Efficacy and Safety of mAnniTol in Bowel Preparation: Assessment of Adequacy and Presence of Intestinal levelS of Hydrogen and Methane During Elective Colonoscopy aFter mAnnitol or Standard Split 2-liter Polyethylene Glycol Solution Plus asCorbaTe - a Phase II/III, International, Multicentre, Randomized, Parallel-group, endoscOpist-bliNded, Dose-finding/Non-inferiority Study - SATISFACTION
Phase: PHASE2
Conditions: Elective Colonoscopy
Sponsor: NTC srl

 
 
 
CLINICAL TRIAL PROTOCOL 
Efficacy and Safety of mAnniTol in bowel preparation: assessment of 
adequacy and presence of Intestinal levelS of hydrogen and methane 
during elective colonoscopy aFter mAnnitol or standard split 2-liter 
polyethylene glycol solution plus asCorbaTe – a phase II/III, International, 
multicentre, randomized, parallel-group, endoscOpist-bliNded, dose-
finding/non-inferiority study - SATISFACTION 
 
PROTOCOL NUMBER: Mannitol_03-2018 
EudraCT NUMBER: 2019-002856-18 
VERSION: 6.0 
DATE: 21 JANUARY 2021 
 
 
 
 
 
CONFIDENTIAL: FURTHER DISSEMINATION MAY ONLY BE MADE WITH THE EXPRESSED 
WRITTEN PERMISSION OF NTC S.r.l. 
 

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Table of Contents 
List of Figures ........................................................................................................................................................... iv 
AMENDMENT 1 .......................................................................................................................................................... 4 
AMENDMENT 2 .......................................................................................................................................................... 5 
AMENDMENT 3 .......................................................................................................................................................... 6 
STATEMENT OF COMPLIANCE ............................................................................................................................ 10 
1 
PROTOCOL SUMMARY .............................................................................................................................. 11 
1.1 
Synopsis ............................................................................................................................................... 11 
1.2 
Schedule of Activities (SoA) ................................................................................................................ 19 
1.2.1 
Phase II – Dose finding/pharmacokinetic sub-study ..................................................................... 19 
1.2.2 
Phase III – Non-inferiority ............................................................................................................ 21 
2 
INTRODUCTION .......................................................................................................................................... 23 
2.1 
Overview .............................................................................................................................................. 23 
2.2 
Risk/Benefit Assessment ...................................................................................................................... 28 
2.2.1 
Known Potential Risks ................................................................................................................. 28 
2.2.2 
Known Potential Benefits ............................................................................................................. 30 
2.2.3 
Assessment of Potential Risks and Benefits ................................................................................. 30 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 31 
4 
STUDY DESIGN ............................................................................................................................................ 34 
4.1 
Overall Design ...................................................................................................................................... 34 
4.1.1 
Phase II ......................................................................................................................................... 36 
4.1.2 
PHASE II - Pharmacokinetic sub-study ....................................................................................... 38 
4.1.3 
Phase III ........................................................................................................................................ 40 
4.2 
End of Study Definition ....................................................................................................................... 42 
5 
STUDY POPULATION ................................................................................................................................. 43 
5.1 
Inclusion Criteria .................................................................................................................................. 43 
5.2 
Exclusion Criteria ................................................................................................................................. 43 
5.3 
Screen Failures ..................................................................................................................................... 44 
6 
STUDY INTERVENTION ............................................................................................................................. 45 
6.1 
Study Intervention Administration ....................................................................................................... 45 
6.1.1 
Study Intervention Description ..................................................................................................... 45 
6.1.2 
Dosing and Administration ........................................................................................................... 45 
6.2 
Preparation/Handling/Storage/Accountability ...................................................................................... 47 
6.2.1 
Acquisition and accountability ..................................................................................................... 47 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .................................................................... 47 
6.2.3 
Drug Storage and Stability ............................................................................................................ 47 
6.2.4 
Preparation .................................................................................................................................... 47 
6.3 
Study Intervention Compliance ............................................................................................................ 48 
6.4 
Concomitant medications ..................................................................................................................... 48 
6.4.1 
Prohibited Concomitant Medications ........................................................................................... 48 
6.4.2 
Permitted Concomitant Medications ............................................................................................ 48 
6.4.3 
Rescue therapy .............................................................................................................................. 48 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................... 49 
7.1 
Discontinuation of Study Intervention ................................................................................................. 49 
7.2 
Participant Discontinuation/Withdrawal from the Study...................................................................... 49 
7.3 
Lost to Follow-Up ................................................................................................................................ 49 

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STUDY ASSESSMENTS AND PROCEDURES .......................................................................................... 50 
8.1 
Assessments ......................................................................................................................................... 50 
8.1.1 
Phase II ......................................................................................................................................... 50 
8.1.2 
Phase II - Pharmacokinetic substudy ............................................................................................ 52 
8.1.3 
Phase III ........................................................................................................................................ 54 
8.1.4 
Laboratory tests (phase II and phase III) ...................................................................................... 56 
8.2 
Safety .................................................................................................................................................... 57 
8.3 
Adverse Events and Serious Adverse Events ....................................................................................... 57 
8.3.1 
Definition of Adverse Events (AE) .............................................................................................. 57 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................................................... 58 
8.3.3 
Classification of an Adverse Event ............................................................................................... 58 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ............................................. 59 
8.3.5 
Non-serious Adverse Event Reporting ......................................................................................... 59 
8.3.6 
Serious Adverse Event Reporting ................................................................................................. 59 
8.3.7 
Reporting of Pregnancy ................................................................................................................ 60 
9 
STATISTICAL CONSIDERATIONS ............................................................................................................ 61 
9.1 
Sample Size Determination .................................................................................................................. 61 
9.2 
Randomization ..................................................................................................................................... 62 
9.3 
Populations for Analyses ...................................................................................................................... 63 
9.4 
Statistical Analyses............................................................................................................................... 63 
9.4.1 
Analysis of variables .................................................................................................................... 64 
9.4.2 
Analysis of safety ......................................................................................................................... 66 
9.4.3 
Planned Interim Analyses ............................................................................................................. 67 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .................................. 68 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ................................................................... 68 
10.1.1 
Informed Consent Process ............................................................................................................ 68 
10.1.2 
Study Discontinuation and Closure .............................................................................................. 68 
10.1.3 
Confidentiality and Privacy .......................................................................................................... 69 
10.1.4 
Future Use of Stored Specimens and Data ................................................................................... 69 
10.1.5 
Clinical Monitoring ...................................................................................................................... 70 
10.1.6 
Quality Assurance and Quality Control ........................................................................................ 70 
10.1.7 
Data Handling and Record Keeping ............................................................................................. 71 
10.1.8 
Protocol Deviations ...................................................................................................................... 72 
10.1.9 
Insurance ....................................................................................................................................... 72 
10.1.10 
Publication and Data Sharing Policy ............................................................................................ 72 
10.1.11 
Conflict of Interest Policy ............................................................................................................. 73 
11 
ABBREVIATIONS ........................................................................................................................................ 74 
12 
REFERENCES................................................................................................................................................ 75 
13 
APPENDICES ................................................................................................................................................ 79 
13.1 
Appendix 1 Boston Bowel Preparation Scale ....................................................................................... 79 
13.2 
Appendix 2 Bristol Stool Form Scale ................................................................................................... 80 
13.3 
Appendix 3 Ottawa Bowel Preparation Scale ...................................................................................... 81 
 
List of Figures 
FIGURE 4-1 
STUDY DESIGN ....................................................................................................................................... 35 

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AMENDMENT 1 
The purpose of this amendment is to implement the suggestions put forward by the Italian 
Medicines Agency (AIFA) following review of the original study protocol. The changes to the 
protocol are as follows: 
• The protocol now explicitly states that phase III will begin only once all data collected 
from phase II necessary for establishing the optimal mannitol dose have been analysed 
(Section 4.1.3). 
• Section 4.1.1 now specifies that should two or all three doses tested in phase II prove to be 
equally safe and effective, the lowest dose will be selected for phase III of the study. 
• To ensure that screening assessments are performed within a time frame such as to properly 
evaluate patient eligibility and, in particular, that the pregnancy test is performed not more 
than 7 days prior to the day of colonoscopy, Section 4.1 and the schedule of activities now 
state that Visit 2 must take place not more than 7 days prior to the day of colonoscopy.  
• Section 5 has been updated to better define the study population. 
• Section 6.4 now indicates permitted and prohibited concomitant medications. 
• Section 9.2 has been added to detail randomization procedures. 
The number of sites and Countries involved in the phase II of the study have also been updated. 
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strikethrough red font for deletions and red underline for insertions. 
 
 

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AMENDMENT 2 
This amendment was drawn up to align the protocol with the recommendations of the German 
Federal Institute for Drugs and Medical Devices (BfArM) and has been modified as follows: 
• The rationale for the chosen mannitol doses to be tested in the phase II dose-finding 
study/pharmacokinetic sub-study has been complemented (Section 2.1 and Section 4.1.1). 
The references reported in Section 12 have been updated accordingly. 
• The reference to Moviprep® Summary of Product Characteristics in Section 2.2.1 has been 
updated to its most recent version. 
• A schematic diagram of the phase II/III study design has been added in Section 4.1. 
• The end of study definition has been further articulated (Section 4.2). 
• The time period for serious adverse event reporting to the sponsor by the investigator has 
been clarified (Section 8.3.6). 
• It has been clarified that any urine specific gravity change from the reference normal range 
will be recorded and managed as an expected adverse event, as the event is to be considered 
part of the pharmacological profile of mannitol (Section 2.2.1 and Section 8.1.4). 
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strikethrough red font for deletions and red underline for insertions. 
 
 

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AMENDMENT 3 
This amendment was drawn up to align the protocol with the recommendations of the German 
Ethics Committee of Mainz and has been modified as follows: 
• Exclusion criteria have been implemented to exclude patients with severe acute 
inflammatory bowel disease and chronically active bowel disease (Section 1.1 and Section 
5.2). 
• The ability to provide written informed consent has been explicitly mentioned as inclusion 
criterion (Section 1.1 and Section 5.1). 
• In light of a more conservative perspective in terms of patient safety, the stopping rule 
foreseen in the phase II dose-finding study to limit patient exposure to an ineffective 
mannitol dose causing repetition of colonoscopy has been revised by reducing from 50% 
to 25% the failure rate entailing the discontinuation of enrolment (Section 1.1 and Section 
4.1.1). 
Moreover, the reference to Moviprep® Summary of Product Characteristics in Section 2.2.1 has 
been corrected with the reference to the simplified Investigational Medicinal Product Dossier 
(IMPD) for Moviprep®, in response to a further recommendation of BfArM.  
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strikethrough red font for deletions and red underline for insertions.  
 
 

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AMENDMENT 4 
The purpose of this amendment is to provide changes and clarifications to the protocol regarding 
study background information, study assessments and procedures, selection of the dose for phase 
III, AE reporting and statistical methods.  
Accordingly, the protocol has been modified as follows: 
• It has been corrected in the Schedule of Activities (Section 1.2) that the urinalysis at Visit 
4 is to be performed 4 hours and 8 hours after the end of study drug self-administration, as 
stated in the text. 
• Additional background information has been added to Section 2.1 and Section 2.2.  
• It has been clarified that intestinal gas measurement performed during colonoscopy in each 
colon segment will be in % Vol for H2 and % of Lower Explosion Level (LEL) for CH4 
(Section 1.1, Section 3, Section 9.4.2). For the assessment of CH4 concentration in each 
colon segment, CH4 (% LEL) will then be converted in % Vol (Section 9.4.2). 
• It has been clarified that one of the selection criteria of the dose to be used in the 
comparative non-inferiority phase (phase III) will be the rate of patients in safe conditions, 
defined as the absence of potentially dangerous levels of H2 and CH4 in each colon segment 
(Section 1.1, Section 4.1.1, Section 9.4.1). 
• It has been clarified that a change of a given parameter is to be considered clinically 
significant if it causes an additional control or a medical intervention (Section 1.1, Schedule 
of Activities, Section 3, Section 4, Section 8, Section 9.4.2). 
• It has been specified that also systolic and diastolic blood pressure will be monitored during 
colonoscopy in the comparative non-inferiority phase (phase III), and any clinically 
significant abnormal finding will be recorded on the eCRF (Section 1.1, Section 1.2.2, 
Section 3, Section 4.1.3, Section 8.1.3 and Section 9.4.2). 
• The protocol now explicitly states that CO2 insufflation and water-aided techniques for 
colon distension (e.g. water immersion and water exchange) are not allowed during 
colonoscopy (Section 1.1 and Section 4.1). 
• The considerations underlying the stopping rule applied in phase II are described in more 
detail (Section 4.1.1). 
• It has been clarified that overnight fasting is required before the dietary restrictions which 
are to be followed by patients enrolled in the PK sub-study between 24 hours before and 
the start of mannitol self-administration. Moreover, it has been specified that between 4 
and 8 hours after mannitol intake, patients may eat any food which complies with the 
dietary restrictions, if deemed necessary by the Investigator (Section 1.1, Section 4.1.2, 
Section 6.1.2). 

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• It has been clarified that the laboratory and histological results will be available after the 
completion of the last study procedure on the day of colonoscopy (Section 4.2). 
• Section 6.1.2 now specifies that all patients except those enrolled in the PK sub-study 
should follow dietary recommendations prior to colonoscopy as per local practice at the 
centre. Moreover, it has been clarified that about half a litre (500 mL) of clear liquid should 
be drunk after each litre of Moviprep® according to local practice at the centre. 
• It has been corrected that a standard urinalysis (not a dipstick urinalysis) will be performed 
at Visit 2 and Visit 4 (Table in Section 8.1.4). 
• Section 8.3.4 now specifies that adverse events should be followed until resolution or 
stabilization except for those events deemed to be chronic by the Investigator, such as 
cancer, and that lesions detected during colonoscopy (polyps, adenomas, cancer, etc.) are 
not to be considered as AEs. 
• Clarifications on the calculation of the sample size (Section 9.1) and the planned statistical 
analyses (Section 1.1, Section 9.4.1, Section 9.4.3) have been added. 
• The populations for analyses have been updated (Section 1.1, Section 9.3). Moreover, it 
has been specified that the safety analyses will be performed both on the Safety Set and on 
the modified Safety Set by treatment group, with those on the modified Safety set to be 
considered as supportive (Section 9.4.2). 
• The publication and data sharing policy (Section 10.1.10) has been updated. 
• Section 12 has been updated. 
Changes to the protocol are shown in the track changes version using strike through red font for 
deletions and red underlined for additions. 
 
 

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AMENDMENT 5 
With this amendment, minor clarifications have been added to the protocol, as follows:  
• The estimated dates of the last patient first visit (LPFV) and the last patient last visit 
(LPLV) of the study in Section 1.1 have been updated. 
• Section 1.1, Section 1.2.2, Section 3, Section 4.1.3, Section 8.1.3 and Section 9.4.2 now 
specify that clinically significant changes of pulse oximetry and heart rate measured during 
colonoscopy and blood pressure measured immediately prior and after colonoscopy will 
be recorded. Of note, clinically significant changes of blood pressure measured during 
colonoscopy will also be reported if considered clinically significant by the Investigator. 
• Ranges of the satisfaction scale score and total score of the Bowel Cleansing Impact 
Review (BOCLIR) to be used at Italian sites only to assess acceptability and tolerability of 
the bowel preparation have been corrected (Section 8.1.3), according to the final validated 
Italian version of BOCLIR. In particular, the middle ‘neutral’ option of the satisfaction 
scale present in the original UK English version was removed as part of the adaptation and 
validation process in Italian.  
• Further examples of lesions detected during colonoscopy that are not to be considered AEs 
have been added in Section 8.3.4. 
Changes to the protocol are shown in the track changes version using strike through red font for 
deletions and red underlined for additions. 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and all applicable laws and regulations. The Principal Investigator 
will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor and documented approval from the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) and/or Competent Authority, except where necessary to 
eliminate an immediate hazard to the trial participants. All personnel involved in the conduct of 
this study have completed ICH GCP training. 
The protocol and the informed consent form will be submitted to the IEC/IRB for review and 
approval. Approval of both the protocol and the consent form must be obtained before any 
participant is enrolled. Any substantial amendment to the protocol will require review and approval 
by the IEC/IRB before the changes are implemented. All changes to the consent form will be 
IEC/IRB approved. 
 
 
 

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1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Protocol number 
Mannitol_03-2018 
Title of Study 
Efficacy and safety of mannitol in bowel preparation: assessment of adequacy and 
presence of intestinal levels of hydrogen and methane during elective colonoscopy after 
mannitol or standard split 2-liter polyethylene glycol solution plus ascorbate – a phase 
II/III, international, multicentre, randomized, parallel-group, endoscopist-blinded, dose-
finding/non-inferiority study 
Sponsor 
NTC S.r.l. 
Investigational Sites 
Phase II - dose finding: approximately 13 sites located in Italy, Germany and France.  
Phase II pharmacokinetic sub-study: approximately 5 sites located in Italy. 
Phase III - non-inferiority: approximately 50 sites located in Italy, Germany, Russia and France. 
Study Objectives 
Phase II: Dose-finding/Pharmacokinetic sub-study 
o 
To determine the effective and safe dose of mannitol for adequate bowel cleansing to 
be used in the comparative non-inferiority phase of the study (phase III). 
o 
To define the pharmacokinetic profile of the mannitol doses used in dose finding 
through a pharmacokinetic sub-study. 
Phase III: Non-inferiority 
o 
To demonstrate the non-inferiority of mannitol vs. standard split 2L PEG ASC 
(Moviprep®) in bowel cleansing for colonoscopy. 
o 
To assess the safety and tolerability of mannitol. 
o 
To assess the adherence to and acceptability of the bowel preparation with mannitol 
and Moviprep®. 
Study Endpoints 
Phase II - Dose finding  
• 
Primary efficacy endpoint: proportion of patients with adequate bowel cleansing, 
defined as Boston Bowel Preparation Scale (BBPS) total score ≥ 6, with a score for 
each of the three colon segments (right; transverse, including flexures; and left, 
including sigmoid and rectum) ≥ 2 during colonoscopy after standard washing and air 
insufflation for luminal distension. 
• 
Secondary efficacy endpoint: caecal intubation rate, defined as the percentage of 
patients with appendiceal orifice visible to the endoscopist. 
• 
Safety and tolerability 
o Proportion of patients in safe conditions, defined as the absence in each colon 
segment (right, between ileocecal valve and appendix or as close as possible to the 
ileocecal valve in case of obstacles that prevent reaching the valve; transverse, 
including flexures; and left at the sigmoidal-rectum junction, 15-25 cm from anal 
margin) of potentially dangerous levels of H2 and/or CH4 (> 4% Vol and >100% of 
Lower Explosion Level (LEL), which is equal to 5% Vol, respectively) during 
colonoscopy after standard washing and air insufflation for luminal distension. 
o Incidence of adverse events from the beginning of study drug self-administration. 
o Proportion of patients with change from baseline considered clinically significant 
by the Investigator of haematological and chemical parameters (CBC, creatinine, 
BUN, eGFR, ALT, AST, glucose, electrolytes) 4 hours and 8 hours after 
completion of study drug self-administration. 
o Proportion of patients with change during colonoscopy considered clinically 
significant by the Investigator of vital signs (heart rate and pulse oximetry). 

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Of note, a clinically significant change of a given parameter is defined as a change that 
causes an additional control or a medical intervention. 
• 
Adherence and acceptability  
o Adherence: study drug completely taken, partially taken, not taken. 
o Ease of use: numeric rating scale (NRS) (0 = very difficult to 10 = very easy). 
o Taste: NRS (0 = terrible to 10 = very good). 
o Willingness to reuse the preparation (yes/no). 
Phase II - Pharmacokinetic sub-study 
o Cmax: maximum concentration. 
o tmax: time to maximum concentration.  
o AUC0-t0-t: area under concentration-time curve, from 0 to the last blood sampling 
time point with measurable concentration.  
o t1/2: elimination half-life. 
Phase III - Non-inferiority 
• 
Primary efficacy endpoint: proportion of patients with adequate bowel cleansing: 
BBPS total score ≥ 6, with a score for each of the three colon segments (right; 
transverse, including flexures; and left, including sigmoid and rectum) ≥ 2 during 
colonoscopy after standard washing and air insufflation for luminal distension. 
• 
Secondary efficacy endpoints 
o Number, appearance, size, location and histological classification of neoplastic and 
inflammatory colorectal lesions detected.  
o Adenoma detection rate, defined as the percentage of patients with at least one 
adenoma detected. 
o Caecal intubation rate, defined as the percentage of patients with appendiceal 
orifice visible to the endoscopist. 
o Ottawa Scale for bowel cleansing evaluation before washing and air insufflation for 
luminal distension. 
• 
Safety and tolerability 
o Proportion of patients in safe conditions, defined as the absence in each colon 
segment (right, between ileocecal valve and appendix or as close as possible to the 
ileocecal valve in case of obstacles that prevent reaching the valve; transverse, 
including flexures; and left at the sigmoidal-rectum junction, 15-25 cm from anal 
margin) of potentially dangerous levels of H2 and/or CH4 (> 4% Vol and >100% 
LEL, respectively) during colonoscopy after standard washing and air insufflation 
for luminal distension. 
o Incidence of adverse events from the beginning of study drug self-administration.  
o Proportion of patients with change from baseline considered clinically significant 
by the Investigator of haematological and chemical parameters 4 hours and 8 hours 
after completion of study drug self-administration.  
o Proportion of patients with change from baseline considered clinically significant 
by the Investigator of vital signs (heart rate, systolic and diastolic blood pressure) 
measured during visits, as well as clinically significant change of pulse oximetry 
and heart rate measured during colonoscopy and systolic and diastolic blood 
pressure measured immediately prior and after colonoscopy. Of note, clinically 
significant changes of systolic and diastolic blood pressure measured during 
colonoscopy will also be reported if considered clinically significant by the 
Investigator. 
Of note, a clinically significant change of a given parameter is defined as a change that 
causes an additional control or a medical intervention. 
• 
Adherence and acceptability 
o Adherence: study drug completely taken, partially taken, not taken. 
o Bowel Cleansing Impact Review (BOCLIR) (only at Italian centres). 
o Ease of use: NRS (0 = very difficult to 10 = very easy). 

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o Taste: NRS (0 = terrible to 10 = very good). 
o Willingness to reuse the preparation (yes/no). 
Study design 
This is a phase II/III, international, multicentre, randomized, parallel-group, endoscopist-
blinded study that combines a phase II dose-finding study/pharmacokinetic sub-study with 
a phase III non-inferiority study. 
Phase II-dose finding 
The parallel-group dose-finding phase will involve 150 patients randomly assigned (1:1:1 
ratio) to one of the following three treatment groups:  
• 
50 g mannitol powder to be dissolved in 500 ml of water 
• 
100 g mannitol powder to be dissolved in 750 ml of water 
• 
150 g mannitol powder to be dissolved in 1000 ml of water 
Randomization is stratified by centre and by the presence of constipation (yes/no), defined 
as the recurrent use of laxatives or Bristol Stool Form Scale (BSFS) < 3 in the two weeks 
before randomisation. 
To limit patient exposure to an ineffective dose causing repetition of colonoscopy, the 
adequacy of bowel cleansing will be monitored continuously and enrolment in a treatment 
group will be discontinued as soon as 25% of treated patients present inadequate bowel 
cleansing causing repetition of colonoscopy. The stopping rule will be applied in each 
treatment group as follows: 
• 
Up to the 25th enrolled patient, enrolment in a treatment group will be stopped as soon 
as 6 patients present inadequate bowel cleansing causing repetition of colonoscopy.  
• 
From the 26th enrolled patient on (if treatment was not discontinued earlier), 
enrolment will be stopped as soon as 25% of the patients present inadequate bowel 
cleansing causing repetition of colonoscopy. 
The appropriate mannitol dose to be used in phase III will be singled out based on the 
following criteria: 
• 
75% or greater rate of adequate bowel cleansing, defined as BBPS total score ≥ 6, with 
a score for each of the three colon segments (right; transverse, including flexures; and 
left, including sigmoid and rectum) ≥ 2 during colonoscopy after standard washing 
and air insufflation for luminal distension.  
• 
Rate of patients in safe conditions defined as the absence of potentially dangerous 
levels of H2 and CH4 in each colon segment (right, between ileocecal valve and 
appendix or as close as possible to the ileocecal valve in case of obstacles that prevent 
reaching the valve; transverse, including flexures; and left at the sigmoidal-rectum 
junction, 15-25 cm from anal margin) after standard washing and air insufflation for 
luminal distension). 
• 
Clinical judgment based on the caecal intubation rate, the incidence of adverse events, 
treatment adherence and acceptability (ease of use, taste and willingness to reuse the 
preparation). 
Should two or all three doses prove to be equally safe and effective, the lowest dose will 
be selected for phase III of the study. 
Phase II-Pharmacokinetic sub-study 
A single-group design for each mannitol dose will be implemented. Mannitol is contained 
in foods in a certain amount. To minimize the error of measuring mannitol plasma 
concentration after the intake of the investigational drug, dietary restrictions are required, 
after overnight fasting, between 24 hours before and the start of drug self-administration, 
while fasting is required afterwards up to 8 hours after mannitol intake. Of note, between 
4 and 8 hours after mannitol intake, patients may eat any food which complies with the 
dietary restrictions based on the INRAN tables, if deemed necessary by the Investigator. 
Venous blood samples will be drawn from a sub-group of at least 10 patients in each dose 
group at the following times: 

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• 
T0 (baseline before mannitol self-administration) 
• 
T1 (1 hour ± 5 min after completion of mannitol self-administration) 
• 
T2 (2 hours ± 5 min after completion of mannitol self-administration)  
• 
T4 (4 hours ± 10 min after completion of mannitol self-administration, before 
colonoscopy) 
• 
T8 (8 hours ± 10 min after completion of mannitol self-administration, after 
colonoscopy) 
If patients do not undergo all PK evaluations, the sub-study sample size will be increased 
to guarantee at least 8 PK evaluations for each assessment time. 
Phase III-Non-inferiority 
A parallel-group design will be implemented to test the non-inferiority of bowel cleansing 
with the mannitol dose selected in phase II against standard split 2L PEG ASC. Phase III 
will begin only once all data collected from phase II necessary for establishing the optimal 
mannitol dose have been analysed. The non-inferiority study will involve 696 subjects 
randomized in a 1:1 ratio to one of the two cleansing agents. Randomization is stratified 
by centre. 
Study visits  
In both phases, the study will consist of four visits:  
Visit 1 (≤ 28 days before the day of colonoscopy): after signed written informed consent 
is obtained from the patient, information concerning demographics, medical history, 
concomitant medications and indications for colonoscopy will be collected in the 
electronic case report form (eCRF). 
Visit 2 (≤ 7 days before the day of colonoscopy): to complete the verification of 
inclusion/exclusion criteria, a blood sample will be drawn to assess the haematological 
and chemical parameters of all patients and to perform a pregnancy test for women of 
childbearing potential. Assessments include a urinalysis and the measurement of vital 
signs (heart rate and blood pressure). 
Visit 3 (≤ 7 days before the day of colonoscopy): if eligibility criteria are met, the BSFS 
will be administered (only in phase II), randomization will be performed, study drug will 
be dispensed and verbal and written instructions for its use will be provided. Patients will 
be given a form on which to indicate date and time of start and end of study drug self-
administration.  
More than one visit may take place on the same day. 
Visit 4 (day of colonoscopy): 
• Phase II - dose finding 
A blood and urine sample will be collected 4 hours ± 30 minutes and 8 hours ± 30 minutes 
after the end of study drug self-administration.  
After completion of bowel preparation and prior to colonoscopy, patients will complete 
the questionnaires on the acceptability of and adherence to the study drug to which they 
were assigned. The blinded endoscopist will then perform the scheduled colonoscopy 
using a standard colonoscope recording data on bowel cleansing using the BBPS and 
measuring intestinal gas (H2, CH4 and O2) concentrations. The endoscopist will also 
confirm caecal intubation, defined as identification of the appendiceal orifice. Drugs 
administered for the procedure will be recorded. 
Vital signs (heart rate and blood pressure) will be measured prior to colonoscopy. Oxygen 
saturation and heart rate will be measured continuously during colonoscopy, but only 
clinically significant abnormal findings will be recorded on the eCRF, where clinically 
significant means that these abnormal findings cause an additional control or a medical 
intervention. 
The incidence of adverse events will be recorded.  

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• Phase II - pharmacokinetic sub-study 
Patients participating in the pharmacokinetic sub-study will sign a separate informed 
consent form. Venous blood samples will be drawn at the time points mentioned 
previously and analysed at a centralized bioanalytical laboratory only for the 
determination of mannitol concentrations. 
• Phase III - non-inferiority 
Along with the assessments described for phase II (dose finding), the following additional 
assessments will be performed: 
o H2, CH4 and O2 levels will be measured following the introduction of the 
colonoscope in the sigmoidal-rectum junction (15-25 cm from anal margin) before 
standard washing and air insufflation. 
o Number, appearance, size location and histological classification of neoplastic and 
inflammatory colorectal lesions detected. 
o Ottawa Scale for bowel cleansing evaluation before washing and air insufflation for 
luminal distension. 
o Bowel Cleansing Impact Review (BOCLIR) (at Italian centres only). 
In both phases, the study drugs will not be blinded, but all endoscopists will not be aware 
of group allocation; patients and site personnel involved in the randomization of the patient 
and management of the study drugs will be instructed not to disclose group allocation to 
the endoscopists. 
Number of Patients 
The study population is made up of 846 adult patients scheduled for elective (screening, 
surveillance or diagnostic) colonoscopy; 50 patients in each of the three mannitol dose groups 
for phase II, and 348 patients in each of the two treatment groups for phase III. 
Inclusion Criteria 
1. Ability of patient to consent and provide signed written informed consent  
2. Age ≥ 18 years 
3. Males and females scheduled for elective (screening, surveillance or diagnostic) 
colonoscopy to be prepared and performed according to the European Society of 
Gastrointestinal Endoscopy (ESGE) Guideline  
4. Patients willing and able to complete the entire study and to comply with 
instructions  
Exclusion Criteria 
1. Pregnancy or breastfeeding. Females of childbearing potential must have a negative 
pregnancy test at Visit 2 and must practice one of the following methods of birth 
control throughout the study period (unless postmenopausal or surgically sterile, or 
whose sole sexual partner has had a successful vasectomy): oral, implantable, or 
injectable contraceptives (for a minimum of three months before study entry) in 
combination with a condom; intrauterine device in combination with a condom; 
double barrier method (condom and occlusive cap with spermicidal 
foam/gel/film/cream/suppository). 
2. Severe renal failure: glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 
estimated by means of simplified MDRD equation. 
3. Severe heart failure: NYHA Class III-IV. 
4. Severe anaemia (Hb ≤ 8 g/dl). 
5. Severe acute and chronically active Inflammatory Bowel Disease; patients in 
clinical remission (Crohn's Disease Activity Index - CDAI < 150 for Crohn Disease 
and Partial Mayo Score ≤ 2 for Ulcerative Colitis) are allowed. 
6. Chronic liver disease Child-Pugh class B or C. 
7. Electrolyte disturbances (Na, Cl, K, Ca or P out of normal ranges). 
8. Recent (< 6 months) symptomatic acute ischemic heart disease. 
9. History of significant gastrointestinal surgeries, including colon resection, sub-total 
colectomy, abdominoperineal resection, de-functioning colostomy or ileostomy, 
Hartmann’s procedure and other surgeries involving the structure and function of 
the colon. 

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10. Use of laxatives, colon motility altering drugs and/or other substances (e.g. 
simethicone) that can affect bowel cleansing or visibility during colonoscopy within 
24 hours prior to colonoscopy. 
11. Suspected bowel obstruction or perforation. 
12. Indication for partial colonoscopy. 
13. Patients who have received an investigational drug or therapy within 5 half-lives of 
the first visit.  
14. Patients previously screened for participation in this study. 
15. Hypersensitivity to the active ingredients or to any of the excipients of the study 
drugs. 
16. Contraindication to Moviprep® (only for phase III). 
Study Products 
• 
Test (phase II and phase III): mannitol solution (Pearlitol® PF) 
• 
Standard: (phase III): 2L PEG ASC (Moviprep®)  
Key Study 
Procedures 
A schedule of assessments is available in Section 1.2 
The main assessments of the study are as follows: 
• Evaluation of bowel preparation 
The Boston Bowel Preparation Scale (BBPS) uses a four-point scoring system applied to 
each of the three segments of the colon. Each segment is scored from 0 to 3, with total 
score ranging from 0 to 9. 
• Measurement of intestinal H2, CH4 and O2 concentrations 
Intestinal H2, CH4 and O2 concentrations will be measured in each colon segment (right, 
between ileocecal valve and appendix or as close as possible to the ileocecal valve in case 
of obstacles that prevent reaching the valve; transverse, including flexures; and left at the 
sigmoidal-rectum junction, 15-25 cm from anal margin) after standard washing and air 
insufflation for luminal distension using a multi-gas detector (Dräger X-am® 8000). Of 
note, CO2 insufflation and water-aided techniques for colon distension (e.g. water 
immersion and water exchange) will not be allowed. The gas detector has no direct contact 
with the patient’s body but is connected through a one-way pump and a filter to a polyvinyl 
catheter inserted into the working channel of the colonoscope. The intestinal gases are 
conveyed to the gas detector by a one-way pump that prevents the return of gases to the 
colonoscope. Use of any electrocautery device is allowed only during withdrawal and after 
washing and air insufflation. If H2 and/or CH4 levels are potentially dangerous, any 
electrosurgical procedure must be avoided. In phase III only, intestinal H2, CH4 and O2 
will be measured following the introduction of the colonoscope in the sigmoidal-rectum 
junction (15-25 cm from anal margin) before standard washing and air insufflation. 
• Blood sampling for pharmacokinetics 
Patients participating in the pharmacokinetic sub-study will have blood draws before 
mannitol self-administration (T0), and 1 hour (T1), 2 hours (T2), 4 hours (T4) and 8 hours 
(T8) after completion of mannitol self-administration. 
• Safety 
The assessment of overall safety consists in recording and evaluating all adverse events, 
haematological and chemical parameters, and vital signs. 
Statistical 
considerations 
Populations for analyses 
The following populations will be used for the statistical analyses: 
• 
Safety set: all patients who take the study preparation, even only partially. 
• 
Modified Safety set: all patients who take the study preparation, even only partially, 
and who do not meet significant protocol violations that regard inclusion/exclusion 
criteria.  
• 
PK population (only for the pharmacokinetic sub-study): all randomized patients who 
complete the mannitol treatment and have at least one PK assessment, regardless of 
the outcome of colonoscopy.  

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• 
Full Analysis Set (FAS): all randomized patients who take the study preparation, even 
only partially, undergo colonoscopy, and have a BBPS available for at least one colon 
segment after standard washing and air insufflation for luminal distension.  
• 
Per protocol (PP): all randomized patients who meet the following criteria: 
o Treatment with the study drug completed. 
o Colonoscopy completed adequately in the absence of pathological obstruction that 
prevents reaching the right colon, including cecum, (i.e. endoscope does not find 
obstacles other than faecal material), and without acute deterioration of general 
conditions causing the suspension of the procedure. 
o BBPS and H2 and CH4 measurement are available for all colon segments after 
standard washing and air insufflation for luminal distension. 
o No significant protocol violations that regard inclusion/exclusion criteria or that can 
impact evaluations.  
Analysis of primary variables 
Phase II – dose finding 
The identification of the effective and safe mannitol dose to be used in the non-inferiority 
assessment will be performed at the end of dose finding based on the following criteria: 
• 
75% or greater rate of adequate bowel cleansing defined as BBPS total score ≥ 6, with 
a score for each of the three colon segments (right; transverse, including flexures; and 
left, including sigmoid and rectum) ≥ 2 during colonoscopy after standard washing 
and air insufflation for luminal distension.  
• 
Rate of patients in safe conditions defined as the absence of potentially dangerous 
levels of H2 and CH4. 
• 
Clinical judgment based on the caecal intubation rate, the incidence of clinically 
significant adverse events, treatment adherence and acceptability. 
Descriptive statistics and 95% CI of the proportion of patients with adequate bowel 
cleansing will be provided for each dose. Logistic regression models will be applied to 
assess the influence of the two stratification factors and other potential prognostic factors 
on dose response. No between-group comparisons will be performed. The decision will be 
made on the basis of descriptive statistics and 95% CIs.  
Phase III – non-inferiority 
The proportion of patients with adequate bowel cleansing (BBPS total score ≥ 6, score ≥ 2 
for each segment) will be calculated to evaluate the non-inferiority of the test drug vs the 
standard drug. 
Non-inferiority will be assessed by computing the two-tailed 95% confidence interval (CI) 
of the difference between the two proportions πT–πS. Non-inferiority is met if the 95% CI 
does not cross the predefined non-inferiority margin Δ = -0.08 and lies entirely to the right 
of the margin. Furthermore, if the 95% CI lies entirely to the right of 0, it will be possible 
to claim for the superiority of the mannitol solution (Pearlitol® PF). 
The non-inferiority margin πT–πS = -0.08 corresponds to a relative risk πT/πS = 0.906 
when the proportion of successes in the standard group is 0.85. Should the proportion of 
successes in the standard group be lower than 0.85, the non-inferiority margin will be 
adjusted in order to have a relative risk of at least 0.906.  
The analysis will be performed on both the FAS and PP populations. Results from the two 
populations will have equal importance. 
Duration of the 
study 
Estimated date of the first visit of the first patient (FPFV): 15/03/2020 
Estimated date of the first visit of the last patient (LPFV): 01/09/2021 
Estimated date of the last visit of the last patient (LPLV): 29/09/2021 
Participant 
Duration 
The duration of the study for each patient is variable and depends on the time elapsing between 
the pre-colonoscopy visits and scheduled colonoscopy but should not be longer than 28 days. 

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Version and date 
V6.0, 21 January 2021 

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1.2 SCHEDULE OF ACTIVITIES (SOA) 
 
1.2.1 
PHASE II – DOSE FINDING/PHARMACOKINETIC SUB-STUDY 
 
Visit 
Pre-colonoscopy period1 
Day of 
colonoscopy 
V4 
V1 
(≤ 28 days 
before V4) 
V2 
(≤ 7 days 
before V4) 
V3 
(≤ 7 days 
before V4) 
 
Written informed consent 
X 
 
 
 
Demographics, medical history, 
indication for colonoscopy 
X 
 
 
 
Concomitant medications 
X 
X 
X 
X 
Drugs used for colonoscopy 
 
 
 
X 
Blood sampling for standard 
haematology, clinical chemistry and 
electrolyte levels 
 
X 
 
X2 
Urinalysis 
 
X 
 
X2 
Vital signs 
 
X3 
 
X3 
Pulse oximetry and heart rate 
 
 
 
X4 
Pregnancy test 
 
X5 
 
 
Inclusion/exclusion criteria 
verification 
 
 
X 
 
Bristol Stool Form Scale 
 
 
X 
 
Randomization 
 
 
X 
 
Dispensation of study drug and 
instructions 
 
 
X 
 
Questionnaires on adherence and 
acceptability 
 
 
 
X6 
Blood sampling for pharmacokinetic 
sub-study 
 
 
 
X7 
Colonoscopy 
 
 
 
X 
Measurements of intestinal gas 
concentrations 
 
 
 
X 
Boston Bowel Preparation Scale 
 
 
 
X 
Confirmation of caecal intubation 
 
 
 
X 

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Adverse events8 
X 
X 
X 
X 
1 More than one visit may take place on the same day. 
24 hours and 8 hours after end of study drug self-administration. 
3Heart rate, diastolic and systolic blood pressure at Visit 2 and at Visit 4 prior to colonoscopy. 
4 Only clinically significant abnormal oxygen saturation and heart rate values obtained during 
colonoscopy are to be recorded on the eCRF, where clinically significant means that these 
abnormal finding cause an additional control or a medical intervention. 
5A blood beta hCG pregnancy test is required for women of childbearing potential. 
64 hours after end of study drug self-administration, before colonoscopy. 
7Only for patients who signed the separate informed consent form for the pharmacokinetic sub-
study. Before mannitol self-administration (T0 - baseline), and 1 hour (T1), 2 hours (T2), 4 hours 
(T4) and 8 hours (T8) after completion of mannitol self-administration.  
8Adverse events are to be collected from signature of the informed consent form up to and including 
the day of colonoscopy. 
 

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1.2.2 
PHASE III – NON-INFERIORITY 
 
Visit 
Pre-colonoscopy period1 
Day of 
colonoscopy 
V4 
V1 
(≤ 28 days 
before V4) 
V2 
(≤ 7 days 
before V4) 
V3 
(≤ 7 days 
before V4) 
 
Written informed consent 
X 
 
 
 
Demographics, medical history, 
indication for colonoscopy 
X 
 
 
 
Concomitant medications 
X 
X 
X 
X 
Drugs used for colonoscopy 
 
 
 
X 
Blood sampling for standard 
haematology, clinical chemistry and 
electrolyte levels 
 
X 
 
X2 
Urinalysis 
 
X 
 
X2 
Vital signs 
 
X3 
 
X3 
Pulse oximetry, diastolic and systolic 
blood pressure and heart rate 
 
 
 
X4 
Pregnancy test  
 
X5 
 
 
Inclusion/exclusion criteria 
verification 
 
 
X 
 
Randomization 
 
 
X 
 
Dispensation of study drug and 
instructions 
 
 
X 
 
Questionnaire on adherence and 
acceptability 
 
 
 
X6 
Bowel Cleansing Impact Review 
 
 
 
X7 
Colonoscopy 
 
 
 
X 
Measurements of intestinal gas 
concentrations 
 
 
 
X 
Boston Bowel Preparation Scale 
 
 
 
X 
Ottawa Scale 
 
 
 
X 
Detection of colorectal lesions 
 
 
 
X 
Confirmation of caecal intubation 
 
 
 
X 
Adverse events8 
X 
X 
X 
X 

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1 More than one visit may take place on the same day. 
24 hours and 8 hours after end of study drug self-administration. 
3 Heart rate, diastolic and systolic blood pressure at Visit 2 and Visit 4 prior to colonoscopy. 
4 Only clinically significant abnormal oxygen saturation and heart rate values obtained during 
colonoscopy and diastolic and systolic blood pressure values measured immediately prior and 
after colonoscopy are to be recorded on the eCRF, where clinically significant means that these 
abnormal finding cause an additional control or a medical intervention. Of note, clinically 
significant changes of diastolic and systolic blood pressure measured during colonoscopy will also 
be reported if considered clinically significant by the Investigator. 
5A blood beta hCG pregnancy test is required for women of childbearing potential. 
64 hours after end of study drug self-administration, before colonoscopy. 
7Only for Italian centres. 4 hours after end of study drug self-administration, before 
colonoscopy. 
8Adverse events are to be collected from signature of the informed consent form up to and including 
the day of colonoscopy. 
 
 

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2 
INTRODUCTION 
 
2.1 OVERVIEW 
Effective colorectal screening relies on colonoscopy, the current standard method for imaging the 
mucosa of the entire colon. The diagnostic accuracy of colonoscopy depends largely on the quality 
of colonic cleansing. Large-scale reviews have shown rates of incomplete colonoscopy, defined as 
the inability to achieve caecal intubation and mucosal visualization effectively, to be between 10% 
and 20%, well over the targets recommended by the U.S. Multi-Society Task Force on Colorectal 
Cancer (Salzmann et al., 2015). Inadequate bowel cleansing can lead to missed lesions, increased 
complications, unnecessarily prolonged examinations and additional patient discomfort (Parra-
Blanco et al., 2014). 
Wong et al. conducted a study on 5470 colon rectal cancer (CRC) screening patients aimed at 
evaluating the factors independently associated with the quality of bowel preparation. Poorer 
bowel preparation quality was associated with longer caecal intubation time and longer 
colonoscopy withdrawal time (both P < 0.001). The detection of colorectal neoplasia and advanced 
neoplasia was used as the outcome measure controlling for the recognized risk factors of CRC. 
Compared with subjects with excellent bowel preparation, those with good (AOR = 0.354, 95% CI 
0.270–0.464, P < 0.001) and fair or poor (AOR = 0.406, 95% CI 0.303–0.545, P < 0.001) bowel 
cleansing were significantly less likely to have colorectal neoplasia detected. The same applied to 
colorectal advanced neoplasia and neoplastic lesions sized ≥5 mm in diameter (Wong et al., 2016). 
The European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter 
study was a prospective observational study of 5832 patients conducted at 21 centers from 11 
countries. The detection of polyps of any size depended on cleansing quality: odds ratio (OR) 1.73: 
95% confidence interval (CI)[1.28, 2.36] for intermediate-quality compared with low-quality 
preparation; and OR 1.46: 95% CI[1.11, 1.93] for high-quality compared with low-quality 
preparation. For polyps >10 mm in size, corresponding ORs were 1.0 for low-quality cleansing, 
OR 1.83: 95% CI[1.11, 3.05] for intermediate-quality cleansing, and OR 1.72: 95% CI[1.11, 2.67] 
for high-quality cleansing. The authors concluded that cleansing quality critically determines 
quality, difficulty, speed, and completeness of colonoscopy (Froehlich et al., 2005). 
Rex et al. conducted a study aimed at measuring the impact of bowel preparation on total direct 
cost as well as procedure time and volume. For 200 consecutive outpatient colonoscopies in 
persons with intact colons both at a private university hospital and at a public university hospital, 
the authors recorded the time spent suctioning fluid and feces from the colon and the time spent 
washing the colon to clean the mucosa. The endoscopist were asked to designate examinations that 
should be repeated at an interval sooner than would otherwise be recommended because of 
imperfect preparation. Suctioning fluid and washing occupied 6% and 1.5% of total examination 
time (including insertion and withdrawal) at the public hospital and 9% and 1.3% at the private 

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hospital. Patients at the public hospital were more likely to have an aborted examination (6.5% vs 
1%, p = 0.004) and to be brought back earlier than suggested or required by current practice 
standards because of imperfect bowel preparation (20% vs 12.5%, p = 0.04). Cost analysis 
indicated that to complete the initial examinations and the first round of surveillance, imperfect 
bowel preparation resulted in a 12% increase in costs at the university hospital and a 22% increase 
at the public hospital (Rex et al., 2002). 
Two single-center studies quantifying adenoma miss rates based on repeated colonoscopies done 
shortly after sub-optimally prepared examinations yielded similar results with overall adenoma 
miss rates reported as 42% and 47%. On a per-patient basis, at least one adenoma was missed in 
25% and 34% of these two cohorts. The miss rate for advanced lesions (previously quantified as 
0–7% in tandem colonoscopy studies) was 27% in one study, with the other study reporting 18% 
for missed lesions that if identified would have changed the surveillance schedule (Lebwohl et al., 
2013; Lebwohl et al., 2011; Chokshi et al., 2012).  
In Europe, the most commonly used preparations for colonoscopy are osmotic laxatives, 
represented in most cases by polyethylene glycol (PEG). PEG-based cleansing agents are available 
in 4 L (high volume) or 2 L (low volume) formulations and are to be taken either on the same day 
or split between 2 days (split-dose regimen). Currently, the split dose 4L PEG-ELS preparation 
(PEG with electrolytes) is considered to deliver the highest quality for colon preparation (Hassan 
et al., 2013, Bechtold et al., 2016, Salzmann et al., 2015). However, 15% of patients self-
administering PEG-ELS find it intolerable due to its unpleasant taste, large volume or nausea 
(Marshall et al., 1993). Therefore, other preparations have been conceived to reduce the drawbacks 
associated with PEG-ELS.  
Sodium phosphate preparations are hyperosmotic cleansing agents given as an alternative to PEG 
because of the smaller volume required, and consequently better patient compliance (Markowitz 
et al., 2009). However, the use of sodium phosphate solutions has raised concerns regarding 
phosphate-induced renal disease (FDA safety alert, 2006) and the European Society of 
Gastrointestinal Endoscopy (ESGE) guidelines no longer recommend the routine use of sodium 
phosphate (Hassan et al., 2013).  
The newest agent in the hyperosmotic category is a combination of sodium picosulfate and 
magnesium oxide in a low volume preparation (approximately 2 L). Efficacy in terms of bowel 
cleansing is comparable to sodium phosphate and PEG-ELS (Renault et al., 2008, Katz et al., 
2013). However, due to reported electrolyte abnormalities in the elderly, sodium picosulfate should 
be used with great caution in this population and should be avoided in patients with renal 
insufficiency (Bechtold et al., 2016). 
Not only the volume of administered fluid, but also the timing of preparation is reported to have a 
significant impact on the quality of bowel preparation. Giving part of the bowel preparation on the 

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same day as the colonoscopy was reported to result in higher-quality colonoscopy compared with 
the ingestion of the entire preparation on the day or evening before colonoscopy (Salzmann, 2010).  
In study evaluating the efficacy and tolerability of a split-dose PGE-ELS plus bisacodyl and a 
regular diet, 187 patients were randomly assigned to receive either 3 L of PGE-ELS (n = 96; Group 
A) with a liquid diet on the day before colonoscopy, or 2 L of PGE-ELS, one tablet of bisacodyl, 
and a minimally restricted diet on the day before colonoscopy, and then 1 L of the same solution 
on the day of colonoscopy (n = 91; Group B). Colon cleansing was significantly better in Group 
B with regard to the overall quality of the preparation (p < 0.05). Compliance was significantly 
higher in Group B as evidenced by the lower number of patients who discontinued the preparation 
(4 vs. 15; p = 0.02) because of side effects such as nausea or vomiting. The degree of discomfort, 
adverse events, and willingness to retake the preparation were not significantly different between 
the groups. The authors concluded that colonic preparation with split-dose polyethylene glycol-
electrolyte provided better quality colon cleansing and higher compliance, with less dietary 
restrictions, than preparation with whole-dose polyethylene glycol-electrolyte (El Sayed et al., 
2003). 
In a single-blind, active control, randomized study of 895 patients, Marmo et al. evaluated the 
degree of colon cleansing comparing split-dosage versus non-split-dosage of two different PEG 
volumes (low-volume PEG + ascorbic acid vs standard-volume PEG-electrolyte solution). Overall 
compliance was excellent (97%) for both preparation methods. PEG plus ascorbic acid produced 
the same degree of cleansing as standard-volume PEG-electrolyte solution (77% vs 73.4%, 
respectively, within the split-dosage group and 41.7% vs 44.3%, respectively, within the non-split-
dosage group). Independently of PEG volumes, the split-dosage regimen produced markedly 
superior cleansing results over the same-day method (good/excellent 327/435, 75.2% vs 186/433, 
43.0%, P = .00001). The degree of bowel cleansing affected both caecal intubation (failed 
intubation 11.7% with fair/poor preparation vs 1.2% with good/excellent preparation, P = .00001) 
and polyp detection rates (12.2% with fair/poor vs 24.6% with good/excellent preparation, P = 
.001). Aborted procedures were significantly more frequent in the non-split-dosage arm (21.2% vs 
6.9%, odds ratio [OR] 3.60 [2.29-5.77], P < .0001 (Marmo et al., 2010). 
The ideal method of bowel preparation for colonoscopy is thus one that provides a combination of 
effectiveness, safety, ease of self-administration, low cost and good patient acceptance. While the 
current available preparations offer effectiveness and safety at a reasonable level, up to 20%-25% 
of all colonoscopies are reported to have inadequate bowel preparation (Johnson et al., 2014) and 
patient acceptance is still an issue.  
Mannitol is a sugar alcohol only partly absorbed following oral administration. It acts as an osmotic 
laxative by increasing osmolarity in the gut and consequently the amount of fluid that is retained 
in the bowel and excreted. Mannitol was widely used in the late ‘70s and early ‘80s as a bowel 
cleansing prep agent for colonoscopy thanks to its effectiveness, ease of self-administration related 

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to reduced volumes, high patient acceptance and lack of significant systemic side effects. Eleven 
clinical studies investigating the safety and efficacy of mannitol as a bowel cleansing agent were 
published between 1980 and 2018. All published studies used doses of mannitol between 50 g and 
150 g, always given in a single dose. Mannitol at the dose of 50 g showed some effectiveness as 
bowel cleansing agent: 18 out of 21 patients treated with mannitol combined with saline irrigation 
showed a good cleansing outcome compared with saline alone (11 out of 21) or mannitol alone 
(12 out of 20) (Minervini et al., 1980), and 17 out of 19 patients treated with mannitol alone had a 
satisfactory or excellent result (Gilmore et al., 1981). Mannitol at 100 g showed comparable 
efficacy results to several bowel cleansing agents, including sodium phosphate, 4 L and 2 L PEG, 
and substantially presented a similar incidence of adverse events (Macedo et al., 2003; Miki et al., 
2008; Mendoza et al., 2008; Viera et al., 2012; Kaiser-Júnior et al., 2018). At the dose of 150 g, 
mannitol was as effective as sodium picosulfate with a similar safety profile (Müller et al., 2007). 
In summary, 533 patients were treated with mannitol in comparative trials and its efficacy was 
found to be comparable to that of the comparators; most bowel preparations were at least adequate, 
with the number of excellent or good preparations ranging from 66% to 90% and very few poor or 
unsatisfactory results (see Investigator’s Brochure for more details). 
Currently, mannitol is commonly used in Brazil, although off-label, where it is still the most 
popular formulation for bowel cleansing. In Europe and the US, mannitol is currently not used for 
bowel cleansing due to some cases of intestinal explosion (one lethal) that, despite the absence of 
controlled clinical trials, have been attributed to the presence of a mixture of methane, hydrogen 
and oxygen during the execution of diathermy-electrocautery after biopsy. A systematic review of 
the medical research published from 1952 to 2006 was conducted by Ladas et al. (2007). A total 
of 20 cases of colonic gas explosion were identified, 14 of which had been preceded by bowel 
preparation with mannitol and sorbitol (Josemanders et al., 2006). Due to these reported cases of 
intestinal explosion after the use of diathermy-electrocautery during colonoscopy in patients 
treated with mannitol for bowel preparation, the use of mannitol for bowel cleansing has been 
limited as summarized in the guidelines of the ESGE, which state: “Mannitol has also been used 
for bowel preparation; it seems to be as effective and as well tolerated as OSP (NaP) or PEG. 
However, its use has almost been abandoned because of the explosion risk when diathermy is used 
during colonoscopy" (Hassan et al., 2013).  
Notably, at the time when the cases of intestinal explosion were reported, mannitol was one of the 
most commonly used laxatives, since others such as PEG had not yet been developed. Furthermore, 
routine techniques performed nowadays during colonoscopy such as air insufflation, suction and 
washing most likely remove residual gases, if present, or reduce their concentrations below those 
associated with the risk of intestinal explosion (Macedo et al., 2003, Avgerinos 1984).  
Recent scientific literature indicate that safety problems reported in the past do not seem to be an 
issue in regions where mannitol is used for this indication. Currently available scientific data 
indicate that the baseline concentration of CH4 in the bowel is not only related to the type of 

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laxative used but is also attributable to other factors such as bowel flora, constipation, sorbitol 
malabsorption, and prior antibiotic use (Ladas et al., 2007, Attaluri et al. 2010, Corazza et al. 
1988). Individuals can be categorized as methane producers and non-producers, about 35% and 
65% of the healthy western population respectively (Bond et al., 1971), regardless of the method 
of intestinal preparation. Recently, methane production has been also linked to intestinal transit 
time (Triantafyllou et al., 2014). 
Hydrogen and methane are produced by fermentation of non-absorbable (e.g. lactulose, mannitol) 
or incompletely absorbed carbohydrates (e.g. lactose, fructose, sorbitol) by the colonic flora and 
are potentially dangerous at levels ≥ 4% Vol (H2) and ≥ 5% Vol (CH4), in presence of an O2 
concentration ≥ 5% Vol. The production of H2 is affected by dietary intake and the period of fasting 
prior to measurement, whereas the production of CH4 is unrelated to diet. 
Potentially dangerous concentrations of H2 and/or CH4 may be present even with the most 
commonly used bowel preparation methods, particularly also in patients prepared with PEG, as 
demonstrated by the study of Gallagher (Gallagher et al. 1992). The aim of this study was to 
compare intracolonic gas compositions after administration of PEG and mannitol preparations for 
full colonoscopy and phosphate enema for left-sided colonoscopy. Its purpose was to establish if 
explosion is still a potential occurrence after preparations with PEG, that does not interact with 
colonic bacteria. Patients were prepared whit PEG (N=23), phosphate enema (N=34) and mannitol 
(N=4). Air insufflation was used in all procedures. High concentrations of hydrogen were detected 
in 3 out of 38 gas samples in the PEG group, in 2 of 41 samples in the phosphate enema group and 
in one of the 8 samples in the mannitol group. All patients had a coexisting intracolonic oxygen 
concentration > 5%. The results of this study proved that potentially dangerous concentrations of 
hydrogen may occur even with the currently most used preparations. Therefore, for the new 
preparations it is relevant to compare the proportion of patients who may have potentially 
dangerous H2 and/or CH4 levels with the preparations currently in use. 
To address any remaining concerns related to a more frequent accumulation of colonic gas to 
potentially dangerous levels following bowel preparation with mannitol, this study will be 
conducted with particular attention on safe bowel preparation, comparing the proportion of patients 
without potentially dangerous levels of H2 and CH4  after preparation with mannitol and PEG.    
The purpose of this dose finding/comparative efficacy study is to first single out the most 
appropriate dose of mannitol for bowel preparation and, subsequently, demonstrate the non-
inferiority of the efficacy of mannitol vs standard split 2L PEG ASC (Moviprep®) in bowel 
preparation for colonoscopy. The selected doses of mannitol to be investigated in the dose finding/ 
comparative efficacy study are 50 g, 100 g and 150 g, since this range includes the minimum and 
maximum mannitol doses used effectively in the proposed indication, as reported in published 
literature. The study includes a pharmacokinetic sub-study to define the pharmacokinetic profile 
of the mannitol doses proposed. 

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2.2 RISK/BENEFIT ASSESSMENT 
 
2.2.1 
KNOWN POTENTIAL RISKS  
Mannitol 
The safety and tolerability of mannitol were reported in 433 patients receiving mannitol in 
comparative clinical trials. The most frequent adverse events (AE) reported in these trials were 
serum electrolyte changes, nausea and abdominal pain. Other AE’s were vomiting, abdominal 
distension and increased haematocrit. In general safety and tolerability were comparable between 
mannitol and its comparators.  
Intestinal gas levels were measured in 127 patients receiving mannitol in five clinical trials 
conducted between 1981 and 2016. In general, higher gas levels, especially of H2, were measured 
in the mannitol patients if the procedure was performed without air insufflation, otherwise no 
differences were reported between mannitol and the comparators. No differences were found in 
O2 and CH4 levels.  
A recent clinical study evaluated intestinal gas concentrations in three intestinal segments during 
introduction and withdrawal of the colonoscope with minimum air insufflation or suction. 
Intermittent infusions of small quantities of water were used as necessary. The study did not find 
elevated levels in any of the 50 patients examined with mannitol (Paulo et al., 2016).  
To ensure patient safety in this study, colon H2 and CH4 concentrations will be measured during 
colonoscopy and all electrosurgical procedures will be avoided should gas concentrations reach 
potentially dangerous levels. 
Anaphylactic/anaphylactoid reactions, as well as other hypersensitivity/infusion reactions have 
been reported with mannitol. Patients with known hypersensitivity to mannitol will be excluded 
from the study. 
Patients with pre-existing renal disease, or those receiving potentially nephrotoxic drugs, are at 
increased risk of renal failure following administration of mannitol. Patients with severe renal 
disease will be excluded from this study. 
Accumulation of mannitol (due to insufficient renal excretion) and dehydration due to diarrhoea 
may result in hypervolemia, overexpansion of extracellular fluid, which may lead to or exacerbate 
existing congestive heart failure. Patients with severe symptomatic congestive heart failure or 
recent ischemic heart disease will be excluded from this study. 
Mannitol-induced osmotic diuresis and dehydration due to diarrhoea may cause or worsen 
dehydration/hypovolemia, haemoconcentration and electrolyte imbalances. Administration of 
mannitol may also cause hyperosmolality. Patients with pre-existing electrolyte disturbances will 

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be excluded from this study. Furthermore, electrolyte levels and plasma osmolality will be 
monitored throughout the study. 
Laxatives are contraindicated in patients with bowel obstruction, therefore these patients and those 
with a history of colonic resection will be excluded from this study. 
Of note, urine specific gravity may decrease because of osmotic diuresis caused by the well-known 
pharmacological profile of mannitol. Urine specific gravity out of normal ranges will be collected 
and managed as expected adverse event. 
See the Investigator’s Brochure for more details. 
Polyethylene glycol + ascorbate (PEG ASC) (Moviprep®) 
In the Moviprep® trials, abdominal distension, anal discomfort, thirst, nausea, vomiting, sleep 
disturbance and abdominal pain were the most common adverse reactions. Dehydration may occur 
as a result of diarrhoea and/or vomiting. Isolated cases of urticaria, rhinorrhoea, dermatitis, and 
anaphylactic reaction have been reported with PEG-based products. 
Contraindications for the use of Moviprep® 
− 
Hypersensitivity to the active ingredients or other components of Moviprep® 
− 
Intestinal obstruction or perforation 
− 
Gastric emptying disorders 
− 
Ileus 
− 
Phenylketonuria 
− 
Glucose-6-phosphate dehydrogenase deficiency 
− 
Toxic megacolon 
Patients with contraindications will not be enrolled in this study. 
Precautions for the use of polyethylene glycol + ascorbate (PEG ASC) (Moviprep®) 
PEG-ASC should be administered with caution to fragile patients in poor health or patients with 
serious clinical impairment such as: 
− 
Impaired gag reflex, or with a tendency to aspiration or regurgitation 
− 
Impaired consciousness 
− 
Severe renal insufficiency (creatinine clearance <30 mL/min) 
− 
Cardiac impairment (NYHA grade III or IV)  
− 
Patients at risk of arrhythmia, for example those on treatment for cardiovascular disease or 
who have thyroid disease 
− 
Dehydration 
− 
Severe acute inflammatory bowel disease 

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− 
The medicinal product contains aspartame, which is a source of phenylalanine. This may 
be harmful for people with phenylketonuria. 
See the simplified Investigational Medicinal Product Dossier (IMPD) for the reference product 
Moviprep® for more details. 
2.2.2 
KNOWN POTENTIAL BENEFITS  
The ideal method of bowel preparation for colonoscopy is a combination of effectiveness, safety, 
ease of self-administration, good patient acceptance and low cost. While current available 
preparations offer effectiveness and safety at a reasonable level, patient acceptance can still be 
improved. A bowel cleansing agent such as mannitol, which has a much better flavour than other 
cleansing agents, requires low volume and is self-administered the morning of the procedure (and 
thus does not interfere with sleep), is expected to improve patient compliance and thus the success 
of the procedure. 
2.2.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
In light of what outlined previously, the risk connected with this study is considered to be very low 
and is minimized by the use of a gas detector that will help performing electrocautery, if necessary, 
in safe conditions. Further information about the gas detector is available in the Gas Detector 
Technical Documentation. The expectation is to show that mannitol is not inferior to 2L PEG ASC 
in terms of bowel cleansing, while better in terms of patient acceptance. The development of oral 
mannitol for bowel cleansing and the conduct of this study are therefore justified. 
 

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3 
OBJECTIVES AND ENDPOINTS 
 
Phase II - Dose Finding/Pharmacokinetic sub-study 
Objectives 
Endpoints 
To determine the effective and safe dose 
of mannitol for adequate bowel 
cleansing to be used in the comparative 
non-inferiority phase of the study (phase 
III). 
Primary efficacy endpoint 
• 
Proportion of patients with adequate bowel cleansing, 
defined as Boston Bowel Preparation Scale (BBPS) 
total score ≥ 6, with a score for each of the three colon 
segments (right; transverse, including flexures; and left, 
including sigmoid and rectum) ≥ 2 during colonoscopy 
after standard washing and air insufflation for luminal 
distension. 
Secondary efficacy endpoint 
• 
Caecal intubation rate, defined as the percentage of 
patients with appendiceal orifice visible to the 
endoscopist. 
Safety and tolerability 
• 
Proportion of patients in safe conditions, defined as the 
absence in each colon segment (right, between ileocecal 
valve and appendix or as close as possible to the 
ileocecal valve in case of obstacles that prevent 
reaching the valve; transverse, including flexures; and 
left at the sigmoidal-rectum junction, 15-25 cm from 
anal margin) of potentially dangerous levels of H2 
and/or CH4 (> 4% Vol and >100% of Lower Explosion 
Level (LEL), respectively) during colonoscopy after 
standard washing and air insufflation for luminal 
distension. 
• 
Incidence of adverse events from the beginning of study 
drug self-administration.  
• 
Proportion of patients with change from baseline 
considered clinically significant by the Investigator of 
haematological and chemical parameters (CBC, 
creatinine, BUN, eGFR, ALT, AST, glucose, 
electrolytes) 4 hours and 8 hours after completion of 
study drug self-administration, where clinically 
significant means that the change causes an additional 
control or a medical intervention. 
• 
Proportion of patients with change during colonoscopy 
considered clinically significant by the Investigator of 
vital signs (heart rate and pulse oximetry), where 
clinically significant means that the change causes an 
additional control or a medical intervention. 

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Phase II - Dose Finding/Pharmacokinetic sub-study 
Objectives 
Endpoints 
Adherence and acceptability 
• 
Adherence: study drug completely taken, partially 
taken, not taken 
• 
Ease of use: numeric rating scale (NRS) (0 = very 
difficult to 10 = very easy) 
• 
Taste: NRS (0 = terrible to 10 = very good) 
• 
Willingness to reuse the preparation (yes/no) 
To define the pharmacokinetic profile of 
the mannitol doses used in dose finding 
through a pharmacokinetic sub-study. 
• 
Cmax: maximum concentration   
• 
tmax: time to maximum concentration  
• 
AUC0-t0-t: area under concentration-time curve, from 0 
to the last blood sampling time point with measurable 
concentration  
• 
t1/2: elimination half-life 
 
Phase III - Non-Inferiority 
Objectives 
Endpoints 
To demonstrate the non-inferiority of 
mannitol vs. standard split 2L PEG ASC 
(Moviprep®) in bowel cleansing for 
colonoscopy. 
Primary Efficacy endpoint 
• 
Proportion of patients with adequate bowel 
cleansing, defined as BBPS total score ≥ 6, with a 
score for each of the three colon segments (right; 
transverse, including flexures; and left, including 
sigmoid and rectum) ≥ 2 during colonoscopy after 
standard washing and air insufflation for luminal 
distension. 
Secondary efficacy endpoints 
• 
Number, appearance, size, location and histological 
classification of neoplastic and inflammatory 
colorectal lesions detected.  
• 
Adenoma detection rate, defined as the percentage 
of patients with at least one lesion detected. 
• 
Caecal intubation rate, defined as the percentage of 
patients with appendiceal orifice visible to the 
endoscopist. 
• 
Ottawa Scale for bowel preparation before washing 
and air insufflation for luminal distension. 
To assess the safety and tolerability of 
mannitol.  
• 
Proportion of patients in safe conditions, defined as 
the absence in each colon segment (right, between 
ileocecal valve and appendix or as close as possible 
to the ileocecal valve in case of obstacles that 

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Phase III - Non-Inferiority 
Objectives 
Endpoints 
prevent reaching the valve; transverse, including 
flexures; and left at the sigmoidal-rectum junction, 
15-25 cm from anal margin) of potentially 
dangerous levels of H2 and/or CH4 (> 4% Vol and 
>100% LEL, respectively) during colonoscopy after 
standard washing and air insufflation for luminal 
distension. 
• 
Incidence of adverse events from the beginning of 
study drug self-administration.  
• 
Proportion of patients with change from baseline 
considered clinically significant by the Investigator 
of haematological and chemical parameters (CBC, 
creatinine, BUN, eGFR, ALT, AST, glucose, 
electrolytes) 4 hours and 8 hours after completion of 
study drug self-administration, where clinically 
significant means that the change causes an 
additional control or a medical intervention. 
• 
Proportion of patients with change from baseline 
considered clinically significant by the Investigator 
of vital signs (heart rate, systolic and diastolic blood 
pressure) measured during visits, as well as 
clinically significant change of pulse oximetry and 
heart rate measured during colonoscopy and systolic 
and diastolic blood pressure measured immediately 
prior and after colonoscopy, where clinically 
significant means that the change causes an 
additional control or a medical intervention. Of note, 
clinically significant changes of systolic and 
diastolic blood pressure measured during 
colonoscopy will also be reported if considered 
clinically significant by the Investigator. 
To evaluate adherence to and acceptability 
of bowel preparation with mannitol and 
with Moviprep®. 
 
• 
Adherence: study drug completely taken, partially 
taken, not taken 
• 
Bowel Cleansing Impact Review (BOCLIR) (only at 
Italian centres) 
• 
Ease of use: NRS (0 = very difficult to 10 = very 
easy) 
• 
Taste: NRS (0 = terrible to 10 = very good) 
• 
Willingness to reuse the preparation (yes/no) 
 
 
 

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4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
This is a phase II/III, international, multicentre, randomized, parallel-group, endoscopist-blinded 
study that combines a phase II dose-finding study/pharmacokinetic sub-study with a phase III non-
inferiority efficacy study (see Figure 4-1). The population for phase III will not include the patients 
who participated in phase II.

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Figure 4-1 
Study design 
 

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In both phases, the study drugs will not be blinded, but all endoscopists performing study 
colonoscopies will not be aware of group allocation; patients and site personnel involved in the 
randomization of the patient and management of the study drugs will be instructed not to disclose 
group allocation to the endoscopists. Experienced endoscopists will undergo specific training to 
decrease inter-observer variability in the evaluation of bowel cleansing and to refine intestinal gas 
measurement techniques. 
Details of all the assessments to be performed are available in the schedule of activities (SoA) in 
Section 1.2 and in Section 8. 
4.1.1 
PHASE II  
The parallel-group dose-finding phase will be conducted at approximately 8 centres and will 
involve 150 patients randomly assigned (1:1:1 ratio) to one of the following three treatment 
groups:  
• 50 g mannitol powder to be dissolved in 500 ml of water 
• 100 g mannitol powder to be dissolved in 750 ml of water 
• 150 g mannitol powder to be dissolved in 1000 ml of water 
Of note, these doses of mannitol have been selected as this range includes the minimum (50 g) and 
maximum (150 g) mannitol doses used effectively in the proposed indication, as reported in 
published literature. Please refer to Section 2.1 for further details. 
Randomization is stratified by centre and by the presence of constipation (yes/no), defined as the 
recurrent use of laxatives or Bristol Stool Form Scale (BSFS) < 3 in the two weeks prior to 
randomisation. 
To limit patient exposure to an ineffective dose causing repetition of colonoscopy, the adequacy 
of bowel cleansing will be monitored continuously and enrolment in a treatment group will be 
discontinued as soon as 25% of treated patients present inadequate bowel cleansing causing 
repetition of colonoscopy. The stopping rule, mainly guided by clinical considerations, will be 
applied in each treatment group as follows: 
• Up to the 25th enrolled patient, enrolment in a treatment group will be stopped as soon as 
6 patients present inadequate bowel cleansing causing repetition of colonoscopy (i.e. if 
among the initial 15 patients enrolled in a treatment group, 6 need to repeat the cleansing 
procedure, the treatment group will be immediately discontinued).  
• From the 26th enrolled patient on (if treatment was not discontinued earlier), enrolment will 
be stopped as soon as 25% of patients present inadequate bowel cleansing causing 
repetition of colonoscopy (i.e. if among the initial 32 patients enrolled in a treatment group, 
8 need to repeat the cleansing procedure, the treatment group will be immediately 
discontinued). 

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The appropriate mannitol dose to be used in the comparative non-inferiority phase (phase III) will 
be singled out at the end of dose-finding based on the following criteria: 
• 75% or greater rate of adequate bowel cleansing.  
• Rate of patients in safe conditions, defined as absence of potentially dangerous levels of 
H2 and CH4 in each colon segment (right, between ileocecal valve and appendix or as close 
as possible to the ileocecal valve in case of obstacles that prevent reaching the valve; 
transverse, including flexures; and left at the sigmoidal-rectum junction, 15-25 cm from 
anal margin) after standard washing and air insufflation for luminal distension). 
• Clinical judgment based on the caecal intubation rate, the incidence of adverse events, 
treatment adherence and acceptability (considering ease of use, taste and willingness to 
reuse the preparation). 
Should two or all three doses prove to be equally safe and effective, the lowest dose will be selected 
for phase III of the study. 
Study visits 
Phase II of the study consist of four visits:  
Visit 1 (≤ 28 days before the day of colonoscopy): after signed written informed consent is 
obtained, information concerning demographics, medical history, concomitant medications and 
indications for colonoscopy will be collected in the electronic case report form (eCRF). The 
incidence of adverse events will be recorded.  
Visit 2 (≤ 7 days before the day of colonoscopy): to complete the verification of 
inclusion/exclusion criteria, a blood sample will be drawn to assess the haematological and 
chemical parameters (including electrolyte levels) of all patients and to perform a pregnancy test 
for women of childbearing potential. Assessments include a urinalysis and the measurement of 
vital signs (blood pressure and heart rate). The incidence of adverse events will be recorded.  
Visit 3 (≤ 7 days before the day of colonoscopy): if inclusion/exclusion criteria are met, the Bristol 
Stool Form Scale (BSFS) will be administered, randomization will be performed, study drug will 
be dispensed and verbal and written instructions for its use will be provided. The date and time of 
colonoscopy will be communicated and reported on a form given to the patient. On the same form, 
patients will indicate date and time of start and end of study drug self-administration. The incidence 
of adverse events will be recorded.  
More than one visit may take place on the same day.  
Visit 4 (day of colonoscopy): 
A blood and urine sample will be collected at the following time points: 
• 4 hours ± 30 minutes after the end of study drug self-administration 
• 8 hours ± 30 minutes after the end of study drug self-administration 

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After completion of bowel preparation, prior to colonoscopy, patients will fill in the questionnaire 
on acceptability and adherence.  
The blinded endoscopist will then perform the scheduled colonoscopy using a standard 
colonoscope recording data on bowel cleansing using the BBPS and measuring intestinal gas 
concentrations in each colon segment after standard washing and air insufflation. Of note, CO2 
insufflation and water-aided techniques for colon distension (e.g. water immersion, water 
exchange) will not be allowed. The endoscopist will also confirm caecal intubation, defined as 
identification of the appendiceal orifice. Drugs administered for the procedure will be recorded. 
Intestinal gas (H2, CH4 and O2) concentrations in each segment will be measured using a multi-
gas detector (Dräger X-am® 8000). Further information is available in the Gas Detector Technical 
Documentation. Use of any electrocautery device is allowed only during withdrawal and after 
washing and air insufflation. If H2 and/or CH4 levels are potentially dangerous, any electrosurgical 
procedure must be avoided. 
Vital signs (heart rate and blood pressure) will be measured prior to colonoscopy. Oxygen 
saturation and heart rate will be measured continuously during colonoscopy, but only clinically 
significant abnormal findings will be recorded on the eCRF, where clinically significant means 
that these abnormal findings cause an additional control or a medical intervention. 
The incidence of adverse events will be recorded.  
4.1.2 
PHASE II - PHARMACOKINETIC SUB-STUDY 
Patients accepting to be included in the sub-study of phase II will be enrolled sequentially until the 
required sample size (10 evaluable patients in each dose group) is reached. If patients do not 
undergo all PK evaluations, the sub-study sample size will be increased to guarantee at least 8 PK 
evaluations for each assessment time. 
Dietary restrictions based on the INRAN tables (Carnovale and Marletta 2007) are required, after 
overnight fasting, between 24 hours before and the start of mannitol self-administration. Thus, 
foods containing a significant amount of soluble sugars are to be forbidden for the PK sub-study. 
Patients enrolled in the pharmacokinetic sub-study have to avoid any food intake and drink only 
water between the start of mannitol self-administration and 8 hours after mannitol intake. Of note, 
between 4 and 8 hours after mannitol intake, patients may eat any food devoid of soluble sugars 
according to the INRAN tables, if deemed necessary by the Investigator. Patients will be allowed 
to eat without restrictions 8 hours after drug self-administration. 
 

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Study visits 
Patients enrolled in the pharmacokinetic sub-study will follow the same scheme of phase II of the 
study that consists of four visits:  
Visit 1 (≤ 28 days before the day of colonoscopy): after signed written informed consent is 
obtained, information concerning demographics, medical history, concomitant medications and 
indications for colonoscopy will be collected in the electronic case report form (eCRF). The 
incidence of adverse events will be recorded.  
Visit 2 (≤ 7 days before the day of colonoscopy): to complete the verification of 
inclusion/exclusion criteria, a blood sample will be drawn to assess the haematological and 
chemical parameters (including electrolyte levels) of all patients and to perform a pregnancy test 
for women of childbearing potential. Assessments include a urinalysis and the measurement of 
vital signs (blood pressure and heart rate). The incidence of adverse events will be recorded.  
Visit 3 (≤ 7 days before the day of colonoscopy): if inclusion/exclusion criteria are met, the Bristol 
Stool Form Scale (BSFS) will be administered, randomization will be performed, study drug will 
be dispensed and verbal and written instructions for its use will be provided. The date and time of 
colonoscopy will be communicated and reported on a form given to the patient. On the same form, 
patients will indicate date and time of start and end of study drug self-administration. The incidence 
of adverse events will be recorded.  
More than one visit may take place on the same day. 
Visit 4 (day of colonoscopy): 
A blood and urine sample will be collected at the following time points: 
• 4 hours ± 30 minutes after the end of study drug self-administration 
• 8 hours ± 30 minutes after the end of study drug self-administration 
In addition, in order to measure mannitol blood levels, venous blood samples will be drawn at the 
following times: 
• T0 (baseline, before mannitol self-administration) 
• T1 (1 hour ± 5 min after completion of mannitol self-administration) 
• T2 (2 hours ± 5 min after completion of mannitol self-administration)  
• T4 (4 hours ± 10 min after completion of mannitol self-administration, before colonoscopy) 
• T8 (8 hours ± 10 min after completion of mannitol self-administration, after colonoscopy) 
After completion of bowel preparation, prior to colonoscopy, patients will fill in the questionnaire 
on acceptability and adherence.  

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The blinded endoscopist will then perform the scheduled colonoscopy using a standard 
colonoscope recording data on bowel cleansing using the BBPS and measuring intestinal gas 
concentrations in each colon segment after standard washing and air insufflation. Of note, CO2 
insufflation and water-aided techniques for colon distension (e.g. water immersion and water 
exchange) will not be allowed. The endoscopist will also confirm caecal intubation, defined as 
identification of the appendiceal orifice. Drugs administered for the procedure will be recorded. 
Intestinal gas concentrations in each segment will be measured using a multi-gas detector (Dräger 
X-am® 8000). Please refer to the Gas Detector Technical Documentation for further details. Use 
of any electrocautery device is allowed only during withdrawal and after washing and air 
insufflation. If H2 and/or CH4 levels are potentially dangerous, any electrosurgical procedure must 
be avoided. 
Vital signs (heart rate and blood pressure) will be measured prior to colonoscopy. Oxygen 
saturation and heart rate will be measured continuously during colonoscopy, but only clinically 
significant abnormal findings will be recorded on the eCRF, where clinically significant means 
that these abnormal findings cause an additional control or a medical intervention. 
The incidence of adverse events will be recorded.  
4.1.3 
PHASE III 
A parallel-group design will be implemented to test the non-inferiority of bowel cleansing with 
the mannitol dose selected in phase II against standard split 2-liter polyethylene glycol plus 
ascorbate solution (Moviprep®). Phase III will begin only once all data collected from phase II 
necessary for establishing the optimal mannitol dose have been analysed. The non-inferiority study 
will be conducted in 4 countries (Italy, Germany, Russia and France) and involve 696 subjects 
randomized in a 1:1 ratio to one of the two study drugs. Randomization will be stratified by centre. 
Study visits 
Phase III of the study consists of four visits:  
Visit 1 (≤ 28 days before the day of colonoscopy): after signed written informed consent is 
obtained, information concerning demographics, medical history, concomitant medications and 
indications for colonoscopy will be collected in the electronic case report form (eCRF). The 
incidence of adverse events will be recorded.  
Visit 2 (≤ 7 days before the day of colonoscopy): to complete the verification of 
inclusion/exclusion criteria, a blood sample will be drawn to assess the haematological and 
chemical parameters (including electrolyte levels) of all patients and to perform a pregnancy test 
for women of childbearing potential. Assessments include a urinalysis and the measurement of 
vital signs (blood pressure and heart rate). The incidence of adverse events will be recorded.  

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Visit 3 (≤ 7 days before the day of colonoscopy): if inclusion/exclusion criteria are met, 
randomization will be performed, study drug will be dispensed and verbal and written instructions 
for its use will be provided. The date and time of colonoscopy will be communicated and reported 
on a form given to the patient. On the same form, patients will indicate date and time of start and 
end of study drug self-administration. The incidence of adverse events will be recorded.  
More than one visit may take place on the same day. 
Visit 4 (day of colonoscopy): 
A blood and urine sample will be collected at the following time points: 
• 4 hours ± 30 minutes after the end of study drug self-administration 
• 8 hours ± 30 minutes after the end of study drug self-administration 
After completion of bowel preparation, prior to colonoscopy, patients will fill in the questionnaire 
on acceptability and adherence. The Bowel Cleansing Impact Review (BOCLIR) is also to be 
completed, but only by patients enrolled at Italian centres. 
The blinded endoscopist will then perform the scheduled colonoscopy using a standard 
colonoscope recording data on bowel cleansing using the BBPS and Ottawa scale. The endoscopist 
will confirm caecal intubation, defined as identification of the appendiceal orifice, and record the 
number, appearance, size, location and histological type of neoplastic and inflammatory colorectal 
lesions detected.  
The endoscopist will measure intestinal gas concentrations in each colon segment after standard 
washing and air insufflation. Of note, CO2 insufflation and water-aided techniques for colon 
distension (e.g. water immersion and water exchange) will not be allowed. H2, CH4 and O2 levels 
are also to be measured following the introduction of the colonoscope in the sigmoidal-rectum 
junction (15-25 cm from anal margin) before standard washing and air insufflation. Drugs 
administered for the procedure will be recorded. 
Intestinal gas concentrations in each segment will be measured using a multi-gas detector (Dräger 
X-am® 8000). Detailed information is available in the Gas Detector Technical Documentation. 
Use of any electrocautery device is allowed only during withdrawal and after washing and air 
insufflation. If H2 and/or CH4 levels are potentially dangerous, any electrosurgical procedure must 
be avoided. 
Vital signs (heart rate and blood pressure) will be measured prior to colonoscopy. Oxygen 
saturation, blood pressure and heart rate will be measured during colonoscopy, but only clinically 
significant abnormal findings of oxygen saturation and heart rate measured during colonoscopy 
and blood pressure measured immediately prior and after colonoscopy will be recorded on the 
eCRF, where clinically significant means that these abnormal findings cause an additional control 

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or a medical intervention. Of note, clinically significant changes of blood pressure measured 
during colonoscopy will also be reported if considered clinically significant by the Investigator. 
The incidence of adverse events will be recorded.  
4.2 END OF STUDY DEFINITION 
A participant is considered as having completed the study if he or she has completed the procedures 
in the SoA. Of note, the results of the laboratory tests performed at Visit 4 (day of colonoscopy) 
and the histological evaluation of colorectal lesions detected during colonoscopy will be available 
after the participant has completed the last procedure of the study on the day of colonoscopy. The 
end of the phase II/III study is defined as completion of the last procedure in the trial globally, 
namely the last visit of the last patient enrolled in the phase III study (i.e. last patient last visit, 
LPLV). 
 
 

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5 
STUDY POPULATION 
The study population is made up of 846 adult patients scheduled for elective (screening, 
surveillance or diagnostic) colonoscopy; 50 patients in each of the three mannitol dose groups for 
phase II, and 348 patients in each of the two treatment groups for phase III (the selected mannitol 
dose and 2L PEG ASC). The population for phase III will not include the patients who participated 
in phase II. 
5.1 INCLUSION CRITERIA 
To be eligible to participate in this study, a subject must meet all the following criteria: 
1. Ability of patient to consent and provide signed written informed consent  
2. Age ≥ 18 years 
3. Males and females scheduled for elective (screening, surveillance or diagnostic) colonoscopy 
to be prepared and performed according to ESGE guidelines 
4. Patients willing and able to complete the entire study and to comply with instructions  
5.2 EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Pregnancy or breast feeding. Females of childbearing potential must have a negative 
pregnancy test at Visit 2 and must practice one of the following methods of birth control 
throughout the study period (unless postmenopausal or surgically sterile, or whose sole 
sexual partner has had a successful vasectomy): oral, implantable, or injectable 
contraceptives (for a minimum of three months before study entry) in combination with a 
condom; intrauterine device in combination with a condom; double barrier method (condom 
and occlusive cap with spermicidal foam/gel/film/cream/suppository). 
2. Severe renal failure: glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 estimated by 
means of simplified MDRD equation. 
3. Severe heart failure: NYHA Class III-IV. 
4. Severe anaemia (Hb < 8 g/dl). 
5. Severe acute and chronically active Inflammatory Bowel Disease; patients in clinical 
remission (Crohn's Disease Activity Index - CDAI < 150 for Crohn Disease (Best et al., 1976) 
and Partial Mayo Score ≤ 2 for Ulcerative Colitis (Schroeder et al., 1987)) are allowed. 
6. Chronic liver disease Child-Pugh class B or C. 
7. Electrolyte disturbances (Na, Cl, K, Ca or P out of normal ranges) 
8. Recent (< 6 months) symptomatic acute ischemic heart disease. 

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9. History of significant gastrointestinal surgeries, including colon resection, sub-total 
colectomy, abdominoperineal resection, de-functioning colostomy or ileostomy, Hartmann’s 
procedure and other surgeries involving the structure and function of the colon. 
10. Use of laxatives, colon motility altering drugs and/or other substances (e.g. simethicone) that 
can affect bowel cleansing or visibility during colonoscopy within 24 hours prior to 
colonoscopy. 
11. Suspected bowel obstruction or perforation. 
12. Indication for partial colonoscopy. 
13. Patients who have received an investigational drug or therapy within 5 half-lives of the first 
visit.  
14. Patients previously screened for participation in this study. 
15. Hypersensitivity to the active ingredients or to any of the excipients of the study drugs.  
16. Contraindications to Moviprep® (only for phase III). 
5.3 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but do not 
subsequently begin the investigational treatment. A minimum set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
 

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6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION ADMINISTRATION 
 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
• Test (phase II and phase III): mannitol solution (Pearlitol® PF) 
• Standard: (phase III): polyethylene glycol plus ascorbate solution (2L PEG ASC) 
(Moviprep®)  
6.1.2 
DOSING AND ADMINISTRATION 
Patients should be advised to allow for appropriate time to travel to the colonoscopy unit. 
Upon enrolment, patients will be instructed on what food and drinks are allowed and forbidden for 
bowel preparation according to the procedures applied at each centre. The use of prokinetic agents 
as adjuncts to bowel preparation is not recommended. 
Dietary recommendations as per local practice at the centre should be followed prior to 
colonoscopy. In addition, it is strongly recommended that additional liquids should be drunk 
following treatment according to local practice at the centre.  
Patients enrolled in the pharmacokinetic sub-study should drink only one litre of water. Moreover, 
as mannitol is contained in foods in a certain amount, to minimize the error of measuring mannitol 
plasma concentration after the intake of the investigational drug, dietary restrictions based on the 
INRAN tables (Carnovale and Marletta 2007) are required, after overnight fasting, between 24 
hours before and the start of mannitol self-administration. Thus, foods containing a significant 
amount of soluble sugars are to be forbidden for the PK sub-study. Patients enrolled in the 
pharmacokinetic sub-study have to avoid any food intake and drink only water between the start 
of mannitol intake and 8 hours after drug self-administration. Of note, between 4 and 8 hours after 
mannitol intake, patients may eat any food devoid of soluble sugars according to the INRAN 
tables, if deemed necessary by the Investigator. Patients will be allowed to eat without restrictions 
8 hours after mannitol self-administration. 
Mannitol 
Patients will be randomly assigned to one of the following three treatment groups in a 1:1:1 ratio:  
• 50 g mannitol powder 
• 100g mannitol powder 
• 150g mannitol powder 

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The product must be dissolved in water prior to self-administration as follows: 
1) Open the sachet and pour the mannitol powder in a container larger than one litre. 
2) Add room temperature water in the recommended amount for each dosage according to 
the table below and stir until the powder is completely dissolved (about 5 minutes). 
Mannitol per Dose (g) 
Water for dose reconstitution (mL) 
Concentration (g/mL) 
after reconstitution 
50  
500  
0.10  
100  
750  
0.13 
150  
1000  
0.15 
3) Drink the prepared solution within 30 minutes for 50 and 100 g doses and 60 minutes for 
the 150 g dose. 
4) Drink about one litre of clear liquid in the next hour according to local practice at the centre 
to prevent dehydration. Patients enrolled in the pharmacokinetic sub-study should drink 
only one litre of water in the next hour and follow the dietary restrictions and fasting 
instructions previously described.  
Participants will be instructed to drink mannitol the day of the colonoscopy and self-
administration must be completed at least 4 hours before colonoscopy. 
2L PEG ASC (Moviprep®) 
The route of administration is oral. One treatment consists of two litres of Moviprep® taken 
according to split-dose regimen. During treatment it is strongly recommended to drink about half 
a litre (500 mL) of clear liquid after each litre of Moviprep® to prevent dehydration, according to 
local practice at the centre.   
The first litre of Moviprep® is prepared by dissolving one sachet A and one sachet B together in 
water to make one litre of solution. The reconstituted solution must be drunk over a period of one 
to two hours the evening before colonoscopy. About half a litre of clear liquid should be drunk in 
the next hour to prevent dehydration according to local practice at the centre. This process should 
be repeated with a second litre of Moviprep® prepared by dissolving one sachet A and one sachet 
B together in water to make one litre of solution in the early morning of the day of the procedure. 
As previously mentioned, about half a litre of clear liquid should be drunk in the next hour to 
prevent dehydration according to local practice at the centre. Ensure consumption of Moviprep® 
as well as of any other clear fluids has finished at least four hours before the start of colonoscopy.  

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6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
Study drugs will be provided by the Sponsor. An unblinded Investigator, or a pharmacist or other 
appropriate individual who is designated by the Investigator, will maintain accurate records of 
study drug delivery to the study site, the inventory at the site, the use for each subject, and the 
return to the sponsor or alternative disposition of unused products. 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING   
Mannitol: powder for oral solution packaged in sachets.  
The quali-quantitative composition of Pearlitol® PF is 100% mannitol powder. 
Moviprep®: powder for oral solution packaged in two sachets: 
Sachet A contains the following active ingredients: 
• Macrogol 3350: 100 g 
• Sodium sulfate: 7.5 g 
• Sodium chloride: 2.691 g 
• Potassium chloride: 1.015 g 
Sachet B contains the following active ingredients: 
• Ascorbic acid: 4.7 g 
• Sodium ascorbate: 5.9 g 
Excipients with known effect: 
• Aspartame: 0.175 g 
• Dextrose: 0.120 g  
Study drug labels will comply with legal requirements and will be printed in the local language.  
6.2.3 
DRUG STORAGE AND STABILITY 
Sachets of mannitol are to be stored at a temperature below 25°C. Reconstituted solutions are also 
to be stored below 25°C. Solutions should be kept covered. 
Sachets of PEG-ASC are to be stored at a temperature below 25°C. Reconstituted solutions are 
also to be stored below 25°C and may be refrigerated. Solutions should be kept covered. 
6.2.4 
PREPARATION 
Mannitol and PEG ASC are to be prepared by stirring the powder in amounts of room temperature 
water as indicated in Section 6.1.2. 

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6.3 STUDY INTERVENTION COMPLIANCE 
Subjects will be asked to return all unused drug at the visit prior to colonoscopy. Adherence to 
protocol instructions will be evaluated prior to colonoscopy. 
6.4 CONCOMITANT MEDICATIONS 
Medications to be reported on the eCRF are concomitant prescription medications, over-the-
counter medications and supplements. 
6.4.1 
PROHIBITED CONCOMITANT MEDICATIONS 
The use of laxatives, colon motility altering drugs and/or other substances (e.g. simethicone) that 
can affect bowel cleansing or visibility during colonoscopy within 24 hours prior to colonoscopy 
is prohibited. 
6.4.2 
PERMITTED CONCOMITANT MEDICATIONS 
All concomitant medications related to either pre-existing medical conditions (which are already 
present at baseline or occur after baseline prior to the day of colonoscopy) or execution of 
colonoscopy (such as analgesic and sedative drugs) are permitted and are to be reported separately 
on the eCRF. 
6.4.3 
RESCUE THERAPY 
Not applicable. 
 

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
If a clinically significant finding is identified after enrolment, the Investigator or qualified designee 
will determine if any change in participant management is needed. Any new clinically significant 
finding leading to discontinuation from study treatment will be reported as an adverse event (AE). 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. An 
Investigator may discontinue or withdraw a participant from the study for the following reasons: 
• Pregnancy. 
• If any AE or other medical condition or situation occurs such that continued participation 
in the study would not be in the best interest of the participant. 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
eCRF. 
7.3 LOST TO FOLLOW-UP 
For patients whose status is unclear because they fail to appear for study visits without stating an 
intention to withdraw from the study, the Investigator should make every effort to contact the 
patient, family or family physician and document the steps taken to contact the patient, e.g. dates 
of telephone calls, etc. Patients lost to follow up should be recorded as such on the eCRF. 
 
 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 ASSESSMENTS  
A schedule of assessments is available in Section 1.2 
8.1.1 
PHASE II  
The following assessments will be performed during phase II of the study: 
• Informed consent, demographic features (age, sex and ethnicity), medical history and 
indication for colonoscopy are collected at Visit 1.  
• Fulfilment of inclusion/exclusion criteria is definitively assessed at Visit 3. 
• Evaluation of bowel preparation – Boston Bowel Preparation Scale (BBPS) 
The BBPS was developed to limit inter-observer variability in the rating of bowel preparation 
quality, while preserving the ability to distinguish various degrees of bowel cleanliness. Subjective 
terms such as “excellent,” “good,” “fair,” “poor,” and “unsatisfactory” are replaced by a four-point 
scoring system applied to each of the three broad regions of the colon: the right colon (including 
the cecum and ascending colon), the transverse colon (including the hepatic and splenic flexures), 
and the left colon (including the descending colon, sigmoid colon, and rectum). The points are 
assigned as follows: 
- 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 or opaque liquid. 
Each of the three segments of the colon (right, transverse, left) is thus scored from 0 to 3, with 
total score ranging from 0 to 9, and is to be completed at Visit 4 after standard washing and air 
insufflation for luminal distension. 
See Appendix 1 for a visual representation of BBPS scoring. 
• Confirmation of caecal intubation, defined as identification of the appendiceal orifice. 
• Measurement of intestinal gas concentrations 

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Intestinal H2, CH4 and O2 concentrations will be measured in each colon segment (right, between 
ileocecal valve and appendix or as close as possible to the ileocecal valve in case of obstacles that 
prevent reaching the valve; transverse, including flexures; and left at the sigmoidal-rectal junction, 
15-25 cm from anal margin) after standard washing and air insufflation for luminal distension 
using a multi-gas detector (Dräger X-am® 8000). The gas detector has no direct contact with the 
patient’s body but is connected through a one-way pump and a filter to a polyvinyl catheter inserted 
into the working channel of the colonoscope. The intestinal gases are conveyed to the gas detector 
by a one-way pump that prevents the return of gases to the colonoscope. Further information is 
available in the Gas Detector Technical Documentation. Use of any electrocautery device is 
allowed only during withdrawal and after washing and air insufflation. If H2 and/or CH4 levels are 
potentially dangerous, any electrosurgical procedure must be avoided.  
• Vital signs (heart rate, systolic and diastolic pressure) are measured at Visit 2 and at Visit 
4 prior to colonoscopy. 
• Clinically significant abnormal oxygen saturation and heart rate values obtained during 
colonoscopy will be recorded on the eCRF, where clinically significant means that these 
abnormal findings cause an additional control or a medical intervention. 
• Standard haematology, clinical chemistry and urinalysis tests are performed at Visit 2 and 
Visit 4. See Section 8.1.4 for details. A blood beta hCG pregnancy test is required for 
women of childbearing potential at Visit 2. 
• Bristol Stool Form Scale 
The Bristol Stool Form Scale (BSFS) is a 7-point scale (from 1 = separate hard lumps, like nuts 
[hard to pass] to 7 = watery, no solid pieces [entirely liquid]) used extensively in clinical practice 
and research for stool form measurement and has undergone validity and reliability testing (Blake 
et al, 2016). The BSFS is evaluated at Visit 3. See Appendix 2. 
• Patient reported outcomes 
The following information will be collected from the patient through patient questionnaires at Visit 
4 following completion of study drug self-administration but prior to colonoscopy: 
- 
Adherence: study drug completely taken, partially taken, not taken 
- 
Ease of use: NRS (0 = very difficult to 10 = very easy) 
- 
Taste: NRS (0 = terrible to 10 = very good) 
- 
Intention to reuse the preparation (yes/no) 
• Concomitant medications are collected at each visit, drugs for colonoscopy at Visit 4. 
• The incidence of adverse events will be recorded.  

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8.1.2 
PHASE II - PHARMACOKINETIC SUBSTUDY 
The following assessments will be performed in patients participating in the phase II 
pharmacokinetic sub-study: 
• Informed consent, demographic features (age, sex and ethnicity), medical history and 
indication for colonoscopy are collected at Visit 1.  
• Fulfilment of inclusion/exclusion criteria is definitively assessed at Visit 3. 
• Evaluation of bowel preparation – Boston Bowel Preparation Scale (BBPS) 
The BBPS was developed to limit inter-observer variability in the rating of bowel preparation 
quality, while preserving the ability to distinguish various degrees of bowel cleanliness. Subjective 
terms such as “excellent,” “good,” “fair,” “poor,” and “unsatisfactory” are replaced by a four-point 
scoring system applied to each of the three broad regions of the colon: the right colon (including 
the cecum and ascending colon), the transverse colon (including the hepatic and splenic flexures), 
and the left colon (including the descending colon, sigmoid colon, and rectum). The points are 
assigned as follows: 
- 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 or opaque liquid. 
Each of the three segments of the colon (right, transverse, left) is thus scored from 0 to 3, with 
total score ranging from 0 to 9, and is to be completed at Visit 4 after standard washing and air 
insufflation for luminal distension. 
See Appendix 1 for a visual representation of BBPS scoring. 
• Confirmation of caecal intubation, defined as identification of the appendiceal orifice. 
• Measurement of intestinal gas concentrations 
Intestinal H2, CH4 and O2 concentrations will be measured in each colon segment (right, between 
ileocecal valve and appendix or as close as possible to the ileocecal valve in case of obstacles that 
prevent reaching the valve; transverse, including flexures; and left at the sigmoidal-rectal junction, 
15-25 cm from anal margin) after standard washing and air insufflation for luminal distension 

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using a multi-gas detector (Dräger X-am® 8000) not directly connected to the patient. See Section 
8.1.1 and the Gas Detector Technical Documentation for further details. 
• Vital signs (heart rate, systolic and diastolic pressure) are measured at Visit 2 and at Visit 
4 prior to colonoscopy. 
• Clinically significant abnormal oxygen saturation and heart rate values obtained during 
colonoscopy will be recorded on the eCRF, where clinically significant means that these 
abnormal findings cause an additional control or a medical intervention. 
• Standard haematology, clinical chemistry and urinalysis tests are performed at Visit 2 and 
Visit 4. See Section 8.1.4 for details. A blood beta hCG pregnancy test is required for 
women of childbearing potential at Visit 2. 
• Blood sampling for pharmacokinetics 
In order to measure blood levels of mannitol, patients participating in the pharmacokinetic sub-
study will have blood draws before mannitol self-administration (T0 - baseline), and 1 hour (T1), 
2 hours (T2), 4 hours (T4) and 8 hours (T8) after completion of mannitol self-administration.  
The tubes containing the blood samples are to be gently inverted a few times for complete mixing 
with the anticoagulant and maintained in refrigerated conditions until shipment to the centralized 
bioanalytical laboratory (see Study Manual for details).  
• Bristol Stool Form Scale 
The Bristol Stool Form Scale (BSFS) is a 7-point scale (from 1 = separate hard lumps, like nuts 
[hard to pass] to 7 = watery, no solid pieces [entirely liquid]) used extensively in clinical practice 
and research for stool form measurement and has undergone validity and reliability testing (Blake 
et al, 2016). The BSFS is evaluated at Visit 3. See Appendix 2. 
• Patient reported outcomes 
The following information will be collected from the patient through patient questionnaires at Visit 
4 following completion of study drug self-administration but prior to colonoscopy: 
- 
Adherence: study drug completely taken, partially taken, not taken 
- 
Ease of use: NRS (0 = very difficult to 10 = very easy) 
- 
Taste: NRS (0 = terrible to 10 = very good) 
- 
Intention to reuse the preparation (yes/no) 
• Concomitant medications are collected at each visit, drugs for colonoscopy at Visit 4. 
• The incidence of adverse events will be recorded.  

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8.1.3 
PHASE III 
The following assessments will be performed during phase III of the study: 
• Informed consent, demographic features (age, sex and ethnicity), medical history and 
indication for colonoscopy are collected at Visit 1.  
• Fulfilment of inclusion/exclusion criteria is definitively assessed at Visit 3. 
• Evaluation of bowel preparation – Boston Bowel Preparation Scale (BBPS) 
The BBPS is to be completed at Visit 4 after standard washing and air insufflation for luminal 
distension. See Section 8.1.1 for scoring details and Appendix 2 for a visual representation of BBPS 
scoring 
• Evaluation of bowel preparation – Ottawa Scale (OS) 
The OS total score ranges from 0 to 14 and is calculated by adding up the scores for each of the 
three segments of the colon (right, middle, left including sigmoid and rectum), each receiving a 
score on a 5-point scale (0-4), where 0 = perfect preparation, 1 = presence of clear liquid that does 
not require suction, 2 = presence of liquid that must be suctioned, 3 = presence of stool that must 
be flushed, 4 = presence of not-washable stool plus the overall amount of colonic fluid graded 
using a 3-point scale (0-2). Adequate preparation = OS < 6 (Rostom et al., 2004). The evaluation 
is performed at Visit 4 before washing and air insufflation for luminal distension. See Appendix 3 
for a visual representation of Ottawa Scale scoring. 
• Colorectal lesions 
The following features of colorectal lesions detected during colonoscopy at Visit 4 are to be 
recorded on the eCRF: 
- Number 
- Appearance (peduncolated, not peduncolated) 
- Size (< 5 mm, 5-9 mm, 10-19 mm, ≥ 20 mm) 
- Location (right; transverse, including flexures; and left, including sigmoid and rectum) 
- Histological classification (hyperplastic; inflammatory; tubular adenoma with low grade 
(LG) dysplasia < 10 mm or ≥ 10 mm; tubular adenoma with high grade (HG) dysplasia < 10 
mm or ≥ 10 mm; adenoma with villous component > 20% with LG or HG dysplasia; sessile 
serrated adenoma; adenoma; advanced adenoma; invasive cancer) 
• Confirmation of caecal intubation, defined as identification of the appendiceal orifice. 
• Measurement of intestinal gas concentrations 

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Intestinal H2, CH4 and O2 concentrations will be measured in each colon segment (right, between 
ileocecal valve and appendix or as close as possible to the ileocecal valve in case of obstacles that 
prevent reaching the valve; transverse, including flexures; and left at sigmoidal-rectal junction, 15-
25 cm from anal margin) after standard washing and air insufflation for luminal distension using 
a multi-gas detector (Dräger X-am® 8000) not directly connected to the patient. See Section 8.1.1 
and the Gas Detector Technical Documentation for further details.  
Intestinal H2, CH4 and O2 concentrations will be measured following the introduction of the 
colonoscope in the sigmoidal-rectum junction (15-25 cm from anal margin) also before standard 
washing and air insufflation. 
• Vital signs (heart rate, systolic and diastolic pressure) are measured at Visit 2 and at Visit 
4 prior to colonoscopy. 
• Clinically significant abnormal oxygen saturation and heart rate values obtained during 
colonoscopy, as well as clinically significant abnormal systolic and diastolic blood pressure 
values obtained immediately prior and after colonoscopy will be recorded on the eCRF, 
where clinically significant means that these abnormal findings cause an additional control 
or a medical intervention. Of note, clinically significant changes of systolic and diastolic 
blood pressure measured during colonoscopy will also be reported if considered clinically 
significant by the Investigator. 
• Standard haematology, clinical chemistry and urinalysis tests are performed at Visit 2 and 
Visit 4. See Section 8.1.4 for details. A blood beta hCG pregnancy test is required for 
women of childbearing potential at Visit 2. 
• Bowel Cleansing Impact Review (BOCLIR) (Italian sites only). 
The BOCLIR is a measure of the acceptability and tolerability of bowel cleansers consisting of 
three unidimensional scales (satisfaction, symptoms and activity limitations) with good 
psychometric and scaling properties. Item responses are summed to provide scale scores. In the 
final validated Italian version of BOCLIR, the satisfaction scale contains eight items (each item 
using a 4-point scale from 0 to 3) and the score ranges from 0 (highly satisfied) to 24 (highly 
dissatisfied). The symptoms scale includes 14 items (each item using a 4-point scale from 0 to 3) 
and the score ranges from 0 (no symptoms) to 42 (severe symptoms). The activity limitations scale 
is made up of 12 items (each item using a 4-point scale from 0 to 3) and the score ranges from 0 
(no effect on activities) to 36 (activities greatly affected). The total score is the sum of the three 
scales and ranges from 0 to 102. Patients who report a worse experience in terms of the three 
factors score higher on the BOCLIR scale. The BOCLIR allows accurate assessment of patient 
response to bowel cleansing preparations (Doward et al., 2013). The BOCLIR questionnaire is 
completed at Visit 4 by patients following completion of study drug self-administration but prior 
to colonoscopy at Italian sites because only the Italian language version is validated for use in 
clinical trials.  

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• Patient reported outcomes 
The following information will be collected from the patient through questionnaires at Visit 4 
following completion of the bowel cleansing procedure but prior to colonoscopy: 
- 
Adherence: study drug completely taken, partially taken, not taken 
- 
Ease of use: NRS (0 = very difficult to 10 = very easy) 
- 
Taste: NRS (0 = terrible to 10 = very good) 
- 
Intention to reuse the preparation (yes/no) 
• Concomitant medications are collected at each visit, drugs for colonoscopy at Visit 4. 
• The incidence of adverse events will be recorded. 
8.1.4 
LABORATORY TESTS (PHASE II AND PHASE III) 
Standard urinalysis, haematological and blood chemistry tests will be performed at Visit 2 (pre-
colonoscopy visit) and at Visit 4, 4 hours ± 30 minutes and 8 hours ± 30 minutes after the end of 
study drug self-administration. A blood beta hCG pregnancy test is required for women of 
childbearing potential at Visit 2. The lab tests to be performed are listed in the Table below and 
are to be performed in both phase II and phase III. 

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Laboratory Assessments 
Haematology 
Serum chemistry 
Urine analysis  
• Haematocrit (Hct) 
• Haemoglobin (Hb) 
• Mean corpuscular 
haemoglobin (MCH) 
• Mean corpuscular 
haemoglobin 
concentration (MCHC) 
• Mean corpuscular 
volume (MCV) 
• Platelet count 
• Red blood cell (RBC) 
count  
• White blood cell 
(WBC) count  
 with differential  
 
• Alanine aminotransferase 
(ALT) 
• Aspartate aminotransferase 
      (AST)  
• Total bilirubin 
• Direct bilirubin 
• Blood Urea Nitrogen (BUN)  
• Creatinine 
• eGFR estimated by means of 
      simplified MDRD equation 
• Potassium  
• Sodium 
• Phosphorus 
• Calcium 
• Chloride 
• Glucose  
• Pregnancy test (beta hCG at 
Visit 2) 
• 
Appearance 
• 
pH 
• 
Protein 
• 
Glucose 
• 
Ketone bodies 
• 
Indicators of blood 
and WBCs 
• 
Specific gravity* 
• 
Urobilinogen 
*Urine specific gravity may decrease because of osmotic diuresis caused by mannitol. The event is to be 
considered expected. 
 
 
8.2 SAFETY 
The assessment of overall safety consists in recording and evaluating all adverse events, 
haematological and chemical parameters (see Section 8.1.4), and vital signs. The following adverse 
events are of particular interest in this study: 
− Nausea, vomiting, abdominal pain, bloating, thirst, dizziness, sleep disturbance, 
hypotension 
− Acute disruption of electrolyte homeostasis 
− Complications 
of 
colonoscopy: 
colonic 
perforation, 
bleeding, 
cardiovascular 
complications, explosion 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 

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An adverse event can be defined as any untoward medical occurrence in a subject to whom a 
medicinal product is administered and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
The following guidelines will be used to describe severity.  
• Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”. 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All AEs must have their relationship to study intervention assessed by the clinician who examines 
and evaluates the participant based on temporal relationship and his/her clinical judgment. 
Investigators are to judge the causal relationship of the event with the study intervention as 
“suspected”, “unsuspected” or “unknown”. 
8.3.3.3 EXPECTEDNESS  
The Sponsor will be responsible for determining whether an AE is expected or unexpected. An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the reference safety information. 

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8.3.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care, or upon review by a study 
monitor. 
All AEs including local and systemic reactions will be captured on the appropriate case report 
form (eCRF). Information to be collected includes event description (a diagnosis and not 
symptoms should be provided, if possible), time of onset, clinician’s assessment of severity, 
relationship to study drugs, and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The Investigator will record all reportable events with onset dates occurring any time after 
informed consent is obtained up to and including the day of colonoscopy. Events will be followed 
for outcome information until resolution or stabilization, except for those events deemed to be 
chronic by the Investigator, such as cancer. Lesions detected during colonoscopy (polyps, 
adenomas, cancer, diverticulosis, hernia, etc.) are not to be considered as AEs. 
8.3.5 
NON-SERIOUS ADVERSE EVENT REPORTING  
All identified non-serious AEs (related and unrelated) must be recorded and described on the 
eCRF. 
8.3.6 
SERIOUS ADVERSE EVENT REPORTING  
Every SAE, regardless of suspected causality, occurring after the subject has provided informed 
consent up to and including the day of colonoscopy, must be reported to the sponsor immediately 
but not later than 24 hours after site awareness. 
Any SAE experienced after this period should only be reported to the sponsor if the Investigator 
suspects a causal relationship to the study treatment. Recurrent episodes, complications, or 
progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the Investigator receiving the follow-up information. 

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Information about all SAEs will be recorded using the e-safety tool of the eCRF. In case of 
technical difficulties, SAE notification can be carried out using a paper SAE form and by 
contacting OPIS, a contract research organization (CRO), via email at all_phv@opis.it or by fax 
using the following number: +39 0362 633622. 
All SAEs will be followed until satisfactory resolution or until the site Investigator deems the event 
to be chronic. Other supporting documentation of the event may be requested by the study sponsor 
and should be provided as soon as possible. The study sponsor will be responsible for notifying 
Health Authorities of any unexpected fatal or life-threatening suspected adverse reaction as soon 
as possible, but in no case later than 7 calendar days after the sponsor's initial receipt of the 
information. 
8.3.7 
REPORTING OF PREGNANCY  
Pregnant women will not be permitted to participate in this study. A negative pregnancy test will 
be required to enter the study. The Investigator shall report all pregnancy exposures occurring in 
a female patient within 24 hours to the sponsor using the e-pregnancy tool of the eCRF. In case of 
technical difficulties, pregnancy notification can be carried out using a paper pregnancy form and 
by contacting the CRO via email at all_phv@opis.it or by fax using the following number: +39 
0362 633622. The Investigator should counsel the subject and discuss the risks of continuing with 
the pregnancy and the possible effects on the foetus potentially induced by participation in the 
study. Monitoring of the subject should continue until conclusion of the pregnancy. 

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9 
STATISTICAL CONSIDERATIONS  
 
9.1 SAMPLE SIZE DETERMINATION 
The total number of patients to be enrolled is approximately 846; 150 patients (50 in each mannitol 
dose group) for phase II dose finding, and 696 patients (348 in each treatment group) for the phase 
III non-inferiority study. The population for phase III will not include the patients who participated 
in phase II. 
Phase II - Dose finding 
The sample size is based on the precision of the estimate within each treatment group, i.e. the 95% 
confidence interval of the proportion of patients in each treatment group with adequate bowel 
cleansing (BBPS total score ≥ 6, with BBPS ≥ 2 for each segment). 
The table below shows the precision of the estimate for different rates of adequate bowel cleansing 
with a sample size of 50 patients. 
Rates of adequate bowel 
cleansing (%) 
Estimate Precision (%) 
(i.e. 95% CI*) 
75 
±12 
80 
±11 
85 
±10 
* Confidence interval estimated through normal approximation of 
binomial distribution without continuity correction. 
Phase II - Pharmacokinetic sub-study 
The expected sample size (10 patients in each dose group) is based on feasibility criteria.  
Phase III - non-inferiority 
The sample size is based on the proportion of patients with adequate bowel cleansing (BBPS total 
score ≥ 6, with BBPS ≥ 2 for each segment). When the sample size in each group is 313, a two-
group large-sample normal approximation test of difference of proportions with a one-sided 0.025 
significance level will have 80% power to reject the null hypothesis that the test preparation is 
inferior to the standard preparation in favour of the alternative hypothesis that the test proportion 
is not inferior to the standard preparation (the difference in success proportions, πT - πS, is -0.08 
or farther from zero in the same direction), assuming that the expected difference in success 
proportions is 0 and the proportion of successes in the standard group is 0.85 (the success rate for 
Moviprep® as reported in Bisschops R. et al., 2019, Choi et al., 2018 and Kwon et al., 2016 varies 
from 85% to 89%). 
A proportion of patients with adequate bowel cleansing 8% lower than the expected 85% for gold 
standard Moviprep® would give a 77% success rate for mannitol, which falls within the 70-88.5% 
range reported for PEG-ASC (Repici et al., 2012; Choi et al., 2018; Hassan et al., 2013). 

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Sample size for two-group test of equivalence in proportions (large equal n's) 
Test significance level, α (one-sided) 
0.025 
Standard proportion, πS 
0.85 
Equivalence limit difference, πT - πS, Δ0 
-0.08 
Test expected proportion, πT 
0.85 
Expected difference, πT - πS, Δ1 
0 
Power (%) 
80 
N per group 
313 
Sample size was computed based on normal approximation of binomial distribution without continuity 
correction 
The non-inferiority margin πT–πS = -0.08 corresponds to a relative risk πT/πS = 0.906. Should the 
proportion of successes in the standard group be lower than 0.85, the non-inferiority margin will 
be adjusted in order to have a relative risk of at least 0.906 (e.g. if the proportion of successes 
observed in the standard group is 0.80, the non-inferiority margin πT–πS will be set equal to = -
0.075, corresponding to a relative risk equal to 0.906). 
The total sample size (626) is adjusted to 696 patients (348 in each treatment group) considering 
an expected rate of dropouts and major protocol deviations of about 10% (using Freedman’s 
formula (Control Clin Trials, 1990): n’= 100*n/(100-x), where x is the expected percent dropout 
rate). 
The correctness of the assumptions used to compute the sample size for phase III of the study will 
be re-evaluated at the end of phase II and, if needed, the sample size will be re-estimated. 
9.2 RANDOMIZATION 
At Visit 3, all eligible subjects will be randomized via eCRF to one of the treatment groups 
according to the study phase. The Investigator or his/her delegate will confirm that the subject has 
fulfilled all the inclusion/exclusion criteria in the eCRF. The eCRF will assign a randomization 
number to the subject, which will be used to link the subject to the treatment and will specify a 
unique medication number for the package of study treatment to be dispensed to the subject. The 
subject’s randomization number will not be shown in the eCRF: only the medication number will 
be made available. 
For each phase of the study a stratified subject randomization list will be produced in balanced 
blocks through a validated SAS program.  
Phase II – dose finding: the randomization will be stratified by centre and by the presence of 
constipation (yes/no), defined as the recurrent use of laxatives or Bristol Stool Form Scale (BSFS) 
< 3 in the two weeks before randomisation. 
Phase III – non-inferiority: the randomization will be stratified by centre. 

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9.3 POPULATIONS FOR ANALYSES 
The following populations will be used for the statistical analyses: 
• Safety set: all patients who take the study preparation, even only partially. Patients will be 
analysed according to the study drug dose actually received. 
• Modified Safety set: all patients who take the study preparation, even only partially, and 
who do not meet significant protocol violations that regard inclusion/exclusion criteria. 
Patients will be analysed according to the study drug dose actually received. 
• PK population (only for the pharmacokinetic sub-study): all randomized patients who 
complete the mannitol treatment and have at least one PK assessment, regardless of the 
outcome of colonoscopy. Patients will be analysed according to the study drug dose 
actually received. 
• Full Analysis Set (FAS): all randomized patients who take the study preparation, even only 
partially, undergo the colonoscopy, and have a BBPS available for at least one colon 
segment after standard washing and air insufflation for luminal distension. According to 
the Intention to Treat (ITT) principle, patients will be analysed according to the study drug 
dose assigned at randomization. 
• Per protocol (PP): all randomized patients who meet the following criteria: 
o 
Treatment with the study drug completed. 
o 
Colonoscopy completed adequately in absence of pathological obstruction that 
prevents reaching the right colon, including the cecum (i.e. endoscope does not find 
obstacles other than faecal material) and without acute deterioration of general 
conditions causing procedure suspension. 
o 
Bowel cleansing assessment and gas measurement are available for all colon 
segments after standard washing and air insufflation for luminal distension. 
o 
No significant protocol violations that regard inclusion/exclusion criteria or that can 
condition evaluations.  
Patients will be analysed according to the study drug dose actually received. 
9.4 STATISTICAL ANALYSES 
Continuous data will be summarized with standard descriptive statistics (mean, standard deviation, 
median, minimum and maximum, 1st and 3rd quartiles). Categorical data will be summarized by 
frequencies and percentages. 
No statistical test will be performed for between-group differences in demographic and baseline 
features (demographics and medical history). 
Medical history and adverse events will be described according to System Organ Classes (SOC) 
and Preferred Terms (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) and 

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will be presented by treatment group. Previous/concomitant medications will be presented by 
treatment group using the World Health Organization Drug Dictionary (WHO-DD). 
All analyses will be performed using SAS® version 9.4 
9.4.1 
ANALYSIS OF VARIABLES 
Phase II - Dose finding 
Efficacy 
The appropriate mannitol dose to be used in the comparative non-inferiority phase (phase III) will 
be singled out at the end of dose-finding based on the following criteria: 
• 75% or greater rate of adequate bowel cleansing.  
• Rate of patients in safe conditions, defined as the absence of potentially dangerous levels 
of H2 and CH4 in each colon segment (right, between ileocecal valve and appendix or as 
close as possible to the ileocecal valve in case of obstacles that prevent reaching the valve; 
transverse, including flexures; and left at the sigmoidal-rectum junction, 15-25 cm from 
anal margin) after standard washing and air insufflation for luminal distension). 
• Clinical judgment based on the caecal intubation rate, the incidence of adverse events, 
treatment adherence and acceptability (considering ease of use, taste and willingness to 
reuse the preparation). 
Should two or all three doses prove to be equally safe and effective, the lowest dose will be selected 
for phase III of the study. 
Descriptive statistics and Wald 95% CI of the proportion of patients with adequate bowel cleansing 
will be provided for each dose.  
In addition, a logistic regression model will be applied to assess the influence of the two 
stratification factors (constipation in the two weeks before the start of preparation for colonoscopy 
and centre) on dose response. A patient is considered a responder if he/she presents adequate bowel 
cleansing. In case of unbalanced enrolment among centres, a pooling approach will be adopted. 
A supportive stepwise logistic regression model will also be applied to assess the influence on 
dose response of potential prognostic factors (i.e. age and previous unsuccessful bowel cleansing 
procedures) in addition to the two stratification factors. Based on the results from this model, the 
need to modify the stratification factors for phase III will be evaluated and the study protocol 
amended, if needed. 
No between-group comparisons will be performed. The decision on the dose to be selected for 
phase III will be made on the basis of descriptive statistics and corresponding 95% CIs and on the 

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results of the logistic regression models. Endpoints will be analysed on the PP population. Results 
from the FAS will be used as supportive. 
Caecal intubation rate 
Descriptive statistics and Wald 95% CI of the caecal intubation rate will be provided for each dose. 
Adherence and acceptability 
Descriptive statistics and Wald 95% CIs of the following adherence and acceptability variables 
will be provided for each dose: 
• Adherence 
• NRS score for ease of use and taste 
• Willingness to reuse the preparation 
Phase II - Pharmacokinetic sub-study 
The pharmacokinetic parameters (Cmax, tmax, AUC0-t0-t, t1/2) of each dose will be analysed 
descriptively on the PK population. 
Phase III - Non-inferiority 
Primary efficacy analysis 
The proportion of patients with adequate bowel cleansing (BBPS total score ≥ 6, score ≥ 2 for each 
segment) during colonoscopy after standard washing and air insufflation for luminal distension 
will be calculated to evaluate the non-inferiority of the test drug vs the standard drug. 
Non-inferiority will be assessed by computing the two-tailed Wald 95% confidence interval (CI) 
of the difference between the two proportions πT - πS. Non-inferiority is met if the 95% CI does 
not cross the predefined non-inferiority margin Δ = -0.08 and lies entirely to the right of the margin 
(i.e. non-inferiority will be demonstrated if the lower bound of the two-sided 95% CI of the 
difference is > -0.08). 
The non-inferiority margin πT–πS = -0.08 corresponds to a relative risk πT/πS = 0.906 when the 
proportion of successes in the standard group is 0.85. Should the proportion of successes in the 
standard group be lower than 0.85, the non-inferiority margin will be adjusted in order to have a 
relative risk of at least 0.906 (e.g. if the proportion of successes observed in the standard group is 
0.80, the non-inferiority margin πT–πS will be set equal to = -0.075, corresponding to a relative 
risk equal to 0.906). 
If the 95% CI of the difference lies completely to the right of 0, the test treatment can be considered 
superior to the standard treatment at a 5% significance level. 
The Wald method for non-inferiority of proportions will be applied (Dann RS, 2008). 

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The analysis will be performed on both the FAS and PP populations. Results from both populations 
will have equal importance. 
Secondary efficacy analyses 
The analysis of secondary variables will be performed on the FAS. No between-group inferential 
analysis will be performed. Descriptive statistics and 95% CIs of the between-group differences 
will be applied on the following variables: 
• Number, appearance, size, location and histological classification of neoplastic and 
inflammatory colorectal lesions detected 
• Adenoma detection rate 
• Caecal intubation rate 
• Ottawa bowel preparation scale 
Confidence intervals for proportions will be calculated based on the Wald method. 
Adherence and acceptability 
The analysis of adherence variables will be performed on the FAS. No between-group inferential 
analysis will be performed. Descriptive statistics and Wald 95% CIs of the between-group 
differences will be applied on the following variables: 
• Bowel Cleansing Impact review (BOCLIR) scales 
• Adherence 
• NRS score for ease of use and taste 
• Willingness to reuse the preparation 
9.4.2 
ANALYSIS OF SAFETY 
Descriptive statistics both on the Safety set and on the modified Safety set for both phase II and 
phase III will be performed on: 
• Proportion of patients with presence/absence of potentially dangerous levels of H2 and CH4 
(> 4% Vol and >100% LEL, which is equal to 5% Vol, respectively) in each colon segment 
during colonoscopy after standard washing and air insufflation for luminal distension. 
• H2, CH4 and O2 concentrations, expressed in % Vol, in each colon segment (right, between 
ileocecal valve and appendix or as close as possible to the ileocecal valve in case of 
obstacles that prevent reaching the valve; transverse, including flexures; and left, at the 
sigmoidal-rectum junction, 15-25 cm from anal margin) after standard washing and air 
insufflation for luminal distension. CH4 (% LEL) will be converted into % Vol by means 
of the following formula: (CH4 in % LEL)*5/100. 
• Proportion of patients with adverse events and the number and types of events occurred. 

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• Proportion of patients with change from baseline (Visit 2) considered clinically significant 
by the Investigator of haematological and chemical parameters, where clinically significant 
means that the change causes an additional control or a medical intervention. 
• Proportion of patients with change from baseline (Visit 2) considered clinically significant 
by the Investigator of vital signs (heart rate, systolic and diastolic blood pressure) (phase 
III only) and proportion of patients with clinically significant change of pulse oximetry and 
heart rate measured during colonoscopy, as well as systolic and diastolic blood pressure 
measured immediately prior and after colonoscopy (phase III only), where clinically 
significant means that the change causes an additional control or a medical intervention. 
Of note, clinically significant changes of blood pressure measured during colonoscopy will 
also be reported if considered clinically significant by the Investigator. 
The analyses on the modified Safety set will be considered as supportive. 
For phase III only, descriptive statistics will be provided on intestinal gas concentrations following 
the introduction of the colonoscope in the rectum/sigma before standard washing and air 
insufflation. 
9.4.3 
PLANNED INTERIM ANALYSES  
The final analyses will be performed at the end of phase II and at the end of phase III (no formal 
interim analysis will be performed). Ongoing data monitoring during phase II will be conducted 
to properly apply the stopping rule described in Section 4.1.1. 
 
 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, benefits and risks are 
given to the participant and written documentation of informed consent is required prior to 
undertaking any study-related procedures.  
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
approved by the IEC/IRB and the participant will be asked to read and review the document. The 
Investigator will explain the research study to the participant and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The participants should have the opportunity to discuss the study with 
their family or surrogates and think about it prior to agreeing to participate. The participant will 
sign the informed consent document prior to any procedures being done specifically for the study. 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document will be given to 
the participants for their records. The informed consent process will be conducted and documented 
in the source document (including the date), and the form signed, before the participant undergoes 
any study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, Investigator, IEC/IRB, Sponsor and 
regulatory authorities. 
Circumstances that may warrant termination or suspension include, but are not limited to: 

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• Determination of unexpected, significant, or unacceptable risk to participants 
• Insufficient compliance with protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IEC/IRB and/or regulatory authorities. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating Investigators, 
their staff, and the sponsor. This confidentiality is extended to cover testing of biological samples 
in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or data will be released to any unauthorized third party without 
prior written approval of the sponsor. All research activities will be conducted in as private a 
setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IEC/IRB, 
regulatory agencies or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the Investigator, including but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IEC/IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the CRO (OPIS) working on behalf of the Sponsor. This will 
not include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. Only the study centre 
will be able to link the study ID number to the patient’s identity. The study data entry and study 
management systems used by clinical sites and by OPIS research staff will be secured and 
password protected.  
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Not applicable. All biologic samples will be destroyed following the completion of study-specific 
assessments indicated in this protocol. 
 

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10.1.5 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is compliant with the currently approved protocol/amendment(s), with ICH GCP, and 
with applicable regulatory requirements.  
The field monitor will visit the site to check the completeness of patient records, the accuracy of 
entries on the eCRFs, the adherence to the protocol and to GCP, the progress of enrolment, and to 
ensure that study drug is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the field monitor during these visits.  
The Investigator must maintain source documents for each patient in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information. All information on eCRFs must be traceable to these source documents in the patient's 
file. The Investigator must also keep the original informed consent form signed by the patient (a 
signed copy is given to the patient). 
Monitoring standards require full verification for the presence of informed consent, adherence to 
inclusion/exclusion criteria, documentation of SAEs, and of data that will be used for all variables. 
Additional checks of the consistency of the source data with the eCRFs are performed according 
to the study-specific Monitoring Plan (MP). No information in source documents about the identity 
of the patients will be disclosed. 
10.1.6 QUALITY ASSURANCE AND QUALITY CONTROL 
Following written standard operating procedures, monitors will verify that the trial is being 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonization Good Clinical Practice (ICH GCP) and 
applicable regulatory requirements. 
The investigational site will provide direct access to all trial-related facilities, source 
data/documents and reports for the monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
Independent audits may be conducted to ensure monitoring practices are performed consistently 
across all participating sites and that monitors are following the MP. Independent audits may be 
conducted by the Sponsor to ensure monitoring practices are performed consistently across all 
participating sites and that monitors are following the MP. 
 
 

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10.1.7 DATA HANDLING AND RECORD KEEPING  
 
10.1.7.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection 
Designated Investigator staff will enter the data required by the protocol on the eCRF using fully 
validated software that conforms to 21 CFR Part 11 and GCP requirements. Designated 
Investigator site staff will not be given access to the electronic data capture system until they are 
trained.  
Web-based software will be used, and no installation procedure is needed. Each site will be 
authorized by the administrator to access the eCRF. Each site-qualified personnel will be allowed 
to access the eCRF by means of a login mask requiring user ID and password and may read, 
modify, and update only the information previously reported at his or her site and according to 
their profile. Each page reports site code and subject code. 
On-line validation programs will check for data discrepancies and, by generating appropriate error 
messages, allow the data to be confirmed or corrected before transfer to the CRO working on 
behalf of the sponsor. The Investigator will certify that the data entered on the eCRF are complete 
and accurate.  
After database lock, the Investigator will receive a CD-ROM of subject data for archiving at the 
investigational site. 
Database management and quality control 
The CRO (OPIS) working on behalf of the Sponsor will review the data entered on the eCRF by 
investigational staff for completeness and accuracy and instruct site personnel to make any 
necessary corrections or additions. The Data Manager will perform the cleaning session by 
reviewing the warning messages raised by on-line checks and by running post-entry checks by 
means of validation programs and data listings specific for the study. If clarifications are needed, 
the Data Manager will raise queries by means of data query forms through the web application. 
Designated Investigator site staff will be required to respond to queries and the Data Manager will 
make the correction to the database according to the responses. 
Data collection and query flows, as well as the on-line and off-line checks, are detailed in the Data 
Management Plan and Data Validation documents. 
Concomitant medications and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomic Therapeutic Chemical (ATC) 
classification system. Medical history/current medical conditions and AEs will be coded using the 
MedDRA. 

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All protocol deviations will be verified and documented, and the database will be locked and made 
available for data analysis after these actions have been completed and the database has been 
declared complete and accurate. 
10.1.7.2 STUDY RECORDS RETENTION  
The Investigator should maintain the trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations and/or 
guidelines. The Investigator/institution should take measures to prevent accidental or premature 
destruction of these documents.  
Essential documents (paper and electronic) should be retained for a period of not less than fifteen 
(15) years from the completion of the study unless the sponsor provides written permission to 
dispose of them or requires their retention for an additional period because of applicable laws, 
regulations and/or guidelines. The subjects’ medical files will be archived in accordance with the 
national laws. 
10.1.8 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol and International 
Conference on Harmonization Good Clinical Practice (ICH GCP). Noncompliance may be either 
on the part of the participant, the Investigator, or the study site staff. In case of deviations, 
corrective actions are to be developed by the site and implemented promptly. It is the responsibility 
of the site to avoid any protocol deviations and of the site staff and monitors to use continuous 
vigilance to identify and report deviations. All deviations and relevant actions taken must be 
properly documented. 
10.1.9 INSURANCE 
The Sponsor certifies that it has taken out a liability insurance policy covering this clinical trial. 
This insurance policy is in accordance with local laws and requirements. The insurance of the 
Sponsor does not relieve the Investigator and collaborators from any obligation to maintain their 
own liability insurance policy. An insurance certificate will be provided to the IEC/IRB and/or 
regulatory authorities. 
10.1.10 PUBLICATION AND DATA SHARING POLICY 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the Sponsor. 
This study will ensure that the public has access to the published results of the research.  

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As the study involves more than one centre, the first publication must be related to data collected 
from all patients enrolled and analysed under the Sponsor’s responsibility. The Investigator shall not 
publish or communicate data collected at only one centre or part of the centres before the 
publication of the complete results of the study unless prior written authorization from the 
Sponsor has been provided. 
Enrolment of patients in the study will be competitive. Therefore, pending confirmation from the 
journal accepting the manuscript, the main publication reporting the results of each phase of 
the study will include as main authors the names of the Chairman of the study, National 
Coordinators and Principal Investigators of the five centres enrolling the most patients in 
each phase of the study. Names of Principal Investigators of all other sites will be mentioned 
in the full list of participating centres added to the text of the publications. 
Any publication and/or communication project regarding the study and/or its results, whether 
obtained during the study or after the study end, shall be submitted to the Sponsor at least 30 
days for a publication and 15 days for an abstract before the planned date of communication 
and/or submission for a publication. The Sponsor shall make comments on the project within 
15 days of receipt of the project for a publication and within 7 days for an abstract. The 
Investigator who submitted the project shall take the Sponsor's comments into due consideration. 
Nevertheless, should the Investigator who submitted the project decide not to modify the project 
according to the Sponsor's comments, he/she shall provide the Sponsor with the grounds for 
his/her decision in writing. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial 
as any research project that prospectively assigns human subjects to intervention or concurrent 
comparison or control groups to study the cause-and-effect relationship between a medical 
intervention and a health outcome. ICMJE policy requires that all clinical trials be registered in a 
public trials registry such as ClinicalTrials.gov. 
10.1.11 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
 
 

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11 ABBREVIATIONS 
 
AE 
Adverse Event 
ATC 
Anatomic Therapeutic Chemical 
BBPS 
Boston Bowel Preparation Scale 
BfArM 
German Federal Institute for Drugs and Medical Devices 
BSFS 
Bristol Stool Form Scale 
BOCLIR 
Bowel Cleansing Impact Review 
CDAI 
Crohn's Disease Activity Index 
CI 
Confidence Interval 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
Contract Research Organization 
eCRF 
electronic Case Report Form 
ESGE 
European Society of Gastrointestinal Endoscopy 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IMPD 
Investigational Medicinal Product Dossier 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
LEL 
Lower Explosion Level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MP 
Monitoring Plan 
NRS 
Numeric Rating Scale 
OS 
Ottawa Scale 
PEG 
Polyethylene Glycol 
PEG ASC 
Polyethylene Glycol Ascorbate 
PEC-ELS 
Polyethylene Glycol and electrolytes 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 

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13 APPENDICES 
 
13.1 APPENDIX 1 BOSTON BOWEL PREPARATION SCALE  
 
From: Lorenzo-Zúñiga V, Moreno-de-Vega V, Boix J. Preparation for colonoscopy: types of 
scales and cleaning. Rev. Esp Enferm Dig. 2012; 104: 426-431.) 
 
 
 

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13.2 APPENDIX 2 BRISTOL STOOL FORM SCALE 
 
 
 
 

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13.3 APPENDIX 3 OTTAWA BOWEL PREPARATION SCALE 
 
From: Lorenzo-Zúñiga V, Moreno-de-Vega V, Boix J. Preparation for colonoscopy: types of 
scales and cleaning. Rev. Esp Enferm Dig. 2012; 104: 426-431.)