Conditions: Digestive System Disease
Keywords: Bowel preparation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 250
Healthy volunteers: no

Brief summary:
The purpose of the protocol is to demonstrate that Eziclen®/Izinova®, an osmotic sulphate-based laxative preparation given on the day before colonoscopy has non-inferior efficacy to Klean-Prep® (polyethylene glycol (PEG)-electrolytes) on colon cleansing in adolescents aged 12 to 17 years (inclusive) with a body weight \>40 kg, scheduled to undergo a colonoscopy for a routinely accepted diagnostic indication.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Eziclen®/Izinova® intervention 2: Klean-Prep®
Intervention descriptions: intervention 1: Oral solution taken the evening before the colonoscopy intervention 2: Oral solution taken the evening before the colonoscopy

Protocol document:
Prot_000.pdf: 
IPSEN GROUP 
F-FR-58800-003 
 
CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 1/103 
 
 
EFFICACY, SAFETY AND TOLERABILITY OF A BOWEL CLEANSING 
PREPARATION (EZICLEN®/IZINOVA®) IN PAEDIATRIC SUBJECTS UNDERGOING 
COLONOSCOPY: A PHASE III, MULTICENTRE, RANDOMISED, COMPARATIVE 
STUDY VERSUS KLEAN-PREP® (PEG-ELECTROLYTES), ADMINISTERED ON THE 
DAY BEFORE COLONOSCOPY, INVESTIGATOR-BLINDED, NON-INFERIORITY IN 
ADOLESCENTS OF 12 TO 17 YEARS OF AGE (INCLUSIVE) >40 KG. 
 
STUDY PROTOCOL 
STUDY number: F-FR-58800-003 
 
EASYKID 
EudraCT number: 2016 002265 60 
Final Version 7.0 (including Amendment #6): 02 March 2020 
 
Sponsor’s Medically Responsible Person: 
Study Sponsor 
Ipsen Pharma SAS 
Ipsen Group 
65 quai Georges Gorse, 
Ipsen Group 
92100 Boulogne-Billancourt, France 
65 quai Georges Gorse, 
Tel: +33 (0)1 58 33 50 00 
92100 Boulogne-Billancourt, France 
Fax: +33 (0)1 58 33 50 01 
Tel:
 
Fax:
 
Monitoring Office: 
Co-ordinating Investigator: 
ICTA 
 
11 rue du Bocage 
Children's Memorial Health Institute 
21121 Fontaine-Les-Dijon 
 
Gastroenterology, Hepatology  
FRANCE 
& Nutrition Disorders 
Tel: 
 
Al Dzieci Polskich 20 
Fax:
 
Warszawa 4730 
 
 
POLAND 
 
Tel:
 
Fax
Pharmacovigilance/Emergency Contact: 
 Ipsen Innovation,  
ZI de Courtaboeuf - 5 avenue du Canada - 91940 Les Ulis - France 
Tel:
Tel:
For SAEs reporting: 
Fax: 
Email:
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol [F-FR-58800-003] entitled Efficacy, safety and tolerability of 
a bowel cleansing preparation (Eziclen®/Izinova®) in paediatric subjects undergoing 
colonoscopy: a Phase III, multicentre, randomised, comparative study versus Klean-Prep® 
(PEG-Electrolytes), administered on the day before colonoscopy, investigator-blinded, non-
inferiority in adolescents of 12 to 17 years of age (inclusive) >40 kg. I am aware of my 
responsibilities as an investigator under the guidelines of Good Clinical Practice (GCP), local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
   
NAME:  
TITLE: 
PRINCIPAL  
 
 
SIGNATURE: 
 
INVESTIGATOR 
     
DATE: 
OFFICE: 
 
 
 
 
 
   
Sponsor's Representative Signature: 
NAME:
TITLE: 
 
SIGNATURE: 
 
DATE: 
OFFICE: Ipsen Pharma SAS 
 
Medical Department 
 
Medical Affairs Consumer HealthCare 
 
65 quai Georges Gorse  
 
92100 Boulogne-Billancourt, France 
 
 
PPD


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 [COORDINATING INVESTIGATOR’S AGREEMENT] 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol [number F-FR-58800-003] entitled Efficacy, safety and 
tolerability of a bowel cleansing preparation (Eziclen®/Izinova®) in paediatric subjects 
undergoing colonoscopy: a phase III, multicentre, randomised, comparative study versus 
Klean-Prep® (PEG-Electrolytes), administered on the day before colonoscopy, investigator-
blinded, non-inferiority in adolescents of 12 to 17 years of age (inclusive) >40 kg. I am aware 
of my responsibilities as a coordinating investigator under the guidelines of Good Clinical 
Practice (GCP), local regulations (as applicable) and the study protocol. I agree to conduct the 
study according to these guidelines and to appropriately direct and assist the staff under my 
control, who will be involved in the study. 
   
NAME: 
 
TITLE: 
COORDINATING 
 
 
SIGNATURE: 
 
INVESTIGATOR 
   
   
DATE: 
OFFICE: 
Children's Memorial Health Institute 
 
Gastroenterology, Hepatology & Nutrition Disorders 
 
Al Dzieci Polskich 20 
 
Warszawa 4730 
 
POLAND 
PPD


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PAGE 4/103 
 
 
SUMMARY OF CHANGES 
The current version of the protocol was released on 02 March 2020 and includes all 
amendments. Amendment forms were prepared and are provided in Appendix 1 to Appendix 6 
(Table 1). 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
13 January 2017 
Appendix 1 
2 
23 March 2017 
Appendix 2 
3 
17 July 2017 
Appendix 3 
4 
16 March 2018 
Appendix 4 
5 
26 July 2018 
Appendix 5 
6 
02 March 2020 
Appendix 6 


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SYNOPSIS 
Name of sponsor/company: IPSEN GROUP 
Name of finished product: Eziclen®/Izinova® 
Name of active ingredients: sodium sulphate anhydrous, potassium sulphate, magnesium 
sulphate heptahydrate 
Title of study: Efficacy, safety and tolerability of a bowel cleansing preparation 
(Eziclen/Izinova®) in paediatric subjects undergoing colonoscopy: a Phase III, 
multicentre, randomised, comparative versus Klean-Prep® (PEG-Electrolytes), 
administered on the day before colonoscopy, investigator-blinded, non-inferiority study 
in adolescents of 12 to 17 years of age (inclusive) >40 kg. 
Study number: F-FR-58800-003  
Number of planned centres: around 25 centres  
Planned study period: 
From Q4 2017 to Q2 2020 
Phase of development: 
Phase III 
Objectives:  
Primary objective: 
To demonstrate that Eziclen®/Izinova®, an osmotic sulphate-based laxative preparation 
given on the day before colonoscopy has non-inferior efficacy to Klean-Prep® 
(polyethylene glycol (PEG)-electrolytes) on colon cleansing in adolescents aged 12 to 17 
years (inclusive) with a body weight >40 kg, scheduled to undergo a colonoscopy for a 
routinely accepted diagnostic indication 
Secondary objectives: 
• 
To compare efficacy of Eziclen®/Izinova® versus Klean-Prep® on overall and 
segmental cleansing and colonoscopy quality indicators  
• 
To assess compliance with preparation administration in both study arms 
• 
To compare safety, acceptability and tolerability of Eziclen®/Izinova® versus 
Klean-Prep®  
Methodology:  
• 
Multicentre, investigator-blinded, randomised Phase III comparative study 
• 
In adolescents (male and female) >40 kg with routine indication for colonoscopy 
• 
Eziclen®/Izinova® solution: oral administration at 3/4 adult dose versus Klean-
Prep® (70 mL/kg, maximum 4000 mL), both administered as 1-day regimen on the 
evening before colonoscopy 
• 
Subjects will be hospitalised from baseline (Visit 1, Day 1) to completion of 
colonoscopy (Visit 2, Day 2) 
• 
The maximum duration of the study for each subject will be 47 days: Baseline (Visit 
1) and treatment administration on Day 1, colonoscopy (Visit 2) on Day 2, phone 
contact (Visit 3) at Day 4 ±1, 30-day follow-up at the final visit (Visit 4) on Day 32 
(-5/+15, i.e. ranging from Day 27 to Day 47) 


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Number of subjects planned:  
A total of 250 male and female adolescents will be randomised in order to have 240 
evaluable subjects. 
Diagnosis and criteria for inclusion:  
Inclusion criteria: 
Subject MUST satisfy all of the following entry criteria before being allowed to participate 
in the study: 
(1) 
Provision of signed informed consent form (ICF) to participate in the study obtained 
from the adolescent's parent(s)/ legal representative and a signed assent form from 
the adolescent according to local law 
(2) 
Male or female subjects between 12 to 17 years of age (inclusive) 
(3) 
Body weight more than 40 kg 
(4) 
Female of childbearing potential must have a negative pregnancy test 
(5) 
If female, and of child-bearing potential, subject must use an acceptable form of 
birth control (hormonal birth control, intrauterine device (IUD), double-barrier 
method, or depot contraceptive)  
(6) 
Routinely accepted indication for undergoing colonoscopy, including but not limited 
to polyposis coli diagnosis or surveillance, gastrointestinal bleeding, unexplained 
diarrhoea or constipation, surveillance of inflammatory bowel disease or 
confirmation of mucosal healing, abdominal pain, abnormal endosonography or 
manometry, anaemia of unknown aetiology, cancer surveillance 
(7) 
In the investigator’s judgment, the parent(s)/legal representative are/is mentally 
competent to provide informed consent for the subject to participate in the study 
(8) 
In the investigator’s judgement, subject is able and willing to follow study 
procedures including drug administration and response to questionnaires 
Exclusion criteria: 
If any of the following apply, the subject MUST NOT enter/continue in the study: 
(1) 
Subject with known or suspected ileus, gastrointestinal obstruction, gastric retention 
(gastroparesis), rectal impaction, toxic colitis, severe ulcerative colitis or toxic 
megacolon, advanced carcinoma, swallowing disorders 
(2) 
Subject with known or suspected inflammatory bowel disease (Crohn’s disease, 
ulcerative colitis) in moderate to severe active phase defined by PCDAI >30 
(Crohn’s disease) or PUCAI >34 (ulcerative colitis) 
(3) 
Subject with bowel perforation or increased risk of bowel perforation, including 
connective tissue disorders or recent bowel surgery 
(4) 
Subject with previous significant gastrointestinal surgery (e.g. colostomy, 
colectomy, gastric bypass, stomach stapling) 
(5) 
Subject with uncontrolled pre-existing electrolyte abnormalities, or with electrolyte 
abnormalities based on Visit 1 laboratory results such as hypernatremia, 
hyponatremia, hyperphosphatemia, hypokalaemia, hypocalcaemia, uncorrected 
dehydration, or secondary to the use of medications such as diuretics or angiotensin 
converting enzyme (ACE) inhibitors judged clinically significant by the investigator 


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(6) 
Subject with a prior history or current condition of severe renal (estimated 
glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 as calculated by 
using the Schwartz bedside equation* [Schwartz et al, 2009]**), liver (ascites, 
Child-Pugh C), cardiac insufficiency (including congestive heart failure all grades) 
or hyperuricemia 
*The estimated GFR will be calculated in patients with elevated creatinine at baseline. 
** Schwartz GJ and Work DF. Measurement and Estimation of GFR in Children and Adolescents. Clin J Am Soc 
Nephrol. 2009; 4: 1832–1843 
 
(7) 
Female subject who is pregnant or lactating 
(8) 
Subject who has participated in another investigational drug treatment within the last 
90 days before the first study visit 
(9) 
Subject with phenylketonuria 
(10) Subject with history of asthma or hypersensitivity to any ingredient of either drug 
product 
(11) Subject for whom intake of substances likely to affect gastrointestinal motility or 
urinary flow rate is required 
(12) Subject with requirement to take any other oral medication within 3 hours of starting 
the bowel preparation, as this may impact medication absorption 
(13) Subject with tendency for nausea and/or vomiting 
(14) Subject with impaired consciousness that predisposes them to pulmonary aspiration 
or who have known swallowing disorders 
(15) Subject with history of major medical/psychiatric conditions that, in the judgment 
of the investigator, would compromise safety in the study 
(16) Subject with mental or psychiatric condition rendering the subject unable to 
understand the nature, scope and possible consequences of the study, and/or 
evidence of an uncooperative attitude 
(17) Subject with a condition that, in the opinion of the investigator, might increase the 
risk to the subject or decrease the chance of obtaining satisfactory data needed to 
achieve the objectives of the study 
(18) Subject who has previous enrolment in this study or concomitant enrolment in other 
clinical studies 
Test product, dose, mode of administration: 
In this single-blinded study, to ensure an unbiased evaluation of the study preparations, the 
colonoscopist will not be allowed to perform any study drug related activities 
(randomisation, drug dispensing, return and accountability, acceptability, tolerability and 
review of subject’s leaflet/questionnaires). Any failure to maintain blinding of the 
treatment to the colonoscopist will be documented as a protocol violation. Subjects and 
caregivers will be instructed not to discuss their study preparation with the colonoscopist 
or any staff member other than with the study nurse who will collect the questionnaires. 
Eziclen®/Izinova®: 
The bowel cleansing preparation will be given orally on the evening of the day before 
colonoscopy. The total dose administered is 3/4 of the adult dose (product dispensed).  


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Evening before the procedure (e.g., 6:00 pm): 
The two bottles of Eziclen®/Izinova® (180 mL X 2 concentrate sulphate salt solution) are 
to be diluted up to 1000 mL with water, using a 1000 mL graduated measuring glass. A 
total of 250 mL (1/4) of the preparation will be discarded. The remaining 750 mL of the 
preparation (3/4 adult dose) will be divided in two equal portions. The first portion of 
375 mL will be drunk slowly in ½ to 1 hour, followed by an additional 750 mL of water 
over the next hour. The total ingested volume is 1125 mL. 
Approximately 2 hours after the start of drinking the first portion (e.g., 8:00 pm): 
The second 375 mL portion of the Eziclen®/Izinova® preparation will be drunk slowly in 
½ to 1 hour followed by additional 750 mL of water over the next hour. The total ingested 
volume is 1125 mL. 
The total volume of preparation drunk is 750 mL, with an additional 1500 mL of water, for 
a total of 2250 mL. If a subject experiences difficulty in drinking the bowel cleansing 
preparation, a nasogastric tube will be placed, the rate of administration should not exceed 
30 mL/kg/hour.  
Reference therapy, dose and mode of administration:  
Comparator compound: Klean-Prep® (Powder for Oral Solution): 
The comparator, Klean-Prep® is a powder for oral solution packaged in 4 sachets. Each 
treatment pack is composed of 4 sachets with a total of 69 g of the product (powder for oral 
solution) included in each sachet. The complete dose of the preparation will be 
administered on the day prior colonoscopy, in the evening. 
Evening before the procedure (e.g., 6:00 pm) 
The 4 sachets are to be diluted. Each sachet is diluted in one litre of water. 
The dosage will be 70 mL/kg (which corresponds to the approved posology for that class 
of age and/or weight). The maximum volume administered will be 4000 mL. 
The whole solution will be administered in two half doses (1 litre per hour) with a 1-hour 
pause between the two half doses. If a subject experiences difficulty in drinking the bowel 
cleansing preparation, a nasogastric tube will be placed, the rate of administration should 
not exceed 30 mL/kg/hour. 
Other treatments: rescue treatment 
Only if clear discharge has not been obtained 1 hour prior to procedure: 
Normal saline enema, 1000 mL; repeated until clear discharge is obtained. Sodium 
phosphate enemas are not to be used. 
Duration of treatment: 
Subject participation in this study may last up to 47 days. 
Criteria for evaluation: 
Efficacy: 
Primary Endpoints and Evaluations: 
Non-inferiority of Eziclen®/Izinova® versus Klean-Prep® in the cleansing of the colon: 
Blinded overall assessment of preparation efficacy (Cleansing Score) as determined by the 
colonoscopist upon completion of the examination, based on a 4-point scale: 
 


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Score 
Grade 
Description 
4 
Excellent 
No more than small bits of adherent faeces/fluid 
3 
Good 
Small amounts of faeces or fluid not interfering with examination 
2 
Fair 
Enough faeces or fluid to prevent a completely reliable examination 
1 
Poor 
Large amounts of faecal residue, additional cleansing required 
Only perfect preparations graded as excellent (4) or good (3), which allow full, reliable 
examination of the mucosa, will be considered as successful.  
Primary efficacy will be assessed on the basis of preparation success or failure. 
 
Secondary Endpoints and Evaluations: 
• 
Need to place a nasogastric tube to complete preparation 
• 
Time to clear effluent (from first intake of preparation), as reported by the subject 
• 
Need for rescue treatment (saline enema) because of inadequate preparation  
• 
Cleansing Scores assessed by the 4-point scale (poor, fair, good, excellent) 
• 
Overall and segmental Cleansing Scores assessed by Boston Bowel Preparation 
Scale (BBPS) 
• 
Duration of intubation (from colonoscope introduction to caecal intubation) 
• 
Duration of examination, measured by colonoscope withdrawal time from caecum 
• 
Procedure documented as completed (procedures that reached the caecum) 
• 
Treatment compliance: volumes of fluids measured by the caregiver and reported in 
the treatment questionnaire of subject’s leaflet during treatment administration 
• 
Treatment acceptability, assessed by Treatment Acceptability Questionnaire 
completed by caregiver or subject at the time of intake using a 5-point scale 
questionnaire to be filled in by the subject immediately after dosing 
Very badly 
accepted/unacceptable  
Subject showed great displeasure, compromising use of formulation 
 
Badly but accepted 
Subject showed displeasure with dosing but could be coaxed to take 
complete dose 
Neither good nor bad 
Subject showed no apparent displeasure and with little effort was 
coaxed to take complete dose 
Well accepted 
Subject appeared to enjoy the formulation and with little coaxing 
ingested complete dose 
Very well accepted 
Subject appeared eager and ingested complete without special coaxing 
Safety and tolerability: 
• 
Collection of adverse events (AEs) (for up to 30 days following the day of 
colonoscopy) 
• 
Tolerability by a Symptom Scale after each dose of treatment. Subjects will rate their 
preparation related symptoms after intake (stomach cramping, stomach bloating and 


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nausea) on a paediatric 5-point scale, ranging from 1=no symptoms to 5= severely 
distressing symptoms 
• 
Description and histological examination of any colonic biopsy specimens of mucosal 
lesions suspected by the investigator to have been caused by colonic lavage 
• 
Vital signs including body weight and physical examination  
• 
Laboratory data: serum and urinary biochemistry: 
• 
Visit 1 
• 
Day 2 (colonoscopy) 
• 
Visit 4  
Statistical Methods: 
The primary aim of the study is to show that Eziclen®/Izinova® is not inferior to Klean-
Prep® in the proportion of subjects with successful colon cleansing. 
A non-inferiority margin of 15% has been selected for consistency with other studies in 
colon cleansing preparations.  
Therefore assuming a success rate (excellent or good response) of 85% in both the 
Eziclen®/Izinova® and Klean-Prep® groups, a one-sided alpha of 0.025 and 90% power, 
120 subjects are required per treatment group. Assuming a rate of dropout / non-
compliance to protocol of 4% based on previous studies and taking into account that 
subjects will be hospitalised), 125 subjects will be randomised in each treatment group, i.e. 
250 subjects in total. Enrolment will be completed once 250 subjects have been 
randomised. 
 
The primary endpoint of treatment success will be tested sequentially (hierarchical 
structure) with the first test being non-inferiority test based upon the treatment difference. 
A rejection of the null hypothesis will trigger superiority testing based upon the treatment 
difference. 
The two hypothesis tests are hierarchically structured so that the second test (superiority) 
will only be considered if the first test (non-inferiority) is rejected. The superiority test is 
powered to detect an absolute difference of 18%. There is no alpha adjustment for the 
second test as a result of the hierarchical testing. 
 
The primary efficacy analysis will be based on the modified Intention To Treat (mITT) 
population and will include all randomised subjects who received even a partial dose of 
study treatment and produced a primary efficacy assessment. Subjects who do not undergo 
colonoscopy because of inadequate preparation or preparation-related AEs will be 
considered as failures. In addition, robustness of primary efficacy results will be assessed 
by repeating the primary analysis on the Per Protocol (PP) population and will include all 
subjects in the ITT population, who have undergone the colonoscopy procedure and for 
whom no major protocol violations/deviations occurred. 
 
The proportion of subjects with successful colon cleansing (graded as excellent or good) 
will be summarised along with the 95% confidence interval (CI) using the standard Wald 
asymptotic CI. The primary efficacy endpoint will be analysed using a logistic regression 
model including country as stratification variable, the interaction between country and 


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treatment will be also investigated. The formal hypothesis test result (p-value) for treatment 
difference will be presented together with a two-sided 95% CI for the difference in success 
rates. The non-inferiority will be demonstrated if the lower limit of the 95% CI of that 
difference is higher than -15%. 
 
The schedule of procedures and assessments during the study is summarised below.  
Study Procedures and Assessments 
Study Period 
Baseline/ 
Treatment 
Colonoscopy 
Phone 
contact 
End of Study 
(or in case of Early 
Withdrawal*) 
Visit 
1 
2 
3 
4 
Day 
Day 1 
Day 2 
Day 4 
Day 32 
Window 
 
 
±1 
-5/+15 i.e. Day 27 to 
Day 47  
Eligibility Criteria 
X 
 
 
 
Demographic Data 
X 
 
 
 
Blood Pregnancy Test [a] 
X 
 
 
 
Informed Consent 
(parent(s) or legal 
representative) 
X 
 
 
 
Assent (subject)  
X 
 
 
 
Medical and Surgical 
History 
X 
 
 
 
Indication(s) for 
Colonoscopy 
X 
 
 
 
Prior and Concomitant 
Medication [b] 
X 
X 
 
X 
Prior and Concomitant 
Non-Drug Therapy [b] 
X 
X 
 
X 
AEs [c] 
X[d] 
X 
X[e] 
X 
Physical Examination   
X 
 
 
X 
Vital Signs (Temperature, 
blood pressure (BP) and 
heart rate (HR) 
X 
X 
 
X 
Body Weight and height[f]  
X 
X 
 
X 
Blood sample collection 
[g], [h] 
X[i] 
X[j] 
 
X 
Urine sample collection[k] 
X 
X 
 
X 
Blood and urine 
sulphates[l] 
X 
X[j] 
 
X 
RANDOMISATION [m] 
X 
 
 
 
Study treatment 
dispensation (with 
explanation of treatment 
administration) 
X 
 
 
 
Subject/caregiver leaflet 
dispensation by study nurse 
(with explanation of 
questionnaires including 
compliance measurement) 
X 
 
 
 
Subject takes treatment 
preparation  
X 
 
 
 


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Completion of leaflet 
questionnaires by subject/ 
caregiver/ nurse 
 
 
 
 
• 
Treatment 
/ 
Compliance  
X 
 
 
 
• 
Treatment 
Acceptability  
X 
 
 
 
• 
Symptom 
Scale 
(Tolerability)  
X 
 
 
 
Collection of leaflet 
questionnaires by study 
nurse  
 
X 
 
 
Drug accountability/ study 
administration compliance 
by unblinded site member 
 
X 
 
 
Colonoscopy assessment 
[n] 
 
X 
 
 
Subject status at the end of 
the visit 
X 
X 
X 
X 
*Early withdrawal will be anytime from Visit 1 
[a] If applicable. Urine pregnancy test will be performed only when blood tests including pregnancy have 
been performed prior to Visit 1. 
[b] Prior and concomitant medication and non-drug therapy will from 7 days before baseline and for any 
action taken by the investigator 
[c] AEs will be actively collected by the investigator and subjects will be instructed to contact the 
investigator if they experience any AEs 
[d] At baseline, AEs will be collected from the date of informed consent and assent signature 
[e] The investigator will contact the subject by phone on Day 4±1 to collect data on potential AEs  
[f] Height will be measured at Baseline only 
[g] Local laboratory (blood): biochemistry including: anion gap, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), creatine phosphokinase (CPK), lactic dehydrogenase (LDH), gamma-glutamyl 
transferase (GGT), total and conjugated bilirubin, creatinine, urea, serum electrolytes (sodium, 
potassium, chloride, calcium, magnesium, phosphorus, bicarbonate), alkaline phosphatase, albumin, 
total protein, C reactive protein (CRP), uric acid, creatinine clearance (calculated GFR), osmolality 
[h] Laboratory assessments performed within 10 days or less prior to inclusion may be used to determine 
eligibility upon investigator agreement. 
[i] Additional local laboratory haematology: complete blood count (CBC), international normalised ratio 
(INR). 
[j] Blood sampling during anaesthesia 
[k] Local laboratory urine analysis (by dipstick), microscopic examination 
[l] Collection of blood and urine sample for central laboratory sulphate dosage  
[m] Randomisation if satisfactory biochemistry results 
[n] Colonoscopy assessment: Rescue treatment, cleansing Score, BBPS, start time of colonoscopy, time of 
caecal intubation, caecum reached, withdrawal time, diagnosis/findings  
 


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Subject’s Leaflet Collected Information 
 
During/after Dose 1 
Day 1 
During/after Dose 2 
Day 1 
Treatment/Compliance Questionnaire[a]  
X  
X 
Treatment Acceptability Questionnaire 
X 
X 
Symptom Scale (Tolerability) 
X 
X 
Information about time to bowel movement 
and time to first clear watery stool. 
 
X 
a 
Treatment/Compliance questionnaire will collect information about: preparation of treatment, 
treatment intakes (recording of residual volumes, start/end times) for Eziclen®/Izinova® or 
Klean-Prep®. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 19 
1 
BACKGROUND INFORMATION ............................................................................ 21 
1.1 
Introduction ................................................................................................................... 21 
1.2 
Name and Description of Investigational Medicinal Product ................................... 22 
1.3 
Findings from Nonclinical and Clinical Studies ......................................................... 22 
1.4 
Known and Potential Risks and Benefits to Human Subjects .................................. 24 
1.5 
Selection of Investigational Medicinal Products and Dosages .................................. 25 
1.6 
Compliance Statement .................................................................................................. 25 
1.7 
Population to Be Studied .............................................................................................. 26 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 27 
2.1 
Purpose of the Study ..................................................................................................... 27 
2.2 
Study Objectives ........................................................................................................... 27 
2.2.1 
Primary Objective ........................................................................................ 27 
2.2.2 
Secondary Objectives .................................................................................. 27 
3 
STUDY DESIGN ........................................................................................................... 28 
3.1 
General Design and Study Schema ............................................................................. 28 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 28 
3.2.1 
Primary Efficacy Endpoints and Evaluations ........................................... 28 
3.2.2 
Secondary Endpoints and Evaluations ...................................................... 29 
3.2.2.1 
Efficacy Endpoints: ...................................................................................... 29 
3.2.2.2 
Safety and Tolerability Variables ................................................................ 30 
3.3 
Randomisation and Blinding ....................................................................................... 30 
3.4 
Study Treatments and Dosage ..................................................................................... 30 
3.5 
Study Duration .............................................................................................................. 32 
3.6 
Stopping Rules and Discontinuation Criteria ............................................................ 32 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability ......... 33 
3.7.1 
Investigational Medicinal Product Storage and Security .......................... 33 
3.7.2 
Investigational Medicinal Product Preparation ........................................ 33 
3.7.3 
Investigational Medicinal Product Accountability and destruction ......... 33 
3.8 
Maintenance of Randomisation and Blinding ............................................................ 33 
3.9 
Source Data Recorded on the Case Report Form ...................................................... 34 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 35 
4.1 
Inclusion Criteria .......................................................................................................... 35 
4.2 
Exclusion Criteria ......................................................................................................... 35 
4.3 
Subject Withdrawal Criteria and Procedures ........................................................... 36 
5 
STUDY PROCEDURES .............................................................................................. 38 
5.1 
Study Schedule .............................................................................................................. 38 


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5.2 
Study Visits .................................................................................................................... 40 
5.2.1 
Prescreening Period .................................................................................... 40 
5.2.2 
Baseline/Treatment visit (Visit 1) ............................................................... 40 
5.2.3 
Colonoscopy (Visit 2, Day 2) ....................................................................... 42 
5.2.4 
Procedures after Study Treatment .............................................................. 42 
5.2.4.1 
Phone Contact (Visit 3) ................................................................................ 42 
5.2.4.2 
End of Study Visit (Visit 4) or Early Withdrawal Visit ................................ 43 
6 
TREATMENT OF SUBJECTS ................................................................................... 44 
6.1 
Study Drugs Administered ........................................................................................... 44 
6.1.1 
Eziclen®/Izinova® ...................................................................................... 44 
6.1.2 
Klean-Prep® ................................................................................................ 44 
6.1.3 
Rescue Treatment ........................................................................................ 45 
6.2 
Prior and Concomitant Medication and Non-drug /Therapy .................................. 45 
6.3 
Procedures for Monitoring Subject Compliance ....................................................... 45 
7 
ASSESSMENT OF EFFICACY .................................................................................. 46 
7.1 
Primary Efficacy Endpoints and Evaluations ............................................................ 46 
7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 46 
7.3 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 46 
7.3.1 
Primary Efficacy Assessment ..................................................................... 47 
7.3.2 
Secondary Efficacy Assessment .................................................................. 47 
7.3.2.1 
Boston Bowel Preparation scale .................................................................. 47 
7.3.2.2 
Treatment/Compliance ................................................................................. 47 
7.3.2.3 
Treatment Acceptability Questionnaire ....................................................... 48 
8 
ASSESSMENT OF SAFETY ....................................................................................... 49 
8.1 
Adverse Events .............................................................................................................. 49 
8.1.1 
Definition of an Adverse Event .................................................................. 49 
8.1.2 
Categorisation of Adverse Events ............................................................... 49 
8.1.2.1 
Intensity Classification ................................................................................. 49 
8.1.2.2 
Causality Classification ............................................................................... 49 
8.1.2.3 
Assessment of Expectedness ......................................................................... 49 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 50 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 50 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 50 
8.1.3 
Recording and Follow-up of Adverse Events ............................................. 50 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 50 
8.1.5 
Pregnancy .................................................................................................... 52 
8.1.6 
Deaths .......................................................................................................... 52 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 52 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other investigators ....... 52 


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8.2 
Clinical Laboratory Tests ............................................................................................ 53 
8.2.1 
Haematology ................................................................................................ 53 
8.2.2 
Blood Biochemistry ..................................................................................... 53 
8.2.3 
Urinalysis ..................................................................................................... 53 
8.2.4 
Pregnancy Test ............................................................................................ 54 
8.3 
Physical Examination ................................................................................................... 54 
8.4 
Vital Signs ...................................................................................................................... 54 
8.5 
Histological examination of colonic biopsy ................................................................. 54 
8.6 
Symptom Scale .............................................................................................................. 54 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 55 
10 
STATISTICS ................................................................................................................. 56 
10.1 Analyses Populations .................................................................................................... 56 
10.1.1 
Populations Analysed .................................................................................. 56 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 56 
10.2 Sample Size Determination .......................................................................................... 56 
10.3 Significance Testing and Estimations ......................................................................... 57 
10.4 Statistical/Analytical Methods ..................................................................................... 57 
10.4.1 
Demographic and Other Baseline Characteristics .................................... 57 
10.4.2 
Homogeneity of Treatment Groups ............................................................ 57 
10.4.3 
Subject Disposition and Withdrawals ......................................................... 57 
10.4.4 
Pharmacokinetic Data ................................................................................ 57 
10.4.5 
Efficacy Evaluation ..................................................................................... 58 
10.4.6 
Adjustment for Country/Centre Effect ....................................................... 58 
10.4.7 
Safety Evaluation ........................................................................................ 58 
10.5 Subgroup Analyses ....................................................................................................... 59 
10.6 Interim Analyses ........................................................................................................... 59 
11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 60 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 61 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................... 61 
12.1.1 
Protocol Amendments ................................................................................. 61 
12.1.2 
Protocol Deviations, Violations and Exceptions ........................................ 61 
12.2 Information to Study Personnel .................................................................................. 61 
12.3 Study Monitoring .......................................................................................................... 61 
12.4 Audit and Inspection .................................................................................................... 62 
12.5 Data Quality Assurance ................................................................................................ 62 
13 
ETHICS ......................................................................................................................... 63 
13.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 63 
13.2 Informed Consent and Assent ..................................................................................... 63 
13.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 64 


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13.4 Confidentiality Regarding Study Subjects ................................................................. 64 
14 
DATA HANDLING AND RECORD KEEPING ....................................................... 65 
14.1 Data Recording of Study Data ..................................................................................... 65 
14.2 Data Management ......................................................................................................... 65 
14.2.1 
eCRF ............................................................................................................ 65 
14.2.2 
Subject/Caregiver Leaflet/Questionnaires ................................................. 66 
14.3 Record Archiving and Retention ................................................................................. 67 
15 
FINANCING AND INSURANCE ............................................................................... 68 
15.1 Contractual and Financial Details ............................................................................... 68 
15.2 Insurance, Indemnity and Compensation .................................................................. 68 
16 
REPORTING AND PUBLICATIONS OF RESULTS ............................................. 69 
16.1 Publication Policy ......................................................................................................... 69 
16.2 Clinical Study Report ................................................................................................... 69 
17 
REFERENCES .............................................................................................................. 70 
18 
LIST OF APPENDICES .............................................................................................. 71 
 


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LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Primary Efficacy Responder Analysis - BLI800-301/302 Studies ................... 23 
 
 
 
Table 4 
Study Procedures and Assessments ................................................................... 38 
Table 5 
Subject’s Leaflet Collected Information ........................................................... 39 
Table 6 
Blood Volume Calculation .................................................................................. 40 
Table 7 
Secondary Endpoints and Evaluations .............................................................. 46 
Table 8 
Cleansing Score .................................................................................................... 47 
Table 9 
Boston Bowel Preparation Scale ........................................................................ 47 
Table 10 
Treatment Acceptability Questionnaire Categories ......................................... 48 
Table 11 
Symptom Scale ..................................................................................................... 54 
 
LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................................ 28 
 
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LIST OF ABBREVIATIONS 
 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
BBPS 
Boston Bowel Preparation Scale 
BP 
Blood pressure 
CA 
Competent Authorities 
CBC 
Complete blood count 
CI 
Confidence interval 
CMC-SC 
Chemistry, Manufacturing and Control Supply Chain 
CMH 
Cochran-Mantel-Hænszel 
CPK 
Creatine phosphokinase 
CRC 
Colorectal cancer 
CRO 
Contract research organisation 
CRP 
C reactive protein 
CSR 
Clinical study report 
D 
Day 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
ELS 
electrolyte lavage solution 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transpeptidase 
HR 
Heart rate 
IB 
Investigator’s brochure 
IBD 
Inflammatory bowel disease 
ICF 
Informed consent form 


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ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalised ratio 
IRB 
Institutional review board 
ITT 
Intention to treat 
IUD 
Intrauterine device 
LC 
Left colon 
LDH 
Lactic dehydrogenase 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention to treat 
PEG 
polyethylene glycol 
PDD 
Protocol Deviation Document 
PI 
Package insert 
PP 
Per protocol 
RBC 
Red blood cell 
RC 
Right colon 
SAE 
Serious adverse event 
SAP 
Statistical and analysis plan 
SAS® 
Statistical Analysis System® 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TC 
Transverse colon 
TEAE 
Treatment emergent adverse event 
TMF 
Trial master file 
US 
United States  
WBC 
White blood cell 
WHO 
World Health Organisation 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Bowel cleansing is a procedure used before bowel visualisation (colonoscopy, videocapsule, 
radiology). Colonoscopy is considered to be the gold standard investigation for assessing the 
colonic mucosa. In adult patients, this bowel visualisation procedure is not only used for 
screening for colorectal cancer (CRC), but also for diagnosis of colonic diseases (such as 
inflammatory bowel disease (IBD), ulcers, diverticula), investigation of abdominal pain, 
unexplained anorectal haemorrhage or diarrhoea, confirmation of abnormalities revealed by 
other radiological examinations and performing colorectal surgery, such as polypectomy or 
mucosectomy. In the paediatric setting, the indications for colonoscopy are not the same as in 
adults and vary depending on the age group considered. Indications include diagnosis and 
surveillance of IBD including documentation of mucosal healing, exploration of rectal 
bleeding, chronic diarrhoea, anaemia, abdominal pain, diagnosis and surveillance of polyposis 
coli syndromes, failure to thrive or weight loss, rejection of intestinal transplant and follow-up 
of colorectal diseases [1]. 
 
As colonoscopy is conducted under anaesthesia in paediatric patients, inadequate preparation 
not allowing clear visualisation of the mucosa is even less acceptable than in the adult patient 
setting [2].  
A wide variety of preparations are used in paediatrics (excluding sodium phosphates 
preparations) but there is no standard bowel cleansing regimen in children. Safety and 
effectiveness of large-volume polyethylene glycol-based solutions have been shown. However, 
these preparations are often poorly tolerated due to the salty taste and the large volume to be 
ingested over a relatively short period for a successful colonoscopy preparation. A number of 
bowel preparation regimens are used, but compliance is often poor and results unsatisfactory. 
Indeed, as in adults, reports of inadequate preparations involve up to one third of the patients, 
leading to extended procedure time, incomplete examination, or need for repeat procedure [1].  
 
Eziclen®/Izinova® is a hyperosmotic bowel preparation, composed of sodium sulphate 
anhydrous, potassium sulphate and magnesium sulphate heptahydrate, indicated for cleansing 
of the colon as a preparation for colonoscopy in adults only. It was developed in the United 
States (US) by Braintree Laboratories, and has been marketed in the US since 2010 under the 
trade name of SUPREP. In Europe, it was approved by the European Medicines Agency 
(EMA) in 2013 and is marketed under the trade name Eziclen® or Izinova®. The current study 
is the second study being conducted as part of the Paediatric Investigational Plan for 
Eziclen®/Izinova®.  
The pivotal studies demonstrating the safety and efficacy of Eziclen®/Izinova® in adults are 
summarised in Section 1.3. 
Klean-Prep®, the comparator, is a Macrogol-based isosmotic laxative containing 59.000 g 
macrogol 3350, 5.685 g anhydrous sodium sulphate, 1.685 g sodium bicarbonate, 1.465 g 
sodium chloride, and 0.7425 g potassium chloride.  The compound is approved for use in adults 
in many European countries, and in children in some European countries including France, the 
Netherlands and the United Kingdom.  


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1.2 
Name and Description of Investigational Medicinal Product 
Eziclen®/Izinova® is a hyperosmotic laxative preparation composed of sulphate salts of 
sodium, potassium and magnesium, the major constituent being sodium sulphate (73%). The 
mechanism of action of Eziclen®/Izinova® relies primarily on the limited capacity of the 
gastrointestinal system to absorb sulphate. The absorption of sulphate in the gastrointestinal 
tract follows a saturable active transport process with the kidneys as the primary pathway for 
excretion of absorbed sulphate [1, 3]. The osmotic effect of unabsorbed sulphate anions and the 
associated cations draws water into the intestines, increasing the water content of the stool and 
causing watery diarrhoea, which leads to effective bowel cleansing. Absorption studies with 
very large amounts of sodium sulfate (8 g anhydrous sodium sulphate) demonstrated 
incomplete absorption, which was associated with severe diarrhoea [4]. 
A more detailed description of the product is given in Section 3.4. 
1.3 
Findings from Nonclinical and Clinical Studies 
Two phase III studies were conducted in adults comparing Eziclen®/Izinova® to a Food and 
Drug Administration (FDA) approved preparation polyethylene glycol (PEG) + ascorbic acid 
[5]. The BLI800-301 Study evaluated Eziclen®/Izinova® as a 1-day preparation, completed on 
the day prior to colonoscopy. The BLI800-302 Study utilised a 2-day (or “split-dose”) regimen 
in which half the preparation was taken the evening prior to colonoscopy, and the remaining 
half completed on the morning of the procedure. It should be noted that the split dose 
preparation is not the favoured mode of administration in children as anaesthesia guidelines 
require 6 hours of fasting prior to colonoscopy in the paediatric setting. 
The primary efficacy analysis in both phase III studies supported the conclusion that 
Eziclen®/Izinova® is equivalent to PEG + ascorbic acid with respect to cleansing efficacy 
(cumulative data shown below in Table 2). 


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Table 2 
Primary Efficacy Responder Analysis - BLI800-301/302 Studies 
Responder[a] 
Eziclen®/Izinova® 
n (%) 
PEG + ascorbic 
acid n (%) 
95% CI 
p[b] 
p[c] 
All Patients (n) 
      Success  
      Fail 
375 
334 (89.5%) 
39 (10.5%) 
376 
330 (87.8%) 
46 (12.2%) 
 
-2.8, 6.3 
 
0.410 
 
<0.001 
301 Patients (n) 
  Success  
  Fail 
194 
159 (82.4%) 
 34 (17.6%) 
193 
155 (80.3%) 
38 (19.7%) 
 
-5.7, 9.8 
 
0.614 
 
<0.001 
302 Patients (n) 
      Success  
      Fail 
181 
175 (97.2%) 
 5 (2.8%) 
183 
175 (95.6%) 
8 (4.4%) 
 
-2.2, 5.4 
 
0.391 
 
<0.001 
a 
A successful treatment is defined as bowel cleansing graded either excellent or good (grading score = 
3 or 4) by the blinded colonoscopist 
b 
p-value for the difference between treatments 
c 
p-value for the non-inferiority hypothesis using an equivalence margin of 15% 
 
Adverse events (AEs) were also evaluated in the Phase III studies. The only treatment emergent 
AE category with a frequency greater than 3% was gastrointestinal (Eziclen®/Izinova®=4.5% 
and PEG+ascorbic acid=4.3%). The expected symptoms of nausea and vomiting were the most 
frequent (1.3% each) within the gastrointestinal category. There was no difference between 
Eziclen®/Izinova® and PEG+ascorbic acid in the frequency of any treatment-emergent adverse 
events (TEAEs), including those that were gastrointestinal in origin. No clinically significant 
differences between groups were seen in laboratory testing of serum chemistry and 
haematology. At the 1-month follow-up visit, no change in serum creatinine was observed for 
Eziclen®/Izinova® patients. 
The first study in the Paediatric Investigation Plan was a phase II study (BLI800-501) 
comparing two split-dose regimens of Eziclen®/Izinova® bowel preparation in paediatric 
subjects aged 12 – 17 years, who underwent colonoscopy for a routinely accepted indication. 
The FDA approved adult dose of Eziclen®/Izinova® (two 6-ounce doses, i.e. 180 mL) was 
compared to a lower volume dose (corresponding to a 3/4 adult dose or two 4.5-ounce doses 
i.e. 135 mL) to evaluate differences in safety, efficacy and tolerance. A total of 29 subjects were 
enrolled and took the bowel preparation (16 subjects from the 6-ounce group, 13 subjects from 
the 4.5-ounce group).  
The primary efficacy variable for the study was the proportion of “successful” preparations for 
colonoscopy (rated as “good” or “excellent” by the colonoscopist). Secondary measures 
included segmental cleansing and accepted quality indicators (adequate preparation, caecal 
intubation). There was no difference in preparation success between the two 
Eziclen®/Izinova® dose groups, with 81% of subjects having a successful preparation in the 6-
ounce group, and 83% in the 4.5-ounce group. Adequate preparations were achieved in 
approximately 86% of subjects (88% in the 6-ounce group, 83% in the 4.5-ounce group). These 
efficacy rates are lower than those reported using Eziclen®/Izinova® in adult clinical studies 
[5, 6], but comparable to evening only regimens [5, 7]. The 4.5-ounce dose group had more 
excellent preparations and less residual stool and fluid segmentally, although these differences 
did not reach statistical significance (except for fluid in the sigmoid colon/rectum), likely due 
to the small sample size.  


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The goal of the current study is to compare the safety, efficacy and tolerability of 
Eziclen®/Izinova® (4.5-ounce dose regimen, 3/4 adult dose) in adolescents undergoing 
colonoscopy compared to a standard PEG- electrolyte lavage solution (ELS) preparation 
approved in paediatric subjects (Klean-Prep®). 
Further details of Eziclen®/Izinova® may be found in the investigator’s brochure (IB) [8]. 
1.4 
Known and Potential Risks and Benefits to Human Subjects 
Eziclen®/Izinova® is an osmotic low volume, sulphate-based bowel cleansing solution, whose 
absorption in the gut is limited, thus preserving renal function. Sulphate salts do not alter the 
normal balance of serum calcium salts. In the nonclinical toxicology and human pharmacology 
studies, there was no evidence of urinary calcium precipitation [9]. The absorption of 
magnesium occurs by both an unsaturable passive and saturable active transport systems [10]. 
Thus, the fractional absorption of magnesium is inversely proportional to the amount ingested. 
With the quantities present in Eziclen®/Izinova® formulation, the relative absorption of 
sulphates and magnesium is low. On the basis of serum magnesium measurements, no subject 
in the Eziclen®/Izinova® clinical phase I and II studies developed hypermagnesaemia.  
In adult patients, the overall safety profile of Eziclen®/Izinova® was favourable and the 
preparation was well tolerated. The safety profile of Eziclen®/Izinova® is similar to that of 
PEG preparations, the gold standard in this indication. As a result of lower volume of solution 
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to be ingested, patient willingness to undergo and complete a bowel cleansing regimen prior to 
any procedure requiring a clean bowel may be improved. The benefit-risk assessment of the 
compound as a bowel cleansing agent prior to colonoscopy can thus be considered favourable 
in its indication in the adult patient. 
Eziclen®/Izinova® has demonstrated its efficacy in adult patients in three randomised 
controlled phase III studies and two phase IV studies. Eziclen®/Izinova® studies reported an 
excellent or good quality of bowel preparation in over 90% of patients (pooled data, 1-day and 
split-dose). In comparison with other agents, it has been shown to be non-inferior and equivalent 
to PEG+ascorbic acid when administered as a 1-day or a split-dose regimen [5]. Split-dose 
Eziclen®/Izinova® was superior to 1-day sulphate free PEG (4 L), although this may reflect 
differences in the dosing regimen rather than differences between the preparations [6]. In the 
phase IV studies, a split-dose regimen of Eziclen®/Izinova® was formally demonstrated to be 
superior in its efficacy to a sodium picosulphate plus magnesium citrate split-dose regimen and 
to either Eziclen®/Izinova® or PEG+Electrolytes 4L same-day regimens [11]. The 
Eziclen®/Izinova® same-day regimen was equivalent to PEG+electrolytes. Compliance, as 
measured by completion of the entire preparation, observed with Eziclen®/Izinova® was high: 
≥97% for split-dose and ≥93% for 1-day administration. The efficacy of Eziclen®/Izinova® 
observed in the elderly population was similar to that in younger adults. 
 
Additional information regarding risks and benefits to human subjects may be found in the IB 
for Eziclen®/Izinova® [8]. For Klean-prep®, refer to the summary of product characteristics 
(SmPC) [12]. 
1.5 
Selection of Investigational Medicinal Products and Dosages 
The dosages to be evaluated in this investigator-blind study (i.e. 750 mL of Eziclen®/Izinova® 
solution + 1500 mL of water the day before colonoscopy) were selected on the basis of studies 
conducted in adults and a study conducted in children aged 12 to less than 18 years (Study 
BLI800-501 (Efficacy and tolerability of a bowel cleansing preparation in paediatric subjects 
undergoing colonoscopy)). 
A more detailed description of administration procedures is given in Section 6.1.  
1.6 
Compliance Statement 
The study will be conducted in compliance with independent ethics committees/institutional 
review boards (IECs/IRBs), informed consent regulations, the Declaration of Helsinki and 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. 
Any episode of noncompliance will be documented. 
The study will also be conducted in compliance with the FDA, 21 CFR Part 11, Electronic 
Records, Electronic Signatures and FDA, Guidance for Industry (Computerised Systems Used 
in Clinical Trials), a regulation which provides criteria for acceptance by the FDA of electronic 
records, e-signatures and hand-written signatures executed to electronic records as equivalent 
to paper records and hand-written signatures on paper. 
In addition, the study will adhere to all local regulatory requirements. 
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form (ICF), assent form, any consent or assent form updates, subject 
emergency study contact cards, subject recruitment procedures (e.g. advertisements), any 
written information to be provided to subjects and a statement from the IEC/IRB that they 


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comply with GCP requirements. The IEC/IRB approval must identify the protocol version as 
well as the documents reviewed. 
1.7 
Population to Be Studied 
The study will enrol adolescents aged 12 to 17 years (inclusive), with body weight >40 kg, 
scheduled to undergo colonoscopy for a routine indication. 


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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
The purpose of the present study is to compare the efficacy, safety and tolerability of 
Eziclen®/Izinova® to those of Klean-Prep® in adolescents aged 12 to 17 years (inclusive) with 
body weight >40 kg scheduled to undergo a colonoscopy for a routinely accepted indication. 
2.2 
Study Objectives 
2.2.1 
Primary Objective  
The primary objective of the study is to demonstrate that Eziclen®/Izinova®, an osmotic 
sulphate-based laxative preparation given on the day before colonoscopy has non-inferior 
efficacy to Klean-Prep® (PEG-electrolytes) on colon cleansing in adolescents aged 12 to 17 
years (inclusive) with a body weight >40 kg, scheduled to undergo a colonoscopy for a routinely 
accepted diagnostic indication. 
2.2.2 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• 
To compare efficacy of Eziclen®/Izinova® versus Klean-Prep® on overall and 
segmental cleansing and colonoscopy quality indicators 
• 
To assess compliance with preparation administration in both study arms 
• 
To compare safety, acceptability and tolerability of Eziclen®/Izinova® versus Klean-
Prep® 


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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a multicentre, investigator-blinded, randomised phase III comparative study conducted 
in adolescents (male and female) >40 kg scheduled to undergo colonoscopy. It is planned to 
enrol subjects from around 25 centres. Subjects will be randomised in two parallel arms to 
receive either Eziclen®/Izinova® or Klean-Prep®. Efficacy, safety and tolerability will be 
assessed. Eziclen®/Izinova® solution will be orally administered at 3/4 adult dose. Its efficacy 
will be compared to Klean-Prep® (70 mL/kg). Both solutions will be administered as a 1-day 
regimen on the evening before colonoscopy. A total of 250 male or female subjects aged 12 to 
17 years (inclusive) scheduled to undergo colonoscopy will be randomised in this study in order 
to have 240 evaluable subjects. The maximum duration of the study for each subject will be 47 
days:  
• 
Enrolment and Baseline visit at Day 1 
• 
Treatment (Eziclen®/Izinova® or Klean-Prep®) will be administered on Day 1 
• 
Colonoscopy will be performed on Day 2 
• 
Subjects will be contacted by phone on Day 4 ±1 
• 
Subjects will come for a final follow-up visit on Day 32 (-5/+15 i.e. ranging from Day 
27 to Day 47) 
 
An overview of the study design is presented in Figure 1. 
Figure 1 Study Design 
 
V1=Visit 1, V2=Visit 2, V3=Visit 3, V4=Visit 4 
 
3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Efficacy Endpoints and Evaluations 
Non-inferiority of Eziclen®/Izinova® versus Klean-Prep® in the cleansing of the colon: 
The primary efficacy will be assessed by blinded overall assessment of preparation efficacy 
(Cleansing Score) as determined by the colonoscopist upon completion of the examination, 
based on a 4-point scale: 
Baseline
Colonoscopy
Phone contact
End of study
Visit
V1
V2
V3
V4
Time window
 -/+1
 -5/+15
Day
1
2
3
4
32
Randomisation:
EZICLEN®/IZINOVA® 
or
Klean-Prep®
Treatment
administration
Follow-up period
from day 5 to day 31


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Score 
Grade 
Description 
4 
Excellent 
No more than small bits of adherent faeces/fluid 
3 
Good 
Small amounts of faeces or fluid not interfering with examination 
2 
Fair 
Enough faeces or fluid to prevent a completely reliable examination 
1 
Poor 
Large amounts of faecal residue, additional cleansing required 
 
Only perfect preparations graded as excellent (4) or good (3), which allow full, reliable 
examination of the mucosa, will be considered as successful. 
Primary efficacy will be assessed on the basis of preparation success or failure. 
3.2.2 
Secondary Endpoints and Evaluations 
3.2.2.1 
Efficacy Endpoints: 
• 
Need to place a nasogastric tube to complete preparation 
• 
Time to clear effluent (from first intake of preparation), as reported by the subject 
• 
Need for rescue treatment (saline enema) because of inadequate preparation  
• 
Cleansing Scores assessed by the 4-point scale (poor, fair, good, excellent) 
• 
Overall and segmental Cleansing Scores assessed by Boston Bowel Preparation Scale 
(BBPS) 
• 
Duration of intubation (from colonoscope introduction to caecal intubation) 
• 
Duration of examination, measured by colonoscope withdrawal time from caecum 
• 
Procedure documented as completed (procedures that reached the caecum) 
• 
Treatment compliance: volumes of fluids measured by the caregiver and reported in the 
treatment questionnaire of subject’s leaflet during treatment administration 
• 
Treatment acceptability, assessed by Treatment Acceptability Questionnaire completed 
by caregiver or subject at the time of intake using a 5-point scale questionnaire to be 
filled in by the subject immediately after dosing 
 
Very badly 
accepted/unacceptable  
Subject showed great displeasure, compromising use of formulation 
Badly but accepted 
Subject showed displeasure with dosing but could be coaxed to take 
complete dose 
Neither good nor bad 
Subject showed no apparent displeasure and with little effort was coaxed 
to take complete dose 
Well accepted 
Subject appeared to enjoy the formulation and with little coaxing 
ingested complete dose 
Very well accepted 
Subject appeared eager and ingested complete dose without special 
coaxing 
 


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3.2.2.2 
Safety and Tolerability Variables 
• 
Collection of AEs (for up to 30 days following the day of colonoscopy) 
• 
Tolerability assessed by a Symptom Scale after each dose of treatment. Subjects will rate 
their preparation related symptoms after intake (stomach cramping, stomach bloating and 
nausea) on a paediatric 5-point scale, ranging from 1=no symptoms to 5= severely 
distressing symptoms  
• 
Description and histological examination of any colonic biopsy specimens of mucosal lesions 
suspected by the investigator to have been caused by colonic lavage 
• 
Vital signs including body weight and physical examination 
• 
Laboratory data: serum and urinary biochemistry: 
• 
Visit 1 
• 
Day 2 (colonoscopy) 
• 
Visit 4  
3.3 
Randomisation and Blinding 
The sponsor’s randomisation manager who is a statistician independent from the study will 
prepare two lists for this study.  
• 
List A: a list of randomisation numbers will be produced in blocks, on a balanced ratio 
(one Eziclen®/Izinova®: one Klean-Prep®) and will be stratified by country 
• 
List B: a list of treatment numbers will be produced in blocks, on a balanced ratio (one 
Eziclen®/Izinova®: one Klean-Prep®) 
After eligibility is confirmed, at Visit 1 (Baseline), subjects will be assigned to a randomisation 
number and to the associated treatment arm, in sequential order within each centre and within 
each country.  
This will be provided by the electronic case report form (eCRF) which will assign the subjects 
to the first not-used randomisation number and so in a treatment arm according to the predefined 
randomisation list. 
The investigator will under no circumstances change the randomisation number and the 
treatment arm allocated to the subject. 
Recruitment will stop once 250 subjects have been randomised. Randomised subjects who 
terminate their study participation for any reason before starting the treatment will retain their 
randomisation number (the randomisation number will not be reused). The next subject is given 
the next randomisation number.  
Randomised subjects who leave the study early will not be replaced. 
The sponsor’s randomisation manager will keep the master lists (Lists A and B). A copy of the 
list of randomisation numbers (List A) will be confidentially supplied to the contract research 
organisation (CRO) in charge of the eCRF. Then, a copy of the list of treatment numbers (List 
B) will be confidentially supplied to the Chemistry, Manufacturing and Control Supply Chain 
(CMC-SC) (Beaufour Ipsen Industrie, Rue d’Ethe Virton, 28100 Dreux) and to the CRO in 
charge of the eCRF. The master lists and the copies supplied to the CRO in charge of eCRF and 
to the CMC -SC will be kept confidential in a secure location. Access to these lists must be 
restricted until authorisation is given to release them for final analysis. 
3.4 
Study Treatments and Dosage 
Eziclen®/Izinova®:  


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The bowel cleansing preparation is a concentrate for oral solution packaged in two bottles, each 
of them contains: sodium sulphate anhydrous: 17.510 g, magnesium sulphate heptahydrate: 
3.276 g, potassium sulphate: 3.130 g, sodium benzoate: 
, sucralose: 
 and 
flavouring/taste masking agents (anhydrous citric acid, malic acid and a fruit cocktail flavour): 
 in aqueous liquid form. 
Each treatment pack is composed of two bottles of 180 mL with about 176 mL of concentrate.  
A more detailed description of administration procedures is given in Section 6.1.1.  
 
Klean-prep®: 
Klean-prep® is provided as powder for oral solution in sachets containing a whitish powder 
which, when dissolved in water, gives a clear, colourless solution for oral administration. Each 
sachet contains: macrogol 3350: 59.000 g, anhydrous sodium sulphate: 5.685 g, sodium 
bicarbonate: 1.685 g, sodium chloride: 1.465 g, potassium chloride: 0.7425 g. Klean-prep® 
should be stored at the recommended temperature (not above 25°C). A total of 69 g of the 
product (powder for oral solution) is included in one sachet. Each treatment pack is composed 
of 4 sachets. 
A more detailed description of administration procedures is given in Section 6.1.2. 
 
In this single-blinded study, to ensure an unbiased evaluation of the study preparations, the 
colonoscopist will not be allowed to perform any study drug related activities (randomisation, 
drug dispensing, return and accountability, acceptability, tolerability and review of subject’s 
leaflet/questionnaires). Any failure to maintain blinding of the treatment for the colonoscopist 
will be documented as a protocol violation. Subjects and caregivers will be instructed not to 
discuss their study preparation with the colonoscopist or any staff member other than with the 
study nurse who will collect the questionnaires. 
 
A rescue treatment (normal saline enema, 1000 mL) may be administered only if clear 
discharge has not been obtained 1 hour prior to procedure. This rescue medication will be given 
repeatedly until clear discharge is obtained. Sodium phosphate enemas are not to be used. The 
need for a rescue treatment will be recorded in the eCRF. 
 
The investigational medicinal product (IMP) Eziclen®/Izinova® and Klean-PREP® will be 
packaged and released by the Beaufour Ipsen Industrie, CMC-SC and delivered to the 
investigational sites or deposited in an Interim Storage Facility. A sufficient quantity of 
Eziclen®/Izinova® and Klean-Prep® will be supplied as well as an acknowledgement of 
receipt form. The Sponsor's representative will receive a Certificate of Analysis for the IMP 
batches of the study, Material Safety Data Sheet for both active and comparative treatment, 
Packaging order and the Certificate of Compliance which reflects the product’s release 
statement and will provide them to the sites according to local requirements. 
 
The core label texts for all packaging units will be translated and/or adjusted, to be in 
compliance with applicable regulatory requirements, national laws in force and in accordance 
with the local languages. A non exhaustive description of the core text of the IMP labels is 
displayed below: 
• 
Sponsor name, 
CCI
CCI
CCI


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• 
Study number, 
• 
Pharmaceutical dosage form, 
• 
Route of administration, 
• 
Quantity of dose units, 
• 
Batch number, 
• 
Treatment number, 
• 
Subject number (empty field to be completed by the pharmacist), 
• 
Investigator name 
• 
“Keep out of reach of children”, 
• 
“For clinical study use only”, 
• 
Name, address and telephone number of the sponsor, CRO or investigator (the main 
contact for information on the product, clinical study and emergency unblinding), 
• 
Storage conditions, 
• 
Expiry date. 
The unblinded designee, will only dispense IMPs to subjects included in this study. Each subject 
will only be given the IMP carrying his/her number. The dispensing for each subject will be 
documented in the eCRF by unblinded pharmacist. 
3.5 
Study Duration 
This study will consist of a 1-day enrolment (Day 1, baseline) and investigator-blind label 
dosing period, a 1-day colonoscopy (Day 2) and a 30-day follow-up period (Day 32 (-5/+15, 
i.e. Day 27 to Day 47). Subjects are expected to participate in this study for a minimum of 27 
days and up to 47 days.  
The subject’s participation in the study will be considered to have ended at the time of the last 
visit (30 days after last IMP intake). 
The study will be considered to have started when the first subject has been screened and 
provided signed informed consent. The Baseline visit (Visit 1) will be performed on the same 
day of treatment administration. Subjects meeting all eligibility criteria will be randomised to 
receive either Eziclen®/Izinova® or Klean-Prep® solution. After having received either 
Eziclen®/Izinova® or Klean-Prep® solution, subjects will undergo colonoscopy. Subjects will 
be contacted by phone on Day 4 and will come on Day 32 for a safety follow-up visit. 
As the blood and urine sulfate assay are not standard tests, the samples are transported in batches 
to an overseas central laboratory and processed there. Results are transferred to the study 
database. The last sample is taken at the time of last subject last visit. The estimated duration 
for transfer of the sample to the central laboratory, processing and transfer of the results to the 
database is approximately 6 weeks. In order to ensure that the sulfate data are included in the 
CSR, the end of study is being redefined. The study will be considered to have ended after the 
last subject last external data from central laboratory has been transferred to the database. 
The overall duration of the study will be approximately 32 months (30 months of recruitment 
+ 1 month of follow-up + 6 weeks minimum for last data transfer). 
3.6 
Stopping Rules and Discontinuation Criteria 
There are no formal rules for early termination of this study. During the conduct of the study, 
SAEs will be reviewed (see Section 8.1.4) as they are reported from the study centre to identify 
safety concerns. An Expert Committee will be appointed to review safety data. This Expert 


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Committee will be chaired by the principal investigator. Full details of the operating model for 
this safety data review will be provided in a charter to be produced.  
The study may be terminated by the sponsor at any time. 
A subject may discontinue participation in the study at any time for any reason (e.g. lack of 
efficacy, withdrawal of consent, AE). The investigator and/or sponsor can withdraw a subject 
from the study at any time for any reason (e.g. protocol violation or deviation as defined in 
Section 12.1.2, noncompliance with the protocol conditions or AE). 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability 
3.7.1 
Investigational Medicinal Product Storage and Security 
The unblinded approved representative (e.g. pharmacist), will ensure that all IMP and any other 
study related material is stored in a secured area, under recommended temperature monitored 
storage conditions, in accordance with applicable regulatory requirements. 
3.7.2 
Investigational Medicinal Product Preparation 
The unblinded approved representative (e.g. pharmacist), will ensure that all IMP and 
comparative treatment are reconstituted and dispensed by qualified staff members (Refer to 6.1 
for details). 
3.7.3 
Investigational Medicinal Product Accountability and destruction 
All IMP and any other study related material is to be accounted for on the IMP accountability 
log provided by the sponsor. It is essential that all used and unused supplies are retained for 
verification (by the sponsor or sponsor’s representative). The pharmacist or nurse should ensure 
adequate records are maintained in the IMP accountability log. 
All used and unused components of study preparation must be accounted for on the drug 
inventory log and will be returned to the sponsor at the completion or termination of the study, 
unless instructed otherwise by the sponsor. 
3.8 
Maintenance of Randomisation and Blinding 
This study being investigator-blinded, the eCRF will provide two user profiles: one profile (e.g. 
pharmacist) which will be able to see the treatment arm and another one for the investigator for 
whom this information will be hidden. The tear-off of pack labels will indicate the treatment 
number to be entered in the eCRF, it will be similar for Eziclen®/Izinova® and Klean-Prep®. 
However, the appearance and contents of packs being different, to maintain the blinding for the 
investigator, the randomisation/dispensation of assigned treatment will be done by a 
pharmacist/nurse in charge of this activity. This person will be fully trained about the 
importance of his role in maintaining the blind for the investigator. 
Two sets of individual sealed code break envelopes (refer to List B) will be prepared by the 
sponsor’s randomisation manager to enable emergency code break procedures for individual 
subjects without compromising the blind of the study. One set will be provided to the 
investigational site and one set will be provided to the Global Patient Safety of the sponsor. The 
sending of code-break envelopes “investigator” will have to be coordinated with the sending of 
associated treatment kits. 
Code break envelopes will only be opened in cases of medical emergency when treatment is 
dependent on knowledge of the IMP received.  


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In an emergency situation, which requires the identification of the study treatment group, the 
investigator may break the treatment code immediately, or as quickly as possible if he/she finds 
it is in the best interest of the trial subject.  
Once it has been determined that knowledge of the treatment code is necessary, the investigator 
will ascertain the subject’s identification number and treatment number and then break the blind 
for the subject concerned. The investigator will then sign date and provide reason for the code 
break on the Emergency Code break form and on the code break envelope. 
At the earliest opportunity the investigator is requested to inform the monitor in charge of 
his/her centre that the blind has been broken for an emergency. 
 
Monitors should routinely check the integrity of the envelopes that are stored at the study site. 
They must collect envelopes from the study site prior to study close out and ensure that they 
are all intact. If envelope(s) have been opened at the site or by the sponsor’s representative, the 
monitor must ensure a written explanation is clearly documented (opener’s name, dated 
signature and reason for opening) on the visit status page of the eCRF. 
Confirmation of the integrity of all code break envelopes at study completion must be 
documented in the trial master file (TMF). All sets of the sealed individual subject envelopes 
must be kept in the TMF in the co-ordinating office at study completion for proof of integrity. 
3.9 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 CFR Part 11. As required by 
GCP, the sponsor assigned monitor will verify, by direct reference to the source documents, 
that the data required by the protocol are accurately reported on the eCRF.  
The source documents must, as a minimum, contain a statement that the subject is included in 
a clinical study, the date that informed consent was obtained prior to participation in the study, 
the identity of the study, diagnosis and eligibility criteria, visit dates (with subject status), IMP 
administration and any AEs and associated concomitant medication. 
As required by ICH GCP Section 6.4.9, if some items are recorded directly on the eCRF and 
are considered as source data, the identification of these data must be documented and agreed 
between the investigator and the sponsor. 
Definitions for source data and source documents are given below: 
• 
Source Data: All original records and certified copies of original records of clinical 
findings, observations, or other activities necessary for the reconstruction and evaluation 
of the study. Source data are contained in source documents (original records or certified 
copies). 
• 
Source Documents: Original documents, data and records (e.g. hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x rays, subject files and records 
kept at the pharmacy, at the laboratories and at medicotechnical departments involved in 
the clinical study). 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel, and by local and possibly foreign, Competent Authorities (CA). This 
information is included in the informed consent. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subject MUST satisfy all of the following entry criteria before being allowed to participate in 
the study: 
(1) 
Provision of signed ICF to participate in the study obtained from the adolescent's 
parent(s)/ legal representative and a signed assent form from the adolescent according to 
local law 
(2) 
Male or female subjects between 12 to 17 years of age (inclusive) 
(3) 
Body weight more than 40 kg 
(4) 
Female of childbearing potential must have a negative pregnancy test 
(5) 
If female, and of child-bearing potential, subject must use an acceptable form of birth 
control (hormonal birth control, intrauterine device (IUD), double-barrier method, or 
depot contraceptive)  
(6) 
Routinely accepted indication for undergoing colonoscopy, including but not limited to 
polyposis coli diagnosis or surveillance, gastrointestinal bleeding, unexplained diarrhoea 
or constipation, surveillance of inflammatory bowel disease or confirmation of mucosal 
healing, abdominal pain, abnormal endosonography or manometry, anaemia of unknown 
aetiology, cancer surveillance 
(7) 
In the investigator’s judgment, the parent(s)/legal representative are/is mentally 
competent to provide informed consent for the subject to participate in the study 
(8) 
In the investigator’s judgement, subject is able and willing to follow study procedures 
including drug administration and response to questionnaires 
4.2 
Exclusion Criteria 
If any of the following apply, the subject MUST NOT enter/continue in the study: 
(1) 
Subject with known or suspected ileus, gastrointestinal obstruction, gastric retention 
(gastroparesis), rectal impaction, toxic colitis, severe ulcerative colitis or toxic 
megacolon, advanced carcinoma, swallowing disorders 
(2) 
Subject with known or suspected inflammatory bowel disease (Crohn’s disease, 
ulcerative colitis) in moderate to severe active phase defined by PCDAI >30 (Crohn’s 
disease) or PUCAI >34 (ulcerative colitis) 
(3) 
Subject with bowel perforation or increased risk of bowel perforation, including 
connective tissue disorders or recent bowel surgery 
(4) 
Subject with previous significant gastrointestinal surgery (e.g. colostomy, colectomy, 
gastric bypass, stomach stapling) 
(5) 
Subject with uncontrolled pre-existing electrolyte abnormalities, or with electrolyte 
abnormalities based on Visit 1 laboratory results such as hypernatremia, hyponatremia, 
hyperphosphatemia, hypokalaemia, hypocalcaemia, uncorrected dehydration, or 
secondary to the use of medications such as diuretics or angiotensin converting enzyme 
(ACE) inhibitors judged clinically significant by the investigator 
(6) 
Subject with a prior history or current condition of severe renal (estimated glomerular 
filtration rate (eGFR) less than 30 mL/min/1.73 m2 as calculated by using the Schwartz 
bedside equation* [13]), liver (ascites, Child-Pugh C), cardiac insufficiency (including 
congestive heart failure all grades) or hyperuricemia 


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*The estimated GFR will be calculated in patients with elevated creatinine at baseline. 
 
(7) 
Female subject who is pregnant or lactating 
(8) 
Subject who has participated in another investigational drug treatment within the last 90 
days before the first study visit 
(9) 
Subject with phenylketonuria 
(10) Subject with history of asthma or hypersensitivity to any ingredient of either drug product 
(11) Subject for whom intake of substances likely to affect gastrointestinal motility or urinary 
flow rate is required 
(12) Subject with requirement to take any other oral medication within 3 hours of starting the 
bowel preparation, as this may impact medication absorption 
(13) Subject with tendency for nausea and/or vomiting 
(14) Subject with impaired consciousness that predisposes them to pulmonary aspiration or 
who have known swallowing disorders 
(15) Subject with history of major medical/psychiatric conditions that, in the judgment of the 
investigator, would compromise safety in the study 
(16) Subject with mental or psychiatric condition rendering the subject unable to understand 
the nature, scope and possible consequences of the study, and/or evidence of an 
uncooperative attitude 
(17) Subject with a condition that, in the opinion of the investigator, might increase the risk 
to the subject or decrease the chance of obtaining satisfactory data needed to achieve the 
objectives of the study 
(18) Subject who has previous enrolment in this study or concomitant enrolment in other 
clinical studies 
4.3 
Subject Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, 
pregnancy (see Section 8.1.5), or other reasons concerning the health or wellbeing of the 
subject, or in the case of lack of cooperation. In addition, a subject may be withdrawn from the 
study as described in Sections 3.6, 5.2.4.2, 6.2 and 8.1.7.  
Should a subject decide to withdraw from the study after administration of IMP, or should the 
investigator decide to withdraw the subject, all efforts will be made to complete and report the 
observations up to the time of withdrawal as thoroughly as possible. A complete final evaluation 
at the time of the subject’s withdrawal should be made (see Section 5.2.4.2) and an explanation 
given of why the subject is withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the eCRF. If a subject 
withdraws consent, every attempt will be made to determine the reason. If the reason for 
withdrawal is an AE or a clinically significant laboratory test abnormality, monitoring will 
continue until the event has resolved or stabilised, until the subject is referred to the care of a 
local health care professional, or until a determination of a cause unrelated to the IMP or study 
procedure is made. The specific AE or test result(s) must be recorded on the eCRF. All 
evaluations should be performed, according to the protocol, on the last day the subject receives 
IMP, or as soon as possible thereafter. If the final visit is conducted more than 47 days after the 


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dose of IMP, all safety evaluations will be performed. It is not planned to collect efficacy data 
after Visit 2. 


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5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in Table 4.  
Table 4 
Study Procedures and Assessments 
Study Period 
Baseline/ 
Treatment 
Colonoscopy 
Phone 
contact 
End of Study 
(or in case of Early 
Withdrawal*) 
Visit 
1 
2 
3 
4 
Day 
Day 1 
Day 2 
Day 4 
Day 32 
Window 
 
 
±1 
-5/+15 i.e. Day 27 to 
Day 47  
Eligibility Criteria 
X 
 
 
 
Demographic Data 
X 
 
 
 
Blood Pregnancy Test [a] 
X 
 
 
 
Informed Consent (parent(s) 
or legal representative) 
X 
 
 
 
Assent (subject)  
X 
 
 
 
Medical and Surgical History 
X 
 
 
 
Indication(s) for 
Colonoscopy 
X 
 
 
 
Prior and Concomitant 
Medication [b] 
X 
X 
 
X 
Prior and Concomitant Non-
Drug Therapy [b] 
X 
X 
 
X 
AEs [c] 
X[d] 
X 
X[e] 
X 
Physical Examination   
X 
 
 
X 
Vital Signs (Temperature, 
blood pressure (BP) and 
heart rate (HR) 
X 
X 
 
X 
Body Weight and height[f]  
X 
X 
 
X 
Blood sample collection [g], 
[h] 
X[i] 
X[j] 
 
X 
Urine sample collection[k] 
X 
X 
 
X 
Blood and urine sulphates[l] 
X 
X[j] 
 
X 
RANDOMISATION [m] 
X 
 
 
 
Study treatment dispensation 
(with explanation of 
treatment administration) 
X 
 
 
 
Subject/caregiver leaflet 
dispensation by study nurse 
(with explanation of 
questionnaires including 
compliance measurement) 
X 
 
 
 
Subject takes treatment 
preparation  
X 
 
 
 
Completion of leaflet 
questionnaires by subject/ 
caregiver/ nurse 
 
 
 
 
• 
Treatment 
/ 
Compliance  
X 
 
 
 
• 
Treatment 
Acceptability  
X 
 
 
 


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Study Period 
Baseline/ 
Treatment 
Colonoscopy 
Phone 
contact 
End of Study 
(or in case of Early 
Withdrawal*) 
• 
Symptom 
Scale 
(Tolerability)  
X 
 
 
 
Collection of leaflet 
questionnaires by study nurse  
 
X 
 
 
Drug accountability/ study 
administration compliance by 
unblinded site member 
 
X 
 
 
Colonoscopy assessment [n] 
 
X 
 
 
Subject status at the end of 
the visit 
X 
X 
X 
X 
*Early withdrawal will be anytime from Visit 1 (Refer to Section 3.6) 
[a] If applicable. Urine pregnancy test will be performed only when blood tests including pregnancy have been 
performed prior to Visit 1. 
[b] Prior and concomitant medication and non-drug therapy will from 7 days before baseline and for any action 
taken by the investigator 
[c] AEs will be actively collected by the investigator and subjects will be instructed to contact the investigator if 
they experience any AEs 
[d] At baseline, AEs will be collected from the date of informed consent and assent signature 
[e] The investigator will contact the subject by phone on Day 4±1 to collect data on potential AEs  
[f] Height will be measured at Baseline only 
[g] Local laboratory (blood): biochemistry including: anion gap, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), creatine phosphokinase (CPK), lactic dehydrogenase (LDH), gamma-glutamyl 
transferase (GGT), total and conjugated bilirubin, creatinine, urea, serum electrolytes (sodium, potassium, 
chloride, calcium, magnesium, phosphorus, bicarbonate), alkaline phosphatase, albumin, total protein, C 
reactive protein (CRP), uric acid, creatinine clearance (calculated GFR), osmolality 
[h] Laboratory assessments performed within 10 days or less prior to inclusion may be used to determine 
eligibility upon investigator agreement. 
[i] Additional local laboratory haematology: complete blood count (CBC), international normalised ratio (INR), 
(Section 8.2.1) 
[j] Blood sampling during anaesthesia 
[k] Local laboratory urine analysis (by dipstick), microscopic examination 
[l] Collection of blood and urine sample for central laboratory sulphate dosage  
[m] Randomisation if satisfactory biochemistry results 
[n] Colonoscopy assessment: Rescue treatment, cleansing Score, BBPS, start time of colonoscopy, time of caecal 
intubation, caecum reached, withdrawal time, diagnosis/findings.  
 
Table 5 
Subject’s Leaflet Collected Information 
 
During/after Dose 1 
Day 1 
During/after Dose 2 
Day 1 
Treatment/Compliance Questionnaire[a]  
X  
X 
Treatment Acceptability Questionnaire 
X 
X 
Symptom Scale (Tolerability) 
X 
X 
Information about time to bowel movement 
and time to first clear watery stool. 
 
X 
a 
Treatment/Compliance questionnaire will collect information about: preparation of treatment, 
treatment intakes (recording of residual volumes, start/end times) for Eziclen®/Izinova® or Klean-
Prep®. 
 
The total volume of blood drawn for all evaluations throughout this study is approximately 
16.5 mL for each subject. 


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The total amount of blood to be collected from all subjects is presented in Table 6. 
Table 6 
Blood Volume Calculation 
Description 
Number of Samples 
Volume (mL) 
Total Volume (mL) 
Haematology 
1 
3 mL 
3 mL 
Biochemistry 
3 
2.5 mL 
7.5 mL 
Sulphates 
3 
2 mL 
6 mL 
Total Volume (mL)  
 
 
16.5 mL 
5.2 
Study Visits 
5.2.1 
Prescreening Period 
The prescreening period is defined as the period between the visit where the colonoscopy 
indication is posed and the date of Visit 1. During this period, and prior to the study entry, the 
investigator, or a person designated by the investigator, will explain the nature, purpose, 
benefits and risks of participation in the study to each subject and subject’s parent (s) or legal 
representative. An ICF will be provided to each parent/legal representative, and an assent form 
will be provided to each subject during the pre-screening period, when the indication for 
colonoscopy is decided. The documents are to be dated and signed before any study screening 
procedures, according to local IRB/IEC requirements. 
 
5.2.2 
Baseline/Treatment visit (Visit 1) 
Each subject’s assent and subject’s parent(s)/legal representative consent forms, signed and 
dated will be retained by the investigator. The subject will be hospitalised and will be allocated 
a subject number. All subjects must be identifiable throughout the study. The investigator will 
maintain a list of subject numbers and names to enable records to be found at a later date if 
required. The baseline visit (Visit 1) will take place on the day of hospitalisation for bowel 
preparation administration, after retrieving the signed ICF and assent form.  
 
Dietary recommendations for this study are as follows: subjects will come on the morning of 
Visit 1 under fasting conditions. Starting with breakfast, the subjects may only have clear 
liquids on the day prior to colonoscopy until completion of the colonoscopy the following day. 
Non-adherence to the dietary recommendations (nature and date/time) will be recorded in the 
patient leaflet.  
 
The following baseline assessments will be performed by the investigator/study nurse: 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
Demographic data (date of birth1/age, sex),  
• 
Medical and surgical history, including ongoing medical history, as well as any 
significant conditions, including but not limited to major abdominal surgeries (excludes 
appendectomy), renal failure/dysfunction, liver failure/dysfunction, cardiac disorders 
inflammatory bowel disease, polyposis, diabetes, cancer (must indicate type of cancer), 
immune system disorders, electrolyte abnormalities 
• 
Physical examination  
                                                 
1 depending on regulatory requirements, the date of birth may not be collected entirely, only the year will be 
collected 


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• 
Pubertal stage, if available (Tanner stage) 
• 
Body weight and height 
• 
Vital signs (temperature, supine and standing BP and HR) 
• 
Blood sampling: Laboratory assessments performed within 10 days or less prior to 
inclusion may be used to determine eligibility upon investigator agreement. 
a) haematology: international normalised ratio (INR), CBC  
b) biochemistry including: anion gap, ALT, AST, CPK, LDH, GGT, total and conjugated 
bilirubin, albumin, creatinine, urea, serum electrolytes (sodium, potassium, chloride, 
calcium, magnesium, phosphorus, bicarbonate), alkaline phosphatase, total protein, 
CRP, uric acid, creatinine clearance (calculated GFR), osmolality 
• 
Urine analysis by dipstick (pH, protein, ketones, bilirubin, blood, urobilinogen, nitrites, 
leukocytes, glucose and specific gravity, urine microscopic examination 
• 
Blood and urinary samples for sulphate measurement 
• 
Blood pregnancy test, if female of child-bearing potential. Urine pregnancy test will be 
performed only when blood tests including pregnancy have been performed prior to Visit 
1. 
• 
Indication(s) for colonoscopy to be collected 
• 
Randomisation  
• 
Drug accountability, study treatment dispensation by study nurse (with explanation of 
treatment administration) 
• 
Subject/caregiver questionnaires dispensation by study nurse (with explanation of 
questionnaires including compliance measurement) 
• 
Prior and concomitant medications including supplements, herbal medications and non-
prescribed compounds 
• 
Prior and concomitant non-drug therapies and surgical procedures 
• 
Collection of AEs from the time of informed consent signature 
• 
Subject status at the end of the visit  
Records up to the time of premature termination should be completed. In the event that the 
subject was not receiving IMP, the primary reason will be recorded. 
If any Visit 1 serum chemistry result is considered abnormal and clinically significant by the 
investigator result may be checked per investigator’s decision. The abnormal significant result 
will be reported as an AE.  
In case of non-inclusion of the subject, the primary reason will be recorded. 
Following confirmation of eligibility for the study, subjects will be given a 
randomisation/treatment allocation number and allocated to one of the dosing groups specified 
in Section 6.1.  
Caregivers and subjects will be provided with a subject leaflet containing instructions on how 
to administer the study preparation. Caregivers will be provided with a Treatment Acceptability 
Questionnaire (see Section 7.3.2.3) to report their child’s experience with the study preparation, 
and a Symptom Scale to rate subject tolerability (see Section 8.6). Subjects/caregivers will 
complete these questionnaires during and after the treatment administration. 
Subjects will be hospitalised for preparation. The treatment will be prepared by a nurse and 
administration will be monitored as described in Section 3.4. The nurse or caregiver will fill in 


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the questionnaires or ensure that the subject fills in, as appropriate. If a subject is unable to 
complete the preparation, a nasogastric tube will be placed. 
The bowel cleansing preparation will be taken orally on the evening of the day before 
colonoscopy.  
The following procedures will be performed during and after treatment administration:  
x Treatment preparation taken by subject (nasogastric tube may be placed if needed for 
completion of preparation)  
x Completion of subject leaflet (for Eziclen®/Izinova® or Klean-Prep® depending on 
allocated treatment arm) which contains: 
o Treatment administration, compliance, Treatment Acceptability Questionnaires 
and Symptom Scale by subject/caregiver 
o Information about bowel movement and stool 
o Time of first clear watery stool 
5.2.3 
Colonoscopy (Visit 2, Day 2) 
Colonoscopy will be performed on the morning following completion of the preparation.  
Subject’s vital signs and weight will be measured. A blood sample will be collected during 
anaesthesia for sulphate assessment testing by central lab and for biochemistry testing by local 
lab. A urine sample will be collected prior to anaesthesia for sulphate measurement by central 
lab and another one for urinary analysis by local lab. 
The colonoscopy will be performed by a physician according to the site’s standard procedures. 
Cleanliness will be evaluated on a 4-point scale, as shown in Section 7.3.1 as well as using the 
BBPS (See Section 7.3.2.1). Additional data will be collected as outlined in Section 7.2. 
The subject will be discharged from the hospital after the colonoscopy (unless there is a medical 
reason/condition for retaining the subject). 
The following procedures will be performed on day of colonoscopy (Day 2): 
• 
Review and recording of AEs  
• 
Body weight 
• 
Vital signs (temperature, supine BP and HR) 
• 
Blood and urine sample for local lab  
• 
Blood and urine sample for central lab sulphate testing 
• 
Colonoscopy  
• 
Colonoscopy-related assessments, including suspected diagnosis 
• 
Histological examination of colonic biopsy (if needed) 
• 
Drug accountability by unblinded site personal 
• 
Reporting of study administration compliance data (based on subject’s leaflet 
information) by unblinded site personal 
• 
Subject status at the end of the visit 
5.2.4 
Procedures after Study Treatment 
5.2.4.1 
Phone Contact (Visit 3) 
The investigator will contact the subject by phone on Day 4±1 to collect data on potential AEs. 


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5.2.4.2 
End of Study Visit (Visit 4) or Early Withdrawal Visit 
Subjects will return to the study centre 30 days (-5+/15 days) after colonoscopy. A physical 
examination will be performed, vital signs measured and the subject will be queried for 
occurrence of AEs and changes in concomitant medications. If any laboratory result is 
considered clinically significant by the investigator (and documented as an AE), a follow-up 
sample should be collected and sent for analysis. The subject will be followed-up until 
resolution of the AE. 
 
For subjects who complete the study, or for those who withdraw prematurely from the study, 
final evaluations will be performed as soon as possible afterwards. Subjects with ongoing AEs 
or clinically significant laboratory test abnormalities (as determined by the investigator) will be 
monitored as described in Section 8.1.3 and Section 8.1.2.4, respectively. 
The following procedures will be performed at the End of Study (Visit 4, Day 32 (-5/+15 days 
i.e. Day 27 to Day 47), or Early Withdrawal visit: 
• 
Review of AEs 
• 
New or changed concomitant medications 
• 
Concomitant non-drug therapies 
• 
Concomitant surgical procedures 
• 
Physical examination 
• 
Vital signs (temperature, BP and HR) 
• 
Body weight 
• 
Collection of blood and urine samples for blood sulphate measurement by central lab 
• 
Collection of blood for biochemistry analysis and urine for local laboratory analysis 
• 
Subject status at the end of the visit. 


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6 
TREATMENT OF SUBJECTS 
6.1 
Study Drugs Administered 
Following confirmation of eligibility for the study, subjects will be allocated to one of the 
following treatment groups: 
• 
Eziclen®/Izinova® concentrate sulphate salt solution 
or 
• 
Klean-Prep®, powder for oral solution dosage 
 
6.1.1 
Eziclen®/Izinova® 
The bowel cleansing preparation Eziclen®/Izinova® is a concentrate for oral solution packaged 
in two bottles, each of them contains: sodium sulphate anhydrous: 17.510 g, magnesium 
sulphate heptahydrate: 3.276 g, potassium sulphate : 3.130 g, sodium benzoate: 
 
sucralose: 
 
Each treatment pack is composed of two bottles of 180 mL with about 176 mL of concentrate. 
The bowel cleansing preparation Eziclen®/Izinova® will be given orally on the evening of the 
day before colonoscopy. The total dose administered is 3/4 of the adult dose (product 
dispensed).  
Evening before the procedure (e.g.: 6:00 pm): 
The two bottles of Eziclen®/Izinova® (180 mL X 2 concentrate sulphate salt solution) are to 
be diluted up to 1000 mL with water, using a 1000 mL graduated measuring glass. A total of 
250 mL (1/4) of the preparation will be discarded. The remaining 750 mL of the preparation 
(3/4 adult dose) will be divided in two equal portions. The first portion of 375 mL will be drunk 
slowly in ½ to 1 hour, followed by an additional 750 mL of water over the next hour. The total 
ingested volume is 1125 mL. 
Approximately 2 hours after the start of drinking the first portion (e.g., 8:00 pm): 
The second 375 mL portion of the Eziclen®/Izinova® preparation will be drunk slowly in ½ to 
1 hour followed by additional 750 mL of water over the next hour. The total ingested volume 
is 1125 mL. 
The total volume of preparation drunk is 750 mL, with an additional 1500 mL of water, for a 
total of 2250 mL. If a subject experiences difficulty in drinking the bowel cleansing preparation, 
a nasogastric tube will be placed, the rate of administration should not exceed 30 mL/kg/hour. 
6.1.2 
Klean-Prep® 
The comparator, Klean-Prep® is a powder for oral solution packaged in 4 sachets.  
Each sachet of Klean-Prep® contains the following active ingredients: 59.000 g macrogol 3350, 
5.685 g anhydrous sodium sulphate, 1.685 g sodium bicarbonate, 1.465 g sodium chloride and 
0.7425 g potassium chloride.  
Each treatment pack is composed of 4 sachets with a total of 69 g of the product (powder for 
oral solution) included in each sachet. 
Klean-Prep® (powder for oral solution) will be given orally on the evening of the day before 
colonoscopy. The complete dose of the preparation will be administered on the day prior 
colonoscopy, in the evening. 
Evening before the procedure (e.g.: 6:00 pm): 
CCI
CCI


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The 4 sachets are to be diluted. Each sachet is diluted in 1 litre of water. The dosage will be 
70 mL/kg (which corresponds to the approved posology for that class of age and/or weight).  
The volume to be taken will be calculated based on subject’s weight and reported by study 
nurse or pharmacist on the subject’s leaflet as a reference. The maximum volume administered 
will be 4000 mL. 
The whole solution will be administered in two half doses (1 litre per hour), with a 1-hour pause 
between the two half doses.   
Approximately 2 hours after the start of the drinking the first portion (e.g. 8:00 pm), the second 
portion of Klean-Prep® will be drunk. 
If a subject experiences difficulty in drinking the bowel cleansing preparation a nasogastric tube 
will be placed, the rate of administration should not exceed 30 mL/kg/hour.  
6.1.3 
Rescue Treatment 
A rescue treatment (normal saline enema, 1000 mL) may be administered only if clear 
discharge has not been obtained 1 hour prior to procedure. This rescue medication may be 
repeated until clear discharge is obtained. Sodium phosphate enemas are not to be used. 
6.2 
Prior and Concomitant Medication and Non-drug /Therapy 
The use of concomitant medication will be recorded from 7 days prior to Visit 1 until 
completion of Visit 4 (Day 32(-5/+15), including sedation medications and intravenous fluids 
administered during colonoscopy. 
No concomitant medication is forbidden. However, bowel cleansing will interfere with the 
absorption of medications. Concomitant oral medication administered within 1 to 3 hours of 
the start of the treatment and until the end of the cleansing process may be flushed from the 
gastrointestinal tract and the medication may not be absorbed properly. The therapeutic effect 
of regularly taken oral drugs with a narrow therapeutic index or short half-life (e.g. oral 
contraceptives, antiepileptic drugs, antidiabetics, antibiotics, levothyroxine, digoxin…) may be 
particularly affected. 
Caution is advised in subjects with conditions, or who are using medications, inducing fluid or 
electrolyte disturbances, such as angiotensin converting enzyme inhibitors, calcium channel 
blockers, diuretics, lithium treatment, or other medications that might affect electrolyte levels. 
Caution is also advised when taking medicines known to prolong the QT interval. 
6.3 
Procedures for Monitoring Subject Compliance 
In order to maintain the investigator-blind, administration compliance will be assessed by 
dedicated personnel based on measurement of unused preparation and fluid intake recorded by 
the subject/caregiver on the subject’s leaflet. Data collected on the subject’s leaflet will be 
reviewed outside of the colonoscopist’s presence and will not be made available to the 
colonoscopist. 
Data will be entered in the eCRF by unblinded personnel as single data entry (one person enters 
the data in the eCRF). Data verification will be performed by study monitor during on site visits.  
 


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7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedule in Table 4. 
7.1 
Primary Efficacy Endpoints and Evaluations 
The primary efficacy endpoints are presented in Section 3.2.1.  
Blinded overall assessment of preparation efficacy will be determined by the colonoscopist 
upon completion of the examination, based on the 4-point scale score presented in Section 7.3.1. 
7.2 
Secondary Efficacy Endpoints and Evaluations 
Secondary efficacy endpoints and evaluations are summarised in Table 7. 
Table 7 
Secondary Endpoints and Evaluations 
Endpoint 
Timepoint 
Evaluation 
Colon cleansing 
Visit 2 (Colonoscopy) 
Cleansing Score assessed on 4 levels (4-
point scale (see Section 7.3.1) 
Overall and segmental 
cleansing assessed by 
BBPS 
Visit 2 (Colonoscopy) 
BBPS (see Section 7.3.2.1) Overall score 
[14]. 
Segmental score (left colon (LC), 
transverse colon (TC), right colon (RC)). 
Time to clear effluent 
Treatment 
Time between first intake of prescription 
and first clear watery stool. 
Complete procedure 
Visit 2 (Colonoscopy) 
Number (%) of complete procedures 
defined as procedures that reached the 
caecum 
 
Duration of intubation 
Visit 2 (Colonoscopy) 
Time between the colonoscope 
introduction and the time to reach 
caecum 
 
Duration of examination 
Visit 2 (Colonoscopy) 
Duration of colonoscope withdrawal 
from caecum  
Need for rescue treatment 
because of inadequate 
preparation intake. 
Visit 2 (before colonoscopy) 
Number (%) of procedures that need a 
rescue treatment (saline enema) 
Treatment acceptability 
Treatment 
Level of acceptability of treatment 
assessed using a 5-point Treatment 
Acceptability Questionnaire (see 
Section 7.3.2.3). 
Need for nasogastric tube 
Treatment 
Number (%) of subjects who need a 
nasogastric tube to complete preparation 
Treatment compliance 
Treatment 
Volume of fluid not taken (see Section 
7.3.2.2) 
 
7.3 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data 
Methods for assessing efficacy data are described below. Timing of efficacy assessments are 
discussed in Section 5. Procedures for recording efficacy data are discussed in Section 14.1 and 
methods of analyses are discussed in Section 10.4.5. 


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7.3.1 
Primary Efficacy Assessment 
The primary efficacy variable is the proportion of subjects with successful overall preparation. 
The colonoscopist will be asked to score the quality of the bowel preparation using the 
following Cleansing Score (Table 8). 
Table 8 
Cleansing Score 
Score 
Grade 
Description 
1 
Poor 
Large amounts of faecal residue, additional cleansing required 
2 
Fair 
Enough faeces or fluid to prevent a completely reliable examination 
3 
Good 
Small amounts of faeces or fluid not interfering with examination 
4 
Excellent 
No more than small bits of adherent faeces/fluid 
 
Primary efficacy will be assessed on the basis of preparation success or failure. 
Only perfect preparations graded as excellent (4) or good (3), which allow full, reliable 
examination of the mucosa, will be considered as successful. 
 
7.3.2 
Secondary Efficacy Assessment 
7.3.2.1 
Boston Bowel Preparation scale 
The overall and segmental cleansing as assessed by BBPS [15] is presented in Table 9. 
Table 9 
Boston Bowel Preparation Scale 
Score per segment 
BBPS definition 
0 
Unprepared colon segment with mucosa not seen due to solid stool that 
cannot be cleared 
1 
Portion of mucosa of the colon segment seen, but other areas of the colon 
segment not well seen due to staining, residual stool and/or opaque liquid. 
2 
Minor amount of residual staining, small fragments of stool and/or opaque 
liquid, but mucosa of colon segment seen well. 
3 
Entire mucosa of colon segment seen well with no residual staining, small 
fragments of stool and/or opaque liquid 
 
This information (segmental cleansing) will be collected for the right, transverse and left colon. 
Scores per segment will be summed to provide overall cleansing score. 
7.3.2.2 
Treatment/Compliance  
The treatment questionnaire will be completed by the caregiver or subject after the subject 
completes each dose of preparation. The subject/caregiver will provide information about 
treatment preparation, residual volumes of preparation (volumes not taken by the subject) and 
start and stop times of intake. For the Eziclen®/Izinova® treatment only, information about the 
residual volume of water will be reported. 


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7.3.2.3 
Treatment Acceptability Questionnaire 
The Treatment Acceptability Questionnaire will be completed by the caregiver or subject after 
the subject completes each dose of preparation. Caregivers will be asked to rate subject 
acceptability using the following categories (Table 10).  
Table 10 Treatment Acceptability Questionnaire Categories 
Very badly 
accepted/unacceptable 
Subject showed great displeasure, compromising use of formulation 
Badly but accepted 
Subject showed displeasure with dosing but could be coaxed to take 
complete dose 
Neither good nor bad 
Subject showed no apparent displeasure and with little effort was coaxed to 
take complete dose 
Well accepted 
Subject appeared to enjoy the formulation and with little coaxing ingested 
complete dose 
Very well accepted 
Subject appeared eager and ingested complete dose without special coaxing 


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8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
AEs will be monitored from the time that the subject and parent(s)/legal representative signed 
the informed consent and throughout the study (see Section 3.5 for a definition of the study 
duration) and will be elicited by direct, non-leading questioning or by spontaneous reports. 
Further details for AE reporting can be found in Section 8.1.2. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product. An undesirable medical condition can be 
symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g. laboratory findings, electrocardiogram). In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run in or 
washout periods, even if no IMP has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until the end of the study (as defined in Section 3.5). 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
AEs will be classified as mild, moderate or severe according to the following criteria: 
• 
Mild: symptoms do not alter the subject’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject 
• 
Severe: symptoms definitely hazardous to well-being, significant impairment of function 
or incapacitation. 
8.1.2.2 
Causality Classification 
The relationship of an AE to IMP administration or comparator will be classified according to 
the following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with IMP administration in the sense that it 
is plausible, conceivable or likely. 
• 
Not related: reports including good reasons and sufficient information (e.g. implausible 
time sequence and/or attributable to concurrent disease or other drugs) to rule out a causal 
relationship with IMP administration. 
8.1.2.3 
Assessment of Expectedness 
The expectedness of an AE shall be determined by the sponsor according to the IB for an 
unapproved IMP, or the SmPC or package insert (PI) for an authorised medicinal product that 
is being used according to the terms and conditions of the marketing authorisation. If the IMP 
or comparator has marketing authorisations in several countries with different SmPCs or PIs, 
one will be selected as the reference document for assessing expectedness. 
The reference document for assessing expectedness of AEs/event in this study will be the 
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8.1.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject 
• 
They are considered as clinically significant by the investigator. 
8.1.2.5 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the investigator as clinically significant 
(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.  
8.1.3 
Recording and Follow-up of Adverse Events 
At each visit, the subject should be asked a non-leading question such as: “How have you felt 
since starting bowel cleansing or the last visit/assessment?” 
All observed or volunteered AEs, regardless of treatment group or suspected causal relationship 
to IMP or comparative treatment will be recorded on the AE page(s) of the eCRF.  
 
Each instance of adverse events that occur twice in the split dose regimen (e.g. nausea) will be 
recorded twice on the eCRF, if recovery is documented between both instances. 
 
Events involving drug reactions, accidents, illnesses with onset during the treatment phase of 
the study, or exacerbation’s of pre-existing illnesses should be recorded.  
Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to the sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE (i.e. IMP or other illness). The investigator is required to assess causality and record that 
assessment on the eCRF. Follow-up of the AE, after the date of IMP discontinuation, is required 
if the AE or its sequelae persist. Follow-up, that will include medical care, is required until the 
event or its sequelae resolve or stabilise at a level acceptable to the investigator and the 
sponsor’s clinical monitor or his/her designated representative. 
8.1.4 
Reporting of Serious Adverse Events 
All SAEs (as defined below) regardless of treatment group or suspected relationship to IMP or 
comparator must be reported immediately (within 24 hours of the investigator’s knowledge of 
the event) to the pharmacovigilance contact specified at the beginning of this protocol. If the 
immediate report is submitted by telephone, this must be followed by detailed written reports 
using the SAE report form. 
An SAE is any AE that: 
(1) 
Results in death, 


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(2) 
Is life-threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a more 
severe form, might have caused death, 
(3) 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons (see further), 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions, 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who received the 
IMP, 
(6) 
Is an important medical event that may not result in death, be life-threatening, or require 
hospitalisation but which, based upon appropriate medical judgement, may jeopardise 
the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in in-patient hospitalisation, or the 
development of drug dependency or drug abuse. 
In addition to the above criteria, any additional AE that the sponsor or an investigator considers 
serious should be immediately reported to the sponsor and included in the corporate SAEs 
database system. 
• 
Hospitalisation is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original reason for 
the initial admission, as determined by the investigator or treating physician. For 
protocol-specified hospitalisation in clinical studies, prolongation is defined as any 
extension beyond the length of stay described in the protocol. Prolongation in the absence 
of a precipitating, treatment emergent, clinical AE (i.e. not associated with the 
development of a new AE or worsening of a pre-existing condition) may meet criteria 
for “seriousness” but is not an adverse experience and thus is not subject to immediate 
reporting to the sponsor.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the subject’s 
screening documentation. Hospitalisation for a preplanned or elective treatment/surgical 
procedure should not be reported as an SAE unless there are complications or sequelae 
which meet the criteria for seriousness described above. 
Any SAE must be reported immediately (within 24 hours), independent of the circumstances 
or suspected cause, if it occurs or comes to the attention of the investigator at any time during 
the study period. 
Any AE/SAE with a suspected causal relationship to IMP administration or comparator 
occurring at any other time after completion of the study must be promptly reported. 
The following information is the minimum that must be provided to the sponsor 
pharmacovigilance contact within 24 hours for each SAE: 
• 
Study number 
• 
Centre number 
• 
Subject number 


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• 
AE 
• 
Investigator's name and contact details 
The additional information included in the SAE form must be provided to the sponsor or 
representative as soon as it is available. The investigator should always provide an assessment 
of causality for each event reported to the sponsor. Upon receipt of the initial report, the sponsor 
will ask for the investigator's causality assessment if it was not provided with the initial report. 
The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to separate a primary AE considered as the foremost 
untoward medical occurrence from secondary AEs which occurred as complications. 
8.1.5 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP has interfered 
with a contraceptive method. If pregnancy occurs during the study, the outcome of the 
pregnancy will then need to be collected poststudy  
Information regarding pregnancies must be collected on the AE page of the eCRF and reported 
to the sponsor as an SAE. The sponsor will request further information from the investigator as 
to the course and outcome of the pregnancy using the Standard Pregnancy Outcome Report 
Form.  
The investigator must instruct all female subjects to inform them immediately should they 
become pregnant during the study. The investigator should counsel the subject, discuss the risks 
of continuing with the pregnancy and the possible effects on the foetus. Monitoring of the 
subject should continue until conclusion of the pregnancy, which may involve follow-up after 
the subject’s participation in the study has ended. 
8.1.6 
Deaths 
All AEs resulting in death during the study period must be reported as an SAE within 24 hours 
of the investigator’s knowledge of the event.  
The convention for recording death is as follows:  
• 
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”. 
 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the IMP (see Section 4.3). 
If the IMP or comparator is discontinued due to an SAE, it must be reported immediately to the 
sponsor’s designated representative (see Section 8.1.4). 
In all cases, the investigator must ensure the subject receives appropriate medical follow-up 
(see Section 8.1.3). 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other investigators 
The sponsor will ensure that processes are in place for submission of reports of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring during the study to the CA, IECs 


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and other investigators concerned by the IMP. Reporting will be done in accordance with the 
applicable regulatory requirements. 
8.2 
Clinical Laboratory Tests 
Blood for clinical local laboratory tests will be collected at Visits 1, 2 and 4 for local laboratory. 
At Visit 1: haematology and biochemistry. 
At Visit 2 (during anaesthesia) and Visit 4 or early withdrawal visit: blood biochemistry.  
Blood will be also collected at Visits 1, 2 and 4 for central laboratory serum sulphate testing.  
Urinary sampling will be performed for local laboratory at Visits 1, 2 and 4 (or early withdrawal 
visit). 
Additional urinary sample will be performed at Visits 1, 2 and 4 for sulphate dosage by central 
laboratory. 
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 8.1.2.4 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.  
 
8.2.1 
Haematology 
Blood samples (3 mL) will be collected (in a potassium ethylene diamine tetra acetic acid 
(EDTA) tube) to assess the following parameters: CBC: red blood cell (RBC) count, 
haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin 
(MCH), mean corpuscular haemoglobin concentration (MCHC), white blood cell (WBC) count 
with differential (nutrophils, lymphocytes, monocytes, eosinophils, basophils, and others), 
platelet count and international normalised ratio (INR). 
8.2.2 
Blood Biochemistry 
Blood samples (2.5 mL) will be collected (in an activator gel tube) to assess the following 
parameters by local laboratory: 
Anion gap, ALT, AST, CPK, LDH, GGT, total and conjugated bilirubin, creatinine, urea, serum 
electrolytes (sodium, potassium, chloride, calcium, magnesium, phosphorus, bicarbonate), 
alkaline phosphatase, albumin, total protein, CRP, uric acid, INR, creatinine clearance 
(calculated GFR), osmolality 
Blood samples (2 mL) will be collected for sulphate level dosage by central laboratory at 
Visits 1: Baseline/treatment Visit 2: Colonoscopy and Visit 4: end of study or early withdrawal 
study. 
All the data will be reported in the eCRF by single data entry and monitored during on site 
visits. 
8.2.3 
Urinalysis 
Fresh urine samples (at least 10 mL) will be collected to assess the following parameters: pH, 
protein, ketones, bilirubin, blood, urobilinogen, nitrites, leukocytes, glucose and specific 
gravity by dipstick.  


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Microscopy will be performed, if indicated, but results will not be collected in the eCRF. 
Osmolality and ketones will be measured and the results will be reported 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. 
8.2.4 
Pregnancy Test 
A blood pregnancy test will be performed for all female subjects of childbearing potential at 
Visit 1 and if clinically indicated thereafter. Urine pregnancy test will be performed only when 
blood tests including pregnancy have been performed prior to Visit 1.  
Any adolescent female with childbearing potential becoming pregnant during the study will be 
withdrawn. All pregnancies that occur during the study are to be reported as described in 
Section 8.1.5. 
8.3 
Physical Examination 
Physical examinations will be conducted at Visit 1 and End of Study (Visit 4) /Early 
Withdrawal. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 
the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.4 
Vital Signs 
Blood pressure and HR will be assessed with an automated device so that measurements are 
independent of the observer. Blood pressure and HR will be recorded in standing position and 
after 5 minutes rest in supine position at visit 1, after 5 minutes rest in supine position at Visits 
2 and 4. Absolute values and change from Baseline will be analysed. 
Body temperature and weight will be recorded. 
8.5 
Histological examination of colonic biopsy 
Should any macroscopic lesions suspected by the investigator to be induced by colonic lavage, 
the histological examination of the biopsies will be described and recorded as a TEAE. 
8.6 
Symptom Scale 
This scale will be completed by the subject/caregiver at Visit 1, after treatment intake 
(Table 11). Subjects/caregivers will rate their overall experience of stomach cramping, stomach 
bloating and nausea on a 5-point scale, with 1=no symptoms, 2=mild, 3=bothersome, 
4=distressing and 5=severely distressing symptoms. Symptoms rated from mild (2) to severely 
distressing (5) must be reported as an AE. 
Table 11 Symptom Scale 
 
Overall experience on 5-point scale 
Symptom 
1=no symptoms 
2=mild 
3=bothersome 
4=distressing 
5=severely 
distressing 
Stomach cramping 
 
 
 
 
 
Stomach bloating 
 
 
 
 
 
Nausea 
 
 
 
 
 
 


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9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
Pharmacokinetics and pharmacodynamics are not assessed in this study. 


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10 
STATISTICS 
10.1 
Analyses Populations 
The following population will be used during statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent). 
• 
Safety population: All randomised subjects with at least a partial dose of study 
medication. Subjects will be assessed according to the treatment received. 
• 
Intention to treat (ITT) population: All randomised subjects who received even a 
partial dose of study drug. Subjects will be assessed according to their randomised 
treatment, regardless of the treatment they receive. 
• 
Modified Intention to treat Analysis Set (mITT): All randomised subjects who 
received even a partial dose of study treatment and produced a primary efficacy 
assessment. 
• 
Per protocol (PP) population: All subjects in the ITT population, who have undergone 
the colonoscopy procedure and for whom no major protocol violations/deviations 
occurred. 
10.1.1 
Populations Analysed 
The primary analysis based on the primary efficacy endpoint will be performed on the mITT 
population. In that analysis, subjects who do not undergo colonoscopy because of inadequate 
preparation or preparation-related AEs will be considered as failures. In addition, robustness of 
primary efficacy results will be assessed by repeating the primary analysis on the PP population. 
The analyses of safety data will be performed based on the safety population.  
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses 
Any major protocol deviation will be described in the Protocol Deviation Document (PDD) and 
its impact on inclusion in each analysis population (mITT/PP population) for any subject will 
be specified. The final list of protocol deviations impacting the mITT/PP population will be 
reviewed during the data review meeting held prior to database lock. The list will be updated 
to include any additional major protocol deviations impacting inclusion in the PP population. 
10.2 
Sample Size Determination 
The primary aim of the study is to show that Eziclen®/Izinova® is not inferior to Klean-Prep® 
in the proportion of subjects with successful colon cleansing. 
A non-inferiority margin of 15% has been selected for consistency with other studies in colon 
cleansing preparations.  
Therefore assuming a success rate (excellent or good response) of 85% in both the 
Eziclen®/Izinova® and Klean-Prep® groups, a one-sided alpha of 0.025 and 90% power, 
120 subjects are required per treatment group. Assuming a rate dropout/non-compliance to 
protocol of 4% based on previous studies and taking into account that subjects will be 
hospitalised for treatment administration, 125 subjects will be randomised in each treatment 
group, i.e. 250 subjects in total. Enrolment will be completed once 250 subjects have been 
randomised. 
The primary endpoint of treatment success will be tested sequentially (hierarchical structure) 
with the first test being non-inferiority test based upon the treatment difference. A rejection of 
the null hypothesis will trigger superiority testing based upon the treatment difference. 


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The two hypothesis tests are hierarchically structured so that the second test (superiority) will 
only be considered if the first test (non-inferiority) is rejected. The superiority test is powered 
to detect an absolute difference of 18%. There is no alpha adjustment for the second test as a 
result of the hierarchical testing. 
10.3 
Significance Testing and Estimations 
The primary endpoint of treatment success will be tested sequentially with the first test being 
non-inferiority test based upon the treatment difference. 
A two-sided 95% CI for the difference of the two clinical success rates (Eziclen®/Izinova® 
minus Klean-Prep®) will be calculated. If and only if the lower limit of the CI is greater than 
the lower limit of equivalence region -15%, Eziclen®/Izinova® is proven to be not less 
effective than Klean-Prep®.  
A rejection of the null hypothesis will trigger superiority testing based upon treatment 
difference. If the lower limit of the CI is greater than zero, Eziclen®/Izinova® is proven to be 
superior to Klean-Prep®. 
10.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s Biometry 
Department. 
A statistical and analysis plan (SAP) describing the planned statistical analysis in detail with 
tables, figures and listings templates will be developed as a separate document. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® (version 9.2 
or higher). 
10.4.1 
Demographic and Other Baseline Characteristics 
In order to ensure balance of treatment groups, descriptive summary statistics (n, mean, 
standard deviation (SD), median, minimum, maximum) or frequency counts of demographic 
and baseline data (medical history, prior medications and prior non-drug therapy, etc.) will be 
presented by treatment group and overall for the ITT, mITT and PP populations if they differ 
by more than 10%.  
10.4.2 
Homogeneity of Treatment Groups 
In order to assess the homogeneity of treatment groups at Baseline, descriptive statistics and 
other baseline characteristics will be tabulated for each treatment group along with 95% CI.  
10.4.3 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in each of the ITT, mITT, PP 
and safety populations will be tabulated by country and centre. The reasons for subject 
exclusions from each of the populations will also be tabulated. In addition, the numbers of 
subjects who were randomised, discontinued and completed at each of the study periods (e.g. 
active follow-up) will be tabulated by treatment group. Primary reasons for discontinuation of 
study treatment will be tabulated. 
10.4.4 
Pharmacokinetic Data 
Not applicable. 


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10.4.5 
Efficacy Evaluation 
As indicated in Section 7.1, the primary efficacy variable is the proportion of subjects with 
successful overall preparation evaluated with the scale (from 1 to 4) of the Cleansing Score as 
assessed by the colonoscopist.  
A successful preparation will be defined as excellent (4) or good (3) preparation. 
A failure preparation will be defined as: 
• 
Fair (2) or poor (1) according to bowel cleansing  
• 
Any subject who did not have a colonoscopy based on the investigator’s assessment of 
the cleansing (insufficient faecal output, unclear faecal discharge, etc.) or due to 
preparation related AEs. 
• 
Any subject for whom cleaning was not adequate for evaluation. 
• 
Any subject for whom rescue treatment (saline enema) was needed. 
The proportion of subjects with successful colon cleansing (graded as excellent or good) will 
be summarised along with the 95% confidence interval (CI) using the standard Wald asymptotic 
CI. The primary efficacy endpoint will be analysed using a logistics regression model including 
country as stratified variable, the interaction between country and treatment will be also 
investigated. The formal hypothesis test result (p-value) for treatment difference will be 
presented together with a two-sided 95% CI for the difference in success rates. The non-
inferiority will be demonstrated if the lower limit of the 95% CI of that difference is higher than 
-15%.  
If the non-inferiority is demonstrated, the superiority will be analysed based upon treatment 
difference. If the lower limit of the CI is greater than zero, Eziclen®/Izinova® is proven to be 
superior to the Klean-Prep®. 
Secondary efficacy endpoints are presented in Section 7.2. 
Results will be tabulated by treatment group and overall using descriptive summary statistics 
(mean SD, median, interquartiles and ranges) or frequency count with two-sided 95% CI when 
appropriate. 
Time to clear effluent data will be analysed by using survival methods. The results will be 
presented both in summary tables (number of events, censors, median and interquartile time to 
event with 95% CI…) and graphically in Kaplan-Meier plots by treatment group and overall. 
This will be detailed in the SAP. 
Other secondary endpoints will be analysed using Cochran-Mantel-Hænszel (CMH) chi-square 
for count (percentage) adjusting for country effect and two-way analysis of variance (ANOVA) 
for continuous parameters including treatment, country and their interaction as covariates. 
10.4.6 
Adjustment for Country/Centre Effect 
An adjustment for country effect will be planned for the analysis of primary efficacy by country 
as covariates.  
Descriptive analysis by country will be carried out. 
10.4.7 
Safety Evaluation 
All safety data will be included in the subject data listings. Analyses and summary tables will 
be based upon the safety population. 


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All AEs will be coded according to the MedDRA and will be classified by MedDRA preferred 
term and system organ class. AE listings will be presented by subject, system organ class and 
preferred term. 
Incidence of all reported TEAE and SAEs will be tabulated by treatment group and overall. In 
addition, summary tables will be presented by maximum intensity, drug relationship and 
AEs/TEAEs associated with premature withdrawal of study medication. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
It was not present prior to receiving the first dose of IMP, or  
• 
It was present prior to receiving the first dose of IMP but the intensity increased during 
the active phase of the study.  
All TEAEs will be flagged in the AEs listings. 
Concomitant medication will be coded by using World Health Organisation (WHO) Drug 
Dictionary and will be summarised by treatment group and overall with the number and 
percentage of subjects receiving concomitant medication by drug class and preferred drug 
name. 
Summary statistics (mean, median, SD and range as appropriate) by treatment group and overall 
will be presented for vital signs, BP, HR, clinical laboratory tests (blood and urine sample), 
physical examination, etc. at each assessment with change from Baseline. For laboratory data, 
abnormal values will be flagged in the data listings and a list of clinically significant abnormal 
values will be presented. Shift tables will be presented of the number and percentage of subjects 
with low, normal or high values and normal or abnormal exams. 
Frequency count with two-sided 95%CI when appropriate by treatment group and by overall 
will be presented for symptom questionnaire data (stomach cramping, stomach bloating and 
nausea) on a 5-point scale (see Table 11). 
10.5 
Subgroup Analyses 
Descriptive statistics for primary endpoint may be provided per country. 
10.6 
Interim Analyses 
No interim analysis will be performed. 
An Expert Committee chaired by the principal investigator will review safety data. This review 
will be performed during blind data review meetings. Full details of the operating model for 
this safety data review will be provided in a charter to be produced. 
 


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


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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Protocol Amendments and Protocol Deviations and Violations 
12.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favourable opinion of a written amendment by the IEC/IRB, except when necessary 
to eliminate immediate safety concerns to the subjects or when the change involves only 
logistics or administration. The principal investigator and the sponsor will sign the protocol 
amendment. 
12.1.2 
Protocol Deviations, Violations and Exceptions 
A protocol deviation is nonadherence to protocol specific study procedures or schedules that 
does not involve inclusion/exclusion criteria, primary objective evaluation criteria, and/or GCP 
guidelines. Deviations are considered minor and do not impact the study. 
A protocol violation is any significant divergence from the protocol, i.e. nonadherence on the 
part of the subject, the investigator, or the sponsor to protocol specific inclusion/exclusion 
criteria, primary objective evaluation criteria and/or GCP guidelines. Protocol violations will 
be identified and recorded, by study centre personnel, on the eCRF. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific entry criteria to 
allow subjects to enter a study. If under extraordinary circumstances such action is considered 
ethically, medically and scientifically justified for a particular subject, prior approval from the 
sponsor and the responsible IRB/IEC, in accordance with the Standard Operating Procedure 
(SOP), is required before the subject will be allowed to enter the study. If investigative centre 
personnel learn that a subject who did not meet protocol eligibility criteria was entered in a 
study (a protocol violation), they must immediately inform the sponsor. Such subjects will be 
discontinued from the study, except in an exceptional instance following review and written 
approval by the sponsor and the responsible IRB/IEC, according to the applicable SOP. 
12.2 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of subject management, both before starting any study 
procedures and during the course of the study (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 study centre authorisation form, which includes a clear description of each staff member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
12.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring this data to verify that the rights and wellbeing of 
subjects are protected, that study data are accurate (complete and verifiable to source data) and 
that the study is conducted in compliance with the protocol, GCP and regulatory requirements. 
Sponsor assigned monitors will conduct regular site visits. The investigator will allow direct 
access to all relevant files (for all subjects) and clinical study supplies (dispensing and storage 


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


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13 
ETHICS 
13.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, the 
Declaration of Helsinki and ICH GCP Guidelines (Section 1.6). 
The FDA, 21 CFR Part 11, Electronic Records, Electronic Signatures and FDA, Guidance for 
Industry: Computerised Systems Used in Clinical Trials are a regulations which provides 
criteria for acceptance by the FDA, under certain circumstances, of electronic records, e-
signatures and hand-written signatures executed to electronic records as equivalent to paper 
records and hand-written signatures on paper. 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
ICF, assent form, any consent or assent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided to 
subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has started, 
amendments should be made only in exceptional circumstances. Changes that do not affect 
subject safety or data integrity are classified as administrative changes and generally do not 
require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
13.2 
Informed Consent and Assent 
Prior to study entry, the investigator, or a person designated by the investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject, subject’s 
legally acceptable representative or impartial witness. Written informed consent must be 
obtained prior to the subject entering the study (before initiation of any study-related procedure 
and administration of the IMP) from the subject’s parent(s)/legal representative and an assent 
from the subject. Sufficient time will be allowed to discuss any questions raised by the subject 
and subject’s parent(s)/legal representative. 
The sponsor will provide a sample ICF and a sample assent. The both final versions controlled 
forms must be agreed to by the sponsor and the IEC/IRB and must contain all elements included 
in the sample forms, in language readily understood by the subject and parent(s)/legal 
representative. Each subject’s original consent form and assent form, personally signed and 
dated by the subject and by the subject’s legally acceptable representative, and by the person 
who conducted the informed consent discussion, will be retained by the investigator. The 
investigator will supply subjects and parent(s)/legal representative with a copy of their signed 
informed consent. 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject or as a result of protocol 
amendments. In this instance, approval should always be given by the IEC/IRB. It is the 
investigator’s responsibility to ensure that all subjects subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
previously described. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 


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


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14 
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Recording of Study Data 
In compliance with GCP, the medical records/medical notes, etc, should be clearly marked and 
permit easy identification of a subject’s participation in the specified clinical study. 
The investigator must record all data relating to protocol procedures, laboratory data, safety 
data and efficacy ratings on the eCRFs provided for the study. The investigator, by completing 
the signature log, may formally designate authority to complete eCRFs to appropriately 
qualified staff having certified user access to the eCRF. Subject/caregiver completed 
questionnaires will be printed. 
The unblinded personnel must record all the data relating to IMP administration and subject’s 
leaflet questionnaire. 
 
The investigator must, as a minimum, provide an electronic signature (e-signature) to each case 
report book to attest to the accuracy and completeness of all the data. If any changes are made 
to the eCRF, after a form has been locked and electronically signed, the investigator will be 
required to perform an additional e-signature authorising agreement with any new information 
or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on each 
item entered. 
14.2 
Data Management 
14.2.1 
eCRF 
Electronic Data Capture (EDC) will be utilised for collecting subject data. Each site is required 
to have a computer and internet connection available for site entry of clinical data. All entries 
in the eCRF will be done under the electronic signature of the person performing the action. This 
electronic signature consists of an individual and confidential username and password 
combination. It is declared to be the legally binding equivalent of the handwritten signature. Only 
sponsor authorised users will have access to the eCRF as appropriate to their study responsibilities. 
Users must have successfully undergone software application training prior to entering data into 
the eCRF. 
Data management will be conducted by a CRO, directed by the sponsor’s data management 
department. All data management procedures will be completed in accordance with the sponsor 
and the contracted CRO SOPs. Prior to data being received in-house at the assigned CRO, it will 
be monitored at the investigator site, (for further details please see Section 12.3 Monitoring 
Procedures). The eCRF and other data documentation removed from the investigator site(s) will 
be tracked by the CRO and the monitor. 
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately, and 
suitable queries are raised to resolve any missing or inconsistent data. The investigator will receive 
their data, from the clinical study, in an electronic format (PDF files) which will be an exact copy 
of the eCRF, and will include the full audit trail, for archiving purposes and future reference. 
Any queries generated during the data management process will also be tracked by the contracted 
data management CRO/will be raised within the EDC system. It is the central study monitor’s 
responsibility to ensure that all queries are resolved by the relevant parties. 


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The sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history and any medical terms (e.g. concomitant non-drug therapy, 
concomitant surgeries) will be performed by the CRO, directed by the sponsor’s Biometry Group, 
and reviewed and approved by the sponsor. Concomitant medications will be coded using 
WHODRUG and AEs/medical history terms will be coded using MedDRA. 
Each subject will be identified with a unique subject identification number. All study documents 
related to a subject will be identified with this subject number. 
Subject’s leaflet where all information with regards to treatment Administration questionnaire, 
Information about subject’s bowel movement, Treatment Acceptability Questionnaire and 
Symptoms Scale completed by the subject/caregiver will be single-entered by unblinded 
personnel at the Investigational site in the eCRF put in place by the sponsor. The principal 
investigator will ensure that these data are complete and accurately represent the study subject 
information by electronically signing the e-CRF.  
 
Subject’s leaflet where all information with regards to treatment administration questionnaire 
will be used to enter some (summary) data in e-CRF by the authorised staff at the investigational 
site in the e-CRF. 
14.2.2 
Subject/Caregiver Leaflet/Questionnaires 
After randomisation at Visit 1 the subject will be provided with: 
- Either the Eziclen®/Izinova® leaflet 
- Or the Klean-Prep® leaflet 
 
The subject’s leaflet will be printed on single copy paper and provided to the principal 
investigator/study nurse who will file it in the subject’s medical/study file 
 
The leaflet will contain: 
• 
Section 1: for Dose 1 
a) 
The Treatment administration questionnaire for Dose 1 
b) 
The Treatment Acceptability Questionnaire after Dose 1 
c) 
Symptoms Scale 
 
• 
Section 2: for Dose 2 
a) 
The Treatment administration questionnaire for Dose 2 
b) 
The Treatment Acceptability Questionnaire after Dose 2 
c) 
Symptoms Scale 
 
• 
Section 3: after preparation intake but before colonoscopy 
Questions to subject: 
• 
Information about bowel movement (Time of first bowel movement, Time of first clear 
watery stool, Did you wake up during the night to have a bowel movement?). 
• 
If it was necessary, would you agree to undergo preparation with this product again? 


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14.3 
Record Archiving and Retention 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed by 
the monitor when closing out the site. The sponsor will inform the investigator, in writing, as to 
when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 


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


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


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17 
REFERENCES 
1. 
Hunter A, Mamula P. Bowel preparation for pediatric colonoscopy procedures. J Pediatr 
Gastroenterol Nut. 2010;51 (3):254-61 
2. 
Rembacken B, Hassan C, Riemann JF et al. Quality in screening colonoscopy: position 
statement of the European Society of Gastrointestinal Endoscopy (ESGE). Endoscopy 
2012; 44(10):957-68 
3. 
Florin T, Neale G, Gibson GR et al. Metabolism of dietary sulphate: absorption and 
excretion in humans. Gut. 1991;32(7):766-73 
4. 
Cocchetto DM, Levy G. Absorption of orally administered sodium sulfate in humans. J 
Pharm Sci. 1981;70(3):331-3 
5. 
Di Palma JA, Rodriguez R, McGowan J et al. A randomized clinical study evaluating the 
safety and efficacy of a new, reduced-volume, oral sulfate colon-cleansing preparation 
for colonoscopy. Am J Gastroenterol. 2009;104:2275-84 
6. 
Rex DK, Di Palma JA, Rodriguez R et al. A randomized clinical study comparing 
reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage 
solution as preparation for colonoscopy. Gastrointest Endosc. 2010;72:328-336 
7. 
Bitoun A, Ponchon T, Barthet M, Coffins B, Dugue C, Halphen M:  Results of a 
prospective randomized multicenter controlled trial comparing a new 2-L ascorbic acid 
plus polyethylene glycol and electrolyte solution vs. sodium phosphate solution in 
patients undergoing elective colonoscopy.  Aliment Pharmacol Ther. 2006;24:1631-42 
8. 
Eziclen®/Izinova® Investigator brochure 
9. 
Braintree protocol of Study 006-181. A comparison of the safety and efficacy of BLI800 
oral sulfate solution to Fleet EZ-Prep and NuLYTELY in normal volunteers. Study 
initiated on 11 June 2006 and completed on 05 February 2007. Final Study report from 
28 April 2008 published in EDMS on 07 July 2011 
10. 
Hardwick LL, Jones MR, Brautbar N et al. Magnesium absorption: mechanisms and the 
influence of vitamin D, calcium and phosphate. J Nutr. 1991;121(1):13-23 
11. 
Rex DK, DiPalma JA, McGowan J et al. A comparison of oral sulfate solution with 
sodium picosulfate: magnesium citrate in split doses as bowel preparation for 
colonoscopy. Gastrointest Endosc 2014;1-11 
12. 
Klean-Prep® Summary of Product Characteristics 
13. 
Schwartz GJ and Work DF. Measurement and Estimation of GFR in Children and 
Adolescents. Clin J Am Soc Nephrol. 2009; 4: 1832–1843 
14. 
Calderwood AH, Jacobson BC. Comprehensive validation of the Boston Bowel 
Preparation Scale. Gastrointest Endosc. 2010; 72(4): 686-92 
15. 
Lai EJ, Calderwood AH, Doros G et al. The Boston Bowel Preparation Scale: A valid 
and reliable instrument for colonoscopy-oriented research. Gastrointest Endosc. 
2009;69(32):620–25 
 


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18 
LIST OF APPENDICES 
Appendix 1 Protocol Amendment #1 ....................................................................... 72 
Appendix 2 Protocol Amendment #2 ....................................................................... 80 
Appendix 3 Protocol Amendment #3 ....................................................................... 83 
Appendix 4 Protocol Amendment #4 ....................................................................... 85 
Appendix 5 Protocol Amendment #5 ....................................................................... 91 
Appendix 6 Protocol Amendment #6 ....................................................................... 99 
 


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Appendix 1 Protocol Amendment #1 
 
STUDY NUMBER: 
F-FR-58800-003 
PROTOCOL TITLE: 
Efficacy, Safety and Tolerability of a Bowel 
Cleansing Preparation (Eziclen®/Izinova®) in 
Paediatric Subjects Undergoing Colonoscopy: a 
Phase III, Multicentre, Randomised, 
Comparative Study Versus Klean-Prep® (PEG-
Electrolytes), Administered on the Day Before 
Colonoscopy, Investigator-Blinded, Non-
Inferiority in Adolescents of 12 to 17 Years of 
Age (Inclusive) ≥40 Kg. 
OLD PROTOCOL VERSION NUMBER & 
DATE 
 
Final Version: 12 August 2016 
NEWAMENDED PROTOCOL VERSION 
NUMBER & DATE 
 
Final Version 2.0 (including Amendment 1): 13 
January 2017 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: 
Version Date 
12 August 2016 
13 January 2017 
Page  
Section 
WAS 
IS 


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1 
Front 
page 
Efficacy, Safety and Tolerability of 
a Bowel Cleansing Preparation 
(Eziclen®/ Izinova®) in Paediatric 
Subjects Undergoing Colonoscopy: 
a Phase III, Multicentre, 
Randomised, Comparative Study 
Versus Klean-Prep® (PEG-
Electrolytes), Administered on the 
Day Before Colonoscopy, 
Investigator-Blinded, Non-
Inferiority in Adolescents of 12 to 
17 Years of Age (Inclusive) ≥40 
Kg. 
Efficacy, Safety and Tolerability of a 
Bowel Cleansing Preparation 
(Eziclen®/Izinova®) in Paediatric 
Subjects Undergoing Colonoscopy: a 
Phase III, Multicentre, Randomised, 
Comparative Study Versus Klean-
Prep® (PEG-Electrolytes), 
Administered on the Day Before 
Colonoscopy, Investigator-Blinded, 
Non-Inferiority in Adolescents of 12 to 
17 Years of Age (Inclusive) >40 Kg. 
1 
Front 
page 
Pharmacovigilance/Emergency 
Contact: 
 
 
Pharmacovigilance/Emergency 
Contact: 
 
 
 
 
 
5 
Synopsis 
– Title of 
the study 
Title of study: Efficacy, safety and 
tolerability of a bowel cleansing 
preparation 
(Eziclen/Izinova®) in paediatric 
subjects undergoing colonoscopy: a 
Phase III, multicentre, randomised, 
comparative versus Klean-Prep® 
(PEG-Electrolytes), administered 
on the day 
before colonoscopy, investigator-
blinded, non-inferiority study in 
adolescents of 12 to 17 years of age 
(inclusive) Ӌ40 kg. 
Title of study: Efficacy, safety and 
tolerability of a bowel cleansing 
preparation 
(Eziclen/Izinova®) in paediatric 
subjects undergoing colonoscopy: a 
Phase III, multicentre, randomised, 
comparative versus Klean-Prep® 
(PEG-Electrolytes), administered on 
the day before colonoscopy, 
investigator-blinded, non-inferiority 
study in adolescents of 12 to 17 years 
of age (inclusive) >40 kg. 
5 
Synopsis 
- 
Objective
s 
Primary objective: 
To demonstrate that 
Eziclen®/Izinova®, an osmotic 
sulphate-based laxative preparation 
given on the day before 
colonoscopy has non-inferior 
efficacy to Klean-Prep® 
(polyethylene glycol (PEG)-
electrolytes) on colon cleansing in 
adolescents aged 12 to 17 years 
(inclusive) with a body weight ≥ 40 
kg, scheduled to undergo a 
colonoscopy for a routinely 
accepted diagnostic indication 
Primary objective: 
To demonstrate that 
Eziclen®/Izinova®, an osmotic 
sulphate-based laxative preparation 
given on the day before colonoscopy 
has non-inferior efficacy to Klean-
Prep® 
(polyethylene glycol (PEG)-
electrolytes) on colon cleansing in 
adolescents aged 12 to 17 years 
(inclusive) with a body weight >40 kg, 
scheduled to undergo a colonoscopy 
for a routinely accepted diagnostic 
indication 
PPD
PPD


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5 
Synopsis 
- 
Methodol
ogy 
In adolescents (male and female) 
≥40 kg with routine indication for 
colonoscopy 
In adolescents (male and female)  
> 40 kg with routine indication for 
colonoscopy 
6 
Synopsis 
- 
Inclusion 
criteria 
(3) Body weight more than or equal 
to 40 kg 
(3) Body weight more than 40 kg 
6 
Synopsis 
- 
Exclusion 
criteria 
(1) Subject with known or 
suspected ileus, gastrointestinal 
obstruction, gastric retention 
(gastroparesis), rectal impaction, 
toxic colitis, severe ulcerative 
colitis or toxic megacolon, 
swallowing disorders 
(1) Subject with known or suspected 
ileus, gastrointestinal obstruction, 
gastric retention 
(gastroparesis), rectal impaction, toxic 
colitis, severe ulcerative colitis or toxic 
megacolon, advanced carcinoma, 
swallowing disorders 
6 
Synopsis 
- 
Exclusion 
criteria 
(5) Subject with uncontrolled pre-
existing electrolyte abnormalities, 
or with electrolyte 
abnormalities based on Visit 1 
laboratory results such as 
hypernatremia, hyponatremia, 
hyperphosphatemia, hypokalaemia, 
hypocalcaemia, uncorrected 
dehydration, or secondary to the 
use of diuretics or angiotensin 
converting enzyme (ACE) 
inhibitors judged clinically 
significant by the investigator 
(5) Subject with uncontrolled pre-
existing electrolyte abnormalities, or 
with electrolyte 
abnormalities based on Visit 1 
laboratory results such as 
hypernatremia, hyponatremia, 
hyperphosphatemia, hypokalaemia, 
hypocalcaemia, uncorrected 
dehydration, or secondary to the use of 
medications such as diuretics or 
angiotensin converting enzyme (ACE) 
inhibitors judged clinically significant 
by the investigator 
6 
Synopsis 
- 
Exclusion 
criteria 
(6) Subject with a prior history or 
current condition of severe renal 
(estimated 
glomerular filtration rate (GFR) 
less than 30 mL/min/1.73 m2), liver 
(Child-Pugh C) 
or cardiac insufficiency (including 
congestive heart failure grade III 
and IV) 
(6) Subject with a prior history or 
current condition of severe renal 
(estimated glomerular filtration rate 
(GFR) less than 30 mL/min/1.73 m2), 
liver (ascites, Child-Pugh C),  
cardiac insufficiency (including 
congestive heart failure all grades) or 
hyperuricemia 
7 
Synopsis 
- 
Exclusion 
criteria 
(10) Subject with history of 
hypersensitivity to any ingredient 
of either drug product 
(10) Subject with history of asthma or 
hypersensitivity to any ingredient of 
either drug product 


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11-12 
Synopsis 
- 
Schedule 
of 
procedure 
and 
assessmen
ts 
Table “Schedule of procedure and 
assessments” 
Urine pregnancy Test 
 
Footnote: 
[a] If applicable 
Table “Schedule of procedure and 
assessments” 
Blood pregnancy test 
 
Footnote: 
[a] If applicable. Urine pregnancy test 
will be performed only when blood tests 
including pregnancy have been 
performed prior to Visit 1. 
(…) 
[h] Laboratory assessments performed 
within 10 days or less prior to inclusion 
may be used to determine eligibility 
upon investigator review and agreement 
25 
1.7 
Populatio
n to Be 
Studied 
The study will enrol adolescents 
aged 12 to 17 years (inclusive), 
with body weight ≥ 40 kg, 
scheduled to undergo colonoscopy 
for a routine indication. 
The study will enrol adolescents aged 
12 to 17 years (inclusive), with body 
weight > 40 kg, scheduled to undergo 
colonoscopy for a routine indication. 
26 
2.1 
Purpose 
of 
the 
Study 
The purpose of the present study is 
to compare the efficacy, safety and 
tolerability of Eziclen®/Izinova® 
to those of Klean-Prep® in 
adolescents aged 12 to 17 years 
(inclusive) with body weight ≥40 
kg scheduled to undergo a 
colonoscopy for a routinely 
accepted indication 
The purpose of the present study is to 
compare the efficacy, safety and 
tolerability of Eziclen®/Izinova® to 
those of Klean-Prep® in adolescents 
aged 12 to 17 years (inclusive) with 
body weight > 40 kg scheduled to 
undergo a colonoscopy for a routinely 
accepted indication 
26 
2.2.1 
Primary 
Objective 
The primary objective of the study 
is to demonstrate that 
Eziclen®/Izinova®, an osmotic 
sulphate-based laxative preparation 
given on the day before 
colonoscopy has non-inferior 
efficacy to Klean-Prep® (PEG-
electrolytes) on colon cleansing in 
adolescents aged 12 to 17 years 
(inclusive) with a body weight ≥40 
kg, scheduled to undergo a 
colonoscopy for a routinely 
accepted diagnostic indication. 
The primary objective of the study is 
to demonstrate that 
Eziclen®/Izinova®, an osmotic 
sulphate-based laxative preparation 
given on the day before colonoscopy 
has non-inferior efficacy to Klean-
Prep® (PEG-electrolytes) on colon 
cleansing in adolescents aged 12 to 17 
years (inclusive) with a body weight 
>40 kg, scheduled to undergo a 
colonoscopy for a routinely accepted 
diagnostic indication. 
27 
3.1 
General 
Design 
and Study 
Schema 
This is a multicentre, investigator-
blinded, randomised phase III 
comparative study conducted in 
adolescents (male and female) ≥40 
kg 
This is a multicentre, investigator-
blinded, randomised phase III 
comparative study conducted in 
adolescents (male and female) >40 kg 


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31 
3.6 
Stopping 
Rules and 
Discontin
uation 
Criteria 
There are no formal rules for early 
termination of this study. During 
the conduct of the study, SAEs will 
be reviewed (see Section 8.1.4) as 
they are reported from the study 
centre to identify safety concerns 
There are no formal rules for early 
termination of this study. During the 
conduct of the study, SAEs will be 
reviewed (see Section 8.1.4) as they 
are reported from the study centre to 
identify safety concerns. An Expert 
Committee will be appointed to 
review safety data. This Expert 
Committee will be chaired by the 
principal investigator. Full details of 
the operating model for this safety 
data review will be provided in a 
charter to be produced. 
34 
4.1 
Inclusion 
Criteria 
3) Body weight more than or equal 
to 40 kg 
3) Body weight more than 40 kg 
34 
4.2 
Exclusion 
Criteria 
(1) Subject with known or 
suspected ileus, gastrointestinal 
obstruction, gastric retention 
(gastroparesis), rectal impaction, 
toxic colitis, severe ulcerative 
colitis or toxic megacolon, 
swallowing disorders 
(1) Subject with known or suspected 
ileus, gastrointestinal obstruction, 
gastric retention 
(gastroparesis), rectal impaction, toxic 
colitis, severe ulcerative colitis or toxic 
megacolon, advanced carcinoma, 
swallowing disorders 
34 
4.2 
Exclusion 
criteria 
(5) Subject with uncontrolled pre-
existing electrolyte abnormalities, 
or with electrolyte 
abnormalities based on Visit 1 
laboratory results such as 
hypernatremia, hyponatremia, 
hyperphosphatemia, hypokalaemia, 
hypocalcaemia, uncorrected 
dehydration, or secondary to the 
use of diuretics or angiotensin 
converting enzyme (ACE) 
inhibitors judged clinically 
significant by the investigator 
(5) Subject with uncontrolled pre-
existing electrolyte abnormalities, or 
with electrolyte 
abnormalities based on Visit 1 
laboratory results such as 
hypernatremia, hyponatremia, 
hyperphosphatemia, hypokalaemia, 
hypocalcaemia, uncorrected 
dehydration, or secondary to the use of 
medications such as diuretics or 
angiotensin converting enzyme (ACE) 
inhibitors judged clinically significant 
by the investigator 
34 
4.2. 
Exclusion 
criteria 
(6) Subject with a prior history or 
current condition of severe renal 
(estimated 
glomerular filtration rate (GFR) 
less than 30 mL/min/1.73 m2), liver 
(Child-Pugh C) 
or cardiac insufficiency (including 
congestive heart failure grade III 
and IV) 
(6) Subject with a prior history or 
current condition of severe renal 
(estimated glomerular filtration rate 
(GFR) less than 30 mL/min/1.73 m2), 
liver (ascites, Child-Pugh C),  
cardiac insufficiency (including 
congestive heart failure all grades) or 
hyperuricemia 


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35 
4.2. 
Exclusion 
criteria 
(10) Subject with history of 
hypersensitivity to any ingredient 
of either drug product 
(10) Subject with history of asthma or 
hypersensitivity to any ingredient of 
either drug product 
36 
5.1. Study 
Schedule 
Table4 
Urine pregnancy Test 
Table4 
Blood pregnancy test 
37 
5.1. Study 
Schedule 
Table 4 
Footnote: 
[a] If applicable.  
 
Table 4 
Footnote: 
[a] If applicable. Urine pregnancy test 
will be performed only when blood tests 
including pregnancy have been 
performed prior to Visit 1. 
(…) 
[h] Laboratory assessments performed 
10 days or less prior to inclusion may be 
used to determine eligibility upon 
investigator review and agreement 
38 
5.2.2 
Baseline/
Treatment 
visit 
(Visit 1) 
Blood sampling: 
 
 
 
 
a) Haematology: CBC 
b) biochemistry including: anion 
gap, ALT, AST, CPK, LDH, GGT, 
total and conjugated 
bilirubin, albumin, creatinine, urea, 
serum electrolytes (sodium, 
potassium, chloride, 
calcium, magnesium, phosphorus, 
bicarbonate), alkaline phosphatase, 
total protein, 
CRP, uric acid, international 
normalised ratio (INR), creatinine 
clearance (calculated 
GFR), osmolality 
Blood sampling: Laboratory 
assessments performed within 10 
days or less prior to inclusion may 
be used to determine eligibility upon 
investigator agreement 
a) Haematology: CBC 
b) biochemistry including: anion gap, 
ALT, AST, CPK, LDH, GGT, total 
and conjugated 
bilirubin, albumin, creatinine, urea, 
serum electrolytes (sodium, potassium, 
chloride, 
calcium, magnesium, phosphorus, 
bicarbonate), alkaline phosphatase, 
total protein, 
CRP, uric acid, international 
normalised ratio (INR), creatinine 
clearance (calculated 
GFR), osmolality 
 
39 
5.2.2 
Baseline/t
reatment 
visit 
Urine pregnancy test, if female of 
child-bearing potential 
Blood pregnancy test, if female of 
child-bearing potential. Urine 
pregnancy test will be performed 
only when blood tests including 
pregnancy have been performed 
prior to Visit 1.  


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43 
6.2  Prior 
and 
Concomit
ant 
Medicatio
n and 
Non-drug 
/Therapy 
… may be particularly affected. 
… may be particularly affected. 
Caution is advised in subjects with 
conditions, or who are using 
medications, inducing fluid or 
electrolyte disturbances, such as 
angiotensin converting enzyme 
inhibitors, calcium channel blockers, 
diuretics, lithium treatment, or other 
medications that might affect 
electrolyte levels. Caution is also 
advised when taking medicines 
known to prolong the QT interval.  
48 
8.1.3 
Recording 
and 
Follow-up 
of 
Adverse 
Events 
Follow-up is required until the 
event or its sequelae resolve or 
stabilise at a level acceptable to the 
investigator and the sponsor’s 
clinical monitor or his/her 
designated representative. 
Follow-up, that will include medical 
care, is required until the event or its 
sequelae resolve or stabilise at a level 
acceptable to the investigator and the 
sponsor’s clinical monitor or his/her 
designated representative. 
52 
8.2.4 
Pregnanc
y test 
A urine pregnancy test (…). 
A blood pregnancy test (…). Urine 
pregnancy test will be performed 
only when blood tests including 
pregnancy have been performed 
prior to Visit 1.  
57 
10.6 
Interim 
Analyses 
No interim analysis will be 
performed. 
No interim analysis will be performed. 
An Expert Committee chaired by the 
principal investigator will review 
safety data. This review will be 
performed 
during 
data 
review 
meetings. Full details of the operating 
model for this safety data review will 
be provided in a charter to be 
produced. 
 
SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-58800-003 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Final Version 2.0 (including Amendment 1): 13 January 2017 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
Request of ANSM on Inclusion/Exclusion criteria, addition of 
information regarding safety data review.  
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 


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CONFIDENTIAL 
 
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PAGE 79/103 
 
 
 
LOCAL CONSENT FORM UPDATE  
Yes 
  
No 
   
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
No 
 
(tick one) 
 
STATISTICAL & ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
No 
 
 
 
(tick one) 
 


IPSEN GROUP 
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CONFIDENTIAL 
 
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PAGE 80/103 
 
 
Appendix 2 Protocol Amendment #2 
 
 
STUDY NUMBER: 
F-FR-58800-003 
PROTOCOL TITLE: 
Efficacy, Safety and Tolerability of a Bowel 
Cleansing Preparation (Eziclen®/Izinova®) in 
Paediatric Subjects Undergoing Colonoscopy: a 
Phase III, Multicentre, Randomised, 
Comparative Study Versus Klean-Prep® (PEG-
Electrolytes), Administered on the Day Before 
Colonoscopy, Investigator-Blinded, Non-
Inferiority in Adolescents of 12 to 17 Years of 
Age (Inclusive) >40 Kg. 
OLD PROTOCOL VERSION NUMBER & 
DATE 
Final Version 2.0 (including Amendment 1): 13 
January 2017 
NEWAMENDED PROTOCOL VERSION 
NUMBER & DATE 
Final Version 3.0 (including Amendment 2): 23 
March 2017 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: 
Version Date 
13 January 2017 
23 March 2017 
Page  
Section 
WAS 
IS 


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PAGE 81/103 
 
 
6 
Synopsis 
(6) Subject with a prior history or 
current condition of severe renal 
(estimated glomerular filtration rate 
(GFR) less than 30 mL/min/1.73 
m2), liver (ascites, Child- Pugh C), 
cardiac insufficiency (including 
congestive heart failure all grades) 
or hyperuricemia 
(6) Subject with a prior history or 
current condition of severe renal 
(estimated glomerular filtration rate 
(eGFR) less than 30 mL/min/1.73 m2 
as calculated by using the Schwartz 
bedside equation* [Schwartz et al, 
2009]**), liver (ascites, Child-Pugh 
C), cardiac insufficiency (including 
congestive heart failure all grades) or 
hyperuricemia 
*The estimated GFR will be calculated in 
patients with elevated creatinine at baseline. 
** Schwartz GJ and Work DF. 
Measurement and Estimation of GFR in 
Children and Adolescents. Clin J Am Soc 
Nephrol. 2009; 4: 1832–1843 
34 
4.2 
Exclusion 
criteria 
(6) Subject with a prior history or 
current condition of severe renal 
(estimated glomerular filtration rate 
(GFR) less than 30 mL/min/1.73 
m2), liver (ascites, Child-Pugh C), 
cardiac insufficiency (including 
congestive heart failure all grades) 
or hyperuricemia 
(6) Subject with a prior history or 
current condition of severe renal 
(estimated glomerular filtration rate 
(eGFR) less than 30 mL/min/1.73 m2 
as calculated by using the Schwartz 
bedside equation* [13], liver (ascites, 
Child-Pugh C), cardiac insufficiency 
(including congestive heart failure all 
grades) or hyperuricemia 
*The estimated GFR will be calculated in 
patients with elevated creatinine at baseline.  
69 
17 
Reference
s 
 
(13) Schwartz GJ and Work DF. 
Measurement and Estimation of 
GFR in Children and 
Adolescents. Clin J Am Soc 
Nephrol. 2009; 4: 1832–1843 
 
 


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CONFIDENTIAL 
 
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PAGE 82/103 
 
 
SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-58800-003 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Amendment 2 Final Version 3.0: 23 March 2017 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
Request of BfArM on Exclusion criteria, adding details of the 
method to calculate eGFR 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
  
No 
   
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
No 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN 
(RAP) UPDATE 
Yes 
 
No 
 
 
 
(tick one) 
 
 
 
 


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CONFIDENTIAL 
 
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PAGE 83/103 
 
 
Appendix 3 Protocol Amendment #3 
 
STUDY NUMBER: 
F-FR-58800-003 
PROTOCOL TITLE: 
Efficacy, Safety and Tolerability of a Bowel 
Cleansing Preparation (Eziclen®/Izinova®) in 
Paediatric Subjects Undergoing Colonoscopy: a 
Phase III, Multicentre, Randomised, 
Comparative Study Versus Klean-Prep® (PEG-
Electrolytes), Administered on the Day Before 
Colonoscopy, Investigator-Blinded, Non-
Inferiority in Adolescents of 12 to 17 Years of 
Age (Inclusive) >40 Kg. 
OLD AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Final Version 3.0 (including Amendment 2): 23 
March 2017 
NEW AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Final Version 4.0 (including Amendment 3): 17 July 
2017 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: 
Version Date 
23 MARCH 2017 
17 JULY 2017 
Page  
Section 
WAS 
IS 
5 
Planned 
study 
period 
From January 2017 to January 2018 
 
From Q4 2017 to Q4 2018 
 


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-58800-003 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Final Version 4.0 (including Amendment 3): 17 July 2017 
 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
To update the study timelines 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL & ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 
 


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Appendix 4 Protocol Amendment #4 
 


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CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 86/103 
 
 
 
STUDY NUMBER: 
F-FR-58800-003 
PROTOCOL TITLE: 
Efficacy, Safety and Tolerability of a Bowel 
Cleansing Preparation (Eziclen®/Izinova®) in 
Paediatric Subjects Undergoing Colonoscopy: a 
Phase III, Multicentre, Randomised, 
Comparative Study Versus Klean-Prep® (PEG-
Electrolytes), Administered on the Day Before 
Colonoscopy, Investigator-Blinded, Non-
Inferiority in Adolescents of 12 to 17 Years of 
Age (Inclusive) >40 Kg. 
OLD PROTOCOL VERSION 
NUMBER & DATE 
Final Version 4.0 (including Amendment #3): 
17 July 2017 
NEWAMENDED PROTOCOL 
VERSION NUMBER & DATE 
Final Version 5.0 (including Amendment #4): 
16 March 2018 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: 
Version Date 
17 July 2017 
16 March 2018 
Page  
Section 
WAS 
IS 
1 
Cover 
 
 
 
 
 
1 
Cover 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
2 
Signature 
page 
Sponsor's Representative Signature: 
 
 
 
 
 
 
 
 
65 quai Georges Gorse  
 
92100 
Boulogne-
Billancourt, France 
Sponsor's Representative Signature: 
 
 
 
 
 
 
 
 
 
 
65 quai Georges Gorse  
 
92100 Boulogne-Billancourt, 
France 
PPD
PPD
PPD
PPD
PPD
PPD


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9 
Synopsis-
Criteria for 
Evaluation 
Safety and tolerability 
• 
Collection of adverse events 
(AEs) (for up to 30 days 
following 
the 
day 
of 
colonoscopy) 
• 
Tolerability by a Symptom 
Scale 
after 
each 
dose 
of 
treatment. Subjects will rate 
their 
preparation 
related 
symptoms after intake (stomach 
cramping, stomach bloating and 
nausea) on a paediatric 5-point 
scale, 
ranging 
from 
1=no 
symptoms 
to 
5= 
severely 
distressing symptoms 
• 
Description 
and 
histological 
examination of any colonic 
biopsy specimens of mucosal 
lesions 
suspected 
by 
the 
investigator to have been caused 
by colonic lavage 
Safety and tolerability 
• 
Collection of adverse events (AEs) 
(for up to 30 days following the day 
of colonoscopy) 
- 
Diagnosis or diagnostic 
findings 
made 
at 
colonoscopy 
will 
be 
reported as such and will 
not be reported as AEs 
unless the investigator 
observes mucosal lesions 
that he/she suspects to be 
related or possibly related 
to the colonic lavage. Such 
lesions will be biopsied. In 
this 
situation 
only, 
description 
of 
the colonoscopy findings 
and 
histological 
examination results will 
be reported as AEs. 
• 
Tolerability by a Symptom Scale 
after each dose of treatment. 
Subjects will rate their preparation 
related symptoms after intake 
(stomach 
cramping, 
stomach 
bloating and nausea) on a paediatric 
5-point scale, ranging from 1=no 
symptoms 
to 
5= 
severely 
distressing symptoms 
12 
Synopsis-
Study 
procedure 
and 
Assessments 
Indication for Colonoscopy 
Colonoscopy efficacy 
assessment [n] 
[n] Colonoscopy assessment: 
Rescue treatment, cleansing Score, 
BBPS, start time of colonoscopy, 
time of 
caecal intubation, caecum reached, 
withdrawal time 
Indication(s) for Colonoscopy 
Colonoscopy  
assessment [n] 
[n] Colonoscopy assessment: Rescue 
treatment, cleansing Score, BBPS, start 
time of colonoscopy, time of 
caecal intubation, caecum reached, 
withdrawal time, diagnosis/findings 
(except if AE) 
29 
3.2.2.2. 
Safety and 
Tolerability 
Variables 
• 
Collection of adverse events 
(AEs) (for up to 30 days 
following 
the 
day 
of 
colonoscopy) 
• 
Tolerability by a Symptom 
Scale 
after 
each 
dose 
of 
treatment. Subjects will rate 
their 
preparation 
related 
symptoms after intake (stomach 
• 
Collection of adverse events (AEs) 
(for up to 30 days following the day 
of colonoscopy) 
- 
Diagnosis 
or 
diagnostic 
findings 
made 
at 
colonoscopy 
will 
be 
reported as such and will 
not be reported as AEs 
unless 
the 
investigator 
PPD


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CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 88/103 
 
 
cramping, stomach bloating and 
nausea) on a paediatric 5-point 
scale, 
ranging 
from 
1=no 
symptoms 
to 
5= 
severely 
distressing symptoms 
• 
Description 
and 
histological 
examination of any colonic 
biopsy specimens of mucosal 
lesions 
suspected 
by 
the 
investigator to have been caused 
by colonic lavage 
 
observes mucosal lesions 
that he/she suspects to be 
related or possibly related 
to the colonic lavage. Such 
lesions will be biopsied. In 
this 
situation 
only, 
description 
of 
the colonoscopy 
findings 
and 
histological 
examination results will be 
reported as AEs. 
• 
Tolerability by a Symptom Scale 
after each dose of treatment. 
Subjects will rate their preparation 
related symptoms after intake 
(stomach 
cramping, 
stomach 
bloating and nausea) on a paediatric 
5-point scale, ranging from 1=no 
symptoms 
to 
5= 
severely 
distressing symptoms 
37 
5.1. Study 
Schedule 
Indication for Colonoscopy 
Colonoscopy efficacy 
assessment [n] 
Indication(s) for Colonoscopy 
Colonoscopy  
assessment [n] 
[n] Colonoscopy assessment: Rescue 
treatment, cleansing Score, BBPS, start 
time of colonoscopy, time of caecal 
intubation, caecum reached, 
withdrawal time, diagnosis/findings 
(except if AE, see Section 3.2.2.2.) 
40 
5.2.2. 
Baseline/Tre
atment visit 
(Visit 1) 
Indication for colonoscopy to be 
collected 
Indication (s) for colonoscopy to be 
collected.  
41 
5.2.3. 
Colonoscopy 
(Visit 2, Day 
2) 
The following procedures will be 
performed on day of colonoscopy 
(Day 2): 
• 
… 
• 
Colonoscopy 
• 
Colonoscopy-related 
assessments 
• 
Histological examination of 
colonic biopsy (if needed) 
The following procedures will be 
performed on day of colonoscopy (Day 
2): 
• 
… 
• 
Colonoscopy 
• 
Colonoscopy-related assessments, 
including suspected diagnosis 
• 
Histological examination of 
colonic biopsy (if needed) 
• 
Diagnosis or diagnostic findings 
made at colonoscopy will be 
reported as such and will not be 
reported as AEs unless the 
investigator observes mucosal 
lesions that he/she suspects to be 
related or possibly related to the 
colonic lavage. Such lesions will 


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be biopsied. In this situation 
only, description of the 
colonoscopy findings and 
histological examination results 
will be reported as AEs. 
48 
8.1.1 
Definition of 
an adverse 
event 
This definition includes events 
occurring from the time of the 
subject giving informed consent 
until the end of the study (as 
defined in Section 3.5). 
This definition includes events 
occurring from the time of the subject 
giving informed consent 
until the end of the study (as defined in 
Section 3.5). 
Because colonoscopy is performed as 
a diagnostic procedure in this study, 
this definition specifically excludes 
diagnosis or diagnostic findings 
made during colonoscopy, such as 
ulcerative colitis, Crohn’s disease or 
inflammatory bowel disease. These 
will not be reported as AEs unless 
the investigator observes mucosal 
lesions that he/she suspects to be 
related or possibly related to the 
colonic lavage. Such lesions will be 
biopsied. In this situation only, 
description of the colonoscopy 
findings and histological 
examination results will be reported 
as AEs. 
54 
8.5 
8.5 Histological examination of 
colonic biopsy 
Should any macroscopic lesions 
suspected by the investigator to be 
induced by colonic 
lavage, the histological examination 
of the biopsies will be described 
and recorded as a 
TEAE. 
8.5 Diagnosis made at colonoscopy 
Diagnosis or diagnostic findings 
made at colonoscopy will be 
reported as such and will not be 
reported as AEs unless the 
investigator observes mucosal 
lesions that he/she suspects to be 
related or possibly related to the 
colonic lavage. Such lesions will be 
biopsied. 
 
8.6 Histological examination of 
colonic biopsy 
Should any macroscopic lesions 
suspected by the investigator to be 
induced by colonic lavage, the 
histological examination of the 
biopsies will be described and 
recorded as a TEAE. 
 


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-58800-003 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Final Version 5.0 (including Amendment #4): 16 March 2018  
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
Collect diagnosis/findings from colonoscopy 
Clarify to investigators that diagnoses made at colonoscopy are not 
to be reported as AEs. 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
  
No 
   
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
No 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN 
(RAP) UPDATE 
Yes 
 
No 
 
 
 
(tick one) 
 
 


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CONFIDENTIAL 
 
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PAGE 91/103 
 
 
Appendix 5 Protocol Amendment #5 
 
STUDY NUMBER: 
F-FR-58800-003 
PROTOCOL TITLE: 
Efficacy, Safety and Tolerability of a Bowel 
Cleansing Preparation (Eziclen®/Izinova®) in 
Paediatric Subjects Undergoing Colonoscopy: a 
Phase III, Multicentre, Randomised, 
Comparative Study Versus Klean-Prep® (PEG-
Electrolytes), Administered on the Day Before 
Colonoscopy, Investigator-Blinded, Non-
Inferiority in Adolescents of 12 to 17 Years of 
Age (Inclusive) >40 Kg. 
OLD PROTOCOL VERSION 
NUMBER & DATE 
Final Version 5.0 (including Amendment #4): 
16 March 2018 
NEWAMENDED PROTOCOL 
VERSION NUMBER & DATE 
Final Version 6.0 (including Amendment #5): 
26 July 2018 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: 
Version Date 
16 March 2018 
26 July 2018 
Page  
Section 
WAS 
IS 


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CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 92/103 
 
 
9 
Synopsis-
Criteria for 
Evaluation 
Safety and tolerability 
• 
Collection of adverse events 
(AEs) (for up to 30 days 
following the day of 
colonoscopy) 
- 
Diagnosis or diagnostic 
findings made at 
colonoscopy will be 
reported as such and 
will not be reported as 
AEs unless the 
investigator observes 
mucosal lesions that 
he/she suspects to be 
related or possibly 
related to the colonic 
lavage. Such lesions 
will be biopsied. In this 
situation only, 
description of 
the colonoscopy 
findings and 
histological 
examination results 
will be reported as 
AEs. 
• 
Tolerability by a Symptom 
Scale after each dose of 
treatment. Subjects will rate 
their preparation related 
symptoms after intake 
(stomach cramping, stomach 
bloating and nausea) on a 
paediatric 5-point scale, 
ranging from 1=no 
symptoms to 5= severely 
distressing symptoms 
 
Safety and tolerability 
• 
Collection of adverse events (AEs) 
(for up to 30 days following the day 
of colonoscopy) 
• 
Tolerability by a Symptom Scale 
after each dose of treatment. 
Subjects will rate their preparation 
related symptoms after intake 
(stomach 
cramping, 
stomach 
bloating and nausea) on a paediatric 
5-point scale, ranging from 1=no 
symptoms 
to 
5= 
severely 
distressing symptoms 
• 
Description 
and 
histological 
examination of any colonic biopsy 
specimens of mucosal lesions 
suspected by the investigator to 
have been caused by colonic 
lavage 


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CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 93/103 
 
 
12 
Synopsis – 
Study 
procedures 
and 
assessments 
[g] Local laboratory (blood): 
biochemistry including: anion 
gap, alanine aminotransferase 
(ALT), aspartate aminotransferase 
(AST), creatine phosphokinase 
(CPK), lactic dehydrogenase 
(LDH), gamma-glutamyl 
transferase (GGT), total and 
conjugated bilirubin, creatinine, 
urea, serum electrolytes (sodium, 
potassium, chloride, calcium, 
magnesium, phosphorus, 
bicarbonate), alkaline 
phosphatase, albumin, total 
protein, C reactive protein (CRP), 
uric acid, international normalised 
ratio (INR), creatinine clearance 
(calculated GFR), osmolality 
… 
[i] Additional local laboratory 
haematology: complete blood 
count (CBC). 
… 
[n] Colonoscopy assessment: Rescue 
treatment, cleansing Score, BBPS, 
start time of colonoscopy, time of 
caecal intubation, caecum reached, 
withdrawal 
time, 
diagnosis/findings (except if AE) 
[g] Local laboratory (blood): biochemistry 
including: anion gap, alanine 
aminotransferase (ALT), aspartate 
aminotransferase (AST), creatine 
phosphokinase (CPK), lactic 
dehydrogenase (LDH), gamma-
glutamyl transferase (GGT), total and 
conjugated bilirubin, creatinine, urea, 
serum electrolytes (sodium, potassium, 
chloride, calcium, magnesium, 
phosphorus, bicarbonate), alkaline 
phosphatase, albumin, total protein, C 
reactive protein (CRP), uric acid, 
creatinine clearance (calculated GFR), 
osmolality 
… 
 
[i] Additional local laboratory 
haematology: complete blood count 
(CBC), international normalised 
ratio (INR). 
… 
[n] 
Colonoscopy 
assessment: 
Rescue 
treatment, cleansing Score, BBPS, start 
time of colonoscopy, time of caecal 
intubation, caecum reached, withdrawal 
time, diagnosis/findings 
29 
3.2.2.2. 
Safety and 
Tolerability 
Variables 
Safety and tolerability 
• 
Collection of adverse events 
(AEs) (for up to 30 days 
following 
the 
day 
of 
colonoscopy) 
- 
Diagnosis or diagnostic 
findings 
made 
at 
colonoscopy 
will 
be 
reported as such and 
will not be reported as 
AEs 
unless 
the 
investigator 
observes 
mucosal 
lesions 
that 
he/she suspects to be 
related 
or 
possibly 
related to the colonic 
lavage. 
Such lesions 
will be biopsied. In this 
situation 
only, 
description 
of 
the colonoscopy 
findings 
and 
histological 
Safety and tolerability 
• 
Collection of adverse events (AEs) 
(for up to 30 days following the day 
of colonoscopy) 
• 
Tolerability by a Symptom Scale 
after each dose of treatment. 
Subjects will rate their preparation 
related symptoms after intake 
(stomach 
cramping, 
stomach 
bloating and nausea) on a paediatric 
5-point scale, ranging from 1=no 
symptoms 
to 
5= 
severely 
distressing symptoms 
• 
Description 
and 
histological 
examination of any colonic biopsy 
specimens of mucosal lesions 
suspected by the investigator to 
have been caused by colonic 
lavage 
 


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CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 94/103 
 
 
examination results will 
be reported as AEs. 
• 
Tolerability by a Symptom 
Scale 
after 
each 
dose 
of 
treatment. Subjects will rate 
their 
preparation 
related 
symptoms after intake (stomach 
cramping, stomach bloating and 
nausea) on a paediatric 5-point 
scale, 
ranging 
from 
1=no 
symptoms 
to 
5= 
severely 
distressing symptoms 
38 
5.1. Study 
Schedule 
[g] Local laboratory (blood): 
biochemistry including: anion gap, 
alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), 
creatine phosphokinase (CPK), 
lactic dehydrogenase (LDH), 
gamma-glutamyl transferase 
(GGT), total and conjugated 
bilirubin, creatinine, urea, serum 
electrolytes (sodium, potassium, 
chloride, calcium, magnesium, 
phosphorus, bicarbonate), alkaline 
phosphatase, albumin, total protein, 
C reactive protein (CRP), uric acid, 
international normalised ratio 
(INR), creatinine clearance 
(calculated GFR), osmolality 
… 
[i] Additional local laboratory 
haematology: complete blood 
count (CBC) (Section 8.2.1) 
 
[n] Colonoscopy assessment: Rescue 
treatment, cleansing Score, BBPS, start 
time of colonoscopy, time of caecal 
intubation, caecum reached, 
withdrawal time, diagnosis/findings 
(except if AE, see Section 3.2.2.2.) 
[g] Local laboratory (blood): biochemistry 
including: anion gap, alanine 
aminotransferase (ALT), aspartate 
aminotransferase (AST), creatine 
phosphokinase (CPK), lactic 
dehydrogenase (LDH), gamma-
glutamyl transferase (GGT), total and 
conjugated bilirubin, creatinine, urea, 
serum electrolytes (sodium, potassium, 
chloride, calcium, magnesium, 
phosphorus, bicarbonate), alkaline 
phosphatase, albumin, total protein, C 
reactive protein (CRP), uric acid, 
creatinine clearance (calculated GFR), 
osmolality 
 
… 
[i] Additional local laboratory 
haematology: complete blood count 
(CBC), international normalised 
ratio (INR) (Section 8.2.1) 
 
[n] Colonoscopy assessment: Rescue 
treatment, cleansing Score, BBPS, start 
time of colonoscopy, time of caecal 
intubation, caecum reached, withdrawal 
time, diagnosis/findings. 
40 
5.2.2 
Baseline/ 
Treatment 
visit (Visit 1) 
• 
Blood sampling: 
Laboratory 
assessments performed within 
10 days or less prior to inclusion 
may be used to determine 
eligibility 
upon 
investigator 
agreement. 
a) haematology: CBC  
b) biochemistry including: anion 
gap, ALT, AST, CPK, LDH, 
GGT, total and conjugated 
bilirubin, albumin, creatinine, 
urea, 
serum 
electrolytes 
(sodium, potassium, chloride, 
• 
Blood 
sampling: 
Laboratory 
assessments performed within 10 
days or less prior to inclusion may 
be used to determine eligibility 
upon investigator agreement. 
c) haematology: 
international 
normalised ratio (INR), CBC  
d) biochemistry 
including: 
anion 
gap, ALT, AST, CPK, LDH, 
GGT, 
total 
and 
conjugated 
bilirubin, 
albumin, 
creatinine, 
urea, serum electrolytes (sodium, 
potassium, 
chloride, 
calcium, 


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CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
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calcium, 
magnesium, 
phosphorus, 
bicarbonate), 
alkaline 
phosphatase, 
total 
protein, 
CRP, 
uric 
acid, 
international normalised ratio 
(INR), creatinine clearance 
(calculated GFR), osmolality 
magnesium, 
phosphorus, 
bicarbonate), 
alkaline 
phosphatase, total protein, CRP, 
uric acid, creatinine clearance 
(calculated GFR), osmolality 
41 
5.2.3. 
Colonoscopy 
(Visit 2, Day 
2) 
The following procedures will be 
performed on day of colonoscopy 
(Day 2): 
• 
… 
• 
Colonoscopy 
• 
Colonoscopy-related 
assessments, including 
suspected diagnosis 
• 
Histological examination of 
colonic biopsy (if needed) 
• 
Diagnosis or diagnostic 
findings made at colonoscopy 
will be reported as such and 
will not be reported as AEs 
unless the investigator observes 
mucosal lesions that he/she 
suspects to be related or 
possibly related to the colonic 
lavage. Such lesions will be 
biopsied. In this situation only, 
description of the colonoscopy 
findings and histological 
examination results will be 
reported as AEs. 
 
The following procedures will be 
performed on day of colonoscopy (Day 
2): 
• 
… 
• 
Colonoscopy 
• 
Colonoscopy-related assessments, 
including suspected diagnosis 
• 
Histological examination of 
colonic biopsy (if needed) 
 


IPSEN GROUP 
F-FR-58800-003 
 
CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
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48 
8.1.1 
Definition of 
an adverse 
event 
This definition includes events 
occurring from the time of the 
subject giving informed consent 
until the end of the study (as 
defined in Section 3.5). 
Because colonoscopy is performed 
as a diagnostic procedure in this 
study, this definition specifically 
excludes diagnosis or diagnostic 
findings made during colonoscopy, 
such as ulcerative colitis, Crohn’s 
disease or inflammatory bowel 
disease. These will not be reported 
as AEs unless the investigator 
observes mucosal lesions that 
he/she suspects to be related or 
possibly related to the colonic 
lavage. Such lesions will be 
biopsied. In this situation only, 
description of the colonoscopy 
findings and histological 
examination results will be reported 
as AEs. 
This definition includes events 
occurring from the time of the subject 
giving informed consent 
until the end of the study (as defined in 
Section 3.5). 
 
52 
8.2.1 
Haematology 
Blood samples (3 mL) will be 
collected (in a potassium ethylene 
diamine tetra acetic acid (EDTA) 
tube) to assess the following 
parameters: CBC: red blood cell 
(RBC) 
count, 
haemoglobin, 
haematocrit, 
mean 
corpuscular 
volume (MCV), mean corpuscular 
haemoglobin 
(MCH), 
mean 
corpuscular 
haemoglobin 
concentration (MCHC), white blood 
cell (WBC) count with differential 
(neutrophils, 
lymphocytes, 
monocytes, eosinophils, basophils, 
and others) and platelet count. 
Blood samples (3 mL) will be collected 
(in a potassium ethylene diamine tetra 
acetic acid (EDTA) tube) to assess the 
following parameters: CBC: red blood 
cell 
(RBC) 
count, 
haemoglobin, 
haematocrit, mean corpuscular volume 
(MCV), 
mean 
corpuscular 
haemoglobin 
(MCH), 
mean 
corpuscular haemoglobin concentration 
(MCHC), white blood cell (WBC) 
count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils, 
basophils, and others),  platelet count 
and international normalised ratio 
(INR). 
52 
8.2.2 Blood 
Biochemistry 
Anion gap, ALT, AST, CPK, LDH, 
GGT, total and conjugated 
bilirubin, creatinine, urea, serum 
electrolytes (sodium, potassium, 
chloride, calcium, magnesium, 
phosphorus, bicarbonate), alkaline 
phosphatase, albumin, total protein, 
CRP, uric acid, INR, creatinine 
clearance (calculated GFR), 
osmolality 
Anion gap, ALT, AST, CPK, LDH, 
GGT, total and conjugated bilirubin, 
creatinine, urea, serum electrolytes 
(sodium, potassium, chloride, calcium, 
magnesium, phosphorus, bicarbonate), 
alkaline phosphatase, albumin, total 
protein, CRP, uric acid, creatinine 
clearance (calculated GFR), osmolality 
53 
8.5 
8.5 Diagnosis made at colonoscopy 
Diagnosis or diagnostic findings 
made at colonoscopy will be 
 


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PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
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reported as such and will not be 
reported as AEs unless the 
investigator observes mucosal 
lesions that he/she suspects to be 
related or possibly related to the 
colonic lavage. Such lesions will be 
biopsied. 
 


IPSEN GROUP 
F-FR-58800-003 
 
CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 98/103 
 
 
SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-58800-003 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Final Version 6.0 (including Amendment #5): 26 July 2018  
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
German competent authorities refused the Version 5.0 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
  
No 
   
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
No 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN 
(RAP) UPDATE 
Yes 
 
No 
 
 
 
(tick one) 


IPSEN GROUP 
F-FR-58800-003 
 
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PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 99/103 
 
 
Appendix 6 Protocol Amendment #6 


IPSEN GROUP 
F-FR-58800-003 
 
CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 100/103 
 
 
 
STUDY NUMBER: 
F-FR-58800-003 
PROTOCOL TITLE: 
Efficacy, Safety and Tolerability of a Bowel 
Cleansing Preparation (Eziclen®/Izinova®) in 
Paediatric Subjects Undergoing Colonoscopy: a 
Phase III, Multicentre, Randomised, 
Comparative Study Versus Klean-Prep® (PEG-
Electrolytes), Administered on the Day Before 
Colonoscopy, Investigator-Blinded, Non-
Inferiority in Adolescents of 12 to 17 Years of 
Age (Inclusive) >40 Kg. 
OLD PROTOCOL VERSION 
NUMBER & DATE 
Final Version 6.0 (including Amendment #5): 
26 July 2018 
NEWAMENDED PROTOCOL 
VERSION NUMBER & DATE 
Final Version 7.0 (including Amendment #6): 
02 March 2020 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: 
Version Date 
26 July 2018 
02 March 2020 
Page  
Section 
WAS 
IS 
5 
Synopsis – 
Planned 
study period 
From Q4 2017 to Q4 2018 
From Q4 2017 to Q2 2020 
 
32 
3.4 
[…] 
The unblinded investigator, or 
designee, will only dispense 
IMPs to subjects included in this 
study. Each subject will only be 
given the IMP carrying his/her 
number. The dispensing for each 
subject will be documented in the 
eCRF by unblinded pharmacist. 
[…] 
The unblinded designee, will only 
dispense IMPs to subjects included 
in this study. Each subject will only 
be given the IMP carrying his/her 
number. The dispensing for each 
subject will be documented in the 
eCRF by unblinded pharmacist. 
32 
3.5 
[…] 
 
 
 
 
 
 
 
 
 
 
[…] 
As the blood and urine sulfate 
assay are not standard tests, the 
samples 
are 
transported 
in 
batches to an overseas central 
laboratory and processed there. 
Results are transferred to the 
study database. The last sample is 
taken at the time of last subject 
last visit. The estimated duration 
for transfer of the sample to the 
central 
laboratory, 
processing 
and transfer of the results to the 


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CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
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The overall duration of the study 
will be approximately 13 months 
(12 months of recruitment + 1 
month of follow-up). 
[…] 
The study will be considered to 
have ended after the last subject 
has completed the last follow-up 
period in the study. 
database 
is 
approximately 
6 
weeks. In order to ensure that the 
sulfate data are included in the 
CSR, the end of study is being 
redefined. The study will be 
considered to have ended after the 
last subject last external data from 
central 
laboratory 
has 
been 
transferred to the database. 
The overall duration of the study 
will be approximately 32 months 
(30 months of recruitment + 1 
month of follow-up + 6 weeks 
minimum for last data transfer). 
33 
3.7.1 
The unblinded investigator, or an 
approved 
representative 
(e.g. 
pharmacist), will ensure that all 
IMP and any other study related 
material is stored in a secured 
area, 
under 
recommended 
temperature monitored storage 
conditions, in accordance with 
applicable 
regulatory 
requirements. 
The 
unblinded 
approved 
representative 
(e.g. pharmacist), 
will ensure that all IMP and any 
other study related material is stored 
in 
a 
secured 
area, 
under 
recommended 
temperature 
monitored storage conditions, in 
accordance 
with 
applicable 
regulatory requirements. 
 
33 
3.7.2 
The unblinded investigator, or an 
approved 
representative 
(e.g. 
pharmacist), will ensure that all 
IMP and comparative treatment 
are reconstituted and dispensed 
by 
qualified 
staff 
members 
(Refer to 6.1 for details). 
The 
unblinded 
approved 
representative 
(e.g. pharmacist), 
will ensure that all IMP and 
comparative 
treatment 
are 
reconstituted and dispensed by 
qualified staff members (Refer to 
6.1 for details). 
34 
3.8 
[…] 
 
At the earliest opportunity the 
investigator 
is 
requested 
to 
inform the blinded monitor in 
charge of his/her centre that the 
blind has been broken for an 
emergency. 
[…] 
At the earliest opportunity the 
investigator is requested to inform 
the monitor in charge of his/her 
centre that the blind has been broken 
for an emergency. 
 
56 
10.1.2 
Any major protocol deviation 
will be described in the Protocol 
Deviation Document (PDD) and 
its impact on inclusion in each 
analysis population (mITT/PP 
population) for any subject will 
be specified. The final list of 
Any major protocol deviation will 
be 
described 
in 
the 
Protocol 
Deviation Document (PDD) and its 
impact on inclusion in each analysis 
population (mITT/PP population) 
for any subject will be specified. 
The final list of protocol deviations 


IPSEN GROUP 
F-FR-58800-003 
 
CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 102/103 
 
 
protocol deviations impacting the 
mITT/PP population will be 
reviewed during the blind data 
review meeting held prior to 
database 
lock, 
before 
any 
unblinding of treatment groups. 
The list will be updated to 
include any additional major 
protocol deviations impacting 
inclusion in the PP population. 
impacting the mITT/PP population 
will be reviewed during the data 
review meeting held prior to 
database lock. The list will be 
updated to include any additional 
major protocol deviations impacting 
inclusion in the PP population. 
 
59 
10.6 
[…] 
An Expert Committee chaired by 
the principal investigator will 
review safety data. This review 
will be performed during data 
review meetings. Full details of 
the operating model for this 
safety data review will be 
provided in a charter to be 
produced. 
[…] 
An Expert Committee chaired by the 
principal investigator will review 
safety data. This review will be 
performed during blind data review 
meetings. 
Full 
details 
of 
the 
operating model for this safety data 
review will be provided in a charter 
to be produced. 
 


IPSEN GROUP 
F-FR-58800-003 
 
CONFIDENTIAL 
 
PROTOCOL: FINAL (INCLUDING AMENDMENT #6): 02 MARCH 2020 
PAGE 103/103 
 
 
SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-58800-003 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Final Version 7.0 (including Amendment #6): 02 March 2020 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
- Modification of the end of study definition 
- Correction of minor inconsistencies 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
  
No 
   
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
No 
 
(tick one) 
 
STATISTICAL & ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
No 
 
 
 
(tick one) 
 

SAP_001.pdf: 
'RFXPHQW1DPHIIUVWDWSODQ
$SSURYHG
&OLQLFDO
*07
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*07
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*07
&OLQLFDO
*07
&OLQLFDO
*07
PPD
PPD
PPD
PPD
PPD


IPSEN GROUP 
F-FR-58800-003 
CONFIDENTIAL 
 
SAP final version 4.0: 25 August 2020 
1/62 
 
 
STATISTICAL ANALYSIS PLAN 
 
EFFICACY, SAFETY AND TOLERABILITY OF A BOWEL CLEANSING 
PREPARATION (EZICLEN®/IZINOVA®) IN PAEDIATRIC SUBJECTS UNDERGOING 
COLONOSCOPY: A PHASE III, MULTICENTRE, RANDOMISED, COMPARATIVE 
STUDY VERSUS KLEAN-PREP® (PEG-ELECTROLYTES), ADMINISTERED ON THE 
DAY BEFORE COLONOSCOPY, INVESTIGATOR-BLINDED, NON-INFERIORITY IN 
ADOLESCENTS OF 12 TO 17 YEARS OF AGE (INCLUSIVE) > 40 KG. 
 
PROTOCOL VERSION AND DATE: 
FINAL VERSION 7.0 – 02 MARCH 2020 
 
 
SAP Version 
Date 
Final version 4.0 
25 August 2020 
 


IPSEN GROUP 
F-FR-58800-003 
CONFIDENTIAL 
 
SAP final version 4.0: 25 August 2020 
2/62 
 
STUDY NUMBER: 
F-FR-58800-003 
EUDRACT NUMBER 
2016 002265 60 
PROTOCOL TITLE: 
EFFICACY, SAFETY AND TOLERABILITY OF A 
BOWEL 
CLEANSING 
PREPARATION 
(EZICLEN®/IZINOVA®) 
IN 
PAEDIATRIC 
SUBJECTS UNDERGOING COLONOSCOPY: A 
PHASE 
III, 
MULTICENTRE, 
RANDOMISED, 
COMPARATIVE STUDY VERSUS KLEAN-PREP® 
(PEG-ELECTROLYTES), 
ADMINISTERED 
ON 
THE 
DAY 
BEFORE 
COLONOSCOPY, 
INVESTIGATOR-BLINDED, 
NON-INFERIORITY 
IN ADOLESCENTS OF 12 TO 17 YEARS OF AGE 
(INCLUSIVE) > 40 KG. 
SAP VERSION: 
Final Version 4.0 
SAP DATE: 
25 August 2020 
 
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 
Study Statistician 
 
Keyrus Biopharma 
18-20 Rue Clément Bayard 
92300 Levallois-Perret 
France 
Tel: 
 
 
 
Clinical Study 
Coordinator 
 
Ipsen Consumer Healthcare 
GMA - Clinical Operations 
65 Quai Georges Gorse 
92100 Boulogne Billancourt, France 
Tel.: 
 
 
 
Medical 
Development 
Director 
 
Ipsen Consumer Healthcare 
65 Quai Georges Gorse 
92100 Boulogne Billancourt, France 
Tel.: 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


IPSEN GROUP 
F-FR-58800-003 
CONFIDENTIAL 
 
SAP final version 4.0: 25 August 2020 
3/62 
 
RESPONSIBILITY NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Study statistician 
 
Biotrial Biometrics 
7-9 Rue Jean-Louis Bertrand 
35042 Rennes Cedex, France 
Tel.: 
 
 
 
Reviewer 
statistician 
 
Biotrial Biometrics 
7-9 Rue Jean-Louis Bertrand 
35042 Rennes Cedex, France 
Tel.: 
 
 
 
 
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
PPD


IPSEN GROUP 
F-FR-58800-003 
CONFIDENTIAL 
 
SAP final version 4.0: 25 August 2020 
4/62 
 
History of Changes 
Old Version 
Number 
Date Old 
Version 
Date New 
Version 
Reason for Change 
Page 
Section 
Was 
Is 
1 
 
11JUN2018 
(v1.0) 
18JUN2018 
(v2.0) 
Protocol version 5.0 (dated 18JAN2018) 
was indicated in SAP version 1.0, but this 
protocol was in fact not approved, so 
Protocol version 4.0 (dated 17JUL2017) 
was corrected in SAP version 2.0. 
1 
 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Following to protocol amendment version 
5, protocol version 6.0 is then applicable. 
14 
21 
1.4.2.1 
3.1.2 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
The endpoint “duration of intubation” has 
been 
renamed 
to 
“time 
to 
caecal 
intubation”, 
and 
the 
endpoint 
“time 
between the last intake of fluids and the 
start of colonoscopy procedure” has been 
added. 
16 
22 
1.4.2.2 
3.1.3 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Following to protocol amendment, safety 
assessments have been reviewed: 
- 
AE collection has been specified, 
i.e. “at Visit 4 Day 32 -5/+15”. 
- 
Sentence 
about 
diagnosis 
and 
diagnostic 
findings 
has 
been 
removed, 
and 
description 
of 
mucosal lesions has been added. 
- 
And, the international normalised 
ratio (INR) is not considered as a 
biochemistry parameter anymore 
but as a haematology one. 
22 
3.1.5 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Since the secondary endpoints are not 
supposed to be tested for superiority 
according 
to 
the 
protocol, 
the 
corresponding sentence has been reviewed 
to specify that they will be tested for 
descriptive purpose only. 
23 
3.2.1 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
The secondary analyses will also be 
repeated on the PP population, and the 
other efficacy analyses will be repeated on 
the mITT population, if they differ from 
more than 10% from the ITT population; 
since this is important to check the 
robustness of the results if the populations 
differ too much. 


IPSEN GROUP 
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SAP final version 4.0: 25 August 2020 
5/62 
 
23 
3.2.1.1 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Primary analysis has been updated in order 
to clarify the SAS codes used for each step. 
Interaction should be included in the 
primary model if it is significant and not 
assessed in a separate table, so this has 
been revised. 
A robustness analysis using bootstrap 
method has been added. 
If 
no 
significant 
treatment*country 
interaction is observed in the primary 
model, then the interaction will not be 
investigated in the robustness analyses on 
PP population. 
24 
25 
28 
3.2.1.2.1 
3.2.1.2.2 
3.2.1.2.6 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Interaction analyses have been clarified to 
be checked systematically in the models 
and analyses by country have been added. 
26 
3.2.1.2.4 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
The reason for non-completion will also be 
described. 
27 
3.2.1.2.5 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
The times for KM estimates have been 
revised (e.g. addition of 15h and 18h for 
time to clear effluent) to be more 
consistent. 
29 
3.2.1.2.8 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
The proportion of subjects who needed a 
nasogastric tube to complete preparation 
will also be tabulated by dose, in addition 
of overall summary. 
29 
3.2.1.2.9 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
The overall treatment acceptability will be 
derived as the average of the scores 
observed at each dose and analysed using a 
two-way ANOVA. 
29 
3.2.1.2.10 18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
The volume taken will also be described. 
Interaction analysis has been clarified and 
analysis by country has been added. 
In addition, analyses by sex, age class and 
weight class have been added 
NA 
NA 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
New section 3.2.1.3.4 
The endpoint “time between the last intake 
of fluids and the start of colonoscopy 
procedure” has been added. 


IPSEN GROUP 
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33 
3.2.2.1 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Causality of SAEs and TEAEs leading to 
death have been added in the summary 
table of AEs. 
Tables with TEAEs with incidence >= 5 % 
and with TEAEs by decreasing frequency 
of PT have been added. 
The summary table of AEs will also be 
provided by sex, age class and weight 
class. 
95 % CI of proportions will only be 
displayed in summary tables, and not in the 
tables by SOC/PT. 
34 
3.2.2.2 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
As no normal range for sulfate is available, 
corresponding 
analyses 
have 
been 
removed. 
The 
formula 
for 
laboratory 
data 
standardisation has been specified. 
34 
3.2.2.3 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Categories for weight, blood pressure and 
heart variations have been specified. 
34 
3.2.2.4 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Tolerability 
will 
also 
be 
described 
according to use of nasogastric tube, sex, 
age class and weight class. 
36 
3.2.5 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Summaries will also be provided by 
country. 
36 
3.2.6 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Demography will also be provided by sex, 
age class and weight class.. 
38 
3.2.8 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
All major deviations will be described and 
not only those having an impact on 
populations. 
40 
3.2.15 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Subgroups analyses on country, sex, age 
class and weight class have been added. 
41 
5 
18JUN2018 
(v2.0) 
26FEB2020 
(v3.0) 
Changes from the protocol have been 
specified, i.e. replication of secondary 
analysis on PP population, additional 
subgroup analyses and addition of an 
endpoint (“time between the last intake of 
fluids and the start of colonoscopy 
procedure”). 
19 
1.4.2.3 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Addition 
of 
haematology 
as 
other 
assessment. 


IPSEN GROUP 
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20 
1.4.3 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Removal of “(except if AE)” in the 
footnote n of table 5. 
23 
2.1.2 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Specification that only major deviations 
impacting analyses will be considered as 
excluding 
from 
the 
per 
protocol 
population. 
27 
3.2.1.1 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Addition of option first in the proc logistic 
used for bootstrap to be consistent with the 
primary model. 
30/31 
3.2.1.2.3 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Addition of timepoints for the description 
of time to clear effluent. 
36 
3.2.1.3.1 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Addition of timepoints for the description 
of time to first bowel movement. 
39 
3.2.2.1 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Addition of table on related TEAEs. 
39 
3.2.2.2 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Removal of “Laboratory data will be 
displayed in Standard International (SI) 
units.” Since it is specified below. 
Addition of  
- 
the derivation of abnormal status 
according to normal ranges, 
- 
a threshold for eGFR normal 
values, 
- 
a sensitivity analysis of sulfate 
according to fasting status. 
Precision that there is no normal range for 
pH and specific gravity, so standardisation 
will not be performed and no shift table 
will be provided. 
41 
3.2.2.6 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Removal that findings could be reported as 
AEs. 
41 
3.2.4 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Addition of a flow chart with the number 
of subjects in each analysis population. 
49 
5 
26FEB2020 
(v3.0) 
25AUG2020 
(v4.0) 
Modification of the per protocol definition. 


IPSEN GROUP 
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CONFIDENTIAL 
 
SAP final version 4.0: 25 August 2020 
8/62 
 
TABLE OF CONTENTS 
1 
INFORMATION TAKEN FROM THE PROTOCOL ............................................. 13 
1.1 
Study purpose ................................................................................................................ 13 
1.2 
Study objectives ............................................................................................................. 13 
1.2.1 
Primary objective ......................................................................................... 13 
1.2.2 
Secondary objectives ................................................................................... 13 
1.3 
Study design ................................................................................................................... 13 
1.3.1 
Study population ......................................................................................... 14 
1.3.1.1 
Inclusion Criteria ......................................................................................... 14 
1.3.1.2 
Exclusion Criteria ........................................................................................ 14 
1.3.2 
Study exposure ............................................................................................ 15 
1.4 
Methods and procedures .............................................................................................. 15 
1.4.1 
Subject identification and allocation to study treatment ........................... 15 
1.4.2 
Subjects assessments ................................................................................... 16 
1.4.2.1 
Efficacy assessments .................................................................................... 16 
1.4.2.2 
Safety assessments ....................................................................................... 18 
1.4.2.3 
Other assessments ........................................................................................ 19 
1.4.2.4 
Withdrawal/discontinuation ......................................................................... 19 
1.4.3 
Schedule of assessments ............................................................................. 20 
1.4.4 
Planned sample size .................................................................................... 21 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................... 22 
2.1 
Efficacy .......................................................................................................................... 22 
2.1.1 
Intention-To-Treat population (ITT) ......................................................... 22 
2.1.1 
Modified Intention-To-Treat population (mITT) ...................................... 22 
2.1.2 
Per Protocol population (PP) ..................................................................... 22 
2.2 
Safety .............................................................................................................................. 22 
2.3 
Pharmacokinetics .......................................................................................................... 22 
2.4 
Other populations ......................................................................................................... 22 
2.4.1 
Screened population .................................................................................... 22 
2.5 
Primary populations ..................................................................................................... 23 
3 
STATISTICAL METHODS ........................................................................................ 23 
3.1 
Statistical analysis strategy .......................................................................................... 23 
3.1.1 
Primary efficacy endpoint ........................................................................... 23 
3.1.2 
Secondary efficacy endpoints ..................................................................... 23 
3.1.3 
Safety endpoints .......................................................................................... 23 
3.1.4 
Multiplicity .................................................................................................. 24 
3.1.5 
Significance testing and estimation ............................................................ 24 
3.2 
Analysis methods ........................................................................................................... 24 
3.2.1 
Efficacy ........................................................................................................ 24 


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3.2.1.1 
Primary efficacy analyses ............................................................................ 24 
3.2.1.2 
Secondary efficacy analyses ........................................................................ 29 
3.2.1.3 
Other efficacy analyses ................................................................................ 36 
3.2.2 
Safety ........................................................................................................... 38 
3.2.2.1 
Adverse events .............................................................................................. 38 
3.2.2.2 
Laboratory data ........................................................................................... 39 
3.2.2.3 
Vital signs ..................................................................................................... 40 
3.2.2.4 
Tolerability ................................................................................................... 40 
3.2.2.5 
Physical examination ................................................................................... 40 
3.2.2.6 
Colonoscopy findings ................................................................................... 41 
3.2.3 
Missing data and outliers ............................................................................ 41 
3.2.3.1 
Missing data ................................................................................................. 41 
3.2.3.2 
Missing or incomplete dates ........................................................................ 41 
3.2.3.3 
Outliers ........................................................................................................ 41 
3.2.4 
Subject disposition ....................................................................................... 42 
3.2.5 
Withdrawals ................................................................................................. 42 
3.2.6 
Demographic and baseline characteristics ................................................ 42 
3.2.7 
Medical and surgical history ...................................................................... 44 
3.2.8 
Subject compliance ..................................................................................... 44 
3.2.9 
Prior and concomitant therapies ................................................................ 45 
3.2.10 
Derived data ................................................................................................. 45 
3.2.11 
Rules and data formats ............................................................................... 45 
3.2.12 
Pooling of centres ........................................................................................ 46 
3.2.13 
Interim analysis ........................................................................................... 46 
3.2.14 
Role of expert safety data review committee .............................................. 46 
3.2.15 
Covariates and analysis of subgroups ........................................................ 46 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 47 
4.1 
Hardware ....................................................................................................................... 47 
4.2 
Software ......................................................................................................................... 47 
4.3 
Validation programs ..................................................................................................... 47 
4.4 
Restitution of the programs ......................................................................................... 47 
5 
CHANGES FROM PROTOCOL ................................................................................ 47 
6 
REFERENCES .............................................................................................................. 48 
7 
APPENDICES ............................................................................................................... 49 
 


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LIST OF TABLES 
Table 1 
Cleansing Score .................................................................................................... 16 
Table 2 
Secondary Endpoints and Evaluations .............................................................. 17 
Table 3 
Boston Bowel Preparation Scale ........................................................................ 17 
Table 4 
Treatment Acceptability Questionnaire Categories ......................................... 18 
Table 5 
Study Procedures and Assessments ................................................................... 20 
Table 6 
Subject’s Leaflet Collected Information ........................................................... 21 
Table 7 
Time to Clear Effluent (hours) ........................................................................... 30 
Table 8 
Time to caecal intubation (minutes) .................................................................. 32 
Table 9 
Time to First Bowel Movement (hours)............................................................. 36 
Table 10 
Tanner Grading Scale to assess the genital development in male subjects .... 43 
Table 11 
Tanner Grading Scale to assess the pubic hair development in male 
subjects ................................................................................................................. 43 
Table 12 
Tanner Grading Scale to assess the breast development in female subjects . 43 
Table 13 
Tanner Grading Scale to assess the pubic hair development in female 
subjects ................................................................................................................. 44 
 
LIST OF FIGURES 
Figure 1 
Study flow chart ................................................................................................... 13 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE: 
Adverse Event 
ALT: 
Alanine aminotransferase 
AST: 
Aspartate aminotransferase 
ATC: 
Anatomic Therapeutic Class 
ANOVA: 
Analysis of Variance 
BBPS: 
Boston Bowel Preparation Scale 
BMI: 
Body Mass Index 
BP: 
Blood pressure 
CBC: 
Complete Blood Count 
CI: 
Confidence Interval 
CMH: 
Cochran-Mantel-Haenszel 
CPK: 
Creatine Phosphokinase 
CRP: 
C reactive protein 
eCRF: 
Electronic Case Report Form 
eGFR: 
Estimated Glomerular Filtration Rate 
GGT: 
Gamma-Glutamyl Transferase 
HR: 
Heart Rate 
ICH: 
International Conference on Harmonisation 
IMP: 
Investigational Medicinal Product 
INR: 
International Normalised Ratio 
ITT: 
Intention-To-Treat 
KM: 
Kaplan-Meier 
LC: 
Left colon 
LDH: 
Lactic Dehydrogenase 
MCH: 
Mean Cell Haemoglobin 
MCHC: 
Mean Cell Haemoglobin Concentration 
MCV: 
Mean Cell Volume 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
Modified Intention-To-Treat 
PEG: 
PolyEthylene Glycol 
PP: 
Per Protocol 
PT: 
Preferred term 
RBC: 
Red blood cell 
RC: 
Right colon 
SAE: 
Serious Adverse Event 
SAP: 
Statistical Analysis Plan  


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SAS®: 
Statistical Analysis System® 
SD: 
Standard Deviation 
SI: 
Standard International 
SOC: 
System Organ Class 
TC: 
Transverse colon 
TEAE: 
Treatment Emergent Adverse Event 
TFL: 
Table, figure and listing 
V: 
Visit 
WBC: 
White blood cell 
WHO-DD: 
World Health Organization – Drug dictionary 
 


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1 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1 
Study purpose 
The purpose of the present study is to compare the efficacy, safety and tolerability of 
Eziclen®/Izinova® to those of Klean-Prep® in adolescents aged 12 to 17 years (inclusive) 
with body weight >40 kg scheduled to undergo a colonoscopy for a routinely accepted 
indication. 
1.2 
Study objectives 
1.2.1 
Primary objective 
The primary objective of the study is to demonstrate that Eziclen®/Izinova®, an osmotic 
sulfate-based laxative preparation given on the day before colonoscopy has non-inferior 
efficacy to Klean-Prep® (Polyethylene glycol (PEG)-electrolytes) on colon cleansing in 
adolescents aged 12 to 17 years (inclusive) with a body weight > 40 kg, scheduled to undergo 
a colonoscopy for a routinely accepted diagnostic indication. 
1.2.2 
Secondary objectives 
The secondary study objectives are: 
• 
To compare efficacy of Eziclen®/Izinova® versus Klean-Prep® on overall and 
segmental cleansing and colonoscopy quality indicators, 
• 
To assess compliance with preparation administration in both study arms, 
• 
To compare safety, acceptability and tolerability of Eziclen®/Izinova® versus Klean-
Prep®. 
1.3 
Study design 
This is a multicentre, investigator-blinded, randomised phase III comparative study conducted 
in adolescents (male and female) > 40 kg scheduled to undergo colonoscopy. It is planned to 
enroll subjects from around 25 centres. Subjects will be randomised in 2 parallel arms to 
receive either Eziclen®/Izinova® or Klean-Prep®. 
An overview of the study design is presented in Figure 1 below. 
Figure 1 Study flow chart 
 
V1=Visit 1, V2=Visit 2, V3=Visit 3, V4=Visit 4. 
At baseline visit (Visit 1), subjects meeting all eligibility criteria will be randomised to 
receive either Eziclen®/Izinova® or Klean-Prep® solution. The treatment will be 
administered on the same day (Day 1). After having received either Eziclen®/Izinova® or 
Klean-Prep® solution, subjects will undergo colonoscopy on the next day (Day 2). Subjects 
will be contacted by phone on Day 4 and will come on Day 32 for a safety follow-up visit. 
Baseline
Colonoscopy
Phone contact
End of study
Visit
V1
V2
V3
V4
Time window
 -/+1
 -5/+15
Day
1
2
3
4
32
Randomisation:
EZICLEN®/IZINOVA® 
or
Klean-Prep®
Treatment
administration
Follow-up period
from day 5 to day 31


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1.3.1 
Study population 
A total of 250 male or female subjects aged 12 to 17 years (inclusive) scheduled to undergo 
colonoscopy will be randomised in this study in order to have 240 evaluable subjects. 
1.3.1.1 
Inclusion Criteria 
Subject MUST satisfy all of the following entry criteria before being allowed to participate in 
the study: 
(1) 
Provision of signed informed consent form to participate in the study obtained from the 
adolescent's parent(s)/ legal representative and a signed assent form from the adolescent 
according to local law 
(2) 
Male or female subjects between 12 to 17 years of age (inclusive) 
(3) 
Body weight more than 40 kg 
(4) 
Female of childbearing potential must have a negative pregnancy test 
(5) 
If female, and of child-bearing potential, subject must use an acceptable form of birth 
control (hormonal birth control, intrauterine device, double-barrier method, or depot 
contraceptive)  
(6) 
Routinely accepted indication for undergoing colonoscopy, including but not limited to 
polyposis coli diagnosis or surveillance, gastrointestinal bleeding, unexplained 
diarrhoea or constipation, surveillance of inflammatory bowel disease or confirmation 
of mucosal healing, abdominal pain, abnormal endosonography or manometry, anaemia 
of unknown aetiology, cancer surveillance 
(7) 
In the investigator’s judgment, the parent(s)/legal representative are/is mentally 
competent to provide informed consent for the subject to participate in the study 
(8) 
In the investigator’s judgement, subject is able and willing to follow study procedures 
including drug administration and response to questionnaires 
1.3.1.2 
Exclusion Criteria 
If any of the following apply, the subject MUST NOT enter/continue in the study: 
(1) 
Subject with known or suspected ileus, gastrointestinal obstruction, gastric retention 
(gastroparesis), rectal impaction, toxic colitis, severe ulcerative colitis or toxic 
megacolon, advanced carcinoma, swallowing disorders 
(2) 
Subject with known or suspected inflammatory bowel disease (Crohn’s disease, 
ulcerative colitis) in moderate to severe active phase defined by PCDAI >30 (Crohn’s 
disease) or PUCAI >34 (ulcerative colitis) 
(3) 
Subject with bowel perforation or increased risk of bowel perforation, including 
connective tissue disorders or recent bowel surgery 
(4) 
Subject with previous significant gastrointestinal surgery (e.g. colostomy, colectomy, 
gastric bypass, stomach stapling) 
(5) 
Subject with uncontrolled pre-existing electrolyte abnormalities, or with electrolyte 
abnormalities based on Visit 1 laboratory results such as hypernatremia, hyponatremia, 
hyperphosphatemia, hypokalaemia, hypocalcaemia, uncorrected dehydration, or 
secondary to the use of medications such as diuretics or angiotensin converting enzyme 
(ACE) inhibitors judged clinically significant by the investigator 
(6) 
Subject with a prior history or current condition of severe renal (estimated glomerular 
filtration rate (eGFR) less than 30 mL/min/1.73 m2 as calculated by using the Schwartz 


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bedside equation* [1]), liver (ascites, Child-Pugh C), cardiac insufficiency (including 
congestive heart failure all grades) or hyperuricemia 
*The estimated GFR will be calculated in patients with elevated creatinine at baseline. 
(7) 
Female subject who is pregnant or lactating 
(8) 
Subject who has participated in another investigational drug treatment within the last 
90 days before the first study visit 
(9) 
Subject with phenylketonuria 
(10) Subject with history of asthma or hypersensitivity to any ingredient of either drug 
product 
(11) Subject for whom intake of substances likely to affect gastrointestinal motility or 
urinary flow rate is required 
(12) Subject with requirement to take any other oral medication within 3 hours of starting 
the bowel preparation, as this may impact medication absorption 
(13) Subject with tendency for nausea and/or vomiting 
(14) Subject with impaired consciousness that predisposes them to pulmonary aspiration or 
who have known swallowing disorders 
(15) Subject with history of major medical/psychiatric conditions that, in the judgment of 
the investigator, would compromise safety in the study 
(16) Subject with mental or psychiatric condition rendering the subject unable to understand 
the nature, scope and possible consequences of the study, and/or evidence of an 
uncooperative attitude 
(17) Subject with a condition that, in the opinion of the investigator, might increase the risk 
to the subject or decrease the chance of obtaining satisfactory data needed to achieve 
the objectives of the study 
(18) Subject who has previous enrolment in this study or concomitant enrolment in other 
clinical studies 
1.3.2 
Study exposure 
This study will consist of a 1-day enrolment (Day 1, baseline) and investigator-blind label 
dosing period, a 1-day colonoscopy (Day 2) and a 30-day follow-up period (Day 32 (-5/+15, 
i.e. Day 27 to Day 47). Subjects are expected to participate in this study for a minimum of 
27 days and up to 47 days. The subject’s participation in the study will be considered to have 
ended at the time of the last visit (30 days after last Investigational Medicinal Product (IMP) 
intake). 
The overall duration of the study will be approximately 13 months (12 months of recruitment 
+ 1 month of follow-up). 
1.4 
Methods and procedures 
1.4.1 
Subject identification and allocation to study treatment 
All subjects enrolled will be identifiable throughout the study. The investigator will maintain 
a list of subject numbers and names to enable records to be found at a later date if required. 
After eligibility is confirmed, at V1 (Baseline), subjects will be assigned to a randomisation 
number and to the associated treatment arm, in sequential order within each centre and within 
each country.  


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This will be provided by the electronic case report form (eCRF) which will assign the subjects 
to the first not-used randomisation number and so in a treatment arm according to the 
predefined randomisation list. 
The investigator will under no circumstance change the randomisation number and the 
treatment arm allocated to the subject. 
Recruitment will stop once 250 subjects have been randomised. Randomised subjects who 
terminate their study participation for any reason before starting the treatment will retain their 
randomisation number (the randomisation number will not be reused). The next subject is 
given the next randomisation number.  
Randomised subjects who leave the study early will not be replaced. 
1.4.2 
Subjects assessments 
1.4.2.1 
Efficacy assessments 
Blinded overall assessment of preparation efficacy will be determined by the colonoscopist 
upon completion of the examination, based on a 4-point scale. The colonoscopist will score 
the quality of the bowel preparation using the following Cleansing Score (Table 1). 
Table 1 
Cleansing Score 
Score 
Grade 
Description 
4 
Excellent 
No more than small bits of adherent faeces/fluid 
3 
Good 
Small amounts of faeces or fluid not interfering with examination 
2 
Fair 
Enough faeces or fluid to prevent a completely reliable examination 
1 
Poor 
Large amounts of faecal residue, additional cleansing required 
The primary efficacy will be assessed on the basis of preparation success or failure. The 
primary efficacy variable is the proportion of subjects with a successful overall preparation. 
Only perfect preparations graded as excellent (4) or good (3), which allow full, reliable 
examination of the mucosa, will be considered as successful. 
 
The secondary efficacy endpoints are summarised below (Table 2): 


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Table 2 
Secondary Endpoints and Evaluations 
Endpoint 
Timepoint 
Evaluation 
Colon cleansing 
V2 (Colonoscopy) 
Cleansing Score assessed on 4 levels (4-point scale, 
see Table 1). 
Overall and segmental 
cleansing assessed by 
Boston Bowel Preparation 
Scale (BBPS) 
V2 (Colonoscopy) 
BBPS (see Table 3) Overall score [1]. 
Segmental scores (left colon (LC), transverse 
colon (TC), right colon (RC)). 
Time to clear effluent 
(hours) 
V1 (Treatment) 
Time between first intake of prescription and first 
clear watery stool. 
Complete procedure 
V2 (Colonoscopy) 
Number (%) of complete procedures defined as 
procedures that reached the caecum. 
Time to caecal  intubation 
(minutes) 
V2 (Colonoscopy) 
Time between the colonoscope introduction and the 
time to reach caecum. 
Duration of examination 
(minutes) 
V2 (Colonoscopy) 
Time between the caecum is reached and the 
withdrawal of the colonoscope. 
Need for rescue treatment 
because of inadequate 
preparation intake. 
V2 (before colonoscopy) 
Number (%) of procedures that need a rescue 
treatment (saline enema). 
Treatment acceptability 
V1 (Treatment) 
Level of acceptability of treatment assessed using a 5-
point Treatment Acceptability Questionnaire (see 
Table 4). 
Need for nasogastric tube 
V1 (Treatment) 
Number (%) of subjects who need a nasogastric tube 
to complete preparation. 
Treatment compliance 
V1 (Treatment) 
Percentage of volume of fluid taken relative to the 
planned volume of fluid to be taken  
Time between the last 
intake of fluids and the 
start of colonoscopy 
procedure (hours) 
V1 (Treatment) and V2 
(Colonoscopy) 
Time between the end of treatment administration and 
the start of colonoscopy. 
 
The overall and segmental cleansing as assessed by BBPS [1] is presented in Table 3. 
Table 3 
Boston Bowel Preparation Scale 
Score per 
segment 
BBPS definition 
0 
Unprepared colon segment with mucosa not seen due to solid stool that cannot be cleared 
1 
Portion of mucosa of the colon segment seen, but other areas of the colon segment not well 
seen due to staining, residual stool and/or opaque liquid. 
2 
Minor amount of residual staining, small fragments of stool and/or opaque liquid, but 
mucosa of colon segment seen well. 
3 
Entire mucosa of colon segment seen well with no residual staining, small fragments of 
stool and/or opaque liquid 
Scores for the right colon (RC), transverse colon (TC) and left colon (LC) will be collected. 
Scores per segment will be summed to provide overall cleansing score. 
 
The Treatment Acceptability Questionnaire will be completed by the caregiver or subject after 
the subject ends the intake of preparation. Caregivers will be asked to rate subject 
acceptability using the following categories (Table 4). 


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Table 4 
Treatment Acceptability Questionnaire Categories 
Very badly accepted/unacceptable 
Subject showed great displeasure, compromising use of formulation 
Badly but accepted 
Subject showed displeasure with dosing but could be coaxed to take 
complete dose 
Neither good nor bad 
Subject showed no apparent displeasure and with little effort was coaxed to 
take complete dose 
Well accepted 
Subject appeared to enjoy the formulation and with little coaxing ingested 
complete dose 
Very well accepted 
Subject appeared eager and ingested complete dose without special coaxing 
 
The compliance will be assessed from the treatment questionnaire which will be completed by 
the caregiver or subject after the subject ends the intake of preparation. The subject/caregiver 
will provide information about treatment preparation, residual volumes of preparation 
(volumes not taken by the subject) and start and stop times of intake. For the 
Eziclen®/Izinova® treatment only, information about the residual volume of water will be 
reported. 
 
1.4.2.2 
Safety assessments 
• 
Adverse events (AEs) occurring during the study, from signature of informed consent 
up to 30 days after colonoscopy (collected at Visit 4 Day 32 -5/+15), and with the 
following categorizations: 
- 
Seriousness (Yes/No), 
- 
Intensity (Mild/Moderate/Severe), 
- 
Causality (i.e. relationship to study treatment, as Related/Not related). 
• 
Tolerability by a Symptom Scale after each dose of treatment. Subjects/caregivers will 
rate the preparation related symptoms after intake (stomach cramping, stomach bloating 
and nausea) on a paediatric 5-point scale, with 1=no symptom, 2=mild, 3=bothersome, 
4=distressing and 5=severely distressing symptoms. 
• 
Description and histological examination of any colonic biopsy specimens of mucosal 
lesions suspected by the investigator to have been caused by colonic lavage. 
• 
Vital signs including body weight and physical examination: (systolic and diastolic) 
blood pressure (BP) and heart rate (HR) will be assessed with an automated device so 
that measurements are independent of the observer. BP and HR will be recorded in 
standing position and after 5 minutes rest in supine position at V1, after 5 minutes rest 
in supine position at V2 and V4. Absolute values and change from Baseline (V1) will 
be analysed. Body temperature and weight will be recorded at V1, V2 and V4. 
• 
Local laboratory data at V1, V2 and V4: 
- 
Serum biochemistry including: anion gap, alanine aminotransferase (ALT), 
aspartate 
aminotransferase (AST), 
creatine 
phosphokinase (CPK), 
lactic 
dehydrogenase (LDH), gamma-glutamyl transferase (GGT), total and conjugated 
bilirubin, creatinine, urea, serum electrolytes (sodium, potassium, chloride, 
calcium, magnesium, phosphate, bicarbonate), alkaline phosphatase, albumin, 
total protein, C reactive protein (CRP), uric acid, creatinine clearance, eGFR 
(calculated in the eCRF using the Schwartz bedside equation [1]: eGFR = 0.41 * 
height (cm)/Scr (mg/dl), where Scr is the serum creatinine) and osmolality. 


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- 
Urinalysis by dipstick including pH, protein, ketones, bilirubin, blood, 
urobilinogen, nitrites, leukocytes, glucose and specific gravity microscopic 
examination. 
• 
Blood and urine sulfates dosages by central laboratory at V1, V2 and V4. 
1.4.2.3 
Other assessments 
Haematology collected at V1 as baseline characteristics. 
1.4.2.4 
Withdrawal/discontinuation 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, 
pregnancy, or other reasons concerning the health or wellbeing of the subject, or in the case of 
lack of cooperation. In addition, a subject may be withdrawn from the study as described in 
Sections 3.6, 5.2.4.2, 6.2 and 8.1.7 of the protocol. 
Should a subject decide to withdraw from the study after administration of IMP, or should the 
investigator decide to withdraw the subject, all efforts will be made to complete and report the 
observations up to the time of withdrawal as thoroughly as possible. A complete final 
evaluation at the time of the subject’s withdrawal should be made and an explanation given of 
why the subject is withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the eCRF. If a 
subject withdraws consent, every attempt will be made to determine the reason. If the reason 
for withdrawal is an AE or a clinically significant laboratory test abnormality, monitoring will 
continue until the event has resolved or stabilised, until the subject is referred to the care of a 
local health care professional, or until a determination of a cause unrelated to the IMP or 
study procedure is made. The specific AE or test result(s) must be recorded on the eCRF. All 
evaluations should be performed, according to the protocol, on the last day the subject 
receives IMP, or as soon as possible thereafter. If the final visit is conducted more than 
47 days after the dose of IMP, all safety evaluations will be performed. It is not planned to 
collect efficacy data after V2. 


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1.4.3 
Schedule of assessments 
Table 5 
Study Procedures and Assessments 
Study Period 
Baseline/ 
Treatment 
Colonoscopy 
Phone 
contact 
End of Study 
(or in case of Early 
Withdrawal*) 
Visit 
1 
2 
3 
4 
Day 
Day 1 
Day 2 
Day 4 
Day 32 
Window 
 
 
±1 
-5/+15 i.e. Day 27 to Day 47 
Eligibility Criteria 
X 
 
 
 
Demographic Data 
X 
 
 
 
Blood Pregnancy Test [a] 
X 
 
 
 
Informed Consent (parent(s) 
or legal representative) 
X 
 
 
 
Assent (subject)  
X 
 
 
 
Medical and Surgical History 
X 
 
 
 
Indication(s) for Colonoscopy 
X 
 
 
 
Prior and Concomitant 
Medication [b] 
X 
X 
 
X 
Prior and Concomitant Non-
Drug Therapy [b] 
X 
X 
 
X 
AEs [c] 
X[d] 
X 
X[e] 
X 
Physical Examination   
X 
 
 
X 
Vital Signs (Temperature, 
blood pressure (BP) and heart 
rate (HR)) 
X 
X 
 
X 
Body Weight and height[f]  
X 
X 
 
X 
Blood sample collection [g], 
[h] 
X[i] 
X[j] 
 
X 
Urine sample collection[k] 
X 
X 
 
X 
Blood and urine sulfates[l] 
X 
X[j] 
 
X 
RANDOMISATION [m] 
X 
 
 
 
Study treatment dispensation 
(with explanation of treatment 
administration) 
X 
 
 
 
Subject/caregiver leaflet 
dispensation by study nurse 
(with explanation of 
questionnaires including 
compliance measurement) 
X 
 
 
 
Subject takes treatment 
preparation  
X 
 
 
 
Completion of leaflet 
questionnaires by subject/ 
caregiver/ nurse 
 
 
 
 
• 
Treatment 
/ 
Compliance  
X 
 
 
 
• 
Treatment 
Acceptability  
X 
 
 
 
• 
Symptom 
Scale 
(Tolerability)  
X 
 
 
 
Collection of leaflet 
questionnaires by study nurse  
 
X 
 
 
Drug accountability/ study 
administration compliance by 
 
X 
 
 


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Study Period 
Baseline/ 
Treatment 
Colonoscopy 
Phone 
contact 
End of Study 
(or in case of Early 
Withdrawal*) 
unblinded site member 
Colonoscopy assessment [n] 
 
X 
 
 
Subject status at the end of the 
visit 
X 
X 
X 
X 
*Early withdrawal will be anytime from Visit 1 
[a] If applicable. Urine pregnancy test will be performed only when blood tests including pregnancy have been 
performed prior to Visit 1. 
[b] Prior and concomitant medication and non-drug therapy will from 7 days before baseline and for any action 
taken by the investigator 
[c] AEs will be actively collected by the investigator and subjects will be instructed to contact the investigator if 
they experience any AEs 
[d] At baseline, AEs will be collected from the date of informed consent and assent signature 
[e] The investigator will contact the subject by phone on Day 4±1 to collect data on potential AEs  
[f] Height will be measured at Baseline only 
[g] Local laboratory (blood): biochemistry including: anion gap, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), creatine phosphokinase (CPK), lactic dehydrogenase (LDH), gamma-glutamyl 
transferase (GGT), total and conjugated bilirubin, creatinine, urea, serum electrolytes (sodium, potassium, 
chloride, calcium, magnesium, phosphate, bicarbonate), alkaline phosphatase, albumin, total protein, C 
reactive protein (CRP), uric acid, creatinine clearance (calculated GFR), osmolality 
[h] Laboratory assessments performed within 10 days or less prior to inclusion may be used to determine 
eligibility upon investigator agreement. 
[i] Additional local laboratory haematology: complete blood count (CBC), international normalised ratio (INR) 
[j] Blood sampling during anaesthesia 
[k] Local laboratory urine analysis (by dipstick), microscopic examination 
[l] Collection of blood and urine sample for central laboratory sulfate dosage  
[m] Randomisation if satisfactory biochemistry results 
[n] Colonoscopy assessment: Rescue treatment, cleansing Score, BBPS, start time of colonoscopy, time of caecal 
intubation, caecum reached, withdrawal time, diagnosis/findings. 
 
Table 6 
Subject’s Leaflet Collected Information 
 
During/after Dose 1 
Day 1 
During/after Dose 2 
Day 1 
Treatment/Compliance Questionnaire[a]  
X  
X 
Treatment Acceptability Questionnaire 
X 
X 
Symptom Scale (Tolerability) 
X 
X 
Information about time to bowel movement 
and time to first clear watery stool. 
 
X 
[a] Treatment/Compliance questionnaire will collect information about: preparation of treatment, treatment 
intakes (recording of residual volumes, start/end times) for Eziclen®/Izinova® or Klean-Prep®. 
 
1.4.4 
Planned sample size 
The primary aim of the study is to show that Eziclen®/Izinova® is non-inferior to Klean-
Prep® in the proportion of subjects with successful colon cleansing. 
A non-inferiority margin of 15 % has been selected for consistency with other studies in colon 
cleansing preparations. 
Therefore assuming a success rate (excellent or good response) of 85 % in both the 
Eziclen®/Izinova® and Klean-Prep® groups, a one-sided alpha of 0.025 and 90 % power, 
120 subjects are required per treatment group. Assuming a rate dropout/non-compliance to 
protocol of 4 % based on previous studies and taking into account that subjects will be 
hospitalised for treatment administration, 125 subjects will be randomised in each treatment 


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group, i.e. 250 subjects in total. Enrolment will be completed once 250 subjects have been 
randomised. 
The primary endpoint of treatment success will be tested sequentially (hierarchical structure) 
with the first test being non-inferiority test based upon the treatment difference. A rejection of 
the null hypothesis will trigger superiority testing based upon the treatment difference. 
The two hypothesis tests are hierarchically structured so that the second test (superiority) will 
only be considered if the first test (non-inferiority) is rejected. The superiority test is powered 
to detect an absolute difference of 18 %. There is no alpha adjustment for the second test as a 
result of the hierarchical testing. 
 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) 
2.1 
Efficacy 
2.1.1 
Intention-To-Treat population (ITT) 
The ITT population is: 
All randomised subjects who received even a partial dose of study drug.  
Subjects will be assessed according to their randomised treatment, regardless of the treatment 
they receive. 
2.1.1 
Modified Intention-To-Treat population (mITT) 
The mITT population is: 
All randomised subjects who received even a partial dose of study treatment and produced a 
primary efficacy assessment. 
Subjects will be assessed according to their randomised treatment, regardless of the treatment 
they receive. 
2.1.2 
Per Protocol population (PP) 
The PP population is: 
All subjects in the ITT population, who have undergone the colonoscopy procedure and for 
whom no major protocol violation/deviation impacting analyses (as defined in the Protocol 
Deviation Document) occurred. 
2.2 
Safety 
The safety population is: 
All randomised subjects with at least a partial dose of study medication.  
Subjects will be assessed according to the treatment received. 
2.3 
Pharmacokinetics 
Not applicable. 
2.4 
Other populations 
2.4.1 
Screened population 
The screened population is: 
All subjects screened (i.e. who signed the informed consent). 


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2.5 
Primary populations 
The primary analysis based on the primary efficacy endpoint will be performed on the mITT 
population. In that analysis, subjects who do not undergo colonoscopy because of inadequate 
preparation or preparation-related AEs will be considered as failures. In addition, robustness 
of primary efficacy results will be assessed by repeating the primary analysis on the PP 
population. 
The analyses of safety data will be performed based on the safety population. 
3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with ICH E9 guideline [3], will be 
based on the pooled data from the individual study sites, unless otherwise stated, and will be 
performed by Biotrial Biometrics, France, managed by the sponsor’s Biometry Department. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® (version 9.4 
or higher) [4] 
3.1.1 
Primary efficacy endpoint 
The primary efficacy endpoint is the proportion of subjects with a successful overall 
preparation (i.e. graded as excellent (4) or good (3) based on a 4-point scale). 
3.1.2 
Secondary efficacy endpoints 
The secondary efficacy endpoints are: 
• 
the need to place a nasogastric tube to complete preparation, 
• 
the time to clear effluent (from first intake of preparation), as reported by the subject, 
• 
the need for rescue treatment (saline enema) because of inadequate preparation, 
• 
the colon cleansing scores assessed by the 4-point scale (poor, fair, good, excellent), 
• 
the overall and segmental cleansing scores assessed by BBPS, 
• 
the time to caecal intubation (from colonoscope introduction to caecal intubation), 
• 
the duration of examination, measured by colonoscope withdrawal time from caecum, 
• 
the procedure documented as completed (procedures that reached the caecum), 
• 
the treatment compliance: volumes of fluids measured by the caregiver and reported in 
the treatment questionnaire of subject’s leaflet during treatment administration, 
• 
the treatment acceptability, assessed by a Treatment Acceptability Questionnaire 
completed by the caregiver or the subject at the time of intake using a 5-point scale 
questionnaire to be filled in immediately after dosing, 
• 
the time between the last intake of fluids and the start of colonoscopy procedure. 
 
3.1.3 
Safety endpoints 
The safety endpoints are: 
• 
Collection of adverse events (AEs) (for up to 30 days following the day of colonoscopy 
(collected at Visit 4 Day 32 -5/+15)); 
• 
Tolerability of the preparation by a Symptom Scale after each dose of treatment rated 
by the subjects on related symptoms after intake (stomach cramping, stomach bloating 
and nausea) on a paediatric 5-point scale, ranging from 1=no symptom to 5= severely 
distressing symptoms; 


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• 
Description and histological examination of any colonic biopsy specimens of mucosal 
lesions suspected by the investigator to have been caused by colonic lavage; 
• 
Vital signs including body weight and temperature, systolic and diastolic BP and HR; 
• 
Local laboratory data: serum and urinary biochemistry, at baseline, at colonoscopy and 
at the end of study; 
• 
Blood and urine sulfates assessed at central laboratory. 
3.1.4 
Multiplicity 
No adjustment for multiple testing is planned in this study, since the primary endpoint of 
treatment success will be tested sequentially (hierarchical structure) with the first test being 
non-inferiority test based upon the treatment difference. A rejection of the null hypothesis will 
trigger superiority testing based upon the treatment difference, so that the second test 
(superiority) will only be considered if the first test (non-inferiority) is accepted. 
3.1.5 
Significance testing and estimation 
The primary endpoint of treatment success will be tested sequentially with the first test being 
a non-inferiority test based upon the treatment difference. 
A two-sided 95 % confidence interval (CI) for the difference of the two clinical success rates 
(Eziclen®/Izinova® minus Klean-Prep®) will be calculated. If and only if the lower limit of 
the CI is greater than the lower limit of equivalence region -15%, Eziclen®/Izinova® will be 
proven to be not less effective than Klean-Prep®. 
A rejection of the null hypothesis will trigger superiority testing based upon treatment 
difference. If the lower limit of the CI is greater than zero, Eziclen®/Izinova® will be proven 
to be superior to Klean-Prep®. 
The secondary endpoints will be tested for descriptive purpose only. 
3.2 
Analysis methods 
Descriptive statistics will be presented as follows: 
• 
Continuous variables: number of observations, number of missing data, mean, standard 
deviation (SD), median, quartiles, minimum and maximum; 
• 
Dichotomous or categorical variables: frequency and percentage of each of the 
categories and number of missing data. 
All study data will be at least presented in listings. 
3.2.1 
Efficacy 
The primary efficacy analysis will be performed on the mITT population as well as on the PP 
population to assess the robustness of the results. The secondary efficacy analyses will be 
performed on the ITT population and repeated on the mITT and PP if they differ from ITT 
from more than 10 %. The other efficacy analyses will be performed on the ITT population 
and repeated on the mITT if it differs from ITT from more than 10 %. 
3.2.1.1 
Primary efficacy analyses 
The primary endpoint of treatment success will be tested sequentially (hierarchical structure) 
with the first test being non-inferiority test based upon the treatment difference. A rejection of 
the null hypothesis will trigger superiority testing. 
The two hypothesis tests are hierarchically structured so that the second test (superiority) will 
only be considered if the first test (non-inferiority) is accepted. The superiority test is powered 


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to detect an absolute difference of 18 %. There is no alpha adjustment for the second test as a 
result of the hierarchical testing. 
The primary efficacy analysis will be based on the mITT population and repeated on the PP 
population in order to assess the robustness of the results. 
The primary efficacy variable is the proportion of subjects with successful overall preparation 
evaluated with the scale (from 1 to 4) of the Cleansing Score as assessed by the colonoscopist. 
A successful preparation will be defined as excellent (4) or good (3) preparation. 
A failure preparation will be defined as: 
• 
Fair (2) or poor (1) according to colon cleansing score, 
• 
Any subject who did not have a colonoscopy based on the investigator’s assessment of 
the cleansing (insufficient faecal output, unclear faecal discharge, etc.) or due to 
preparation related AEs, 
• 
Any subject for whom cleaning was not adequate for evaluation, 
• 
Any subject for whom rescue treatment (saline enema) was needed. 
The proportion of subjects with successful colon cleansing (graded as excellent or good) will 
be summarised along with the 95 % CI using the standard Wald asymptotic CI using the 
following SAS code: 
proc 
freq 
data=ADCC(where=(PARAM='Successful 
overall 
preparation' 
and 
MITTFL='Y'));  
table AVALC / missing binomial(level='Yes' cl=wald);  
by TRTP; 
run; 
The primary efficacy endpoint will be analysed using a logistic regression model including 
treatment and country as covariates as well as the interaction between treatment and country if 
it is significant (i.e. p < 0.10, as interaction tests have low power) using the following SAS 
code providing the adjusted proportions with their 95 % CI thank to ilink option, and with the 
option firth in the model with interaction since there might otherwise be a quasi-complete 
separation of data points affecting the validity of the model: 
proc logistic data=ADCC(where=(PARAM='Successful overall preparation' and 
MITTFL='Y')); 
class 
TRTP(ref='KLEAN-PREP') 
COUNTRYC(ref='Largest 
country') 
/ 
param=glm; 
model AVALC(EVENT='Yes') = TRTP COUNTRYC TRTP*COUNTRYC / 
link=logit firth; 
lsmeans TRTP / cl ilink; 
ods output lsmeans=lsm ModelANOVA=TestInter; 
run; 
N.B.: TRTP*COUNTRYC, firth and ModelANOVA=TestInter will be removed if the 
interaction is not significant. 
The formal hypothesis test result (p-value) for treatment difference will be presented together 
with a two-sided 95 % CI for the treatment difference in success rates. The non-inferiority 
will be demonstrated if the lower limit of the 95 % CI of that difference is higher than -15 %. 
The treatment difference and its p-value assessed for -15 % margin will be estimated using the 


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following SAS code, since the logistic procedure does not provide adjusted treatment 
differences: 
proc 
freq 
data=ADCC(where=(PARAM='Successful 
overall 
preparation' 
and 
MITTFL='Y')); 
table TRTP / nopercent norow nocum; 
ods output OneWayFreqs=TRTfreq; 
run; 
data estimates; 
merge TRTfreq lsm; 
by TRTP; 
AVALC="N"; Count=Frequency*(1-Mu); output; 
AVALC="Y"; Count=Frequency*Mu; output; 
keep TRTP Frequency Mu AVALC Count; 
run; 
proc freq data=estimates order=data; 
table TRTP*AVALC / alpha=0.05 riskdiff(noninf margin=0.15 column=2); 
weight Count; 
ods output PdiffNoninf=NonInf; 
run; 
If the non-inferiority is demonstrated, the superiority will be analysed based upon treatment 
difference. If the lower limit of the CI is greater than zero, Eziclen®/Izinova® will be proven 
to be superior to Klean-Prep®. The following SAS code will be used to get the superiority p-
value: 
proc freq data=estimates order=data; 
table TRTP*AVALC / alpha=0.05 riskdiff(sup column=2); 
weight Count; 
ods output PdiffSup=Sup; 
run; 
A robustness analysis of primary efficacy results will be assessed by repeating the primary 
analysis on the PP population.  
Furthermore, the robustness of the results will be assessed by using another SAS procedure in 
the mITT, since the adjusted difference cannot be assessed directly from the proc logistic 
inducing a potential bias. Then the SAS procedure genmod will be used with identity link 
including treatment and country as covariates, using the following example of SAS code: 
proc genmod data=ADCC(where=(PARAM='Successful overall preparation' and 
MITTFL='Y')); 
class TRTP(ref='KLEAN-PREP') COUNTRYC(ref='Largest country'); 
model AVALC(EVENT='Yes') = TRTP COUNTRYC / link=identity; 
lsmeans TRTP / diff cl; 
run; 
No p-value will be displayed for the genmod model, since this would not be equivalent to the 
ones provided for the logistic procedure analysis.  


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In addition, the robustness of the results will be assessed in the mITT population by repeating 
the procedure logistic and estimating the 95 % CI of the treatment difference using the 
bootstrap method: 
x The adjusted proportions will be estimated using the proc logistic model; 
x 10’000 random samples will be generated using a proc surveyselect from the observed 
data with treatment and country as stratification and with seed=111; 
x The adjusted proportions for each sample will be estimated using the same proc 
logistic model by replicate; 
x The treatment differences will be derived for each sample; 
x The 2.5 and 97.5 percentiles of the 10’000 estimated treatment differences will be 
considered for the 95 % CI of the treatment difference.  
The following SAS code will be used: 
proc logistic data=ADCC(where=(PARAM='Successful overall preparation' and 
MITTFL='Y')); 
class 
TRTP(ref='KLEAN-PREP') 
COUNTRYC(ref='Largest 
country') 
/ 
param=glm; 
model AVALC(EVENT='Yes') = TRTP COUNTRYC / link=logit firth; 
lsmeans TRTP / cl ilink; 
ods output lsmeans=lsm; 
run; 
proc transpose data=lsm out=_lsm; 
var Mu; 
id TRTP; 
run; 
data diff; 
set _lsm; 
diff = EZICLEN – KLEAN-PREP; 
run; 
proc surveyselect data=ADCC(where=(PARAM='Successful overall preparation' and 
MITTFL='Y')) out=samples method=urs samprate=1 rep=10000 outhits seed=111; 
strata TRTP COUNTRYC; 
run; 
proc sort data=samples; by replicate; run; 
proc logistic data=samples; 
by replicate; 
class replicate TRTP(ref='KLEAN-PREP') COUNTRYC(ref='Largest country') / 
param=glm;  
model AVALC(EVENT='Yes') = TRTP COUNTRYC / link=logit; 
lsmeans TRTP / cl ilink; 
ods output lsmeans=lsm_boot(keep=replicate TRTP Mu); 
run; 


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proc sort data=lsm_boot; by replicate; run; 
proc transpose data=lsm_boot out=_lsm_boot; 
var Mu; 
by replicate; 
id TRTP; 
run; 
data final; 
set _lsm_boot; 
diff = EZICLEN - KLEAN-PREP; 
run; 
proc sort data=final; by diff; run; 
proc univariate data=final noprint; 
var diff; 
output out=ci95(rename=(Q2_5=Lower Q97_5=upper Q50=median)) pctlpre=Q 
pctlpts=2.5 50 97.5; 
run; 
No p-value will be displayed for this robustness analysis. 
Finally, primary efficacy results will be repeated in the mITT by country using the main 
model with the treatment * country interaction in order to get the treatment effect by country 
as follows: 
proc logistic data=ADCC(where=(PARAM='Successful overall preparation' and 
MITTFL='Y')); 
class 
TRTP(ref='KLEAN-PREP') 
COUNTRYC(ref='Largest 
country') 
/ 
param=glm; 
model AVALC(EVENT='Yes') = TRTP COUNTRYC TRTP*COUNTRYC / 
link=logit firth; 
lsmeans TRTP*COUNTRYC / cl ilink; 
run; 
The adjusted proportions by country with their 95 % CI and the treatment difference with 
their 95 % CI derived using proc freq as above by country will be presented, but p-values will 
not be displayed. 
And primary analysis will also be repeated in the mITT by age class, weight class and sex 
using the main model with the treatment * country interaction if it is significant in the primary 
model, as well as the treatment * subgroup interaction as follows: 
proc logistic data=ADCC(where=(PARAM='Successful overall preparation' and 
MITTFL='Y')); 
class 
TRTP(ref='KLEAN-PREP') 
COUNTRYC(ref='Largest 
country') 
SUBGROUP(ref='First class') / param=glm; 
model AVALC(EVENT='Yes') = TRTP COUNTRYC TRTP*COUNTRYC 
TRTP*SUBGROUP / link=logit firth; 
lsmeans TRTP*SUBGROUP / cl ilink; 
run; 


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The adjusted proportions by subgroup with their 95 % CI and the treatment differences with 
their 95 % CI will be presented, but p-values will not be displayed. 
3.2.1.2 
Secondary efficacy analyses 
Analysis of secondary efficacy endpoints will be performed on the ITT population and could 
be duplicated on mITT if there is a difference of more than 10% of subjects between ITT and 
mITT. 
 
3.2.1.2.1 Colon cleansing score 
The colon cleansing scores will be assessed by the 4-point scale (see Table 1) and will be 
presented by treatment group using descriptive summary statistics (mean, SD, median, 
quartiles and ranges) and using a two-way analysis of variance (ANOVA) including treatment 
and country as well as the interaction between treatment and country, if it is significant (i.e. 
p < 0.10), as covariates using the following SAS code: 
proc mixed data=ADCC(where=(PARAM='Cleansing score' and ITTFL='Y')); 
class TRTP COUNTRYC; 
model AVAL = TRTP COUNTRYC TRTP*COUNTRYC; 
lsmeans TRTP / diff cl; 
run; 
The adjusted mean scores, the adjusted treatment difference with their 95 % CI and the p-
value of difference will be summarised.  
In addition, this analysis will also be produced per country so that mean scores and the 
estimated treatment differences will also be provided per country using the following SAS 
code. 
proc mixed data=ADCC(where=(PARAM='Cleansing score' and ITTFL='Y')); 
class TRTP COUNTRYC; 
model AVAL = TRTP COUNTRYC TRTP*COUNTRYC; 
lsmeans TRTP*COUNTRYC / diff cl; 
run; 
 
3.2.1.2.2 Overall and segmental cleansing scores assessed by BBPS 
The overall (LC + TC + RC) and segmental (LC, TC, RC) cleansing scores will be assessed 
by BBPS (see Table 3) and will be presented by treatment group using descriptive summary 
statistics (mean, SD, median, quartiles and ranges) and using a two-way analysis of 
variance (ANOVA) including treatment and country as well as the interaction between 
treatment and country, if it is significant (i.e. p < 0.10), as covariates using the following SAS 
code: 
proc mixed data=ADCC(where=(PARAM=’BBPS - Global Score’/’BBPS - Left colon 
score’/’BBPS - Transverse colon score’/’BBPS - Right colon score’ and ITTFL='Y')); 
class TRTP COUNTRYC; 
model AVAL = TRTP COUNTRYC TRTP*COUNTRYC; 
lsmeans TRTP / diff cl; 
run; 


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The adjusted mean scores, the adjusted treatment differences with their 95 % CI and the p-
value of difference will be summarised.  
In addition, this analysis will also be produced per country so that mean scores and the 
estimated treatment differences will also be provided per country using the following SAS 
code. 
proc mixed data=ADCC(where=(PARAM=’BBPS - Global Score’/’BBPS - Left colon 
score’/’BBPS - Transverse colon score’/’BBPS - Right colon score’ and ITTFL='Y')); 
class TRTP COUNTRYC; 
model AVAL = TRTP COUNTRYC TRTP*COUNTRYC; 
lsmeans TRTP*COUNTRYC / diff cl; 
run; 
 
The proportion of subjects with successful overall preparation, assessed by the total score of 
the BBPS, will also be presented. Successful overall preparation will be defined based on a 
global BBPS score ≥ 6 for the sum of the 3 segments (right, transverse and left colon) and will 
be presented by treatment group using frequency count with two-sided 95 % CI and analysed 
using Cochran-Mantel-Hænszel (CMH) chi-square for the proportions adjusting for country 
effect. The general association statistic will be used to assess the test significance. 
The SAS Freq procedure will be used as follows: 
proc freq data= ADCC(where=(PARAM=’Successful overall preparation BBPS’ and 
ITTFL='Y')); 
table COUNTRYC*TRTP*AVALC / CMH; 
run; 
The difference of proportions with the 95 % CI and p-value will be summarised.  
 
3.2.1.2.3 Time to clear effluent 
The time to clear effluent as reported by the subject as the time between first intake of 
prescription and first clear watery stool will be assessed and will be analysed using survival 
methods.  
Table 7 specifies the event and censoring dates to be used in the analysis of time to clear 
effluent. 
Table 7 
Time to Clear Effluent (hours) 
Event 
Time of event 
Outcome 
Clear watery stools 
Time of clear watery stools 
Event 
No clear watery stools with colonoscopy 
Time of colonoscope introduction 
Censored 
No clear watery stools without colonoscopy 
Time of start of treatment + 12h 
Censored 
The distribution of time to clear effluent will be estimated using the Kaplan-Meier (KM) 
product limit method. The results will be presented in a summary table and a KM plot will 
also be constructed. 
The summary table will present by treatment group the numbers and percentages of subjects 
with occurrence of clear watery stool and the numbers and percentages of censored subjects. 
The summary will also include the median time to clear effluent as well as the 25th and 75th 


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percentiles with their two-sided 95 % CI, the percentage and 95 % CIs of subjects who had 
clear watery stool at 2, 3, 4, 5, 6, 9, 12, 15, 18 and 24 hours from KM estimates. 
Confidence intervals for median time to clear effluent as well as the 25th and 75th percentile 
CIs will be calculated using the method of Brookmeyer and Crowley (1982) [5], which is the 
default method within SAS® version 9 and higher. 
Kaplan-Meier curves will be constructed by treatment group and will display the number of 
subjects at risk at 1, 1.5, 2, 2.5, 3, 3.5, 6, 9, 12, 15, 18 and 24 hours. 
In addition, the treatment difference will be tested using a Cox proportional hazards model 
adjusted on country and the association with treatment will be further explored by presenting 
separate KM plots for each country. 
The SAS Phreg procedure will be used as follows: 
Proc Phreg Data=ADTTE(where=(PARAMCD=’Time to Clear Effluent (hours)’ and 
ITTFL='Y')); 
Class TRTP(ref='KLEAN-PREP') COUNTRYC(ref='Largest country'); 
Model AVAL*CNSR(1) = TRTP COUNTRYC / Ties = EXACT; 
Run; 
 
3.2.1.2.4 Complete procedure 
The proportion of complete procedure (defined as procedures (i.e. colonoscopies) that reached 
the caecum) will be assessed. It will be tabulated by treatment group using frequency count 
with two-sided 95 % CI and analysed using Cochran-Mantel-Hænszel (CMH) chi-square for 
the proportions adjusting for country effect. The general association statistic will be used to 
assess the test significance. 
The SAS Freq procedure will be used as follows: 
proc freq data=ADPR(where=(PRTRT=’COLONOSCOPY’ and AVISITN=2 and 
ITTFL='Y')); 
table COUNTRYC*TRTP*PROCCUR / CMH; 
run; 
The difference of proportions with the 95 % CI and p-value will be summarised. 
The reasons for non-completion will also be presented. 
 
3.2.1.2.5 Time to caecal intubation 
The time to caecal intubation (from colonoscope introduction to caecal intubation) will be 
assessed and will be analysed using survival methods on subjects who performed 
colonoscopy. 
Table 8 specifies the event and censoring dates to be used in the analysis of time to clear 
effluent. 


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Table 8 
Time to caecal intubation (minutes) 
Event 
Time of event 
Outcome 
Caecal intubation 
Time of caecal intubation 
Event 
Procedure (i.e. colonoscopy) did not reach the 
caecum 
Time of withdrawal of colonoscope 
Censored 
The distribution of time to caecal intubation will be estimated using the Kaplan-Meier (KM) 
product limit method. The results will be presented in a summary table and a KM plot will 
also be constructed. 
The summary table will present by treatment group the numbers and percentages of subjects 
with occurrence of caecal intubation and the numbers and percentages of censored subjects. 
The summary will also include the median time to caecal intubation as well as the 25th and 
75th percentiles with their two-sided 95 % CI, the percentage and 95 % CIs of subjects who 
had caecal intubation at 5, 10, 15, 20, 25, 30, 45 and 60 minutes from KM estimates. 
Confidence intervals for median time to caecal intubation as well as the 25th and 75th 
percentile CIs will be calculated using the method of Brookmeyer and Crowley (1982) [5], 
which is the default method within SAS® version 9 and higher. 
Kaplan-Meier curves will be constructed by treatment group and will display the number of 
subjects at risk at 5, 10, 15, 20, 25, 30, 45 and 60 minutes. 
In addition, the treatment difference will be tested using a Cox proportional hazards model 
adjusted on country and the association with treatment will be further explored by presenting 
separate KM plots for each country. 
The SAS Phreg procedure will be used as follows: 
Proc Phreg Data=ADTTE(where=(PARAMCD=’Time to caecal intubation' and 
ITTFL='Y')); 
Class TRTP(ref='KLEAN-PREP') COUNTRYC(ref='Largest country'); 
Model AVAL*CNSR(1) = TRTP COUNTRYC / Ties = EXACT; 
Run; 
 
3.2.1.2.6 Duration of examination 
The duration of examination (in minutes), measured by the difference between the time of 
caecum intubation and the time of withdrawal of the colonoscope, will be assessed. Subjects 
for whom the caecum was not reached will be excluded from this analysis. The results will be 
presented by treatment group using descriptive summary statistics (mean, SD, median, 
quartiles and ranges) and using a two-way ANOVA including treatment and country as well 
as the interaction between treatment and country, if it is significant (i.e. p < 0.10), as 
covariates using the following SAS code: 
proc mixed data=ADCC(where=(PRTRT=’COLONOSCOPY’ and AVISITN=2 and 
ITTFL='Y')); 
class TRTP COUNTRYC; 
model ADUREXA = TRTP COUNTRYC TRTP*COUNTRYC; 
lsmeans TRTP / diff cl; 
run; 


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The adjusted mean durations of examination, the adjusted treatment difference with their 
95 % CI and the p-value of difference will be summarised.  
In addition, this analysis will also be produced per country so that mean durations and the 
estimated treatment differences will also be provided per country using the following SAS 
code. 
proc mixed data=ADCC(where=(PRTRT=’COLONOSCOPY’ and AVISITN=2and 
ITTFL='Y')); 
class TRTP COUNTRYC; 
model ADUREXA = TRTP COUNTRYC TRTP*COUNTRYC; 
lsmeans TRTP*COUNTRYC / diff cl; 
run; 
 
3.2.1.2.7 Rescue treatment 
The proportion of procedures that need a rescue treatment (saline enema) because of 
inadequate preparation intake will be assessed. It will be tabulated by treatment group using 
frequency count with two-sided 95 % CI and analysed using Cochran-Mantel-Hænszel 
(CMH) chi-square for the proportions adjusting for country effect. The general association 
statistic will be used to assess the test significance. 
The SAS Freq procedure will be used as follows: 
proc 
freq 
data=ADCM(where=(CMCAT='RESCUE 
MEDICATION' 
and 
CMTRT='ENEMA' and ITTFL='Y')); 
table COUNTRYC*TRTP*CMOCCUR / CMH; 
run; 
The difference of proportions with the 95 % CI and p-value will be summarised.  
 
3.2.1.2.8 Need for a nasogastric tube 
The proportion of subjects who needed a nasogastric tube to complete preparation will be 
assessed and the reason for placing it will be collected. They will be tabulated by treatment 
group using frequency count with two-sided 95 % CI and analysed using Cochran-Mantel-
Hænszel (CMH) chi-square for the proportions adjusting for country effect. The general 
association statistic will be used to assess the test significance. 
The SAS Freq procedure will be used as follows: 
proc freq data=ADEX(where=(EXTRT=' EZICLEN/IZINOVA' and ITTFL='Y')); 
table COUNTRYC*TRTP*NASOTUBE / CMH; 
run; 
The difference of proportions with the 95 % CI and p-value will be summarised.  
The proportion of subjects who needed a nasogastric tube to complete preparation will also be 
tabulated by dose. 
 
3.2.1.2.9 Treatment acceptability 
The treatment acceptability at the time of intake after dose 1 and after dose 2 will be assessed 
by a Treatment Acceptability Questionnaire completed by the caregiver or the subject using a 


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5-point scale questionnaire (see Table 4). It will be tabulated for each dose and overall (by 
taking the average of the 2 doses then considered as a score as follows: 1= Very badly 
accepted/unacceptable, 2= Badly but accepted, 3= Neither good nor bad, 4= Well accepted 
and 5= Very well accepted) by treatment group.  
The acceptability for each dose will be assessed using frequency count with two-sided 95 % 
CI and analysed using Cochran-Mantel-Hænszel (CMH) chi-square for the proportions 
adjusting for country effect. The row mean scores differ statistic will be used to assess the test 
significance. 
The SAS Freq procedure will be used as follows: 
proc 
freq 
data=ADQS(where=(QSCAT='TREATMENT 
ACCEPTABILITY 
QUESTIONNAIRE' and PARAMCD in (‘TRTA011’,’TRTA012‘) and ITTFL='Y')); 
table COUNTRYC*TRTP*QSORRES / CMH; 
by QSGRPID; 
run; 
The p-value of difference will be summarised.  
The overall acceptability will be presented by treatment group using descriptive summary 
statistics (mean, SD, median, quartiles and ranges) and using a two-way ANOVA including 
treatment and country as well as the interaction between treatment and country, if it is 
significant (i.e. p < 0.10), as covariates using the following SAS code: 
proc 
mixed 
data=ADQS(where=(QSCAT='TREATMENT 
ACCEPTABILITY 
QUESTIONNAIRE' and PARAMCD=‘TRTA01’ and ITTFL='Y')); 
class TRTP COUNTRYC; 
model COMPLIPCT = TRTP COUNTRYC TRTP*COUNTRYC; 
by ASPID; 
lsmeans TRTP / diff cl; 
run; 
The adjusted mean score, the adjusted treatment difference with their 95 % CI and the p-value 
of difference will be summarised.  
 
3.2.1.2.10 
Treatment compliance 
According to the instructions of use provided in the prescription, subjects should get for 
Eziclen®/Izinova® 750 mL of preparation followed by an additional 750 mL of water at first 
and second dose, that is to say a total volume of 2250 mL, and for Klean-Prep® 70 mL/kg of 
preparation according to the weight split into 2 doses with a maximum global volume 
administered of 4000 mL (2000 mL per dose). The volumes taken will be presented by 
treatment group using descriptive summary statistics (mean, SD, median, quartiles and 
ranges). No comparison will be performed since treatment administration schemes are 
different. 
The treatment compliance will be assessed as the percentage of volume of fluid taken relative 
to the planned volume of fluid to be taken using the volumes of fluids measured by the 
caregiver and reported in the treatment questionnaire of subject’s leaflet during treatment 
administration by dose and overall for the preparation for Klean-Prep® and for the 
preparation, the water and the total for Eziclen®/Izinova®. Then the percentage of 
compliance will be presented by treatment group using descriptive summary statistics (mean, 


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SD, median, quartiles and ranges) and using a two-way ANOVA including treatment and 
country as well as the interaction between treatment and country, if it is significant (i.e. 
p < 0.10), as covariates using the following SAS code: 
proc mixed data=ADEX(where=(EXCAT='COMPLIANCE' and EXSCAT='Overall' 
and ITTFL='Y')); 
class TRTP COUNTRYC; 
model COMPLIPCT = TRTP COUNTRYC TRTP*COUNTRYC; 
by ASPID; 
lsmeans TRTP / diff cl; 
run; 
The adjusted mean compliances, the adjusted treatment difference with their 95 % CI and the 
p-value of difference will be summarised.  
In addition, this analysis will also be produced per country so that mean compliances and the 
estimated treatment differences will also be provided per country using the following SAS 
code. 
proc mixed data= ADEX(where=(EXCAT='COMPLIANCE' and EXSCAT='Overall' 
and ITTFL='Y')); 
class TRTP COUNTRYC; 
model COMPLIPCT = TRTP COUNTRYC TRTP*COUNTRYC; 
lsmeans TRTP*COUNTRYC / diff cl; 
run; 
Moreover, this analysis will also be produced per sex, age class and weight class, so that mean 
compliances and the estimated treatment differences will also be provided per subgroup using 
the following SAS code and adding the treatment*country interaction if it is significant. 
proc mixed data= ADEX(where=(EXCAT='COMPLIANCE' and EXSCAT='Overall' 
and ITTFL='Y')); 
class TRTP COUNTRYC SUBGROUP; 
model COMPLIPCT = TRTP COUNTRYC SUBGROUP TRTP*SUBGROUP; 
lsmeans TRTP*SUBGROUP / diff cl; 
run; 
Additionally, a subject will be considered as compliant with the instructions of use provided 
in the prescription if he/she drinks the whole preparation (volume = 100 %). The proportion 
of subjects compliant with the instructions of use provided in the prescription will be 
presented using summary statistics with the 95 % CI by treatment group and analysed using 
Cochran-Mantel-Hænszel (CMH) chi-square for the proportions adjusting for country effect. 
The general association statistic will be used to assess the test significance. 
The SAS Freq procedure will be used as follows: 
proc freq data=ADEX(where=(EXCAT='COMPLIANCE' and EXSCAT='Overall' and 
ITTFL='Y')); 
table COUNTRYC*TRTP*COMPLI / CMH; 
by ASPID; 
run; 
The difference of proportions with the 95 % CI and p-value will be summarised. 


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Finally, the compliance will be presented by categories (100 %, ]100-75], ]75-50] and 
< 50 %). The proportion of subjects in each category will be presented using summary 
statistics with the 95 % CI by treatment group and analysed using Cochran-Mantel-Hænszel 
(CMH) chi-square for the proportions adjusting for country effect. The row mean scores differ 
statistic will be used to assess the test significance. 
The SAS Freq procedure will be used as follows: 
proc freq data=ADEX(where=(EXCAT='COMPLIANCE' and EXSCAT='Overall' and 
ITTFL='Y')); 
table COUNTRYC*TRTP*COMPLICL / CMH; 
by ASPID; 
run; 
The difference of proportions with the 95 % CI and p-value will be summarised.  
The percentage of compliance, the proportion of patients considered as compliant and the 
compliance in categories will be described after each dose and overall. For the 
Eziclen/Izinova treatment group, the compliance will be also described separately for active 
treatment and hydration after each dose and overall. 
 
3.2.1.3 
Other efficacy analyses 
Analysis of other efficacy endpoints will be performed on the ITT population. 
3.2.1.3.1 Time to first bowel movement 
The time to first bowel movement defined as the time between first intake of prescription and 
first bowel movement will be assessed and analysed using survival methods. 
Table 9 specifies the event and censoring dates to be used in the analysis of time to first bowel 
movement. 
Table 9 
Time to First Bowel Movement (hours) 
Event 
Time of event 
Outcome 
First bowel movement 
Time of first bowel movement 
Event 
No bowel movement with colonoscopy 
Time of colonoscope introduction 
Censored 
No bowel movement without colonoscopy 
Time of first intake of prescription + 12 hours 
Censored 
The distribution of time to first bowel movement will be estimated using the Kaplan-
Meier (KM) product limit method. The results will be presented in a summary table and a KM 
plot will also be constructed. 
The summary table will present by treatment group the numbers and percentages of subjects 
with occurrence of first bowel movement and the numbers and percentages of censored 
subjects. The summary will also include the median time to first bowel movement as well as 
the 25th and 75th percentiles with their two-sided 95 % CI, the percentage and 95 % CIs of 
subjects who had first bowel movement at 1, 1.5, 2, 2.5, 3, 3.5, 6, 9, 12, 15 and 18 hours from 
KM estimates. 
Confidence intervals for median time to first bowel movement as well as the 25th and 75th 
percentile CIs will be calculated using the method of Brookmeyer and Crowley (1982) [5], 
which is the default method within SAS® version 9 and higher. 
Kaplan-Meier curves will be constructed by treatment group and will display the number of 
subjects at risk at 1, 1.5, 2, 2.5, 3, 3.5, 6, 9, 12, 15 and 18 hours. 


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In addition, The treatment difference will be tested using a Cox proportional hazards model 
adjusted on country and the association with treatment will be further explored by presenting 
separate KM plots for each country. 
The SAS Phreg procedure will be used as follows: 
Proc Phreg Data=ADTTE(where=(PARAMCD='Time to first bowel movement' and 
ITTFL='Y')); 
Class TRTP(ref='KLEAN-PREP') COUNTRYC(ref='Largest country'); 
Model AVAL*CNSR(1) = TRTP COUNTRYC / Ties = EXACT; 
Run; 
 
3.2.1.3.2 Wake-up during the night to have a bowel movement 
The proportion of patients who wake-up during the night to have a bowel movement will also 
be tabulated by treatment group using frequency count with two-sided 95 % CI and analysed 
using Cochran-Mantel-Hænszel (CMH) chi-square for the proportions adjusting for country 
effect. The general association statistic will be used to assess the test significance. 
The SAS Freq procedure will be used as follows: 
proc freq data=ADCE(where=(CETERM='NIGHTLY BOWEL MOVEMENT' and 
ITTFL='Y')); 
table COUNTRYC*TRTP*CEOCCUR / CMH; 
run; 
The difference of proportions with the 95 % CI and p-value will be summarised.  
 
3.2.1.3.3 Satisfaction 
The satisfaction will be also assessed through the question "If it was necessary, would you 
agree to undergo preparation with this product again?". It will also be tabulated by treatment 
group using frequency count with two-sided 95 % CI and analysed using Cochran-Mantel-
Hænszel (CMH) chi-square for the proportions adjusting for country effect. The general 
association statistic will be used to assess the test significance. 
The SAS Freq procedure will be used as follows: 
proc freq data=ADQS(where=(QSTEST='AGREE TO TAKE PRODUCT AGAIN' and 
ITTFL='Y')); 
table COUNTRYC*TRTP*QSORRES / CMH; 
run; 
The difference of proportions with the 95 % CI and p-value will be summarised.  
3.2.1.3.4 Time between the last intake of fluids and the start of colonoscopy procedure 
The time between the last intake of fluids and the start of colonoscopy procedure will be 
presented by treatment group using descriptive summary statistics (mean, SD, median, 
quartiles and ranges) and using a two-way analysis of variance (ANOVA) including treatment 
and country as well as the interaction between treatment and country, if it is significant (i.e. 
p < 0.10), as covariates using the following SAS code: 
proc mixed data=ADEX(where=(PARAM=’Time between the last intake of fluids and 
the start of colonoscopy procedure’ and ITTFL='Y')); 
class TRTP COUNTRYC; 


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model AVAL = TRTP COUNTRYC TRTP*COUNTRYC; 
lsmeans TRTP / diff cl; 
run; 
The adjusted mean times, the adjusted treatment difference with their 95 % CI and the p-value 
of difference will be summarised.  
In addition, this analysis will also be produced per country so that mean scores and the 
estimated treatment differences will also be provided per country using the following SAS 
code. 
proc mixed data=ADEX(where=(PARAM=’Time between the last intake of fluids and 
the start of colonoscopy procedure’ and ITTFL='Y')); 
class TRTP COUNTRYC; 
model AVAL = TRTP COUNTRYC TRTP*COUNTRYC; 
lsmeans TRTP*COUNTRYC / diff cl; 
run; 
 
3.2.2 
Safety 
The analyses of safety data will be performed based on the safety population. 
3.2.2.1 
Adverse events 
All AEs will be coded according to MedDRA (last version used for coding during the study 
course) and will be classified by MedDRA preferred term (PT) and system organ class (SOC). 
AE listings will be presented by subject, SOC and PT for all AEs, serious AEs (SAEs) and 
AEs leading to withdrawal on the safety population. 
A TEAE is defined as any AE that occurs during the active phase of the study if: 
• 
it was not present prior to receiving the first dose of IMP  
or 
• 
it was present prior to receiving the first dose of IMP but the intensity increased during 
the active phase of the study. 
All TEAEs will be flagged in the AEs listings. 
An overall summary table of all AEs will be presented with the number of AEs and the 
numbers and percentage of subjects with exact 95 % CI for each of the following categories: 
• 
Any AEs, 
• 
Any SAEs, 
• 
Causality of SAEs, 
• 
Any TEAEs, 
• 
Intensity of TEAEs, 
• 
Causality of TEAEs, 
• 
Causality and intensity of TEAEs, 
• 
Any TEAEs leading to death, 
• 
Any TEAEs leading to withdrawal. 
In the event of multiple AEs being reported by the same subject, each subject is counted for 
each intensity level, each causality level or each intensity and causality combined level. That 
means that the total number of subjects for all levels of intensity/causality might be higher 


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than the overall number of subjects with at least one AE. Related adverse events are those 
events with causality missing or related. 
Incidence by SOC/PT of all reported TEAEs, related TEAEs, SAEs and TEAEs leading to 
withdrawal of study medication will be tabulated by treatment group and overall. In addition, 
summary tables by SOC/PT will present TEAEs by maximum intensity and drug relationship 
and will present TEAEs with incidence >= 2 %. And a summary table will present TEAEs by 
decreasing frequency of PT. 
In the event of multiple occurrence of the same AE (same PT) being reported by the same 
subject, the maximum intensity (severe > missing > moderate > mild) and the most serious 
causality (related > not related) for each concerned PT will be chosen. 
Moreover, the summary table will be duplicated by sex, age class and weight class, as well as 
the summary table of the incidence of TEAEs by SOC and PT. 
Additionally, lesions suspected to be caused by colonic lavage (identified during the potential 
histological examinations of taken colonic biopsy specimens) will be recorded as AEs with 
the mention "suspected to be caused by colonic lavage" in the verbatim term by the 
investigator. The occurrence (Yes/No) of such AEs will be summarised for the treated 
subjects for whom the colonoscopy was done by treatment group and overall as well as the 
incidence by SOC/PT. The result of the biopsy will be listed. 
3.2.2.2 
Laboratory data 
Laboratory data (haematology, biochemistry, and urinalysis) will be collected locally, while 
urine and blood sulfates will be assessed centrally. They will be listed in SI units and 
abnormal values will be derived using original normal ranges when available rather than using 
the investigator assessment and flagged (High [H], Low [L], clinically significant [C]), where 
applicable.  
For eGFR, a threshold will be used and values ≥ 75 mL/min/1.73 m² will be considered as 
normal, while the other ones will be considered as low. 
Any unscheduled laboratory assessments will be flagged [U] in the listings. 
A listing will present all values for a subject with at least one clinically significant abnormal 
laboratory value for biochemistry and urinalysis. 
The baseline will be defined as the last measurement collected prior to the first dose of study 
drug. 
As more than one laboratory will be involved in the study for the measurement of laboratory 
values, a standardisation method will be required in order to take into account the multiple 
reference ranges [6] for haematology, biochemistry, and urinalysis parameters with normal 
ranges. The site which has analysed the largest number of blood samples will be used as the 
reference site. The following formula will be used: 
ܵݐܽ݊݀ܽݎ݀݅ݏ݁݀ ݒ݈ܽݑ݁ൌܮோ൅ሺݔെܮ௑ሻܷோെܮோ
ܷ௑െܮ௑
 
With LR the reference site lower limit, UR the reference site upper limit, LX the local site 
lower limit, UX the local site upper limit and x the non standardised value assessed in the local 
laboratory. 
If a standardised value is negative it will be replaced by 0. 
For pH and specific gravity no normal range is available, so no standardisation will be applied 
and no shift table will be provided. 


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For continuous urinalysis data and biochemistry, summary statistics will be presented by 
treatment group at each scheduled assessment for actual values and changes from baseline. 
Shift tables (based on local assessment) from baseline to each post baseline visit will be 
presented of the number and percentage of subjects with [low, normal or high values] at each 
visit. 
For categorical urinalysis data (absent/trace/positive and normal/abnormal) frequency tables, 
by treatment group, will be presented at each scheduled assessment. Shift tables from baseline 
to each post baseline visit will be presented for the number and percentage of subjects with 
[normal, abnormal]. 
For blood and urine sulfates, summary statistics (mean, median, SD, minimum and 
maximum) will be presented by treatment group at each scheduled assessment for actual 
values and changes from baseline. In addition, mean plots by visit and treatment group will 
also be provided. Finally, sulfates are supposed to be collected fasted, and since some 
assessments have been performed non-fasted, a sensitivity analysis will be made to describe 
actual values and changes from baseline by treatment group and fasting status at each 
scheduled assessment. 
3.2.2.3 
Vital signs 
Vital signs (including body weight and temperature, systolic and diastolic BP and HR) will be 
listed at each assessment by treatment group and subject. Any unscheduled vital signs will be 
flagged [U] in the listing. 
Baseline values will be defined as the last vital signs measurement collected prior to the first 
dose of study drug. 
Summary statistics for weight, temperature, BP and HR will be presented at each scheduled 
assessment for actual values and changes from baseline by treatment group. 
Additionally, a frequency table describing the variations at post-baseline visits will be 
provided with the following categories: 
• 
Weight: < -2 kg, [-2; -1 kg[, [-1; 1 kg[, [1; 2 kg] > 2 kg. 
• 
BP and HR: < -20 unit, [-20; -10 unit[, [-10; 10 unit[, [10-20 unit] and > 20 unit. 
 
3.2.2.4 
Tolerability 
Tolerability will be collected using a Symptom Scale after each dose of treatment for stomach 
cramping, stomach bloating and nausea on a paediatric 5-point scale (with 1=no symptom, 
2=mild, 3=bothersome, 4=distressing and 5=severely distressing symptoms). 
Each symptom after each dose will be described by treatment group using a frequency table. 
Additionally, each symptom after each dose will be summarised by treatment group as well as 
the total score (sum of the three symptoms). 
Finally, each symptom after each dose will be summarised by treatment group and use of 
nasogastric tube (Yes/No), as well as sex, age class and weight class. 
3.2.2.5 
Physical examination 
A listing with the date of examination and the status of the examination (performed/not 
performed) will be provided by treatment group, subject and examination date. 


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3.2.2.6 
Colonoscopy findings 
Diagnosis or diagnostic findings made at colonoscopy will be reported as such and coded 
using SOC and PT. The colonoscopy findings, when reported, will then be described for 
incidence by SOC and PT by treatment group. 
 
3.2.3 
Missing data and outliers 
3.2.3.1 
Missing data 
No missing value will be replaced, except for the primary analysis where the missing 
preparation evaluations (because of colonoscopy not done because of inadequate preparation 
or preparation-related AEs) will be considered as failures. 
In the description of qualitative parameters, subjects with a value counted as “missing” at a 
visit will be identified as subjects being not assessed. 
If a value required a retest, the last reliable non-missing value will be taken into account if 
measured before the first intake of treatment; 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 retest or 
unscheduled 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. 
Any repeat or additional assessments performed will be included in the individual subject data 
listings. 
3.2.3.2 
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/concomitant medication is missing / incomplete, it is assumed to have 
occurred during the study treatment phase (i.e. a TEAE for AEs) except if the partial 
onset date or other data [stop date, …] indicates differently). 
• 
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 (i.e. for an AE started in FEB2004 after the  administration performed on 
31JAN2004, the days since last dose will be “≥ 2”, similarly the duration of ongoing AEs or 
medication will be “≥ xx” according to the start and last visit dates). 
3.2.3.3 
Outliers 
A search of outliers should be performed before the database lock and actions with the 
sponsor should be defined. 


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3.2.4 
Subject disposition 
A listing of the randomisation numbers will be presented by treatment group and subject. 
The number and percentage of subjects screened and included in each population will be 
presented by treatment group for the screened population and by country and centre. In 
addition, a flow chart will be provided with the number of subjects in each analysis 
population as well as colonoscopy performed and completed. 
A listing of the inclusion and exclusion criteria will be provided by treatment group and 
subject, and subject eligibility will also be listed. 
The reasons for subject exclusions from each population will also be tabulated by treatment 
group and overall on the randomised population. 
A summary table will present the extent of subject exposure in the study for each treatment 
group by deriving the study duration defined as the number of days from the date of consent 
to the last study visit. 
Listings of dates of assessments (relative day), of hospitalization entry and discharge and of 
study duration will be presented by treatment group and subject. The number and percentage 
of subjects at each planned visit during the study will be presented by treatment group and 
overall for the Safety population. 
3.2.5 
Withdrawals 
Discontinued subjects will be listed and the numbers of subjects who were randomised, 
performed colonoscopy, discontinued and completed will be tabulated by treatment group and 
by country. Primary reasons for discontinuation of study treatment will be tabulated. 
Number of subjects by visit will be provided by treatment as well as by country. 
3.2.6 
Demographic and baseline characteristics 
The baseline is the last available assessment before administration of the IMP. 
All demographic and baseline characteristics will be listed by treatment group and subject. 
Summary statistics (n, mean, SD, median, minimum, maximum) or frequency counts will be 
provided for demographic and baseline characteristics (sex, country, age, age range ([12-14[ / 
[14-16[ / [16-18[), height, body weight, weight range (]40-50] / ]50-60] / >60 kg) and BMI at 
baseline) by treatment group and overall for the ITT, mITT and PP populations if they differ 
by more than 10 %. Demographic and baseline characteristics will also be provided by 
country, age class weight class and sex on the ITT population. 
Pubertal stage, if available, measured using Tanner stage for boys and girls will also be 
described at baseline using frequency counts by sex and overall, by treatment group and 
overall for the ITT population and mITT population if they differ by more than 10 %. The 
Tanner Grading Scale [7 & 8] based on a 5-point scale will be used to assess pubertal stage as 
follows: 


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Table 10 Tanner Grading Scale to assess the genital development in male subjects 
Grade 
Description 
 
Tanner I 
Prepubertal: testes, scrotum, and penis of about same size and 
proportion as in early childhood. 
Typically age ≤ 9 years.  
Tanner II 
Enlargement of scrotum and testes. Skin of scrotum reddens 
and changes in texture. 
Typically age 9 to 11 years.  
Tanner III 
Enlargement of penis, at first mainly in length. Further growth 
of testes and scrotum. 
Typically age 11 to 12.5 years.  
Tanner IV 
Increased size of penis with growth in breadth and 
development of glans. Testes and scrotum larger, scrotal skin 
darkened. 
Typically age 12.5 to 14 years.  
Tanner V 
Genitalia adult in size and shape. 
Typically age ≥ 14 years.  
 
Table 11 Tanner Grading Scale to assess the pubic hair development in male subjects 
Grade 
Description 
 
Tanner I 
Prepubertal: vellus over pubes is not further developed than 
over abdominal wall. 
Typically age ≤ 10 years.  
Tanner II 
Sparse growth of long, slightly pigmented, downy hair, straight 
or slightly curled, chiefly at base of penis. 
Typically age 10 to 11.5 years.  
Tanner III 
Considerably darker, coarser, and more curled hair. Hair 
spreads sparsely over junction of pubes. 
Typically age 11.5 to 13 years.  
Tanner IV 
Hair now adult in type, but area covered is still considerably 
smaller than in adult. No spread to medial surface of thighs. 
Typically age 13 to 15 years.  
Tanner V 
Spread up linea alba (male-type pattern) 
Typically age ≥ 15 years.  
 
Table 12 Tanner Grading Scale to assess the breast development in female subjects 
Grade 
Description 
 
Tanner I 
No glandular tissue; areola follows the skin contours of the 
chest (prepubertal). 
Typically age ≤ 10 years.  
Tanner II 
Breast bud forms, with small area of surrounding glandular 
tissue; areola begins to widen.  
Typically age 10 to 11.5 years.  
Tanner III 
Breast begins to become more elevated, and extends beyond 
the borders of the areola, which continues to widen but remains 
in contour with surrounding breast. 
Typically age 11.5 to 13 years.  
Tanner IV 
Increased breast size and elevation; areola and papilla form a 
secondary mound projecting from the contour of the 
surrounding breast.  
Typically age 13 to 15 years.  
Tanner V 
Breast reaches final adult size; areola returns to contour of the 
surrounding breast, with a projecting central papilla.  
Typically age ≥ 15 years.  
 


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Table 13 Tanner Grading Scale to assess the pubic hair development in female subjects 
Grade 
Description 
 
Tanner I 
Prepubertal: vellus over pubes is not further developed than 
over abdominal wall. 
Typically age ≤ 10 years.  
Tanner II 
Sparse growth of long, slightly pigmented, downy hair, straight 
or slightly curled, chiefly along labia. 
Typically age 10 to 11.5 years.  
Tanner III 
Considerably darker, coarser, and more curled hair. Hair 
spreads sparsely over junction of pubes. 
Typically age 11.5 to 13 years.  
Tanner IV 
Hair now adult in type, but area covered is still considerably 
smaller than in adult. No spread to medial surface of thighs. 
Typically age 13 to 15 years.  
Tanner V 
Adult in quantity and type with distribution of horizontal (or 
classically "feminine") pattern. 
Typically age ≥ 15 years.  
 
Moreover, the indication(s) for colonoscopy will also be described using frequency counts by 
treatment group and overall for the ITT population and mITT population if they differ by 
more than 10 %. Indications classified under category "Other" in the eCRF will be described 
as other and will be listed in a separate listing. 
Additionally, haematology measured at baseline (including CBC: red blood cell (RBC) count, 
haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin 
(MCH), mean corpuscular haemoglobin concentration (MCHC), white blood cell (WBC) 
count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils, and 
others), platelet count and international normalised ratio (INR)) will also be described using 
summary statistics (n, mean, SD, median, minimum, maximum) after standardisation (see 
section 3.2.2.2 and reference 6) by treatment group and overall for the ITT population.  
Moreover, a frequency table will be presented of the number and percentage of subjects with 
[low, normal or high values] at baseline. 
Furthermore, female subjects of child-bearing potential have to perform a pregnancy test prior 
to baseline and the corresponding information will be listed when available. 
3.2.7 
Medical and surgical history 
Medical and surgical history, including ongoing medical history, as well as any significant 
conditions, including but not limited to major abdominal surgeries (excludes appendectomy), 
renal failure/dysfunction, liver failure/dysfunction, cardiac disorders inflammatory bowel 
disease, polyposis, diabetes, cancer (must indicate type of cancer), immune system disorders, 
electrolyte abnormalities will be coded using MedDRA current version at Ipsen coding 
department at the time of database lock. 
Listings will present the SOC, PT and reported term and will be sorted by treatment group, 
subject, chronological start date, SOC, PT and reported term. 
A frequency table of the number and percentage of subjects will be provided for all medical 
and surgical history by SOC and PT by treatment group and overall for the ITT population. 
3.2.8 
Subject compliance 
A listing will be presented for drug administration for treatment preparation, residual volumes 
of preparation (volumes not taken by the subject) and start and stop times of intake by subject 
for each treatment group. In addition, information about the residual volume of water will be 
reported and listed for the Eziclen®/Izinova® treatment only. 
Subject compliance to instructions of use is considered as a secondary endpoint and is 
described in section 3.2.1.2.10. 


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All major protocol deviations, defined prior to database freeze, will be listed by treatment 
group and subject. Additionally all major protocol deviations will be summarised on the ITT 
population and those with impact on the populations will also be described. 
3.2.9 
Prior and concomitant therapies 
Medications will be coded using World Health Organization – Drug dictionary (WHO-DD) 
with the current version at Ipsen coding department at the time of database lock. The 
therapeutic class will correspond to the second level of Anatomic Therapeutic Class (ATC) 
code, which corresponds to the first 3 digits. 
Non-drug therapies and surgical procedures will be coded using MedDRA Dictionary with the 
current version at Ipsen coding department at the time of database lock.  
The date of first administration of study drug (study day 1) will be used as the cut-off date for 
the definition of prior and concomitant. A drug that started before study day 1 and is 
continuing at time of day 1 will be considered as both, prior and concomitant. Prior, 
concomitant and both prior and concomitant will be flagged P, C and PC respectively, in all 
listings. 
Prior and concomitant medications will be listed with the therapeutic class, preferred name 
and reported term and they will be sorted by treatment group, subject, chronological start date, 
therapeutic class, preferred name and reported term. 
Frequency tables of the number and percentage of subjects with at least one prior medication 
will be provided by therapeutic class and preferred name for the ITT population. 
A similar table will be presented for concomitant medications. 
Prior and concomitant non-drug therapies will be listed with the SOC, PT and reported term 
and they will be sorted by treatment group, subject, chronological start date, SOC, PT and 
reported term.  
Concomitant surgical procedures will be listed with the SOC, PT and reported term and they 
will be sorted by treatment group, subject, chronological start date, SOC, PT and reported 
term.  
3.2.10 
Derived data 
The derived data are data which are calculated according to Analysis Data Model (ADaM) 
standard from the raw data in the eCRF, not included in the Study Data Tabulation 
Model (SDTM) database, and displayed in the individual data listings. The list of derived data 
is displayed in Appendix 1. 
3.2.11 
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the number of 
decimal places used does not imply undue precision). Raw data will be presented to the 
number of decimal places collected, and derived data will be presented to an appropriate 
number of decimal places. The appropriate number of decimal places will be determined by 
general practice, mathematical rationale or scientific rationale (e.g. age should be presented in 
whole numbers).  
For summary statistics, the following will be presented n, arithmetic mean, SD, median and 
the range (minimum, maximum). 
Mean, SD and median values will be reported to one decimal place greater than the 
raw/derived data that they summarise. Minimum and maximum values will be reported with 
the same precision as the raw data. 


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Percentages will be reported to 1 decimal place and 0 % will not be presented. Percentages 
will be calculated using a denominator of all subjects in a specified population with available 
data. The denominator will be specified in a footnote to the tables for clarification if 
necessary.  
All values below or above a limit of detection (e.g. < 0.1 or > 100) will be listed as such. For 
each parameter for which it is possible to have values below or above a limit of quantification, 
the rule to be used in the statistical tables is to replace values below or above a limit of 
quantification by the limit of quantification. 
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 
[ddmmmyyyy] and times in the format [hh:mm]. 
3.2.12 
Pooling of centres 
It is not planned to perform subgroup analyses on individual or groups of centres but efficacy 
analyses will be adjusted on countries.  
3.2.13 
Interim analysis 
No interim analysis will be performed. 
3.2.14 
Role of expert safety data review committee 
An Expert Committee will be appointed to review safety data. This Expert Committee will be 
chaired by the international coordinator and be composed of the coordinators from each 
country involved. Two reviews will be performed during data review meeting, first when 
50 subjects will be included (i.e. when 20 % of the planned number of subjects have 
undergone colonoscopy corresponding to Visit 2 at Day 2) and second when 125 subjects will 
be included (when 50 % of the subjects have reached the Visit 2 at Day 2). Blinded 
descriptive tables will be produced by the study statistician on enrollment and disposition by 
country and overall, baseline characteristics (including age, sex, medical history, concomitant 
medications and indication for colonoscopy) safety with description of AEs (including overall 
summary of AEs and frequency tables by SOC and PT on SAEs, AEs, TEAEs, related 
TEAEs, AE leading to withdrawal and AE leading to death) and tolerability. Additionally, 
supporting individual blinded data listings on lab data, AEs, and tolerability will be provided. 
3.2.15 
Covariates and analysis of subgroups 
Descriptive statistics for primary endpoint may be provided per country, age range ([12-14[ / 
[14-16[ / [16-18[ years), weight range (]40-50] / ]50-60] / >60 kg) and sex. 
Exploratory analyses will be presented by repeating the primary analysis in the mITT by age 
class, weight class and sex using the main model with additional term for subgroup and the 
interaction treatment * subgroup, as well as the treatment * country interaction if found 
significant in the primary analysis, as follows: 
proc logistic data=ADCC(where=(PARAM='Successful overall preparation' and 
MITTFL='Y')); 
class 
TRTP(ref='KLEAN-PREP') 
COUNTRYC(ref='Largest 
country') 
SUBGROUP(ref=’Class1’) / param=glm; 
model AVALC(EVENT='Yes') = TRTP COUNTRYC /* TRTP*COUNTRYC 
*/ SUBGROUP TRTP*SUBGROUP / link=logit lackfit firth; 
lsmeans TRTP*SUBGROUP / cl; 
run; 


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4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Hardware 
The statistical analysis will be performed using a PC on a Windows 7 operating system. 
4.2 
Software 
All tables, figures and listings (TFLs) will be produced and statistical analysis performed 
using SAS version 9.4 or higher [5]. All outputs will be in Microsoft Word Format. 
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 
double-programming for the primary endpoint and 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 QC 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 
It was planned in the protocol to tabulate the efficacy and safety (laboratory, vital signs and 
tolerability) results by treatment group and overall, but this is not relevant to pool them so 
only description by treatment group will be provided. 


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It was planned in the protocol to include the interaction treatment*country in the ANOVAs of 
the applicable secondary endpoints, but as for the primary analysis the interaction will rather 
be investigated and kept only if it is significant. 
It was not planned in the protocol to perform secondary analyses on mITT and PP, but it was 
decided to take into account the significant difference in terms of number of patients between 
ITT and the mITT and PP populations in order to assess the robustness of the results.  
It was not planned in the protocol to present the primary endpoint according to subgroups (age 
class, weight class and sex), but descriptive statics have been added to explore the primary 
results. 
It was not planned in the protocol to describe the time between the last intake of fluids and the 
start of colonoscopy procedure, but as this factor has been shown to be a major contributor to 
quality in adult patients it has been decided to add this description (Hassan et al.). 
It was planned in the protocol to exclude from the PP population all subjects with major 
deviations, but some major deviations do not have an impact on the analyses, so they have 
been identified in the Protocol Deviation Document and the definition of the PP population 
has been updated to only consider the deviations having an impact on the analyses. 
 
6 
REFERENCES 
1 
Schwartz GJ and Work DF. Measurement and Estimation of GFR in Children 
and Adolescents. Clin J Am Soc Nephrol. 2009; 4: 1832–1843 
2 
Lai EJ, Calderwood AH, Doros G, Fix OK, Jacobson BC. The Boston Bowel 
Preparation Scale: A valid and reliable instrument for colonoscopy-oriented 
research. Gastrointest Endosc. 2009;69(32):620–625. 
3 
International Conference on Harmonisation (ICH) E9 and Federal register 
Vol. 63, No. 179 (September 1998). 
4 
SAS, Version 9.3. SAS Institute Inc., Cary, NC, USA, 2012. 
5 
Brookmeyer, R. and Crowley, J. (1982), “A Confidence Interval for the 
Median Survival Time” Biometrics, 38, 29–41. 
6 
Karvanen J. The statistical basis of laboratory data normalization. Drug 
Information Journal. 2003;37(1):101-107. 
7 
Marshall WA, Tanner JM (February 1970). "Variations in the pattern of 
pubertal changes in boys". Arch. Dis. Child. 45 (239): 13–23. 
8 
Marshall WA, Tanner JM (June 1969). "Variations in pattern of pubertal 
changes in girls". Arch. Dis. Child. 44 (235): 291–303. 
9 
Hassan et al, Bowel preparation for colonoscopy: European Society of 
Gastrointestinal Endoscopy (ESGE) Guideline – Update 2019, Endoscopy 
2019; https://doi.org/10.1055/a-0959-0505 
 


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7 
APPENDICES 
 
Appendix 1 Derived data 
 
The following derived data will be calculated: 
(1) 
Treatment group 
Treatment groups will be defined as “Eziclen/Izinova” and “Klean-Prep”. 
(2) 
Study duration 
Study duration (days) will be calculated as (last visit attended - date of informed consent) + 1. 
(3) 
Successful treatment preparation 
• 
A successful preparation will be derived from a colon cleansing scored as excellent (4) 
or good (3). 
• 
A failure preparation will be defined as: 
- 
Fair (2) or poor (1) according to colon cleansing score, 
- 
Any subject who did not have a colonoscopy based on the investigator’s 
assessment of the cleansing (insufficient faecal output, unclear faecal discharge, 
etc.) or due to preparation related AEs, 
- 
Any subject for whom cleaning was not adequate for evaluation, 
- 
Any subject for whom rescue treatment (saline enema) was needed. 
(4) 
Time to clear effluent 
It is defined as the time (expressed in hours) from the first intake of prescription to the first 
clear watery stool occurrence if any, or to the time of colonoscope introduction, if no clear 
watery stool is observed before the beginning of the procedure and then the time will be 
considered as censored for the survival analysis. See section 3.2.1.2.3. 
(5) 
Completion of the procedure 
"Yes" if the colonoscopy reached the caecum and the item "Was physician able to reach the 
caecum?" is "Yes", "No" otherwise. 
(6) 
Duration of the intubation 
It is defined as the time (expressed in minutes) from colonoscope introduction to caecal 
intubation. 
(7) 
Duration of the examination 
It is defined as the time (expressed in minutes) from caecal intubation to colonoscope 
withdrawal. 
(8) 
Need of a rescue treatment 
"Yes" if a rescue medication was administered and the item "Was any enema needed to 
achieve preparation?" is "Yes", "No" otherwise. 
(9) 
Need of a nasogastric tube to complete preparation 
"Yes" if a nasogastric tube was inserted and the item "Was a nasogastric tube inserted?" is 
"Yes" at dose 1 or dose 2, "No" otherwise. 
(10) Compliance in percentage 
The percentage of compliance is defined as (planned volume - residual volume) / planned 
volume, adding up the solution and water volume where applicable. 


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The planned volume is 750 mL for Eziclen (375 mL per dose), 1500 mL for hydration 
(750 mL per dose) and 70 mL/kg for Klean-Prep® with a maximum of 4000 mL (maximum 
2000 mL per dose). 
(11) Compliance with the instructions of use 
A subject is considered as compliant with the instructions of use if he/she drinks the whole 
preparation (100 % of compliance) and any required further fluid intake (100 % of 
compliance). 
The planned volume is 750 mL for Eziclen (375 mL per dose), 1500 mL for hydration 
(750 mL per dose) and 70 mL/kg for Klean-Prep® with a maximum of 4000 mL (maximum 
2000 mL per dose). 
(12) Compliance in class 
The compliance in class is defined from the compliance in percentage as follows: 
- 
100 %, 
- 
]100-75], 
- 
]75-50], 
- 
< 50 %. 
(13) Lesions caused by colonic lavage 
Histological examination results of lesions caused by colonic lavage will be identified among 
the adverse events by looking for the term "colonic lavage" in the verbatim term, since the 
investigator should identified the suspected lesions using "suspected to have been caused by 
colonic lavage". The occurrence (Yes/no) will then be derived for each subject. 
(14) Baseline 
Baseline will be derived as the last available assessment before administration of the IMP. 
(15) Changes from baseline 
Changes from baseline will be calculated as a difference from baseline (e.g. assessment at the 
visit – assessment at baseline). 
(16) 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 (current version at the time of database 
lock). 
(17) Prior and concomitant flags 
The date of first administration of study treatment (study day 1) is used as the cut-off date for 
the definition of prior and concomitant medications. A drug started before study day 1 and 
continuing at time of Day 1 is considered as both, prior and concomitant. Prior, concomitant 
and both prior and concomitant will be coded as P, C and PC respectively. 
(18) Concomitant therapy duration 
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 – start date) + 1” day(s). If the 
start date or the end date are partial, the duration will be presented as an inequality “≥xx” 
day(s) [i.e. ≥2 where start date=31JAN2004 and end date=FEB2004 or start date=JAN2004 


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and end date=01FEB2004] but if both are partial or one is missing the duration will not be 
presented. 
(19) Adverse event duration 
If the start and end dates of the adverse event 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=31JAN2004 and end date=FEB2004 or start date=JAN2004 and end 
date=01FEB2004]. 
 


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Appendix 2 Data presentation and tables, figures and listings' templates 
Data listings are presented for all screened subjects. 
Footnotes should be used to clarify ambiguities (e.g. the denominator used to calculate a 
percentage or notes for the programmer). If the number of footnotes is high, they could be 
presented only in the last page, with on each page the following footnote “See last page for 
listing notes”. The order of the footnotes for key symbols (*, ~) will be in the order that they 
appear in the listing. 
The title of each generated TFL should appear bookmarked within Word (one single 
bookmark per TFL) to allow document publishing by Ipsen. 
 
TFLs templates are provided in a separate document 
 
 
The TFLs will be presented in landscape, in a fixed font (Courier New) with a minimum 
size 8 and according to the standard margins defined in procedure 
. 
The page number of each TFL shell (n of N) represent n=page number of the listing and 
N=total number of pages for that specific TFL. 
Each TFL must be presented in an independent, separate Word file for each ICH heading (e.g. 
Listings 16.2.9.X combined in one file). 
 
A statistical appendix for inclusion in the study report will be provided. 
All the SAS outputs produced during the statistical analyses will be included without 
reworking the data (raw output). 
For the logistic regression, the output of the LOGISTIC procedure within SAS will be 
presented. The results of the model checking procedures done through the robustness analyses 
will also be included. 
For the ANOVA, the output of the MIXED procedure within SAS will be presented. This will 
include the overall ANOVA table, parameter estimates, least square means for the treatment 
group with 95% CIs and the associated p-values. 
For the CMH analyses, the output of the FREQ procedure within SAS will be presented. This 
will include the frequency table and CMH statistics. 
This output should contain the study number, the date, the number of pages printed by SAS 
and the table number to which it refers. Any other relevant information will be added in the 
statistical appendix. 
 
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Appendix 3 List of tables, figures and listings 
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