Clinical trial NCT01928862
Conditions: Need for Bowel Preparation
Sponsor: Ferring Pharmaceuticals
Start date: 2014-06-03; Completion date: 2017-03-16
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To study the efficacy and safety of Prepopik® in children aged 9 to 16 years for overall colon cleansing in preparation of colonoscopy

Detailed description:

Arms: arm 1: Prepopik® ½ Sachet x 2 (9-12 years) arm 2: Prepopik® 1 Sachet x 2 (9-12 years) arm 3: Local standard of care arm 4: Prepopik® 1 Sachet x 2 (13-16 years) arm 5: Local standard of care
Interventions: intervention 1: Prepopik® ½ Sachet x 2 (9-12 years) intervention 2: Prepopik® 1 Sachet x 2 (9-12 years) intervention 3: Oral polyethylene glycol (PEG) based preparation (9-12 years) intervention 4: Prepopik® 1 Sachet x 2 (13-16 years) intervention 5: Oral polyethylene glycol (PEG) based preparation (13-16 years)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_000.pdf: 
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CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A Randomized, Assessor-Blind, Multicenter, Dose-Ranging Study Comparing the Safety and 
Efficacy of Prepopik® versus Polyethylene Glycol Preparation (Local Standard of Care) in 
Children Aged 9 Years to 16 Years
000103
IND Number:
101,738
Investigational Medicinal Product:
PREPOPIK® (sodium picosulfate, magnesium oxide, and 
anhydrous citric acid)
Indication:
Bowel preparation for pediatric colonoscopy
Phase:
Phase I/II-Post Approval Pediatric Study
Name and Address of Sponsor:
Ferring International Pharmascience Center U.S., Inc. 
(FIPCUS)
100 Interpace Parkway
Parsippany, NJ 07054
P: 973-796-1600
F: 973-796-1699
GCP Statement:
This trial will be performed in compliance with GCP
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in any 
form, without prior written consent of an authorized officer of Ferring Pharmaceuticals A/S or another company within the 
Ferring Group.


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CONFIDENTIAL
SYNOPSIS
TITLE OF TRIAL
A Randomized, Assessor-Blind, Multicenter, Dose-Ranging Study Comparing the Safety and Efficacy 
of Prepopik® versus Polyethylene Glycol Preparation (Local Standard of Care) in Children Aged 9 
Years to 16 Years
TRIAL SITE(S)
Approximately 6-8 sites in the United States (US)
PLANNED TRIAL PERIOD
October 2013 to May 2015
CLINICAL PHASE
Phase I/II-Post Approval 
Pediatric Study
OBJECTIVES
Primary objective
!
To describe the efficacy of Prepopik in children aged 9 years to 16 years for overall colon 
cleansing in preparation for colonoscopy based on the Aronchick scale by including oral 
polyethylene glycol (PEG) based preparation/local standard of care as a reference group
Secondary objectives
!
To describe the safety of Prepopik in children aged 9 years to 16 years through the collection of 
adverse events (AEs), clinical laboratory tests, and physical examination
!
To describe the completion of prep as directed to colon cleansing by Prepopik in preparation for 
colonoscopy in children aged 9 years to 16 years
!
To describe the tolerability and satisfaction of colon cleansing by Prepopik in preparation for 
colonoscopy in children aged 9 years to 16 years, as assessed by a standardized subject 
questionnaire administered at the study site before colonoscopy
!
To evaluate pharmacokinetic (PK) characteristics of Prepopik in children aged 9 years to 16 
years


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ENDPOINTS
Primary endpoint
!
Proportion of subjects classified as success defined by “excellent” or “good” in the Aronchick 
scale
Secondary endpoints
!
Incidence of adverse events and abnormal findings in clinical laboratory test and physical 
examination
!
Proportion of subjects who took the assigned dose for the IMP
!
Frequency of each category of the Tolerability and Satisfaction Questionnaire 
!
PK exposure will be assessed utilizing a sparse sampling of subjects (Sparse sampling means no 
need for special PK time)
METHODOLOGY
Pediatric subjects, aged 9-16 years, requiring colonoscopy, who fulfill all screening criteria, and sign 
an informed consent and assent (as required), will be randomized to one of the treatment arms by the 
age group.  Subjects aged 9 years to 12 years will be randomized into 3 arms: Prepopik ½ sachet x2, 
Prepopik 1 sachet x2, or standard of care. Subjects aged 13 years to 16 years will be randomized into 2 
arms: Prepopik 1 sachet x2 or local standard of care.  The designated unblinded coordinator will 
instruct the subject and his/her parent/guardian on the use of the bowel preparation, and along with the 
subject and his/her parent/guardian, will sign a nondisclosure affidavit form (APPENDIX 1), which 
will prevent the subject and the unblinded study coordinator from disclosing the bowel preparation 
treatment the subject used. Treatment will be blinded to the endoscopist and his/her assistant(s) 
assessing the efficacy of the tested preparations.
Colon cleansing will be performed using Prepopik for oral administration or oral PEG base 
preparation/local standard of care for oral solution.
There are two Prepopik dosing regimens, each requires two separate dosing times:
• “Split Dose” method is the preferred method 
• “Day Before” method is the alternative method if “Split Dose” is not appropriate  (see Section 
5 for dosing and fluid instructions)
Subjects randomized to the “Split Dose” Prepopik group will begin treatment (1st dose) 1 day before 
colonoscopy between 5:00 and 9:00 PM, and will complete the treatment (2nd dose) ≥6 hours after on 
the next day, and at least 5 hours prior but no later than 9 hours prior to colonoscopy. Prepopik is 
reconstituted by mixing the powdered contents of the sachet in a cup with approximately 5 ounces of 
cold water. Following each administration of Prepopik, subjects will consume approximately five 
8 ounce glasses of clear liquids after the first administration and at least three 8 ounce glasses of clear 
liquids after the second administration (all of the clear liquids should not be water). 


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Subjects randomized to the oral PEG based preparation/local standard of care, will follow appropriate 
label and/or institutional instructions.
On the day before the procedure (24 hours prior), all subjects will be limited to a liquid diet only. 
Special meal instructions for diabetic subjects are provided in APPENDIX 2. The coordinator who 
dispenses the drug will instruct the subject and his/her parent/guardian about the exact requirements 
during the Randomization Visit (Visit 2).  Subjects will return to the site 5 (∀2) days following their 
colonoscopy for a laboratory sample (chemistry and hematology).  Subjects/parents or guardians will 
have a telephone assessment on Day 28 after the colonoscopy procedure. 
Efficacy of the 2 tested preparations will be evaluated by a blinded endoscopist using the Aronchick 
scale for overall colon cleansing. A standardized subject questionnaire administered on the day of 
colonoscopy and prior to sedation and the procedure will assess tolerability and satisfaction of the 
product. 
Pharmacokinetic assessments will be performed on a subset of subjects (10 subjects ages 9 years to 12 
years; 5 subjects ages 13 years to 16 years). Assessments will consist of baseline and in the ~ times of 
Cmax after the various analytes (time based on PK assessment of healthy volunteers).
NUMBER OF SUBJECTS
A sufficient number of subjects will be screened to ensure up to approximately 75 (for 9-12 years old, 
15 subjects for the Prepopik ½ sachet x2, the Prepopik 1 sachet x2, and standard of care group;  for 13-
16 years old, 15 subjects for the Prepopik 1 sachet x2 and standard of care). For PK sampling, 
approximately 5 subjects per treatment group (a total of 15, 5 aged 13-16 years and 10 aged 9-12 years) 
will be assessed.
MAIN CRITERIA FOR INCLUSION / EXCLUSION
Inclusion Criteria
1. Male or female, aged 9 years to 16 years, inclusive, being scheduled to undergo elective 
colonoscopy 
2. Females of childbearing potential must undergo a pregnancy test at screening and again at 
randomization
3. Subjects must have had #3 spontaneous bowel movements (SBM) per week for 1 month prior 
to the colonoscopy
4. Subjects should be willing, able, and competent to complete the entire procedure and to comply 
with study instructions
5. Written informed consent and assent obtained at screening 


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Exclusion Criteria
1. Acute surgical abdominal conditions (e.g., acute obstruction or perforation) 
2. Hospitalized for inflammatory bowel disease
3. Any prior colorectal surgery, excluding appendectomy, hemorrhoid surgery, or prior 
endoscopic surgical procedures (subjects with diagnostic colonoscopy are not excluded)
4. Colon disease (history of colonic cancer, toxic megacolon, toxic colitis, idiopathic 
pseudo-obstruction, hypomotility syndrome, colon resection)
5. Ascites
6. Gastrointestinal disorder (active ulcer, outlet obstruction, retention, gastroparesis, ileus)
7. Upper gastrointestinal surgery (gastric resection, gastric banding, gastric bypass)
8. Significant cardiovascular disease as determined by the investigator
9. If subject has a history of renal insufficiency, serum creatinine and potassium must be within 
normal limits 
10. Participation in an investigational study within 30 days prior to receiving study medication (or 
within 60 days for investigational drugs with an elimination half-life >15 days)
11. Any clinically significant laboratory value at screening, including pre-existing electrolyte 
abnormality, based on clinical history that the Investigator feels may affect the study evaluation
12. Hypersensitivity to active ingredients 
Exclusionary Medications
The following medications exclude subjects’ participation in the study and/or must be suspended prior 
to the procedure:
1. Lithium
2. Laxatives (suspend for 24 hours prior to procedure.  Laxatives as part of the SOC colonoscopy 
prep are not prohibited.)
3. Constipating drugs (suspend for 2 days prior to procedure)
4. Antidiarrheals (suspend for 72 hours prior to procedure)
5. Oral iron preparations (suspend for 1 week prior to procedure)
MEDICINAL PRODUCTS
!
Prepopik® (sodium picosulfate 10 mg; magnesium oxide 3.5 g and anhydrous citric acid 12 g) 
for oral solution
!
Oral PEG based preparation/local standard of care


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DURATION OF TREATMENT
Prepopik: “Split Dose” treatment starts 1 day before colonoscopy (first sachet or first ½ sachet 
reconstituted), and completes* on the day of colonoscopy (second sachet or second ½ sachet 
reconstituted). *“Day Before” treatment option completes evening before colonoscopy.
Subjects randomized to the oral PEG based preparation (no enema or suppository)/local standard of 
care, will follow appropriate label and/or institutional instructions.
STATISTICAL METHODS
Sample size:
A total of at least 45 subjects will be exposed to Prepopik. In the two Phase 3 studies for adults, 83% 
and 84.2% of subjects were classified as success after bowel preparation with Prepopik. With 45 
subjects, if 80% of subjects are classified as success in this study, the exact 95% confidence interval of 
the success rate will be calculated as 65% - 90%.
Statistical methods:
The primary efficacy endpoint will be the proportion of subjects classified as success defined by 
excellent or good in the Aronchick scale. The primary efficacy analysis will be based on the ITT 
dataset. The proportion will be presented by treatment group within each age group, for all Prepopik 1 
sachet groups combined, for all Prepopik groups combined, and all standard of care groups combined 
with the 95% confidence interval. 
The treatment group difference will be assessed by constructing the 95% confidence interval of the 
difference in proportions between each Prepopik group and standard of care within each age group, all 
Prepopik 1 sachet groups combined and all standard of care groups combined, and all Prepopik groups 
combined and all standard of care groups combined. 
The analyses will be conducted for the PP populations as well. 
The following secondary endpoints will be summarized in the same manner as the primary endpoint: 
proportion of subjects who completed colon cleansing, proportion of subject who record treatment as 
tolerable or better and proportion who rate treatment as satisfactory as provided on the Tolerability and 
Satisfaction Questionnaire, and proportion of subjects who completed colonoscopy procedure.
All the safety data will be summarized descriptively.


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DOCUMENT APPROVAL
The Principal Investigator and Ferring International Pharmascience Center U.S., Inc.  agree to conduct 
the study as outlined in this protocol with reference to national/local regulations and in accordance with 
current Good Clinical Practice (GCP) guidelines.  Any modification to the protocol must be agreed 
upon by both the Principal Investigator and Ferring and documented in writing.  By written agreement 
to this protocol, the Investigator agrees to allow direct access to all documentation, including source
data, to authorized individuals representing Ferring (including monitoring staff and auditors), to 
Institutional Review Boards/Independent Ethics Committees (IRBs/IECs) and/or to domestic and 
foreign regulatory authorities.  
FERRING REPRESENTATIVE
___________________________________________
________________
Name: Raymond E. Joseph, MD
Date (dd/mm/yyyy)
Title:
Associate Vice President, Gastroenterology
Principal Investigator
Print Name: _____________________________________
Site Name: _____________________________________
Address: _______________________________________
_______________________________________________
_______________________________________________
________________
Principal Investigator Signature
Date (dd/mm/yyyy)


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TABLE OF CONTENTS
Page
SYNOPSIS...............................................................................................................................................................2
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................................13
1
INTRODUCTION .....................................................................................................................................14
1.1
Background.....................................................................................................................................14
1.2
Scientific Justification for Conducting the Trial.............................................................................15
1.3
Benefit / Risk Aspects.....................................................................................................................16
2
TRIAL OBJECTIVES AND ENDPOINTS ............................................................................................18
2.1
Objectives .......................................................................................................................................18
2.2
Endpoints........................................................................................................................................18
3
INVESTIGATIONAL PLAN ...................................................................................................................19
3.1
Overall Trial Design .......................................................................................................................19
3.1.1
Trial Design Diagram ........................................................................................................21
3.1.2
Trial Schedule....................................................................................................................21
3.2
Planned Number of Trial Sites and Subjects ..................................................................................22
3.3
Interim Analysis..............................................................................................................................22
3.4
Data Monitoring Committee (DMC) ..............................................................................................22
3.5
Discussion of Overall Trial Design and Choice of Control Groups ...............................................22
3.5.1
Trial Design .......................................................................................................................22
3.5.2
Selection of Endpoints.......................................................................................................22
3.5.3
Blinding / Unblinding........................................................................................................22
3.5.4
Selection of Doses in the Trial...........................................................................................23
3.5.5
Selection and Timing of Dose for Each Subject................................................................24
3.5.6
Withdrawal Criteria ...........................................................................................................24
3.5.7
Follow-up...........................................................................................................................24
4
SELECTION OF TRIAL POPULATION..............................................................................................25
4.1
Trial Population ..............................................................................................................................25
4.1.1
Inclusion Criteria ...............................................................................................................25
4.1.2
Exclusion Criteria..............................................................................................................25
4.2
Method of Assigning Subjects to Treatment Groups......................................................................26
4.2.1
Recruitment........................................................................................................................26
4.2.2
Randomization...................................................................................................................26
4.3
Restrictions .....................................................................................................................................26
4.3.1
Prior and Concomitant Therapies ......................................................................................26
4.3.2
Prohibited Therapy ............................................................................................................27
4.3.3
Other Restrictions..............................................................................................................27
5
TREATMENTS .........................................................................................................................................28
5.1
Treatments Administered................................................................................................................28
5.2
Characteristics and Source of Supply .............................................................................................29


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5.2.1
Prepopik.............................................................................................................................29
5.2.2
Oral PEG Based Preparation..............................................................................................29
5.3
Packaging and Labeling..................................................................................................................29
5.3.1
Prepopik.............................................................................................................................29
5.3.2
Oral PEG Based Preparation..............................................................................................29
5.4
Conditions for Storage and Use......................................................................................................29
5.4.1
Prepopik.............................................................................................................................30
5.4.2
Oral PEG Based Preparation..............................................................................................30
5.5
Treatment Compliance....................................................................................................................30
5.5.1
Dispensing and Accountability..........................................................................................30
5.5.2
Assessment of Compliance................................................................................................30
5.6
Return and Destruction of Medicinal Products and Auxiliary Supplies.........................................30
6
TRIAL PROCEDURES............................................................................................................................31
6.1
Screening Visit (Visit 1) .................................................................................................................31
6.2
Randomization Visit (Visit 2).........................................................................................................31
6.3
Procedure/Colonoscopy Visit (Visit 3)...........................................................................................32
6.4
Follow-up Visits (Visits 4 and 5)....................................................................................................33
6.5
Trial Flow Chart..............................................................................................................................34
7
TRIAL ASSESSMENTS...........................................................................................................................35
7.1
Assessments Related to Endpoints..................................................................................................35
7.2
Other Assessments..........................................................................................................................35
7.2.1
Physical Examinations.......................................................................................................35
7.2.2
Vital Signs .........................................................................................................................36
7.2.3
Clinical Laboratory Variables............................................................................................36
7.3
Drug Concentration Measurements ................................................................................................37
7.4
Handling of Biological Samples.....................................................................................................37
8
ADVERSE EVENTS .................................................................................................................................38
8.1
Adverse Event Definition ...............................................................................................................38
8.2
Collection and Recording of Adverse Events.................................................................................38
8.2.1
Collection of Adverse Events ............................................................................................38
8.2.2
Recording of Adverse Events ............................................................................................39
8.3
Pregnancy and Pregnancy Outcome ...............................................................................................41
8.4
Serious Adverse Events ..................................................................................................................42
8.4.1
Serious Adverse Event Definition .....................................................................................42
8.4.2
Collection, Recording and Reporting of Serious Adverse Events.....................................43
8.5
Follow-up of Adverse Events and Serious Adverse Events ...........................................................43
8.5.1
Follow-up of Adverse Events with Onset during the Trial................................................43
8.5.2
Collection of Serious Adverse Events with Onset after Last Trial Visit ...........................44
9
STATISTICAL METHODS.....................................................................................................................45
9.1
Determination of Sample Size ........................................................................................................45
9.2
Subject Disposition.........................................................................................................................45
9.3
Protocol Deviations.........................................................................................................................45


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9.4
Analysis Sets...................................................................................................................................45
9.4.1
Intention-to-Treat (ITT) Dataset........................................................................................45
9.4.2
Per Protocol (PP) Dataset ..................................................................................................45
9.4.3
Safety Dataset....................................................................................................................45
9.5
Trial Population ..............................................................................................................................46
9.5.1
Demographics and other Baseline Characteristics.............................................................46
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations........................46
9.6
Endpoint Assessments ....................................................................................................................46
9.6.1
General Considerations......................................................................................................46
9.6.2
Primary Efficacy Endpoint ................................................................................................46
9.6.3
Secondary Endpoint(s).......................................................................................................47
9.7
Extent of Exposure and Treatment Compliance.............................................................................47
9.8
Safety..............................................................................................................................................47
9.8.1
General Considerations......................................................................................................47
9.8.2
Adverse Events..................................................................................................................47
9.8.3
Safety Laboratory Variables..............................................................................................47
9.8.4
Other Safety Variables.......................................................................................................48
9.8.5
Vital Signs .........................................................................................................................48
9.8.6
Physical Findings...............................................................................................................48
9.9
Interim Analyses.............................................................................................................................48
10
DATA HANDLING...................................................................................................................................49
10.1
Source Data and Source Documents...............................................................................................49
10.2
e-CRF..............................................................................................................................................49
10.3
Data Management...........................................................................................................................50
10.4
Provision of Additional Information...............................................................................................50
11
MONITORING PROCEDURES .............................................................................................................51
11.1
Periodic Monitoring........................................................................................................................51
11.2
Audit and Inspection.......................................................................................................................51
11.3
Confidentiality of Subject Data ......................................................................................................51
12
CHANGES IN THE CONDUCT OF THE TRIAL................................................................................52
12.1
Protocol Amendments.....................................................................................................................52
12.2
Deviations from the Protocol..........................................................................................................52
12.3
Premature Trial Termination ..........................................................................................................52
13
REPORTING AND PUBLICATION ......................................................................................................53
13.1
Clinical Trial Report.......................................................................................................................53
13.2
Confidentiality and Ownership of Trial Data .................................................................................53
13.3
Publications and Public Disclosure.................................................................................................53
13.3.1 Publication Policy..............................................................................................................53
13.3.2 Public Disclosure Policy....................................................................................................54
14
ETHICAL AND REGULATORY ASPECTS.........................................................................................55
14.1
Independent Ethics Committee or Institutional Review Board (IRB) ............................................55
14.2
Regulatory Authority(ies) Authorization / Approval / Notification ...............................................55


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14.3
End-of-Trial and End-of-Trial Notification....................................................................................55
14.4
Ethical Conduct of the Trial............................................................................................................55
14.5
Subject Information and Consent ...................................................................................................55
14.6
Compliance Reference Documents.................................................................................................56
15
LIABILITIES AND INSURANCE ..........................................................................................................57
15.1
ICH-GCP Responsibilities..............................................................................................................57
15.2
Liabilities and Insurance.................................................................................................................57
16
ARCHIVING .............................................................................................................................................58
16.1
Investigator File..............................................................................................................................58
16.2
Trial Master File .............................................................................................................................58
17
REFERENCES ..........................................................................................................................................59
APPENDICES.......................................................................................................................................................62
APPENDIX 1: Subject’s Confidential Non-Disclosure Affidavit...............................................................63
APPENDIX 2: Dietary Guidelines for Diabetics.........................................................................................64
APPENDIX 3: Subject’s Tolerability and Satisfaction Questionnaire........................................................65


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LIST OF TABLES 
Table 1-1
Summary of Benefits and Risks of Prepopik ....................................................................... 17
Table 3-1
Overview of Study Treatment Groups by Age..................................................................... 19
Table 6-1
Schedule of Assessments ..................................................................................................... 34
Table 7-1
Aronchick Scale ................................................................................................................... 35


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ADR
adverse drug reaction
AE
adverse event
Cmax
maximumconcentration
CRF
case report form
DMC
Data Monitoring Committee
ECG
electrocardiogram
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
ICH
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
IMP
investigational medicinal product
IRB
Institutional Review Board
ITT
intent-to-treat
IVRS
interactive voice response system
MedRA
medical dictionary for regulatory activities
NDA
new drug application
PEG
polyethylene glycol
PK
pharmacokinetic
PP
per protocol
PREA
Pediatric Research Equity Act
SAE
serious adverse event
SBM
spontaneous bowel movement defined as a bowel movement that occurs in the absence of a 
laxative use or manual disimpaction
SOC
standard of care
US
United States
V
visit


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1
INTRODUCTION
1.1
Background
Colonoscopy is a well-established and routinely used procedure for diagnostic exploration and 
therapeutic procedures of the colon mucosa in all age groups. The overall success of the procedure is 
directly related to the ability of the pre-investigational bowel preparation to purge the colon of all fecal 
material, thereby allowing unobstructed visualization of the bowel wall. Inadequate colon cleansing 
can lead to inaccurate results, as well as increasing the time it may take to conduct the procedure and 
increasing the risk of complications.1 A poor quality bowel preparation may require that the 
examination be repeated, resulting in additional health care costs, as well as inconvenience to the 
patient.2  
Ideally, bowel cleansing should clear the colon of all solid material and cause no damage to the colonic 
mucosa. It should also be easy to administer, well tolerated by the patient with few adverse events
(AEs), and cause minimal clinically relevant shifts in the patient’s fluid and electrolyte balance. Colon 
cleansing is not a pleasant procedure for the patient; therefore, compliance with any colon cleansing 
agent is critical. Accordingly, pretreatment with a colon cleansing agent should be suitable for the 
patient to self-administer at home with minimal inconvenience and relatively short duration. All of the 
above bowel cleansing parameters are especially true for the pediatric subject.
Prepopik® (sodium picosulfate, magnesium oxide and citric acid) powder for oral solution, which 
cleanses the colon by means of a combination of 2 established purgative mechanisms, fulfills all of 
these criteria. Prepopik was approved in the United States (US) on 16 July 2012 for cleansing of the 
colon as a preparation for colonoscopy in adults #18 years of age.
The combination of sodium picosulfate with magnesium oxide and citric acid is currently approved for 
adult and pediatric use for colon cleansing in 34 countries around the world. The product, under the 
trade names Picolax, PicoSalax, Pico-Salax, Picoprep, or Prepopik (hereafter referred to as Prepopik), 
is currently marketed in Austria, Canada, Czech Republic, Denmark, France, Germany, Hungary, 
Ireland, Jordan, Malta, Netherlands, Norway, Portugal, Romania, Slovakia, United Kingdom, and the 
US. 
The active drug substances in each pouch of Prepopik are sodium picosulfate (10 mg), a stimulant 
cathartic, plus magnesium oxide (3.5 g) and citric acid (12.0 g) which, upon mixing with water, form 
magnesium citrate, an osmotic laxative. Magnesium citrate, as an osmotic laxative, acts in both the 
small and large intestine to increase the bulk of the intestinal contents by causing the retention of water 
within the intestinal lumen. A possible additional action on cholecystokinin, which may increase 
intestinal fluid and electrolyte accumulation, has been reported.3 Magnesium citrate has a rapid effect, 
producing a semi-liquid stool in approximately 3 hours. Sodium picosulfate, a stimulant cathartic, acts 
directly on the nerve endings in the colon to induce peristalsis. The purgative effect is exerted only 
after hydrolysis of picosulfate, by colonic bacteria, to the active metabolite bis-(p-hydroxy-phenyl)-
pyridyl-2-methane.4 Sodium picosulfate has a slower action than magnesium citrate, taking between 
6 and 10 hours to exert its effect.5,6 Thus, the combination of these 2 therapeutically active components 


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produces an efficient dual-action cleansing effect, enabling enhanced visibility for colonoscopy without 
mucosal harm.
Another important advantage of Prepopik is the ease with which patients can administer the preparation 
and how well it is tolerated. The preparation consists of a low-volume drink with a pleasant orange 
taste, followed by the consumption of clear fluids of the patient’s choice, with no forced-time schedule. 
It has not escaped our attention that this combination should make the product desirable for all patients, 
pediatric patients and, in particular, the especially non-compliant adolescents. Prepopik will likely 
result in improved patient compliance, thus promoting more complete and timely screening procedures.
Only further pediatric-driven research can establish this fact.
1.2
Scientific Justification for Conducting the Trial
The ideal pediatric bowel preparation should be effective, safe, and easily accepted by children. 
Currently, no bowel preparation serves the needs of all children. An important limitation of 
colonoscopy in children is inadequate bowel preparation. These variables certainly have a potential for 
improvement.
Prepopik has been shown to be an effective and well-tolerated method for bowel preparation compared 
with polyethylene glycol (PEG) with electrolyte solution in children.7
Polyethylene glycol is a long-chain polymer of ethylene oxide. Many products have an average 
molecular weight of 3350 g/mole and these are given the name PEG-3350. There is a perception that
PEG is safe because it is minimally absorbed from the stomach and intestines. However, little is known 
regarding whether absorption in children differs from adults, especially in children who are 
constipated, have underlying intestinal disease, or are very young.
In this study, the efficacy and safety of Prepopik will be compared with oral PEG based preparation 
(local standard of care) in children 9 to 16 years of age in order to fulfill a post-marketing requirement 
for the US Food and Drug Administration (FDA) and to add to the body of knowledge in colon 
cleansing in this population.  There is a long history of sodium picosulfate and magnesium citrate usage 
in colon cleansing in both adults and children.
Prepopik was first used in pediatrics in the United Kingdom in approximately 1980 and is currently 
used in several Western health arenas. Over 30 years’ experience indicates that 12-18-year-old subjects 
respond well to the adult dosing. The current dosages used in pediatrics in the European Union for ages 
9-18 years is 1 sachet (x2). In Canada, current pediatric dosage is ½ sachet (x2) for ages 9-12 years and 
1 sachet (x2) for ages 13-18 years.  This dosage has been studied in a well-controlled trial from the 
Toronto Hospital for Sick Children. It aimed to compare bowel preparation for colonoscopy in 
children with PicoSalax or PEG with electrolyte solution. Thirty five of PicoSalax patients (81%) were 
satisfied or very satisfied with the clean out compared with 19 (48%) in the PEG group (p=.001).7
Therefore, in our study, the younger group will compare adult dose (1 sachet x2 as in the European 
Union) and ½ the adult dose (1/2 sachet x2, Canadian dose). Pharmacokinetics will be evaluated to 
assess potential age-related differences in systemic exposure to major constituents (picosulfate and 
magnesium).


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1.3
Benefit / Risk Aspects
Since the original application was approved in 1980 in the United Kingdom, the colon-cleansing effects 
of Prepopik have been clearly demonstrated in clinical practice in both adults and 
children.7,8,9,10,11,12,13,14,15,16,17,18,19 Furthermore, the cumulative worldwide exposure through 
31 December 2010 is estimated to be 22,751,499 treatments, with a post-marketing adverse reaction 
reporting rate of <1 in 10,000 treatments. Thus, Prepopik has a global record of effectiveness and a 
safety profile established in clinical practice in adults and children.1,7,8,9,12,13,16,20,21,22,23,24,25,26,27
The effectiveness of any colon cleansing regimen must be achieved without sacrificing patient safety. 
While oral sodium phosphate products are highly effective and well tolerated, the risk of acute 
phosphate nephropathy has resulted in a Black Box warning for high-risk groups, including people 
>55 years of age, those who suffer from kidney disease, acute colitis, or delayed bowel emptying, and 
those who take certain medications that affect kidney function, to use the products with caution. 
Although PEG products are effective and reduce the amount of fluid shifts observed with other osmotic 
and stimulant laxatives, the large volume of salty fluid is poorly tolerated, frequently resulting in 
adverse effects that impact compliance as well as the overall effectiveness of the regimen. 
In the phase 3 studies in adults, Prepopik demonstrated an acceptable safety profile for use in colon 
cleansing prior to colonoscopy. Among treatment-emergent AEs considered by the investigator to be
possibly or probably related to study drug, only nausea (2.8%), headache (2.2%), and vomiting (1.2%) 
were experienced by >1.0% of subjects who received Prepopik. No deaths occurred and the incidence 
of subjects who experienced serious AEs (SAEs) or prematurely discontinued from study due to AEs 
was <1.0%. Similar results were observed for subjects who received the active comparator, HalfLytely, 
in the adult registration trials.
Additionally, clinical laboratory evaluation confirmed the safety of Prepopik in phase 3 studies. Bowel 
preparations can cause considerable dehydration, particularly in patient sub-populations such as the 
elderly or children, or those with cardiac disease or renal failure, and the resulting hemodynamic 
changes can prove hazardous to frail patients. Clinically insignificant changes in laboratory values 
consistent with expected shifts in fluid status as a result of the colon cleansing procedure tended to be 
greater following dosing with Prepopik compared with HalfLytely in the phase 3 studies, but shifts in 
these parameters resolved, and results were generally comparable between the treatment groups within 
24-48 hours after the procedure. Adequate hydration should be maintained in all subjects during dosing 
with Prepopik to prevent electrolyte deficiencies such as hyponatremia or hypokalemia. The emphasis 
on additional fluid consumption in the dosage and administration of Prepopik aids in alleviating this 
risk.
The magnesium component of the Prepopik product led to transient increased magnesium levels in 
adult subjects following dosing in the phase 3 studies; however, the levels returned to baseline within 
24-48 hours after the procedure without sequelae. 
Assessments of vital signs and centralized evaluation of electrocardiogram (3000 ECGs) data from the 
phase 3 studies showed no signal for Prepopik on any cardiac electro-physiological functions. 


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Based on the worldwide safety data reported during the period covered by the periodic safety update 
reports (01 June 1990 – 31 December 2010), the overall benefit-risk profile of Prepopik remains 
favorable. Review of literature has revealed no important new safety findings. The safety profile of 
Prepopik is broadly consistent with the known risks as reported in the most current Summary of 
Product Characteristics for Prepopik. Predictably, cumulative safety data indicate that, overall, 
gastrointestinal disorders were the most commonly reported type of reaction, including vomiting, 
diarrhea, nausea, and abdominal pain. No novel or unexpected AEs were recorded in the adult 
registration trials.
A summary of the benefits and risks of Prepopik is provided in Table 1-1. Prepopik offers a significant 
improvement over other currently marketed products in the US, with an ideal balance of efficacy,
safety and tolerability for cleansing of the colon as a preparation for colonoscopy.
Table 1-1
Summary of Benefits and Risks of Prepopik
Benefits
Risks
Easy to consume
!
Good taste
!
Low volume of preparation
!
Ability to consume clear liquids of choice
!
Ability to consume additional liquids at own pace
!
Expected high compliance
Transient increases in magnesium due to the magnesium 
component of the preparation
Expected shifts in fluid status due to colon cleansing
Potential for hypovolemia if sufficient additional clear 
liquids are not consumed
Proven dual-action components
!
Non-inferior to a proven product
!
Well established safety profile
!
Phosphate-free preparation
Two different dosing regimens
!
Flexible scheduling of procedure
Split-dose dosing regimen
!
Superior overall efficacy
!
Superior cleansing of ascending colon
Similar efficacy and safety profile in demographic 
subgroups


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary objective
!
To describe the efficacy of the Prepopik in children aged 9 years to 16 years for overall colon 
cleansing in preparation for colonoscopy based on the Aronchick scale by including oral 
polyethylene glycol (PEG) based preparation/local standard of care as a reference group
Secondary objectives
!
To describe the safety of Prepopik in children aged 9 years to 16 years through the collection of 
AEs, clinical laboratory tests, and physical examination
!
To describe the completion of prep as directed to colon cleansing by Prepopik in preparation 
from colonoscopy in children aged 9 years to 16 years
!
To describe the tolerability and satisfaction of colon cleansing by Prepopik in preparation for 
colonoscopy in children aged 9 years to 16 years as assessed by a standardized subject 
questionnaire administered at the study site before colonoscopy
!
To evaluate pharmacokinetic (PK) characteristics of Prepopik in children aged 9 years to 16 
years
2.2
Endpoints
Primary Endpoint
!
Proportion of subjects classified as success defined by “excellent” or “good” in the Aronchick 
scale 
Secondary Endpoints
!
Incidence of adverse events and abnormal findings in clinical laboratory test and physical 
examination
!
Proportion of subjects who took the assigned dose for the IMP
!
Frequency of each category of the Tolerability and Satisfaction Questionnaire 
!
PK exposure will be assessed utilizing a sparse sampling of subjects (Sparse sampling means no 
need for special PK time)


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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
This study is a randomized, assessor-blind, multicenter, dose-ranging study. Subjects undergoing an 
elective complete colonoscopy will randomly receive one of the following products:
!
“Split Dose” Prepopik: 2 divided doses given the night before (first dose) and approximately 5 
hours prior (second dose) to procedure. A dose is defined for one subset of subjects aged 
9 years to 12 years as ½ sachet, for another subset of subjects aged 9 years to 12 years per 
randomization as 1 sachet and for subjects aged 13 to 16 years as 1 sachet. For “Day Before” 
Prepopik and fluids see Section 5.
!
Oral PEG based preparation/local standard of care per appropriate label and/or institutional 
instructions.
Table 3-1
Overview of Study Treatment Groups by Age
Treatment Group
Age Group
Total
9-12 years
13-16 years
Prepopik: ½ sachet
15
0
15
Prepopik: 1 sachet
15
15
30
Standard of care
15
15
30
Total subjects
45
30
75
Pediatric subjects requiring colonoscopy, who fulfill all screening criteria, and sign an informed 
consent and assent (as required), will be randomized. One of the treatment arm products will be 
provided to the subject in a randomized fashion. The designated unblinded coordinator will instruct the 
subject and his/her parent/guardian on the use of the bowel preparation, and along with the subject and 
his/her parent/guardian, will sign a nondisclosure affidavit form (APPENDIX 1), which will prevent 
the subject and the unblinded coordinator from disclosing the bowel preparation treatment the subject 
used. Treatment will be blinded to the endoscopist and his/her assistant(s) assessing the efficacy of the 
2 tested preparations when local or institutional methods are used.  Their dosage timing and diet will be 
captured in the data. This approach had been used successfully in the Prepopik adult trials.
Colon cleansing will be performed using Prepopik for oral administration or oral PEG based
preparation/local standard of care for oral solution.


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Subjects randomized to the “Split Dose” Prepopik group will begin treatment (1st dose) 1 day before 
colonoscopy between 5:00 and 9:00 PM, and will complete the treatment (2nd dose) ≥6 hours after on 
the next day, and at least 5 hours prior but no later than 9 hours prior to colonoscopy. Additionally, if 
the subject is in the hospital, instructions will be written to follow as close as possible the 
aforementioned dosage schedule. Prepopik is reconstituted by mixing the powdered contents of the 
sachet in a cup with approximately 5 ounces of cold water. Following each administration of Prepopik, 
subjects will consume approximately five 8 ounce glasses of clear fluids after the first administration 
and at least three 8 ounce glasses of clear fluids after the second administration. For “Day Before” 
Prepopik and fluids see section 5.
Subjects randomized to the oral PEG based preparation/local standard of care will follow appropriate 
label and/or institutional instructions.
On the day before the procedure (24 hours prior), all subjects will be limited to a liquid diet only. 
Special meal instructions for diabetic subjects are provided in APPENDIX 2. The coordinator who 
dispenses the drug will instruct the subject and his/her parent/guardian about the exact requirements 
during the Randomization Visit (Visit 2).  
Subjects will return to the site 5 (∀2) days following their colonoscopy for a laboratory sample 
(chemistry, hematology and coagulation).  Subjects/parents or guardians will have a telephone 
assessment on Day 28 after the colonoscopy procedure. 
Efficacy of the tested preparations will be evaluated by an assessor-blinded endoscopist using the 
Aronchick scale for overall colon cleansing. A standardized subject questionnaire administered on the 
day of colonoscopy and prior to sedation and the procedure will assess tolerability and satisfaction of 
the product (to be filled out by the subject and/or guardian).


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3.1.1
Trial Design Diagram
Subjects participating in PK subset will remain in the clinical research unit for needed blood draws at 
V2 and V3.
3.1.2
Trial Schedule
First patient first visit is estimated for October 2013 and last patient last visit is expected in May 2015. 
The expected overall duration of the trial will be approximately 20 months.


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3.2
Planned Number of Trial Sites and Subjects
Approximately 6-8 sites in the US are planned. A sufficient number of subjects will be screened to 
ensure up to approximately 75 (~15 subjects per treatment arm).
3.3
Interim Analysis
No interim analysis is planned.
3.4
Data Monitoring Committee (DMC)
No DMC will be established for this study.
3.5
Discussion of Overall Trial Design and Choice of Control Groups
3.5.1
Trial Design
The study design is assessor-blinded and randomized. Blinding treatment to the endoscopist and his/her 
assistant(s) assessing the efficacy of the tested preparations removes possible bias. A placebo-
controlled design would not be practical or ethical in this study as subjects would be required to have a 
second colonoscopy.
3.5.2
Selection of Endpoints
The primary endpoint, overall colon cleansing prior to colonoscopy, will be assessed by a blinded 
assessor endoscopist using the Aronchick scale. The Aronchick scale is a validated instrument that has 
been widely used and universally accepted, and has been previously used in pivotal trials that led to 
new drug application (NDA) approval, including the approval of HalfLytely.28 However, this study will 
compare Prepopik to oral PEG local standard of care preparations. Essentially, each endoscopic center 
has its own preparation concoction based on some combination of diet PEG 3350 sports drinks, enemas
and stimulant laxatives.  
Each investigational site will be trained on the use of the Aronchick Scale both at the investigator 
meeting and at initial site visit; subjects will not be initiated until all assessing gastroenterologists 
involved in the study at the investigational site are confident in using this tool.
3.5.3
Blinding / Unblinding
Blinding
The study treatment(s) will be allocated according to computer-generated randomization codes 
prepared for all study sites. Treatment is blinded to the endoscopist and his/her assistant(s) performing 
the colonoscopy and assessing the efficacy of the tested preparations.
Prior to the start of the study, the investigator will assign a coordinator to act as the unblinded 
coordinator. This person will be responsible for distribution and accountability of the drug. The 
unblinded coordinator will instruct each subject as to the proper administration and the timing of the 
drug administration. This person will be available to answer the subject’s and parent’s/guardian’s 
questions regarding the study drug and its administration.


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The integrity of blinding will be further preserved by requiring each subject or parent/guardian and the 
unblinded coordinator to sign a nondisclosure affidavit form instructing subjects/parents/guardians and 
the unblinded coordinator not to disclose the treatment groups to the endoscopist performing the 
colonoscopy and his/her assistants.
Unblinding of Individual Subject Treatment
In case of an emergency, the emergency decoding envelope will be available to the investigator and the 
sponsor's medical officer. Breaking of the blind in individual subjects is only permitted in case of a 
serious, unexpected or other important AE, when the knowledge of the investigational product in 
question is required for therapeutic decisions for the management of the subject.
If it is necessary to unblind an individual subject’s treatment for the purposes of expedited reporting to 
the authorities, only those individuals within Ferring Pharmaceuticals whose responsibility it is to 
report this information will know the identity of the IMP. Every attempt will be made to ensure that all 
other study and site personnel will continue to remain blinded throughout the course of the study.
As far as the emergency permits, the need to break the blind will be agreed by the investigator and the 
sponsor. It should be recorded in the CRF that the blind is broken, why, when, and by whom. 
In case of accidental unblinding (e.g., the subject tells the assessor), the same documentation as for 
emergency unblinding must be obtained, i.e., the code envelope must be opened and why, when, and 
by whom must be noted both on the code envelope and in the CRF, and the event must also be recorded 
in the subject’s medical record.
It may be necessary to unblind an individual subject’s treatment for the purposes of expedited reporting 
to the authorities and/or IRBs. In that situation, every effort will be made to maintain blinding of 
sponsor personnel involved in data analysis and interpretation. Other personnel may be unblinded for 
suspected unexpected serious adverse reactions, including trial site staff as well as staff acting on 
behalf of Ferring.
Information on whether the blind has been broken for any subjects must be collected before the 
database is declared clean and is released to the statistician.
3.5.4
Selection of Doses in the Trial
Doses of Prepopik are age-adjusted and follow the pediatric dosing instructions in the prescribing 
information of the product marketed for many years in other countries. That is, a dose of Prepopik is 
defined as either ½ or 1 sachet (x2) for subjects aged 9 years to 12 years and 1 sachet (x2) for subjects 
aged 13 to 16 years. This dosage is based on the EU dose and Canadian data.  Both areas have
extensive hands-on experience with the preparation7.
The oral PEG based preparation/local standard of care will be administered per appropriate label and/or 
institutional instructions (with complete documentation as it will vary from site to site).


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3.5.5
Selection and Timing of Dose for Each Subject
Each subject will be randomly assigned to one of the following products:
!
“Split Dose” Prepopik: 2 doses with the first dose the night before and the second dose given 
approximately >6 hours after but at least 5 hours prior to the procedure.
!
Oral PEG based preparation/local standard of care per appropriate label and/or institutional 
instructions.
Complete dosing (including “Day Before” option), as well as, timing instructions for the study drugs 
are found in Section 5.
3.5.6
Withdrawal Criteria
Every subject has the right to refuse further participation in the study at any time and without providing 
reasons. A subject's participation is to terminate immediately upon his/her request. The investigator 
should seek to obtain the reason and record this in the case report form (CRF).
If, at the time of refusal, a dose of the investigational product has already been administered, the 
subject must be advised to agree to follow-up safety investigations, which will include all procedures 
outlined in the follow-up visit.
The subject may be withdrawn from the study at any time at the discretion of the investigator; the 
reason should be discussed with the sponsor prior to discontinuing the subject and the reason fully 
documented in the CRF. Should the subject, during the course of the study, develop conditions, which 
would have prevented him/her entry into the study according to the exclusion criteria, he/she must be 
withdrawn immediately. 
The withdrawal of subjects from the study will be agreed by the investigator and the sponsor.
3.5.7
Follow-up 
During Visit 4 (5 [∀2] days after colonoscopy) the subject will return to the site for a laboratory 
sample (chemistry and hematology), urinalysis, orthostatic vital signs and an assessment of any AEs
and concomitant medications.
At Visit 5 (28 [∀5] days after colonoscopy), the investigator or coordinator will interview the subject or 
parent/guardian via phone about any changes in concomitant medications, concomitant illness, or any 
new illnesses since the last visit. New illnesses or worsening in concomitant illnesses should be 
reported as AEs.


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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
Subjects who meet all of the following criteria will be eligible for the study:
1. Male or female, aged 9 years to 16 years, inclusive, being scheduled to undergo an elective 
colonoscopy 
2. Females of childbearing potential must undergo a pregnancy test at screening and again at 
randomization
3. Subjects must have had #3 spontaneous bowel movements (SBM) per week for 1 month prior 
to the colonoscopy
4. Subjects should be willing, able, and competent to complete the entire procedure and to comply 
with study instructions
5. Written informed consent and assent obtained at screening
4.1.2
Exclusion Criteria
The presence of any of the following excludes a subject from study enrollment:
1. Acute surgical abdominal conditions (e.g., acute obstruction or perforation)
2. Hospitalized for inflammatory bowel disease
3. Any prior colorectal surgery, excluding appendectomy, hemorrhoid surgery, or prior 
endoscopic surgical procedures (subjects with diagnostic colonoscopy are not excluded)
4. Colon disease (history of colonic cancer, toxic megacolon, toxic colitis, idiopathic 
pseudo-obstruction, hypomotility syndrome, colon resection)
5. Ascites
6. Gastrointestinal disorder (active ulcer, outlet obstruction, retention, gastroparesis, ileus)
7. Upper gastrointestinal surgery (gastric resection, gastric banding, gastric bypass)
8. Significant cardiovascular disease as determined by the investigator
9. If subject has a history of renal insufficiency, serum creatinine and potassium must be within 
normal limits 
10. Participation in an investigational study within 30 days prior to receiving study medication (or 
within 60 days for investigational drugs with an elimination half-life >15 days)
11. Any clinically significant laboratory value at screening, including pre-existing electrolyte 
abnormality, based on clinical history that the Investigator feels may affect the study evaluation


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12. Hypersensitivity to active ingredients
4.2
Method of Assigning Subjects to Treatment Groups
4.2.1
Recruitment
The site will recruit subjects based on the inclusion/exclusion criteria and local recruitment practices. 
Recruitment materials cannot be used prior to Institutional Review Board (IRB) approval. 
Each trial site will require potential participants to undergo a Screening Visit prior to randomization to 
a treatment group. Each patient will receive a unique screening number which must be entered in a 
screening log that must be maintained at each trial site. The screening number will be allocated 
sequentially in the order in which the patients are screened. The results of each screening should be 
recorded in the screening log. Selected data for screened patients should also be entered in the CRF, 
along with the reason for screening failure if the patient is not randomized to treatment. Under no 
circumstances will patients screened in the trial be permitted to be re-screened for a second time in this 
trial.
4.2.2
Randomization
At a clinic visit preceding the colonoscopy (Visit 2), eligible pediatric subjects will be randomized to 
one of the treatment arms by the age group.  Subjects aged 9 years to 12 years will be randomized to 
Prepopik ½ sachet x2, Prepopik 1 sachet x2, or standard of care in 1:1:1 ratio. Subjects aged 13 years to 
16 years will be randomized to Prepopik 1 sachet x2 or oral PEG based preparation/standard of care in 
1:1 ratio. Randomization numbers will be allocated sequentially to the subjects at each site. This will 
occur in the order in which the subjects are enrolled.
Under no circumstances will subjects enrolled in the study be permitted to re-enroll for a second time 
in this study.
4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
Details of all concomitant medications within 7 days of screening and throughout the study will be 
collected. The indication for their use and start and stop date and times must be recorded in the source 
data and CRF at all visits. Required information includes the drug name, strength, and formulation, 
route of administration, dosing frequency, and duration of treatment. Any changes (including new 
therapies) must be recorded at each subsequent study visit.


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4.3.2
Prohibited Therapy
The following medications exclude subjects’ participation in the study and/or must be suspended prior 
to the procedure:
1. Lithium
2. Laxatives (suspend for 24 hours prior to procedure.  Laxatives as part of the SOC colonoscopy 
prep are not prohibited.)
3. Constipating drugs (suspend for 2 days prior to procedure)
4. Antidiarrheals (suspend for 72 hours prior to procedure)
5. Oral iron preparations (suspend for 1 week prior to procedure)
4.3.3
Other Restrictions
On the day before the procedure, subjects are limited to a liquid diet only. The unblinded coordinator, 
who dispenses the study drug, will instruct the subject and parent/guardian about the exact 
requirements during Visit 2. Diet intake will be collected on the CRF.


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5
TREATMENTS
5.1
Treatments Administered
Subjects will be randomized to one of the treatment arms by the age group.  Subjects aged 9 years to 12 
years will be randomized to Prepopik ½ sachet x2, Prepopik 1 sachet x2, or standard of care. Subjects 
aged 13 years to 16 years will be randomized to Prepopik 1 sachet x2 or standard of care.
Dose: Prepopik (sodium picosulfate, magnesium oxide and citric acid) powder for oral solution 
administered in a divided dose.  There are two dosing regimens, each requires two separate dosing 
times:
• “Split Dose” method is the preferred method 
• “Day Before” method is the alternative method if “Split Dose” is not appropriate  
Preparation: Prepopik is reconstituted by mixing the contents of the sachet in a cup with 5 ounces of 
cold water.
“Split Dose” 
Day before colonoscopy procedure:
!
First dose between 5:00 PM and 9:00 PM 
Day of colonoscopy procedure:
Second dose is given ≥ 6 hours after first dose and approximately 5 hours before but no more than 9 
hours prior to the procedure
“Day Before”
Day before colonoscopy procedure:
!
First dose: during afternoon or early evening before the colonoscopy 
!
Second dose: 6 hours later during evening before colonoscopy 
Following the first administration of Prepopik, subjects will consume five 8-ounce glasses of clear 
liquids over the next few hours and following the second administration, subjects will consume at least 
three 8-ounce glasses of clear liquids (all of the clear liquids should not be water).
For those subjects needing to consume the ½ sachet, reconstitution should be completed as follows: 
mix the contents of the sachet in a cup with 5 ounces of cold water; stir thoroughly for three minutes; 
measure half of the total volume (2.5 ounces); discard the remaining fluid.
The oral PEG based preparation/local standard of care will be administered per appropriate label and/or 
institutional instructions.


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5.2
Characteristics and Source of Supply
All medicinal products are provided by Ferring Pharmaceuticals and will be handled according to the 
principles of Good Manufacturing Practice (GMP).
5.2.1
Prepopik
Dose: Prepopik is a white crystalline powder for oral solution. Each sachet of Prepopik contains:
!
sodium picosulfate 10.0 mg
!
magnesium oxide, light 3.5 g
!
citric acid, anhydrous 12.0 g
Magnesium oxide and citric acid react in water solution to form magnesium citrate, a safe and well-
known colon cleanser.
Prepopik will be supplied in boxes containing 2 foil sachets each.  
5.2.2
Oral PEG Based Preparation
Oral polyethylene glycol based (no enema or suppository) as per standard of care-exact solution 
administered will be documented by unblinded study coordinator at the site and recorded as to type and 
timing of diet and colon cleansing agent.
5.3
Packaging and Labeling
5.3.1
Prepopik
Packaging and labeling of the medicinal product will be performed under the responsibility of the IMP 
Department at Ferring Pharmaceuticals A/S in accordance with GMP and national regulatory 
requirements.
The label of the investigational product contains one self-adhesive tear-off portion to be affixed to the 
drug accountability binder. The drug accountability binder will be managed by the unblinded 
coordinator, and will not be available to the blinded staff conducting the assessments.
5.3.2
Oral PEG Based Preparation
See Section 5.2.2.
5.4
Conditions for Storage and Use
The investigator will ensure that the investigational products are stored in appropriate conditions in a 
secure location with controlled access. The temperature in the storage compartment shall be regularly 
monitored with a minimum/maximum thermometer and the values documented. Deviations in storage 
temperature must be reported to sponsor without delay, the IMP cannot be used until acceptance from 
the sponsor is received.
The unblinded coordinator will dispense the medication only to the identified subjects of this study, 
following the procedures described in this study protocol and documented in the subject dispensing log. 


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Drug inventory/dispensing will be documented in the source and the drug accountability binder for 
each subject. The investigator is responsible for all drug supplies. Written documentation is mandatory. 
After completion of the study, all unused investigational product will be returned to the sponsor.  
5.4.1
Prepopik
Prepopik should be stored in the original package at temperatures not exceeding 25°C (77°F) and 
protected from light. 
5.4.2
Oral PEG Based Preparation
See Section 5.2.2.
5.5
Treatment Compliance
5.5.1
Dispensing and Accountability
The IMP will only be dispensed to subjects who meet all the selection criteria. A drug-dispensing log 
will be maintained detailing the dates and quantities of investigational products dispensed to each 
subject, as well as the batch numbers. The monitor will verify the drug accountability during the study. 
Any unused investigational product, either not dispensed or returned by a subject will be accounted for 
and returned to the sponsor.
5.5.2
Assessment of Compliance
Subjects will be considered compliant if dosing occurs within ∀30 minutes of specified timings. The 
time of administration will be provided to the subject/parent/guardian by the coordinator who dispenses 
the drug and will be verbally confirmed with the coordinator. Subject’s response to “Have you taken 
the medication within specified time periods?” will be documented in the CRF by the coordinator 
during the procedure visit (Visit 3). 
5.6
Return and Destruction of Medicinal Products and Auxiliary Supplies
The trial medication delegate at the site should ensure that the destruction of used medicinal products is 
done in accordance with local legislation/national requirements, after the drug accountability has been 
finalized, verified by the monitor, and signed off by the Investigator.
After completion of the study, all unused investigational product will be returned to the sponsor as 
instructed by Ferring IMP Department and in accordance with local requirements, after the drug 
accountability has been finalized, verified by the monitor, and signed off by the Investigator.


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6
TRIAL PROCEDURES
6.1
Screening Visit (Visit 1)
Prior to or at the Screening Visit, the subject and parent/guardian must receive a detailed explanation of 
the study and must sign the Informed Consent Form/assent as appropriate after having sufficient time 
to consider his/her participation in the study. After the subject/parent or guardian has signed the 
Informed Consent/Assent Form, the investigator will:
!
Obtain a thorough medical history and record demographic data
!
Review inclusion/exclusion criteria
!
Document any concomitant medications up to 7 days prior
!
Measure body weight and height
!
Measure orthostatic vital signs (blood pressure and pulse)
!
Perform a complete physical examination 
!
Obtain laboratory sample:  chemistry, hematology and coagulation
!
Urinalysis
!
Urine pregnancy test (onsite) for adolescent female subjects of childbearing potential
!
Schedule date of colonoscopy (∃42 days from Visit 1)
!
Schedule Visit 2 (date of randomization) (Visit 2 ≤14 days from Visit 3)
6.2
Randomization Visit (Visit 2)
The Randomization Visit (Visit 2) takes place ≤14 days from the Procedure (Visit 3).  This visit may 
be combined with Visit 1 if all laboratory results are obtained prior to randomization.
If the study screening requirements, including positive laboratory results, are met:
!
Urine pregnancy test (onsite) for adolescent female subjects of childbearing potential
!
Measure orthostatic vital signs (blood pressure and pulse)
!
Perform a directed physical examination
!
Document any concomitant medications
!
AEs (recorded by study personnel)
!
Assign subject randomization number 
!
Dispense study medication
!
Instruct the subject (and parent/guardian) how to self-administer the study medication and 
provide them with detailed information, complete with assigned times of drug administration
If  the subject is participating in the PK subset, an additional laboratory sample will be obtained for 
baseline Mg ++.  The baseline Mg++ sample can be obtained at any time prior to IMP dosing.


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6.3
Procedure/Colonoscopy Visit (Visit 3)
The Procedure Visit (Visit 3) takes place ∃42 days from Visit 1. 
Before colonoscopy, the following will be performed/recorded/checked:
!
Treatment completed
!
Perform a directed physical examination 
!
Acceptability and tolerability questionnaire completed by subject or parent/guardian
!
Obtain vital signs
!
Obtain laboratory sample: chemistry, hematology, coagulation
!
Urinalysis
!
AEs (recorded by study personnel)
!
Document any concomitant medications
!
Perform study drug accountability
!
If the subject is participating in the PK subset, laboratory samples will be obtained at Hours 6, 
8, 10 and 12 after first dose
The subject or parent/guardian should be instructed to fill out the questionnaire during the visit in a 
private area prior to contact with the investigator and return the completed questionnaire to the study 
coordinator. If the coordinator is not available during the procedure, the subject/parent or guardian will 
place the completed questionnaire in a sealed envelope and provide it to a member of the surgical team. 
The study coordinator should check each questionnaire for completion and, if the subject did not 
answer all/some of the questions, note the reasons on the first page of the questionnaire. No one 
(including study coordinator or a family member or guardian) should interpret questions or response 
choices for the subject.
During the colonoscopy procedure, the blinded gastroenterologist will use the Aronchick Scale to score 
the quality of the bowel preparation of the study drug for overall colon cleansing and record the 
outcome of the colonoscopy.
Post-colonoscopy, the following will be performed/recorded/checked:
!
AEs (additional to those recorded prior to colonoscopy)
!
Measure orthostatic vital signs (blood pressure and pulse)


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6.4
Follow-up Visits (Visits 4 and 5)
During Visit 4 (5 (±2) days after colonoscopy), the following will be obtained:
!
AEs
!
Document any concomitant medications
!
Obtain laboratory sample: chemistry, hematology and coagulation
!
Urinalysis
!
Measure orthostatic vital signs (blood pressure and pulse)
During Visit 5 (28 [∀5] days after colonoscopy), the investigator or coordinator will interview the 
subject or parent/guardian via phone about any changes in concomitant medications, concomitant 
illness, or any new illnesses since the last visit. New illnesses or worsening in concomitant illnesses 
should be reported as AEs.


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6.5
Trial Flow Chart
Table 6-1
Schedule of Assessments
Visit 
V1a
Screening
V2a
Randomization
V3
Procedure
V4
Follow-up
V5b
Follow-up
Day
≤ - 42
Days
≤ - 14
Days
Colonoscopy
T = 0
5 Days
∀2 Days
28 Days
∀5 Days
Informed consent
x
Inclusion/exclusion criteria 
x
Demographic and medical history
x
Body weight and height
x
Urine pregnancy test
x
x
Schedule colonoscopy
x
Laboratory (chemistry, hematology, 
coagulation)
x
x
x
PK assessment
xc
xc
Baseline Mg++
xd
xd
xd
Urinalysis
x
x
x
Physical examinatione
x
x
x
Orthostatic vital signs (blood pressure, 
pulse)
x
x
x
x
Concomitant medications
x
x
x
x
x
Adverse events
x
x
x
x
Randomization
x
Study medication dispensed
xf,g
Subject questionnaireh
x
Perform colonoscopy
x
Score overall colon – Aronchick Scale 
x
Drug accountability
x
PK=pharmacokinetic
a.    Visits 1 and 2 can be combined if all laboratory results are obtained prior to randomization.
b.     Via telephone.
c.
If the subject is participating in the PK subset, laboratory samples will be obtained at baseline and hours 6, 8, 10 and 12 after first dose.
d.     The baseline Mg++ sample can be obtained at any time prior to IMP dosing.
e.    Complete physical examination at Visit 1 and directed physical examination at Visits 2 and 3.  
f.
“Split Dose” Prepopik first dose between 5:00 PM and 9:00 PM 1 day before colonoscopy and second dose is given approximately ≥6 
hours after on the next day but at least 5 hours prior to but no more than 9 hours prior to colonoscopy. Subjects will consume five 8-ounce 
glasses of clear liquids following the first administration of Prepopik and at least three 8-ounce glasses of clear liquids following the 
second administration. “Day Before” Prepopik option see Section 5.
g.
Polyethylene glycol based as per standard of care-exact solution administered will be documented by unblinded study coordinator at 
the site.
h.
Subject or parent/guardian will be instructed to complete the questionnaire prior to contact with the Investigator (and prior to sedation 
for colonoscopy) and to return it to the study coordinator. If the coordinator is not available during the procedure, the subject is to 
place the completed questionnaire in a sealed envelope to be given to the coordinator.


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7
TRIAL ASSESSMENTS
7.1
Assessments Related to Endpoints
The efficacy of the overall colon cleansing will be measured by a blinded gastroenterologist using the 
Aronchick Scale. The overall colon will be graded as “Excellent.” “Good, “Fair,” or “Inadequate” 
according to the definitions below: 
Table 7-1
Aronchick Scale
Scale
Description
Excellent
>90% of mucosa seen, mostly liquid stool, minimal suctioning needed for adequate 
visualization
Good
>90% of mucosa seen, mostly liquid stool, significant suctioning needed for adequate 
visualization
Fair
>90% of mucosa seen, mixture of liquid and semisolid stool, could be suctioned and/or washed
Inadequate
<90% of mucosa seen, mixture of semisolid and solid stool which could not be suctioned or 
washed
The subject is considered to be a responder if overall colon cleansing = “excellent” or “good” on this 
4-point scale.
The endoscopist will record in the CRF whether or not the colonoscopy was completed. If the 
colonoscopy was not completed, he/she will need to state the reason why and whether a repeat is 
required.
A secondary efficacy endpoint will be assessed by the Subject’s Tolerability and Satisfaction 
Questionnaire, administered to the subject prior to the colonoscopy during Visit 2. The 7 questions are:
1. How easy was it to drink the bowel cleanout regimen (1=very easy, 2=easy, 3=okay, 
4=difficult, 5=very difficult)? 
2. How did the bowel cleanout regimen taste (1=very good, 2=good, 3=okay, 4=bad, 5=very bad)?
3. For each of the following questions, mark the box with your answer (1=never, 2=rarely, 
3=sometimes, 4=often, 5=very often)
How often did your tummy hurt since you started the cleanout?
How often did you feel fullness in your tummy since you started the cleanout?
How often did you wake up last night?
How often did you feel sick to your stomach (nausea) since you started the cleanout?
How much were you bothered by going to the bathroom since you started your cleanout?
The Subject’s Tolerability and Satisfaction Questionnaire is attached as APPENDIX 3.
7.2
Other Assessments
7.2.1
Physical Examinations
A complete physical examination will be conducted at the investigational site at Visit 1. At Visits 2 and 
3, a directed physical examination will be performed. Height and weight will be measured at Visit 1 
only.  


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After study drug administration, any new abnormal findings or worsening of an ongoing abnormal 
condition will be recorded as an AE.
7.2.2
Vital Signs
Orthostatic vital signs (supine and standing blood pressure and pulse) will be measured at Visits 1 
through 4.  
7.2.3
Clinical Laboratory Variables
All laboratory measurements will be performed using appropriately validated methods by the study 
site’s local laboratory. All sites should follow their local regulations for sample handling and storage. 
Laboratory values will be reported to the investigator and sponsor (or the sponsor’s representative) and 
will be entered into the eCRF database, which will be maintained by a clinical research organization 
selected by the Sponsor. 
Out-of-range values will be described in the reference ranges to be provided by the local laboratory. 
Investigators will assess all out of range values as being either clinically significant or not clinically 
significant via the eCRF.
Sites will be specially instructed to review all laboratory results in order to determine if the subject is 
eligible for study participation, and to determine any AEs post study drug administration.
Samples will be collected during Visits 1, 3 and 4 for determination of the following test values:
!
Hematology panel: 
o
Full complete blood count and differential 
!
Coagulation panel:
o
Prothrombin time, activated partial thromboplastin time
!
Full chemistry panel:
o
Calculated creatinine clearance
o
Serum magnesium (Mg++)
o
Serum chemistry: glucose, blood urea nitrogen, potassium, sodium, chloride, calcium, total 
protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, bicarbonate and gamma glutamyl transferase
!
Urinalysis panel
In addition, urine pregnancy tests will be performed at the local laboratory for female subjects of 
childbearing potential at Visits 1 and 2.


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7.3
Drug Concentration Measurements
For subjects that are participating in the PK subset, blood samples for measurement of picosulfate and 
magnesium plasma concentrations will be collected from approximately 15 subjects in the 3 Prepopik 
groups. Magnesium will be collected pre-dose at Visits 1, 2 or 3.). Picosulfate will be collected at Visit
3 (colonoscopy) in the (6-12 hour) window after the first dose of Prepopik. Sampling times at Visit 3 
are at Hours 6, 8, and 12 for picosulfate concentrations and at Hour 10 for magnesium concentrations.
Analysis of the samples for sodium picosulfate and magnesium oxide will be performed by 
 
7.4
Handling of Biological Samples
Sampling tubes, material for shipment of urine and blood samples, and a laboratory manual detailing 
all sample collection and shipment procedures will be provided and distributed by the local safety 
laboratory at each individual trial site. Sampling tubes, material for shipment of PK blood samples, and 
a laboratory manual detailing all sample collection and shipment procedures will be provided and 
distributed by the central PK laboratory to all trial sites. The volume of blood withdrawn from subjects 
is restricted to a minimum to allow evaluation of PK.
Any remaining blood samples not already analyzed for the trial will be stored at the central laboratory
until the clinical trial report has been finalized.


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An AE is any untoward medical occurrence in a subject participating in a clinical trial. It includes:
!
Any unfavorable and unintended sign, symptom or disease temporally associated with the use 
of the IMP, whether or not considered to be caused by the IMP
!
AEs commonly observed and AEs anticipated based on the pharmacological effect of the IMP
!
Any laboratory abnormality, vital sign or finding from physical or gynecological examination 
assessed as clinically significant by the investigator (note: findings from assessments and 
examinations done during screening are not AEs, but are recorded as medical history.)
!
Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for any 
medical, nursing or pharmacy consultation, or reasons for admission to hospital or surgical 
procedures
!
Overdoses and medication errors with and without clinical consequences
An adverse drug reaction (ADR) is an AE evaluated by the investigator as being probably or possibly 
causally related to treatment with the IMP. 
A serious ADR is an SAE evaluated by the investigator and/or by Ferring as being probably or possibly 
causally related to treatment with the IMP (further described in Section 8.2.2).
An unexpected AE is an AE not identified in nature, severity, or frequency in the section “Undesirable 
Effects” in the sponsor’s current Investigator’s Brochure and current approved label.
A treatment-emergent AE is any AE that begins during the treatment period, or is a worsening of a 
pre-existing medical condition. The treatment period is the period during which a subject receives IMP.
8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the last visit.
The sources of AEs cover:
!
The subject’s response to questions about his/her health (a standard non-leading question such 
as “How have you been feeling since your last visit?” is asked at each visit).
!
Symptoms spontaneously reported by the subject.
!
Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities.


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!
Other information relating to the subject’s health becoming known to the investigator 
(e.g., hospitalization).
8.2.2
Recording of Adverse Events
The investigator must record all AEs in the Adverse Event Log provided in each subject’s CRF with 
information about the:
!
AE
!
Date and time of onset (time can be omitted, if applicable)
!
Intensity
!
Causal relationship to IMP
!
Action taken to IMP
!
Other action taken
!
Date and time of outcome (time can be omitted, if applicable)
!
Outcome
!
Seriousness.
Each of the items in the Adverse Event Log is described in detail in the following sections.
Adverse Event
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis/symptom should be entered per record.
If a subject suffers from the same AE more than once and the subject recovers in between the events, 
the AEs should be recorded separately. If an AE changes in intensity, a worst-case approach should be 
used when recording the event, i.e., the highest intensity and the longest duration of the event.a
Note the following: A procedure is not an AE; the reason for conducting the procedure is. 
Hospitalization is not an AE; the reason for hospitalization is. Death is not an AE, but the cause of 
death is (an exception is sudden death of unknown cause, which is an AE).
                                                
a
Exception: if an AE with onset before the first IMP administration (i.e., a pre-treatment AE) changes in intensity, 
this must be recorded as two separate events. The initial AE should be recorded with outcome “not yet recovered” 
and the date and time of outcome is when the intensity changed. The second AE should be recorded with date and 
time of onset when the intensity changed. 


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Date and Time of Onset
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the AE is an 
abnormal clinically significant laboratory test or outcome of an examination, the onset date is the date 
the sample was taken or the examination was performed. 
Intensity
The intensity of an AE must be classified using the following 3-point scale:
Mild:
Awareness of signs or symptoms, but no disruption of usual activity
Moderate:
Event sufficient to affect usual activity (disturbing)
Severe:
Inability to work or perform usual activities (unacceptable)
Causal Relationship to IMP
The possibility of whether the IMP caused the AE must be classified as one of the following:
Reasonable possibility: 
There is evidence or argument to suggest a causal relationship between the IMP and the AE. The AE
may occur as part of the pharmacological action of the IMP or may be unpredictable in its occurrence.
Examples: 
!
AEs that are uncommon but are known to be strongly associated with IMP exposure
!
AEs that are not commonly associated with IMP exposure, but the event occurs in association 
with other factors strongly suggesting causation, such as a strong temporal association or the 
event recurs on rechallenge
No reasonable possibility:
There is no reasonable evidence or argument to suggest a causal relationship between the IMP and the 
AE.
Examples:
!
known consequences of the underlying disease or condition under investigation
!
AEs common in the trial population, which are also anticipated to occur with some frequency 
during the course of the trial, regardless of IMP exposure


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Action Taken to IMP
The action taken to the IMP in response to an AE must be classified as one of the following:
!
No change (medication schedule maintained or no action taken)
!
Withdrawn
!
Interrupted
!
Dose reduced
!
Dose increased
Other Action Taken
Adverse events requiring therapy must be treated with recognized standards of medical care to protect 
the health and well-being of the subject. Appropriate resuscitation equipment and medicines must be 
available to ensure the best possible treatment of an emergency situation.
If medication is administered to treat the AE, this medication should be entered in the Concomitant 
Medication Log.
Date and Time of Outcome
The date and time (time can be deleted/omitted, if applicable) the subject recovered or died.
Outcome
The outcome of an AE must be classified as one of the following:
!
Recovered (fully recovered or the condition has returned to the level observed at initiation of 
trial treatment)
!
Recovered with sequelae (resulted in persistent or significant disability/incapacity)
!
Recovering
!
Not yet recovered
!
Fatal
8.3
Pregnancy and Pregnancy Outcome
If a pregnancy occurs, the IMP should be immediately stopped and Pharmacovigilance at Ferring 
Pharmaceuticals must be informed. The mother and the fetus must be followed-up at least until the 
birth of the infant and 1 month after the birth of the infant. In general, the follow-up will include the 
course; duration, and the outcome of the pregnancy, as well as neonatal health. If a pregnancy results in 
an abnormal outcome (birth defect/congenital anomaly), this must be reported as an SAE to 
Pharmacovigilance at Ferring Pharmaceuticals.


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In cases in which a fetus may have been exposed through transmission of the IMP via semen following 
paternal exposure, and the pregnancy results in an abnormal outcome (birth defect/congenital 
anomaly), this must be reported as an SAE to Pharmacovigilance at Ferring Pharmaceuticals.
8.4
Serious Adverse Events
8.4.1
Serious Adverse Event Definition
Serious Adverse Events during the Trial
An event is defined a serious 
adverse event if it:
Guidance
results in death
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within four weeks after the treatment ends and irrespective 
of the causal relationship to the IMP. The death of a subject enrolled in a trial is per 
se not an event, but an outcome.
is life-threatening
The term life-threatening refers to an AE in which the subject was at immediate risk 
of death at the time of the event. It does not refer to an event, which may have caused 
death if it were more severe.
requires in-patient hospitalization
or prolongation of existing 
hospitalization
The term hospitalization means that the subject was admitted to hospital or that 
existing hospitalization was extended as a result of an event. Hospitalization
describes a period of at least 24 hours. Over-night stay for observation, stay at 
emergency room or treatment on an out-patient basis do not constitute a 
hospitalization. However, medical judgment must always be exercised and when in 
doubt the case should be considered serious (i.e. if case fulfills the criterion for a 
medically important event). Hospitalizations for administrative or social purposes do 
not constitute an SAE. Hospital admissions and/or surgical operations planned before 
trial inclusion are not considered AEs, if the illness or disease existed before the 
subject was enrolled in the trial, provided that the condition did not deteriorate during 
the trial.
results in persistent or significant 
disability/incapacity
Disability/incapacity means a substantial disruption of a person’s ability to conduct 
normal life functions. In doubt, the decision should be left to medical judgment by 
the investigator.
is a congenital anomaly/birth 
defect
Congenital anomaly/birth defect observed in any offspring of the subject conceived 
during treatment with the IMP.
is an important medical event
Important medical events are events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
Examples of important medical events include AEs that suggest a significant hazard, 
contraindication or precaution, occurrence of malignancy or development of drug 
dependency or drug abuse. Medical and scientific judgment should be exercised in 
deciding whether events qualify as medically important.
Important medical events include any suspected transmission of an infectious agent 
via a medicinal product. Any organism virus or infectious particle (e.g. prion protein 
transmitting Transmissible Spongiform Encephalopathy), pathogenic or non-
pathogenic, is considered an infectious agent. A transmission of an infectious agent 
may be suspected from clinical symptoms or laboratory findings indicating an 
infection in a subject exposed to a medicinal product.


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8.4.2
Collection, Recording and Reporting of Serious Adverse Events
SAE Reporting by the Investigator
All SAEs must be reported immediately to Ferring Pharmacovigilance as soon as it becomes known to 
the investigator but not later than within 24 hours of his/her knowledge of the occurrence of an SAE.
The investigator is responsible for submitting the completed SAE Report Form with the fullest possible 
details within 3 calendar days of his/her knowledge of the SAE.
The SAE Report Form is available in the investigator’s file. The SAE report form should be completed 
in accordance with the instructions provided on the form and sent to Ferring Pharmacovigilance using 
the contact details below.
Pharmacovigilance, Ferring Pharmaceuticals Inc.
Copies from CRFs regarding demographics, AEs, medical history, and concomitant medication are
mandatory for initial reports and for follow-up reports if any changes have been made since the initial 
report.
Additional information relevant to the SAE, such as hospital records, results from investigations, e.g.,
laboratory parameters, invasive procedures, scans and x-rays, and autopsy results can be faxed or 
scanned and e-mailed to Ferring Pharmacovigilance using the contact details in the section above. In 
any case, this information must be supplied by the investigator upon request from Ferring. On any 
copies provided, such details such as subject’s name, address, and hospital ID number should be 
concealed and instead subject number should be provided.
The investigator will supply Ferring and the IRB with any additional requested information such as 
results of post-mortem examinations and hospital records.
Expedited Reporting by Ferring
Ferring will report all AEs that are serious, unexpected, and with a reasonable possible causality to 
the IMP, as judged by either the investigator or Ferring, to the relevant parties within the stipulated 
timelines.
Serious AEs will be considered reportable regardless of whether or not the IMP was used in accordance 
with the provisions in the protocol, Investigator’s Brochure, and labeling.
8.5
Follow-up of Adverse Events and Serious Adverse Events 
8.5.1
Follow-up of Adverse Events with Onset during the Trial
During the trial, the investigator must follow-up on each AE until it is resolved or until the medical 
condition of the subject is stable.


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After the subject’s last visit, the investigator must follow-up on any AE classified as serious or 
considered to have a reasonable possible causality to the IMP until it is resolved or until the medical 
condition of the subject is stable. All such relevant follow-up information must be reported to Ferring. 
If the event is a chronic condition, the investigator and Ferring may agree that further follow-up is not 
required.
8.5.2
Collection of Serious Adverse Events with Onset after Last Trial Visit
If an investigator becomes aware of an SAE after the subject’s last visit, and he/she assesses the SAE to 
have a reasonable possible causality to the IMP, the case will have to be reported to Ferring, regardless 
how long after the end of the trial this takes place.


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9
STATISTICAL METHODS
Details of the statistical methodology will be provided in a separate Statistical Analysis Plan. All 
tabulations will be done by treatment arm. All individual patient data will be listed by domain.
9.1
Determination of Sample Size
A total of at least 45 subjects will be exposed to Prepopik. In the two Phase 3 studies for adults, 83% 
and 84.2% of subjects were classified as success after bowel preparation with Prepopik. With 45 
subjects, if 80% of subjects are classified as success in this study, the exact 95% confidence interval of 
the success rate will be calculated as 65% - 90%.        
9.2
Subject Disposition
All subjects screened and randomized will be accounted for. All post-randomization discontinuations 
will be summarized by time of, and reason for, discontinuation and presentation by category will 
present the frequency and corresponding percentages. The number of subjects screened and not 
randomized will be presented with the main reason for their non-inclusion.
9.3
Protocol Deviations
Major or minor protocol deviations will be defined and documented prior to database lock. 
9.4
Analysis Sets
All randomized subjects who received any study drug will be included in one or more of the following 
analysis datasets.
9.4.1
Intention-to-Treat (ITT) Dataset
The ITT Dataset will include all subjects who are randomized independent of whether or not the 
subject receives study treatment dose. Subjects who do not have an efficacy assessment for the data 
(Aronchick Scale) will be scored as a non-responder. Analyses for the ITT will be conducted according 
to the randomized treatment.
9.4.2
Per Protocol (PP) Dataset
Subjects with major protocol deviations will be excluded from the PP (per-protocol) Analysis Set. 
Subjects not taking the study medication in the prescribed time intervals will be excluded from the PP 
analysis set. These subjects will be identified prior to breaking the study blind.
9.4.3
Safety Dataset
All subjects consuming at least one dose of study medication will be included in the Safety Analysis 
Set. Analyses for the Safety Dataset will be conducted according to the treatment actually received.


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9.5
Trial Population
9.5.1
Demographics and other Baseline Characteristics
Descriptive statistics of demographics, and other baseline characteristics will be presented by treatment 
group for the ITT, PP and safety populations. For quantitative variables, all summaries will include the 
sample size, mean, median, standard deviation, minimum, and maximum. For the qualitative variables, 
the summaries will include the number and percentage of subjects for each outcome.
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations
Medical history, concomitant medications and the physical examination results will be summarized and 
listed by subject and any abnormalities noted on the listings.
9.6
Endpoint Assessments
9.6.1
General Considerations
Nominal p-values and confidence intervals will be presented to aid in interpretation of the summary of 
data. 
Qualitative data will be summarized by presenting the total number of subjects, frequency and 
percentages within categories by treatment group. The quantitative data will be summarized by 
presenting the number of subjects, the mean and standard deviation, median, minimum and maximum 
by treatment group. 
9.6.2
Primary Efficacy Endpoint
The primary efficacy endpoint will be the proportion of subjects classified as success defined by 
excellent or good in the Aronchick scale. The primary efficacy analysis will be based on the ITT
dataset. 
The proportion will be presented by treatment group within each age group, for all Prepopik 1 sachet
groups combined, for all Prepopik groups combined, and all standard of care groups combined with the 
95% confidence interval. 
The treatment group difference will be assessed by constructing the 95% confidence interval of the 
difference in proportion between each Prepopik group and standard of care within each age group, all 
Prepopik 1 sachet groups combined and all standard of care groups combined, and all Prepopik groups 
combined and all standard of care groups combined. 
The analyses will be conducted for the PP populations as well. 


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9.6.3
Secondary Endpoint(s)
The following secondary endpoints will be summarized in the same manner as the primary endpoint: 
proportion of subjects who completed colon cleansing, proportion of subject who record treatment as 
tolerable or better and proportion who rate treatment as satisfactory as provided on the Tolerability and 
Satisfaction Questionnaire, and proportion of subjects who completed colonoscopy procedure.
9.7
Extent of Exposure and Treatment Compliance
The total study treatment exposure will be summarized and listed by study treatment group for the 
Safety Analysis Set.
The number and proportion of subjects deviating from the treatment regimen will be tabulated by age 
and treatment group. The amount of study drug consumed and the timing of treatment administration 
for each subject according to the instructions will be presented in a data listing.
9.8
Safety
9.8.1
General Considerations
The safety analysis will include all randomized and dosed subjects, i.e., the Safety Analysis Set. 
Complete listings and summary tables for all safety information, including AEs, clinical laboratory 
vital signs, and physical examination, data will be included in the final report.
9.8.2
Adverse Events
All AEs will be coded by the most current version of MedRA (Medical Dictionary for Regulatory 
Activities) for system organ class and preferred term.  
All AEs will be listed by subject, and the incidence of treatment-emergent AEs will be presented by 
treatment group, causality (relationship to the study medication), and intensity (severity). Deaths, 
SAEs, and AEs leading to discontinuation will be listed.
9.8.3
Safety Laboratory Variables
All clinical laboratory values outside normal range will be listed separately by subject number, 
including demographic information and flagging values.
Continuous clinical laboratory safety data will be summarized by treatment group and nominal time 
point (V1 and V3 pre and post colonoscopy) using descriptive statistics: sample size, mean, median, 
standard deviation, minimum, and maximum values. Changes from pre-treatment will be summarized 
in the same way. 
Categorical clinical laboratory safety data will be summarized by treatment group and nominal time 
point using the number and percentage of subjects in each category.


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9.8.4
Other Safety Variables
9.8.5
Vital Signs
Each vital sign will be summarized by treatment group and nominal time point using descriptive 
statistics: sample size, mean, median, standard deviation, minimum, and maximum values. In addition 
changes from pre-treatment will be summarized in the same way.
Incidence of markedly abnormal changes in vital sign values will be summarized by treatment group.
9.8.6
Physical Findings
Physical examination at each evaluation will be listed for the safety dataset. Subjects with abnormal 
values will be noted on the data listings.
9.9
Interim Analyses
No interim analysis is planned.


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10
DATA HANDLING
10.1
Source Data and Source Documents
Source Data – ICH Definition
Source data are defined as all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents (original records or certified 
copies). The investigator will permit study-related monitoring, audit(s), IRB review(s) and regulatory 
inspection(s), with a direct access to all the required source records.
Source Documents - ICH Definition
Source documents are defined as original documents, data, and records (e.g. hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-
technical departments involved in the clinical trial).
Trial-specific Source Data Requirements – Ferring
An investigator shall retain the source records for a period of 2 years following the date a marketing 
application is approved for the drug for the indication for which it is being investigated; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and FDA is notified. For each subject enrolled, the investigator will 
indicate in the source record(s) that the subject participates in this study, and will record all study 
specific information including: any AE, any concomitant therapy, primary response variable/s, progress 
notes and status at treatment end, and the end of the subject’s participation. 
10.2
e-CRF
In the trial an e-CRF system provided by an independent third party will be used for data capture. The 
system is fully validated and access at all levels to the system is granted/revoked following Sponsor 
and vendor procedures, in accordance with regulatory requirements and system requirements. The e-
CRF system and the database are hosted at an independent third party. After the trial database is 
declared clean and is released to the statistician, a final copy of the database will be stored at the 
Sponsor within the SAS Drug Development system. The Investigator will also receive a copy of the 
trial site’s final and locked data as write-protected Portable Document Format (PDF) files produced by 
the third party. The Investigator will approve/authorise the e-CRF entries for each patient with an 
electronic signature which equals a handwritten signature. 


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Trial data has to be entered into the system within a maximum of three working days after the patient 
has attended the visit. Errors occurring in the e-CRF will be corrected electronically. 
Such corrections/modifications will be automatically tracked by an audit trail detailing the date and 
time of the correction and the name of the person making the correction.Study data from Visit 3 must 
be entered prior to Visit 4.
10.3
Data Management 
A data management plan will be created under the responsibility of Ferring’s Biometrics Department. 
The data management plan will be issued before data collection begins and will describe all functions, 
processes, and specifications for data collection, cleaning, and validation.
The data management plan will describe captured methods, who is authorized to enter the data, 
decisions about ownership of data, source data storage, which data will be transferred (including timing 
of transfers), the origin and destination of the data, and who will have access to the data at all times.
10.4
Provision of Additional Information
On request, the investigator will provide the sponsor with additional data relating to the study, or 
copies of relevant source records, duly anonymized. This is important when errors in data transcription 
are encountered. In case of particular issues or governmental queries, it may be necessary to have 
access to the complete study documents, provided that the subjects' confidentiality is maintained and 
protected in accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
Periodic Monitoring
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference on Harmonization (ICH)-GCP, standard operating procedures, applicable 
regulatory requirements, maintenance of study-related source records, and completeness, accuracy and 
verifiability of all CRF entries compared to source data. The investigator will cooperate with the 
monitor to ensure that any discrepancies that may be identified are resolved. When the first few 
subjects are enrolled at the center, a monitoring visit will take place shortly afterwards.
11.2
Audit and Inspection
The investigator will make all the study-related source data and records, both paper and electronic, 
available to a quality assurance auditor mandated by the sponsor, or to domestic or foreign regulatory 
inspectors, after reasonable notice. The main purposes of an audit or inspection are to confirm that the 
rights and well-being of the subjects have been adequately protected, compliance with the protocol and 
standard operating procedures has been adhered to, and that all data relevant for the evaluation of the 
investigational product have been processed and reported in compliance with ICH-GCP and applicable 
regulatory requirements.
The subject/parent or guardian must be informed by the investigator and in the Informed Consent 
Documents that authorized Ferring representatives and representatives from regulatory authorities and 
IRBs may wish to inspect their medical records. During audits/inspections the auditors/inspectors may 
copy relevant parts of the medical records. No personal identification apart from the 
screening/randomization number will appear on these copies.
The investigator should notify Ferring without any delay of any inspection by a regulatory authority or 
IRB.
11.3
Confidentiality of Subject Data
The investigator will ensure that the confidentiality of the subjects' data will be preserved. In the CRF 
or any other documents submitted to the sponsor, the subjects will not be identified by their names, but 
by an identification system consisting of their initials and assigned number in the study. Documents not 
intended for submission to the sponsor, e.g., the confidential subject identification code and the signed 
informed consent forms, will be maintained by the investigator in strict confidence.


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12
CHANGES IN THE CONDUCT OF THE TRIAL
12.1
Protocol Amendments
Any change to this protocol will be documented in a protocol amendment, issued by the sponsor, and 
agreed upon by the investigator and the sponsor prior to its implementation. 
Significant amendments will be submitted for consideration to the approving IRB(s) and regulatory 
authorities, in accordance with local regulations. 
An approval is required for a significant amendment, e.g. one which could affect the safety of the 
subjects, or which entails a significant change of the scope/design of the study.
12.2
Deviations from the Protocol
Deviations from the protocol are discouraged. If deviations do occur, the investigator must inform the 
monitor, and the implications of the deviation must be reviewed and discussed. Any deviation must be 
documented on the protocol violation page in the source document and CRF with the visit number and 
type of violation. Any significant violations as determined by the sponsor and/or IRB must be reported 
to the IRB. Any paper documentation must be kept in the Investigator’s File and in the Trial Master 
File.
12.3
Premature Trial Termination
Both the investigator (with regard to his participation) and the sponsor reserve the right to terminate the 
study at any time. Should this become necessary, the procedures will be agreed upon after consultation 
between the 2 parties. In terminating the study, the sponsor and the investigator will ensure that 
adequate consideration is given to the protection of the best interests of the subjects. Regulatory 
authorities and IRB(s) will be informed.
In addition, Ferring reserves the right to terminate the participation of individual trial sites. Conditions 
that may warrant termination include, but are not limited to, insufficient adherence to protocol 
requirements and failure to enter subjects at an acceptable rate.


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13
REPORTING AND PUBLICATION
13.1
Clinical Trial Report
The data and information collected during this study will be reported in a study report prepared by the 
sponsor. The final report may be used for the further development of the investigational product as 
considered necessary by the sponsor.
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from the 
trial will be the exclusive property of Ferring. The investigator and any other persons involved in the 
trial will protect the confidentiality of this proprietary information belonging to Ferring.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
At the end of the trial, one or more manuscripts for joint publication may be prepared in collaboration 
between the investigator(s) offered authorship and Ferring. In a multi-site trial based on the 
collaboration of many sites, any publication of results must acknowledge all sites. Results from 
multi-site trials must be reported in entirety in a responsible and coherent manner and results from 
subsets should not be published in advance or without clear reference to the primary publication of the 
entire trial.
Authorship is granted based on the International Committee of Medical Journal Editors (ICMJE)
criteria (see current official version: http/www.ICMJE.org). The total number of authors is based on the 
guideline from the relevant journal or congress. In the event of any disagreement in the content of a 
publication, both the investigator’s and Ferring’s opinion will be fairly and sufficiently represented in 
the publication.
Any external contract research organization or laboratory involved in the conduct of this trial has no 
publication rights regarding this trial.
If the investigator wishes to independently publish/present any results from the trial, the draft 
manuscript/presentation must be submitted in writing to Ferring for comment prior to submission. 
Comments will be given within 4 weeks from receipt of the draft manuscript. This statement does not 
give Ferring any editorial rights over the content of a publication, other than to restrict the disclosure of 
Ferring’s intellectual property. If the matter considered for publication is deemed patentable by Ferring, 
scientific publication will not be allowed until after a filed patent application is published. Under such 
conditions, the publication will be modified or delayed at the investigator’s discretion, to allow 
sufficient time for Ferring to seek patent protection of the invention.


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13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is the 
responsibility of Ferring to register the trial in an appropriate registry, i.e., www.ClinicalTrials.gov, 
which is sponsored by the National Institutes of Health.


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14
ETHICAL AND REGULATORY ASPECTS
14.1
Independent Ethics Committee or Institutional Review Board (IRB)
An IRB will review the study protocol and any amendments and advertisements used for recruitment. 
The IRB will review the subject information sheet and the informed consent form, their updates (if 
any), and any written materials given to the subjects. A list of all IRBs consulted and the name of the 
committee chair/s will be included in the study report.
14.2
Regulatory Authority(ies) Authorization / Approval / Notification
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility.
14.3
End-of-Trial and End-of-Trial Notification
At the end of the study, the IRB will be notified in writing.  
14.4
Ethical Conduct of the Trial
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki (World Medical Association Declaration of Helsinki, 55th WMA General 
Assembly, Tokyo 2004), in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements.
14.5
Subject Information and Consent
The investigator (or the person delegated by the investigator) will obtain a freely given written consent 
from each subject/parent or guardian after an appropriate explanation of the aims, methods, anticipated 
benefits, potential hazards, and any other aspects of the trial which are relevant to the subject’s/parent’s 
or guardian’s decision to participate. The trial subject/parent or guardian must be given ample time to 
consider participation in the trial, before the consent is obtained. The Informed Consent Documents
and Assent (as per state regulations) must be signed and dated by the subject/parent or guardian and the 
investigator who has provided information to the subject/parent or guardian regarding the trial before 
any information regarding the subject is obtained.
The investigator (or the person delegated by the investigator) will explain that the subject/parent or 
guardian is completely free to refuse to have his or her information included in the trial or to withdraw 
consent at any time, without any consequences for his/her further care and without the need to justify 
his/her decision.
The subject/parent or guardian will receive a copy of the Subject Information and his/her signed 
Informed Consent and Assent form.


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If new information becomes available that may be relevant to the trial subject’s/parent’s or guardian’s
willingness to have his or her data be included in the trial, a new Subject Information and Informed 
Consent Form (Assent) will be forwarded to the IRB(s) (and regulatory authorities, if required). The 
trial subjects/parent or guardian will be informed about this new information and re-consent will be 
obtained.
Each subject/parent or guardian who provided informed consent for this retrospective study will be 
informed that the monitor(s), quality assurance auditor(s) mandated by Ferring, IRB representatives or 
regulatory authority inspector(s), in accordance with applicable regulatory requirements, may review 
his/her source records and data. Data protection will be handled in compliance with national/local 
regulations.
For subjects not qualified to give their legal consent, the written informed consent must be obtained 
from the guardian in accordance with national/local regulations. If such subjects can understand the 
risks and benefits of the trial, they should also be informed and provide their written assent.
14.6
Compliance Reference Documents
The Helsinki Declaration and the consolidated ICH-GCP shall constitute as the main reference 
guidelines for ethical and regulatory conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitor and the investigator will be as defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The investigator is responsible for adhering to the ICH-GCP responsibilities of investigators, for 
dispensing the IMP in accordance with the approved protocol or an approved amendment, and for its 
secure storage and safe handling throughout the trial.
15.2
Liabilities and Insurance
In case of any damage or injury occurring to a subject in association with the IMP or the participation 
in the trial, Ferring has contracted an insurance which covers the liability of Ferring, the investigator 
and other persons involved in the trial in compliance with the laws in the countries involved.


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16
ARCHIVING
16.1
Investigator File
The investigator is responsible for maintaining all the records, which enable the conduct of the trial at 
the site to be fully understood, in compliance with ICH-GCP. The trial documentation including all the 
relevant correspondence should be kept by the investigator for at least 15 years after the completion or 
discontinuation of the trial, if no further instructions are given by Ferring.
The investigator is responsible for the completion and maintenance of the confidential subject 
identification code which provides the sole link between named subject source records and anonymous 
CRF data for Ferring. The investigator must arrange for the retention of this Subject Identification Log 
and signed Informed Consent Documents for at least 15 years after the completion or discontinuation 
of the trial.
No trial site document may be destroyed without prior written agreement between the investigator and 
Ferring. Should the investigator elect to assign the trial documents to another party, or move them to 
another location, Ferring must be notified. Documents may be transferred to Ferring Global Quality 
Assurance, for example if the investigator retires and the documents no longer can be archived by the 
site.
16.2
Trial Master File
Ferring will archive the trial master file in accordance with ICH-GCP and applicable regulatory 
requirements.


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17
REFERENCES
1. Wexner SD, Beck DE, Baron TH, Fanelli RD, Hyman N, Shen B, et al. A consensus document 
on bowel preparation before colonoscopy: prepared by a task force from the American Society of 
Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy 
(ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Surg 
Endosc. 2006;20:1147-60.
2. Lebwohl B, Kastrinos F, Glick M, Rosenbaum AJ, Wang T, Neugut AI. The impact of 
suboptimal bowel preparation on adenoma miss rates and the factors associated with early repeat 
colonoscopy. Gastrointest Endosc. 2011;73(6):1207-14.
3. Harvey RF, Read AE. Saline purgatives act by releasing cholecystokinin. Lancet. 1973;2:185-7.
4. Jauch R, Hankwitz R, Beschke K, Pelzer H. Bis-(p-hydroxyphenyl)-pyridyl-2-
methane: the 
common laxative principle of bisacodyl and sodium picosulfate. Arzneimittelforschung. 
1975;25:1796-1800.
5. Martindale. The Complete Drug Reference. 33rd Edition. SC Sweetman (editor). London & 
Chicago: Pharmaceutical Press; 2002.
6. [Dollery C, editor. Therapeutic Drugs. Second edition. Edinburgh: Churchill Livingstone; 1999.
7. Turner D, Benchimol EI, Dunn H, Griffiths AM, Frost K, Scaini V, et al. Pico-Salax versus 
polyethylene glycol for bowel cleanout before colonoscopy in children: a randomized controlled 
trial. Endoscopy. 2009;41(12):1038-45.  
8. De Lacey G, Benson M, Wilkins R, Spencer J, Cramer B. Routine colonic lavage is unnecessary 
for double-contrast barium enema in outpatients. BMJ (Clin Res Ed). 1982;284(6321):1021-2. 
9. Fork FT, Ekberg O, Nilsson G, Rerup C, Skinhøj A. Colon cleansing regimens. A clinical study 
in 1200 patients. Gastrointest Radiol. 1982;7(4):383-9. 
10. Atkin WS, Hart A, Edwards R, Cook CF, Wardle J, McIntyre P, et al. Single blind, randomised 
trial of efficacy and acceptability of oral Picolax versus self administered phosphate enema in 
bowel preparation for flexible sigmoidoscopy screening. BMJ. 2000;320(7248):1504-8; 
discussion 1509. 
11. Bartram CI, Mootoosamy IM, Lim IK. Washout versus non-washout (Picolax) preparation for 
double-contrast barium enemas. Clin Radiol. 1984;35(2):143-6. 
12. Evans M, Walker-Smith J, Williams C. Safety of Picolax in inflammatory bowel disease. BMJ. 
1989;299(6707):1101-2. 


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13. Heymann TD, Chopra K, Nunn E, Coulter L, Westaby D, Murray-Lyon IM. Bowel preparation at 
home: prospective study of adverse effects in elderly people. BMJ. 1996;313(7059):727-8. 
14. Kawakami E, Portorreal A, Scuissiatto ML, Machado RS, Raguza D, Lozano L. Bowel 
preparation for colonoscopy with sodium picosulfate and magnesium citrate in children and 
adolescents. Arq Gastroenterol. 2004;41(1):33-6.
15. Lee JR, Ferrando JR. Variables in the preparation of the large intestine for double contrast barium 
enema examination. Gut. 1984;25(1):69-72. 
16. McDonagh AJ, Singh P, Pilbrow WJ, Youngs GR. Safety of Picolax (sodium picosulfate-
magnesium citrate) in inflammatory bowel disease. BMJ. 1989;299(6702):776-7. 
17. Roe AM, Jamison MH, MacLennan I. Colonoscopy preparation with Picolax. J R Coll Surg 
Edinb. 1984;29(2):103-4. 
18. Takada H, Ambrose NS, Galbraith K, Alexander-Williams J, Keighley MR. Quantitative 
appraisal of Picolax (sodium picosulfate/magnesium citrate) in the preparation of the large bowel 
for elective surgery. Dis Colon Rectum. 1990;33(8):679-83. 
19. Thomson J, Phull P. Audit of bowel preparation with Picolax (sodium picosulfate plus 
magnesium citrate) for colonoscopy. Int J Clin Pract. 2006;60(5):602-3. 
20. Barker P, Trotter T, Hanning C. A study of the effect of Picolax on body weight, cardiovascular 
variables and haemoglobin concentration. Ann R Coll Surg Engl. 1992;74(5):318-9. 
21. Burden RJ, Way CF, Spargo PM. Picolax; an unusual cause of metabolic acidosis. Paediatr 
Anaesth. 1998;8(4):365. 
22. Hanning CD. Bowel preparation at home in elderly people. Give a simultaneous infusion of 
saline in frail patients. BMJ. 1997;314(7073):74. 
23. Lewis M, Rugg-Gunn F, Don C, Woods W. Bowel preparation at home in elderly people. 
Patients should be warned not to drink too much or too little fluid. BMJ. 1997;314(7073):74. 
24. Barkun A, Chiba N, Enns R, Marcon M, Natsheh S, Pham C, et al. Commonly used preparations 
for colonoscopy: efficacy, tolerability, and safety—a Canadian Association of Gastroenterology 
position paper. Can J Gastroenterol. 2006;20(11):699-710. 
25. Belsey J, Epstein O, Heresbach D. Systematic review: oral bowel preparation for colonoscopy. 
Aliment Pharmacol Ther. 2007;25(4):373-84. 
26. Hookey LC, Vanner S. A review of current issues underlying colon cleansing before 
colonoscopy. Can J Gastroenterol. 2007;21(2):105-11. 


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27. Tan JJ, Tjandra JJ. Which is the optimal bowel preparation for colonoscopy—a meta-analysis. 
Colorectal Dis. 2006;8(4):247-58.
28. Aronchick CA, Lipshutz WH, Wright SH, et al. Validation of an instrument to assess colon 
cleansing [abstract]. Am J Gastroenterol. 1999;94:2667.


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APPENDICES


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APPENDIX 1: Subject’s Confidential Non-Disclosure Affidavit
CONFIDENTIAL NON-DISCLOSURE AFFIDAVIT
I, ____________________________________, agree to keep confidential my study medication 
assignment provided to me by: _______________________, Study Coordinator.
On this date: _________________________, I agree not to discuss or to disclose the type of study
medication, pharmacokinetic blood draws (if applicable) or the timing of the dosage assigned to me 
with the study doctor performing my colonoscopy and anyone other than the above Study Coordinator 
in order to protect the integrity of the data being collected for this clinical research study. I understand 
that the study doctor performing my colonoscopy will not know my study medication assignment and 
will not be allowed to ask me questions about my study medication assignment. If I have questions 
concerning my study medication assignment, I agree to use the following contact information.  
Study Contact: _________________________________________
Study Contact Number:  __________________________________
SIGNATURES
I have read this affidavit and understand the above information. The content and meaning of this 
information has been explained to me.  
_________
_____________________
___________________________
Date/Time
Print Subject Name      
   
Subject Signature
  
________
_____________________
___________________________
Date/Time
Name of Person conducting      
Signature of Person conducting   
Discussion
      
Discussion
Copy of signed/dated confidential non-disclosure affidavit given to subject on (date) __________ by 
___________ (initials)


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APPENDIX 2: Dietary Guidelines for Diabetics
Additional Guidelines
For Diabetes Management
Even though you will be on a diet of clear fluids for the whole day before your colonoscopy 
examination, it is still possible for you to get sufficient carbohydrates in this diet. Besides drinking lots 
of fluids you must remember that these fluids need to contain sufficient amounts of carbohydrate. If 
you don’t drink enough fluids your blood sugars may go low, or surprisingly, they may begin to go 
higher.
Guidelines
!
Follow the directions of the doctor for taking your insulin or pills.
!
Your blood sugars should be monitored regularly. Please discuss this with your doctor, nurse or 
dietitian.
!
You must meet your needs for more fluids. Drink a lot of water, clear soup, clear broth, sugar-
free drinks, sugar-free popsicles, and sugar-free jello. Do not drink anything red. Your goal is to 
drink at least one tall glass of fluid every hour, and have plenty of fluids as your meals for the 
day. There is no restriction to these.
!
In addition to fluids, you must also meet your needs for carbohydrate every hour. See the list 
below for the drink ideas and portion sizes for your hourly need during the day.
To get enough carbohydrate during the day, take one choice from this list every waking hour:
!
one quarter cup white grape juice
!
one half cup regular soda pop
!
one third cup regular Kool-Aid
!
one quarter cup sherbet
!
one third cup apple juice
!
one quarter cup regular jello
!
one half popsicle
!
two hard candies
Call the doctor……
!
If you have persistent nausea or vomiting
!
If you have questions or worries.
  


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APPENDIX 3: Subject’s Tolerability and Satisfaction Questionnaire

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
A Randomized, Assessor-Blind, Multicenter, Dose-Ranging Study Comparing the Safety and 
Efficacy of Prepopik™ versus Polyethylene Glycol Preparation (Local Standard of Care) in 
Children Aged 9 Years to 16 Years
000103
Investigational Product:
PREPOPIK (sodium picosulfate, magnesium oxide, and 
anhydrous citric acid)
Indication:
Bowel preparation for pediatric colonoscopy
Phase:
Phase I/II-Post Approval Pediatric Study
Author:
Date of issue:
16 February 2017
Version:
Final 2.0
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group


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Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes
2.0
16Feb2017
In addition to the pre-specified 95% 
confidence intervals (CIs), 90% CIs will 
also be produced.
1.0
Summaries for pre-specified orthostatic 
changes in vital signs are added.
Additional clarity on what is considered a 
major protocol deviation is added.
Summary table and listing for the 
pharmacokinetic concentration data is 
added.


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Signed Agreement on Statistical Analysis Plan
Author:  
_______________________________ 
________________
              
Date (dd/mm/yyyy)
             
             
Review:
_______________________________ 
________________
Date (dd/mm/yyyy)
 Gastroenterology
Ferring International Pharmascience Center, Copenhagen
_______________________________
________________
Date (dd/mm/yyyy)
 US Pharmacovigilance
Ferring International Pharmascience Center U.S
_______________________________
________________
Date (dd/mm/yyyy)
Ferring International Pharmascience Center U.S
_______________________________
________________
Date (dd/mm/yyyy)
 Clinical Operations
Ferring International Pharmascience Center U.S
Approval:
________________________________
________________
Date (dd/mm/yyyy)
 Biometrics
Ferring International Pharmascience Center U.S


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 4
1
Introduction.......................................................................................................................................... 6
1.1
Definitions/ Abbreviations........................................................................................................ 6
1.1.1
Definition of Terms .................................................................................................. 6
1.1.2
Abbreviations............................................................................................................ 7
2
Trial Objectives and Endpoints.......................................................................................................... 8
2.1
Objectives ................................................................................................................................. 8
2.1.1
Primary Objective..................................................................................................... 8
2.1.2
Secondary Objectives ............................................................................................... 8
2.2
Endpoints .................................................................................................................................. 8
2.2.1
Primary Endpoint...................................................................................................... 8
2.2.2
Secondary Endpoints................................................................................................ 8
3
Trial Design .......................................................................................................................................... 9
3.1
General Design Considerations................................................................................................. 9
3.1.1
Dosage Selection ...................................................................................................... 9
3.1.2
Blinding.................................................................................................................... 9
3.2
Determination of Sample Size ................................................................................................ 10
4
Subject Disposition ............................................................................................................................ 11
5
Protocol Deviations............................................................................................................................ 12
6
Analysis Sets....................................................................................................................................... 13
6.1
Intention-To-Treat Analysis Set.............................................................................................. 13
6.2
Per Protocol Analysis Set........................................................................................................ 13
6.3
Safety Analysis Set ................................................................................................................. 13
6.4
Pharmacokinetics Analysis Set ............................................................................................... 13
7
Trial Population................................................................................................................................. 14
7.1
Demographics and Other Baseline Characteristics................................................................. 14
7.1.1
Demographics......................................................................................................... 14
7.1.2
Vital Signs at Baseline............................................................................................ 14
7.1.3
Laboratory Parameters at Baseline......................................................................... 14
7.2
Medical History....................................................................................................................... 14
7.3
Prior and Concomitant Medications and Other Safety Evaluations........................................ 14
7.4
Physical Examination.............................................................................................................. 15
8
Exposure and Treatment Compliance ............................................................................................. 16
8.1.1
Extent of Exposure ................................................................................................. 16
8.1.2
Treatment Compliance ........................................................................................... 16
9
Efficacy ............................................................................................................................................... 17
9.1
General Considerations........................................................................................................... 17
9.2
Primary Endpoint(s)................................................................................................................ 17
9.3
Secondary Endpoint(s)............................................................................................................ 17
9.4
Pharmacokinetic Endpoints..................................................................................................... 18
10
Safety................................................................................................................................................... 19


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10.1
General Considerations........................................................................................................... 19
10.2
Adverse Events ....................................................................................................................... 19
10.2.1
Overview of Treatment-Emergent Adverse Events................................................ 19
10.2.2
Incidence of Adverse Events .................................................................................. 19
10.2.3
Data Listings........................................................................................................... 20
10.3
Safety Laboratory Variables ................................................................................................... 20
10.3.1
Summary Statistics ................................................................................................. 20
10.3.2
Laboratory Variable Changes Relative to Normal Range ...................................... 20
10.3.3
Markedly Abnormal Changes................................................................................. 20
10.3.4
Data Listings........................................................................................................... 21
10.4
Vital Signs............................................................................................................................... 21
10.4.1
Summary Statistics ................................................................................................. 21
10.4.2
Markedly Abnormal Changes................................................................................. 21
10.4.3
Data Listings........................................................................................................... 21
10.5
Physical Examination.............................................................................................................. 22
11
Interim Analyses ................................................................................................................................ 23
12
Deviations from Protocol Analysis ................................................................................................... 24
13
References........................................................................................................................................... 25
14
Tables, Listings and Figures ............................................................................................................. 26
Appendix 1
Markedly Abnormal Laboratory Safety Values and Vital Signs ..................................... 27


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1
Introduction
This document describes the planned statistical analyses for Trial 00103 based on protocol version 
3, dated 8 July 2013, protocol version 4, dated 21 Aug 2013 and protocol version 5, dated 28 July 
2014.
1.1
Definitions/ Abbreviations
1.1.1
Definition of Terms
Terms
Definitions
Analysis set
Data included in a specific analysis
Aronchick Scale
see Protocol section 7.1
Baseline
The last observed value collected prior to the start of treatment
Change from baseline
Difference between a data value at an analysis time point minus 
the corresponding baseline value
Concomitant 
medications
Medication taken during the study
Percent change from 
baseline
Numerical percent difference between baseline value and post-
baseline value at a given study visit
Preparation
In this study, this term and the term “treatment,” which is 
generally used in clinical trials, may be used interchangeably
Prior medications
Medications taken before entering the study
Randomization
The unpredictable allocation of a subject to a particular treatment 
(or preparation) in a clinical trial
Randomized
Subject randomized to trial treatment
Responder
A responder will be defined for the Aronchick Scale as subject 
rated as excellent or good during the colonoscopy
Screened
Subject who enters Screening
Screening
Questions and assessments performed to determine if a person 
qualifies to enter a clinical trial
TEAE
Any adverse event that occurs during or after the start of 
treatment or begins prior to preparation and increases in intensity 
during and/or after the start of preparation


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1.1.2
Abbreviations
Abbreviations
Meaning of abbreviations in document
AE
adverse event
ATC
Anatomic-Therapeutic-Chemical
CI
confidence interval
CRF
case report form
IMP
investigational medicinal product
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PEG
polyethylene glycol
PK
pharmacokinetic
PP
per-protocol
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SD
standard deviation
TEAE
treatment-emergent adverse event
US
United States
V
visit
WHO
World Health Organization


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2
Trial Objectives and Endpoints
2.1
Objectives
2.1.1
Primary Objective

To describe the efficacy of the Prepopik in children aged 9 years to 16 years for overall 
colon cleansing in preparation for colonoscopy based on the Aronchick scale by 
including oral polyethylene glycol (PEG) based preparation/local standard of care as a 
reference group
2.1.2
Secondary Objectives

To describe the safety of Prepopik in children aged 9 years to 16 years through the 
collection of adverse events (AEs), clinical laboratory tests, and physical examination

To describe the completion of prep as directed to colon cleansing by Prepopik in 
preparation from colonoscopy in children aged 9 years to 16 years

To describe the tolerability and satisfaction of colon cleansing by Prepopik in 
preparation for colonoscopy in children aged 9 years to 16 years as assessed by a 
standardized subject questionnaire administered at the study site before colonoscopy

To evaluate pharmacokinetic (PK) characteristics of Prepopik in children aged 9 years to 
16 years
2.2
Endpoints
2.2.1
Primary Endpoint

Proportion of subjects classified as success defined by “excellent” or “good” in the 
Aronchick scale
2.2.2
Secondary Endpoints

Incidence of adverse events and abnormal findings in clinical laboratory test and 
physical examination

Proportion of subjects who took the assigned dose for the IMP [investigational medicinal 
product]

Frequency of each category of the Tolerability and Satisfaction Questionnaire 

PK exposure will be assessed utilizing a sparse sampling of subjects (Sparse sampling 
means no need for special PK time)


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3
Trial Design
This study is a randomized, assessor-blind, multicenter, dose-ranging study. Subjects undergoing an 
elective complete colonoscopy will randomly receive one of the following products:

Prepopik: 2 divided doses given the night before (first dose) and approximately 5 hours 
prior (second dose) to procedure. A dose is defined for one subset of subjects aged 9 
years to 12 years as ½ sachet, for another subset of subjects aged 9 years to 12 years per 
randomization as 1 sachet and for subjects aged 13 to 16 years as 1 sachet.

Oral PEG based preparation/local standard of care per appropriate label and/or 
institutional instructions.
See Section 3.1.1 of the protocol for the trial design diagram.
3.1
General Design Considerations
This is an age-stratified, parallel-group design with three treatment arms in the younger ages and 
two treatment arms in the older ages as shown in Table 1.
Table 1
Overview of Study Treatment Groups by Age
Age Group
Treatment Group
9-12 years
13-16 years
Total
Prepopik: ½ sachet
15
0
15
Prepopik: 1 sachet
15
15
30
Standard of care
15
15
30
Total subjects
45
30
75
3.1.1
Dosage Selection
Selection of doses for this study are based on current dosages in Canada and the European Union.  
In Canada, current pediatric dosage is ½ sachet (x2) for ages 9-12 years and 1 sachet (x2) for ages 
13-18 years.  This dosage has been studied in a well-controlled trial from the Toronto Hospital for 
Sick Children.  It aimed to compare bowel preparation for colonoscopy in children with PicoSalax 
or PEG with electrolyte solution. Thirty five of PicoSalax patients (81%) were satisfied or very 
satisfied with the clean out compared with 19 (48%) in the PEG group (p=.001).7  The current 
dosages used in pediatrics in the European Union for ages 9-18 years is 1 sachet (x2). Therefore, in 
our study, the younger group (ages 9-12 years) will compare adult dose (1 sachet x2 as in the 
European Union) and ½ the adult dose (1/2 sachet x2, Canadian dose) while the older group (ages 
13-16 years) will use the adult dose.
3.1.2
Blinding
Blinding treatment to the endoscopist and his/her assistant(s) assessing the efficacy of the tested 
preparations removes possible bias. A placebo-controlled design would not be practical or ethical in 
this study as subjects would be required to have a second colonoscopy.


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The integrity of blinding will be further preserved by requiring each subject or parent/guardian and 
the unblinded coordinator to sign a nondisclosure affidavit form instructing 
subjects/parents/guardians and the unblinded coordinator not to disclose the treatment groups.
3.2
Determination of Sample Size
Approximately 6-8 sites in the US are planned. A sufficient number of subjects will be screened to 
ensure up to approximately 75 (~15 subjects per treatment arm).
A total of at least 45 subjects will be exposed to Prepopik. In the two Phase 3 studies for adults, 
83% and 84.2% of subjects were classified as success after bowel preparation with Prepopik. With 
45 subjects, if 80% of subjects are classified as success in this study, the exact 95% confidence 
interval of the success rate will be calculated as 65% - 90%.


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4
Subject Disposition
All subjects screened will be accounted for. The number of subjects screened but not 
randomized/allocated to treatment will be presented with the reason(s) for screen failure in a data 
listing.
The number and percentage of subjects randomized, beginning treatment, having a colonoscopy, 
completing, and withdrawing from the study will be tabulated for each treatment group, overall and 
by age group.  The denominator for the percentages is the total number of subjects in the given 
treatment group, or the combined sample as appropriate. Reasons for early withdrawal will be 
tabulated by treatment group. Individual subject listings of study completion information will be 
produced, including the reason for early withdrawal.
The number of subjects included and excluded from safety and efficacy populations will be 
summarized for each treatment group. In addition, the reason(s) for exclusion from each population 
will be summarized. Individual subject listings of reasons for exclusion from the analysis 
populations will be produced. In addition, a separate subject listing of any eligibility violations will 
be produced.
The number and percentage of subjects randomized, treated, completing/withdrawing from the 
study and included/excluded from safety and efficacy populations will also be tabulated by study 
site.


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5
Protocol Deviations
Major and minor protocol deviations will be defined and documented prior to database lock. Major 
protocol deviations which exclude the subject from the PP analysis set will include the following:

Key violations of the protocol inclusion or exclusion criteria

Significant violation of the dosing regimen as recorded on the eCRF including the 
amount of study preparation, and timing of receiving study medication

Receiving study medication other than randomized assignment

Taking exclusionary medications during the study and/or prior to the procedure, as 
described in the protocol. Exclusionary medications include:
o
Lithium
o
Laxatives (suspended for 24 hours prior to procedure)
o
Constipating drugs (suspended for 2 days prior to procedure)
o
Antidiarrheals (suspended for 72 hours prior to procedure)
o
Oral iron preparations (suspended for 1 week prior to procedure)


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6
Analysis Sets
6.1
Intention-To-Treat Analysis Set
The ITT analysis set will include all subjects who are randomized independent of whether or not 
the subject receives study treatment dose. Subjects who do not have an efficacy assessment for the 
data (Aronchick Scale) will be scored as a non-responder. Analyses for the ITT will be conducted 
according to the randomized treatment.
6.2
Per Protocol Analysis Set
Subjects with major protocol deviations that potentially impact efficacy will be excluded from the 
PP (per-protocol) analysis set.  Subjects not taking the study medication in the prescribed time 
intervals will be excluded from the PP analysis set. These subjects will be identified prior to 
breaking the study blind. Analyses for the PP will be conducted according to the randomized 
treatment.
6.3
Safety Analysis Set 
All subjects consuming at least one dose of study medication will be included in the Safety 
Analysis Set. Analyses for the Safety Dataset will be conducted according to the treatment actually 
received.
6.4
Pharmacokinetics Analysis Set
The pharmacokinetic (PK) analysis set will include all subjects from whom PK samples are 
obtained.


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7
Trial Population
7.1
Demographics and Other Baseline Characteristics
Descriptive statistics of demographics, and other baseline characteristics will be presented for the 
ITT, PP and safety populations by treatment group, overall and by age group. For quantitative 
variables, all summaries will include the sample size, mean, median, standard deviation, minimum, 
and maximum. For the qualitative variables, the summaries will include the number and percentage 
of subjects for each outcome.
7.1.1
Demographics
The demographics variables to be summarized are: age in years, age group (9-12, 13-16), race, 
ethnicity, child-bearing potential, height and weight.
7.1.2
Vital Signs at Baseline
Baseline vital signs include systolic and diastolic blood pressure and pulse in the supine and 
standing positions. The change from supine to standing in systolic and diastolic blood pressures 
will also be presented as a measure of orthostatic change.
7.1.3
Laboratory Parameters at Baseline
The baseline laboratory parameter assessments include the blood chemistry, hematology, and 
coagulation test values.
7.2
Medical History
Medical history will be coded using MedDRA version 16.1 or later.  Summaries will be presented 
by preferred term within System Organ Class for each treatment group, overall and by age group.
7.3
Prior and Concomitant Medications and Other Safety Evaluations
Prior and concomitant medications will be coded using the latest version of the World Health 
Organization (WHO) Drug Reference List.  Summaries will be presented by preferred terms within 
Anatomic-Therapeutic-Chemical (ATC) class 1 and 2 for each treatment group, overall and by age 
group.
Separate summaries will be generated for prior medications and concomitant medications. Prior 
medications and concomitant medications are defined as follows:

Prior medications are medications taken exclusively before receipt of study treatment.  
That is, the stop date of the medication is before the date of first study treatment 
administration.

Concomitant medications are medications taken during the treatment period.  That is, the 
medication was not stopped before the date of first study treatment administration AND 
was not started after the last visit date (i.e., visit 6).


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If the timing of the dose of a medication cannot be established in relation to the start of study 
treatment administration, it will be considered as concomitant medication.
7.4
Physical Examination
Physical examination findings (normal, abnormal; clinically significant or not) will be summarized 
by treatment group, overall and by age group.


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8
Exposure and Treatment Compliance
The date and time of each dose of study treatment, the number of glasses of liquid, the number of 
glasses of water and whether the doses were administered within the correct time frame will be 
listed.
8.1.1
Extent of Exposure
The number and percentage of subjects receiving each dose of study treatment will be summarized 
by treatment group, overall and by age group for the Safety analysis set.
8.1.2
Treatment Compliance
The number and percentage of subjects taking each dose within the specified time frame, as well as 
the required number of glasses of liquid will be summarized by treatment group, overall and by age 
group.  The number of glasses of liquid and number of glasses of water will be summarized by the 
number of non-missing values, mean, median, minimum, maximum, and standard deviation by 
treatment group, overall and by age group.


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9
Efficacy
9.1
General Considerations
For quantitative variables, all summaries will include the sample size, mean, median, standard 
deviation, minimum, and maximum. For the qualitative variables, the summaries will include the 
number and percentage of subjects for each outcome.
Nominal p-values and confidence intervals will be presented to aid in interpretation of the summary 
of data.
SAS® (version 9.2) will be used for generation of analyses.
9.2
Primary Endpoint(s)
The number and percentage of subjects with each category of the Aronchick scale will be displayed 
by treatment group, overall and by age group.  In addition, the number and percentage of subjects 
classified as a responder (Excellent or Good rating) will be included in the summary.  Specifically, 
for the overall summaries, the Prepopik 1 sachet and the standard of care groups for the two age 
groups will be combined; and, all Prepopik groups will be combined.
The treatment group difference will be assessed by constructing the 90% and 95% confidence 
intervals (CIs) of the difference in proportions between each Prepopik group and standard of care 
within each age group.  Additionally, the 90% and 95% CIs of the difference in proportions 
between the following combined groups will be constructed:

Prepopik 1 sachet versus combined standard of care

All Prepopik groups combined versus combined standard of care
The 90% and 95% confidence intervals will be multiplied by 100 so as to present the resulting 
interval as percentages.
The analyses will be performed for the ITT and PP populations.  The ITT population is the primary 
population and the PP population is supportive.
9.3
Secondary Endpoint(s)
The following secondary endpoints will be summarized in the same manner as the primary 
endpoint: 

proportion of subjects who completed colon cleansing

proportion of subjects who completed the colonoscopy procedure

proportion of subjects with responses to the individual questions on the Tolerability and 
Satisfaction Questionnaire


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Additionally, based on the individual questions subjects responses will be categorized as tolerable 
and as satisfactory according to the following algorithms:

Tolerable is defined as a response of 1 (Never) or 2 (Rarely) to the five items specified in 
question 3.

Satisfactory is defined as a response of 1(Very Easy) or 2 (Easy) on question 1 and a 
response of 1 (Very Well) or 2 (Well) on question 2.
9.4
Pharmacokinetic Endpoints
For subjects that participated in the pharmacokinetic sub-study, the picosulfate and magnesium 
plasma concentrations will be summarized for the Prepopik treatment groups, overall and by age 
group. The summary will include the mean, median, standard deviation, minimum, maximum, 
coefficient of variation, geometric mean and geometric mean coefficient of variation. A listing of 
the concentration data will also be produced.
Analysis of the population pharmacokinetic endpoints is described in a separate document.


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10
Safety
10.1
General Considerations
Safety parameters will be evaluated for the safety analysis data set. Subjects will be summarized by 
actual treatment received.
10.2
Adverse Events
All AEs will be coded using MedDRA version 16.1 or later. The relation between AEs and study 
medication will be characterized as having a reasonable possibility or not. The intensity of AEs will 
be characterized as mild, moderate, or severe. 
Treatment-emergent AEs are those adverse events which begin after the start of study treatment or 
which worsen after the start of study medication.  Any event with partial date information reported 
on or after the date of the first dose of study treatment will be considered treatment-emergent.  Only 
treatment-emergent AEs will be summarized.
Written narratives will be issued for all serious AEs (including deaths) and AEs leading to 
withdrawal.
10.2.1
Overview of Treatment-Emergent Adverse Events
An AE overview summary table will be prepared including the number of subjects reporting an AE, 
the percentage of subjects (%) with an AE, and the number of events (E) reported, for the following 
categories:

Treatment-emergent adverse events

Deaths 

Serious adverse events 

Adverse events leading to withdrawal 

Severe and life threatening adverse events 

Adverse drug reactions
10.2.2
Incidence of Adverse Events
The number and percentage of patients experiencing a specific TEAE, as well as the number of 
events reported, will be tabulated by SOC, preferred term, and treatment group, overall and by age 
group.  Additional summary tables will be provided for AEs by maximum intensity and by 
relationship to study treatment. Additional summaries for related AEs, serious AEs, AEs leading to 
withdrawal, and AEs leading to death will be generated. Non-serious AEs with an incidence of 5% 
or greater in any treatment group will also be summarized.


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10.2.3
Data Listings
Supportive data listings will be provided for:

All adverse events

Serious adverse events 

Adverse events leading to death

Adverse events leading to withdrawal
A mapping of adverse event verbatim terms to MedDRA preferred terms and system organ class 
will also be created.
10.3
Safety Laboratory Variables
Baseline for all laboratory analyses will be the values obtained at the last assessment prior to the 
first dose of study treatment. Treatment-emergent laboratory data will include tests completed after 
the first dose of study treatment through the residual time of drug effect. End of trial will include 
the last post-baseline observations during the trial.
10.3.1
Summary Statistics
At each nominal time point, the actual value and change from baseline (pre-treatment) will be 
summarized using the number of non-missing observations, mean, median, minimum, maximum 
and standard deviation for each treatment group, overall and by age group.
10.3.2
Laboratory Variable Changes Relative to Normal Range
Changes relative to normal ranges will be presented with shift tables showing the total number of 
subjects, and number and percentage of subjects who experienced a shift from baseline.  The 
following categories for shift tables are defined:

Low: 
Values which are below the lower reference range limit;

Normal: 
Values which are within the lower and upper reference range;

High: 
Values which are above the upper reference range limit.
For all haematology and clinical chemistry variables, shift tables will be prepared to compare 
baseline values to the worst post-treatment value.
10.3.3
Markedly Abnormal Changes
A summary table will be prepared that displays for each laboratory variable the number and 
percentage of subjects with normal baseline values who had at least one pre-specified markedly 
abnormal value anytime during the treatment period. The summary table will be presented by 
treatment group, overall and by age group. Pre-specified markedly abnormal criteria for laboratory 
tests are given in Appendix 1.


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10.3.4
Data Listings
All clinical laboratory values outside normal range will be listed separately by subject number, 
including demographic information and abnormal flag values.
10.4
Vital Signs
Baseline for all vital signs analyses will be the values obtained at the last assessment prior to the 
first dose of study treatment. Treatment-emergent vital signs data will include tests completed after 
the first dose of study treatment through the time of residual drug effect. End of trial will include 
the last post-baseline observation during the trial.
10.4.1
Summary Statistics
At each nominal time point, the actual value and change from baseline (pre-treatment) will be 
summarized using the number of non-missing observations, mean, median, minimum, maximum 
and standard deviation for each treatment group, overall and by age group.  In this study, blood 
pressure and pulse are first measured after at least 5 minutes resting in supine position and after 3 
minutes in standing position. Summaries will be provided for vital signs recorded in the supine and 
standing positions, as well as the change from supine to standing (orthostatic measurement).
10.4.2
Markedly Abnormal Changes
Summary tables will be prepared displaying the number and percentage of subjects with normal 
baseline values who had one or more pre-specified markedly abnormal treatment-emergent values. 
Summaries will be provided by treatment group, overall and by age group.  Pre-specified markedly 
abnormal criteria for vital signs are given in Appendix 1.
For orthostatic changes in blood pressure and pulse rate, the following criteria are suggestive of 
fluid volume depletion [1]:

a decrease in systolic blood pressure greater than or equal to 20 mmHG within 3 minutes 
of standing,

a decrease in diastolic blood pressure greater than or equal to 10 mmHG within 3 
minutes of standing, or

an increase in heart rate (pulse rate) greater than or equal to 30 beats per minute (bpm) in 
the presence of a drop in blood pressure (systolic, diastolic or both).
The number and percentage of subjects whose changes meet these pre-specified criteria will be 
summarized by treatment group, overall and by age group.
10.4.3
Data Listings
Data listings will be prepared for all subjects, including flags for any abnormal vital signs value or 
abnormal orthostatic measure at any time-point.


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10.5
Physical Examination
The number and percentage of subjects having an abnormal physical exam at Screening, or with a 
change from Screening, will be summarized by body system for each treatment group, overall and 
by age group. 
Physical examination findings at each evaluation will be listed for the safety dataset. Subjects with 
abnormal findings will be noted on the data listings.


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11
Interim Analyses
No interim analyses are planned for this study.


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12
Deviations from Protocol Analysis
The following are a list of changes and/or additions from the protocol specified analyses:

In addition to the pre-specified 95% CIs, 90% CIs will also be computed and displayed.

Additional summaries for pre-specified orthostatic changes in blood pressure will be 
provided.

Pharmacokinetic concentration summaries and listings will be provided.


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13
References
[1]
Clinical Practice Guideline: Orthostatic vital sings full version. Emergency Nurses 
Association. December 2011.


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14
Tables, Listings and Figures
The document with tables, listings, and figures (TLF) shells is presented in a separate document.


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Appendix 1
Markedly Abnormal Laboratory Safety Values and 
Vital Signs
HEMATOLOGY
Variable
Units
Age
Markedly Abnormal Criteria
Low (≤)
High (≥)
Hemoglobin
g/dL
6 mo-18 yr
8
18
RBC
x106/mm3
6 mo-18 yr
3.5
6
Hematocrit
%
6 mo-18 yr
30
50
Reticulocytes
%
6 mo to 12 yr
NA
1
> 12 yr:
NA
2
MCV
Fl
6 mo-18 yr
70
100
MCH
pg
6 mo-18 yr
20
35
MCHC
g/dL
6 mo-18 yr
30
NA
Leukocytes
x103/mm3
6 mo to 18 yr
4
20
Neutrophils
x103/mm3
6 mo-18 yr
1
10
Lymphocytes
x103/mm3
2-18 yr
1
10
Eosinophils
%*
All ages
NA
5
Monocytes
%*
6 mo-18 yr
NA
5
Basophils
%*
6 mo-18 yr
NA
1
Platelets
x103/mm3
6 mo-18 yr
50
750
*The percentage indicates the relative number of each type of leucocytes in the blood. The absolute 
count is calculated by multiply the relative value (%) by the total leukocyte count/100.


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CHEMISTRY
Variable
Units
Age
Markedly Abnormal Criteria
Low
High
ALT
U/L
1-19yr  
Not applicable
≥ 3x NL
AST
U/L
1-19yr 
Not applicable
≥ 3x NL
Total protein
g/L
> 1yr 
≤ 40
≥80
Albumin
g/L
All 
≤ 25
> 60
Alkaline 
phosphatase
U/L
All 
Not applicable
≥ 3x NL
Total bilirubin
μmol/L
> 5d 
Not applicable
≥ 34*
C-reactive 
protein
mg/L
All
Not applicable
≥ 10
Total 
cholesterol
mmol/L
All 
Not applicable
≥ 6
Tryglicerides
mmol/l
All
Not applicable
≥ 1.9
Creatinin
μmol/L
24m-11yr 
12-18yr 
Not applicable
≥100
≥120
Glucose
mmol/L
24m-11yr
12-18yr
≤ 2.5
≤2.8
> 8
> 10
GGT
U/L
All 
Not applicable
≥ 3x NL
Creatine kinase
U/L
> 3m
Not applicable
≥ 300
LDH
U/L
All
Not applicable
≥ 700
Urea nitrogen
Mmol/L
All
Not applicable
≥ 8.0
Uric acid
μmol/L
6-11yr 
12-19yr:
M
F  
Not applicable
≥ 500
M ≥ 600
F  ≥ 500
Potassium 
mmol/L
> 2m
≤3
≥6
Sodium
mmol/L
All
≤ 130
≥ 150
Calcium total
mmol/L
All
≤1.8
≥ 3
Chloride
mmol/L
All
≤90
≥115
Phosphorus, 
inorganic
mmol/L
4-11yr 
12-15yr 
16-19yr 
≤ 0.9
≤ 0.9
≤ 0.6
≤ 0.6
≥ 2.8
≥ 2.5
≥ 2.2


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HEMOSTASIS AND COAGULATION
Variable
Units
Age
Markedly Abnormal Criteria
Low
High
Coagulation factor 
VIII
% of normal 
ranges
U/dl
All
All
≤ 30
≤ 30
Not applicable
Coagulation factor 
IX
% of normal 
ranges
U/dl
All
All
≤ 30
≤ 30
Not applicable
Von Willebrand 
protein
VWF:RCo 
activity(%)
All
≤ 20
Not applicable
Fibrinogen
g/L
All
Not applicable
≥ 5
Prothrombin Time 
(PT)
seconds
All 
NA
≥ 20
Partial 
Thromboplastin 
Time (APTT)
seconds
6 mo-18 yr
≤20
≥ 50
* Applicable only for term healthy newborns


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ECG 
Variable
Baseline 
Normal Value
Markedly Abnormal Treatment-
Emergent Value
Duration of PR interval
3-8 yr:   90-160
9-16 yr: 90-180
3-8 yr 180 msec
9-16 yr 200 msec
Duration of QRS interval
3-8 yr: ≤ 100
9-16 yr: ≤110
3-8 yr 110 msec
9-16 yr 120
Duration of QTc interval
Not applicable*
450 msec 
Duration of QTc interval
Not applicable
Increase from baseline of 30 msec
* We do not list a lower limit of normal but the literature often defines the short QT syndrome as a 
QTc <300 ms.
PULSE RATE
Age
Markedly Abnormal Criteria
Low
High
7 years ≤x < 9 years
≤66
≥114
9 years ≤x < 11 years
≤66
≥114
11 years ≤x < 13 years girls
11 years ≤x < 13 years boys
≤66
≤61
≥114
≥109
13 years ≤x < 15 years girls
13 years ≤x < 15 years boys
≤61
≤56
≥109
≥104
15 years ≤x < 17 years girls
15 years ≤x < 17 years boys
≤56
≤51
≥104
≥99
RESPIRATORY RATE (breaths/min)
Age
Markedly Abnormal Criteria
Low
High
5 years <= x < 12 years
≤10
≥40
12 years <= x < 16 years
≤7
≥40
16 years <= x 
≤7
≥30


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Markedly abnormal blood pressure levels for BOYS by age
(height fixed at 50% percentile)
Age
(years)
Unit
SBP
Lower 
limit (≤)
SBP
Upper limit 
(≥)
DBP
Lower 
limit (≤)
DBP
Upper 
limit (≥)
8 years <= x < 9 years
mm Hg
74
124
32
86
9 years <= x < 10 years
mm Hg
76
125
33
87
10 years <= x < 11 years
mm Hg
77
127
34
88
11 years <= x < 12 years
mm Hg
79
129
35
89
12 years <= x < 13 years
mm Hg
81
131
35
89
13 years <= x < 14 years
mm Hg
84
134
36
90
14 years <= x < 15 years
mm Hg
86
136
36
90
15 years <= x < 16 years
mm Hg
89
139
37
91
16 years <= x < 17 years
mm Hg
92
141
39
93
Markedly abnormal blood pressure levels for GIRLS by age
(Height fixed at 50 % percentile)
Age
(years)
Unit
SBP
Lower 
limit (≤)
SBP
Upper 
limit (≥)
DBP
Lower 
limit (≤)
DBP
Upper 
limit (≥)
8 years <= x < 9 years
mm Hg
74
123
33
84
9 years <= x < 10 years
mm Hg
76
124
34
85
10 years <= x < 11 years
mm Hg
78
126
35
86
11 years <= x < 12 years
mm Hg
80
128
36
87
12 years <= x < 13 years
mm Hg
81
130
37
88
13 years <= x < 14 years
mm Hg
83
132
38
89
14 years <= x < 15 years
mm Hg
85
134
39
90
15 years <= x < 16 years
mm Hg
86
135
40
91
16 years <= x < 17 years
mm Hg
87
136
41
92