
decoding of the therapeutic class will be done from the latest version of WHO-Drug 
Dictionary.  
 
Age 
Age (years) will be calculated as follows and truncated to the largest integer that is 
less than or equal to the calculated result: 
Age = (date of first Visit - birth date + 1)/365.25. 
 
BMI 
BMI (kg/m2) at Baseline will be derived as Weight (kg)/[Height(cm)/100]2 
measured at first visit and rounded to the nearest decimal.  
 
Season of randomisation 
Season of randomisation will be derived from the month of the randomisation date 
as follows: 
• 
Summer: if month (randomisation date) is from April to October inclusive,  
• 
Winter: if month (randomisation date) is from November to March 
inclusive). 
 
Duration since diagnosis of current acute diarrhoea 
Duration since current diarrhoea diagnosis (in hours) will be defined using the 
date/time of diarrhoea onset as recorded in the “History of current acute diarrhoea 
episode” eCRF page:  
Duration (hours) = (date/time of randomisation – date/time of diarrhoea onset). 
 
AE duration 
If the start and end dates of the AE are identical then “<1” day will be presented. If 
the duration is greater than 24 hours then it will be calculated as (end date - start 
date) +1 and presented in days. If the recorded end date is CONT. (for continuing), 
the end date will be listed as “ongoing” and the duration will be approximated as “≥ 
(last attended visit date – start date)+1” day(s). If the start date or the end date are 


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partial the duration will be presented as a superior inequality “≥xx” day(s) (i.e., ≥2 
where start date = 31 January 2004 and end date = February 2004 or start date = 
January 2004 and end date = 01 February 2004]. 
 
Time since last treatment intake for adverse event 
If the start date of the adverse event is identical to the date of last administration 
intake, then”<1” day will be presented. If the time to onset is greater than 24 hours 
then it will be calculated as (start date – last treatment intake date) +1 and presented 
in days.  
If the start date is partial, the time since 1st treatment intake will be presented as a 
superior inequality (i.e., for an AE started in February 2004 after the last treatment 
intake performed on 31 January 2004, the time since last treatment intake will be as 
“≥2” days). If the start date is missing the time since last treatment intake will not be 
presented. 
 
Concomitant therapy duration: 
The duration of concomitant treatments will be calculated as (end date – start date) 
+ 1. If the recorded end date is CONT. (for continuing), the end date will be listed as 
“ongoing” and the duration will be approximated as “≥ (last attended visit date – 
start date)+1” day(s). If the start date or the end date are partial, the duration will be 
presented as an inequality “≥ xx” day(s) (i.e. ≥2 where start date=31JAN2004 and 
end date=FEB2004 or start date=JAN2004 and end date=01FEB2004) but if both 
are partial or one is missing, the duration will not be presented. 
 
Medical and surgical history duration 
The duration of medical and surgical history will be calculated as (end date – start 
date) + 1. If the recorded end date is CONT. (for continuing), the end date will be 
listed as “ongoing” and the duration will be approximated as “≥ (visit 1 day 1 date – 
start date)+1” day(s). If the start date or the end date are partial, the duration will be 
presented as an inequality “≥ xx”day(s) (i.e. ≥2 where start date=31JAN2004 and 
end date=FEB2004 or start date=JAN2004 and end date=01FEB2004) but if both 
are partial or one is missing the duration will not be presented. 
3.2.13 
Visit windows (optional) 
All data will be organised and analysed according to the scheduled visits outlined in 
the protocol. As defined by the protocol, visit 1 (baseline visit) has to be performed 
within 48 hours after onset of diarrhoea. Visit 2 will correspond to Day 5 or Day 6 
and Visit 3 (if any) will correspond to Day 9 or Day10. 
3.2.14 
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the 
number of decimal places used does not imply undue precision).  Raw data will be 
presented to the number of decimal places collected, and derived data will be 
presented to an appropriate number of decimal places.  The appropriate number of 
decimal places will be determined by general practice, mathematical rationale or 
scientific rationale (e.g. age should be presented in whole numbers).  
For summary statistics, the following will be presented n, number of missing values, 
arithmetic mean, standard deviation, median and the range (minimum, maximum). 


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Mean, median, standard deviation and standard errors of the mean (SE) values will 
be reported to one decimal place greater than the raw/derived data that they 
summarise. Minimum and maximum values will be reported with the same 
precision as the raw data. 
Percentages will be reported to one decimal place and 0% will not be presented.  
Percentages will be calculated using a denominator of all subjects in a specified 
population. Missing values will not be accounted for in denominator. The 
denominator will be specified in a footnote to the tables for clarification if 
necessary.  
Lower and upper confidence interval values should be presented to one decimal 
place more than the raw/derived data (i.e., to the same number of decimal places as 
the mean). 
Percentiles (e.g., 25%, 75%) should be presented to one decimal place more than the 
raw/derived data.  
Time-to-event endpoints will be descriptively summarized using Kaplan-Meier 
(KM) product-limit estimators.  
P-values will be reported to four decimal places (e.g.: p=0.0037), after rounding. P-
values which are less than 0.0001 will be presented as ‘<0.0001’. 
All text fields must be left justified and numeric or numeric with some text 
specification (e.g.: not done, unknown, <4.5, …) must be decimal justified.  Dates 
will be presented in the format [yyyy-mm-dd] and times in the format [hh:mm]. 
3.2.15 
Pooling of Centres 
Regarding the primary endpoint, it is planned to assess and adjust the treatment 
comparison by computing the median of time to recovery for diosmectite and 
placebo for each country (subgroups analysis).  
Subjects are planned to be recruited in seven countries: Algeria, Czech Republic, 
Egypt, Lebanon, Poland, Romania and Tunisia. 
3.2.16 
Interim analysis 
No interim analysis will be performed. 
3.2.17 
Role of independent data monitoring committee (DMC)/interim data review 
committee [if applicable] 
No independent data monitoring committee/interim data review committee will be 
used in this study. 
3.2.18 
Covariates and analysis of subgroups 
Subgroups analyses on the primary endpoint are planned for the following group of 
variables: 
Time since diarrhoea onset 
• 
≤ median (reference) 
• 
> median  
Country (largest country to be used as reference) 
• 
Algeria  
• 
Czech Republic,  


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• 
Poland,  
• 
Tunisia  
• 
Egypt 
• 
Lebanon 
Season of randomisation: 
• 
Winter (reference)  
• 
Summer  
Virology subgroup:  
• 
Positive (reference): at least Presence of one of the following:  
(a) 
Adenovirus ,  
(b) 
Rotavirus,  
(c) 
Norovirus,  
• 
Negative: no presence and at least one absence among all above tests  
• 
Not done or missing result for all tests. 
Bacteriology subgroup: 
• 
Positive (reference): at least Presence of one of the following:  
(a) 
Enteropathogenic or enterotoxigenic E. Coli  
(b) 
Staphylococcus aureus,  
(c) 
Shigella,  
(d) 
Salmonella,  
(e) 
Campylobacter,  
(f) 
Yersinia enterocolitica,  
• 
Negative: no presence and at least one absence among all above tests  
• 
Not Done or missing result for all tests. 
Parasitology subgroup: 
• 
Positive (reference): at least Presence of one of the following:  
(a) 
Aemibiasis (entamoeba histolytica) 
(b) 
Giardia/lamblia 
• 
Negative: no presence and at least one absence  among all above tests 
• 
Not done or missing result for all tests. 
Covariables used in mixed models will be: 
o Number of stools 24 hours before randomisation (baseline) as 
recorded in the “History of current acute diarrhoea episode” eCRF 
page and calculated as follows: Number of stools during the first 12-
hour period + Number of stools during the second 12-hour period.  
o Number of watery stools 24 hours before randomisation (baseline) 
calculated as follows: Number of watery stools during the first 12-
hour period + Number of watery stools during the second 12-hour 
period. 
Missing values will not be replaced.  


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4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Hardware 
The statistical analysis will be performed using a computer on a Windows 7 
operating system.  
4.2 
Software 
All tables, listings and figures will be produced and statistical analysis performed 
using SAS version 9.3 or higher.  All outputs will be provided as individual.rtf files 
following GEN014 template and compiled in bookmarked .pdf files as per ICH 
section (e.g. 14.1, 14.2 …). 
4.3 
Validation programs 
BIOTRIAL will provide a Validation Plan to IPSEN identifying the methods of 
validation and quality control (QC).  
The Program Reviewer is responsible for reviewing each project program and 
output associated with the deliverable product. Program logs are reviewed for 
logical, syntax and fatal errors. The review in SAS includes, but is not limited to, all 
ERRORS, 
WARNINGS, 
BY-VALUE 
merge 
messages, 
NOTES, 
and 
UNINITIALIZED variables. Program logs are also reviewed for accurate and 
consistent variable and observation counts following each procedure and data step. 
The Reviewing/QC Statistician is responsible for checking and reviewing the work 
produced using whatever method he/she feels is appropriate (e.g., SAS code review, 
hand calculation, etc.) to reassure of the quality of the output. 
Outputs are reviewed for typographical errors, misspellings and nonsensical values 
or results and to check the consistency with the statistical and analysis plan. Outputs 
are cross-checked against each other for accuracy and consistency. For statistical 
tables, listings, appendix listings, and figures, this procedure includes comparison of 
subject group numbers, counts of subjects at each observation point, and 
consistency of results for variables between outputs. 
Findings of the quality control reviews are communicated to the party responsible 
for making necessary changes. The programs will be retested after modifications. 
After final review, and when no further changes are required to produce the 
deliverable, the Program Reviewer and Reviewing/QC Statistician need to complete 
and sign the CRO’s Validation Checklist/Sign-off Sheet, to indicate that they have 
successfully performed all of their responsibilities. 
Copies of the internal QC forms produced for the validation process and the CRO’s 
sign-off forms will be provided to the sponsor to support the validation. 
4.4 
Restitution of the programs 
All programs (including Macros and analysis datasets programs and corresponding 
datasets) producing the tables, listings and statistical output along with associated 
logs should be given to the sponsor after each planned delivery (including when the 
mock TLFs are released). 
5 
CHANGES FROM PROTOCOL 
Not applicable. 


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6 
REFERENCES 
1. 
Khediri F, Mrad AI, Azzouz M, Doughi H, Najjar T, Mathiex-Fortunet H, 
Garnier P, Cortot A (2011). Efficacy of diosmectite (Smecta®) in the 
Treatment of Acute Watery Diarrhoea in Adults: A Multicentre, Randomised, 
Double-Blind, Placebo-Controlled, Parallel Group Study. Gastroenterol Res 
Pract;783:196. 
2. 
Cox DR. Regression models and life tables J Roy Statist Soc B. 1972;34:187- 
220. 
7 
DATA PRESENTATION 
Data listings are presented for all randomized subjects (ITT population) ordered by 
treatment, subject number and, where applicable, by visit/time-point. 
Footnotes should be used to clarify ambiguities (e.g. the denominator used to 
calculate a percentage or notes for the programmer). If the number of footnotes is 
high, they could be presented only in the last page, with on each page the following 
footnote “See last page for listing notes”. The order of the footnotes for key symbols 
(*, ~) will be in the order that they appear in the listing. 
The title of each generated table, listing and figure should appear bookmarked 
within Word (one single bookmark per table/listing/figure) to allow document 
publishing by IPSEN.