Clinical trial NCT03045926
Conditions: Chronic Functional Diarrhea of Unknown Origin
Sponsor: Ipsen
Start date: 2016-08-01; Completion date: 2017-05-09
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to assess the concentration of elemental impurities in blood and urine after chronic administration of Smecta® in subjects with chronic functional diarrhoea. For exploratory purposes, the potential effects of diosmectite on bowel microbiote composition will be investigated.

Detailed description:

Arms: arm 1: 5 weeks of diosmectite 3g, 3 times daily.
Interventions: intervention 1: Diosmectite (Smecta®)
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
Page 1 of 66 
 
Protocol Title: 
ASSESSMENT OF ELEMENTAL IMPURITIES LEVEL AFTER CHRONIC 
ADMINISTRATION OF DIOSMECTITE (SMECTA®)  
IN SUBJECTS WITH CHRONIC DIARRHOEA 
 
Protocol D-FR-00250-108 
 
Protocol Amendment #2 Version 4.0, dated 07-SEPT-2016 
 
Sponsor/Manufacturing Authorisation Holder:  
Ipsen Pharma SAS 
65, quai Georges Gorse 
92100 Boulogne-Billancourt, France 
 
EUDRACT number: 2016-002111-18 
 
IND #N/A 
 
Serious adverse event reporting:  
Fax: 
 
Email:
 
 
Pharmacovigilance contact details:  
 Global Patient Safety, Ipsen Biopharm Ltd 
102 Park Drive, Milton Park, Oxfordshire, OX14 4RY, England 
Tel: 
 
Mob:
 
 
The person listed above is the qualified Physician designated by the Sponsor who is 
responsible for all study-site related pharmacovigilance decisions, for example in emergency 
situations (for serious adverse events). 
 
Study Conduct Compliance Statement 
This study will be conducted in compliance with the protocol, in accordance with the International 
Conference on Harmonisation Good Clinical Practice (CPMP/ICH 135/35) together with such other good 
clinical practice requirements and the ethical principles that have their origin in the Declaration of 
Helsinki, as well as with all currently applicable laws and regulations of the country where the study will 
be conducted. 
This material is confidential and is the property of Aepodia S.A. and the Sponsor.  Do not disclose or use 
except as authorised. 
 
 
PPD
PPD
PPD
PPD
PPD


 
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Sponsor Authorised Protocol Approver 
Name, Title: Isabelle Paty, PhD - VP Early Development and Clinical Pharmacology 
Address: 
Ipsen Innovation, 5, avenue du Canada, 91966 Les Ulis Cedex, France 
Name, Title: Hélène Mathiex-Fortunet, MD - VP Drug Development- Primary Care Global 
Business Unit.  
Address: 
Ipsen Pharma SAS, 65 quai Georges Gorse 92100 Boulogne-Billancourt, 
France 
Sponsor’ Medical Monitor Responsible for the Study 
Name, Title:  
, Primary Care 
Global Business Unit. 
Address:  
Ipsen Pharma SAS, 65 quai Georges Gorse 92100 Boulogne-Billancourt, 
France 
Phone:  
 
Fax:   
 
Email:  
 
 
The person listed above is the qualified Physician designated by the Sponsor who is 
responsible for all study-site related medical decisions that have to be taken. 
Coordinating Investigator 
Name, Title: Tjerk Bosje, MD 
Address: 
PRA Health Sciences, Van Swietenlaan 6, 9728 NZ Groningen, the 
Netherlands  
Phone:  
  
Fax:   
 
Email:  
  
Monitoring Provider 
Name, Title:  
 
Address:  
Aepodia France SARL, 3 avenue du Canada, 91940 Les Ulis, France 
Phone:  
 
Fax: 
 
 
Email:  
 
Data Management Provider 
Name, Title: 
 
Address: 
Biotrial, 7-9 rue Jean-Louis Bertrand, CS 34246, 35042 Rennes Cedex, France 
Phone:  
 
Fax: 
 
 
Email:  
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
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Statistic Provider 
Name, Title: 
  
Address: 
Biotrial, 7-9 rue Jean-Louis Bertrand, CS 34246, 35042 Rennes Cedex, France 
Phone:  
 
Fax: 
 
 
Email:  
 
Bioanalytical Laboratory for Assessment of Blood and Urine Level of Impurities  
Name, Title: 
  
Address: 
Quality Assistance S.A., Technoparc de Thudinie, 2, DONSTIENNES, 6536, 
Belgium 
Phone:  
 
Email:  
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
Page 4 of 66 
 
 Agreement on Protocol – Signature Page 
 
Protocol Title: 
ASSESSMENT OF ELEMENTAL IMPURITIES LEVEL AFTER 
CHRONIC ADMINISTRATION OF DIOSMECTITE (SMECTA®) IN SUBJECTS WITH 
CHRONIC DIARRHEA 
Protocol Version Number: 4.0 
Protocol Version Date: 
07-SEPT-2016 
By signing below, I hereby confirm that I have read, discussed and understood the above 
mentioned version of the protocol D-FR-00250-108 and the background information 
concerning the study drug.  I attest that I will carry out the study according to this protocol. 
I also agree that the work will be performed according to Good Clinical Practice (GCP) 
guidelines, the ethical principles, and all currently applicable laws and regulations of the 
country(ies) where the study will be conducted. 
 
Investigator 
 
 
Sponsor 
 
Name 
 
 
Name: 
Hélène Mathiex-Fortunet, 
MD  
Title: 
 
 
Title: 
VP Drug Development- 
Primary Care Global 
Business Unit, Ipsen Pharma 
SAS 
Date: 
 
 
Date: 
 
Signature: 
 
 
Signature 
 
 
 
 
Name: 
Isabelle Paty, PhD  
 
 
 
Title: 
VP Early Development and 
Clinical Pharmacology, 
Ipsen Innovation 
 
 
 
Date: 
 
 
 
 
Signature 
 
 


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
Page 5 of 66 
 
SYNOPSIS 
 
Title 
ASSESSMENT OF ELEMENTAL IMPURITIES LEVEL AFTER CHRONIC 
ADMINISTRATION OF DIOSMECTITE (SMECTA®) IN SUBJECTS WITH 
CHRONIC DIARRHOEA 
Study Alias 
D-FR-00250-108 
EudraCT Number 
2016-002111-18 
Investigational Product 
Diosmectite (Smecta®) 
Type of Study 
Phase I, open label, non comparative study to assess the level of the Class I and 
IIa elemental impurities as defined by ICHQ3D* (e.g. lead, arsenic, cadmium…) 
in blood and urine samples after chronic administration of Smecta® in subjects 
with chronic diarrhoea. 
*ICHQ3D is a new guidance developed to provide a global policy for limiting 
elemental impurities in drug products and ingredients. As lead is a naturally 
constituent of Smecta®, present in a significant amount, and a Class I elemental 
impurities, the level of this element has been selected as the primary endpoint.   
Investigational Site 
The study will be performed in multiple Clinical Research Units in Europe. 
Study Duration 
The overall study duration is expected to be approximately 8 months from first 
subject screened to last subject discharged from the study. 
Each subject will be in the study for approximately 5,5 months, including 3 to 6 
weeks for screening activities, 5 weeks of treatment, and 12 weeks of post-dose 
follow-up period. 
Objectives 
Primary: 
 
To assess the concentration of lead in blood, one of the Class I elemental 
impurities defined by ICH Q3D guidelines, after chronic administration of 
Smecta® in subjects with chronic functional diarrhoea. 
Secondary: 
 
To assess blood concentration of other Class I and IIa elemental impurities 
of interest (i.e. arsenic, cadmium, mercury, cobalt, vanadium, nickel and 
barium) and of aluminium after chronic administration of Smecta® in 
subjects with chronic functional diarrhoea;  
 
To assess urinary lead levels and urinary levels of other selected Class I and 
IIa elemental impurities of interest (i.e. arsenic, cadmium, mercury, cobalt, 
vanadium, nickel and barium), and aluminium after chronic administration 
of Smecta®;  
 
To further assess the safety and tolerance of Smecta® after chronic 
administration.  
Exploratory (ancillary study): 
 
To assess the bowel microbiote composition, stools consistency and 
frequency after chronic administration of Smecta® in subjects with chronic 
functional diarrhoea. 
 
Additional blood samples will be biobanked in order to further potentially 
assay other elemental impurities levels (see Attachment #5); 
 
Plasma samples will be biobanked in order to further potentially assay lead 
in plasma. 
Endpoints 
Primary Endpoints:  
 
Changes in BLL from baseline during treatment and post-treatment follow-
up period.   
Secondary Endpoints: 
 
Change from baseline of concentrations of other selected Class I elemental 


 
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impurities (i.e. arsenic, barium) and Class IIa elemental impurities (i.e.: 
cadmium, mercury, cobalt, vanadium, nickel) and aluminium in blood 
during treatment and post-treatment follow-up period.  
 
Change from baseline of urinary concentrations of selected Class I and IIa 
elemental impurities (arsenic, barium, cadmium, mercury, cobalt, 
vanadium, nickel) and aluminium in urine at the end of Smecta® 
administration and during follow-up period.  
 
Safety Endpoints: 
o 
physical examination, vital signs, ECG,  
o 
standard clinical laboratory tests,  
o 
adverse events and Treatment Emergent Adverse Events (TEAE) 
o 
additional medical monitoring visit at the discretion of the Investigator 
and in case of adverse reactions. 
Exploratory endpoints: 
 
Change from baseline of the microbiote characteristics during Smecta® 
treatment and follow up. 
 
Change from baseline of consistency of stools (as rated according to Bristol 
scale over 24h by the subject) and frequency at different study visits.
 
Change from baseline of blood and urine dosages of other elemental 
impurities as lithium (Li), antimony (Sb), molybdenium (Mo), copper (Cu), 
Tin (Sn) and chromium (Cr) at the end of Smecta® administration and 
during follow-up period.  
 
Change from baseline of plasma concentration of lead at the end of 
Smecta® administration and during follow-up period 
Study Design 
Prospective, open label, non-comparative study with treatment of Diosmectite 
(Smecta®, 3g) TID over 5 weeks. 
Number of Subjects 
A total of 35 subjects will be enrolled in order to ensure at least 29 subjects 
completing the study. It is planned to enrol a minimum of 40% of each gender, 
with gender distributed approximately equally between sites (e.g. no site with less 
than 35% of one gender). 
Treatment: route, strength, 
regimen  
Diosmectite (Smecta® 3g/sachet, powder for oral suspension. 
Three sachets per day (TID), morning, noon, and evening. 
For the purpose of this study, Smecta® should be taken fasting and at least one 
hour before meal, except for breakfast at least ½ hour before. 
Reference/Control 
Treatment: route, strength, 
regimen 
NA 
Drug administration 
Smecta® orange/vanilla 3g, sachet to be put in suspension in a glass of water. 
Main Inclusion/Exclusion 
Criteria 
- Male or female subjects, between 18 and 60 years old inclusive, BMI between 
19 and 32 kg/m2 inclusive (minimum body weight of 50 kg at screening). 
- Functional chronic diarrhoea defined as loose or watery stools occurring in at 
least 75% of stools for the last 3 months (with symptom onset at least 6 months 
before diagnosis).  
- No history of suspected organic or drug induced cause to chronic  diarrhoea. 
Study Evaluation Criteria: 
Impurities concentrations in 
blood and in urine and 
Safety 
Blood lead levels (BLL) timepoints: 
• 
Screening (Day -42 to Day -21) 
• 
Day – 1 (Baseline) 
• 
Day 1 and Day 35: 
- 2 hours after the first dose,  
- immediately before second dose,  
- 3h post lunch dose,  
- immediately before the third dose,  


 
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- 3h post evening dose 
- 6h post evening dose 
• 
Day 2: On pre-dose before dosing (morning, approximately 8am)  
• 
Days 8, 15, 22, and 29 visits: at pre-dose of any of the three dosing 
occasions of the day, 
• 
Day 36, in the morning, 
• 
Post-treatment follow-up period: 
- Day 65, Day 95, and Day 125 (end-of-study)  
Urine collections (24-hour) at: 
• 
Baseline (Day-1), 
• 
Day 35, 
• 
Post-treatment follow-up period:  Day 65 and Day 95  
Safety Endpoints will be assessed at different timepoints:  
 
physical examination, vital signs, ECG,  
 
clinical laboratory blood tests, 
 
Adverse Events and Treatment Emergent Adverse Events (TEAE). 
Lead and other elemental 
impurities levels reporting 
Methodology 
Blood lead and urine lead levels will be measured by a validated bioanalytical 
assay inductively coupled plasma mass spectrometry (ICP-MS). 
Blood Lead Level (BLL) and other elemental impurities levels will be reported as 
well as uLL (urinary lead level) and plasma lead levels.  
Statistical Methodology: 
elemental impurities, 
population definitions, and 
Safety 
 
All available data will be descriptively analysed as one treatment cohort.  
BLL (and other elemental impurities) at the Screening and pre-dose (Day-1) will 
be averaged and considered as the BLL Baseline. BLL and change from baseline 
at each time points will be reported. Descriptive statistics will be reported for 
those parameters. 
uLL (urinary lead level) at baseline and at each time point will be reported. 
Change from baseline of uLL at each time point will be reported. Descriptive 
statistics will be reported for those parameters 
 
Safety population: Any subject receiving at least one sachet of Diosmectite will 
be analysed for safety  
Intent-to-treat (ITT) population: All subject receiving at least one sachet of 
Diosmectite and having one pre-dose BLL and at least one post-dose BLL  
Per protocol population: All subjects who completed the last post-treatment 
follow-up visit. 
Interim analyses: no formal interim analyses are planned to be conducted during 
the study. However BLL at screening and pre-dose, as well BLL obtained during 
the study will be analysed and reviewed on an ongoing basis for potential study 
adjustments (e.g.: check the assumptions taken for sample size calculation). 
 


 
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TABLE OF CONTENTS 
 
SYNOPSIS ................................................................................................................................ 5 
TABLE OF CONTENTS ......................................................................................................... 8 
RATIONALE FOR PROTOCOL AMENDMENT #2 ....................................................... 12 
LIST OF DEFINITIONS AND ABBREVIATIONS........................................................... 13 
1 
STUDY DRUG BACKGROUND INFORMATION ................................................. 16 
1.1 
Investigational Medicinal Product Name ................................................................... 16 
1.2 
Findings from Nonclinical and Clinical Studies ......................................................... 16 
1.3 
Known and Potential Risks .......................................................................................... 17 
1.4 
Selection of Investigational Medicinal Product Dose and Dose Regimen ................ 17 
1.5 
Study Population ........................................................................................................... 17 
1.6 
Potential Benefits to Participants ................................................................................ 17 
1.7 
Rationale for the Study ................................................................................................. 17 
2 
STUDY OBJECTIVES ................................................................................................. 20 
2.1 
Primary Objective ......................................................................................................... 20 
2.2 
Secondary Objectives ................................................................................................... 20 
2.3 
Exploratory Objectives ................................................................................................. 20 
3 
INVESTIGATIONAL PLAN ...................................................................................... 21 
3.1 
Overall Study Design .................................................................................................... 21 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 21 
3.2.1 
Pharmacokinetics of Lead, other Impurities Endpoints and Evaluations 
Methods ....................................................................................................... 21 
3.2.2 
Exploratory Endpoints ................................................................................ 22 
3.2.2.1 
Microbiote assessment ................................................................................. 22 
3.2.2.2 
Biobank ........................................................................................................ 22 
3.2.3 
Safety Endpoints and Evaluations ............................................................. 22 
3.3 
Subjects Managements ................................................................................................. 22 
3.3.1 
Study Visits and Procedures ....................................................................... 22 
3.3.1.1 
Screening Period .......................................................................................... 23 
3.3.1.2 
Baseline ........................................................................................................ 23 
3.3.1.3 
Treatment Period ......................................................................................... 23 
3.3.1.4 
Post-Treatment Period ................................................................................. 24 
3.3.1.5 
End-of-Study (EoS)/Early Discontinuation Visit (ED) (Visit 10) ................ 24 
3.3.2 
Subjects Disposition .................................................................................... 24 
3.3.3 
Study Duration ............................................................................................ 24 
3.4 
Study Conduct ............................................................................................................... 24 
3.5 
Rationale for the Study Design .................................................................................... 24 
4 
POPULATION RECRUITMENT, ENROLMENT AND WITHDRAWAL .......... 25 
4.1 
Definitions ...................................................................................................................... 25 
4.2 
Recruitment of Population ........................................................................................... 25 


 
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4.3 
Inclusion Criteria .......................................................................................................... 26 
4.4 
Exclusion Criteria ......................................................................................................... 26 
4.5 
Randomisation .............................................................................................................. 27 
4.6 
Discontinuation of an Individual Subject ................................................................... 27 
4.6.1 
Discontinuation / Withdrawal Criteria....................................................... 27 
4.6.2 
Follow-up Procedures for Drop-out Subjects ............................................ 28 
4.6.3 
Replacement Strategy .................................................................................. 28 
4.7 
Discontinuation of Study Site(s) .................................................................................. 28 
4.8 
Discontinuation of Subject's Recruitment .................................................................. 28 
4.9 
Study Termination ........................................................................................................ 28 
5 
STUDY TREATMENT ................................................................................................ 29 
5.1 
Study Drug and Treatment of Subjects ...................................................................... 29 
5.1.1 
Investigational Drug Formulation ............................................................. 29 
5.1.2 
Study Drug Administration ......................................................................... 30 
5.2 
Blinding .......................................................................................................................... 30 
5.3 
Product complaint ......................................................................................................... 30 
6 
STUDY RESTRICTIONS ............................................................................................ 31 
6.1 
Study Drug Administration ......................................................................................... 31 
6.2 
Concomitant Therapy(ies) ........................................................................................... 31 
6.3 
Lifestyle Restrictions .................................................................................................... 32 
7 
STUDY ASSESSMENTS ............................................................................................. 33 
7.1 
Safety Assessments ........................................................................................................ 33 
7.1.1 
Adverse Events ............................................................................................ 33 
7.1.1.1 
Definition ..................................................................................................... 33 
7.1.1.2 
Adverse Event Collection ............................................................................. 34 
7.1.1.3 
Adverse Events Assessment .......................................................................... 34 
7.1.1.4 
Adverse Event Follow-up ............................................................................. 35 
7.1.1.5 
Clinical Evaluation of Safety ....................................................................... 35 
7.1.1.6 
Serious Adverse Event Assessment .............................................................. 35 
7.1.1.7 
Suspected Unexpected Serious Adverse Reactions ...................................... 36 
7.1.1.8 
Pregnancy .................................................................................................... 36 
7.1.1.9 
Death ............................................................................................................ 37 
7.1.1.10 
Reporting to Competent Authorities, IECs/IRBs and other Investigators ... 37 
7.1.2 
Physical Examination ................................................................................. 37 
7.1.3 
Vital Signs Assessments .............................................................................. 37 
7.1.4 
Electrocardiograms Assessments ............................................................... 37 
7.1.5 
Clinical Safety Laboratory Tests ................................................................ 38 
7.1.5.1 
Urinalysis ..................................................................................................... 38 
7.1.5.2 
Pregnancy Test ............................................................................................. 38 
7.1.5.3 
Investigator’s Review ................................................................................... 38 
7.1.5.4 
Sample Handling, Storage and Destruction ................................................ 39 


 
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7.1.6 
Additional Definitions or Special Procedures............................................ 39 
7.2 
Efficacy Assessment(s) .................................................................................................. 39 
7.3 
Assessments of lead levels and other elemental impurities ....................................... 39 
7.3.1 
Sampling Schedule ...................................................................................... 39 
7.3.2 
Sampling Method for Pharmacokinetic Measurements ............................ 39 
7.3.3 
Bio-analytical Method ................................................................................. 40 
7.3.4 
Parameter Estimation ................................................................................. 40 
7.4 
Pharmacodynamic Assessment(s) ............................................................................... 40 
7.5 
Exploratory Assessment(s) ........................................................................................... 40 
7.6 
Compliance to Study Procedures ................................................................................ 41 
7.6.1 
Compliance to Protocol ............................................................................... 41 
7.6.2 
Compliance to Timing of Procedures ......................................................... 41 
8 
STATISTICAL ANALYSES ....................................................................................... 42 
8.1 
Data Analysis Plan ........................................................................................................ 42 
8.1.1 
General Considerations .............................................................................. 42 
8.1.2 
Determination of Sample Size .................................................................... 42 
8.1.3 
Study Participant Disposition ..................................................................... 42 
8.1.4 
Study Participant Characteristics ............................................................... 42 
8.1.5 
Statistical Evaluation of Safety ................................................................... 42 
8.1.6 
Analyses and Statistical Inference ............................................................. 43 
8.2 
Preliminary and/or Interim Analysis .......................................................................... 43 
9 
DATA HANDLING AND RECORD KEEPING ....................................................... 44 
9.1 
Data Capture ................................................................................................................. 44 
9.2 
Data Handling ............................................................................................................... 44 
9.3 
Record Keeping ............................................................................................................. 44 
10 
REGULATORY AND ETHICAL CONSIDERATIONS ......................................... 45 
10.1 Subject Information Sheet and Consent ..................................................................... 45 
10.2 Ethical Review Considerations .................................................................................... 45 
10.3 Regulatory Considerations ........................................................................................... 46 
10.4 Final Report Signature ................................................................................................. 46 
11 
INSURANCE AND FINANCE .................................................................................... 47 
11.1 Insurance ....................................................................................................................... 47 
11.2 Financial Agreement ..................................................................................................... 47 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 48 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................... 48 
12.1.1 
Protocol Amendments ................................................................................. 48 
12.1.2 
Protocol Deviations, Violations, and Exceptions ....................................... 48 
12.1.3 
Information to Study Personnel ................................................................. 48 
12.2 Monitoring ..................................................................................................................... 48 
12.3 Investigator’s Regulatory Obligations ........................................................................ 49 
12.3.1 
Audit and Inspection ................................................................................... 49 


 
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12.3.2 
Data Quality Assurance .............................................................................. 49 
13 
PUBLICATION POLICY ............................................................................................ 51 
14 
REFERENCES .............................................................................................................. 52 
15 
ATTACHMENTS ......................................................................................................... 53 
15.1 Attachment 1 – Study Schedule ................................................................................... 53 
15.2 Attachment 2 – Safety Clinical Laboratory Tests ...................................................... 56 
15.3 Attachment 3 – Blood Sampling Summary ................................................................ 57 
15.4 Attachment 4 – List of Excluded Previous and Concomitant Medications ............. 58 
15.5 Attachment 5 – List of Classes I - III Elemental Impurities (ICH Q3D), 
Additional Elements and Strategy for Analyses (Primary (I), Secondary (II), or 
Biobanking) ................................................................................................................... 59 
15.6 Attachment 6 – List of Jobs or Activities bearing risk of lead exposure (INRS 
website, health and safety at work) ............................................................................. 60 
15.7 Attachment 7 – Bristol Stool Form Scale .................................................................... 61 
15.8 Attachment 8 – Protocol Amendment Summary ....................................................... 62 
 
LIST OF FIGURES 
Figure 1 
Study Design and Visits ...................................................................................... 21 
 


 
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RATIONALE FOR PROTOCOL AMENDMENT #2 
 
The overall changes and rationale for the changes made to this protocol are as follows:  
 To add 4 timepoints assessments for the consistency of stools (according to Bristol 
scale) and frequency over 24 hours as assessed by the subject at screening, Day-14,  
Day 65 and Day 125. 
 To clarify the sampling methodologies for the assessment of elemental impurities. 
 To modify a mistake in the Attachment 3 regarding the number of blood samples for 
the assessment of elemental impurities in blood: 23 samples to be taken (instead of 22 
samples), leading to a small increase in the total maximum volume of blood to be 
collected during the study (from 322 ml to 330 ml). 
 Modifications of the Global Patient Safety contact details 
 
All modifications are presented in the Attachment 8. 
 
 
PROTOCOL HISTORY 
Protocol version 
Rationale for amendment 
V.2.0, 11JUL2016 
NA – initial version 
V.3.0, 08AUG2016, 
Amendment #1 
 Clarification on the conditions for Study site discontinuation 
and Study Termination requested by the Ethics Committee 
in Netherlands in order to be more in line with the contract 
signed between Aepodia and the local Clinical Research 
Unit. 
 To modify a typo in the Exclusion criterion # 23 regarding 
the Hepatitis C  
 To add the analysis of the C-Reactive protein at the 
screening visit only 
 To add two timepoints assessments for the microbiote at 
Day 65 and Day 125 visits and explain the optional analysis 
of the post treatment assessments. 
V.4.0, 07SEPT2016, 
Amendment #2 
See rationale for Protocol amendment #2 (above) 


 
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LIST OF DEFINITIONS AND ABBREVIATIONS 
 
DEFINITIONS 
 
Audit 
A systematic and independent examination of the study-related activities and 
documents to determine whether the evaluated study-related activities were 
conducted, and the data were recorded, analysed, and accurately reported according to 
the protocol, Sponsor’s standard operating procedures, good clinical practices, and the 
applicable regulatory requirement(s). 
Complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
Compliance 
Adherence to all the study-related requirements, good clinical practices (GCP) 
requirements and the applicable regulatory requirements. 
End of Study 
End of study (study) is the date of the last visit or last scheduled procedure shown in 
the Study Schedule for the last active subject in the study. 
Enrol / Randomise 
The act of assigning a subject to a treatment. Subjects who are enrolled in the study 
are those who have been assigned to a treatment. 
Enter/Consent 
The act of obtaining informed consent for participation in a clinical study from 
subjects deemed- or potentially eligible to participate in the clinical study. Subjects 
entered into a study are those who sign the informed consent document directly or 
through their legally acceptable representatives. 
Ethics Committee 
A board or committee (institutional, regional, or national) composed of medical 
professional and non-medical members whose responsibility is to verify that the 
safety, welfare, and human rights of the subjects participating in a clinical study are 
protected. 
Investigator 
A Physician responsible for the conduct of a clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the Investigator is the responsible 
leader of the team and may be called the principal Investigator. 
Preliminary 
(interim) 
analysis 
Any analysis intended at any time prior to the formal completion of a study. 
Screen 
The act of determining if an individual meets minimum requirements to become part 
of a pool of potential candidates for participation in a clinical study.  In this study, 
screening involves [invasive or diagnostic procedures and/or tests (for example, 
diagnostic psychological tests, x-rays, blood draws)].  For this type of screening, 
informed consent for these screening procedures and/or tests shall be obtained; this 
consent may be separate from obtaining consent for the study. 
Subject 
An individual who is or becomes a participant in clinical research, either as a recipient 
of the test article or as a control.  A subject may be ether a healthy human or a patient. 
 


 
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ABBREVIATION 
 
A1C 
Haemoglobin A1c 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the (plasma concentration vs. time) curve 
AUC0-∞ 
Area under the (plasma concentration vs. time) curve from time 0 to infinity 
AUC0-X 
Area under the (plasma concentration vs. time) curve from 0 to time X 
AUCt 
Area under the serum concentration time curve from time 0 to last quantifiable timepoint 
Beta HCG 
Beta Human Chorionic Gonadotrophin 
BLL 
Blood Lead Level 
BMI 
Body mass index 
CA 
Competent Authorities 
CFD 
Chronic functional diarrhoea 
Cl 
Clearance 
Cl/F 
Apparent total clearance (from plasma) 
CKD-EPI 
Chronic Kidney Disease Epidemiology collaboration  
Cmax 
Observed maximal (peak) concentration 
Cmin 
Observed minimum concentration 
CThrough 
Concentration at the end of the dosing interval 
CMC-SC 
Chemistry Manufacturing and Control- Supply Chain 
CRF 
Case report form:  a printed or electronic form for recording study subjects’ data during a 
clinical study, as required by the protocol. 
CRO 
Contract research organisation 
CRU 
Clinical research unit 
CV 
Coefficient of variance 
DBP 
Diastolic Blood Pressure 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ED 
Early Discontinuation 
EMA 
European Medicines Agency 
EoS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
GGT  
Gamma-glutamyl transferase 
GMP 
Good manufacturing practices 
HCG 
Human chorionic gonadotrophin 


 
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ABBREVIATION 
 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IAD 
Interim access to data 
IBS 
Irritable bowel syndrome 
ICH 
International conference on harmonisation 
ICP-MS 
Inductively coupled plasma- mass spectrometry 
IEC 
Independent Ethic Committee 
IHMS 
International Human Microbiome Standards 
IRB 
Independent Review Board 
IMP 
Investigational Medicine Product 
MAH 
Marketing Authorisation Holder 
MDRD 
Modification of Diet in Renal Disease  
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not applicable 
NCA 
Non-compartmental approach 
ND 
Not done 
ORS 
Oral rehydration solution 
PBRER 
Periodic Benefit-Risk Evaluation Report 
PDE 
Permitted daily exposure 
PDM 
Pharmacokinetics and Drug Metabolism 
PK 
Pharmacokinetic 
PSUR 
Periodic Safety Updated Report 
SAE 
Serious Adverse Events 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SNSPE 
Système National de Surveillance de Plombémie chez l’Enfant 
SOP 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-life 
tmax 
Time of observed Cmax 
TEAE 
Treatment Emergent Adverse Event 
TID 
Three times a day 
TMF 
Trial master file 
V 
Volume of distribution 
ULL 
Urinary lead level 
WHO 
World Health Organisation 
 


 
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1 
STUDY DRUG BACKGROUND INFORMATION 
1.1 Investigational Medicinal Product Name 
Diosmectite is a natural clay belonging to the dioctahedral smectite family extracted from 
monospecific geological deposits specially selected for their high quality.  
These clay minerals present a complex and stable crystallographic structure which is 
characterised by units made up of tetrahedral silica sheets alternating with sheets in which 
aluminium and magnesium are embedded in an octahedral coordination, strongly binding 
these atoms to the lattice. The conversion of the crude clay into the active pharmaceutical 
ingredient requires a complex and long multi-step process to purify and remove impurities in 
order to yield an off-white to slightly beige, tasteless and odourless, stable, very fine powder 
with consistently high quality. 
Diosmectite is an anti-diarrhoeal gastro-intestinal protectant. Thanks to its leaflet structure 
and high plastic viscosity, diosmectite has a powerful coating property on the gastrointestinal 
mucosa. 
Pharmacological studies reveal that diosmectite: 
 
acts as mucus stabiliser and cytoprotector for gastrointestinal mucosa against aggressive 
agents such as hydrochloric acid, biliary acids salts, and other irritants, 
 
exhibits a high adsorption capacity against enterotoxins, bacteria and virus, 
 
reinforces intestinal mucosa barrier, 
 
restores the epithelial barrier defect induced by the proinflammatory cytokine TNF-α 
(involved in several intestinal disorders: infectious diarrhoea, inflammatory bowel 
diseases and food allergy). 
Diosmectite is marketed in more than 70 countries for the following indications: the treatment 
of acute diarrhoea in children (including infants) in association with oral rehydration solution 
(ORS), the treatment of acute diarrhoea in adults, the symptomatic treatment of chronic 
functional diarrhoea in adults and the symptomatic treatment of pain associated with 
functional bowel diseases in adults. 
For this study diosmectite will be provided as Smecta® Orange-vanilla (as flavouring agents) 
and supplied as sachet of powder for oral suspension; each sachet contains 3 g of diosmectite, 
in the form dioctahedral diosmectite, as active ingredient.   
1.2 Findings from Nonclinical and Clinical Studies 
Reference information about diosmectite can be found in the Summary of Product 
Characteristics (SmPC) of Smecta® as approved in France. 
In addition to multiple clinical studies performed in acute diarrhoea with Smecta®, clinical 
studies after chronic administrations of Smecta® have been performed in patients with 
chronic functional diarrhoea (CFD) and in patients with diarrhoea-predominant irritable 
bowel syndrome (IBS subtype D), according to the Rome II/III Classification (Yao-Zong Y et 
al., 2004, Chang FY et al. 2007, Dumitrascu DL et al. 2004). In these studies, the 
administration of Smecta® was from 2 to 8 weeks with administration of Smecta® three 
times a day (TID). The clinical documentation of Smecta® has been updated regularly for 
periodic review, the Marketing Authorisation Holder (MAH) re-evaluate the data supporting 
the efficacy claims for Smecta®. In parallel, the risk and benefit of Smecta® has been 
regularly reviewed through Periodic Safety Update Reports (PSURs) and Periodic Benefit-
Risk Evaluation Reports (PBRERs) which concluded that the benefit risk ratio for the 
compound in this current indication is favourable. 


 
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1.3 Known and Potential Risks 
From the incidence rates in clinical trials, the most commonly expected adverse drug 
reactions (ADR) following Smecta® administration is constipation, occurring in 
approximately 7% of adults. After administration of Smecta®, rash and urticaria have been 
observed as uncommon and rare ADRs, respectively.  
Additional information regarding risks and benefits after the administration of Smecta® to 
human subjects may be found in the SmPC of the product.  
1.4 Selection of Investigational Medicinal Product Dose and Dose Regimen 
The dose strength of Smecta® 3g TID corresponds to the approved dose for the treatment of 
chronic diarrhoea in adults.  
Typically, chronic diarrhoea is defined as watery or loose stools that last for at least four 
weeks. Therefore, the duration of 5 weeks of treatment with Smecta® has been selected based 
on the likely minimum duration of a repeated chronic treatment course in patients with 
functional chronic diarrhoea. This is further supported by consumer health data collected by 
the MAH.  
1.5 Study Population 
Adult subjects with functional chronic diarrhoea will be enrolled in this study as they 
represent one of the most representative target patient population for Smecta® according to its 
indications and requiring repeated chronic administrations.  
1.6 Potential Benefits to Participants 
Since the study participants will be required to collect repeated blood and urine samples and 
stop their study treatment for 3 months during the follow up, this study has to be considered 
as a study without a direct therapeutic benefit resulting from their participation in this study. 
However subjects enrolled in this study should be improved by Smecta® for their symptoms 
related to their chronic functional diarrhoea during the study treatment period. 
1.7 Rationale for the Study 
The recent ICH guideline on elemental impurities (ICH Q3D, step 4, 2014) imposes to 
perform a risk assessment on medicinal products containing elemental impurities. These 
elemental impurities consist in particular in cadmium, lead, arsenic, mercury, cobalt, 
vanadium, nickel, that may be present in natural constituents of mineral origins such as 
diosmectite extracted from a quarry. 
These elemental impurities have been categorised in ICH Q3D guidelines into 3 classes (refer 
to Attachment #5_Section 15.5) based on their toxicity (based on a permitted daily exposure 
(PDE)) and likelihood of occurrence in the drug product. 
For other elements such as aluminium, manganese or zinc no limiting PDE has been 
established yet.  
Lead has been identified as the major elemental impurity in Smecta®; indeed, in case of 
chronic diarrhoea posology i.e. 3 sachets of diosmectite (Smecta®) or 9 g per day, the lead 
intake could be a total amount of approximately 46.35 μg/day. This amount exceed the 
amount allowed by the new upcoming ICH Q3D guideline which comes in force for existing 
marketed drug in December 2017, and that will limit the lead ingestion PDE to 5 μg/day. 
The amount of other Class I elemental impurities contained in 3 sachets of diosmectite 
(Smecta®) such as arsenic and barium are approximately 4.23 μg/day and 1395 μg/day 
respectively and thus below their respective new PDE (15 μg/day for arsenic and 1460 μg/day 
for barium).    


 
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In vitro studies aiming at reproducing the gastrointestinal environment, have evidenced lead 
and other elements delivery from clay in acid pH, and reintegration of the elements in the clay 
sheets in basic pH environment. Experimental studies in animal models for assessing the 
bioavailability and absorption of elemental impurities have not been evaluated as predictive of 
human exposure.  
However, how much of this lead could be bioavailable for potential stomach and intestine 
absorption in adult patients after chronic oral ingestion of Smecta® is unknown as well as the 
absorption of these elemental impurities. 
From more than 40 years of sales of Smecta®, no adverse events potentially related to 
elemental impurities, particularly saturnism and/or chronic lead intoxication symptoms have 
been reported to Ipsen or to Health Authorities. In addition, no signal within the Ipsen 
Pharmacovigilance Safety Data Base, and notably in targeted body systems (such as nervous 
system, blood and lymphatic, renal and urinary), has been detected. 
Furthermore, declaration of lead intoxication is mandatory in France. Between 1995 and 
2014, neither lead intoxication, nor blood lead level > 100μg/l have been reported in children 
taking Smecta® to the SNSPE (Système National de Surveillance de Plombémie chez 
l’Enfant). 
However, regarding the new ICHQ3D guidelines, Smecta® does not comply with the new 
requirements. Therefore, the MAH considered that in order to perform an appropriate risk 
assessment of elemental impurities contained in Smecta®, including lead as primary 
elemental constituent, clinical data need to be generated in humans after chronic 
administration of Smecta®.  
Lead is a common element found in low concentration in the Earth’s crust. It is widely used in 
industry, particularly in products such as construction materials, paint, batteries and piping. 
Lead causes health problems such as toxicity of the liver, kidneys, hematopoietic system and 
nervous system. During the 70’s and 80’s, concern over lead related health problems led to 
the introduction of unleaded gasoline and the banning of lead based paint (for review see Kim 
et al. 2015). After lead enters the body, it can transit along several pathways depending on its 
source (organic or inorganic). The fraction of lead that is absorbed depend mainly on the 
physical and chemical form. Other important factors are subject’s specific such as age, 
gender, smoking and nutritional status. The half-life of lead in the blood compartment is about 
40 days in adults (99% of circulating lead is contained in the erythrocytes, Rabinowitz, 1991). 
The half-life of lead in blood of children and in pregnant women is reported to be longer due 
to bone remodelling. Residence time in other organs such as bone is much longer and ranges 
from 10 to 30 years. Whole blood and serum/plasma have been used as biological fluid used 
for the assessment of lead exposure both for screening, bio-monitoring and diagnostic 
purposes (Barbosa F et al. 2005, Falq et al. 2011).      
Blood lead level (BLL) from whole blood is the main biomarker used to monitor exposure 
and has been widely used in numerous epidemiological studies.  BLL is a balance between 
recent absorption of lead and a removal of lead stored in the body, especially in bone 
(Christoffersson et al., 1986; Nilsson et al., 1991) and is representative of the internal dose of 
lead in the organism when the exposure is stable (Barbosa et al., 2005). Plasma lead level 
could be a better biomarker, especially at high exposure (workers for example) (Rentschler 
and al, 2012 – Bergdhal and al, 1997). Reference ranges for estimation of a baseline of lead 
level in European Western countries are available for blood (Falq and al, 2011). Estimation of 
blood lead levels have been considered for the current study as the primary endpoint. In 
addition, it is proposed to biobank samples for potential assessment of lead levels in plasma. 


 
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The intestinal microbiota (containing about 90% of the body microorganisms) contributes to 
intestinal homeostasis through direct regulation of the development of the intestinal mucosa 
and maturation of the immune system. Therefore, the intestinal microbiota can be perceived 
as an integral component of the host’s physiology. 
An increasing number of studies emphasizes the diverse roles of the intestinal microbiota. 
These roles are often associated with beneficial physiological effects for the host, reflecting a 
symbiotic and beneficial crosstalk between cells of the intestinal epithelium and the resident 
microbiota. However, the cellular and molecular mechanisms developed by the microbiota in 
order to influence the host’s intestinal cell responses remain poorly understood. 
The understanding of the complex host-microbiota relationship and the possibility to 
modulate these interactions is of key importance for human health. Our knowledge on the 
various contributions of the microbiota to health is still in its infancy and the underlying 
cellular and molecular mechanisms of its interplay with the host intestinal cells remain poorly 
understood (de Wouters et al., 2014). 
We would like to take the opportunity of this study to explore the potential effect of Smecta® 
on the microbiota by collecting selected faecal samples at various time point before, during 
and after the chronic administration of Smecta®. 
 
 


 
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2 
STUDY OBJECTIVES 
2.1 Primary Objective 
To assess the concentration of lead in blood, one of the Class I elemental impurities defined 
by ICH Q3D guidelines, after chronic administration of Smecta® in subjects with chronic 
functional diarrhoea. 
2.2 Secondary Objectives 
 To assess blood concentration of other Class I and IIa elemental impurities of interest 
(i.e. arsenic, cadmium, mercury, cobalt, vanadium, nickel and barium) and of 
aluminium after chronic administration of Smecta® in subjects with chronic 
functional diarrhoea;  
 To assess urinary lead levels and urinary levels of other selected Class I and IIa 
elemental impurities of interest (i.e. arsenic, cadmium, mercury, cobalt, vanadium, 
nickel and barium), and aluminium after chronic administration of Smecta®;  
 To further assess the safety and tolerance of Smecta® after chronic administration.  
2.3 Exploratory Objectives 
 An ancillary study will be conducted during this study to assess the bowel microbiote 
composition, stools consistency and frequency after chronic administration of 
Smecta® in subjects with chronic functional diarrhoea. 
 Additional blood samples will be biobanked in order to further potentially assay other 
elemental impurities levels (see Attachment #5_Section 15.5); 
 Plasma samples will be biobanked in order to further potentially assay lead in plasma. 
 


 
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3 
INVESTIGATIONAL PLAN 
3.1 Overall Study Design 
This is a prospective, open-label, non-comparative, multi-centre, international, without direct 
individual benefit study, assessing the potential absorption of elemental impurities after 
chronic administration of Smecta® in subjects with chronic functional diarrhoea. It is 
intended that a total of 35 subjects will be enrolled (i.e. assigned to a treatment, please see 
section 4.1) to ensure that at least 29 subjects will complete the study. It is planned to have at 
least 40% of each gender in the entire study. 
After a screening period of up to 6 weeks including a baseline assessment, each subject will 
be dosed with Smecta® TID over 5 weeks (Day 1 to Day 35) and then continue to be 
monitored over a post-treatment follow-up period of 3 months until end-of-study visit (see 
Figure 1). Blood samples, urine collections and faecessampling will be obtained at screening 
phase and baseline visit, over the treatment period and then during follow-up period. Potential 
adverse events will be collected and monitored throughout the study.  
No formal interim analysis is planned during the study. However, BLL obtained on screening 
and baseline (prior the first intake of Investigational Medicine Product (IMP)) and during the 
study will be analysed and reviewed on an ongoing basis by the Sponsor for potential study 
adjustments (e.g.: confirm assumptions for sample size calculation). 
 
Figure 1 Study Design and Visits  
 
 
3.2 Primary and Secondary Endpoints and Evaluations 
Concentration of lead, other elemental impurities and other endpoints assessed in this study 
are further described below. 
3.2.1 Pharmacokinetics of Lead, other Impurities Endpoints and Evaluations 
Methods 
Primary Endpoints: 


 
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Changes in BLL from baseline during treatment and post-treatment follow-up period.   
PK parameters of lead may be calculated if feasible. 
Secondary endpoints: 
 Change from baseline of concentrations of other selected Class I elemental impurities 
(i.e. arsenic, barium) and Class IIa elemental impurities (i.e.: cadmium, mercury, 
cobalt, vanadium, nickel) and aluminium in blood during treatment and post-treatment 
follow-up 
period. 
PK parameters of selected Class I and Class IIa impurities may be calculated if 
feasible.  
 Change from baseline of urinary concentrations of selected Class I and IIa elemental 
impurities (arsenic, barium, cadmium, mercury, cobalt, vanadium, nickel) and 
aluminium in urine at the end of Smecta® administration and during follow-up period.  
3.2.2 Exploratory Endpoints 
3.2.2.1 
Microbiote assessment  
Microbiote characteristics will be evaluated during Smecta® treatment and follow up and 
compared to baseline. 
The method of samples and dosing will be detailed in a separated technical document 
developed in collaboration with Institut National de la Recherche Agronomique (INRA) – 
Jouy-en-Josas, France. 
Consistency of stools (recorded and rated according to Bristol scale) (See Attachment 
#7_Section 15.7) and frequency will be assessed over 24h by the subject as described in the 
Study Schedule (See Attachment #1_Section 15.1). 
3.2.2.2 
Biobank 
Blood and urine samples will be stored for potential further dosages of other elemental 
impurities as lithium (Li), antimony (Sb), molybdenium (Mo), copper (Cu), Tin (Sn) and 
chromium (Cr).  
Plasma samples will be biobanked in order to further potentially assay lead in plasma. If 
feasible, PK modelling of lead (and potentially other elemental impurities levels) may be 
performed.  
3.2.3 Safety Endpoints and Evaluations 
Safety Endpoints will be assessed as described in the Schedule of events (see in Attachment 
#1_Section 15.1):  
o physical examination, vital signs, ECG,  
o clinical laboratory blood tests (see in Attachment #2_Section 15.2), 
o Adverse Events and Treatment Emergent Adverse Events (TEAE). 
To note: During the study additional assessments may be performed at the discretion of the 
Investigator in case of adverse events. 
3.3 Subjects Managements 
3.3.1 Study Visits and Procedures 
Study visits and procedures are described in the Study Schedule of Events (see Attachment 
#1_Section 15.1). 
It is planned that subjects will be resident in the Clinical Research Unit (CRU) at particular 
study visits, mainly during 24-hour urine collection. Otherwise, subjects will self-administer 
and come to the CRU at regular interval for drug supply, blood and urine collections as well 


 
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as the review of adverse event as described below in this section and in the schedule of events 
(see Attachment #1_Section 15.1). 
Compliance to diosmectite (Smecta®) intake will be monitored through the use of subject 
diary.  
3.3.1.1 
Screening Period 
The subjects will attend the CRU (Visit 1) to enter the screening period within 21 to 42 days 
prior to dosing Visit 2.  
After a subject has been checked for pre selection criteria, has received complete explanations 
and response(s) to his/her potential questions about the study by the Investigator (or designee) 
and has been given reasonable time to think about it, a signed and dated informed consent 
form will be obtained prior to any study procedures.   
Once informed consent is obtained, subjects will be allocated a study-specific subject number 
which must comply with formatting specifications provided by the Sponsor. 
Demographic data will be collected including race, smoking status, alcohol consumption, and 
dietary habits. 
The screening tests and assessments will then be performed to check compliance with 
Inclusion/Exclusion criteria and study restrictions. The results must be obtained and confirm 
subject’s eligibility prior to dosing on Visit 2 at Day 1. 
3.3.1.2 
Baseline 
The subjects will come back for admission to the CRU (Visit 2), 3 to 6 weeks later at the 
latest on Day -1 in the morning, at the discretion of the Investigator, to be resident in the CRU 
for obtaining a 24-hour urine collection as well as stool sample(s) for baseline evaluation. 
Based on Investigator judgement or if required locally, some of the screening assessments 
may be redone to confirm that subjects are still compliant with the Inclusion/Exclusion 
criteria and study restrictions. 
3.3.1.3 
Treatment Period 
The treatment period will occur from Day 1 (first intake in the morning) to Day 35 (last intake 
in the evening) and subjects will be required to attend the CRU on several occasions during 
the treatment period: 
• 
Day 1 (Visit 2): The subjects will be dosed within the unit with Smecta® at breakfast, 
lunch and dinner time, PK samples will be collected as described in the Schedule of 
events (see Attachment #1_Section 15.1) and the subject will leave the unit on Day 2 
after PK sampling and Smecta® administration in the morning. Subjects will receive a 
box containing Smecta® treatment for a bit more than 2 weeks (20 days) as well as a 
diary to record the drug administration and consistency and frequency of stools at the 
day before the Day 8 visit. 
• 
Out-patient visits (Visits 3 to 6): the subjects will be required to come back to the CRU 
for out-patient visits on Days 8, 15, 22 and 29 for blood sampling for impurities dosing 
and the review of adverse events and concomitant medication. One day before Day 8, 
subject will need to complete the diary with assessment of consistency and frequency 
of stools using the Bristol scale. During those visits, stools will be collected only on 
Day 8. At Day 22 the subjects will receive a second box containing Smecta® treatment 
for the last 2 weeks.   
• 
Days 35-36 (Visit 7): Subjects will come back to the CRU in the morning of Day 35 (or 
the evening before for convenience) in order to start the process to collect urine 
samples, blood and stools sampling. They will be dosed with Smecta® at breakfast, 


 
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lunch and dinner. They will leave the unit in the morning of Day 36 after the 
completion of the 24-hour urine collection and PK sample in the morning.   
3.3.1.4 
Post-Treatment Period 
The subjects will be asked to come back to the CRU at two occasions during the post-
treatment period: these visits should occur at Week 9 (Visit 8) and at Week 13 (Visit 9). At 
Visit 8 and 9, blood sampling will be collected as well as 24-hour urine collection for 
impurities dosing. Stools samples will be collected only at Visit 8 (week 9) and Visit 9 (Week 
13).  
3.3.1.5 End-of-Study (EoS)/Early Discontinuation Visit (ED) (Visit 10) 
Subjects will be discharged from the study after completion of the EoS visit for follow-up 
assessments as described in the Schedule of event (see Attachment #1_Section 15.1) which 
will happen approximately 4 weeks after Visit 9, or earlier in case of early discontinuation. 
3.3.2 Subjects Disposition 
All subjects visits will be out-patient, except for Visit 2 (Day -1 to Day 2), Visit 7 (Day 35 to 
Day 36) and Visits 8 and 9 (where subjects will be hospitalized in the CRU). For 
convenience, subjects may come the evening before the hospitalisation as study assessments 
start early morning. 
3.3.3 Study Duration 
For each individual subject, the study is expected to last approximately 5,5 months, including 
up to 42 days for screening assessments, 35 days of treatment and a 3-month post-treatment 
follow-up period.  
3.4 Study Conduct  
It is planned to dose the subjects based on enrolment capabilities of each Clinical Research 
Units (CRU) and to limit as much as possible the number of cohorts. As there are no safety 
concerns or limitation with the administration of study drug, multiple subjects may be dosed 
at the same interval. The recruitment of subjects will be competitive between the CRUs. 
3.5 Rationale for the Study Design 
Discussion of Design 
The primary objective of the study is to investigate the Blood Lead Levels after the chronic 
oral administration of Smecta® in subjects suffering from chronic functional diarrhoea. In 
each subject, lead concentrations obtained at several occasions during and after dosing with 
Smecta® will be compared to each individual baseline data. Other elemental impurities levels 
will be assessed in blood comparatively to baseline. Moreover, 24h urine level of all these 
impurities will be collected and assessed by mean of validated analytical methods. Samples of 
biobanking will be collected for potential other elemental impurities assessments as well as 
the potential measurement of lead in plasma. Stools samples and the assessment of stool 
consistency and stool frequency will be also collected for microbiote assessment as ancillary 
study. 
Considering the extensive distribution of lead in the body as well as its long term residence 
time, a post-treatment follow-up period of 3-months has been considered appropriate to detect 
any change in the elemental impurities within the frame of a chronic administration of 
Smecta®. 
Dose Selection and Dosing Regimen  
The dose of Diosmectite (i.e. 1 sachet (3g) TID) is the recommended dose for Smecta® in the 
indication of chronic diarrhoea in an adult population. 


 
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For the purpose of this study, and in order to potentially limit variability and increase the 
bioavailability of lead (higher at low pH) dosing of Smecta® will occur in condition of fast 30 
minutes before breakfast, 1 hour before noon lunch and 1 hour before evening dinner.  
Five (5) weeks can be considered as a repeated chronic administration as chronic diarrhoea is 
defined as usually lasting more than 4 weeks. 
Population Selection and Sample Size 
The targeted subject population to assess the primary endpoint are subjects with chronic 
functional diarrhoea, one of the indication of Smecta® with subjects treated daily for several 
weeks. 
Indeed, lead absorption could be different in subjects with normal gastro-intestinal transit time 
from patients with various gastrointestinal disorders of organic origin. Moreover patient with 
acute diarrhoea require a treatment lasting usually for 3 to 7 days that is far from chronic 
condition.  
Important factors, that impact the fraction of lead that is absorbed, may depend on the 
subject’s age, gender, smoking, fasting and nutritional status (Falq et al. 2011); this is why the 
subjects above 60 years of age will not be included in the study. Smoking and nutritional 
status will be part of the demographic data collected in this study. Smecta intake and fasting 
status will be standardized as far as possible. To have approximately equal representation in 
each gender, it is planned to enrol a minimum of 40% of each gender, with gender distributed 
approximately equally between sites (e.g. no site with less than 35% of one gender). 
See Section 8.1.2 for sample size determination. 
4 
POPULATION RECRUITMENT, ENROLMENT AND WITHDRAWAL 
4.1 Definitions 
Screened Subject: 
A screened subject is a subject who correspond to the preselection criteria, who signed the 
Informed Consent and could potentially be enrolled into the study. 
Screening Failure: 
A subject is considered as a screening failure when he/she is not enrolled in the study after 
signing the Informed Consent. 
Subject Enrolment: 
A subject is considered as enrolled in the study when he/she is assigned to a treatment. 
Subject Drop-out: 
A subject will be considered as drop-out when, for any reason, he/she withdraws from the 
study or is discontinued from the study after enrolment. 
4.2 Recruitment of Population  
As described in Section 3.3.1, subjects will be screened within 42 days before dosing on a free 
voluntary basis. The criteria for enrolment must be followed explicitly. If a subject who does 
not meet enrolment criteria is inadvertently enrolled, he/she should be discontinued from the 
study and the Sponsor or its designee must be contacted.   
As illustrated in the Study Schedule of Events (see Section 15.1), eligibility of subjects in the 
study will be based on the results of a screening medical history (including any pre-existing 
conditions, and previous/concomitant medication(s)), physical examination, clinical 
laboratory tests, vital signs and electrocardiogram (ECG). These tests / assessments may be 
performed at any time during the screening period (Day -42 to Day -21, included) after 


 
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Informed Consent signature. Results of tests and assessments required at screening should be 
available to confirm subject’s eligibility prior to first dosing on Day 1. 
4.3 Inclusion Criteria 
Potential study subjects may be entered in the study if they meet all of the following criteria: 
(1) 
Provision of written informed consent prior to any study related procedure. 
(2) 
Male or female subjects aged between 18 and 60 years (inclusive) at the time of giving 
informed consent.  
(3) 
Subjects with chronic functional diarrhoea defined as “Loose (mushy) or watery stools 
according to Bristol scale grade 6 and 7, occurring in at least 75% of stools for the last 
3 months with symptoms onset at least 6 months before diagnosis, without or with pain 
(including Irritable Bowel Syndrome)” as documented in subject’s medical history. 
(4) 
Body Mass Index (BMI) between 19 and 32 kg/m2 (inclusive), with minimum body 
weight of 50 kg, at screening. 
4.4 Exclusion Criteria 
Potential study subjects may not be entered into the study if any of the following apply: 
Exclusion criteria related to the disease: 
(1) 
Identified or strongly suspected organic cause to diarrhoea, e.g. ulcerative colitis, 
Crohn’s disease, Celiac disease, bowel malabsorption, chronic pancreatitis, chronic 
diarrhoea primarily due to diabetes.  
(2) 
Any drug induced diarrhoea. 
Exclusion criteria related to the study drug: 
(3) 
Prior exposure to diosmectite or other clay(s) or charcoal or other compounds of 
mineral origin e.g. talc, kaolin, etc. within 1 month prior to screening.  
(4) 
Except the administration of Smecta® as part of the study treatment, subject should not 
self-administer any other diosmectite, including Smecta or other clays or charcoal or 
other compounds of mineral origin during the study.. 
(5) 
History of any serious adverse reaction or adverse event or hypersensitivity to any 
component of Smecta®. 
(6) 
Active lactose and/or fructose Intolerance, deficit in sucrose/maltase or glucose 
malabsorption as documented in subject’s medical history.  
(7) 
Repeated daily intake of drugs with narrow therapeutic index margin (e.g. digoxin, 
theophylin) (see list in Attachment #4_Section 15.4). 
Exclusion criteria related to primary end point: 
(8) 
Known domestic, leisure or professional exposure to elemental impurities, notably lead, 
arsenic, cadmium, mercury, aluminium as e.g. building workers, metallurgy, auto 
repairers, scrap metal recyclers, painting, pottery, shooting (see complete list in 
Attachment #6_Section 15.6). 
(9) 
Artificial feeding. 
(10) Subjects eating shellfish (crustaceans, molluscs) more than 2 times a week.  
(11) Subjects living in an old building or house using materials containing lead. 
(12) Planned changes either of residency or of professional/leisure activities during the 
study (including follow-up period) that may increase the likely exposure to elemental 
impurities.  
Exclusion criteria related to the ancillary study on digestive microbiota: 


 
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(13) Antibiotic agent intake within the month prior to baseline visit (Day -1). 
(14) Risk of antibiotic treatment course during the study. 
(15) Need for metformin and or proton pump inhibitors (PPI) intake within the month prior 
to baseline or during the study. 
Other Exclusion criteria related to the study protocol: 
(16) Receipt of any investigational agent or study drug within 3 months prior to screening. 
(17) Presence of clinically significant physical, laboratory, vital signs, or ECG findings that, 
in the opinion of the Investigator, Medical Monitor, and/or the Sponsor, may interfere 
with any aspect of study conduct or interpretation of the results. 
(18) History of any major surgery within 6 months prior to screening or anticipated surgery 
during the study. 
(19) Women who are breastfeeding or are planning to become pregnant during the study, 
(20) Positive pregnancy test at screening or baseline.   
(21) Loss or donation of blood >500 ml within 3 months before screening, and/or going to 
donate blood during the study. 
(22) Poor venous access as defined by the Investigator or designee. 
(23) Positive for hepatitis B antigen or hepatitis C virus. 
(24) Positive results for human immunodeficiency virus, or had received diagnosis for 
acquired immunodeficiency syndrome. 
(25) No history or clinically significant symptoms or severe disease, including cardiac, 
neurological, pulmonary, hepatic, biliary, gastrointestinal, endocrinologic, or renal 
disorders, or cancer within the last 5 years (except localised or in situ cancer of the skin 
and cervical cancer in situ). 
(26) Need for special dietary restrictions, unless the restrictions are approved by the 
Investigator. 
(27) Likely to be uncompliant or uncooperative during the study, in the judgment of the 
Investigator. 
(28) Unable to understand the nature, scope and possible consequences of the study, in the 
judgment of the Investigator. 
(29) Any known factor, condition, or disease that might interfere with treatment compliance 
or study conduct such as drug or alcohol dependence or psychiatric disease. 
(30) Sponsor employees or Investigator site personnel directly affiliated with this study, and 
their immediate families.  Immediate family is defined as a spouse, parent, child or 
sibling, whether biological or legally adopted. 
4.5 Randomisation 
No randomisation list will be required for this open-label, non-comparative study. Subjects 
will be identified throughout the study with the subject number assigned at enrolment. 
It is planned to enrol a minimum of 40% of each gender, with gender distributed 
approximately equally between sites (e.g. no site with less than 35% of one gender).  
4.6 Discontinuation of an Individual Subject 
4.6.1 Discontinuation / Withdrawal Criteria 
All subjects are free to interrupt or withdraw their consent to participate in the study at any 
time, for any reason, specified or non-specified, and without penalty. 


 
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A subject may also be discontinued from the study upon Sponsor’s and/or Investigator’s 
decision for any appropriate reason, such as safety related to an adverse event or concomitant 
therapy, major protocol violation or deviation, noncompliance with protocol restrictions, etc. 
Due to the study primary objective it is important that subjects participating to the study 
comply with the full treatment and follow-up schedule. Hence their wish to take part to the 
study up to its end should be fully discussed and confirmed at study entry. This requirement is 
to ensure the study scientific value by ensuring the collection of the full set of data necessary 
for its analysis and does not preclude any subject right to withdraw at any time as stated 
above.  
All cases of discontinuation will be discussed between the Investigator and the Sponsor or its 
representative. 
4.6.2 Follow-up Procedures for Drop-out Subjects 
In case a subject who has already taken study medication(s) drops out or is discontinued from 
the study earlier than study end, he/she should follow the EoS/ED visit assessments (Visit 10) 
as appropriate.  The reason and date for drop-out should be documented. 
Drop-out subjects will have completed their study participation when they have undergone all 
assessments of this last study visit (EoS/ED), and electronic case report form (eCRF) should 
be completed up to these last assessments. 
Data collected prior to subject discontinuation will be kept in study records and shared with 
the Sponsor for study analyses (see Section 9) unless a subject formally specifies his decision 
to withdraw his consent for using data already collected before discontinuation.  
4.6.3 Replacement Strategy 
No replacement of subjects is foreseen in the study. 
4.7 Discontinuation of Study Site(s) 
Study site participation may be discontinued if the Sponsor or its designee, the Investigator 
judges it necessary for any reason within agreed timelines per contract when enrollment of 
subjects has not commenced. 
After the start of subjects enrollment, the study site participation may be discontinued for 
more restrictive reasons described in the contract (ex: request of withdrawal from local 
regulatory authority or the ethics committee of the study site, or for the best interests of the 
subjects’s health, or because sponsor or it designee or the CRU has been declared insolvent or 
a bankruptcy/winding-up petition has been filed…). The contract signed with the CRU will be 
leading in case of discrepancy between the protocol and the contract. 
4.8 Discontinuation of Subject's Recruitment 
Subjects’ recruitment in the study may be stopped at any time upon Sponsor’s decision, e.g. if 
actual data indicate that a sufficient number of subjects have already been enrolled in the 
study or for any other appropriate reason. 
4.9 Study Termination 
The study can be discontinued prematurely if the Sponsor judges it necessary either for 
reasons described in Section 4.7 or for any other appropriate reason.  In that case, best efforts 
should be made that all scheduled procedures and assessment for subjects who are still in the 
study will be performed. 


 
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5 
STUDY TREATMENT 
5.1 Study Drug and Treatment of Subjects 
5.1.1 Investigational Drug Formulation 
Diosmectite, marketed as Smecta®, originating from a single batch number/lot, appropriately 
labelled for its use in clinical trials (Annex 13 of Good Manufacturing Practices (GMP) 
guidelines on IMP) will be provided to the pharmacy of the CRU. 
Dosage Form and Strength of Smecta® 
Smecta® will be provided as sachets, each sachet containing 3 g of diosmectite as powder for 
oral suspension. Excipients include glucose monohydrate, saccharine sodium, orange flavour 
and vanilla flavour.     
Supplies Manufacturing, Packaging and Release 
Smecta® will be manufactured, labelled and packed as individual subject kits by Ipsen 
Pharma (Beaufour Ipsen Industrie (Dreux France) or its delegate who will perform secondary 
labelling, packaging, release and shipment to the CRUs, according to applicable regulations 
and guidelines. 
The batch used for the study will be selected based on the maximal level of lead according to 
the Smecta® specification for batch release (approximately 4.7μg/g).  
A Certificate of Analysis reflecting the product release statement will be issued for the batch 
of Smecta® used in this study, together with a Certificate of Compliance with GMP. 
Labelling 
The label texts for packaging units will be in compliance with Annex 13 of the European 
Union (EU) Guide to GMP and should be translated or adjusted to be in compliance with 
applicable regulatory requirements, national laws in force and local languages. 
Storage 
The Investigator, or designee (e.g. pharmacist), will ensure that IMPs will be stored, and 
returned or destroyed according to applicable regulations. The IMP will be stored at the CRU 
in a secured and locked area, at room temperature, in accordance with applicable regulatory 
requirements and any other specific instructions provided by the Sponsor. 
At the CRU, supplies for this study will not be stored in such a way that they may be 
confounded with supplies being used for another study. 
Investigational Drug Accountability 
Smecta® will be provided to the Investigator, or designee (e.g. Pharmacist), and administered 
to subjects after appropriate instructions as described in Sections 5.1.2 and 6.1. 
The Investigator or designee (e.g.: Pharmacist) will record drug movement and accountability 
on specific drug accountability forms/logs.  Study medication allocation, preparation and 
disposition records, as well as shipping, dispensing and returned drug records, and inventory 
logs must be maintained at the investigational site.  
The dispensing for each subject will also be recorded in the eCRF. 
It is essential that all used and unused supplies are retained for verification by the study 
monitor or designee who will ensure that Smecta® administration in the eCRF, the 
accountability forms/logs and the number of remaining used/unused treatments are consistent.  
At the end of the study after confirmation from Sponsor or its designee, all remaining IMPs 
will be either destroyed at the site (preferred option) or returned to CMC-SC (Beaufour Ipsen 
Industrie – Dreux- France) for destruction (only if site is not able to do it). 


 
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5.1.2 Study Drug Administration 
The Investigator, or designee, will only dose and allocate Smecta® treatment to subjects 
enrolled in this study.  
Two kits of Smecta® will be prepared and provided to subject(s) according to the pre-
determined dosing schedule agreed upfront with the Sponsor or designee; each kit consisting 
of one box, containing 60 sachets of Smecta® covering the administration for 20 days. 
Each subject will be instructed to ingest Smecta® at three occasions, in the morning, at noon 
and in the evening, and every day until the Day 35 visit included. In order to standardize the 
conditions of administration of Smecta® and potentially limit the variability and increase 
bioavailability of lead all along the trial, Smecta® should be taken in fasting and at least one 
hour before meal, except for breakfast at least 30 minutes before. 
The actual time of dosing of all Smecta® ingestions will be recorded by the subject on his/her 
own Diary as well as the start and ending time of the meals, and reported by the site in the 
eCRF, or will be recorded by the site when applicable in the eCRF.  
Subjects will be instructed to contact the Investigator as soon as possible if he/she has a 
complaint or problem with the study drug so that the situation can be assessed. 
5.2 Blinding  
Not applicable (open label study). 
5.3 Product complaint 
Sponsor collects product complaints on study drugs used in clinical trials in order to ensure 
the safety of study participants, monitor quality, and to facilitate process and product 
improvements. 
The Investigator is responsible for handling the following aspects of the product complaint 
process in accordance with the instructions provided for this study: 
• 
Recording a complete description of the product complaint reported and any associated 
adverse events (AEs) using the study-specific complaint forms provided for this 
purpose. 
• 
Faxing the completed product complaint form within 24 hours to Sponsor or designee. 
If the Investigator is asked to return the product for investigation, they will return a copy of 
the product complaint form with the product. 


 
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6 
STUDY RESTRICTIONS 
6.1 Study Drug Administration 
The content of sachet should be reconstituted with water (approximately 200 ml), just before 
ingestion.    
The regimen of intake is three times per day (TID) in fasting state, with consequently the 
following timings: 
- 
at wake up time , at least 30 minutes before breakfast 
- 
in the morning, 1 hour before lunch time 
- 
in the late afternoon, 1 hour before dinner time 
Example : if breakfast at 7:30, lunch at 12:30 and dinner at 19:30,  
Smecta® intake should occur :  
- 
at wake up time and before 7:00 
- 
in the morning at 11:30 
- 
in the late afternoon at 18:30 
If a dose administration is missed, subject is instructed to ingest the missing dose together 
with the next dosing occasion. If no meal at a given day is taken (e.g. breakfast), Smecta® 
should be taken in fasting state anyway and at three occasions (see Section 5.1.2). 
 
6.2 Concomitant Therapy(ies) 
Any other treatment should be taken at least 2 hours before or after the ingestion of Smecta®.  
Drugs with a low therapeutic index are specifically excluded (e.g. digoxin, theophylline) if 
repeated daily intake is needed. 
Antibiotics are forbidden during the study as they could interfere with microbiote evaluation. 
Compounds containing Diosmectite or similar compounds or mine extracts, as well as other 
compounds containing elemental impurities such as antacids (e.g. Maalox) are excluded. 
The list of excluded concomitant medications are listed in Attachment #4_Section 15.4.  
During the study the Investigator should check if the subject has received any concomitant 
medication/therapy that is not permitted at study entry.   
Subjects will provide information about all previous medication taken over the last month and 
investigational drug taken over the last 3 months, and medication taken during the study, and 
this information will be recorded on the appropriate eCRF. 
Contraception 
No specific contraception methods are required for the study participation. A pregnancy test 
will be performed on screening, baseline and end-of-study visit. Women are requested to be 
non pregnant at inclusion and not becoming pregnant during the treatment phase of the study. 
Rescue Medication  
Loperamide will be allowed as rescue medication should the chronic diarrhoea worsen during 
the study.   
The recommended dose regimen will follow the SmPC of loperamide with a maximum daily 
dose not exceeding 12 mg. 
 


 
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6.3 Lifestyle Restrictions 
It is requested that subject refrains from eating shellfish (crustaceans, molluscs), participate in 
shooting or hunting activities on a regular basis, as well as doing pottery (see Exclusion 
criteria).  
Subjects will be asked to comply with internal CRU rules regarding smoking or other 
potential restrictions when resident in the CRU (see Study Schedule in Attachment 
#1_Section15.1). 


 
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7 
STUDY ASSESSMENTS 
Timing of blood lead sampling and urine collections, safety assessments and any other tests is 
specified in the attached study schedule of events table. Maximum blood volume for all tests 
and assays is also documented for each of the tests in the attached summary of blood 
collection volumes (See Attachment 3_Section15.3).   
7.1 Safety Assessments 
The Investigator is responsible for monitoring the safety of the subjects who have entered the 
study and to take appropriate action during the study concerning any event that seems 
unusual, as well as to alert the Sponsor or its assigned representative. 
The Investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or that caused the subject to discontinue before completing the study.  
The subject should be followed until the event is resolved or explained. Frequency of follow-
up evaluation is left to the discretion of the Investigator. 
The Investigator will be responsible for a clinical assessment of the study participants before 
discharge from the study, and for the set-up of a discharge plan if needed. 
The Sponsor Medical Monitor and the Global Patient Safety Physician will monitor safety 
data throughout the course of the study. 
In addition to records of observations made at specific times, unexpected signs and symptoms 
and concomitant medications will be recorded in the clinical study records throughout the 
study. 
Safety Parameters 
The following safety parameters will be collected during this study at specific time points 
described in the study schedule of events: 
• 
Adverse events; 
• 
Physical examination with aural/body temperature and body weight/height 
• 
Vital signs, including heart rate, systolic and diastolic blood pressure; 
• 
12-Lead electrocardiogram (ECG); 
• 
Clinical safety laboratories, including clinical chemistry, haematology, and urinalysis. 
Further routine medical assessments or any additional safety procedures may be performed 
during the study, if warranted and agreed upon between the Sponsor and Investigator, or when 
clinically indicated. 
Any clinically significant findings that result in a diagnosis should be recorded and 
commented on appropriate document. 
7.1.1 Adverse Events  
7.1.1.1 
Definition 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (e.g. nausea, chest pain), signs (e.g. 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g. laboratory 
findings, ECG). 
An AE can include an undesirable medical condition occurring at any time, even if no IMP 
has been administered. 
This definition includes events occurring from the time of the subject giving informed consent 
until the EoS/ED. 


 
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7.1.1.2 
Adverse Event Collection 
AEs will be monitored from the time that a subject gives informed consent and throughout the 
study, and will be elicited by direct, nonleading questioning or by spontaneous reports. 
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 eCRF.  
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They result in a change in IMP schedule of administration (change in dosage, delay in 
administration, IMP discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject, 
• 
They are considered as clinically significant by the Investigator. 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the Investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the Investigator as clinically significant (e.g. 
electrocardiogram changes) 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.  
7.1.1.3 
Adverse Events Assessment 
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 in the eCRF. 
Adverse events will be classified by the Investigator 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. 
If in the duration of an AE there is a change in intensity, each change will be recorded as a 
new episode of the AE. 
The relationship of an AE to IMP administration will be classified by the Investigator 
according to the following: 
• 
Related: Reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose-response relationship, pharmacology) 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 (e.g.; 
implausible time sequence and/or attributable to concurrent disease or other drugs) to 
rule out a causal relationship with IMP administration. 
The expectedness of an AE shall be determined by the Sponsor according to the current 
version of SmPC. 
Any AEs already recorded and designated as “continuing” should be reviewed at each 
subsequent assessment. 


 
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If a subject's treatment is discontinued or changed as a result of an AE, study site personnel 
must clearly report to the Sponsor or its designee the circumstances and data leading to such 
decision. 
7.1.1.4 
Adverse Event Follow-up 
If an AE is still present at the end of the study, reasonable follow-up clinical monitoring (and 
up to 30 days after the end of the study) should be managed by the Investigator or any 
appropriate Physician until event is resolved or stabilised at an acceptable level, as judged by 
the Investigator.  The frequency of follow-up evaluation is left to his/her discretion. 
7.1.1.5 
Clinical Evaluation of Safety 
All study drug and protocol procedure AEs will be listed, and if the frequency of events 
allows, safety data will be summarised using descriptive methodology. 
The incidence of symptoms for each treatment will be presented by severity and by 
association with study drug as perceived by the Investigator.  Symptoms reported to occur 
prior to dosing will be distinguished from those reported as new or increased in severity 
during or after IMP administration. Each symptom will be classified by the most suitable term 
from a version of a medical regulatory dictionary agreed by the Sponsor and other parties 
involved in the study. 
7.1.1.6 
Serious Adverse Event Assessment 
Definition 
A Serious Adverse Event (SAE) is defined as any adverse event that either: 
(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 occurs. It does not include an event that, had it occurred in a more 
severe form, might have caused death, 
(3) 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, 
excluding admission for social or administrative reasons, 
(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. 
(7) 
Other medically important conditions 
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. 
• 
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. 


 
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• 
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. 
SAE Collection and Reporting 
Study site personnel must immediately (within 24 hours) alert the Sponsor’s 
pharmacovigilance contact specified on the front page of the current document of any SAE, 
independent of the circumstances, suspected cause or Investigator's opinion of causality, as 
soon as it occurs or comes to the attention of the Investigator at any time during the study 
period. 
Any SAE with a suspected causal relationship to IMP administration occurring at any other 
time after completion of the study must be promptly reported. 
Any appropriate way of notification may be used. If the immediate report is submitted by 
telephone, this must be followed by detailed written reports using the SAE report form. 
The following information is the minimum that must be provided to the Sponsor’s 
pharmacovigilance contact: 
• 
Study number, 
• 
Investigational site identification, 
• 
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. 
7.1.1.7 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not 
listed in SmPC and that the Investigator identifies as related to IMP or procedure. 
7.1.1.8 
Pregnancy 
Pregnancy tests will be performed in all female subjects of childbearing potential as specified 
in the schedule of assessments (See Attachment #1_ Section15.1). 
Information regarding pregnancies with a conception date either during the study period or 
within 6 months after dosing must be collected and reported to the Sponsor via a Standard 


 
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Pregnancy Outcome Report Form. The Sponsor will request further information from the 
Investigator as to the course and outcome of the pregnancy. Adverse consequences of a 
pregnancy will be regarded as SAEs.  
The Investigator must instruct all female subjects to inform him/her immediately should they 
become pregnant.  
7.1.1.9 
Death 
All AEs resulting in death either during the study period or within 6 months after dosing must 
be reported as a SAE. 
The convention for recording death is as follows: 
• 
AE term: lead cause of death (e.g. multiple organ failure, pneumonia, myocardial 
infarction), 
• 
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”. 
7.1.1.10 Reporting to Competent Authorities, IECs/IRBs and other Investigators 
The Sponsor will ensure that processes are in place for submission of reports of SUSARs 
occurring during the study to the CAs, Independent Ethics Committees (IECs)/Institutional 
Review Boards (IRBs) and other Investigators concerned by the IMP. 
Reporting will be done in accordance with the applicable regulatory requirements. The 
Sponsor must report all SUSARs to EMA’s EudraVigilance database within 15 days. 
Fatal and life-threatening SUSARs should be reported within 7 calendar days, with another 8 
days for completion of the report. 
The Sponsor can prepare additional reports for other authorities (e.g. FDA). 
7.1.2 Physical Examination 
Physical examinations (including body weight (in light clothes and without shoes) and height 
measurements will be evaluated at screening and end-of-study visit (see Study Schedule of 
Events, Section 15.1). 
Clinically significant changes, in the judgement of the Investigator, in physical examination 
findings will be recorded 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. 
7.1.3 Vital Signs Assessments 
After 5 min of rest, supine systolic and diastolic blood pressure (SBP & DBP), heart rate (HR) 
and body temperature (aural) will be assessed at screening and end-of-study visit (see Study 
Schedule of Events, Attachment #1_Section 15.1).  In case of adverse events, additional vital 
signs assessments may be performed at the discretion of the Investigator.  
7.1.4 Electrocardiograms Assessments 
Twelve-lead computerised standard ECGs, with paper printout, will be obtained while subject 
is in resting supine position for at least 5 minutes and until four regular consecutive 
complexes are available, at screening and end-of-study (see Study Schedule of Events, 
Attachment #1_Section 15.1). In case of adverse events, additional ECG assessments may be 
performed at the discretion of the Investigator. 
For each timepoint, computerised standard ECGs will be recorded so that the following 
parameter can be automatically calculated and reported on the ECG paper printout: 


 
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• 
Sinus rhythm, 
• 
RR interval duration or heart rate (HR), 
• 
PR interval duration, 
• 
QRS interval duration, 
• 
QT interval duration, 
• 
QT interval corrected by the appropriate correction method (e.g.: Bazett). 
Automated ECG interval data will be interpreted by a qualified Physician at the site as soon 
after the time of ECG collection as possible, and ideally while the subject is still present. The 
qualified Physician will document his/her review and interpretation (including evaluation of 
clinical significance in case of abnormality) on every ECG printout.  
The paper printouts will be kept in the source documents at site. Only the interpretation and 
abnormalities will be reported in the eCRFs for integration with other clinical study data.  
These paper ECGs may be subject to further review, if appropriate. 
Any clinically significant abnormalities will be recorded as AEs. 
7.1.5 Clinical Safety Laboratory Tests  
Blood and urine samples will be collected for standard clinical laboratory tests, including 
biochemistry, haematology, and urinalysis panels, as well as specific tests such as urine drug 
screening and alcohol tests (and urine/serum pregnancy tests for women of childbearing 
potential) at timepoints indicated in the Study Schedule of Events (see Attachment #1_Section 
15.1).  
The exact lists of parameters to be assessed are given in the Attachment #2_Section 15.2. 
The results of laboratory tests performed during the screening phase must be obtained before 
dosing on Day 1. 
7.1.5.1 
Urinalysis 
Freshly voided urine samples (at least 10 ml) will be collected to perform a dipstick 
assessment of the parameters described in Attachment #2_Section 15.2.  
Microscopy will be performed, if indicated, but results will not be collected in the eCRF. If in 
the opinion of the Investigator there are any clinically significant abnormalities in 
microscopy, they will be recorded as an AE in the eCRF.  
7.1.5.2 
Pregnancy Test 
A Beta-human chorionic gonadotrophin (ßHCG) serum test will be performed for all female 
subjects of childbearing potential at Screening (visit 1) and if clinically indicated thereafter. 
Human chorionic gonadotrophin (HCG) urine test will also be performed on Day-1  (baseline) 
and at the end-of-study visit. It may be repeated at any time during the study according to 
Investigator’s judgement. 
Any subject becoming pregnant during the study will be withdrawn. All pregnancies that 
occur during the study are to be reported as described in Section 7.1.1.8. 
7.1.5.3 
Investigator’s Review 
Investigators must document their review of each laboratory report by signing or initialling 
and dating each report. Laboratory values that fall outside a clinically accepted reference 
range or values that differ significantly from previous values will be evaluated. 
When multiple laboratory values are out of range but not clinically significant, “all labs NCS” 
or a general comment may be written on the laboratory page. However, all clinically 
significant laboratory values must be individually marked with CS. 


 
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The Investigator will review the safety laboratory test results, document the review, and 
record any clinically relevant changes occurring or observed during the study in the AE 
section of the eCRF (see Section 7.1.1 for abnormal laboratory tests that should be recorded 
as AEs). 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to Baseline or to a level deemed acceptable by the 
Investigator and the Sponsor’s clinical monitor (or his/her designated representative) or until 
the abnormality is explained by an appropriate diagnosis.  
7.1.5.4 
Sample Handling, Storage and Destruction 
Full details related to the samples processing, labelling, storage, shipment and destruction 
procedures will be provided to the Investigator via separate instructions and archived in the 
Trial Master File (TMF). 
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results. Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain 
samples to batch the tests run, or to retain the samples until the end of the study to confirm 
that the results are valid. Certain samples may be retained for a longer period, if necessary, to 
comply with applicable laws, regulations, or laboratory certification standards. 
7.1.6 Additional Definitions or Special Procedures  
Not applicable. 
7.2 Efficacy Assessment(s) 
Not applicable. 
7.3 Assessments of lead levels and other elemental impurities 
The assessment of elemental impurities in blood and urine include lead and 8 other elemental 
impurities: i.e. arsenic, cadmium, mercury, cobalt, vanadium, nickel, barium and aluminium. 
Other impurities may be assessed via Biobanking samples (See Attachment #5_Section 15.5). 
7.3.1 Sampling Schedule 
Urine collections (as 24-hour collection) and Blood samples for the measurement of elemental 
impurities will be collected as described in the Schedule of events (see Attachment 
#1_Section 15.1).  
During the outpatient visits, blood samples will be collected pre-dose of any of the 3 dosing 
occasions of that day. 
Taken into account the time window flexibility during the Day 35, the 24-hour urine 
collection should be done whilst subject is still under study treatment (e.g.: if subject performs 
the Day 35 at Day 36, Smecta® will be given until the evening of Day 36, or alternatively if 
subject comes at Day 34, the last Smecta® intake will be done at Day 34 evening).  
7.3.2 Sampling Method for Pharmacokinetic Measurements 
Blood samples (8 ml at each time point) will be collected as described in the Schedule of 
event (see Attachment #1_Section 15.1): 
- 
For determination of lead in blood and 8 other elemental impurities in blood 
(arsenic, cadmium, mercury, cobalt, vanadium, nickel, barium and aluminium) 
- 
Biobanking samples (blood): for potential assessment of other elemental impurities 
levels in blood 
- 
Biobanking samples (serum): for potential assessment of lithium levels in serum 


 
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- 
Biobanking samples (plasma): for potential determination of lead in the plasma. 
. During the study, the nominal sample collection times may be adjusted, but the total number 
of samples will not increase. The exact dates and times of blood sample collection, and 
Smecta® administration must be recorded in the eCRF. 
Specific blood collection, preparation and storage conditions are described in a separate Study 
Laboratory Manual. 
All urine samples collected over the specific 24-hour interval will be pooled and the total 
urine volume measured and recorded in the eCRF. From this pooled volume, 2 aliquots of  1.5 
ml (primary, back-up) each will be obtained for the measurement of elemental impurities. 
Two additional urine aliquots of 1.5 ml (1 primary, 1 back-up) will be collected for the 
biobanking purpose.  
Each tube should be labelled in accordance with the Sponsor’s requirements. Aliquots will be 
shipped on dry ice. 
Unless specified below, specific details of labelling, sampling, storing and shipping 
procedures will be described in separate documentation, and provided by the Sponsor. 
7.3.3 Bio-analytical Method 
Blood and urine samples will be analysed to determine concentrations of elemental impurities 
using a validated, specific and sensitive ICP-MS method by Quality Assistance (Donstiennes, 
Belgium). Assessment of lead and each elementary impurity in blood and urine will be 
performed under the supervision of Ipsen Pharmacokinetics and Drug Metabolism (PDM) 
Department. 
7.3.4 Parameter Estimation 
Individual blood concentrations for each elementary impurities will be listed and summarised 
by timepoint using descriptive statistics for continuous variables (number of available 
observations, mean, median, standard deviation (SD), minimum, maximum, geometric mean, 
and geometric coefficient of variation assuming log-normally distributed data).  
PK parameters of lead may be calculated if feasible. 
Change from baseline by timepoint will be assessed and summarised using descriptive 
statistics. 
Individual urine concentrations for each elementary impurities will be listed and summarised 
by timepoint using descriptive statistics. Change from baseline by timepoint will be assessed 
and summarised using descriptive statistics 
Descriptive summary statistics (the number of observations (n), mean, median, SD and range 
for continuous variables, and n and percentage (%) for categorical/nominal variables) will be 
presented.  
7.4 Pharmacodynamic Assessment(s) 
No pharmacodynamic assessment will be performed during this study. 
7.5 Exploratory Assessment(s) 
Single faces samples will be collected at timepoint defined in the schedule of events (see 
Attachment #1_Section 15.1) and processed according to standardised techniques developed 
by an international consortium (International Human Microbiome Standards, IHMS, 
http://www.microbiome-standards.org/#). Detailed procedures for the collection, handling, 
storage, shipment and analyses of the samples will be described in the specific study manual.  
The stools samples taken after the end of the treatment period (e.g. from Day 65 to Day 125 
visits) will be analysed only in case of a significant change of microbiota is observed during 


 
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the study treatment in order to assess the resilience ( return to the baseline profile) of 
microbiota during the post study treatment period. 
Consistency of stools (recorded and rated according to Bristol scale) (See attachment # 7_ 
Section15.7) and frequency will be assessed over 24h by the subject the day before Screening, 
Day-14, baseline (D-1), Day 8, Day 35, Day 65, Day 95 and Day 125 visits, collected in a 
diary and reported by the site in the eCRF. 
7.6 Compliance to Study Procedures 
7.6.1 Compliance to Protocol 
Every attempt will be made to select subjects who have the ability to understand and comply 
with instructions. Noncompliant subjects may be discontinued from the study. The time and 
day of drug administration will be recorded by the study site when present at the clinical unit 
and by the subject when self-administered (using Subject Diary).  These will be recorded in 
the eCRF by the site. Drug accountability records will be maintained by the study site. 
7.6.2 Compliance to Timing of Procedures 
The specifications in this protocol for the timings and dates of primary tests are given as 
targets, to be achieved within reasonable limits. The scheduled time points may be subject to 
minor deviations within the allowed time windows specified in the Study Schedule of Events 
(see Section 15.1); however, the actual time must always be correctly recorded in the eCRF 
and other relevant source documents. Any excursion outside of these allowed time windows 
might be regarded as protocol violation. 
Any major modification that might affect the conduct of the study, subject safety, and/or data 
integrity will be detailed in a protocol amendment. 


 
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8 
STATISTICAL ANALYSES 
8.1 Data Analysis Plan 
8.1.1 General Considerations 
Statistical analysis will be performed by a Sponsor selected CRO and according to ICH E9 
guidelines and using SAS version 9.3 or higher (See references in Section 14).    
8.1.2 Determination of Sample Size 
The critical limit of 50μg/l of lead is chosen as being the most conservative value taken 
among various guidelines (risk of saturnism, observations under high lead exposure at work). 
The baseline blood lead concentration of 31,4μg/l is considered as being a mean blood lead 
concentration in a survey of 1949 adults (18-74 years old) living in France in 2006-2007 (Falq 
et al. 2011). This population is representative of the French population including different 
socio-demographic characteristics and environment risk factors such as: sex, age, smoking 
status, type of drinking water, leisure activities, age of housing, shellfish/crustacean 
consumption. Considering the inclusion and exclusion criteria defined for the study, the 
enrolled subjects should have BLL levels in the same range as reported in the survey. 
With a standard error to the mean of [0,56], the mean blood lead concentration of 31.4μg/l is 
at confidence 95% to be found within [29.82; 32.98] under similar conditions. The non-
superiority Δ margin is a clinical choice calculated as the difference of: 50 – 31.4 = 18.6μg/l. 
A precision of 15% (CV) of the bioanalytical assay has been considered in the determination 
of sample size. 
Based on the above considerations, a sample size of 29 subjects with baseline mean blood 
lead concentration no greater than 36 μg/l (<36 μg/l), is required to provide 81% power to 
reject the null hypothesis of a difference of means no greater than 18,6 µg/l (≤ 18,6 µg/l 
considered as no difference of means). 
Considering potential drop-out, it is planned to enrol a total of 35 subjects to ensure that at 
least 29 subjects completed the study.  
Subjects who prematurely discontinue after IMP administration will not be replaced. 
8.1.3 Study Participant Disposition 
The numbers and percentages of subjects enrolled and included in the safety population will 
be tabulated. The reasons for subject exclusions from the safety population will also be 
tabulated. In addition, the numbers of subjects who were treated, discontinued and completed 
will be tabulated. 
Primary reasons for discontinuation of study treatment will be tabulated. 
8.1.4 Study Participant Characteristics 
Descriptive summary statistics (n, mean, SD, median, minimum, maximum) or frequency 
counts of demographic and baseline data (medical history, concomitant medications, etc.) will 
be presented for the safety population. 
8.1.5 Statistical Evaluation of Safety 
Safety analyses and summary tables will be based on the safety population. Adverse events 
reported by Investigators will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA 19.0 or higher Version). 
All safety data will be included in the subject data listings. Listings of AEs will be presented 
by subject, system organ class and preferred term. 
All AEs and SAEs occurring during the Screening period will be reported; however, these 
will not be considered in the analysis of TEAEs.  


 
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A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving dose of Smecta®, or 
• 
it was present prior to receiving the dose of Smecta® but the intensity increased during 
the active phase of the study. 
All TEAEs will be flagged in the AEs listings. The incidence of all reported TEAEs and SAEs 
will be tabulated. In addition, summary tables will be presented by maximum intensity, drug 
relationship and TEAEs associated with premature withdrawal of study medication. 
Concomitant medication will be coded by using the World Health Organisation (WHO) Drug 
Dictionary (December 2015 Version or higher) 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) will be presented for vital 
signs (blood pressure and heart rate) and clinical laboratory tests on screening and end-of-
study visit. For laboratory data, abnormal values will be flagged in the data listings and a list 
of clinically significant abnormal values will be presented. For the ECG parameters, clinically 
significant findings will be listed. 
Further details of the statistical analyses will be available in a Statistical Analysis Plan 
developed the CRO per Sponsor agreement and approval. 
8.1.6 Analyses and Statistical Inference 
Individual listings and summary tables of Elemental Impurities concentrations in blood and in 
urine will be provided. 
8.2 Preliminary and/or Interim Analysis 
No formal preliminary or interim analyses are planned for this study.  If an unplanned 
preliminary or interim analysis is deemed necessary, the Sponsor clinical pharmacologist or 
Investigator will consult with the appropriate medical director or designee to determine if it is 
necessary to amend the protocol. 
Blood lead concentrations from screening and baseline will be obtained on an ongoing basis 
to verify that these values are within the 95% confidence interval of the mean blood lead 
concentration of 31,4μg/l used in the determination of sample size (see Section 8.1.2) and 
therefore confirm the assumptions for sample size calculation. If not, the sample size might be 
re-evaluated accordingly. 


 
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9 
DATA HANDLING AND RECORD KEEPING 
9.1 
Data Capture 
The following source data may be generated and handled for further data basing process: 
• 
Paper-based or electronic data captured in Case Report Forms 
• 
Paper-based or electronic data captured systems, other than the case Report Forms 
• 
Paper or electronic data from local or external vendors. 
To ensure accurate, complete, and reliable data, the Sponsor or its representative will provide 
instructional material to the study site(s), as appropriate. Training session will be given during 
a start-up/initiation meeting for instructions on the completion/data entry of any source data 
documents and electronic Case Report Forms. 
The Investigators or their designees must verify that all data entries in the eCRFs are accurate 
and correct. If certain information is not available for a particular timepoint and/or subject, 
specific instructions should be followed, e.g. to document that the procedure was either not 
done (ND) or not applicable (NA). 
Every effort should be made to ensure that all safety evaluations are completed by the same 
individual who made the initial baseline determination. 
9.2 Data Handling 
All or part of the data will be monitored at periodic visit to the study site, according to a 
monitoring plan. All entries in the eCRFs, corrections and alterations are to be made by the 
responsible Investigator or his/her designee. 
Once monitored and cleaned, the paper-based data (either source or transcribed data) that 
have been selected for populating the database will follow a single entry process.  Electronic 
data will be directly entered in the database. 
Details of all data management procedures, from the initial planning to the archiving of final 
datasets/documents following database freeze/lock will be documented in appropriate data 
management and validation plan(s). Among others, these procedures will also describe quality 
control checks, data handling process for any missing, unused or spurious data, as well as 
coding procedures for AE’s, medical history, physical examination and medications. 
9.3 Record Keeping 
The Investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes. 
Depending on the data collected and the type(s) of data, records will be kept following 
storage, and archiving procedures agreed by the Sponsor/Investigator site involved in this 
study, and in accordance to any regulations that are applicable in the country(ies) where the 
study is conducted. 


 
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10 
REGULATORY AND ETHICAL CONSIDERATIONS 
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. The Electronic Data Capture (EDC) 
system will comply with the Food and Drug Administration (FDA), 21 CFR Part 11, 
Electronic Records, Electronic Signatures, and FDA, Guidance for Industry: Computerised 
Systems Used in Clinical Trials. 
In addition, the study will adhere to all local regulatory requirements.  
10.1 
Subject Information Sheet and Consent 
The Investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering, orally and/or in writing, to any 
questions the subject may have throughout the study and sharing any new information that 
may be relevant to the subject’s willingness to continue his or her participation in the study in 
a timely manner. 
The subject information sheet and consent document will be used to explain the potential risks 
and benefits of study participation to the subject in simple terms before the subject is entered 
into the study, and to document that the subject is satisfied with his or her understanding of 
the study and desires to participate.   
The Investigator is ultimately responsible for ensuring that the Ethics Committee (EC) 
approved informed consent is appropriately signed and dated by each subject prior to the 
performance of any study procedures. Informed consent obtained under special circumstances 
may occur only if allowed by local laws and regulations. 
10.2 
Ethical Review Considerations 
The following documents should be submitted to the relevant ECs for review and approval to 
conduct the study (this list may not be exhaustive): 
• 
Protocol/amendment(s) approved by the Sponsor, 
• 
Currently applicable SmPC or package labelling, 
• 
Relevant Investigator’s curriculum vitae, 
• 
Subject information and informed consent document(s) and form(s), 
• 
Subject emergency study contact cards 
• 
Recruitment procedures/materials (advertisements), if any. 
The EC(s) will review all submission documents as required, and a written favourable opinion 
for the conduct of the study should be made available to the Investigator before initiating the 
study. This document must be dated and clearly identify the version number(s) and date(s) of 
the documents submitted/reviewed and should include a statement from the EC that they 
comply with GCP requirements. 
The study may begin at the investigative site(s) only after receiving this dated and signed 
documentation of the EC approval or favourable opinion. 
During the study, any update to the following documents will be sent to the EC either for 
information, or for review and approval, depending on how substantial the modifications are: 
(1) SmPC; (2) reports of SAEs; (3) all protocol amendments and revised informed consent(s), 
if any. 
At the end of the study, the Ethics Committee will be notified about the study completion. 


 
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10.3 
Regulatory Considerations 
This study will be conducted in accordance with applicable laws and regulations, GCPs, and 
the ethical principles that have their origin in the Declaration of Helsinki. 
All or some of the obligations of the Sponsor will be assigned to a Clinical Research 
Organisation (CRO).  
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other trial-related data. 
10.4 
Final Report Signature 
The Investigator or designee will proposed to review and sign the clinical study report for this 
study, indicating agreement with the analyses, results, and conclusion of the report. 


 
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11 
INSURANCE AND FINANCE 
11.1 
Insurance 
The Sponsor declares that it has taken out a product liability insurance covering all subjects 
screened and enrolled in this study in respect to risks involved in the study.  
11.2 
Financial Agreement 
Since this study is to be performed in partnership with a CRO, separate financial agreements 
between the Sponsor and the CRO on one side, and the CRU and the CRO on the other side, 
will be signed prior to initiating the study, outlining overall Sponsor and Investigators 
responsibilities in relation to the study. 


 
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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will provide 
instructional material to the study sites, as appropriate. A start-up training session will be 
done prior to screening start to instruct the Investigators and study coordinators. This session 
will give instruction on the protocol, the completion of the eCRFs, and all study procedures. 
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, 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 a 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. a 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 clinical unit personnel in 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 is required before the subject will be 
allowed to enter the study. 
If investigative clinical unit personnel learn that a subject who did not meet protocol 
eligibility criteria was entered in a study (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. 
12.1.3 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 (e.g. 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 clinical unit 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. 
12.2 
Monitoring 
The Investigator is responsible for the validity of all data collected at the site. 


 
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The Sponsor is responsible for monitoring these data to verify that the rights and well-being 
of subjects are protected, 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. 
Before the study initiation visit, the Sponsor assigned study monitor will write a monitoring 
plan indicating the monitoring procedures and at which occasions during the study monitoring 
visits will be performed. 
Periodic visits will be made to the study site throughout the study at mutually agreeable times.  
Any appropriate communication tools will be set up to ensure the Sponsor and/or its 
representative is/are available for consultation, so they can stay in contact with the study site 
personnel. 
Adequate time and space for monitoring visits should be made available by the Investigator. 
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. 
Quality of the paper-based or electronic data will be reviewed to detect errors in data 
collection and, if necessary, to verify the quality of the data. 
The eCRF is expected to be completed an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits. The study monitor 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 (e.g., laboratory 
print outs) the name must be blacked out permanently by the site personnel, leaving the date 
of birth visible, and annotated with the subject number as identification. 
12.3 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP rules. This includes 
that the study may be audited at any time by a Quality Assurance personnel designated by the 
Sponsor, or by regulatory bodies. The Investigator must adhere to the GCP principles in 
addition to any applicable local regulations.   
If requested, the Investigator will provide the Sponsor, applicable regulatory agencies, and 
applicable Ethics Committee with direct access to any original source documents. 
The Investigator(s) should demonstrate due diligence in recruitment and screening of potential 
study subjects. The enrolment rate should be sufficient to complete the study as agreed with 
the Sponsor. The Sponsor should be notified of any projected delays, which may impact the 
completion of the study. 
12.3.1 Audit and Inspection 
Authorised personnel from external CAs and the Sponsor’s authorised quality assurance 
personnel may carry out inspections and audits. 
12.3.2 Data Quality Assurance 
Monitored eCRF, transferred from the clinical unit to the assigned data management group, 
will be reviewed (secondary monitoring) for completeness, consistency, and protocol 
compliance. 
Reasons should be given in 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 for clarification/correction. The 


 
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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 
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. 


 
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14 
REFERENCES 
Barbosa F Jr, Tanus-Santos JE, Gerlach RF, Parsons PJ. A critical review of biomarkers used 
for monitoring human exposure to lead: advantages, limitations, and future needs. 
Environmental Health Perspectives 2005;113:12:1669-1674. 
Bergdahl IA, Schütz A, Gerhardsson L, Jensen A, Skerfving S. Lead concentrations in human 
plasma, urine and whole blood. Scand J Work Environ Health 1997;23(5):359-363 
Chang FY, Lu CL, Chen CY, Luo JC. Efficacy of dioctahedral smectite in treating patients of 
diarrhoea-predominant irritable bowel syndrome. J Gastroenterol Hepatol 2007; 22:2266-
2272. 
Christoffersson JO, Ahlgren L, Schütz A, Skerfving S, Mattsson S. Decrease of skeletal lead 
levels in man after end of occupational exposure. Arch Environ Health 1986; Sep-
Oct;41(5):312-8. 
De Wouters T, Ledue F, Nepelska M, Dore J, Blottie H, Lapaque N. A Robust and Adaptable 
High Throughput Screening Method to Study Host-Microbiota Interactions in the Human 
Intestine. PLOS ONE. Vol. 9 No. 8 (August 2014) 
Dumitrascu DL, Stanculete M, Mitrea I, Dumitrascu DM, Farcas A.  The effect of two 
antidiarrheal drugs on the psychosocial adjustment to illness in chronic functional diarrhoea. 
Rom J Intern Med 2004; 42:191-197 
Falq G, Zeghnoun A, Pascal M, Vernay M, Le Strat Y, Garnier R, Olichon D, Bretin P, 
Castetbon K, Fréry N. Blood lead levels in the adult population living in France, the French 
Nutrition Health Survey (ENNS 2006-2007). Environment International 2011;37:565-571. 
International Conference on Harmonisation (ICH) E9 and Federal register Vol. 63, No. 179 
(September 1998). 
International Conference on Harmonisation  (ICH) Q3D, Guideline for Elemental Impurities, 
Step 4, 16 December 2014. 
International Human Microbiome Standards http://www.microbiome-standards.org/# 
Kim H-C, Jang T-W, Chae H-J, Choi W-J, Ha M-N, Ye B-J, Kim B-G, Jeon M-J, Kim S-Y 
and Hong Y-S. Evaluation and management of lead exposure. Annals of Occupational and 
Environmental Medicine 2015;27:30. 
Lewis, SJ and KW Heaton, 1997, Stool Form Scale as a Useful Guide to Intestinal Transit 
Time, Scand. J. Gastroenterol, 32(9):920-4.  
Nilsson U1, Attewell R, Christoffersson JO, Schütz A, Ahlgren L, Skerfving S, Mattsson S. 
Kinetics of lead in bone and blood after end of occupational exposure. Pharmacol Toxicol. 
1991 Jun;68(6):477-84. 
Rabinowitz MD. Toxicokinetic of bone lead. Environ Health Perspect 1991; 91:33-37. 
Rentschler G, Broberg K, Lundh T,  Skerfving  S, Long-term lead elimination from plasma 
and whole blood after poisoning, Int Arch Occup Environ Health 2012; 85:311–316 
S. SkerfvingSAS, Version 9.3 SAS Institute Inc. Cary, NC, USA, 2012. 
Yao-Zong Y, Shi-Rong L, Delvaux M. Comparative efficacy of dioctahedral smectite 
(Smecta®) and a probiotic preparation in chronic functional diarrhoea. Dig Liver Dis 2004; 
36:824-828. 
 


 
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15 
ATTACHMENTS 
15.1 
Attachment 1 – Study Schedule 


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
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Study Schedule of Events - Protocol D-FR-00250-108 
 
Screening 
Treatment Period 
Follow up Period 
Weeks: 
 
1 
2 
3 
4 
5 
5 
9 
13 
17 
Visits: 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 (EOS) 
 
Days: 
D-42 to 
D-21 
D-1 (Baseline) 
D1 
D2 
D8 
D15 
D22 
D29 
D35 
D65 
D95 
D125 
Time windows: 
 
+/- 15 min 
+/- 1d 
+/- 1d 
+/-1d 
+/- 1d 
+/- 1d 
+/- 7d 
+/- 7d 
+/- 7d 
Subjects’ disposition: 
Outpatient 
Inpatient 
out 
out 
out 
out 
inpat 
inpat 
 inpat 
out 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent, Demography, Medical & 
Surgical History, Prior Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (incl. Body Height/Weight c) 
and Vital Signs, aural body temperature 
X 
 
 
 
 
 
 
 
 
 
 
X 
12-lead Electrocardiograms (ECGs) 
X 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medication & Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Laboratory (Haematology, 
Biochemistry, Coagulation and Urinalysis) 
Xi 
X 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Test (WOCBP only)d 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Urine Drug Assay & Alcohol test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Smecta® (TID, morning, noon, evening) 
 
 
Xh-----------------------------------------------------Xh 
 
 
 
Biological Samples 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Samples for Elemental Impurities and 
biobanking 
X  
X 
Xa,e 
Xb 
Xb 
Xb 
Xb 
Xb 
Xa,e 
X 
X 
X 
Urine Collection (24-hour) for Elemental 
Impurities 
 
X  
 
 
 
 
 
 
X  
X 
X 
 
Faecal Samples for Microbiota 
Xg 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Consistency of stools (Bristol scale) and 
frequency over 24h by subjectk 
Xj 
X 
 
 
X f 
 
 
 
X 
X 
X 
X 
a  
Six samples on Day 1 (and Day 35): 2 hours after the first dose (ex.: Smecta® intake 7.00am, meal 7.30am, PK 9.00am), immediately before second dose (ex.: PK 
11.30am, Smecta® intake just after at 11h.30, meal at 12.30), 3h post lunch dose (ex.: PK at 2.30pm), immediately before the third dose (ex.: PK at 6.30pm, 
Smecta® intake just after at 6.30pm and meal 7.30pm), 3h post evening dose (ex.: PK at 9.30pm) and 6h post evening dose (ex.: 00.30am), and one sample on Day 
36 in the morning (ex.: PK at 7.00am, Smecta® intake just after at 7.00am and meal 7.30am)
b  
On pre-dose before dosing (morning, approximately 7am on Day 2, and on pre-dose of any of the dosing occasion on the other days)  
c  
Body height only at screening.  


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
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d  
Pregnancy test: serum at screening and urine at baseline and EoS. 
e  
Time window for PK sampling: ± 15 min 
f 
To be performed 24h before the visit 3 
g 
1 sample to be taken at screening visit at the CRU and 1 sample by the subject at home at Day-14 ±1 day 
h 
Smecta® should be taken fasting and at least one hour before meal, except for breakfast at least 30 minutes before. 
i 
C-reactive protein to be analysed only at screening 
j 
Diary to be completed at screening retrospectively to cover the past 24h, and 24h before the Day-14 stool sample 
k 
To the extent possible, to collect the data over approximately 24h preceding the stool sample taken at the visit 24h ( i.e. 1 day or more). 
 


 
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15.2 
Attachment 2 – Safety Clinical Laboratory Tests  
 
Scre/
Bas 
EoS/
ED 
 
Scre/
Bas 
EoS/
ED 
Haematology 
 
 
Clinical Chemistry 
 
 
Haematocrit 
x 
x 
Sodium 
x 
x 
Haemoglobin 
x 
x 
Potassium 
x 
x 
Erythrocyte count (RBC) 
x 
x 
Bicarbonate 
x 
x 
Mean cell volume (MCV) 
x 
x 
Chloride 
x 
x 
Mean cell haemoglobin (MCH) 
x 
x 
Calcium 
x 
x 
Mean cell haemoglobin 
concentration (MCHC) 
x 
x 
Phosphorus 
x 
x 
Leukocytes (WBC) 
x 
x 
Iron 
x 
x 
Absolute counts of: 
 
 
Transferrine saturation 
x 
x 
Neutrophils 
x 
x 
Ferritin 
x 
x 
Lymphocytes 
x 
x 
Glucose (fasting)a  
x 
x  
Monocytes 
x 
x 
Amylase 
x 
x 
Eosinophils 
x 
x 
Lipase 
x 
x 
Basophils 
x 
x 
Urea 
x 
x 
Platelets 
x 
x 
Total cholesterol 
x 
x 
 
 
 
Total protein 
x 
x 
Coagulation 
 
 
Albumin 
x 
x 
Activated partial thromboplastin 
time 
x 
x 
Total bilirubin 
x 
x 
Prothrombin time and derived 
measures of prothrombin ratio 
x 
x 
Conjugated bilirubin 
x 
x 
INR 
x 
x 
Alkaline phosphatase (ALP) 
x 
x 
 
 
 
Aspartate aminotransferase (AST) 
x 
x 
 
 
 
Alanine aminotransferase (ALT) 
x 
x 
 
 
 
Creatinine 
x 
x 
 
 
 
Gamma-glutamyl transferase (GGT) 
x 
x 
 
 
 
Triglycerides (TG) 
x 
x 
 
 
 
eGFR c 
x 
x 
 
 
 
Glycated Haemoglobin (A1C) 
x 
x 
Urinalysis f 
 
 
Uric acid 
x 
x 
pH 
x 
x 
C-reactive protein (CRP) 
xg 
 
Protein 
x 
x 
Specific Tests 
 
 
Glucose 
x 
x 
Ethanol testing d  
x 
 
Ketones 
x 
x 
Urine drug screen d, including at least 
amphetamines, methamphetamines, 
benzodiazepines, cocaine, opiates, 
THC and barbiturates 
x 
 
Bilirubin 
x 
x 
Urobilinogen 
x 
x 
Blood 
x 
x 
Serum Pregnancy test (women of 
child bearing potential) e  
x 
 
Nitrite 
x 
x 
Hepatitis B surface antigen 
x 
 
Microscopic examination of 
sediment (if indicated) b 
Opt. 
Opt. 
Hepatitis C  
x 
 
Pregnancy test e 
x 
x 
HIV 
x 
 
Scre = Screening visit(s), Bas = Baseline, EoS = End of Study, ED = Early Discontinuation, Opt. = Optional 
a 
Glucose measured in fasting conditions 
b 
will not be collected in the eCRF unless clinically significant 
c 
calculated by CKD-EPI or MDRD formula or equivalent (NKDEP 2014)  
d 
Ethanol and urine drug testing to be performed at least once at the admission to the CRU before dosing 
e 
Serum pregnancy test at screening only, on urine at baseline and discharge from the study (EoS/ED) 
f 
Urinalysis performed via dipstick.  
g 
C-reactive protein (CRP) only at Screening visit 


 
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15.3 
Attachment 3 – Blood Sampling Summary 
This table summarises the maximum number of (veni) punctures and blood volumes for all 
blood sampling (screening, safety laboratories and bio-analytical assays) during the study.   
Fewer venipunctures and blood draws may actually occur if needed for safety purposes, but 
this will not require a protocol amendment. 
 
Purpose 
Maximum  
Blood volume 
per sample (ml) 
Maximum 
Number of 
Blood Samples 
Maximum 
Total Volume 
(ml) 
Screening 
 
 
 
Clinical laboratory tests: Haematology and 
Biochemistry, Coagulation, HbA1C, Serology, 
Endocrine, Serum pregnancy test 
25 
1 
25 
Provision for repeat tests (local laboratory) 
20 
1 
20 
Study 
 
 
 
Elemental Impurities assays 
2 
23 
46 
Biobanking for Elemental Impurities 
2 
23 
46 
Biobanking for Plasma lead assay 
4 
23 
92 
Catheter flushes, if any 
2 
12 
24 
Clinical laboratory tests: Haematology and 
Biochemistry, coagulation 
13.5 
2 
27 
 
 
 
 
Provision for unscheduled additional sampling 
50 
1 
50 
Total over 5,5 months 
 
Approximately 330ml 


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
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15.4 
Attachment 4 – List of Excluded Previous and Concomitant Medications  
Exclusion related to study drug: diosmectite (Smecta®). 
Drugs with narrow therapeutic index and requiring daily administrations: e.g.  
Aminophylline, Carbamazepine, Clindamycin, Clonidine, Digoxin, Disopyramide 
Dyphylline, Guanethidine, Isoetharine, Isoproterenol, Levoxyine, Lithium, Metaporterenol, 
Minoxidil, Oxytriphylline, Phenytoin, Prazosin, Primidone, Procainamide, Quinidine, 
Theophylline, Valproate… (non exhaustive list). 
 
Exclusion related to primary end point: 
Any products of mineral origin: 
- 
Diosmectite (except as prescribed in the present study as Smecta®) and similar 
- 
Other clay compounds or mineral extracts (used as medicinal products, medical 
devices or even potentially as food supplement).  
- Clays: Examples included (not limited): Attapulgite (e.g. Actapulgite®, 
Gastropulgite®), montmorillonite beidellitique (e.g. Bedelix®, Gelox®), but also 
Kaolin, Talc 
- 
Activated charcoal. 
 
Compounds containing a significant amount of Aluminium Hydroxyde and/or 
Magnesium Hydroxide such as Maalox®, Xolaam®, Rocgel®, Moxydar®, Gelox®, 
Phosphalugel®, Polysilane®, … 
 
Exclusion related to ancillary study (digestive microbiota): 
- 
Any Antibiotic agents 
- 
Metformin 
- 
PPI (Proton Pump Inhibitor) 


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
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15.5 
Attachment 5 – List of Classes I - III Elemental Impurities (ICH Q3D), 
Additional Elements and Strategy for Analyses (Primary (I), Secondary (II), or 
Biobanking) 
 
Element 
Class  
(Q3D)  
Primary/Secondary/Biobanking 
Cd 
1 
Secondary 
Pb 
1 
Primary 
As 
1 
Secondary 
Hg 
1 
Secondary 
Co 
2A 
Secondary 
V 
2A 
Secondary 
Ni 
2A 
Secondary 
Tl 
2B 
- 
Au 
2B 
- 
Pd 
2B 
- 
Ir 
2B 
- 
Os 
2B 
- 
Rh 
2B 
- 
Ru 
2B 
- 
Se 
2B 
- 
Ag 
2B 
- 
Pt 
2B 
- 
Li 
3 
Biobanking 
Sb 
3 
Biobanking 
Ba 
3 
Secondary 
Mo 
3 
Biobanking 
Cu 
3 
Biobanking 
Sn 
3 
Biobanking 
Cr 
3 
Biobanking 
Al 
Not Listed 
Secondary 
Mn 
Not Listed 
Biobanking 
Zn 
Not Listed 
Biobanking 
B 
Not Listed 
Biobanking 
Ca 
Not Listed 
Biobanking 
Fe 
Not Listed 
Biobanking 
K 
Not Listed 
Biobanking 
Mg 
Not Listed 
Biobanking 
Na 
Not Listed 
Biobanking 
W 
Not Listed 
Biobanking 


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
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15.6 
Attachment 6 – List of Jobs or Activities bearing risk of lead exposure 
(INRS website, health and safety at work) 
 
MAIN ACTIVITIES AREAS EXPOSED TO LEAD 
Building 
 
Work with paints and pipes in old buildings (e.g. removal, repair…), 
 
Cutting or sanding of metallic structures covered with anticorrosive 
paint  
 
roof works (e.g. welding with lead, the use of lead sheets …) 
Manufactory 
 
Manufacturing and recycling of batteries, 
 
Manufacturing of ceramics (e.g. tiles…), 
 
Metal industry, in particular the foundries of brass alloys, 
 
Recycling of electronic products, 
 
Manufacturing of paints,  
 
Plastics processing industry,  
 
Manufacturing of special glasses and crystal, 
 
repair of radiators of machines and heavy trucks 
Handicraft 
 
Manufacturing and repair of stained-glass windows,  
 
Pottery,  
 
Artistic foundry 
 
Jewellery 
Other 
 
firing range 
 
http://www.inrs.fr/risques/plomb/ce-qu-il-faut-retenir.html#f0e92310-6003-4e09-8184-
579e026f02b9 
 
 
 
 
 
 
 
 
 
 


 
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15.7 
Attachment 7 – Bristol Stool Form Scale 
 
 
 
 
 
 
 
Lewis, SJ and KW Heaton, 1997, Stool Form Scale as a Useful Guide to Intestinal Transit 
Time, Scand. J. Gastroenterol, 32(9):920-4. 


 
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15.8 
Attachment 8 – Protocol Amendment Summary 
All additions have been identified by the use of underline and all deletions by strikethroughs. 
 
Front page 
Pharmacovigilance contact details:  
 Global Patient Safety, Ipsen Biopharm Ltd 
190 Bath Road, Slough, Berkshire SL1 3XE, England 102 Park Drive, Milton Park, 
Oxfordshire, OX14 4RY, England 
Tel:
 
Mob:
 
For serious adverse events (SAEs) reporting: 
Fax:
 
 
3.3.1.4 Post-Treatment Period 
The subjects will be asked to come back to the CRU at two occasions during the post-
treatment period: these visits should occur at Week 9 (Visit 8) and at Week 13 (Visit 9). At 
Visit 8 and 9, blood sampling will be collected as well as 24-hour urine collection for 
impurities dosing. Stools samples will be collected only at Visit 8 (week 9) and Visit 9 (Week 
13).  
 
7.3.2.Sampling Method for Pharmacokinetic Measurements 
Blood samples (2 ml each) for determination of elemental impurities concentrations 
measurement in blood will be collected as described in the Schedule of event (see Attachment 
#1_Section 15.1). Additional blood samples (2 ml each) will be biobanked at the timepoints 
described in the Schedule of event (see Attachment #1_Section 15.1), in order to further assay 
other elemental impurities levels in blood. Additional blood samples (4 mL each) will be 
taken and prepared; the resulting plasma samples will be biobanked for potential 
determination of lead in the plasma. 
Blood samples (8 ml at each time point) will be collected as described in the Schedule of 
event (see Attachment #1_Section 15.1): 
- 
For determination of lead in blood and 8 other elemental impurities in blood (arsenic, 
cadmium, mercury, cobalt, vanadium, nickel, barium and aluminium) 
- 
Biobanking samples (blood): for potential assessment of other elemental impurities 
levels in blood 
- 
Biobanking samples (serum): for potential assessment of lithium levels in serum 
- 
Biobanking samples (plasma): for potential determination of lead in the plasma 
During the study, the nominal sample collection times may be adjusted, but the total number 
of samples will not increase. The exact dates and times of blood sample collection, and 
Smecta® administration must be recorded in the eCRF. 
Specific blood collection, preparation and storage conditions are described in a separate Study 
Laboratory Manual. 
All urine samples collected over the specific 24-hour interval will be pooled and the total 
urine volume measured and recorded in the eCRF. From this pooled volume, 2 aliquots of 2 
1.5 ml (primary, back-up) each will be obtained for the measurement of elemental impurities 
PPD
PPD
PPD
PPD


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
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as well as for the biobanking purpose. Two additional urine aliquots of 1.5 ml (1 primary, 1 
back-up) will be collected for the biobanking purpose.  
Each tube should be labelled in accordance with the Sponsor’s requirements. Aliquots will be 
shipped on dry ice. 
Unless specified below, specific details of labelling, sampling, storing and shipping 
procedures will be described in separate documentation, and provided by the Sponsor. 
 
7.5. Exploratory Assessment(s) 
Single faces samples will be collected at timepoint defined in the schedule of events (see 
Attachment #1_Section 15.1) and processed according to standardised techniques developed 
by an international consortium (International Human Microbiome Standards, IHMS, 
http://www.microbiome-standards.org/#). Detailed procedures for the collection, handling, 
storage, shipment and analyses of the samples will be described in the specific study manual.  
The stools samples taken after the end of the treatment period (e.g. from Day 65 to Day 125 
visits) will be analysed only in case of a significant change of microbiota is observed during 
the study treatment in order to assess the resilience ( return to the baseline profile) of 
microbiota during the post study treatment period. 
Consistency of stools (recorded and rated according to Bristol scale) (See attachment # 7_ 
Section15.7) and frequency will be assessed over 24h by the subject the day before at 
Screening, Day-14, baseline (D-1), the day before Visit Day 8, at Day 35, Day 65, and Day 95 
and Day 125 visits, collected in a diary and reported by the site in the eCRF. 
 
 
 
 
 


 
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Study Schedule of Events - Protocol D-FR-00250-108 
 
Screening 
Treatment Period 
Follow up Period 
Weeks: 
 
1 
2 
3 
4 
5 
5 
9 
13 
17 
Visits: 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 (EOS) 
 
Days: 
D-42 to 
D-21 
D-1 (Baseline) 
D1 
D2 
D8 
D15 
D22 
D29 
D35 
D65 
D95 
D125 
Time windows: 
 
+/- 15 min 
+/- 1d 
+/- 1d 
+/-1d 
+/- 1d 
+/- 1d 
+/- 7d 
+/- 7d 
+/- 7d 
Subjects’ disposition: 
Outpatient 
Inpatient 
out 
out 
out 
out 
inpat 
inpat 
 inpat 
out 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent, Demography, Medical & 
Surgical History, Prior Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (incl. Body Height/Weight c) 
and Vital Signs, aural body temperature 
X 
 
 
 
 
 
 
 
 
 
 
X 
12-lead Electrocardiograms (ECGs) 
X 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medication & Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Laboratory (Haematology, 
Biochemistry, Coagulation and Urinalysis) 
Xi 
X 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Test (WOCBP only)d 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Urine Drug Assay & Alcohol test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Smecta® (TID, morning, noon, evening) 
 
 
Xh-----------------------------------------------------Xh 
 
 
 
Biological Samples 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Samples for Elemental Impurities and 
biobanking 
X  
X 
Xa,e 
Xb 
Xb 
Xb 
Xb 
Xb 
Xa,e 
X 
X 
X 
Urine Collection (24-hour) for Elemental 
Impurities 
 
X  
 
 
 
 
 
 
X  
X 
X 
 
Faecal Samples for Microbiota 
Xg 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Consistency of stools (Bristol scale) and 
frequency over 24h by subjectk 
Xj 
X 
 
 
X f 
 
 
 
X 
X 
X 
X 
a  
Six samples on Day 1 (and Day 35): 2 hours after the first dose (ex.: Smecta® intake 7.00am, meal 7.30am, PK 9.00am), immediately before second dose (ex.: PK 
11.30am, Smecta® intake just after at 11h.30, meal at 12.30), 3h post lunch dose (ex.: PK at 2.30pm), immediately before the third dose (ex.: PK at 6.30pm, 
Smecta® intake just after at 6.30pm and meal 7.30pm), 3h post evening dose (ex.: PK at 9.30pm) and 6h post evening dose (ex.: 00.30am), and one sample on Day 
36 in the morning (ex.: PK at 7.00am, Smecta® intake just after at 7.00am and meal 7.30am) 


 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
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b  
On pre-dose before dosing (morning, approximately 7am on Day 2, and on pre-dose of any of the dosing occasion on the other days)  
c  
Body height only at screening.  
d  
Pregnancy test: serum at screening and urine at baseline and EoS. 
e  
Time window for PK sampling: ± 15 min 
f 
To be performed 24h before the visit 3 
g 
1 sample to be taken at screening visit at the CRU and 1 sample by the subject at home at Day-14 ±1 day 
h 
Smecta® should be taken fasting and at least one hour before meal, except for breakfast at least 30 minutes before. 
i 
C-reactive protein to be analysed only at screening 
j 
Diary to be completed at screening retrospectively to cover the past 24h, and 24h before the Day-14 stool sample 
k 
To the extent possible, to collect the data over approximately 24h preceding the stool sample taken at the visit 24h ( i.e. 1 day or more) 
 


 
 
CONFIDENTIAL – Protocol n°: D-FR-00250-108 v.4.0  Date: 07-SEPT-2016 
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15.3 Attachment 3 – Blood Sampling Summary 
This table summarises the maximum number of (veni) punctures and blood volumes for all 
blood sampling (screening, safety laboratories and bio-analytical assays) during the study.   
Fewer venipunctures and blood draws may actually occur if needed for safety purposes, but 
this will not require a protocol amendment. 
 
Purpose 
Maximum  
Blood volume 
per sample (ml) 
Maximum 
Number of 
Blood Samples 
Maximum 
Total Volume 
(ml) 
Screening 
 
 
 
Clinical laboratory tests: Haematology and 
Biochemistry, Coagulation, HbA1C, Serology, 
Endocrine, Serum pregnancy test 
25 
1 
25 
Provision for repeat tests (local laboratory) 
20 
1 
20 
Study 
 
 
 
Elemental Impurities assays 
2 
23 
46 
Biobanking for Elemental Impurities 
2 
23 
46 
Biobanking for Plasma lead assay 
4 
23 
92 
Catheter flushes, if any 
2 
12 
24 
Clinical laboratory tests: Haematology and 
Biochemistry, coagulation 
13.5 
2 
27 
 
 
 
 
Provision for unscheduled additional sampling 
50 
1 
50 
Total over 5,5 months 
 
Approximately 330ml 
 

SAP_001.pdf: 
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IPSEN GROUP 
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STATISTICAL ANALYSIS PLAN 
 
ASSESSMENT OF ELEMENTAL IMPURITIES LEVEL AFTER CHRONIC 
ADMINISTRATION OF DIOSMECTITE (SMECTA®)  
IN SUBJECTS WITH CHRONIC DIARRHEA 
 
 
PROTOCOL VERSION AND DATE: 4.0 – 07 Sept 2016 
 
 
 
SAP Version 
Date 
 
Final Version 1.0 
20 June 2017 


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STUDY NUMBER: 
D-FR-00250-108 
EUDRACT NUMBER 
2016-002111-18 
PROTOCOL TITLE: 
ASSESSMENT OF ELEMENTAL IMPURITIES 
LEVEL AFTER CHRONIC ADMINISTRATION OF 
DIOSMECTITE (SMECTA®)  
IN SUBJECTS WITH CHRONIC DIARRHEA 
SAP VERSION: 
Final Version 1.0 
SAP DATE: 
20 June 2017 
 
Further to your review and agreement to the Statistical Analysis Plan version indicated 
above, please sign to indicate approval for your area of responsibility: 
 
RESPONSIBILITY 
NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Aepodia 
Project Manager 
  
Aepodia S.A.R.L. 
3 Avenue du Canada  
91940 Les Ulis, France 
 
 
Aepodia 
Biometry Coordinator 
 
Aepodia S.A.R.L. 
3 Avenue du Canada  
91940 Les Ulis, France 
 
 
Ipsen  
Statistician 
Tiffany Wang 
Ipsen Innovation 
5 Avenue du Canada 
91940 Les Ulis, France 
 
 
Ipsen 
Medical 
Development 
Director 
Nassima BEKKAT 
Ipsen Innovation 
5 Avenue du Canada 
91940 Les Ulis, France 
 
 
Ipsen 
PK Director 
Quyen NGUYEN 
Ipsen Innovation 
5 Avenue du Canada 
91940 Les Ulis, France 
 
 
Ipsen 
VP Early Development 
and  
Clinical Pharmacology 
 
Isabelle PATY 
Ipsen Innovation 
5 Avenue du Canada 
91940 Les Ulis, France 
 
 
RESPONSIBILITY 
NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Study Statistician 
 
Biotrial Biometrics 
7-9 Rue Jean-Louis Bertrand 
35042 Rennes Cedex, France 
 
 
IMPORTANT: This completed record (with additional sheets, where required), confirms the 
above-mentioned Statistical Analysis Plan version became the Final Statistical Analysis Plan 
PPD
PPD
PPD


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History of Changes 
New 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 ............................................... 8 
1.1 
Study objectives ............................................................................................................... 8 
1.1.1 
Primary objective ........................................................................................... 8 
1.1.2 
Secondary Objectives .................................................................................... 8 
1.1.3 
Exploratory (ancillary study) Objective ....................................................... 8 
1.2 
Study design ..................................................................................................................... 8 
1.2.1 
Study population ........................................................................................... 8 
1.2.2 
Study duration ............................................................................................... 8 
1.3 
Methods and procedures ................................................................................................ 9 
1.3.1 
Subject identification and allocation to study treatment ............................. 9 
1.3.2 
Subjects assessments ..................................................................................... 9 
1.3.2.1 
Efficacy assessments ...................................................................................... 9 
1.3.2.2 
Biological evaluations ................................................................................... 9 
1.3.2.3 
Safety assessments ......................................................................................... 9 
1.3.2.4 
Other Assessments ....................................................................................... 10 
1.3.2.5 
Withdrawal/discontinuation ......................................................................... 11 
1.3.3 
Schedule of assessments ............................................................................. 11 
1.3.4 
Planned sample size .................................................................................... 14 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................... 14 
2.1 
Efficacy population ....................................................................................................... 14 
2.2 
Screened population ..................................................................................................... 14 
2.3 
Included population ...................................................................................................... 14 
2.4 
Safety population .......................................................................................................... 14 
2.5 
Intent-To-Treat (ITT) population ............................................................................... 14 
2.6 
Per Protocol (PP) population ....................................................................................... 14 
3 
STATISTICAL METHODS ........................................................................................ 14 
3.1 
Statistical analysis strategy .......................................................................................... 14 
3.1.1 
Primary endpoint ......................................................................................... 15 
3.1.2 
Secondary endpoints ................................................................................... 15 
3.1.3 
Safety endpoints .......................................................................................... 15 
3.1.4 
Exploratory endpoints ................................................................................. 15 
3.1.5 
Multiplicity .................................................................................................. 15 
3.1.6 
Significance testing and estimation ............................................................ 15 
3.2 
Analysis methods ........................................................................................................... 15 
3.2.1 
Efficacy ........................................................................................................ 15 
3.2.2 
Biological and clinical evaluations ............................................................ 15 
3.2.2.1 
Biological evaluations ................................................................................. 15 
3.2.2.2 
Clinical evaluations ..................................................................................... 16 
3.2.3 
Safety ........................................................................................................... 17 


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3.2.3.1 
Adverse events .............................................................................................. 17 
3.2.3.2 
Laboratory data ........................................................................................... 17 
3.2.3.3 
Physical examination ................................................................................... 18 
3.2.3.4 
Vital signs ..................................................................................................... 18 
3.2.3.5 
ECG .............................................................................................................. 18 
3.2.3.6 
Pregnancy tests ............................................................................................ 19 
3.2.4 
Missing data and outliers ............................................................................ 20 
3.2.4.1 
Missing data ................................................................................................. 20 
3.2.4.2 
Missing or incomplete dates ........................................................................ 20 
3.2.4.3 
Outliers ........................................................................................................ 20 
3.2.5 
Subject disposition ....................................................................................... 20 
3.2.6 
Withdrawals ................................................................................................. 21 
3.2.7 
Demographic and baseline characteristics ................................................ 21 
3.2.8 
Medical and surgical history ...................................................................... 21 
3.2.9 
Subject compliance ..................................................................................... 21 
3.2.10 
Prior and concomitant medications ........................................................... 22 
3.2.11 
Prior medications for Chronic Diarrhoea .................................................. 22 
3.2.12 
Prior and concomitant non-drug therapies ................................................ 22 
3.2.13 
Concomitant surgical procedures ............................................................... 22 
3.2.14 
Hospitalizations ........................................................................................... 22 
3.2.15 
Derived data ................................................................................................. 22 
3.2.16 
Rules and data formats ............................................................................... 22 
3.2.17 
Pooling of Centres ....................................................................................... 23 
3.2.18 
Interim analysis ........................................................................................... 23 
3.2.19 
Role of data review committee (DRC) ........................................................ 23 
3.2.20 
Covariates and analysis of subgroups ........................................................ 23 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 23 
4.1 
Hardware ....................................................................................................................... 23 
4.2 
Software ......................................................................................................................... 23 
4.3 
Validation programs ..................................................................................................... 24 
4.4 
Restitution of the programs ......................................................................................... 24 
5 
CHANGES FROM PROTOCOL ................................................................................ 24 
6 
REFERENCES .............................................................................................................. 24 
7 
APPENDICES TO THE SAP TEMPLATE ............................................................... 25 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
HbA1c: 
AE: 
Ae: 
Haemoglobin A1c  
Adverse Event 
Excreted Amount of Elemental Impurities 
cumulated in urine (ng) 
 
 
ALP: 
Alkaline Phosphatase 
 
 
ALT: 
Alanine aminotransferase  
 
 
APTT: 
Activated Partial Thromboplastin Time 
 
 
AST: 
Aspartate aminotransferase  
 
 
ATC: 
Anatomic Therapeutic Class 
 
 
BLL: 
Blood Lead Level 
 
 
BMI: 
Body Mass Index 
 
 
CRF: 
CRU: 
CV: 
DBP: 
DRC: 
Case Report Form 
Clinical Research Unit 
Coefficient of Variation 
Diastolic Blood Pressure 
Date Review Committee 
 
 
eCRF: 
Electronic Case Report Form 
 
 
ECG: 
EI: 
Electrocardiogram 
Elemental Impurities 
 
 
EOS: 
End Of Study 
 
 
GGT: 
HBs Ag: 
HCV: 
HIV: 
HR: 
Gamma-Glutamyl Transpeptidase 
Hepatitis B surface antigen  
Hepatitis C antibody 
Human Immunodeficiency Virus 
Heart Rate 
 
 
ICH: 
International Conference on Harmonisation 
 
 
IMP: 
Investigational Medicinal Product 
 
 
INR: 
ITT: 
LLOQ: 
LOD: 
International Normalised Ratio 
Intent-To-Treat 
Lower Limit Of Quantification 
Limit Of Detection 
 
 
MCH: 
Mean Cell Haemoglobin 
 
 
MCHC: 
Mean Cell Haemoglobin Concentration 
 
 
MCV: 
Mean Corpuscular Volume 
 
 
MedDRA: 
Medical Dictionary for Regulatory Activities 
 
 


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PP: 
PT: 
Per Protocol 
Preferred Term 
 
 
QRS: 
QRS interval duration 
 
 
QT: 
Time interval for ventricular depolarisation and 
repolarisation 
 
 
QTc: 
Corrected QT interval 
 
 
RBC: 
RR: 
Red Blood Cell 
Respiratory Rate 
 
 
SAP: 
Statistical Analysis Plan  
 
 
SAE: 
Serious Adverse Event 
 
 
SAS®: 
SBP: 
Statistical Analysis System 
Systolic Blood Pressure 
 
 
SD: 
Standard Deviation 
 
 
SI: 
SOC: 
International System 
System Organ Class 
 
 
TEAE: 
TID: 
Treatment Emergent Adverse Event 
Three times a Day 
 
 
TFLs:  
ULOQ: 
VPCI: 
Tables, Figures and Listings  
Upper Limit Of Quantification 
Values of Potential Clinical Importance 
 
 
WBC: 
WHO-DD: 
 
White Blood Cell 
World Health Organisation – 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 assess the concentration of lead in blood, one of the 
Class I elemental impurities defined by International Conference on Harmonisation (ICH) 
Q3D guidelines, after chronic administration of Smecta® in subjects with chronic functional 
diarrhoea. 
1.1.2 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To assess blood concentration of other Class I and IIa elemental impurities of interest 
(i.e. arsenic, cadmium, mercury, cobalt, vanadium, nickel and barium) and of 
aluminium after chronic administration of Smecta® in subjects with chronic functional 
diarrhoea. 
• 
To assess urinary lead levels and urinary levels of other selected Class I and IIa 
elemental impurities of interest (i.e. arsenic, cadmium, mercury, cobalt, vanadium, 
nickel and barium), and aluminium after chronic administration of Smecta®. 
• 
To further assess the safety and tolerance of Smecta® after chronic administration.  
1.1.3 
Exploratory (ancillary study) Objective 
The ancillary study objective is to assess stools consistency and frequency during the 
screening period and after chronic administration of Smecta® in subjects with chronic 
functional diarrhoea. 
The bowel microbiote composition will be assessed in a separate analysis plan. 
1.2 
Study design  
This is a prospective, open-label, non-comparative, multi-centre, international phase I study, 
assessing the potential absorption of elemental impurities after chronic administration of 
Smecta® in subjects with chronic functional diarrhoea.   
After a screening period of up to 6 weeks including a baseline assessment, each subject will 
be dosed with Smecta® three times a day (TID) over 5 weeks (Day 1 to Day 35) and then 
continue to be monitored over a post-treatment follow-up period of 3 months until end-of-
study visit (EOS visit). Blood samples, urine collections and faces sampling will be obtained 
at screening phase and baseline visit, over the treatment period and then during follow-up 
period. Potential adverse events will be collected and monitored throughout the study.  
1.2.1 
Study population 
A total of 35 subjects will be enrolled in order to ensure at least 29 subjects completing the 
study. It is planned to enrol a minimum of 40% of each gender, with gender distributed 
approximately equally between sites (e.g. no site with less than 35% of one gender). 
1.2.2 
Study duration  
The overall study duration is expected to be approximately 8 months from first subject 
screened to last subject discharged from the study. 
Each subject will be in the study for approximately 5 months, including 3 to 6 weeks for 
screening activities, 5 weeks of treatment, and 12 weeks of post-dose follow-up period. 


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1.3 
Methods and procedures  
1.3.1 
Subject identification and allocation to study treatment 
After informed consent is obtained, subjects who are screened will be allocated a subject 
number. All screened subjects must be identifiable throughout the study. The investigator will 
maintain a list of subject numbers and names in a source document to enable records to be 
found at a later date if required. 
1.3.2 
Subjects assessments 
1.3.2.1 
Efficacy assessments 
There is no efficacy assessment in this study. 
1.3.2.2 
Biological evaluations 
Blood Samples for Elemental Impurities and blood and plasma biobanking assessed at: 
• 
Screening (Day -42 to Day -21),  
• 
Day – 1 (Baseline), 
• 
6 samples at Day 1 and at Day 35: 
- 2 hours after the first dose,  
- immediately before second dose, 
- 3h post lunch dose,  
- immediately before the third dose, 
- 3h post evening dose, 
- 6h post evening dose, 
• 
Day 2: On pre-dose before dosing, 
• 
Days 8, 15, 22, and 29 visits: at pre-dose of any of the three dosing occasions of the 
day, 
• 
Day 36, in the morning, 
• 
Post-treatment follow-up period at Day 65, Day 95 and Day 125 (EOS visit)  
Urine Collection (24-hour) for Elemental Impurities assessed at:  
• 
Baseline (Day-1), 
• 
Day 35, 
• 
Post-treatment follow-up period at Day 65 and Day 95  
Consistency of stools (Bristol scale) and frequency over 24h by subject assessed at:  
• 
Screening (Day -42 to Day -21), 
• 
Day -14, 
• 
Baseline (Day-1), 
• 
Day 8, 
• 
Day 35, 
• 
Post-treatment follow-up period at Day 65 and Day 95 and Day 125 (EOS visit) 
1.3.2.3 
Safety assessments 
The safety assessments are: 
• 
Adverse events (AEs) monitored from the time that the subject gives informed consent 
and throughout the study 
• 
Clinical safety assessments: 


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• 
Physical examination at screening and EOS visit; 
• 
Vital signs measured at screening and EOS visit, including supine systolic and 
diastolic blood pressure (SBP & DBP), heart rate (HR), body weight, and aural 
body temperature; 
• 
12-lead electrocardiograms (ECGs) measured at screening and EOS visit, 
including interpretation with clinical significance, sinus rhythm, respiratory rate 
(RR) interval duration or heart rate (HR), PR interval duration, QRS interval 
duration, time interval for ventricular depolarisation and repolarisation (QT) 
interval duration, corrected QT interval (QTc) interval corrected by the Bazett 
correction method; 
• 
Clinical laboratory tests, including clinical significance, measured at screening, D-1 
and EOS visit:  
• 
Haematology: full blood count including red blood cells (RBC) count, 
haemoglobin, haematocrit, mean corpuscular volume (MCV), mean cell 
haemoglobin (MCH), mean cell haemoglobin concentration (MCHC), white 
blood cell (WBC) count with differential count (neutrophils, eosinophils, 
basophils, lymphocytes, monocytes), platelet count; 
• 
Blood biochemistry: urea, creatinine, total bilirubin, conjugated bilirubin, 
chloride, bicarbonate, sodium, potassium, calcium, inorganic phosphate, alkaline 
phosphatase (ALP), 
aspartate 
aminotransferase (AST), 
alanine 
aminotransferase (ALT), 
gamma-glutamyl 
transpeptidase (GGT), 
amylase, 
lipase, albumin, total protein, total cholesterol, triglycerides, fasting glucose, 
iron, transferrine saturation, ferritin, eGFR, haemoglobin A1c (HbA1c), urate,  C 
reactive protein (only at screening);  
• 
Coagulation: activated partial thromboplastin time (APTT), prothrombin time, 
prothrombin ratio, international normalised ratio (INR);  
• 
Urinalysis: pH, proteins, ketones, glucose, bilirubin, urobilinogen, occult blood, 
Nitrite, Microscopic examination of sediment (if indicated)  
• 
Pregnancy tests at screening, D-1 and EOS visit 
1.3.2.4 
Other Assessments 
• 
Demographics (country, sex, race, age) at screening; 
• 
Body height, body weight and BMI at screening, 
• 
Medical and surgical history at screening; 
• 
Urine drug of abuse tests (cannabis and metabolites, cocaine, amphetamines, opiates, 
methamphetamines, barbiturates, benzodiazepines, methadone, ecstasy, and tricyclic 
antidepressants) at screening and Day-1; 
• 
Alcohol breath test at screening and Day-1; 
• 
Substance use (Alcohol, tobacco, caffeine and dietary habits) at screening; 
• 
Serology: Hepatitis B surface antigen (HBs Ag), Hepatitis C antibody (HCV) and Anti-
HIV1+2 antibodies at screening and Day-1; 
• 
Post-menopausal status at screening; 
• 
Prior and concomitant general medications, prior medications for chronic diarrhoea, 
prior and concomitant non-drug therapies and prior and concomitant surgical 
procedures; 


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1.3.2.5 
Withdrawal/discontinuation 
All subjects are free to interrupt or withdraw their consent to participate in the study at any 
time, for any reason, specified or non-specified, and without penalty. 
A subject may also be discontinued from the study upon Sponsor’s and/or Investigator’s 
decision for any appropriate reason, such as safety related to an adverse event or concomitant 
therapy, major protocol deviation, noncompliance with protocol restrictions, etc. Due to the 
study primary objective it is important that subjects participating to the study comply with the 
full treatment and follow-up schedule. Hence their wish to take part to the study up to its end 
should be fully discussed and confirmed at study entry. This requirement is to ensure the 
study scientific value by ensuring the collection of the full set of data necessary for its 
analysis and does not preclude any subject right to withdraw at any time as stated above.  
All cases of discontinuation will be discussed between the Investigator and the Sponsor or its 
representative. 
1.3.3 
Schedule of assessments 
Here are the schedules of assessments extracted from the protocol: 
 


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Study Schedule of Events 
 
 


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1.3.4 
Planned sample size 
The critical limit of 50μg/l of lead is chosen as being the most conservative value taken 
among various guidelines (risk of saturnism, observations under high lead exposure at work). 
The baseline blood lead concentration of 31,4μg/l is considered as being a mean blood lead 
concentration in a survey of 1949 adults (18-74 years old) living in France in 2006-2007 (Falq 
et al. 2011). This population is representative of the French population including different 
socio-demographic characteristics and environment risk factors such as: sex, age, smoking 
status, type of drinking water, leisure activities, age of housing, shellfish/crustacean 
consumption. Considering the inclusion and exclusion criteria defined for the study, the 
enrolled subjects should have BLL levels in the same range as reported in the survey. With a 
standard error to the mean of [0,56], the mean blood lead concentration of 31.4μg/l is at 
confidence 95% to be found within [29.82; 32.98] under similar conditions. The non-
superiority Δ margin is a clinical choice calculated as the difference of: 50 – 31.4 = 18.6μg/l. 
A precision of 15% (coefficient of variation) (CV) of the bioanalytical assay has been 
considered in the determination of sample size. Based on the above considerations, a sample 
size of 29 subjects with baseline mean blood lead concentration no greater than 36 μg/l (<36 
μg/l), is required to provide 81% power to reject the null hypothesis of a difference of means 
no greater than 18,6 μg/l (≤ 18,6 μg/l considered as no difference of means). Considering 
potential drop-out, it is planned to enroll a total of 35 subjects to ensure that at least 29 
subjects completed the study. 
Subjects who prematurely discontinue after investigational medicinal product (IMP) 
administration will not be replaced. 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) 
2.1 
Efficacy population 
There is no efficacy assessment in this study. 
2.2 
Screened population 
The screened population is all screened subjects in the study which have given an informed 
consent. 
2.3 
Included population 
The included population is all included subjects in the study i.e. with a status “included” at the 
end of the baseline visit. 
2.4 
Safety population 
The safety population is all subjects receiving at least one dose of study medication.  
2.5 
Intent-To-Treat (ITT) population 
The ITT population is all subjects receiving at least one dose of study medication and having 
one pre-dose BLL and at least one post-dose BLL. 
2.6 
Per Protocol (PP) population 
The Per Protocol population is all subjects in the ITT population who completed the last post-
treatment follow-up visit without any major protocol deviation. 
 
3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with ICH E9 guideline. 


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Statistical analyses described in this document will be performed by Biotrial Biometrics, 
Rennes, France. 
3.1.1 
Primary endpoint 
The primary endpoint is to assess the absolute change in blood lead level (BLL) from baseline 
during treatment and post-treatment follow-up period. 
3.1.2 
Secondary endpoints 
The secondary endpoints are to assess: 
• 
the absolute change from baseline of concentrations of other selected Class I (i.e. 
arsenic, barium) and Class IIa elemental impurities (i.e.: cadmium, mercury, cobalt, 
vanadium, nickel) and aluminium in blood during treatment and post-treatment follow-
up period. 
• 
the absolute change from baseline of urinary concentrations of selected Class I and IIa 
elemental impurities (arsenic, barium, cadmium, mercury, cobalt, vanadium, nickel) 
and aluminium in urine at the end of Smecta® administration and during follow-up 
period. 
3.1.3 
Safety endpoints 
The safety endpoints are: 
• 
physical examination, vital signs, ECG,  
• 
standard clinical laboratory tests,  
• 
adverse events and treatment emergent adverse events (TEAE). 
3.1.4 
Exploratory endpoints 
Different absolute changes from baseline will be described on the ITT population:  
• 
Absolute changes from baseline of consistency of stools (as rated according to Bristol 
scale over 24h by the subject) and frequency at different study visits. 
• 
The microbiota absolute changes analysis will be described in a specific and separate 
plan. 
3.1.5 
Multiplicity 
There is no plan for multiple testing adjustments in this study.  
3.1.6 
Significance testing and estimation 
The statistical analysis of safety and biological samples is only descriptive therefore no formal 
statistical significance testing will be performed. 
3.2 
Analysis methods 
3.2.1 
Efficacy 
Not applicable. 
3.2.2 
Biological and clinical evaluations 
3.2.2.1 
Biological evaluations 
Biological evaluations concern blood samples for elemental impurities, urine collection (24-
hour) for elemental impurities. 
The baseline for blood concentrations (lead and other elemental impurities) will be the 
average between the available screening and pre-dose (Day-1) values (as defined in Appendix 
1 (5)). 


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For blood lead concentrations, absolute values and changes (as defined in Appendix 1 (6)) 
from BLL baseline will be summarized for all post-baseline time-points on the ITT and the PP 
population.  
Additionally, for all follow-up time points, absolute changes from D36 (in the morning) will 
be calculated and summarized. 
Corresponding listings will be provided on ITT population. 
Plots of mean absolute changes over time (with 95% confidence interval) will be provided on 
ITT and PP population and individual corresponding plots on ITT population (one graph for 
full profile). For blood lead concentrations, same analyses by country will be presented.  
For other elemental impurities blood concentrations, the analysis will also be described in the 
same way as for blood lead concentrations expect for plots of means and individual 
corresponding plots which will be provided only for arsenic and barium parameters. 
The baseline for urine concentrations (lead and other elemental impurities) and Ae parameter 
will be defined as the last available (and reliable if applicable) assessment collected prior to 
receiving dose of Smecta® on Day 1. 
For urine lead concentrations and other elemental impurities, the same approach for blood 
lead concentrations will be done expect that there will be no plots. 
The cumulative amount of EI (Elemental Impurities) excreted in urine (the Ae parameter) will 
be calculated (as defined in Appendix 1 (7)) and summarized at each scheduled assessment 
with absolute changes from baseline and absolute changes from D36 (in the morning) and 
listed on ITT population. Plot of mean of this cumulative amount (with 95% confidence 
interval) will be provided on ITT population if the number of data above the limit of 
quantification is sufficient. 
The volume of urine will be only listed on ITT population.  
For summary statistics, the following will be presented: n, arithmetic mean with its 95% 
confidence interval, standard deviation (SD), median and the range (minimum, maximum).  
Geometric mean with its 95% confidence interval, CV% and geometric CV% will also be 
presented. 
To compute descriptive statistics, all <LOQ values are replaced by the numerical value 
(LOQ/2) throughout the dataset and all <LOD values are replaced by the numerical value 
(LOD/2) throughout the dataset. 
In case of high blood level of lead at one or two of the baseline points, a sensitivity analysis 
may be performed for blood lead concentrations summary tables and figures, excluding the 
patients with such unexpected baseline results to avoid any confounding of the mean study 
results.  
Modeling of lead levels in blood and urine may be performed if deemed necessary. If it is the 
case, the data analysis plan and the analysis will be reported in separate data analysis plan and 
report. 
3.2.2.2 
Clinical evaluations 
Consistency of stools (Bristol scale) and frequency over 24h by subject will be assessed on 
ITT population. 
The baseline will be defined as the last available (and reliable if applicable) assessment 
collected prior to receiving dose of Smecta® on Day 1. 
Number of watery stools (type 6 or 7), non-watery stools (type 1 to 5 inclusive) and total 
number of stools will be calculated for each subject and visit and will be summarised by visit 
with absolute changes from baseline.  


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Mean scores for watery stools, non-watery stools and for all stools will be calculated for each 
subject and visit and will be summarised by visit with absolute change from baseline. 
Corresponding individual listings will be provided. 
Figures of means for numbers of stools and mean scores per visit on all subjects will be 
presented for watery stools, non-watery stools and total number of stools. 
3.2.3 
Safety 
All safety data will be included in the data listings and summary tables will be based on the 
safety population. 
3.2.3.1 
Adverse events  
AEs reported in the case report form (CRF) will be coded using the medical dictionary for 
regulatory activities (MedDRA) Version 19.0 or higher. 
All adverse events and SAEs, including pre-treatment events which occurred during the 
screening period will be reported from the time of consent until the EOS visit. 
Listings will be presented and sorted by subject, start date-time of AEs, primary system organ 
class, preferred term and verbatim text for all adverse events recorded during the study.  
Listings of all AEs, serious adverse events (SAE), adverse events leading to withdrawal and 
listing of deaths will also be presented. 
Treatment Emergent Adverse Events (TEAE) will be flagged (*) in the adverse events listing 
and will be summarised. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving dose of Smecta®, or 
• 
it was present prior to receiving the dose of Smecta® but the intensity increased during 
the active phase of the study, or 
• 
it was present prior to receiving the dose of Smecta®, the intensity is the same but the 
drug relationship became related during the active phase of the study. 
An overall summary table of all AEs will be presented. 
TEAEs will be summarised with the number and percentage of subjects with adverse events 
classified by primary system organ class (SOC) and preferred term (PT). The number of 
occurrences of a TEAE will also be presented. 
In addition, the same summary tables will also be presented for SAEs, TEAEs per decreasing 
frequency, TEAEs by maximum intensity, TEAEs by most serious causality and TEAEs 
leading to withdrawal. 
In the event of multiple adverse events being reported by the same subject, the maximum 
intensity (severe > missing > moderate > mild) and the most serious causality (related > not 
related) will be chosen. 
3.2.3.2 
Laboratory data 
A separate listing of normal ranges for international system (SI) units will be provided by 
gender and age where relevant. 
Laboratory data (haematology, biochemistry, coagulation and urinalysis) will be listed in SI 
units and abnormal values will be flagged (High, [H], Low [L], clinically significant [CS]) 
where applicable. Any unscheduled laboratory assessments will be flagged [U] in the listings. 
In addition, a listing will be presented of all values for a subject with at least one clinically 
significant abnormal laboratory value. 
The baseline will be defined as the last available (and reliable if applicable) assessment 
collected prior to receiving dose of Smecta® on Day 1. 


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For haematology, biochemistry and coagulation, summary statistics will be presented at each 
scheduled assessment and absolute changes from baseline. For haematology and 
biochemistry, shift tables from baseline to post baseline visit (EOS visit) will be presented 
using the number and percentage of subjects with low, normal or high values. 
For continuous urinalysis, summary statistics will be presented at each scheduled assessment 
for actual values and absolute changes from baseline. 
Categorical urinalysis parameters (absent/trace/positive) will be presented in frequency tables 
at each scheduled assessment as well as subjects with low, normal or high urinary values. 
3.2.3.3 
Physical examination 
Physical examination will be listed by subject, timepoint and examination date. 
3.2.3.4 
Vital signs 
Vital signs (supine systolic and diastolic blood pressure (SBP & DBP), heart rate                 
(HR), body weight, and aural body temperature) will be listed at each assessment by subject 
(and so including clinically significant findings). Any unscheduled vital signs will be flagged 
[U] in the listing.  
The baseline will be defined as the last available (and reliable if applicable) assessment 
collected prior to receiving dose of Smecta® on Day 1. 
Summary statistics will be presented at each scheduled assessment for actual values and 
absolute changes from baseline. 
Shift tables for heart rate and blood pressure (systolic and diastolic) will be presented with the 
number and percentages of subjects with values of potential clinical importance (VPCI): 
-Systolic blood pressure (mmHg) will have three categories:  
<120 
Low 
[120-129] Normal 
>129 
High 
-Diastolic blood pressure (mmHg) will have three categories:  
<80 
Low 
[80-84] 
Normal 
>84 
High 
-Heart rate (bpm) will have three categories:  
<60 
Low 
[60-100] 
Normal 
>100 
High 
The VPCI will be flagged in the listings and the flagging identifier specified.  
The temperature will be listed by subject, timepoint and examination date. 
3.2.3.5 
ECG 
Interpretation with clinical significance, sinus rhythm, respiratory rate (RR) interval duration 
or heart rate (HR), PR interval duration, QRS interval duration, time interval for ventricular 
depolarisation and repolarisation (QT) interval duration, corrected QT interval (QTc) 
corrected by the Bazett correction method will be presented. 


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ECG results will be listed at each assessment by subject (and so including clinically 
significant findings).  
Any unscheduled ECGs will be flagged [U] in the listing.  
The baseline will be defined as the last available (and reliable if applicable) assessment 
collected prior to receiving dose of Smecta® on Day 1. 
For continuous ECG parameters (RR, PR, QRS, QT and QTcB), summary statistics will be 
presented at each scheduled assessment for actual values and absolute changes from baseline.  
Shift tables for heart rate, PR interval duration, QRS interval duration, QT interval duration 
and corrected QT interval will be presented with the number and percentages of subjects with 
values of potential clinical importance (VPCI): 
-Heart rate (bpm) will have three categories:  
<60 
Low 
[60-100] 
Normal 
>100 
High 
- PR interval duration (s) will have three categories:  
<0.12 
Low 
[0.12-0.20] 
Normal 
>0.20  
High 
- QRS interval duration (s) will have two categories:  
≤0.12 
Normal 
>0.12 
High 
- QT interval duration (s) will have two categories by each gender stratum:  
Gender stratum 
Normal 
High 
Males  
<0.40 
≥0.40 
Females 
<0.44 
≥0.44 
- Corrected QT interval (ms) will have two categories by each gender stratum:  
Gender stratum 
Normal 
High 
Males  
≤440 
>440 
Females 
≤460 
>460 
The VPCI will be flagged in the listings and the flagging identifier specified.  
For interpretation of clinical significance (within normal limits / abnormal, not clinically 
significant / abnormal, clinically significant / not evaluable), a frequency table will be 
presented, by visit. 
3.2.3.6 
Pregnancy tests 
A listing with the date of examination, the status of the examination (done/not done/not 
applicable) and the result (positive/negative) will be provided by subject, timepoint, 
examination date and method: (serum on screening only or urine). 


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3.2.4 
Missing data and outliers 
3.2.4.1 
Missing data 
No missing value will be imputed. 
If a value required a retest, the last reliable non-missing value will be taken into account if 
measured before the administration of Smecta®; and the first non-missing reliable value for 
post-baseline assessments. An assessment will be considered reliable if it is performed 
without any technical problem and if the result is within the range of plausible values.  
Any repeat or additional assessments performed will be included in the individual subject data 
listings. 
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 database freeze and will be 
documented in the minutes of the data review. 
3.2.4.2 
Missing or incomplete dates 
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: 
The most conservative approach will be systematically considered (i.e. if the onset date of an 
AE is missing / incomplete, it is assumed to have occurred during the study treatment phase 
(e.g. a TEAE for AEs) except if the partial onset date or other data [stop date, …] indicates 
differently). 
A missing/incomplete date of medical history or disease diagnosis will be assumed to have 
occurred before any study treatment. 
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 (e.g. a medication 
with partial start and stop dates could be considered as prior and concomitant treatment). 
Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (e.g. for an AE started in 2004-02 after the administration performed on 2004-01-
31, 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). 
3.2.4.3 
Outliers 
Any outlier which is implausible 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. 
3.2.5 
Subject disposition 
A summary table with the description of the number of subjects in each analysis set (Screened 
Set, Included Set, Safety Set, ITT set and PP set) will be performed by country and overall. 
A summary table with the description of the numbers of screened subjects, screening failure 
subjects, included subjects, treated subjects, study completed subjects (who completed the last 
post-treatment follow-up visit) and the number of subjects who discontinued classified by 
main reason of withdrawal will be performed. A figure for subject disposition and 
corresponding individual listings will be provided. 
A summary table with the number and percentage of subjects at each visit will be performed 
on the safety set. 
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A listing of the inclusion and exclusion criteria not met will be provided by subject, and 
subject eligibility will also be listed on the included population. 
A summary table will present the extent of subject duration in the study (in weeks) for all the 
subjects in the safety population (as defined in Appendix 1 (2)). 
A listing of their study duration (in weeks) will be presented by subject on the safety 
population.  
Listing of re-enrollment of subjects will be listed separately on included population. 
3.2.6 
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. 
3.2.7 
Demographic and baseline characteristics 
All demographic (country, sex, race) and baseline characteristics (age, body height, body 
weight and BMI at baseline) as well as the substance use (alcohol, tobacco, caffeine and 
dietary habits use) will be listed by subject on the safety population. 
Summary statistics will be provided for demographic and baseline characteristics as well as 
the substance use on the safety population. 
For demographic and baseline characteristics, the results will be described by gender and by 
country.  
The results of urine drug of abuse tests, alcohol breath test, post-menopausal status (at 
screening), and serology (at screening and Day-1) will only be provided in subjects data 
listings on the safety population by subject and examination date. 
3.2.8 
Medical and surgical history 
Medical and surgical history will be coded using MedDRA Version 19.0 or higher. 
Listings will present the primary system organ class, the preferred term and the reported term. 
The listings will be sorted by subject, start date, primary system organ class, preferred term 
and reported term on the safety population. 
A frequency table of the number and percentage of subjects will be provided for all medical 
and surgical history by primary system organ class and preferred term for the safety 
population. 
3.2.9 
Subject compliance 
The time and day of drug administration will be recorded by the study site when present at the 
clinical unit and by the subject when self-administered using a diary. 
Compliance to diosmectite (Smecta®) intake will be based on this diary. 
All treatment administration information will be listed by subject, timepoint and date of 
administration on the safety population. 
Three listings will be performed: one for the treatments taken, one for the meals taken, and 
one for the drug accountability. 
Study drug exposure (as defined in Appendix 1 (3)) in weeks will be summarized. 
A summary table will present the global compliance (expressed in percentage as defined in 
Appendix 1 (4)) on the treatment period for the safety population.  
Additionally, compliance will be categorized as follows: < 80% (Under compliance), 80-
120% (Compliance) and > 120% (Over compliance) and will be summarized. 
In the included population, protocol deviations from observed and scheduled times will be 
presented with the reasons for exclusion from the PP population. 


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All the protocol deviations identified will be also listed by subject with the reasons for 
exclusion. 
A protocol deviation specification document will be provided further by Aepodia. 
3.2.10 
Prior and concomitant medications  
Concomitant medication will be coded by using the World Health Organisation – Drug 
Dictionary (WHO-DD) June 2016 Version or higher. 
The therapeutic class will correspond to the second level of anatomic therapeutic class (ATC) 
code, that is, corresponding to the first 3 figures. 
The date and time of baseline (Smecta® on Day 1) will be used as the cut-off date for the 
definition of prior and concomitant medications: 
A prior medication will be defined as a medication stopped prior to the date of baseline.  
A concomitant medication will be defined as a medication which is taken by subject any time 
during the study after the date of baseline. 
A medication that started before the date of baseline and is continuing after will be considered 
as both, prior and concomitant.  
Prior, concomitant and both prior and concomitant medications will be flagged P, C and PC 
respectively, in all listings. 
Listings will be presented for the therapeutic class, preferred name and reported name on the 
safety population. The listings will be sorted by subject, chronological start date, therapeutic 
class, preferred name and reported name. 
Frequency tables of the number and percentage of subjects with at least one prior or, 
concomitant medication will be provided by therapeutic class and preferred name on the 
safety population. 
3.2.11 
Prior medications for Chronic Diarrhoea  
Analysis of prior medications for chronic diarrhoea will be performed as described in section 
3.2.10. 
3.2.12 
Prior and concomitant non-drug therapies 
Prior and concomitant non-drug therapies will be coded using MedDRA Version 19.0 or 
higher. It will be listed by subject, chronological start date, primary system organ class, 
preferred term, and reported term.  
3.2.13 
Concomitant surgical procedures  
Concomitant surgical procedures will be coded using MedDRA Version 19.0 or higher. It will 
be listed by subject, chronological start date, primary system organ class, preferred term, and 
reported term.  
3.2.14 
Hospitalizations 
Dates of hospitalizations occurring during the study will be listed on included population with 
reported term, entry date, and discharge date. 
3.2.15 
Derived data 
The derived data are variables which are calculated from the raw data in the electronic case 
report form (eCRF) and not included in the database and will be included in the listings. 
3.2.16 
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 with the 
number of decimal places collected, and derived data will be presented to an appropriate 


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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, arithmetic mean, standard 
deviation (SD), median and the range (minimum, maximum).  
Mean, median and standard deviation values will be reported with 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. 
CV% and ratio will be presented with one decimal place. 
Percentages will be reported with 1 decimal place and 0% will not be presented. Percentages 
will be calculated using a denominator of all subjects in a specified population. The 
denominator will be specified in a footnote to the tables for clarification if necessary.  
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]. 
3.2.17 
Pooling of Centres 
Two countries (one centre for each) are planned to be involved: Netherlands and United 
Kingdom. 
3.2.18 
Interim analysis 
No formal preliminary or interim analyses are planned for this study. If an unplanned 
preliminary or interim analysis is deemed necessary, the Sponsor clinical pharmacologist or 
Investigator will consult with the appropriate medical director or designee to determine if it is 
necessary to amend the protocol. 
Blood lead concentrations from screening and baseline (Day-1) will be obtained on an 
ongoing basis to verify that these values are within the 95% confidence interval of the mean 
blood lead concentration of 31,4μg/l used in the determination of sample size (see Section 
8.1.2) and therefore confirm the assumptions for sample size calculation. If not, the sample 
size might be re-evaluated accordingly. 
3.2.19 
Role of data review committee (DRC) 
No independent data monitoring committee/interim data review committee will be used in this 
study. 
3.2.20 
Covariates and analysis of subgroups 
No covariates or analysis of subgroups are planned in this study. 
Nevertheless, analyses by country (Netherlands and United Kingdom) will be presented for 
demographic and baseline characteristics and also for blood lead concentrations. 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Hardware 
The statistical analysis will be performed using PC on a Windows 7 operating system. 
4.2 
Software 
All tables, figures and listings (TFLs) will be produced and statistical analysis performed 
using statistical analysis system (SAS®)) version 9.4 [2]. All outputs will be provided as 
individual word files following GEN014 template and compiled in bookmarked .pdf files as 
per ICH section (e.g. 14.1, 14.2 …). 


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4.3 
Validation programs 
Biotrial Biometrics will provide a validation plan to Ipsen identifying the methods of 
validation. 
The study statistician is responsible for reviewing each output associated with the deliverable 
product. Program logs are checked by the statistical programmer for logical, syntax and fatal 
errors. The checks 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 study 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 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 change is required to produce the deliverable, the 
statistical programmer and the study statistician have to complete and sign the quality control 
and statistical analysis results follow-up’s validation checklist, to indicate that they have 
successfully performed all of their responsibilities. Copies of the internal quality control 
forms produced for the validation process will be provided to the sponsor to support the 
validation. 
4.4 
Restitution of the programs 
All programs (including macros and analysis datasets) producing the tables, listings and 
statistical outputs along with associated logs should be given to the sponsor when the TFLs 
and statistical analyses have been finalised. 
5 
CHANGES FROM PROTOCOL 
Changes from the final protocol dated 7 September 2016 are the following:  
Results of plasma samples will not be analysed during the study therefore will not be included 
in the clinical study report neither the biobanking blood samples of other elemental impurities 
that may be dosed after the study upon need or request from Health Agencies. 
Since there was no eligibility criterion on blood lead level at study entry, some dosages could 
evidence an unexpected elevated level at baseline.  
In the protocol, hypothesis for sample size calculation was based on the mean value in 
literature data in France (Falq et al. 2011).  
In case of high blood level of lead at one or two of the baseline points, a sensitivity analysis 
may be performed.  
This analysis will exclude the patients with such unexpected baseline results to avoid any 
confounding of the mean study results.  
6 
REFERENCES 
1. International Conference on Harmonisation (ICH) E9 and Federal register Vol. 63, No. 179 
(September 1998). 
2. SAS, Version 9.4. SAS Institute Inc., Cary, NC, USA, 2012. 


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7 
APPENDICES TO THE SAP TEMPLATE 
Appendix 1: Derived Data 
The following derived data will be calculated: 
(1) 
Study day 
Study day will be defined as ‘-1’ for the day prior to IMP administration and as ‘1’ 
for the day of IMP administration (i.e. day 0 does not exist). 
(2) 
Study duration 
Study duration (weeks) will be calculated as [(last visit attended - date of first IMP 
administration) + 1] / 7. 
(3) 
Study drug exposure 
Study drug exposure (weeks) will be derived using information from diary and will 
be calculated as [(last date of IMP administration - first date of IMP 
administration) + 1] / 7. 
(4) 
Compliance 
Compliance (%) will be calculated as (the total number of sachets taken / the total 
number of expected sachets to be taken) x 100. 
The total number of sachets taken will be derived using information from diary as the 
sum of number of sachets taken when a date of IMP administration is entered. 
The total number of expected sachets to be taken will be derived using information 
from diary based on three sachets per day (TID) (morning, noon, and evening) to be 
taken by the subject as [(last date of IMP administration - first date of IMP 
administration) + 1] x 3. 
(5) 
Baseline 
BLL baseline will be derived as the average between the available screening and pre-
dose (Day-1) values. 
Baseline for other parameters will be derived as the last available (and reliable if 
applicable) assessment before IMP administration. 
(6) 
Absolute change from baseline 
Absolute change from baseline will be calculated as the difference from baseline 
(e.g. assessment at the visit – assessment at baseline). 
(7) 
Ae parameter 
Ae parameter (ng) will be calculated as the cumulated concentration of EI in urine × 
the total volume of urine collected over 24 hours. 
(8) 
Therapeutic Class 
The therapeutic class will correspond to the first 3 digits of the ATC code. The 
decoding of the therapeutic class will be done from the WHO-DD June 2016 Version 
or higher. 
(9) 
Prior and concomitant medication duration 
If the start and end dates of the medication are identical then “<1” day will be 
presented with the duration in hh:mm recorded in the eCRF if it is available. If times 
are available, the duration of concomitant treatments will be calculated as (end 
date/time - start date/time). If at least one time is missing, the duration of 
concomitant treatments will be calculated as (end date - start date) + 1. If the 
recorded end date is continuing at the end of the study then the end date will be listed 
as “ongoing” and the duration will be approximated as “≥(last attended visit date – 


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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=2004-01-31 and end 
date=2004-02 or start date=2004-01 and end date=2004-02-01] but if both are partial 
or one is missing the duration will not be presented. 
(10) AE duration 
If the start and end dates of the AE are identical then “<1” day will be presented with 
the duration in hh:mm recorded in the eCRF if it is available. If times are available, 
the duration will be calculated as (end date/time – start date/time) and presented in 
days hh:mm. If at least one time is missing and 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 continuing at the end of the study, 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 a superior inequality “≥xx” day(s) [i.e. ≥2 where start 
date=2004-01-31 and end date=2004-02 or start date=2004-01 and end date=2004-
02-01]. 
(11) Time since last dose for adverse event 
If the start date of the adverse event is identical to the date of last administration, 
then”<1” day will be presented with the time to onset in hh:mm recorded in the 
eCRF if it is available. If times are available, the time will be calculated as (start 
date/time – last administration date/time) and presented in days hh:mm. If at least 
one time is missing and if the time to onset is greater than 24 hours then it will be 
calculated as (start date - last administration date)+1 and presented in days. If the 
start date and the associated information do not allow to state about the last dose 
received (partial start date or start at administration day without knowing if it started 
before or after the drug intake), all the possible time since last dose will be presented 
[i.e.: if a subject received a daily administration and reported an AE at second 
administration day but without indication about before or after the drug intake the 
time since last dose will be as “2 / <1”]. If the start date is partial, the time since last 
dose will be presented as an superior inequality (i.e.: for an AE started in 2004-02 
after the  only administration performed on 2004-01-31, the time since last dose will 
be as “≥2” days). If the start date is missing the time since last dose will not be 
presented although the AE will be assigned to each dose received before its end date. 


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Appendix 2: List of TFLs 
 
Listings index 
 
16.1.7 Randomisation Scheme and Codes 
Not applicable 
16.2 SUBJECT DATA LISTINGS 
16.2.1 Discontinued subjects 
Listing 16.2.1.1: 
Subject Disposition – Screened Population 
Listing 16.2.1.2: 
Subject Disposition – Study Withdrawals – Screened 
Population 
Listing 16.2.1.3.1: Inclusion Criteria Assessments 
Listing 16.2.1.3.2: Inclusion Criteria not Met – Included Population 
Listing 16.2.1.4.1: Exclusion Criteria Assessments 
Listing 16.2.1.4.2: Exclusion Criteria not Met – Included Population 
Listing 16.2.1.5: 
Assessments Dates – Included Population 
Listing 16.2.1.6: 
Re-enrollment of Subjects – Included Population 
16.2.2 Protocol deviations 
Listing 16.2.2.1: 
Subject Eligibility for the Study – Included Population 
Listing 16.2.2.2: 
Major and Minor Protocol Deviations – Included Population 
Listing 16.2.2.3: 
Reasons for Exclusion from the Populations – Included 
Population 
16.2.3 Subjects excluded from the efficacy analysis 
Not applicable 
16.2.4 Demographic data 
Listing 16.2.4.1: 
Demographics and Baseline Characteristics – Safety 
Population 
Listing 16.2.4.2: 
Alcohol Breath Test – Safety Population 
Listing 16.2.4.3: 
Urine Drug of Abuse Tests – Safety Population 
Listing 16.2.4.4: 
Substance Use – Safety Population 
Listing 16.2.4.5: 
Serology – Safety Population 
Listing 16.2.4.6: 
Postmenopausal Status – Safety Population 
Listing 16.2.4.7.1: Medical and Surgical History – Reported Terms and 
Associated MedDRA Terms – Safety Population 
Listing 16.2.4.7.2: Medical and Surgical History – Safety Population 
Listing 16.2.4.8.1: Prior and Concomitant Medications – WHO-DD Names – 
Safety Population 
Listing 16.2.4.8.2: Prior and Concomitant Medications – Safety Population 
Listing 16.2.4.9.1: Prior Medications for Chronic Diarrhoea – WHO-DD Names 
– Safety Population 
Listing 16.2.4.9.2: Prior Medications for Chronic Diarrhoea – Safety Population 
Listing 16.2.4.10.1: Prior and Concomitant Non-Drug Therapies – Reported 
Terms and Associated MedDRA Terms – Safety Population 


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Listing 16.2.4.10.2: Prior and Concomitant Non-Drug Therapies – Safety  
 
 
Population 
Listing 16.2.4.11.1: Concomitant Surgical Procedures – Reported Terms and 
Associated MedDRA Terms – Safety Population 
Listing 16.2.4.11.2: Concomitant Surgical Procedures – Safety Population 
16.2.5 Compliance 
Listing 16.2.5.1: 
Study Treatment Administration – Safety Population 
Listing 16.2.5.2: 
Meals – Safety Population 
Listing 16.2.5.3: 
Drug Accountability – Safety Population 
Listing 16.2.5.4: 
Study Drug Compliance – Safety Population 
Listing 16.2.5.5: 
Study Duration – Safety Population 
16.2.6 Biological and Clinical Evaluations Data  
Listing 16.2.6.1.1: Individual Blood Concentrations of Lead (Raw Data) – ITT  
                                Population 
Figure 16.2.6.1.2: Individual Graphs for Blood Concentrations of Lead – ITT 
                               Population 
Listing 16.2.6.2: 
Individual Blood Concentrations of Other Selected Class I 
 
Elemental Impurities and Class IIa Elemental Impurities and 
 
Aluminium in Blood (Raw Data) – ITT Population 
Figure 16.2.6.3: 
Individual Graphs for Blood Concentrations of Arsenic and 
                                Barium – ITT Population 
Listing 16.2.6.4: 
Individual Urine Concentrations of Lead (Raw Data),  
                                   Cumulative Amount of Elemental Impurities Excreted and 
                               Volume of Urine – ITT Population 
Listing 16.2.6.5: 
Individual Urine Concentrations of Other Selected Class I 
 
Elemental Impurities and Class IIa Elemental Impurities and 
 
Aluminium in Urine (Raw Data)  – ITT Population 
Listing 16.2.6.6: 
Consistency of Stools and Frequency – ITT Population 
Listing 16.2.6.7: 
Number and Mean Scores for Stools – ITT Population 
16.2.6 Efficacy data 
Not applicable 
16.2.7 Adverse event listings 
Listing 16.2.7.1: 
Adverse Events Key Information 
Listing 16.2.7.2: 
All Adverse Events – Safety Population 
Listing 16.2.7.3: 
Serious Adverse Events – Safety Population 
Listing 16.2.7.4: 
Adverse Events Leading to Withdrawal – Safety Population 
16.2.8 Listing of individual laboratory measurements by subject 
Listing 16.2.8.1: 
Normal Ranges for SI Units 
Listing 16.2.8.2: 
Haematology (SI Units) (Raw Data) – Safety Population 
Listing 16.2.8.3: 
Biochemistry (SI Units) (Raw Data) – Safety Population 
Listing 16.2.8.4: 
Coagulation (SI Units) (Raw Data) – Safety Population 
Listing 16.2.8.5: 
Urinalysis (SI Units) (Raw Data) – Safety Population 


IPSEN GROUP 
D-FR-00250-108 
SAP FINAL VERSION 1.0: 20 JUNE 2017 
 
29/32 
CONFIDENTIAL 
 
Listing 16.2.8.6: 
Pregnancy Test – Safety Population 
16.2.9 Listing of other safety data 
Listing 16.2.9.1: 
Assessment of Physical Examination – Safety Population 
Listing 16.2.9.2: 
Vital Signs (Raw Data) – Safety Population 
Listing 16.2.9.3: 
12-lead ECG (Raw Data) – Safety Population 
16.2.10 Listing of hospitalization Dates – Included Population 
 


IPSEN GROUP 
D-FR-00250-108 
SAP FINAL VERSION 1.0: 20 JUNE 2017 
 
30/32 
CONFIDENTIAL 
 
Tables index 
 
14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT 
INCLUDED IN THE TEXT 
14.1 DEMOGRAPHIC DATA 
Table 
14.1.1: 
Subjects Populations – Screened Population 
Table 
14.1.2.1: 
Subjects Disposition – Screened Population 
Figure 14.1.2.2: 
Subjects Disposition – Screened Population 
Table 
14.1.3: 
Reasons for Screening Failure – Screened Population 
Table 
14.1.4.1: 
Major and Minor Protocol Deviations – Included Population 
Table 
14.1.4.2: 
Reasons for Exclusion from the Populations – Included 
Population 
Table 
14.1.5: 
Subjects Disposition by Visit – Safety Population 
Table 
14.1.6: 
Study Duration – Safety Population 
Table 
14.1.7.1: 
Demographics and Baseline Characteristics (Overall and by 
Gender) – Safety Population 
Table 
14.1.7.2: 
Demographics and Baseline Characteristics (by Country) – 
Safety Population 
Table 
14.1.8: 
Substance Use – Safety Population 
Table 
14.1.9: 
Medical and Surgical History – Safety Population 
Table 
14.1.10: 
Prior and Concomitant Medications – Safety Population 
Table 
14.1.11: 
Prior Medications for Chronic Diarrhoea – Safety Population 
Table 
14.1.12: 
Study Drug Exposure and Compliance – Safety Population 
14.2 BIOLOGICAL AND CLINICAL EVALUATIONS DATA 
14.2.1 Biological Evaluation – ITT population  
Table 
14.2.1.1.1.1:  Blood Concentrations of Lead (Summary Statistics) – ITT 
Population 
Table 
14.2.1.1.1.2: Sensitivity Analysis - Blood Concentrations of Lead 
                                  (Summary Statistics)  
Figure 14.2.1.1.2.1:  Graph for Arithmetic Means of Blood Concentrations of 
                                   Lead (with 95% Confidence Interval) – ITT Population 
Figure 14.2.1.1.2.2:  Sensitivity Analysis - Graph for Arithmetic Means of Blood  
                                   Concentrations of Lead (with 95% Confidence Interval)  
Table 
14.2.1.2.1: Blood Concentrations of Other Selected Class I Elemental 
Impurities and Class IIa Elemental Impurities and Aluminium 
in Blood (Summary Statistics) – ITT Population  
Figure 14.2.1.2.2: Graph for Arithmetic Means of Blood Concentrations of 
Arsenic and Barium (with 95% Confidence Interval) – ITT 
Population  
Table 
14.2.1.3: 
Urine Concentrations of Lead (Summary Statistics) – ITT 
Population 
Table 
14.2.1.4: 
Urine Concentrations of Other Selected Class I Elemental 
Impurities and Class IIa Elemental Impurities and Aluminium 
in Urine (Summary Statistics) – ITT Population  


IPSEN GROUP 
D-FR-00250-108 
SAP FINAL VERSION 1.0: 20 JUNE 2017 
 
31/32 
CONFIDENTIAL 
 
                Table 
14.2.1.5: 
Cumulative Amount of Elemental Impurities Excreted in  
                                                  Urine (Summary Statistics) – ITT Population  
                Table 
14.2.1.6: 
Graph for Arithmetic Means of Cumulative Amount of  
                                                  Elemental Impurities Excreted in Urine (with 95%  
                                                  Confidence Interval) – ITT Population  
14.2.2 Biological Evaluation – PP population 
Table 
14.2.2.1.1.1:  Blood Concentrations of Lead (Summary Statistics) – PP 
                                 Population 
Table 
14.2.2.1.1.2: Sensitivity Analysis - Blood Concentrations of Lead 
                                  (Summary Statistics)  
Figure 14.2.2.1.2.1:  Graph for Arithmetic Means of Blood Concentrations of 
                                   Lead (with 95% Confidence Interval) – PP Population 
Figure 14.2.2.1.2.2:  Sensitivity Analysis - Graph for Arithmetic Means of Blood 
                                   Concentrations of Lead (with 95% Confidence Interval)  
Table 
14.2.2.2.1: Blood Concentrations of Other Selected Class I Elemental 
Impurities and Class IIa Elemental Impurities and Aluminium 
in Blood (Summary Statistics) – PP Population  
Figure 14.2.2.2.2: Graph for Arithmetic Means of Blood Concentrations of 
Arsenic and Barium (with 95% Confidence Interval) – PP 
Population  
Table 
14.2.2.3: 
Urine Concentrations of Lead (Summary Statistics) – PP 
Population 
Table 
14.2.2.4: 
Urine Concentrations of Other Selected Class I Elemental 
Impurities and Class IIa Elemental Impurities and Aluminium 
in Urine (Summary Statistics) – PP Population  
14.2.3 Clinical Evaluation study 
Table 
14.2.3.1: 
Consistency of Stools and Frequency Over 24 Hours – ITT 
Population 
                 Figure    14.2.3.2:      Graph of Means (±SEM) for Numbers of Stools – ITT  
                                               Population 
                 Figure    14.2.3.3:      Graph of Means (±SEM) for Mean Scores of Stools – ITT 
                                                Population 
14.3 SAFETY DATA 
14.3.1 Displays of adverse events 
Table 
14.3.1.1: 
Overall Summary of Adverse Events – Safety Population 
Table 
14.3.1.2: 
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events by Primary System Organ Class and 
Preferred Term – Safety Population 
Table 
14.3.1.3: 
Number (%) of Subjects Reporting Serious Adverse Events 
by Primary System Organ Class and Preferred Term – Safety 
Population 
Table 
14.3.1.4: 
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events Leading to Withdrawal by Primary System 
Organ Class and Preferred Term – Safety Population 


IPSEN GROUP 
D-FR-00250-108 
SAP FINAL VERSION 1.0: 20 JUNE 2017 
 
32/32 
CONFIDENTIAL 
 
Table 
14.3.1.5:  
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events by Decreasing Frequency of Preferred Term 
– Safety Population  
Table 
14.3.1.6: 
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events by Maximum Intensity – Safety Population 
Table 
14.3.1.7: 
Number (%) of Subjects Reporting Treatment Emergent 
Adverse Events by Most Serious Causality – Safety 
Population 
14.3.2 Listings of deaths, other serious and significant adverse events 
14.3.3 Narratives of deaths, other serious and certain other significant adverse 
events 
14.3.4 Abnormal laboratory value listing 
Listing 14.3.4.1:  
Haematology (SI Units): Abnormal Clinically Significant 
Values – Safety Population 
Listing 14.3.4.2:  
Biochemistry (SI Units): Abnormal Clinically Significant 
Values – Safety Population 
Listing 14.3.4.3:  
Coagulation (SI Units): Abnormal Clinically Significant 
Values – Safety Population 
Listing 14.3.4.4:  
Urinalysis (SI Units): Abnormal Clinically Significant Values 
– Safety Population 
14.3.5 Laboratory measurements 
Table 
14.3.5.1.1: Haematology (Summary Statistics) – Safety Population 
Table 
14.3.5.1.2: Haematology (Shift Tables) – Safety Population 
Table 
14.3.5.2.1: Biochemistry (Summary Statistics) – Safety Population 
Table 
14.3.5.2.2: Biochemistry (Shift Tables) – Safety Population 
Table 
14.3.5.3: 
Coagulation (Summary Statistics) – Safety Population 
Table 
14.3.5.4.1: Urinalysis – Quantitative Parameters (Summary Statistics) – 
Safety Population 
Table 
14.3.5.4.2: Urinalysis – Parameters (Frequency Tables) – Safety 
Population 
14.3.6 Other safety data  
Table 
14.3.6.1.1: Vital Signs (Summary Statistics) – Safety Population 
Table 
14.3.6.1.2: Vital Signs (Shift Tables) – Safety Population 
Table 
14.3.6.2.1: ECG (Summary Statistics) – Safety Population 
Table 
14.3.6.2.2: ECG (Shift Tables) – Safety Population 
Table 
14.3.6.2.3: ECG (Interpretation of Clinical Significance) – Safety 
Population