Clinical trial NCT03017235
Conditions: Bowel Preparation
Sponsor: Ferring Pharmaceuticals
Start date: 2017-02-20; Completion date: 2017-10-12
Enrollment: 917 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Oral Solution with PREPOPIK® for colon cleansing in adult subjects undergoing colonoscopy.

Detailed description:

Arms: arm 1: Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid (NaP/MC) Oral Solution arm 2: None
Interventions: intervention 1: Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Oral Solution intervention 2: Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Powder
Intervention descriptions: intervention 1: Supplied as two 160 mL ready-to-drink bottles, per subject, without further reconstitution, before administration. intervention 2: Supplied as two sachets per subject. Subjects will be instructed to reconstitute the medication by combining the contents of one packet with approximately five (5) ounces of cold water and stirring for two to three minutes.

Protocol documents:
Prot_000.pdf: 
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Sodium Picosulfate + Magnesium 
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Trial Code: 000253 
Oral Solution
Clinical Trial Protocol - Amendment 1
Ferring Pharmaceuticals
CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A Randomized, Assessor-Blinded, Multi-Center Study Investigating the Efficacy, Safety, and 
Tolerability of Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Oral Solution
versus Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Powder for Oral 
Solution (PREPOPIK®) for Colon Cleansing in Preparation for Colonoscopy
000253
EudraCT Number:
N/A
IND Number:
101738
Investigational Medicinal Product:
Sodium Picosulfate, Magnesium Oxide and Anhydrous 
Citric Acid Oral Solution
Indication:
Bowel preparation for colonoscopy
Phase:
III
Name and Address of Sponsor:
Ferring International PharmaScience Center U.S., Inc.
(FIPCUS)
100 Interpace Parkway
Parsippany, NJ 07054
P: 973-796-1600 
GCP Statement:
This trial will be performed in compliance with GCP, 
including the archiving of essential documents.
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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SYNOPSIS
TITLE OF TRIAL
A Randomized, Assessor-Blinded, Multi-Center Study Investigating the Efficacy, Safety, and 
Tolerability of Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Oral Solution
versus Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Powder for Oral 
Solution (PREPOPIK®) for Colon Cleansing in Preparation for Colonoscopy
SIGNATORY INVESTIGATOR(S)
Not Applicable
TRIAL SITE(S)
Approximately 10-15 sites in the United States (US) and Canada.
PLANNED TRIAL PERIOD
First patient first visit (FPFV): Q1 2017
Last patient last visit (LPLV): Q4 2017
CLINICAL PHASE
III
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE TRIAL
Sodium picosulfate with magnesium citrate is a low-volume cleansing agent that was developed to 
provide an efficient and well tolerated method of clearing the bowel prior to X-ray examination, 
endoscopy, or surgery. The safety, tolerability, and efficacy of PREPOPIK® were demonstrated in two 
well-controlled clinical trials, and PREPOPIK® was approved in 2012 in the US for cleansing of the 
colon as a preparation for colonoscopy in adults.
PREPOPIK® is currently formulated as a powder for reconstitution with cold water immediately before 
use. A ready to drink oral solution of Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric 
Acid (NaP/MC) has been developed that eliminates the need for the reconstituting and mixing steps by 
the subject. The new oral solution has the same active ingredients in the same quantities as 
PREPOPIK®. The dosage administered to the subject remains the same as that of PREPOPIK®. Thus, 
the Sodium Picosulfate, Magnesium Oxide, Anhydrous Citric Acid (NaP/MC) Oral Solution should be 
as effective as PREPOPIK® in colon cleansing, with a similar safety and tolerability profile.
The current study will be conducted to assess the non-inferiority of a split-dose regimen of NaP/MC
Oral Solution to a split-dose regimen of PREPOPIK® in adult subjects undergoing elective 
colonoscopy. 


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OBJECTIVES
Primary objective 

To demonstrate non-inferiority (NI) of split-dose Sodium Picosulfate, Magnesium Oxide and 
Anhydrous Citric Acid (NaP/MC) Oral Solution in overall colon cleansing in preparation for 
colonoscopy compared with split-dose PREPOPIK®
Secondary objectives

To demonstrate NI of NaP/MC Oral Solution compared with PREPOPIK® in cleansing of the 
right colon

To evaluate the cleansing of the transverse and left colon

To evaluate subjects’ tolerability and satisfaction with the bowel preparation 

To evaluate overall safety through the collection of treatment-emergent AEs and clinically 
significant changes in vital signs, ECGs and laboratory values

To evaluate pharmacokinetic (PK) characteristics of PREPOPIK® and NaP/MC Oral Solution
ENDPOINTS
Primary endpoint: 

Proportion of subjects classified as a responder defined by “excellent” or “good” using the Modified 
Aronchick scale (Aronchick et al, 1999, as cited by the American Society for Gastrointestinal 
Endoscopy [ASGE] et al, 2015)1
Secondary endpoints: 

Proportion of subjects classified as a responder defined by a score ≥2 in the right segment of the 
colon using the Boston Bowel Preparation Scale (BBPS)2 (Appendix C)

Proportion of subjects classified as a responder defined by a score ≥2 in the transverse segment of 
the colon using the BBPS2 (Appendix C)

Proportion of subjects classified as a responder defined by a score ≥2 in the left segment of the 
colon using the BBPS2 (Appendix C)

Frequency of each category of the Mayo Clinic Bowel Prep Tolerability Questionnaire3
(Appendix D)

Incidence of treatment-emergent AEs and clinically significant changes in vital signs, ECGs, and 
laboratory values

Plasma concentration of sodium picosulfate, magnesium and active metabolite bis-(p-
hydroxyphenyl)-pyridyl-2-methane (BHPM)


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METHODOLOGY
The study will be conducted at approximately 10-15 study sites in the US and Canada.
Following appropriate informed consent procedures, subjects who fulfill eligibility criteria and require 
a colonoscopy will be randomized to one of two treatment arms.
Only the subject and the site-designated unblinded coordinator and or pharmacist (if applicable) will 
know the treatment group in which the subject will be participating. The designated unblinded 
coordinator will instruct the subject on the use of the bowel preparation, and both will sign a 
nondisclosure affidavit form, attesting to their agreement that they will not disclose the treatment group 
to anyone. Treatment will be blinded to the designated endoscopist and study site personnel assessing 
the efficacy of the two tested preparations.
Following randomization, subjects will perform colon cleansing using NaP/MC Oral Solution or 
PREPOPIK® as follows:
For each treatment arm, subjects will begin treatment (first dose) the evening before colonoscopy 
between 5:00 and 9:00 PM, and will complete treatment (second dose) the following day, at least 5 
hours, but no more than 9 hours, prior to the colonoscopy.
NaP/MC Oral Solution (supplied as two 160-mL bottles per subject) needs no further reconstitution 
before administration.  
After drinking the first dose, subjects should drink five (5) or more eight-ounce glasses of 
clear liquid within five (5) hours.  
After drinking the second dose, subjects should drink four (4) or more eight-ounce glasses of 
clear liquid within five (5) hours. Subjects should not take anything by mouth within two (2)
hours before the time of the colonoscopy. 
PREPOPIK® (supplied as two packets per subject) is reconstituted using the cup provided. The doses
are prepared by combining the contents of one packet with approximately five (5) ounces of cold water 
and stirring for two to three minutes (in some cases the cup may feel warm, which is normal).
After drinking the first dose, subjects should drink approximately five (5) eight-ounce glasses 
of clear liquid within five (5) hours.  
After drinking the second dose, subjects should drink three (3) eight-ounce glasses of clear 
liquid within five (5) hours. Subjects should stop taking anything by mouth two (2) hours 


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before the time of the colonoscopy.
Note: Liquids with red, purple or blue coloring are not allowed before the colonoscopy. 
Permissible clear liquids include the following, as long as they are not red, purple or blue in color:

Broth/bouillon: chicken, beef, vegetable

Juices without pulp: apple juice, white grape juice, white cranberry juice. 

Water: plain or flavored

Soda: Sprite, Seven Up, ginger ale

Popsicles: orange, lime, lemon

Jell-O: orange, lime, lemon

Other permissible liquids: Gatorade, Crystal Light, Pedialyte, coffee, tea (do not add dairy/non-
dairy cream or milk)
The following diet requirements and restrictions should be followed for subjects admitted into the 
study regardless of the treatment group:
On the day (i.e., 24 hours) before the colonoscopy, all subjects enrolled in the study are limited to a 
clear liquid diet only. Special meal instructions for diabetic subjects are provided in (Appendix B). The
designated unblinded coordinator, who dispenses the study drug, will instruct the subject regarding the 
exact requirements during the randomization visit (See Section 6.2), including the need for correct 
hydration prior to starting bowel preparation. 
For a subset of subjects, pharmacokinetic samples will be collected for sodium picosulfate and BHPM 
concentration. Blood samples will be drawn within 15 minutes before the second dose, and 1 to 2 hours
and 3 to 6 hours after the second dose of Prepopik or NaP/MC Oral Solution. Accurate dosing 
information of both doses and timing of PK samples relative to dosing will be recorded. All study 
subjects will have a PK sample drawn immediately prior to their colonoscopy (approximately 2 hours 
prior to the colonoscopy).
Subjects will return for three follow-up visits: 1-2 days (Visit 4, see Section 6.4), seven days (Visit 5, 
see Section 6.5), and four weeks (Visit 6, see Section 6.6) after the colonoscopy procedure.


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NUMBER OF SUBJECTS
A sufficient number of subjects will be screened to ensure 900 randomized subjects (approximately 
450 subjects per treatment arm).   Approximately 60 subjects (30 subjects per treatment arm) will be 
assessed for additional PK sampling.
CRITERIA FOR INCLUSION / EXCLUSION
Inclusion Criteria
Male or non-pregnant female subjects aged 18 to 80 years, inclusive, being scheduled to 
1.
undergo elective colonoscopy 
Females of childbearing potential must agree to use an adequate contraception during the 
2.
course of the trial. Accepted forms of contraception are: i.e., implants, injectables, hormonal 
intrauterine device, combined hormonal contraceptives, sexual abstinence, and vasectomized 
sexual partner. Premenopausal women who are of childbearing potential must have a negative 
serum pregnancy test result at screening and a negative urine pregnancy test result at
randomization prior to colonoscopy. In the case of oral contraceptive use, women should have 
been taking the same pill consistently for a minimum of twelve (12) weeks before taking study 
medication. Sterilized or postmenopausal women may also participate. Women are considered 
to be postmenopausal and are not considered to be of childbearing potential if they have had 
twelve (12) months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation.
An average of at least 3 spontaneous bowel movements per week for one month prior to the 
3.
colonoscopy
Willing, able, and competent to complete the entire procedure and to comply with study 
4.
instructions
Written informed consent obtained at screening 
5.
Exclusion Criteria
Known or suspected gastrointestinal obstruction, perforation, ileus, or gastric retention 
1.
Acute intestinal or gastric ulceration
2.
Severe acute inflammatory bowel disease (IBD), diverticulits, toxic colitis, or toxic megacolon
3.
Undergoing colonoscopy for foreign body removal or decompression
4.
Reduced level of consciousness or inability to swallow without aspiration
5.
Any prior colorectal surgery (excluding appendectomy, hemorrhoid surgery, or prior 
6.
endoscopic procedures)
Upper gastrointestinal surgery (gastrectomy, gastric banding, gastric by-pass)
7.
Uncontrolled angina and/or myocardial infarction (MI) within last three months, congestive 
8.


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heart failure (CHF), uncontrolled hypertension, or ascites
Severely reduced renal function (<30 mL/min/1.73 m2)
9.
Pregnant or lactating women 
10.
Taking another investigational medicinal product within 30 days prior to receiving study 
11.
medication (or within 60 days for investigational drugs with an elimination half-life greater 
than 15 days)
Any clinically relevant abnormal findings in medical history, physical examination, vital signs, 
12.
electrocardiogram (ECG), clinical chemistry, hematology, coagulation, or urinalysis at 
Screening Visit (V1, see Section  6.1) or Randomization Visit (V2, see Section  6.2), which in 
the opinion of the Investigator(s), might put the subject at risk because of his/her participation 
in the trial
Current alcohol and/or drug abuse as judged by the Investigator
13.
Severe dehydration as judged by the Investigator
14.
Rhabdomyolysis
15.
Chronic nausea and vomiting
16.
Hypermagnesemia
17.
Considered by the Investigator to be unsuitable to participate in the trial for any other reason
18.
Hypersensitivity to any of the ingredients 
19.
Undergoing treatment with Lithium
20.
Exclusionary Medications
The following medications exclude subjects’ participation in the study and/or must be suspended prior 
to the procedure:
Laxatives (within 24 hours prior to procedure)

Constipating drugs such as opiates, anticholinergics, calcium channel blockers, and clonidine 

(within 48 hours prior to procedure)
Antidiarrheals such as loperamide (within 72 hours prior to procedure)

Oral iron preparations (within 1 week prior to procedure)



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MEDICINAL PRODUCTS
NaP/MC Oral Solution supplied as two 160 mL bottles per subject.  No  reconstitution before 
administration will be required: 

First dose administered the day before the colonoscopy between 5:00 and 9:00 PM

Second dose administered the next day (day of colonoscopy) at least 5 hours but not more than 9 
hours prior to the colonoscopy
PREPOPIK® supplied as two packets per subject. One dose is prepared by combining the contents of 
one packet with approximately five (5) ounces of water: 

First packet reconstituted and administered the day before the colonoscopy between 5:00 and 
9:00 PM

Second packet reconstituted and administered the next day (day of colonoscopy) at least 5 hours,
but no more than 9 hours, prior to the colonoscopy
DURATION OF TREATMENT
Treatment and follow-up: 2-day treatment and four week follow-up.


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TRIAL PROCEDURES / ASSESSMENTS
Visit
1
Screening
2
Randomization
3
Procedure
4
Follow-up 
5
Follow-up 
6
Follow-up  
(EOT)
Timing versus Procedure
≤21 Days
≤10 Days
Colonoscopy
(T = 0)
1-2 Days
7 Days
(± 2 Days)
4 Weeks
(± 2 Days)
Informed consent
x
Inclusion/exclusion criteria
x
x
Demographic & Medical History
x
Body weight, Height1
x
x
x
x
x
x
Urine/Serum Pregnancy Test
x
x7
Schedule colonoscopy
x
Laboratory (chemistry, coagulation, 
hematology)
x2
x
x
x
x
PK sampling 
x3,4
Urinalysis
x
x5
x
x
x
ECG
x
x
x
x
x
Physical examination
x
x
x
x
x
Orthostatic vital signs (BP, pulse)
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
Dispense fluid intake diary and 
study medication
x
Subject Tolerability Questionnaire 
x
Perform and video-record 
colonoscopy
x
Score overall colon preparation –
Modified Aronchick scale 
x
Score colon segments preparation –
Boston Bowel Preparation Scale
x
Drug accountability6
x


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1.
Height will only be collected at screening.
2.
Coagulation samples will only be collected at screening.
3.
In a subset of subjects, PK samples for sodium picosulfate and BHPM will be taken 15 minutes before the second dose, and 1 to 2 hours and 
3 to 6 hours  after the second dose of the Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid.
4.
All subjects will have a PK sample drawn immediately prior to colonoscopy (approximately 2 hours prior to the colonoscopy).  
5.
At the colonoscopy visit, the urinalysis panel will include urine osmolality.
6.
Drug accountability will be performed by an unblinded coordinator or unblinded pharmacist (if applicable) and an unblinded monitor only.
7.
Premenopausal women of childbearing potential must have a urine pregnancy test performed within 3 days prior to colonoscopy. For 
women of childbearing potential randomization must occur within 3 days prior to colonoscopy


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STATISTICAL METHODS
Sample Size Calculation
The primary objective of this study is to demonstrate non-inferiority (NI) of NaP/MC Oral Solution to
PREPOPIK® for overall colon cleansing prior to colonoscopy using the Modified Aronchick Scale 
(see Appendix C), as assessed by a blinded endoscopist.1 A subject is considered to be a “responder” if 
overall colon cleansing is either “excellent” or “good” on the Modified Aronchick Scale.
The assumed true responder rate for PREPOPIK® is 84% based on the Modified Aronchick Scale
(FE2009-01 and FE2009-02). It is assumed that the true responder rates of subjects treated with 
PREPOPIK® or NaP/MC Oral Solution are the same. A non-inferiority (NI) margin of 8% was chosen, 
to ensure no more than a 10% relative decrease from the control. Four hundred fifty (450) randomized 
subjects per treatment group are required, in a 1:1 randomization, to maintain 90% power to 
demonstrate the NI of NaP/MC Oral Solution to PREPOPIK® for overall colon cleansing prior to 
colonoscopy at the one-sided 0.025 significance level.
Efficacy:
The primary objective of the trial is to demonstrate the NI of NaP/MC Oral Solution to PREPOPIK®
for colon cleansing in preparation for colonoscopy. The NI margin for the difference between 
treatments (NaP/MC Oral Solution minus PREPOPIK®) will be -8% (absolute). The NI hypothesis to 
be tested for the primary endpoint will be:
H0: π NaP/MC Oral Solution - π PREPOPIK
® ≤-8% 
against the alternative 
H1: π NaP/MC Oral Solution - π PREPOPIK
® > -8%, 
where π NaP/MC Oral Solution and π PREPOPIK
® denote the true percentage of subjects classified as responders 
(i.e., “excellent” and “good” according to the Modified Aronchick Scale [see Appendix C]) among
subjects treated with NaP/MC Oral Solution or PREPOPIK®, respectively, for colon cleansing in 
preparation for colonoscopy.
The null hypothesis (H0) will be tested against the alternative by constructing a 2-sided 95% 
confidence interval for the difference in responder rates. The primary analysis will be adjusted for the 
stratification factor (site) by using the Mantel-Haenszel method to combine results across sites. In 
brief, this corresponds to deriving a weighted average across sites where the weight depends on the 
number of observations in each treatment group in each stratum.  Subjects who do not have an 
excellent or good rating according to the Modified Aronchick Scale (see Appendix C) for any reason


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will be considered treatment failures (i.e., not a responder). If the lower limit of the 95% confidence 
interval is greater than the NI margin (-8%), the null hypothesis will be rejected and it will be claimed 
that NaP/MC Oral Solution is non-inferior to PREPOPIK® with respect to colon cleansing in 
preparation for colonoscopy. The primary efficacy analysis will be conducted for the modified 
intention-to-treat population, defined as all randomized (as planned) subjects who received at least one 
dose of treatment. If the NI criteria are satisfied in both the primary efficacy analysis and the secondary 
efficacy analysis of the right colon, then a test for superiority will be performed for the primary 
efficacy analysis by comparing the lower bound of the confidence interval with 0.0%. If the lower 
bound of the confidence interval is above 0.0%, then superiority will be declared.  
The NI analysis will also be conducted for the per-protocol (PP) population as a sensitivity analysis.  
For the three secondary responder endpoints that are based on BBPS (cleansing of right, left and 
transverse segment), using the mITT population and the analysis methodology described for the 
primary endpoint a 95% two-sided confidence interval for responder rate difference of NaP/MC Oral 
Solution minus PREPOPIK® will be constructed. The NI of NaP/MC Oral Solution compared with 
split-dose PREPOPIK® in cleansing of the right colon will be assessed if and only if non-inferiority is 
demonstrated for the primary endpoint. The NI assessment for this endpoint will be similar to the NI 
assessment of primary endpoint and will be using the same NI margin of -8%.
The responses to Mayo Clinic Bowel Prep Tolerability Questionnaire questions (see Appendix D) will 
be summarized by treatment arm.  All safety data will be summarized descriptively.
PK Assessment:
For PK assessment, blood samples will be collected on a subset of sixty (60) subjects three times on 
the day of colonoscopy. Sixty (60) subjects (approximately 30 per arm) are considered to be sufficient 
to characterize the PK population for sodium picosulfate and BHPM. In addition to this, all subjects 
enrolled in the study, including this PK subset, will have one (1) PK blood sample drawn for sodium 
picosulfate and BHPM immediately prior to their colonoscopy (approximately 2 hours prior to the 
colonoscopy).


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TABLE OF CONTENTS
SYNOPSIS....................................................................................................................................................... 2
TABLE OF CONTENTS ............................................................................................................................. 13
LIST OF TABLES........................................................................................................................................ 17
LIST OF FIGURES...................................................................................................................................... 17
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 18
1
INTRODUCTION ............................................................................................................................. 20
1.1
Background............................................................................................................................. 20
1.2
Scientific Justification for Conducting the Trial..................................................................... 22
1.3
Benefit / Risk Aspects............................................................................................................. 22
2
TRIAL OBJECTIVES AND ENDPOINTS..................................................................................... 23
2.1
Objectives ............................................................................................................................... 23
2.2
Endpoints ................................................................................................................................ 23
3
INVESTIGATIONAL PLAN ........................................................................................................... 24
3.1
Overall Trial Design................................................................................................................ 24
3.1.1
Trial Design Diagram................................................................................................. 24
3.1.2
Overall Design and Control Methods ........................................................................ 25
3.1.3
Trial Schedule............................................................................................................ 26
3.2
Planned Number of Trial Sites and Subjects........................................................................... 27
3.3
Interim Analysis...................................................................................................................... 27
3.4
Data Monitoring Committee (DMC) ...................................................................................... 27
3.5
Safety Review Committee (SRC) ........................................................................................... 27
3.6
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 27
3.6.1
Trial Design ............................................................................................................... 27
3.6.2
Selection of Endpoints ............................................................................................... 27
3.6.3
Blinding/Unblinding .................................................................................................. 28
3.6.3.1
Blinding ...................................................................................................................28
3.6.3.2
Unblinding of Individual Subject Treatment ...........................................................28
3.6.4
Selection of Doses in the Trial................................................................................... 29
3.6.5
Selection and Timing of Dose for Each Subject........................................................ 29
3.6.6
Withdrawal Criteria ................................................................................................... 29
3.6.7
Subject Replacement.................................................................................................. 30
3.6.8
Follow-up Procedures ................................................................................................ 30
4
SELECTION OF TRIAL POPULATION ...................................................................................... 31
4.1
Trial Population....................................................................................................................... 31
4.1.1
Inclusion Criteria ....................................................................................................... 31
4.1.2
Exclusion Criteria ...................................................................................................... 31
4.2
Method of Assigning Subjects to Treatment Groups.............................................................. 32
4.2.1
Recruitment................................................................................................................ 32


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4.2.2
Randomization........................................................................................................... 32
4.3
Restrictions ............................................................................................................................. 33
4.3.1
Water Insufflation During Colonoscopy Insertion..................................................... 33
4.3.2
Prior and Concomitant Therapies .............................................................................. 33
4.3.3
Prohibited Therapy..................................................................................................... 33
4.3.4
Other Restrictions ...................................................................................................... 33
5
TREATMENTS ................................................................................................................................. 34
5.1
Treatments Administered........................................................................................................ 34
5.1.1
Investigational Medicinal Product (IMP)................................................................... 34
5.2
Characteristics and Source of Supply ..................................................................................... 36
5.2.1
Investigational Medicinal Product ............................................................................. 36
5.2.1.1
Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid (NaP/MC) 
Oral Solution............................................................................................................36
5.2.1.2
PREPOPIK®.............................................................................................................36
5.3
Packaging and Labeling.......................................................................................................... 36
5.4
Conditions for Storage and Use .............................................................................................. 37
5.4.1
Investigational Medicinal Product ............................................................................. 37
5.5
Blinding / Unblinding ............................................................................................................. 37
5.5.1
Blinding...................................................................................................................... 37
5.5.2
Unblinding of Individual Subject Treatment ............................................................. 37
5.6
Treatment Compliance............................................................................................................ 38
5.6.1
Dispensing and Accountability.................................................................................. 38
5.7
Assessment of Compliance..................................................................................................... 38
5.8
Return and Destruction of Medicinal Products....................................................................... 38
6
TRIAL PROCEDURES .................................................................................................................... 39
6.1
Screening Visit (Visit 1) ......................................................................................................... 39
6.2
Randomization Visit (Visit 2)................................................................................................. 39
6.3
Procedure/Colonoscopy Visit (Visit 3)................................................................................... 40
6.4
Follow-up Visit (Visit 4)......................................................................................................... 42
6.5
Follow-up Visit (Visit 5)......................................................................................................... 42
6.6
Follow-up Visit (Visit 6)......................................................................................................... 43
6.7
Trial Assessments ................................................................................................................... 44
7
TRIAL ASSESSMENTS ................................................................................................................... 45
7.1
Assessments Related to Endpoints.......................................................................................... 45
7.1.1
The Modified Aronchick Scale.................................................................................. 45
7.1.2
The Boston Bowel Preparation Scale......................................................................... 45
7.1.3
Mayo Clinic Bowel Preparation Tolerability Questionnaire...................................... 47
7.2
Other Assessments.................................................................................................................. 47
7.2.1
Physical Examinations............................................................................................... 47
7.2.2
Orthostatic Vital Signs............................................................................................... 47
7.2.3
Clinical Laboratory Variables.................................................................................... 47
7.2.4
ECG............................................................................................................................ 49


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7.2.5
Fluid Intake and Dosing Diary................................................................................... 49
7.2.6
Other Colonoscopy Assessments............................................................................... 49
7.3
Drug Concentration Measurements......................................................................................... 50
7.4
Handling of Biological Samples ............................................................................................. 50
8
ADVERSE EVENTS ......................................................................................................................... 51
8.1
Adverse Event Definition........................................................................................................ 51
8.2
Collection and Recording of Adverse Events......................................................................... 51
8.2.1
Collection of Adverse Events .................................................................................... 51
8.2.2
Recording of Adverse Events .................................................................................... 52
8.3
Pregnancy and Pregnancy Outcome........................................................................................ 55
8.4
Serious Adverse Events .......................................................................................................... 55
8.4.1
Serious Adverse Event Definition.............................................................................. 55
8.4.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 56
8.5
Follow-up of Adverse Events and Serious Adverse Events.................................................... 58
8.5.1
Follow-up of Adverse Events with Onset During the Trial....................................... 58
8.5.2
Collection of Serious Adverse Events with Onset After Last Visit in the Trial ........ 58
9
STATISTICAL METHODS ............................................................................................................. 59
9.1
Determination of Sample Size ................................................................................................ 59
9.2
Subject Disposition ................................................................................................................. 59
9.3
Protocol Deviations................................................................................................................. 59
9.4
Analysis Sets........................................................................................................................... 60
9.4.1
Intention-to-Treat (ITT) Analysis Set........................................................................ 60
9.4.2
Modified Intention-to-Treat (mITT) Analysis Set..................................................... 60
9.4.3
Per Protocol (PP) Analysis Set................................................................................... 60
9.4.4
Safety Analysis Set .................................................................................................... 60
9.5
Trial Population....................................................................................................................... 60
9.5.1
Demographics and Other Baseline Characteristics.................................................... 60
9.5.2
Medical History ......................................................................................................... 60
9.5.3
Prior and Concomitant Medication............................................................................ 60
9.6
Endpoint Assessments............................................................................................................. 61
9.6.1
General Considerations.............................................................................................. 61
9.6.2
Primary Endpoint(s)................................................................................................... 61
9.6.3
Secondary Endpoint(s)............................................................................................... 62
9.6.3.1
BBPS (Right Colon) ................................................................................................62
9.6.3.2
BBPS (Transverse Colon)........................................................................................62
9.6.3.3
BBPS (Left Colon)...................................................................................................63
9.6.3.4
Tolerability and Satisfaction ....................................................................................63
9.6.3.5
Drug Concentration Measurements/Pharmacokinetics ............................................63
9.7
Extent of Exposure and Treatment Compliance ..................................................................... 63
9.8
Safety ...................................................................................................................................... 63
9.8.1
General Considerations.............................................................................................. 63
9.8.2
Adverse Events .......................................................................................................... 63
9.8.3
Safety Laboratory Variables ...................................................................................... 64


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9.8.4
Other Safety Variables............................................................................................... 65
9.8.4.1
Vital Signs................................................................................................................65
9.8.4.2
ECGs........................................................................................................................65
9.8.4.3
Physical Findings.....................................................................................................65
9.9
Interim Analyses ..................................................................................................................... 65
10
DATA HANDLING ........................................................................................................................... 66
10.1
Source Data and Source Documents....................................................................................... 66
10.2
Electronic Data Capturing System (EDC) .............................................................................. 66
10.3
Patient Reported Outcome (PRO)........................................................................................... 67
10.4
Data Management ................................................................................................................... 67
10.5
Provision of Additional Information....................................................................................... 67
11
MONITORING PROCEDURES ..................................................................................................... 68
11.1
Periodic Monitoring................................................................................................................ 68
11.2
Audit and Inspection............................................................................................................... 68
11.3
Confidentiality of Subject Data............................................................................................... 68
12
CHANGES IN THE CONDUCT OF THE TRIAL........................................................................ 70
12.1
Protocol Amendments............................................................................................................. 70
12.2
Deviations from the Protocol .................................................................................................. 70
12.3
Premature Trial Termination................................................................................................... 70
13
REPORTING AND PUBLICATION .............................................................................................. 71
13.1
Clinical Trial Report ............................................................................................................... 71
13.2
Confidentiality and Ownership of Trial Data.......................................................................... 71
13.3
Publications and Public Disclosure......................................................................................... 71
13.4
Publication Policy ................................................................................................................... 71
13.5
Public Disclosure Policy......................................................................................................... 72
14
ETHICAL AND REGULATORY ASPECTS................................................................................. 73
14.1
Institutional Review Board (IRB)........................................................................................... 73
14.2
Regulatory Authority(ies) Authorization / Approval / Notification........................................ 73
14.3
End-of-Trial and End-of-Trial Notification ............................................................................ 73
14.4
Ethical Conduct of the Trial.................................................................................................... 73
14.5
Subject Information and Consent............................................................................................ 73
14.6
Compliance Reference Documents......................................................................................... 74
15
LIABILITIES AND INSURANCE .................................................................................................. 75
15.1
ICH-GCP Responsibilities...................................................................................................... 75
15.2
Liabilities and Insurance......................................................................................................... 75
16
ARCHIVING...................................................................................................................................... 76
16.1
Investigator File ...................................................................................................................... 76
16.2
Trial Master File...................................................................................................................... 76
17
REFERENCES................................................................................................................................... 77
APPENDICES............................................................................................................................................... 79


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Appendix A
Subject’s Confidential Non-Disclosure Affidavit.................................................. 80
Appendix B
Dietary Guidelines for Diabetics............................................................................. 81
Appendix C
Modified Aronchick Scale and Boston Bowel Preparation Scale ........................ 82
Appendix D
Mayo Clinic Bowel Prep Tolerability Questionnaire............................................ 83
LIST OF TABLES 
Table 1
Trial Assessment Table........................................................................................................ 44
Table 2
Modified Aronchick Scale ................................................................................................... 45
Table 3 
Serious Adverse Events During the Trial ............................................................................ 55
LIST OF FIGURES
Figure 1
Trial Flow Chart................................................................................................................... 24
Figure 2 
The Boston Bowel Preparation Scale................................................................................... 46


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
List of Abbreviations
ADR
Adverse Drug Reaction 
AE
Adverse Event
ALT
Alanine Aminotransferase
ANCOVA 
Analysis of Covariance
ANOVA
Analysis of Variance
ASGE
American Society for Gastrointestinal Endoscopy
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
BBPS
Boston Bowel Preparation Score
BHPM
bis-(p-hydroxyphenyl)-pyridyl-2-methane
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CHF
Congestive Heart Failure
CRF
Case Report Form
CRO
Contract Research Organization 
DMC
Data Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOT
End of Treatment
FDA
Food and Drug Administration
FIPCUS
Ferring International PharmaScience Center U.S.
FPFV
First Patient First Visit
FPLV
First Patient Last Visit
GCP
Good Clinical Practice
GGT
Gamma Glutamyl Transferase
GMP
Good Manufacturing Practice
IBD
Inflammatory Bowel Disease
ICH
International Conference on Harmonization
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IRB
Institutional Review Board
ITT 
Intention-To-Treat
LOCF
Last-Observation-Carried-Forward
MED
Minimum Effective Dose
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial Infarction
mITT
Modified Intention-to-Treat
NaP/MC
Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid
NDA
New Drug Application
NI
Non-Inferiority


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NIH
National Institutes of Health
NIMP
Non-Investigational Medicinal Product
NLM
National Library of Medicine
OC
Observed Cases
PEG
Polyethylene Glycol
PIND
Pre-Investigational New Drug
PK
Pharmacokinetic(s)
PP
Per Protocol
PT
Preferred Term
SAE
Serious Adverse Event
SAP 
Statistical Analysis Plan
SD 
Standard Deviation
SDV
Source Data Validation
SF
Short Form
SOC
System Organ Class
SUSARS
Suspected Unexpected Serious Adverse Reactions
UK
United Kingdom
US
United States
WHODrug
World Health Organization Drug


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1
INTRODUCTION
1.1
Background
A colonoscopy is a minimally invasive endoscopic examination of the colon that is effective as a 
cancer prevention tool, diagnostic method, and therapeutic intervention. In the United States (US), 
where colonoscopy has been the standard for colorectal cancer screening, there has been a 3% annual 
decrease in colorectal cancer incidence each year for the past three decades.4 Regular screening, 
beginning at age 50 for average-risk individuals (age 45 for African Americans), is recommended to 
prevent colorectal cancer.5 However, screen rates remain lower than the American Cancer Society’s 
target rate, with only 63% of adults age 50 years or older having a colonoscopy in 2015.6 Getting 
subjects to participate in screening programs is difficult, and the overall experience—including the 
cleansing procedure—influences subjects’ willingness to undergo screening colonoscopy or repeat 
procedures.7
The diagnostic accuracy of colonoscopy requires thorough visualization of the colonic mucosa, which 
is achieved by thorough bowel cleansing prior to the procedure.2 Bowel cleansing agents are used to 
empty and clean the bowel prior to colonoscopy, and inadequate bowel cleansing can lead to missed 
lesions, prolonged procedure durations, lower cecal intubation rates, need for repeat colonoscopy, or a 
scheduled colonoscopy at an earlier interval.2,8
The ideal bowel preparation procedure should clean the colon of all fecal material, without mucosal 
damage or electrolyte imbalance and with minimal discomfort to the subject.9 Because colon cleansing 
must be performed by the subject, cleansing agents that are associated with good subject compliance 
are preferable. Regimens that cause subject discomfort or adverse reactions, require a large volume of 
fluid, and/or have an unpleasant taste can result in low compliance rates and unsatisfactory cleansing, 
leading to a poor-quality examination.8,10,11 An agent that can be administered as a split dose is 
preferable due to superior bowel cleaning efficacy compared with single-dose administration and a 
better subject experience, as measured by greater willingness by the subject to undergo a future 
colonoscopy.8 In addition, recent evidence confirms that a split-dose regimen results in higher 
adenoma detection rates.12
Sodium picosulfate, magnesium oxide and anhydrous citric acid powder for oral solution is a low-
volume cleansing agent that was developed to provide an efficient, simple and pleasant tasting method 
of clearing the bowel prior to X-ray examination, endoscopy or surgery. The formulation includes a 
stimulant cathartic, sodium picosulfate, together with an osmotic laxative, magnesium citrate, which is 
formed in solution by the reaction of magnesium oxide and anhydrous citric acid. The combined effect 
stimulates peristalsis, and by retaining water in the bowel, provides a washout effect. It has been 
available as Picolax® in the United Kingdom (UK) since 1980, and in Canada as Pico-Salax® since 
2004. In the US, Low-Volume Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid 


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Powder for Oral Solution (PREPOPIK®) was approved in 2012 and is currently indicated for cleaning 
of the colon as a preparation for colonoscopy in adults. 
The current, approved formulation of PREPOPIK® is a powder, supplied as a two-packet treatment (20 
mg sodium picosulfate in divided doses), which is reconstituted by the subject immediately before use. 
PREPOPIK® may be administered as either a split-dose regimen, with the second dose taken on the 
day of the colonoscopy, or as a day-before regimen, in which both doses are taken the evening before 
the colonoscopy.
In the US, the colon cleansing efficacy of PREPOPIK® was established in two randomized, 
Investigator-blinded, active-controlled, multicenter trials in subjects scheduled to have an elective 
colonoscopy. In all, 1195 adult subjects were evaluated in the primary efficacy analyses. Subjects 
ranged in age from 18 to 80 years (mean age 56 years); 61% were female and 39% male. 
Subjects randomized to PREPOPIK® in the two studies were treated with one of two dosing regimens:
In the first study,13 PREPOPIK® was given by “Split-Dose” (evening before and day of) dosing, where 
the first dose was taken the evening before the colonoscopy (between 5:00 and 9:00 PM), followed by 
5 eight-ounce glasses of clear liquid, and the second dose was taken the morning of the colonoscopy (at 
least five hours prior to but no more than nine hours prior to colonoscopy), followed by 3 eight-ounce 
glasses of clear liquid.
In the second study,6 PREPOPIK® was given by “Day-Before” (afternoon/evening before only) dosing, 
where both doses were taken separately on the day before the colonoscopy, with the first dose taken in 
the afternoon (between 4:00 and 6:00 PM), followed by 5 eight-ounce glasses of clear liquid, and the 
second dose taken in the late evening (approximately six hours later, between 10:00 PM and 12:00 
AM), followed by 3 eight-ounce glasses of clear liquid.
The comparator in each study was a preparation containing two liters of polyethylene glycol plus 
electrolyte solution (PEG + E) and two 5-mg bisacodyl tablets, administered the day before the 
procedure. All subjects in both the PREPOPIK® and comparator groups were limited to a clear liquid 
diet on the day (i.e., 24 hours) before the procedure.
The primary efficacy endpoint was the proportion of subjects with successful colon cleansing (“good” 
or “excellent”), as assessed by a blinded colonoscopist using the Modified Aronchick scale.1 With day-
before dosing, PREPOPIK® was non-inferior to the comparator cleansing regimen.6 PREPOPIK®
administered in a split-dose regimen met the pre-specified criteria for superiority to the comparator for 
colon cleansing.6


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Subject acceptance and tolerability were measured and were significantly superior (p<0.0001) with 
PREPOPIK® compared with the PEG + E and bisacodyl tablet regimen in both studies. A greater 
proportion of subjects rated the PREPOPIK® regimen as “very easy” or “easy” to consume and as 
having an “excellent” or “good” taste compared with PEG and bisacodyl tablets.6,13 In addition, subject 
compliance was better with PREPOPIK®: a greater proportion of subjects who received PREPOPIK®
reported having consumed the entire preparation as instructed compared with subjects who received 
PEG and biscodyl tablets. 6,13
In these randomized, multicenter, controlled clinical trials, the adverse reactions nausea, headache, and 
vomiting were the most common ones following PREPOPIK® administration.
Ferring Pharmaceuticals has developed a pre-mixed oral solution of Sodium Picosulfate, Magnesium 
Oxide and Anhydrous Citric Acid (NaP/MC) that eliminates the need for reconstituting and mixing 
steps. The dosage administered to the subject remains the same as that of PREPOPIK®. Thus, NaP/MC 
Oral Solution should be as effective as and have a similar safety and tolerability profile to PREPOPIK®
for colon cleansing in preparation for colonoscopy.
1.2
Scientific Justification for Conducting the Trial
The current study will be conducted to directly compare the NaP/MC Oral Solution with PREPOPIK®
using a split dose regimen for colon cleansing in adult subjects undergoing colonoscopy. 
1.3
Benefit / Risk Aspects
Compared with other existing alternatives for bowel cleansing, PREPOPIK® has a relatively smaller
volume of liquid for the subjects to drink.11 PREPOPIK® is also safe, effective and tolerable.  NaP/MC 
Oral Solution has the same active ingredients, in the same quantities as PREPOPIK® when dosed by 
the patients and is expected to have a similar efficacy, safety, and tolerability profile.
Subjects’ vital signs, ECG, laboratory values, and any AEs reported will be monitored throughout the 
two-day treatment period and during a four-week follow-up period.


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective

To demonstrate non-inferiority (NI) of split-dose NaP/MC Oral Solution in overall colon 
cleansing in preparation for colonoscopy compared with split-dose PREPOPIK®
Secondary Objectives

To demonstrate NI of NaP/MC Oral Solution compared with PREPOPIK® in cleansing of the 
right colon

To evaluate the cleansing of the transverse and left colon

To evaluate subjects’ tolerability and satisfaction with the bowel preparation 

To evaluate overall safety through the collection of treatment-emergent AEs and clinically 
significant changes in vital signs, ECGs and laboratory values

To evaluate pharmacokinetic (PK) characteristics of PREPOPIK® and NaP/MC Oral Solution
2.2
Endpoints
Primary Endpoint 

Proportion of subjects classified as a responder defined by “excellent” or “good” using the Modified 
Aronchick scale (Appendix C).1
Secondary Endpoints

Proportion of subjects classified as a responder defined by a score ≥2 in the right segment of the 
colon using the BBPS (Appendix C)

Proportion of subjects classified as a responder defined by a score ≥2 in the transverse segment of 
the colon using the BBPS (Appendix C)

Proportion of subjects classified as a responder defined by a score ≥2 in the left segment of the 
colon using the BBPS (Appendix C)

Frequency of each category of the Mayo Clinic Bowel Prep Tolerability Questionnaire 
(Appendix D)

Incidence and intensity of treatment-emergent AEs and clinically significant changes in vital 
signs, ECGs, and laboratory values

Plasma concentration of sodium picosulfate, magnesium and BHPM


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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Trial Design Diagram
Figure 1
Trial Flow Chart 


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Subjects participating in the PK subset should remain in the clinical research unit for needed blood 
draws on the day/night before the colonoscopy (Visit 3).
3.1.2
Overall Design and Control Methods
This study is a randomized, assessor-blinded, NI, multi-center study that will be conducted in 
approximately 10-15 study centers in the US and Canada, following approval by appropriate oversight 
bodies and regulatory agencies. 
Following appropriate informed consent procedures, subjects who fulfill eligibility criteria and require 
a colonoscopy will be randomized to one of two treatment arms:

NaP/MC Oral Solution: Supplied as two 160-mL bottles per subject. The medication needs no 
further reconstitution before administration.

PREPOPIK®: Supplied as two packets per subject. Subjects will be instructed to reconstitute
the medication by combining the contents of one packet with approximately five (5) ounces of 
cold water and stirring for two to three minutes (in some cases the cup may feel warm, which is 
normal). 
Only the subject and the site-designated, unblinded coordinator and pharmacist (if applicable) will 
know the treatment group in which the subjects will be participating. The designated unblinded 
coordinator will instruct the subject on the use of the bowel preparation, and both will sign a 
nondisclosure affidavit form (Appendix A), attesting to their agreement that they will not disclose the 
treatment group to anyone. Treatment will be blinded to the designated endoscopist and study site 
personnel assessing the efficacy of the two tested preparations.
For each treatment arm, subjects will begin treatment (first dose) on the evening before the 
colonoscopy between 5:00 PM and 9:00 PM, and will complete the treatment (second dose) the 
following day at least 5 hours, but no more than 9 hours, prior to the colonoscopy.
Subjects randomized to the NaP/MC Oral Solution:
After drinking the first dose, subjects should drink five (5) or more eight-ounce glasses of clear liquid 
within five (5) hours.  After drinking the second dose, subjects should drink four (4) or more eight-
ounce glasses of clear liquid within five (5) hours. Subjects should not take anything by mouth within 
two (2) hours before the time of the colonoscopy. 


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Subjects randomized to PREPOPIK®:
Subjects will be instructed to reconstitute the medication by combining the contents of one packet with 
approximately five (5) ounces of cold water and stirring for two to three minutes (in some cases the 
cup may feel warm, which is normal). 
After drinking the first dose, subjects should drink approximately five (5) eight-ounce glasses of clear 
liquid within five (5) hours.  After drinking the second dose, subjects should drink three (3) eight-
ounce glasses of clear liquid within five (5) hours. Subjects should stop taking anything by mouth two 
(2) hours before the time of the colonoscopy.
Note: Liquids with red, purple, or blue coloring are not allowed before the colonoscopy. 
Permissible clear liquids include the following, as long as they are not red, purple or blue in color: 

Broth/bouillon: chicken, beef, vegetable

Juices without pulp: apple juice, white grape juice and white cranberry juice

Water: plain or flavored

Soda: Sprite, Seven Up, ginger ale

Popsicles: orange, lime, lemon

Jell-O: orange, lime, lemon

Other permissible liquids: Gatorade, Crystal Light, Pedialyte, coffee, tea (do not add dairy/non-
dairy cream or milk)
On the day (i.e., 24 hours) before the procedure, all subjects enrolled in the study are limited to a clear 
liquid diet only. Special meal instructions for diabetic subjects are provided in Appendix B. The 
designated unblinded coordinator, who dispenses the study drug, will instruct the subject regarding the 
exact requirements during the randomization visit (V2, see Section 6.2), including the need for correct 
hydration prior to starting bowel preparation.
Subjects will return for three follow-up visits, 1-2 days (V4, see Section 6.4), seven days (V5, see 
Section 6.5) and four weeks (V6, see Section 6.6) after the colonoscopy procedure.
3.1.3
Trial Schedule
It is anticipated that the first patient first visit (FPFV) will be in the first quarter of 2017 and the last 
patient last visit (LPLV) will be in the fourth quarter of 2017.


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3.2
Planned Number of Trial Sites and Subjects
The study will be conducted at approximately 10-15 sites in the US and Canada. A sufficient number 
of subjects will be screened to ensure enrollment of 900 randomized subjects (approximately 450
subjects per treatment group).
3.3
Interim Analysis
No interim analysis is planned for this study.  
3.4
Data Monitoring Committee (DMC)
No Data Monitoring Committee (DMC) is planned for this trial. 
3.5
Safety Review Committee (SRC)
A Safety Review Committee (SRC) will be established for this program. Cumulative safety outputs 
will be regularly produced for the SRC review. The timing for the generation of these outputs will be 
specified in the SRC documentation.
3.6
Discussion of Overall Trial Design and Choice of Control Groups
3.6.1
Trial Design
The study design is an assessor-blinded and randomized non-inferiority trial. Persons involved in the 
conduct and evaluation of the study will be blinded while the drug dispensing coordinator and subject 
are unblinded.
3.6.2
Selection of Endpoints
NI of split-dose NaP/MC Oral Solution to PREPOPIK® in overall colon cleansing in preparation for 
colonoscopy will be assessed by a blinded endoscopist using the Modified Aronchick scales (Appendix 
C) as the primary endpoint in this study. Results will be expressed as a proportion of subjects classified 
as responders, i.e., “excellent” and “good” according to the Modified Aronchick Scale (see Appendix 
C).
Efficacy of right, transverse, and left colon cleansing will be assessed by the blinded gastroenterologist 
using the Boston Bowel Preparation Scale (BBPS) (Appendix C).
Subject tolerability and satisfaction with the bowel cleansing preparation will be assessed by the 
validated3 Mayo Clinic Bowel Preparation Questionnaire (Appendix D), administered to subjects on 
the day of the colonoscopy and prior to the procedure.


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3.6.3
Blinding/Unblinding
3.6.3.1
Blinding
Study treatment(s) will be allocated according to computer-generated randomization codes prepared for 
all study sites and assigned via IVRS. The randomization assignment will be available only to the 
person dispensing the drug (unblinded coordinator or pharmacist (if applicable)), but not to any other 
personnel involved in the conduct and evaluation of the study until the study database is locked. 
Treatment is blinded to the endoscopist performing the colonoscopy and assessing the efficacy of the 
tested preparations and his/her assistant(s).
Prior to the start of the study, the investigator will assign a coordinator and a pharmacist (if applicable) 
to act as the site-designated unblinded coordinator. These individuals will be the only individuals 
unblinded to the subject’s treatment group and will be responsible for the distribution and 
accountability of the study drug. The unblinded coordinator will instruct each subject how and when to 
properly administer the study drug and will explain any dietary restrictions. The unblinded coordinator
will be available to answer the subject’s questions regarding the study drug and its administration.
The integrity of blinding will be further preserved by requiring each subject, the unblinded coordinator,
and the unblinded pharmacist (if applicable) to sign a nondisclosure affidavit form instructing subjects,
the unblinded coordinator and the unblinded pharmacist (if applicable) not to disclose the assigned 
treatment group to the endoscopist performing the colonoscopy and his/her assistants.
3.6.3.2
Unblinding of Individual Subject Treatment
In case of an emergency, emergency decoding envelope will be available to the investigator and the 
sponsor's medical monitor. Breaking of the blind for individual subjects is only permitted in the 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 and/or IRBs, only those individuals within Ferring Pharmaceuticals whose responsibility 
it is to report this information will know the identity of the IMP. Every effort will be made to maintain 
the blinding of site and sponsor personnel throughout the course of the study. Other personnel may be 
unblinded for suspected unexpected serious adverse reactions, including trial site staff as well as staff 
acting on behalf of Ferring.
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 


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by whom must be noted both on the code envelope and in the CRF, and the disclosure and reason must 
also be recorded in the subject’s medical record.
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.
3.6.4
Selection of Doses in the Trial
NaP/MC Oral Solution is a new liquid formulation that is provided as an oral solution with the same 
active ingredients, in the same quantities as PREPOPIK® when dosed by the patient. The dosage 
administered to the subject remains the same as that of PREPOPIK®.
PREPOPIK® was chosen as the active comparator because when reconstituted it has the same active 
ingredients as the IMP and has been demonstrated to be safe and effective as a colon cleansing 
preparation.
3.6.5
Selection and Timing of Dose for Each Subject
For each treatment arm, the first dose is administered the evening before the colonoscopy between 5:00 
and 9:00 PM. The second dose is administered the next day at least 5 hours but no more than 9 hours 
prior to the colonoscopy.
Each subject will be randomly assigned to one of the following treatments:

Split-dose Low-Volume NaP/MC Oral Solution

Split-dose Low-Volume PREPOPIK®
Complete dosing and timing instructions for the study drugs are found in Section 0.
3.6.6
Withdrawal Criteria 
A subject has the right to withdraw from the trial at any time for any reason, without the need to justify 
their decision. However, the Investigator should record the reason for the subject’s withdrawal, if 
possible. The Investigator also has the right to withdraw subjects. The reason should be discussed with 
the Sponsor prior to withdrawing the subject and that reason should be fully documented in the eCRF.
For any withdrawal, the Investigator will obtain all the required details and document the date and 
main reason for the withdrawal in the eCRF. Should the subject develop conditions during the course 
of the study which would have prevented his/her entry into the study according to the exclusion 
criteria, he/she must be withdrawn immediately.


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If, at the time of withdrawal, a dose of the investigational product has already been administered, the 
subject must be advised that follow-up safety investigations are required, which will include all 
procedures outlined in the follow-up visit. 
Reasons for withdrawal may include:

A subject’s desire to withdraw for any reason

Loss to follow-up (every effort must be made to contact the subject; a certified letter must be 
sent or phone calls on three separate days must be made)

An AE which, in the opinion of the investigator, necessitates withdrawal

A subject’s substantial non-compliance. Before withdrawing a subject from the trial due to 
substantial non-compliance, the investigator should contact the sponsor to discuss the 
withdrawal 

The investigator may withdraw a subject anytime, if it is considered to be in the subject’s best 
interest
3.6.7
Subject Replacement 
Subjects discontinued or withdrawn from the study will not be replaced.
3.6.8
Follow-up Procedures
Subjects will return for three follow-up visits, at 1-2 days (V4, see Section 6.4), seven days (V5, see 
Section 6.5), and four weeks (V6, see Section 6.6) after the colonoscopy procedure.
At each follow-up visit, vital signs, laboratory values, and ECGs will be assessed, and any adverse 
events reported by the subject will be recorded. Adverse events requiring therapy must be treated with 
the recognized standards of medical care to protect the health and well-being of the subject.
New illness or worsening of concomitant illness should be reported as AEs.


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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
Adult subjects age 18-80, scheduled to undergo an elective colonoscopy and who meet all inclusion 
and exclusion criteria may be enrolled in this trial.
4.1.1
Inclusion Criteria
Subjects who meet all of the following criteria will be eligible for the study:
Male or non-pregnant female subjects aged 18 to 80 years, inclusive, being scheduled to 
1.
undergo elective colonoscopy 
Females of childbearing potential must agree to use an adequate contraception during the 
2.
course of the trial. Accepted forms of contraception are: i.e., implants, injectables, hormonal 
intrauterine device, combined hormonal contraceptives, sexual abstinence, and vasectomized 
sexual partner. Premenopausal women who are of childbearing potential must have a 
negative serum pregnancy test result at screening and a negative urine pregnancy test result 
at randomization prior to colonoscopy. In the case of oral contraceptive use, women should 
have been taking the same pill consistently for a minimum of twelve (12) weeks before 
taking study medication. Sterilized or postmenopausal women may also participate. Women 
are considered to be postmenopausal and are not considered to be of childbearing potential if 
they have had twelve (12) months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation.
An average of at least 3 spontaneous bowel movements per week for one month prior to the 
3.
colonoscopy
Willing, able, and competent to complete the entire procedure and to comply with study 
4.
instructions
Written informed consent obtained at screening 
5.
4.1.2
Exclusion Criteria
The presence of any of the following excludes a subject from study enrollment:
Known or suspected gastrointestinal obstruction, perforation, ileus, or gastric retention 
1.
Acute intestinal or gastric ulceration
2.
Severe acute inflammatory bowel disease (IBD), diverticulitis, toxic colitis, or toxic 
3.
megacolon
Undergoing colonoscopy for foreign body removal or decompression
4.
Reduced level of consciousness or inability to swallow without aspiration
5.
Any prior colorectal surgery, excluding appendectomy, hemorrhoid surgery, or prior 
6.
endoscopic procedures


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Upper gastrointestinal surgery (gastrectomy, gastric banding, gastric by-pass)
7.
Uncontrolled angina and/or myocardial infarction (MI) within last three months, congestive 
8.
heart failure (CHF), uncontrolled hypertension, or ascites 
Severely reduced renal function (<30 mL/min/1.73 m2)
9.
Pregnant or lactating women
10.
Taking another investigational medicinal product within 30 days prior to receiving study 
11.
medication (or within 60 days for investigational drugs with an elimination half-life greater 
than 15 days)
Any clinically relevant abnormal findings in medical history, physical examination, vital 
12.
signs, ECG, clinical chemistry, hematology, coagulation, or urinalysis at Screening Visit 
(V1, see Section  6.1) or Randomization Visit (V2, see Section  6.2), which in the opinion of 
the Investigator(s) might put the subject at risk because of his/her participation in the trial
Current alcohol and/or drug abuse as judged by the Investigator
13.
Severe dehydration as judged by the Investigator
14.
Rhabdomyolysis
15.
Chronic nausea and vomiting
16.
Hypermagnesemia
17.
Considered by the Investigator to be unsuitable to participate in the trial for any other reason
18.
Hypersensitivity to any of the  ingredients of the study medication
19.
Undergoing treatment with Lithium
20.
4.2
Method of Assigning Subjects to Treatment Groups
4.2.1
Recruitment
Adult subjects age 18-80 who are being scheduled to undergo an elective colonoscopy will be screened 
to determine if they meet all inclusion/exclusion criteria and are willing to participate in the study. A 
screening log of all subjects considered for participation in the study will be maintained at each study 
site. 
Each subject must receive a detailed explanation of the study and must sign the Informed Consent 
Form after having sufficient time to consider his or her participation in the study. 
Under no circumstances will subjects in the study be permitted to re-screen for a second time in this 
study.
4.2.2
Randomization
The randomization list will be generated by an independent, unblinded statistician prior to the first 
subject’s first visit. Each subject will be randomized (1:1) to one of the two treatment arms, NaP/MC 
Oral Solution or PREPOPIK®, prior to the distribution of study drug. Randomization numbers will be 


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allocated sequentially to the subjects at each site, in the order in which the subjects are randomized at 
the site.  
A subset of subjects will participate in a PK assessment and will have blood samples collected four 
times on the day that the colonoscopy is performed. Approximately 60 randomized subjects will be 
included in this PK sub-group. A subset of sites will be identified as PK sites and subjects for this sub-
group will come from these sites. Randomization will be stratified by site and PK sub-group (whether 
or not a subject participates in the PK sub-group).
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
Water Insufflation During Colonoscopy Insertion
In order to standardize the insufflation procedure during colonoscopy insertion, only air insufflation
will be permitted in this study. Water insufflation is not permitted in this study as a first line practice. 
In the rare event that water insufflation is necessary to complete the procedure, the use of water 
insufflation will be recorded in the eCRF together with the volume of liquid used to complete the 
procedure.
4.3.2
Prior and Concomitant Therapies
Use of any concomitant medication should be recorded in the eCRF.
4.3.3
Prohibited Therapy

The following medications exclude subjects’ participation in the study and/or must be suspended 
prior to the Laxatives (within 24 hours prior to procedure)

Constipating drugs such as opiates, anticholinergics, calcium channel blockers, and clonidine 
(within 48 hours prior to procedure)

Antidiarrheals such as loperamide (within 72 hours prior to procedure)

Oral iron preparations (within one week prior to procedure)
4.3.4
Other Restrictions
On the day before the colonoscopy, subjects are limited to a liquid diet only. The unblinded 
coordinator, who dispenses the study drugs, will instruct the subject(s) about the exact requirements 
during Randomization Visit (V2, see Section 6.2). Diet and liquid intake will be collected on the CRF.


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5
TREATMENTS
5.1
Treatments Administered
Each subject will be randomly assigned to one of the following treatment groups:
• NaP/MC Oral Solution: Supplied as two 160-mL bottles per subject. The medication needs no 
further reconstitution before administration.
• PREPOPIK®: Supplied as two packets per subject. Subjects will be instructed to reconstitute the 
medication by combining the contents of one packet with approximately five (5) ounces of cold 
water and stirring for two to three minutes (in some cases the cup may feel warm, which is normal).
5.1.1
Investigational Medicinal Product (IMP)
Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid (NaP/MC) Oral Solution
Dose: Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid (NaP/MC) Oral Solution
will be provided as two 160-mL bottles to be administered in divided doses. 
The first dose is administered the evening before the colonoscopy between 5:00 PM and 9:00 PM. The 
second dose is administered at least five (5) hours, but no more than nine (9) hours, prior to the 
colonoscopy.
Preparation: NaP/MC Oral Solution is supplied as two 160-mL bottles per subject and needs no 
further reconstitution before administration.
Compliance will be documented in the eCRF. Subjects will be considered compliant if the dosing 
occurs within 30 minutes of specified timings above.
After drinking the first dose, subjects should drink five (5) or more eight-ounce glasses of clear liquid 
within five (5) hours.  After drinking the second dose, subjects should drink four (4) or more eight-
ounce glasses of clear liquid within five (5) hours. Subjects should not take anything by mouth within 
two (2) hours before the time of the colonoscopy.
PREPOPIK®
Dose: PREPOPIK®: Is supplied as two (2) packets per subject. One dose is prepared by combining the 
contents of one packet with approximately five (5) ounces of water. 


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Subjects will take the first dose the evening before the colonoscopy between 5:00 and 9:00 PM and 
will complete the treatment (second dose) the following day at least 5 hours prior but no later than 9 
hours prior to the colonoscopy.
Preparation: Mix the contents of one (1) packet with cold water (approximately five (5) ounces) in 
the cup provided. Stir for two to three minutes and drink the solution. In some cases the cup may feel 
warm, which is normal.
Compliance will be documented in the eCRF. Subjects will be considered compliant if the dosing 
occurs within 30 minutes of specified timings above.
After drinking the first dose, subjects should drink approximately five (5) eight-ounce glasses of clear 
liquid within five (5) hours.  After drinking the second dose, subjects should drink three (3) eight-
ounce glasses of clear liquid within five (5) hours. Subjects should stop taking anything by mouth two 
(2) hours before the time of the colonoscopy.
Note: Liquids with red, purple, or blue coloring are not allowed before the colonoscopy. 
Permissible clear liquids include the following, as long as they are not red, purple or blue in color:

Broth/bouillon: chicken, beef, or vegetable

Juices without pulp: apple juice, white grape juice, white cranberry juice

Water: plain or flavored

Soda: Sprite, Seven Up, ginger ale

Popsicles: orange, lime, lemon

Jell-O: orange, lime, lemon

Other permissible liquids: Gatorade, Crystal Light, Pedialyte, coffee, tea (do not add dairy/non-
dairy cream or milk)
The following diet requirements and restrictions should be followed for subjects admitted into the 
study regardless of the treatment group:
On the day (i.e., 24 hours) before the procedure, subjects are limited to a clear liquid diet only. Special 
meal instructions for diabetic subjects are provided in Appendix B. The unblinded coordinator who 
dispenses the drug will explain any dietary restrictions or requirements during the randomization visit 
(V2, see Section 6.2), including the need for correct hydration prior to starting bowel preparation.


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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
Investigational Medicinal Product
5.2.1.1
Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid (NaP/MC) Oral 
Solution
NaP/MC Oral Solution will be supplied in two (2) 160-mL bottles and contains the following active
ingredients:

Sodium Picosulfate 10.0 mg

Magnesium Oxide, Light 3.5 g

Citric Acid, Anhydrous 12.0 g
Magnesium oxide and anhydrous citric acid react in solution to form magnesium citrate.
NaP/MC Oral Solution is manufactured and supplied by Ferring Pharmaceuticals in boxes containing 
two 160 mL bottles each. 
5.2.1.2
PREPOPIK®
PREPOPIK® is a white crystalline powder for oral solution and will be supplied in two (2) packets. 
Each packet of PREPOPIK® contains the following ingredients:

Sodium Picosulfate 10.0 mg

Magnesium Oxide, Light 3.5 g

Citric Acid, Anhydrous 12.0 g
Magnesium oxide and anhydrous citric acid react in solution to form magnesium citrate.
PREPOPIK® is manufactured and supplied by Ferring Pharmaceuticals for the U.S. market in boxes 
containing two packets and a dosing cup.  
5.3
Packaging and Labeling
Packaging and labeling of the IMPs will be performed under the responsibility of the Ferring IMP
department. All packaging and labeling operations will be performed according to the requirements of 
GMP and national regulatory requirements.
The IMPs will be labeled with trial-specific labels, and the content on the labels will be in accordance 
with ANNEX 13, EudraLex volume 4, and national requirements in the countries where the study will 


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be conducted. The labels will contain a self-adhesive tear-off portion to be affixed to the dispensing log 
maintained at the trial site.
5.4
Conditions for Storage and Use
The Investigator will ensure that the medicinal products will be stored in appropriate conditions in a 
secure location with controlled access. The storage compartment shall be monitored regularly and the 
temperature shall be documented. Deviations in storage temperature must be reported to Ferring 
without delay and the IMPs must not be used until further instructions are received.
5.4.1
Investigational Medicinal Product
NaP/MC Oral Solution should be stored in the original package at temperatures not exceeding 25°C 
(77°F) and protected from light.
PREPOPIK® should be stored in the original package at temperatures not exceeding 25°C (77°F) and 
protected from light. 
5.5
Blinding / Unblinding
5.5.1
Blinding
Treatment is blinded to the endoscopist performing the colonoscopy and assessing the efficacy of the 
tested preparations and his/her assistant(s). Prior to the start of the study, the investigator will assign a 
coordinator and a pharmacist (if applicable) to act as the unblinded coordinator and unblinded 
pharmacist (if applicable). The designated unblinded study coordinator or unblinded pharmacist (if 
applicable) will be responsible for distribution and accountability of the drug and will instruct the 
subject and his/her parent/guardian about the use of the bowel preparation, including dietary 
restrictions. 
5.5.2
Unblinding of Individual Subject Treatment 
Emergency unblinding will be available to the investigator and designated persons at Sponsor via a 
centralized randomization system. In addition, one set of emergency decoding envelopes will be 
available at Sponsor as a back-up for unblinding.
Breaking of the blind in individual subjects is only permitted in case of a suspected unexpected serious 
adverse reaction (SUSAR) or in case of an important AE where the knowledge of the investigational 
product in question is required for therapeutic decisions for the management of the subject.
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 source documentation 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 


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for emergency unblinding must be obtained and the event must also be recorded in the source 
documentation.
It may be necessary to unblind an individual subject’s treatment for the purposes of expedited reporting 
to the authorities or to the site’s Institutional Review Board (IRB), or both. 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 SUSARs, 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.
5.6
Treatment Compliance
5.6.1
Dispensing and Accountability
IMP will be dispensed only to subjects who meet the eligibility criteria and are randomized to a 
treatment group in the trial. The unblinded coordinator or unblinded pharmacist (if applicable) (or 
his/her designated personnel, e.g., trial nurse) will maintain a Drug Dispensing Log detailing the dates 
and quantities of IMP dispensed to, and used by, each subject, as well as the unique batch identifier 
used in the trial. The unblinded monitor will verify the drug accountability during the trial and will 
document any discrepancies. 
5.7
Assessment of Compliance 
Subjects will be considered compliant if dosing occurs within ±30 minutes of specified timings. The 
time of administration will be recorded in a subject diary. This diary will be provided to the subject by 
the unblinded coordinator or unblinded pharmacist who dispenses the drug. The subject diary and 
specified medication time periods will be documented in the eCRF by the unblinded coordinator during 
the procedure at Visit 3. The sponsor and the blinded endoscopist will not have access to this 
information during the trial. 
5.8
Return and Destruction of Medicinal Products
All used medicinal products can be destroyed at the trial site (in accordance with local requirements) 
after drug accountability has been finalized, verified by the unblinded monitor, and signed off by the 
unblinded coordinator or unblinded pharmacist (if applicable).
All unused medicinal products must be returned for destruction, as instructed by the Ferring IMP 
department, after the drug accountability has been finalized, verified by the unblinded monitor, and 
signed off by the unblinded coordinator or unblinded pharmacist (if applicable).  Products will be 
destroyed in accordance with local requirements. 


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6
TRIAL PROCEDURES
6.1
Screening Visit (Visit 1)
Prior to or at the Screening Visit, the subject must receive a detailed explanation of the study and must 
sign the Informed Consent Form after having sufficient time to consider his/her participation in the 
study. After the subject has signed the Informed Consent Form, the following will be performed:

Obtain a thorough medical history and record demographic data

Document any concomitant medications up to seven days prior

Measure body weight and height

Measure orthostatic vital signs (blood pressure and pulse)

Perform a complete physical examination 

Obtain central laboratory sample: chemistry hematology and coagulation

Urinalysis

Serum pregnancy test for females of childbearing potential 

Conduct an ECG 

Schedule date of colonoscopy (≤21 Days from V1)

Schedule Randomization Visit (V2, see Section 6.2): date of randomization (V2 ≤03 days from 
V3)
6.2
Randomization Visit (Visit 2)
Randomization Visit 2 (V2) takes place ≤10 days from the Procedure/Colonoscopy Visit. For females 
of childbearing potential, the Randomization Visit (V2) must occur within three (3) days prior to 
the colonoscopy procedure. Females of childbearing potential must have a negative urine pregnancy 
test result at randomization. For males and postmenopausal women, the Randomization Visit (V2) 
must occur ≤10 days prior to the colonoscopy procedure (see Section 6.3). The following will be 
performed:
If the study screening requirements are met:

Confirm eligibility

Measure orthostatic vital signs (blood pressure and pulse)

Measure body weight


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
Urine pregnancy test (onsite) for females of childbearing potential (For females of 
childbearing potential randomization must occur within three (3) days prior to the 
colonoscopy procedure. Females of childbearing potential must have a negative urine 
pregnancy test result at randomization within 3 days prior to the colonoscopy.)

Assign Subject Randomization number 

Dispense study medication

Instruct the subject how to self-administer the study medication and provide them with a 
Subject Diary Card and detailed information, complete with assigned times of drug 
administration

Provide the Acceptability and tolerability questionnaire to be completed prior to the 
procedure Visit (V3)

Adverse events (recorded by study personnel)

Document any new concomitant medications
6.3
Procedure/Colonoscopy Visit (Visit 3) 
If the subject is participating in the PK subset, additional laboratory samples will be obtained for 
sodium picosulfate and BHPM at the following timepoints:
- 15 minutes before the second dose of IMP
- 1 to 2 hours after the second dose of IMP
- 3 to 6 hours after the second dose of IMP
Immediately prior to the colonoscopy, a PK sample will be obtained for all participating subjects in 
the study (approximately 2 hours prior to the colonoscopy).
Before the colonoscopy, the following will be performed:

Treatment completed

Collect Subject Diary Card

Collect the Acceptability and tolerability completed questionnaire* 

Obtain orthostatic vital signs (blood pressure and pulse)

Measure body weight

Obtain laboratory sample (chemistry, hematology)

Adverse events (recorded by study personnel)

Document any concomitant medications


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
PK subset only: PK samples for sodium picosulfate and BHPM 15 minutes before the second 
dose, and 1 to 2 hours and 3 to 6 hours after the second dose of the IMP

All subjects: PK sample immediately prior to colonoscopy (approximately 2 hours prior to the 
colonoscopy)

Perform study drug accountability by the unblinded coordinator or unblinded pharmacist (if 
applicable)
*Subjects should be instructed to fill out the questionnaire during the visit in a private area prior to 
contact with the Investigator and to return the completed questionnaire to the study coordinator. If the 
coordinator is not available during the procedure, the subject will put 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) should interpret questions or response choices for the subject.
During the colonoscopy procedure, the blinded endoscopist will:

Video-record the colonoscopy

Use the Modified Aronchick Scale (see Appendix C) to score the quality of the bowel 
preparation in the overall colon after use of the study drug 

Use the Boston Bowel Preparation Scale (see Appendix C) to score the quality of the preparation
in the different segments of the colon after use of the study drug 

Record the outcome of the colonoscopy
After the colonoscopy procedure, the following will be performed/recorded:

Adverse events (additional to those recorded prior to colonoscopy)

Measure orthostatic vital signs (blood pressure and pulse)

ECG

Urinalysis (including urine osmolality, which will be collected at this visit only)

Directed physical Examination
The subject will be scheduled to return in 1-2 days for a Follow-Up Visit (V4, see Section 6.4). 


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6.4
Follow-up Visit (Visit 4)
Follow-up visit (Visit 4) takes place 1 – 2 Days after the colonoscopy. The Investigator will perform 
the following:

A directed physical examination

Measure orthostatic vital signs (blood pressure and pulse)

Measure body weight

Interview the subject 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

Obtain central laboratory sample: chemistry and hematology

Urinalysis

ECG
The subject will be scheduled to return in seven (7) days (±2 days) for a Follow-Up Visit (V5, see 
Section 6.5). 
6.5
Follow-up Visit (Visit 5)
Follow-up visit (Visit 5) takes place seven (7) days (±2 days) after the colonoscopy.  The Investigator
will:

Perform a directed physical examination

Measure orthostatic vital signs (blood pressure and pulse)

Measure body weight

Interview the subject 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

Obtain central laboratory sample: chemistry and hematology

Urinalysis

ECG
The subject will be scheduled to return in twenty-eight (28)-Days (± 2 Days) for a Follow-Up Visit 
(V6, see Section 6.6). 


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6.6
Follow-up Visit (Visit 6)
Follow-up visit (Visit 6) takes place twenty-eight (28) Days (± 2 Days) after the colonoscopy. The 
Investigator will:

Perform a directed physical examination

Measure orthostatic vital signs (blood pressure and pulse)

Measure body weight

Interview the subject 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

Obtain central laboratory sample: chemistry and hematology

Urinalysis

ECG


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6.7
Trial Assessments
Table 1
Trial Assessment Table
Visit
1
Screening
2
Randomization
3
Procedure
4
Follow-up 
5
Follow-up 
6
Follow-up  
(EOT)
Timing versus Procedure
≤21 Days
≤10  Days
Colonoscopy
(T = 0)
1-2 Days
7 Days
(± 2 Days)
4 Weeks
(± 2 Days)
Informed consent
x
Inclusion/exclusion criteria
x
x
Demographic & Medical History
x
Body weight, Height1
x
x
x
x
x
x
Urine/Serum Pregnancy Test
x
x7
Schedule colonoscopy
x
Laboratory (chemistry, 
coagulation, hematology)
x2
x
x
x
x
PK sampling 
x3, 4
Urinalysis
x
x5
x
x
x
ECG
x
x
x
x
x
Physical examination
x
x
x
x
x
Orthostatic vital signs (BP, pulse)
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
Dispense fluid intake diary and 
study medication
x
Subject Tolerability Questionnaire 
x
Perform and video-record 
colonoscopy
x
Score overall colon preparation –
Modified Aronchick scale 
x
Score colon segments preparation
– Boston Bowel Preparation Scale
x
Drug accountability6
x
1.
Height will only be collected at screening.
2.
Coagulation samples will only be collected at screening.
3.
In a subset of subjects, PK samples for sodium picosulfate and BHPM will be taken 15 minutes before the second dose, and 1 to 2 hours and 
3 to 6 hours  after the second dose of the Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid.
4.
All subjects will have a PK sample drawn immediately prior to colonoscopy (approximately 2 hours prior to the colonoscopy).  
5.
At the colonoscopy visit, the urinalysis panel will include urine osmolality.
6.
Drug accountability will be performed by an unblinded coordinator or unblinded pharmacist (if applicable) and an unblinded monitor only.
7.
Premenopausal women of childbearing potential must have a urine pregnancy test performed within 3 days prior to colonoscopy. For 


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women of childbearing potential randomization must occur within 3 days prior to colonoscopy
7
TRIAL ASSESSMENTS 
The efficacy of the colon cleansing will be measured by a blinded endoscopist using the Modified 
Aronchick Scale and The Boston Bowel Preparation Scale. The endoscopist performing the 
colonoscopy and evaluation will be blinded to the treatment. 
7.1
Assessments Related to Endpoints
7.1.1
The Modified Aronchick Scale
The efficacy of overall colon cleansing will be measured by a blinded endoscopist using the Modified 
Aronchick scale. The overall colon will be graded as “Excellent”, “Good”, “Fair”, or “Inadequate” 
according to the definitions in Table 2.
Table 2
Modified Aronchick Scale
Grade
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 equals “excellent” or “good” on 
this four-point scale.
The blinded endoscopist will record in the eCRF 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.
7.1.2
The Boston Bowel Preparation Scale


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The efficacy of right colon cleansing, transverse colon cleansing, and left colon cleansing will be 
measured by a blinded endoscopist using the Boston Bowel Preparation Scale after 
washing/suctioning. Colon cleansing will be graded 0, 1, 2, or 3, according to the definitions in The
Boston Bowel Preparation Scale (see  Appendix C). 2
Figure 2
The Boston Bowel Preparation Scale
0
Unprepared colon segment with mucosa not seen due to solid stool that cannot be cleared.
1
Portion of mucosa of the colon segment seen, but other areas of the colon segment not well 
seen due to staining, residual stool, and/or opaque liquid.
2
Minor amount of residual staining, small fragments of stool and/or opaque liquid, but 
mucosa of colon segment seen well.
3
Entire mucosa of colon segment seen well with no residual staining, small fragments of 
stool or opaque liquid.
Each region of the colon receives a “segment score” from 0 to 3, and these segment scores are summed 
for a total BBPS score ranging from 0 to 9. The maximum BBPS score for a perfectly clean colon 
without any residual liquid is 9, and the minimum BBPS score for an unprepared colon is 0. If an
endoscopist aborts a procedure due to an inadequate preparation, then any non-visualized proximal 
segments are assigned a score of 0.
Both the Modified Aronchick scale and BBPS Scale are attached as  Appendix C.


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7.1.3
Mayo Clinic Bowel Preparation Tolerability Questionnaire 
A secondary efficacy endpoint will be assessed by the validated3 Mayo Clinic Bowel Preparation 
Tolerability Questionnaire. This questionnaire will be administered to the subject to the subject at Visit 
3 on the day of the colonoscopy procedure. The Mayo Clinic Bowel Prep Tolerability Questionnaire is 
a simple, comprehensive questionnaire developed to evaluate the tolerability of various types of bowel 
preparations. The Mayo Clinic Bowel Preparation Tolerability Questionnaire is attached as Appendix 
D.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 the other 
scheduled visits (and at early termination if applicable), a directed physical examination will be 
performed. Height will be measured at Visit 1 only, but weight will be measured in every visit.  
After study drug administration, any new abnormal findings or worsening of an ongoing abnormal 
condition will be recorded as an AE.
7.2.2
Orthostatic Vital Signs
Orthostatic vital signs (blood pressure and pulse) will be measured at each scheduled visit (and at early 
termination, if applicable) as follows. Blood pressure and pulse will be measured after at least 5 
minutes of rest in supine position and after 3 minutes in standing position. Standing measurements 
should be repeated after 10 minutes in patients with symptoms of volume depletion (e.g. mild 
dizziness) that have not presented changes in orthostatic vital signs after 3 minutes of standing.
7.2.3
Clinical Laboratory Variables
All laboratory measurements will be performed using appropriately validated methods by a central 
laboratory selected by the Sponsor. Sample handling and storage will be provided to all sites directly 
from the central laboratory. 
Laboratory values will be reported to the Investigator and Sponsor (or the Sponsor’s representative) 
and will automatically be uploaded to a database. The database will be maintained by a clinical 
research organization selected by the Sponsor.
Out of range values will be described in the laboratory manual to be provided by the central laboratory. 
Investigators will assess all out of range values as being either clinically significant or not clinically 
significant via the eCRF. Clinically significant abnormal laboratory measurements should be reported 
as AE.


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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 adverse events post study drug administration. 
Sites will be provided with sampling supplies and materials for shipment and a manual detailing all 
sample collection and shipment procedures.
Following Screening Visit (V1, see Section 6.1), subjects with clinically significant abnormal 
laboratory values will not be randomized into this study.
The following values will be collected and sent out to the central laboratory at all study visits except 
the randomization visit.

Hematology panel:

Full CBC and differential 

Full chemistry panel:

Serum Chemistry: serum osmolality, bicarbonate, fasting glucose, blood urea nitrogen 
(BUN), creatinine, magnesium, potassium, sodium, chloride, calcium, protein total, 
albumin, bilirubin total, alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), and gamma glutamyl transferase (GGT)

Calculated creatinine clearance and BUN/creatinine ratio

Urinalysis panel (at the colonoscopy visit (V3), this includes urine osmolality)
The following values will be collected at the site during the Screening Visit only (see Section 6.1):

Serum pregnancy test for premenopausal female subjects 

Coagulation Panel:

PT, APTT
The following value will be collected during Randomization Visit only (V2, see Section 6.2):

Urine pregnancy test (onsite) for premenopausal female subjects
The Investigator will review the laboratory results and evaluate and document whether the results are 
normal or abnormal and whether abnormal results are non-clinically or clinically significant. The 
Laboratory Report will be signed and dated by the Investigator.


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7.2.4
ECG
A standard 12-lead ECG will be performed as indicated in Table 1 Trial Assessment Table. After at 
least a 5-minute rest in a supine position, an ECG will be obtained at each visit (and at early 
termination, if applicable). Additional ECGs may be obtained if clinically indicated.
At each visit when an ECG is done, the investigator must review and initial the tracing. The tracing 
must then be stored with the subject's source documents.
The baseline ECG performed at the Screening Visit must be reviewed for major abnormalities before 
dosing.
If the ECG findings are clinically relevant and would prevent the subject from participating in the 
study (taking into account the subject's overall status), the subject should not receive the IMP. 
All other abnormalities noted on the baseline ECG are reported in the Medical History eCRF. 
Clinically relevant abnormalities noted after the baseline ECG (Randomization Visit) should be 
recorded as AE 
7.2.5
Fluid Intake and Dosing Diary
Subject should complete the fluid intake diary at the time of the bowel preparation. The goal is to 
record subjects compliance with regards to type and amount of fluid intake during dosing.
The diary will also record the time of the assigned preparation doses. The fluid intake diary will be 
completed for both bowel preparations. The first section of the diary should be completed after the first 
dose of the assigned bowel preparation. The second section of the diary should be completed after the 
second dose and prior to the colonoscopy procedure.
7.2.6
Other Colonoscopy Assessments
Colonoscopies will be video-recorded. Colonoscopy times (time from insertion to cecum and 
withdrawal time) and findings such as number and histology of polyps (i.e. adenomas, hyperplastic) 
identified during the colonoscopy will be collected and registered in the CRF. 
Recommended colonoscopy follow up intervals based on the results of the current procedure will also 
be registered, including those scheduled before the recommended interval of 10 years due to 
inadequate preparation.


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7.3
Drug Concentration Measurements
For approximately sixty (60) subjects in the two (2) PREPOPIK® groups that are participating in the 
PK subset, additional blood samples for measurement of sodium picosulfate and BHPM plasma 
concentrations will be collected. Samples will be obtained for sodium picosulfate and BHPM at Visit 3 
at the following timepoints:
- 15 minutes before the second dose of IMP
- 1 to 2 hours after the second dose of IMP
- 3 to 6 hours after the second dose of  IMP
In addition, all subjects enrolled in the study will have a PK sample for sodium picosulfate and 
BHPM collected immediately prior to their colonoscopy (approximately 2 hours prior to the 
colonoscopy).
Accurate dosing information of both doses and timing of PK samples relative to dosing will be 
recorded.
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 central safety 
laboratory and the PK 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. Shipment of stored PK 
samples from the site to the PK laboratory should be on a prespecified basis. The study sites will ship 
one aliquot of the PK samples on dry ice to the PK laboratory. The remaining PK samples must be kept 
at the study centers as backup samples. These remaining samples will only be disposed of after 
approval by the sponsor (approximately 6 to 12 months after the publication of the clinical study 
report). 
The actual date and time of the PK sample collection will be entered in the eCRF under ‘Blood 
collection for PK’ or ‘Unscheduled blood collection for PK’, as appropriate. Sampling problems will 
be noted in the ‘Reason sample not taken’ section of the eCRF.
Any remaining blood samples that are not analyzed for the trial will be stored at the PK laboratory until 
the clinical trial report has been finalized.


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial. It 
includes: 

Any unfavourable and unintended sign, symptom, or disease, whether or not considered to be 
caused by the IMP

Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP

Any laboratory abnormality, vital sign, or finding from physical examination assessed as 
clinically significant by the Investigator. [Note: pre-existing conditions diagnosed through 
assessments and examinations at the Screening Visit (V1, see Section 6.1) or during the 
screening period are not adverse events, 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 having a reasonable 
possibility of being related to treatment with the IMP. 
A serious ADR is a serious adverse event (SAE) evaluated by the investigator and/or by Ferring as 
having a reasonable possibility of being related to treatment with the IMP.
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 defined as 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.


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The sources of adverse events 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

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 adverse events in the Adverse Event Log provided in each subject’s 
eCRF with information about:

Adverse event

Date and time of onset

Severity

Causal relationship to IMP

Action taken to IMP

Other action taken

Date and time of outcome (or ongoing at trial end if no outcome)

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 adverse event more than once and the subject recovers in between 
the events, the adverse events should be recorded separately. If an adverse event changes in intensity, a


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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 adverse event; the reason for conducting the procedure is. 
Hospitalization is not an adverse event (it is an outcome); the reason for hospitalization is. Death is not 
an adverse event (it is an outcome); the cause of death is (an exception is sudden death of unknown 
cause, which is, itself, an adverse event).
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 adverse event 
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 adverse event must be classified using the following three-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 adverse event 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 adverse event. 
The adverse event may occur as part of the pharmacological action of the IMP or may be unpredictable 
in its occurrence.
Examples: 

Adverse events that are uncommon but are known to be strongly associated with IMP exposure
                                                
a
Exception: if an adverse event with onset before the first IMP administration (i.e., a pre-treatment adverse event) 
worsens in intensity, this must be recorded as two separate events. The initial adverse event should be recorded 
with outcome “not recovered,” and the date and time of outcome is when the intensity changed. The second 
adverse event should be recorded with date and time of onset when the intensity changed. 


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
Adverse events 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 
adverse event.
Examples:

Known consequences of the underlying disease or condition under investigation

Adverse events common in the trial population, which are also anticipated to occur with some 
frequency during the course of the trial, regardless of IMP exposure
Action Taken to IMP
The action taken to the IMP in response to an adverse event must be classified as one of the following:

No change (medication schedule maintained or no action taken)

Withdrawn

Interrupted
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 adverse event, this medication should be entered in the 
Concomitant Medication Log.
Date and Time of Outcome
The date and time the subject recovered or died.
Outcome
The outcome of an adverse event 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)


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
Recovering (the event is improving)

Not recovered

Fatal
8.3
Pregnancy and Pregnancy Outcome
If a pregnancy occurs, the IMP should be immediately stopped and Global Pharmacovigilance at 
Ferring Pharmaceuticals must be informed using the Pregnancy Report Form within 3 calendar days. 
Note that the pregnancy itself is not a serious adverse event (SAE). 
The mother and the fetus must be followed-up at least until the birth of the infant and four to six weeks 
after the birth of the infant. In general, the follow-up will include course, duration, and the outcome of 
the pregnancy, as well as neonatal. If a pregnancy results in an abnormal outcome (birth 
defect/congenital anomaly) this must be reported as a serious adverse event to Global 
Pharmacovigilance at Ferring Pharmaceuticals as described in section 8.4.2.
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 a serious adverse event to Global 
Pharmacovigilance at Ferring Pharmaceuticals as described in section 8.4.2.
8.4
Serious Adverse Events
8.4.1
Serious Adverse Event Definition
Serious adverse events (SAEs) are defined in Table 3.
Table 3
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 
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 


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An event is defined a serious 
adverse event if it:
Guidance
of existing hospitalization
at least 24 hours. Overnight stay for observation, stay at emergency room, or treatment 
on an out-patient basis do not constitute a hospitalization. However, medical judgement 
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 adverse events, 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 judgement 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 judgement 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.
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 and not later than within 24 hours of their knowledge of the occurrence of an SAE.
SAEs (initial and follow-up) that are recorded electronically in the eCRF system should be entered, 
saved and e-signed within 24 hours of awareness of the SAE or changes to an existing SAE. The data 


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will automatically be submitted to Ferring Pharmacovigilance immediately after investigator signature 
or 24 hours after entry, whichever occurs first. 
Follow- up information provided should describe whether the event has resolved or continues, if and 
how it was treated, whether the treatment code was broken or not and whether the subject continued or 
withdrew from study participation. Each re-occurrence, complication, or progression of the original 
event should be reported as a follow-up to that event regardless of when it occurs.
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 24 hours 
of awareness of the SAE or changes to an existing SAE to Ferring Pharmacovigilance using the contact 
details below. The original copy of the SAE Report Form and the fax confirmation sheet must be kept 
with the case report form documentation at the study site. Follow-up information should be provided 
using a new paper SAE Report Form stating that this is a follow-up to a previously reported 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.
Global Pharmacovigilance, Ferring Pharmaceuticals A/S
E-mail: safety.mailbox@ferring.com
Fax: (1) 973-796-1791
Demographics, adverse events, medical history, and concomitant medication will be included in initial 
reports and in follow-up reports if any changes have been made since the initial report. If additional 
information is needed, site personnel may refer to EDC system.
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.


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Expedited Reporting by Ferring
Ferring will report all adverse events that are serious, unexpected and with a reasonable possible 
causality to the IMP as judged by Ferring to the relevant parties within the stipulated timelines.
SAEs 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 adverse event until it is resolved or until the 
medical condition of the subject is stable.
After the subject’s last visit, the investigator must follow-up on any adverse event 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 Visit in the Trial
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
All analyses will be detailed in a separate Statistical Analysis Plan (SAP).
9.1
Determination of Sample Size
The primary objective of this study is to demonstrate NI of NaP/MC Oral Solution to PREPOPIK® for 
overall colon cleansing prior to colonoscopy using the Modified Aronchick Scale (see Appendix C), as 
assessed by a blinded endoscopist.1 A subject is considered to be a “responder” if overall colon 
cleansing is either “excellent” or “good” on the Modified Aronchick Scale. 
The assumed true responder rate for PREPOPIK® is 84% when using the Modified Aronchick Scale
(FE2009-01 and FE2009-02). It is assumed that the true responder rate of subjects treated with 
PREPOPIK® or NaP/MC Oral Solution are the same. A NI margin of 8% was chosen, to ensure no 
more than a 10% relative decrease from the control.  Four hundred and fifty randomized subjects per 
treatment group are required, in a 1:1 randomization, to maintain at least 90% power to demonstrate 
the NI of NaP/MC Oral Solution to PREPOPIK® for overall colon cleansing prior to colonoscopy at 
the one-sided 0.025 significance level.
For PK assessment, blood samples will be collected on a subset of sixty (60) subjects three times on 
the day of colonoscopy. Sixty (60) subjects (approximately 30 per arm) are considered to be sufficient 
to characterize the PK population for sodium picosulfate and BHPM. In addition to this, all subjects 
enrolled in the study, including this PK subset, will have one (1) PK blood sample drawn for sodium 
picosulfate and BHPM immediately prior to their colonoscopy (approximately 2 hours prior to the 
colonoscopy).
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. The number of subjects screened and 
not randomized will be presented. 
9.3
Protocol Deviations
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Ferring or its agents, if any, monitoring the trial to 
request approval of a protocol deviation, as protocol deviations will not be granted.
Major or minor protocol deviations will be defined and documented prior to database lock. Details will 
be provided in the Statistical Analysis Plan and/or in the Clean File document.


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9.4
Analysis Sets
9.4.1
Intention-to-Treat (ITT) Analysis Set 
The ITT analysis set comprises all randomized subjects. The ITT analysis set will be analyzed 
according to randomized treatment.
9.4.2
Modified Intention-to-Treat (mITT) Analysis Set
The primary efficacy analysis will be conducted for the mITT analysis set and is defined as all ITT 
subjects who received at least one dose of treatment. The mITT analysis set will be analyzed according 
to randomized treatment.
9.4.3
Per Protocol (PP) Analysis Set
The PP analysis set comprises all mITT subjects except those excluded as a result of major protocol 
deviations. 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. The PP 
analysis set will be analyzed according to the actual randomized treatment received.
9.4.4
Safety Analysis Set
The safety analysis set comprises all subjects who received any amount of study medication. The 
safety analysis set will be analyzed according to the actual treatment received. 
9.5
Trial Population
9.5.1
Demographics and Other Baseline Characteristics
Descriptive statistics of demographics, other baseline characteristics, and medical history will be 
presented for the mITT and Safety analysis sets separately. In addition, since this is a multi-site trial, a 
summary of demographic and baseline characteristics will be presented by trial site.
9.5.2
Medical History
Medical history recorded at screening visit will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 16.1 or later. Medical history will be listed by treatment and subject, and 
summarized by treatment group, system organ class (SOC), and preferred term (PT) for the subjects in 
the mITT and safety analysis sets, separately.
9.5.3
Prior and Concomitant Medication
Prior and concomitant medications will be coded using World Health Organization Drug (WHODrug) 
Dictionary version 01SEP2013 or later. Medications will be listed by treatment and subject as well as 
summarized by treatment group, Anatomical Therapeutic Chemical (ATC) classification 1st level 


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(alphabetically), and ATC classification 2nd level (in decreasing order of frequency) for the subjects in 
the mITT and safety analysis sets, separately. Medications will be tabulated separately for:
1) Prior medication; i.e., medication taken exclusively prior to first IMP administration, i.e., with 
stop date before date of first IMP administration
2) Concomitant medication, i.e., medication taken after IMP administration (regardless of whether 
the drug began before first IMP administration), i.e., medication that was not stopped before 
date of first IMP administration and not started after the end-of-trial visit
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication.
9.6
Endpoint Assessments
9.6.1
General Considerations
The primary and secondary efficacy analyses will be conducted for the mITT analysis set. Continuous 
variables will be described with the number of non-missing values, mean, standard deviation, median, 
and minimum/maximum values. Categorical variables will be described with the number and 
percentage of subjects within each level.
In order to preserve the type I error in this study, the NI of the cleansing within the right colon will 
only be assessed if NI is demonstrated within the mITT analysis set for the primary endpoint.  
Superiority for the primary endpoint will be assessed if and only if NI is demonstrated for both the 
primary efficacy endpoint and the secondary efficacy endpoint for the right colon.
9.6.2
Primary Endpoint(s)
The difference between the responder rates in overall colon cleansing using NaP/MC Oral Solution or
PREPOPIK® will be assessed. A subject is considered to be a “responder” if overall colon cleansing is 
classified as either “excellent” or “good” by the blinded endoscopist using the Modified Aronchick 
Scale (see Appendix C).1 The NI margin for the difference between treatments (NaP/MC Oral Solution
minus PREPOPIK®) will be -8% (absolute). The NI hypothesis to be tested for the primary endpoint 
will be:
H0: π NaP/MC Oral Solution - π PREPOPIK
® ≤-8% 
against the alternative 
H1: π NaP/MC Oral Solution - π PREPOPIK
® >-8%, 
where π NaP/MC Oral Solution and π PREPOPIK
® denote the true percentage of subjects classified as responders 
(i.e., excellent and good according to the Modified Aronchick Scale (see Appendix C)) among subjects 


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treated with NaP/MC Oral Solution or PREPOPIK®, respectively, for colon cleansing in preparation 
for colonoscopy.
The null hypothesis (H0) will be tested against the alternative by constructing a 2-sided 95% 
confidence interval for the difference in responder rates. The primary analysis will be adjusted for the 
stratification factor (site) by using the Mantel-Haenszel method to combine results across sites. In 
brief, this corresponds to deriving a weighted average across sites where the weight depends on the 
number of observations in each treatment group in each stratum.  Subjects who do not have an 
excellent or good rating according to the Modified Aronchick Scale (see Appendix C) for any reason 
will be considered treatment failures (i.e., not a responder). If the lower limit of the 95% confidence 
interval is greater than the margin (-8%), the null hypothesis will be rejected and it will be claimed that 
NaP/MC Oral Solution is non-inferior to PREPOPIK® with respect to colon cleansing in preparation 
for colonoscopy. If NI is demonstrated for both the primary efficacy endpoint and the secondary 
efficacy endpoint for the right colon (see Section 9.6.3.1), and if the lower bound of the confidence 
interval is above 0% then, superiority will be declared. 
The NI analysis will also be conducted for the per-protocol (PP) population as a sensitivity analysis.  
An additional sensitivity analysis may be performed, where a multiple imputation method will be 
applied to impute for subjects with missing colonoscopy assessment for reasons other than drug 
tolerability and for patients where water insufflation was used. Details of such analysis will be 
described in the analysis plan.
9.6.3
Secondary Endpoint(s)
9.6.3.1
BBPS (Right Colon)
The difference between the responder rates in the right colon cleansing using NaP/MC Oral Solution or
PREPOPIK® will be assessed. A subject is considered to be a “responder” if the BBPS (Right Colon)
score is ≥2. Using the mITT population and the analysis methodology described for the primary 
endpoint a 95% two-sided confidence interval for the responder rate difference of NaP/MC Oral 
Solution minus PREPOPIK® will be constructed. If the NI objective is met for the primary endpoint, 
this CIs will be used to assess the NI of NaP/MC Oral Solution to PREPOPIK® in the cleansing of 
right colon as assessed by BBPS. The NI margin for the testing the difference between treatments 
(NaP/MC Oral Solution minus PREPOPIK®) for cleansing of the right colon is again set to be -8% 
(absolute). Hence, if the lower bound of this confidence interval exceeds -8.0% then NaP/MC Oral 
Solution will be declared non-inferior to PREPOPIK® with respect to the cleansing of the right colon. 
9.6.3.2
BBPS (Transverse Colon)
The responder rate for the transverse colon using BBPS will be analyzed in the same manner as the 
primary endpoint for the mITT analysis set, according to the subjects’ randomized treatment group, 


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and 95% confidence interval for the responder rate of NaP/MC Oral Solution minus PREPOPIK® will 
be presented. A subject is considered to be a “responder” if the BBPS (Transverse Colon) score of the 
transverse colon is ≥2. 
9.6.3.3
BBPS (Left Colon)
The responder rate for the left colon using BBPS will be analyzed in the same manner as the primary 
endpoint for the mITT analysis set according to the subjects’ randomized treatment group, and 95% 
confidence interval for the responder rate of NaP/MC Oral Solution minus PREPOPIK® will be 
presented. A subject is considered to be a “responder” if the BBPS (Left Colon) score of the left colon 
is ≥2. 
9.6.3.4
Tolerability and Satisfaction
Mayo Clinic Bowel Prep Tolerability Questionnaire (see Appendix D) questions 2, 3, 4, 6 (for each 
category), and 9 will be analyzed separately and summary statistics will be provided for all individual 
questions by randomized treatment group for the mITT population. The Wilcoxon Rank Sum 2-sided
test will be used for the treatment comparison of ordered categorical variables.
9.6.3.5
Drug Concentration Measurements/Pharmacokinetics 
Drug concentrations of sodium picosulfate, magnesium and BHPM will be summarized by descriptive 
statistics. Apparent clearance and volume of distribution will be estimated, if possible.
9.7
Extent of Exposure and Treatment Compliance
The total treatment exposure, the amount of study drug reported as consumed, and the reported timing 
of treatment administration 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 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
Safety parameters will be evaluated for the safety analysis set according to actual treatment received.
No formal statistical hypothesis testing will be conducted for the safety parameters.
9.8.2
Adverse Events
Treatment-emergent adverse events (TEAEs) will be summarized overall and tabulated by System 
Organ Class (SOC) and Preferred Term (PT) using Medical Dictionary for Regulatory Activities 
(MedDRA) version 16.1 or later. A TEAE is any adverse event that occurs after the start of IMP and 
within 30 days from the last exposure to IMP, or a pre-treatment adverse event/medical condition that 


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worsens in intensity after the start of IMP and within 30 days from the last exposure to IMP. The total 
number of subjects reporting a TEAE, the percentage of subjects (%) with a TEAE, and the number of 
treatment-emergent adverse Events (E) reported will be presented. 
Summary tables will be prepared for:

All TEAEs

TEAEs by causality (related/unrelated)

TEAEs by intensity

Serious adverse events

Adverse events leading to discontinuation

Adverse events leading to death

Adverse events with an incidence of at least 5%

Non-serious adverse events with an incidence of at least 5%
A data listing will also be provided for all adverse events.
9.8.3
Safety Laboratory Variables
All safety laboratory values outside normal range will be listed separately by subject number, including 
demographic information and flagging values.  
Continuous laboratory safety data will be summarized by treatment group and scheduled time point 
using descriptive statistics: sample size, mean, median, standard deviation, minimum, and maximum 
values. Changes from baseline will be summarized in the same way. 
Categorical laboratory safety data will be summarized separately by treatment group and scheduled
time point using the number and percentage of subjects in each category.
The incidence of clinically significant changes in laboratory values will be summarized separately by 
treatment group and scheduled time point.


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9.8.4
Other Safety Variables
9.8.4.1
Vital Signs
Each vital sign will be summarized by treatment group and scheduled 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. 
The incidence of clinically significant changes in vital signs will be summarized separately by 
treatment group and scheduled time point.
The incidence of markedly abnormal changes in vital sign values will be summarized by treatment 
group.
9.8.4.2
ECGs
The incidence of clinically significant changes in ECGs will be summarized separately by treatment 
group and scheduled time point.
ECGs at each evaluation will be listed for the safety dataset. Subjects with abnormal values will be 
noted on the data listings.
9.8.4.3
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 for this study.


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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).
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
The investigator shall retain all trial documentation including all the source records and relevant 
correspondence for a period of at least 15 years after regulatory approval [or longer if required by local 
laws] after the completion or discontinuation of the trial, if no further instructions are given by Ferring. 
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
Electronic Data Capturing System (EDC)
In the trial an EDC 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 EDC 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 a (including audit trail, electronic signature, and queries) as write-
protected PDF-files produced by the independent third party. The PDF-files will be stored on a CD and 
will be provided to the investigator before access to the eCRF is revoked.


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The Investigator will approve/authorise the EDC entries for each subject with an electronic signature 
which equals a handwritten signature. 
Trial data has to be entered into the system within a maximum of three to five working days after the 
subject 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
Patient Reported Outcome (PRO) 
Subject tolerability and satisfaction with the preparation will be assessed by the validated Mayo Clinic 
Bowel Prep Tolerability Questionnaire3 administered on the day of the colonoscopy and prior to the 
procedure; attached as Appendix D.
10.4
Data Management 
A data management plan will be created under the responsibility of the Biometrics Department of 
Ferring International PharmaScience Center U.S. 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.
A data flow diagram will describe data capture methods, who is authorized to enter data, decision 
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.
10.5
Provision of Additional Information
On request, the Investigator will provide Ferring with additional data relating to the trial, or copies of 
relevant source records, duly anonymized 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, PK 
sample laboratory manuals, International Conference of Harmonisation-Good Clinical Practice (ICH-
GCP), standard operating procedures and applicable regulatory requirements, maintenance of trial-
related source records, completeness, accuracy, and verifiability of eCRF entries compared with source 
data, and verification of drug accountability, and compliance to safety reporting instructions. 
The Investigator will permit the monitor direct access to all source data, including electronic medical 
records, and/or documents in order to facilitate data verification. The Investigator will co-operate with 
the monitor to ensure that any discrepancies that may be identified are resolved. The Investigator is 
expected to be able to meet the monitor during these visits.
For this trial, the first on-site monitoring visit will take place at each site within 4 weeks following the 
first subject randomized.  Subsequent on-site monitoring visits will occur every 6-8 weeks. 
11.2
Audit and Inspection
The Investigator will make all the trial-related source data and trial records available at any time to 
quality assurance auditor(s) mandated by Ferring or to domestic/foreign regulatory inspectors or 
representatives from IRBs who may audit/inspect the trial.
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP, including the Declaration of Helsinki and all other relevant regulations.
The subjects 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. Subjects in 
the EDC system will not be identified by their names, but by an identification system, which consists 
of an assigned number in the trial. Documents that are not for submission to Ferring, e.g., the 
confidential subject identification code and the signed Informed Consent Documents, will be 


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maintained by the Investigator in strict confidence. Handling of subject data will be in accordance with 
all local privacy regulations.


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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 Ferring, and 
agreed upon by the Investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving IRB(s) and regulatory authorities, in accordance with 
local regulations. Changes to the protocol to eliminate immediate hazard(s) to trial subjects may be 
implemented prior to IRB approval/favorable opinion.
12.2
Deviations from the Protocol
If deviations from the protocol occur, the Investigator must inform the monitor, and the implications of 
the deviation must be reviewed and discussed. Any deviation must be documented, either as an answer 
to a query in the eCRF, in a protocol deviation report, or a combination of both. A log of protocol 
deviation reports will be maintained by Ferring. Protocol deviation reports and supporting 
documentation must be kept in the Investigator’s File and the Trial Master File.
12.3
Premature Trial Termination
Both the Investigator (with regard to his/her participation) and Ferring reserve the right to terminate the 
trial at any time. Should this become necessary, the procedures will be agreed upon after consultation 
between the two parties. In terminating the trial, Ferring and the Investigator will ensure that adequate 
consideration is given to the protection of the best interests of the subjects. Regulatory authorities and 
IRBs 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 trial will be reported in a clinical trial report prepared by 
Ferring.
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
13.4
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 their entirety in a responsible and coherent manner and results from 
subsets should not be published in advance of or without clear reference to the primary publication of 
the entire trial.
Authorship is granted based on the 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 CRO 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 comments prior to submission. 
Comments will be given within four 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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13.5
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 public registry, i.e.,
www.ClinicalTrials.gov, a website maintained by the National Library of Medicine (NLM) at the US 
National Institutes of Health (NIH). A summary of the trial results is made publicly available in 
accordance with applicable regulatory requirements. 


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14
ETHICAL AND REGULATORY ASPECTS
14.1
Institutional Review Board (IRB)
An IRB will review the protocol and any amendments and recruitment advertisements. The IRB will 
review the Subject Information Sheet and the Informed Consent Form, their updates (if any), and any 
other written materials given to the subjects. A list of all IRBs to which the protocol has been 
submitted and the names of the committee chairs will be included in the Clinical Trial 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
The trial will be considered ended when the last subject completes the last follow-up visit (V6). 
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 after an appropriate explanation of aims, methods, sources of funding, any possible 
conflicts of interest, anticipated benefits, potential risks of the study and the discomfort it may entail, 
post-study provisions, and any other aspects of the trial which are relevant to the subject’s decision to 
participate. The trial subject must be given ample time to consider participation in the trial, before the 
consent is obtained. The Informed Consent Documents must be signed and dated by the subject and the 
Investigator who has provided information to the subject regarding the trial before the subject is 
exposed to any trial-related procedure, including screening tests for eligibility. Subjects must be given 
the option of being informed about the general outcome and the results of the trial.
The Investigator (or the person delegated by the Investigator) will explain that the subject is 
completely free to refuse to enter the trial or to withdraw from it at any time, without any consequences 
for his/her further care and without the need to justify his/her decision.
The subject will receive a copy of the Subject Information and his/her signed Informed Consent Form.


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If new information becomes available that may be relevant to a trial subject’s willingness to continue 
participation in the trial, a new Subject Information and Informed Consent Form will be forwarded to 
the IRB(s) (and regulatory authorities, if required). The trial subjects will be informed about this new 
information and re-consent will be obtained.
Each subject 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 a legally acceptable representative 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 Declaration of Helsinki, the consolidated ICH-GCP, and other applicable law(s) and guidelines in 
the country where the trial takes place shall constitute 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 are 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
Ferring is, as Sponsor, responsible for ensuring appropriate general/product liability insurance and, as 
required in accordance with applicable laws and regulations, country-specific liability insurance 
coverage for claims made by a trial subject for injury arising from the subject’s participation in the 
trial.


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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 regulatory 
approval, 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 identifiable subject source records and de-
identified data in the clinical database 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 
regulatory approval.
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. If the Investigator retires and the documents can no longer 
be archived by the site, Ferring can arrange having the Investigator File archived at an external archive.
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.
ASGE Standards of Practice Committee, Saltzman JR, Cash BD, et al. Bowel preparation 
before colonoscopy. Gastrointest Endosc. 2015;81(4):781–794.
2.
Lai EJ, Calderwood AH, Doros G, Fix OK, Jacobson BC. The Boston bowel preparation 
scale: a valid and reliable instrument for colonoscopy-oriented research. Gastrointest 
Endosc. 2009;69(3 Pt 2):620–625.
3.
Patel M, Staggs E, Thomas CS, Lukens F, Wallace M, Almansa C. Development and 
validation of the Mayo Clinic Bowel Prep Tolerability Questionnaire. Dig Liver Dis. 
2014;46(9):808–812.
4.
Allen JI. Quality measures for colonoscopy: where should we be in 2015? Curr 
Gastroenterol Rep. 2015;17(3):10.
5.
Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM. American 
College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am 
J Gastroenterol. 2009;104(3):739–750.
6.
Katz PO, Rex DK, Epstein M, et al. A dual-action, low-volume bowel cleanser administered 
the day before colonoscopy: results from the SEE CLEAR II study. Am J Gastroenterol. 
2013;108(3):401–409.
7.
Leitao K, Grimstad T, Bretthauer M, et al. Polyethylene glycol vs sodium 
picosulfate/magnesium citrate for colonoscopy preparation. Endosc Int Open. 
2014;2(4):E230–E234.
8.
Johnson DA, Barkun AN, Cohen LB, et al. Optimizing adequacy of bowel cleansing for 
colonoscopy: recommendations from the US multi-society task force on colorectal cancer. 
Gastroenterology. 2014;147(4):903–924.
9.
Hoy SM, Scott LJ, Wagstaff AJ. Sodium picosulfate/magnesium citrate: a review of its use 
as a colorectal cleanser. Drugs. 2009;69(1):123–136.
10.
Corley DA, Levin TR, Doubeni CA. Adenoma detection rate and risk of colorectal cancer 
and death [author reply]. N Engl J Med. 2014;370(26):2541.
11.
Kim HG, Huh KC, Koo HS, et al. Sodium picosulfate with magnesium citrate (SPMC) plus 
laxative is a good alternative to conventional large volume polyethylene glycol in bowel 
preparation: a multicenter randomized single-blinded trial. Gut Liver. 2015;9(4):494–501.


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12.
Radaelli F, Paggi S, Hassan C, et al. Split-dose preparation for colonoscopy increases 
adenoma detection rate: a randomised controlled trial in an organised screening programme. 
Gut. 2015;Dec 9 [Epub ahead of print].
13.
Rex DK, Katz PO, Bertiger G, et al. Split-dose administration of a dual-action, low-volume 
bowel cleanser for colonoscopy: the SEE CLEAR I study. Gastrointest Endosc. 
2013;78(1):132–141.
14.
Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for colonoscopy. Gastrointest 
Endosc. 2015;81(1):31–53.


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APPENDICES


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Appendix A
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, 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 B
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 your doctor’s directions for taking your insulin or pills.

Your blood sugars should be monitored regularly. Please discuss this with your doctor, nurse or 
dietician.

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 Jell-O. 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 grape juice
One third cup cranberry juice
One half cup orange juice
One half cup regular pop or soda
One third cup regular Kool-Aid
One quarter cup sherbet
One third cup apple juice
One third cup pineapple juice
One half cup grapefruit juice
One quarter cup regular Jell-O
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 C
Modified Aronchick Scale and Boston Bowel Preparation Scale
Modified Aronchick Scale (Aronchick et al, 1999, as cited by ASGE, 2015) 1
Grade
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
Boston Bowel Preparation Scale 2
0
Unprepared colon segment with mucosa not seen due to solid stool that cannot be cleared.
1
Portion of mucosa of the colon segment seen, but other areas of the colon segment not well 
seen due to staining, residual stool, and/or opaque liquid.
2
Minor amount of residual staining, small fragments of stool and/or opaque liquid, but 
mucosa of colon segment seen well.
3
Entire mucosa of colon segment seen well with no residual staining, small fragments of 
stool or opaque liquid.


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Appendix D
Mayo Clinic Bowel Prep Tolerability Questionnaire


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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
A Randomized, Assessor-Blinded, Multi-Center Study Investigating the Efficacy, Safety, and 
Tolerability of Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Oral 
Solution versus Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Powder 
for Oral Solution (PREPOPIK®) for Colon Cleansing in Preparation for Colonoscopy
000253
Investigational Product:
Sodium Picosulfate, Magnesium Oxide and Anhydrous
Citric Acid Oral Solution
Indication:
Bowel preparation for colonoscopy
Phase:
III
Author:
Date of issue:
December 1, 2017
Version:
Amendment 1
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
1
2
Oct 7, 2016
Nov 29, 2017
SAP based on Protocol dated 20 
September 2016

To lower the trigger for 
imputation based sensitivity 
analysis for the primary endpoint.

The Markedly notable analysis 
tables for laboratory, vital signs 
and ECG endpoints has been 
removed.

More justification for the margin 
selection has been added in 
Appendix 5.

The fluid intake summary was 
changed to just include 
information collected in the 
patient dairy card.
None
1 (for the 
amendment  this 
would be the 1
version)


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SignedI agreement on Statistical Analysis Plan
Author:  
_______________________________ 
________________
              
Date (dd/mm/yyyy)
             
 Biometrics
             
Ferring International Pharmascience Center US, Inc
Review:
_______________________________
________________
                              Date (dd/mm/yyyy)
Gastroenterology
Ferring International Pharmascience Center US, Inc
  
         _______________________________
               ________________
                                 Date (dd/mm/yyyy)
 US Pharmacovigilance
Ferring International Pharmascience Center US, Inc
_______________________________
________________
                                                            Date (dd/mm/yyyy)
 Clinical Operations
Ferring International Pharmascience Center US, Inc
Approval:
________________________________
________________
       
               Date (dd/mm/yyyy)
 Biometrics
Ferring International Pharmascience Center US, Inc
                                                
I Can be replaced by a list of reviewers/approvers if sign off can be performed in the REAL system


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TABLE OF CONTENTS
1
Introduction.......................................................................................................................................... 7
1.1
Definitions/ Abbreviations...................................................................................................... 7
1.1.1
Definition of Terms.................................................................................................... 7
1.1.2
Abbreviations ............................................................................................................. 7
2
Trial Objectives and Endpoints.......................................................................................................... 8
2.1
Objectives................................................................................................................................. 8
2.2
Endpoints................................................................................................................................. 8
3
Trial design........................................................................................................................................... 9
3.1
General Design Considerations.............................................................................................. 9
3.1.1
Trial design diagram................................................................................................ 10
3.2
Determination of Sample Size.............................................................................................. 13
4
Subject Disposition ............................................................................................................................ 14
5
Protocol Deviations............................................................................................................................ 15
6
Analysis sets........................................................................................................................................ 16
6.1
Intention-To-Treat Analysis Set .......................................................................................... 16
6.2
Modified Intention-to-Treat (mITT) Analysis Set ............................................................. 16
6.3
Per Protocol Analysis Set ..................................................................................................... 16
6.4
Safety Analysis Set ................................................................................................................ 16
7
Trial population ................................................................................................................................. 17
7.1
Demographics and Other Baseline Characteristics ........................................................... 17
7.1.1
Demographics........................................................................................................... 17
7.2
Medical History..................................................................................................................... 17
7.3
Prior and Concomitant Medication..................................................................................... 17
7.4
Physical Examination ........................................................................................................... 17
8
Exposure and Treatment Compliance ............................................................................................. 18
8.1.1
Extent of Exposure................................................................................................... 18
8.1.2
Treatment Compliance............................................................................................ 18
9
Efficacy ............................................................................................................................................... 19
9.1
General Considerations........................................................................................................ 19
9.2
Primary Endpoint(s)............................................................................................................. 19
9.2.1
Primary Variable(s) Analysis.................................................................................. 19


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9.2.2
Sensitivity Analyses.................................................................................................. 20
9.3
Secondary Endpoint(s) ......................................................................................................... 21
9.3.1
Assessing the Cleansing of the Right Colon........................................................... 21
9.3.2
Assessing the Cleansing of the Transverse Colon ................................................. 21
9.3.3
Assessing the Cleansing of the Left Colon ............................................................. 21
9.3.4
Tolerability and Satisfaction................................................................................... 21
9.3.5
Drug Concentration Measurements/Pharmacokinetics ....................................... 21
9.4
Other Endpoints.................................................................................................................... 22
9.4.1
Subgroup analysis.................................................................................................... 22
10
Safety................................................................................................................................................... 23
10.1
General Considerations........................................................................................................ 23
10.2
Adverse Events...................................................................................................................... 23
10.2.1 Overview of Treatment-Emergent Adverse Events.............................................. 23
10.2.2 Incidence of Adverse Events ................................................................................... 24
10.3
Safety Laboratory Variables................................................................................................ 24
10.3.1 Summary Statistics .................................................................................................. 25
10.3.2 Laboratory Variable Changes Relative to Normal Range ................................... 25
10.3.3 Data Listings............................................................................................................. 25
10.3.4 Urinalysis .................................................................................................................. 25
10.4
Vital Signs and ECG............................................................................................................. 25
10.4.1 Vital Signs................................................................................................................. 25
10.4.1.1
Summary Statistics...............................................................................................................................26
10.4.1.2
Data Listings ........................................................................................................................................26
10.4.2 ECGs ......................................................................................................................... 26
10.4.2.1
Summary Statistics...............................................................................................................................27
10.4.2.2
Data Listings ........................................................................................................................................27
10.5
Other Safety Variables ......................................................................................................... 27
11
Interim analyses................................................................................................................................. 28
12
Deviations from protocol analysis .................................................................................................... 29
13
References........................................................................................................................................... 30
14
Tables, Listings and Figures ............................................................................................................. 32
Appendix 1
Markedly Abnormal Laboratory Safety Values, Vital Signs and ECGs ......................... 33
Appendix 2
Statistical and programming details.................................................................................... 37
Appendix 3
Modified Aronchick Scale and Boston Bowel Preparation Scale ..................................... 39
Appendix 4
Mayo Clinic Bowel Prep Tolerability Questionnaire......................................................... 40


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Appendix 5
Non-inferiority margin justification.................................................................................... 42


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1
Introduction
This document describes the planned statistical analyses for Study 000253 based on protocol 
Amendment 1, Version 2, dated 25 January 2017. 
1.1
Definitions/ Abbreviations
1.1.1
Definition of Terms
Terms
Definitions
ITT
Randomized patients
mITT
Randomized patients that have been treated with IMP
Randomised
Subject randomised to trial treatment
Safety set
Patients that have been treated with IMP
Screened
Subject who enters the screening phase
1.1.2
Abbreviations
Abbreviations Meaning of abbreviations in document
ADR
Adverse Drug Reaction
AE
Adverse Events
AST
Aspartate Aminotransferase
BBPS
Boston Bowel Preparation Score
BHPM
bis-(p-hydroxyphenyl)-pyridyl-2-methane
BMI
Body Mass Index
bpm
Beats per minute
BUN
Blood Urea Nitrogen
CRF
Case Report Form
ECG
Electrocardiogram
FAS
Full-Analysis Set
GGT
Gamma Glutamyl Transferase
IMP
Investigational Medicinal Product
ITT
Intention-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
mmHG
millimeter of mercury
mITT
Modified Intention-to-Treat
NaP/MC
Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid
NI
Non-Inferiority
PK
Pharmacokinetic(s)
PP
Per-Protocol
PT
Preferred Term
SAE
Serious Adverse Event
SD
Standard Deviation
SOC
System Organ Class
WHO
World Health Organization


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2
Trial Objectives and Endpoints
2.1
Objectives
Primary Objective

To demonstrate non-inferiority (NI) of split-dose Sodium Picosulfate, Magnesium Oxide and 
Anhydrous Citric Acid (NaP/MC) Oral Solution in overall colon cleansing in preparation for 
colonoscopy compared with split-dose PREPOPIK®
Secondary Objectives

To demonstrate NI of NaP/MC Oral Solution compared with PREPOPIK® in cleansing of the 
right colon

To evaluate the cleansing of the transverse and left colon

To evaluate subjects’ tolerability and satisfaction with the bowel preparation 

To evaluate overall safety through the collection of treatment-emergent AEs and clinically 
significant changes in vital signs, ECGs and laboratory values

To evaluate pharmacokinetic (PK) characteristics of PREPOPIK® and NaP/MC Oral 
Solution
2.2
Endpoints
Primary Endpoint 

Proportion of subjects classified as a responder defined by “excellent” or “good” using the 
Modified Aronchick scale (Appendix 3 ).
Secondary Endpoints

Proportion of subjects classified as a responder defined by a score ≥2 in the right segment of 
the colon using the BBPS (Appendix 3 ) 

Proportion of subjects classified as a responder defined by a score ≥2 in the transverse segment 
of the colon using the BBPS (Appendix 3 )

Proportion of subjects classified as a responder defined by a score ≥2 in the left segment of the 
colon using the BBPS (Appendix 3 )

Frequency of each category of the Mayo Clinic Bowel Prep Tolerability Questionnaire 
(Appendix 4 )

Incidence and intensity of treatment-emergent AEs and clinically significant changes in vital 
signs, ECGs, and laboratory values

Plasma concentration of sodium picosulfate, magnesium and bis-(p-hydroxyphenyl)-pyridyl-2-
methane (BHPM)


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3
Trial design
This is a randomized, assessor-blinded, multi-center study investigating the efficacy, safety, and 
tolerability of split-dose Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Oral 
Solution versus split-dose Low-Volume Sodium Picosulfate, Magnesium Oxide and Anhydrous 
Citric Acid Powder for Oral Solution (PREPOPIK®) for Colon Cleansing in Preparation for 
Colonoscopy.
3.1
General Design Considerations
Following appropriate informed consent procedures, subjects who fulfil eligibility criteria and 
require a colonoscopy will be randomized to one of the two treatment arms.
Only the subject and the site-designated unblinded coordinator and a pharmacist (if applicable) will 
know the treatment group in which the subject will be participating. The designated unblinded 
coordinator will instruct the subject on the use of the bowel preparation, and both will sign a 
nondisclosure affidavit form, preventing the subject and the unblinded coordinator from disclosing 
the bowel preparation treatment the subject used. Treatment will be blinded to the endoscopist
assessing the efficacy of the two tested preparations.
Following randomization, subjects will perform colon cleansing using split-dose NaP/MC Oral 
Solution or split-dose PREPOPIK®.
NaP/MC Oral Solution (supplied as two 160-mL bottles per subject) needs no further reconstitution 
before administration.  
Subjects randomized to the NaP/MC Oral Solution will begin treatment (first dose) the evening 
before colonoscopy between 5:00 and 9:00 PM, and will complete treatment (second dose) the 
following day, at least 5 hours, but no more than 9 hours, prior to the colonoscopy. After drinking 
the first dose, subjects should drink five (5) or more eight-ounce glasses of clear liquid within five 
(5) hours.  After drinking the second dose, subjects should drink four (4) or more eight-ounce 
glasses of clear liquid within five (5) hours. Subjects should not ingest anything within two (2) 
hours before the time of the colonoscopy. 
PREPOPIK® (supplied as two sachets per subject) is reconstituted using the cup provided. The 
doses are prepared by combining the contents of one sachet with approximately five (5) ounces of 
cold water and stirring for two to three minutes (in some cases the cup may feel warm, which is 
normal).
Subjects randomized to PREPOPIK® will begin treatment (first dose) the evening before the 
colonoscopy between 5:00 and 9:00 PM, and will complete treatment (second dose) the following 
day, at least five (5) hours, but no more than nine (9) hours, prior to the colonoscopy. After 
drinking the first dose, subjects should drink approximately five (5) eight-ounce glasses of clear 
liquid within five (5) hours.  After drinking the second dose, subjects should drink three (3) eight-


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ounce glasses of clear liquid within five (5) hours. Subjects should stop taking anything by mouth 
two (2) hours before the time of the colonoscopy.
For a subset of subjects, pharmacokinetic samples will be collected for picosulfate and BHPM
concentration. Blood samples will be drawn within 15 minutes before the second dose, and 1 to 2 
hours and 3 to 6 hours after the second dose of Prepopik or NaP/MC Oral Solution. Accurate 
dosing information of both doses and timing of PK samples relative to dosing will be recorded. All 
study subjects will have a PK sample drawn immediately prior to their colonoscopy.
Subjects will return for three follow-up visits: 24-48 hours (Visit 4), seven days (Visit 5), and four 
weeks (Visit 6) after the colonoscopy procedure.
3.1.1
Trial design diagram
Figure 1
Trial Flow Chart 


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Table 1
Trial Assessment Table
Visit
1
Screening
2
Randomization
3
Procedure
4
Follow-up 
5
Follow-up 
6
Follow-
up  
(EOT)
Timing versus Procedure
(≤21) 
Days
(≤10) 
Days
Colonoscopy
(T = 0)
24 – 48 
Hours
7 Days
(± 2 Days)
4 Weeks
(± 2 
Days)
Informed consent
x
Inclusion/exclusion criteria
x
x
Demographic & Medical History
x
Body weight, Height1
x
x
x
x
x
x
Urine/Serum Pregnancy Test
x
x
Schedule colonoscopy
x
Laboratory (chemistry, 
coagulation, hematology)
x2
x
x
x
x
PK sampling 
x3, 4
Urinalysis
x
x
x
x
x
ECG
x
x
x
x
x
Physical examination
x
x
x
x
x
Orthostatic vital signs (BP, pulse)
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
Dispense fluid intake diary and 
study medication
x
Subject Tolerability Questionnaire 
x
Perform and video-record  
colonoscopy
x
Score overall colon preparation –
Modified Aronchick scale 
x
Score colon segments preparation 
– Boston Bowel Preparation Scale
x
Drug accountability
x
1.
Height will only be collected at screening.
2.
Coagulation samples will only be collected at screening.
3.
In a subset of subjects, PK samples for sodium picosulfate and BHPM will be taken 15 minutes before the second dose, and 1 to 2 hours 
and 3 to 6 hours  after the second dose of  the Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid.
4.
All subjects will have a PK sample drawn immediately prior to colonoscopy.  


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3.2
Determination of Sample Size
The primary objective of this study is to demonstrate NI of NaP/MC Oral Solution to PREPOPIK® 
for overall colon cleansing prior to colonoscopy using the Modified Aronchick Scale (see Appendix 
3 ), as assessed by a blinded endoscopist. A subject is considered to be a “responder” if overall 
colon cleansing is either “excellent” or “good” on the Modified Aronchick Scale. 
The assumed true responder rate for PREPOPIK® is 84% when using the Modified Aronchick 
Scale (FE2009-01 and FE2009-02). It is assumed that the true responder rate of subjects treated 
with PREPOPIK® or NaP/MC Oral Solution are the same. A NI margin of 8% was chosen, to 
ensure no more than a 10% relative decrease from the control. For details on the margin 
justification please see Appendix 5 . Four hundred and fifty randomized subjects per treatment 
group are required, in a 1:1 randomization, to maintain at least 90% power to demonstrate the NI of 
NaP/MC Oral Solution to PREPOPIK® for overall colon cleansing prior to colonoscopy at the one-
sided 0.025 significance level.
For PK assessment, on a subset of subjects, blood sample will be collected four times on the day of 
colonoscopy. Approximately sixty (60) randomized subjects will be included in this PK sub-group. 
Sixty (60) subjects (approximately 30 per arm) are considered to be sufficient to characterize the 
population PK for picosulfate and BHPM. In addition to this, all subjects enrolled in the study will 
have a PK blood sample drawn for BHPM and picosulfate immediately prior to their colonoscopy. 
The PK assessment on all subjects will be used to explore the potential correlation between AEs 
and concentration levels of picosulfate, BHPM and magnesium.


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4
Subject Disposition
All subjects screened will be accounted for. All post-randomization discontinuation and reasons for 
discontinuation will be summarized by treatment group. The number of patients in each patient 
population will also be summarized by treatment group. Associated listing will also be produced.
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. 


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5
Protocol Deviations
Major protocol deviations are a subset of protocol deviations that may significantly impact the 
completeness, accuracy, and/or reliability of the study data or that may significantly affect a 
subject's rights, safety, or well-being. A subset of these major protocol deviations will lead to 
exclusion of the data from the PP analysis set. 
Some of the criteria for major protocol deviation are listed below:

significant deviation  in the time of IMP dosing, 

taking the wrong IMP , or

not following treatment regimen as specified in the protocol.
Regular blinded review of protocol deviations will be conducted prior to data base lock. The rating 
of protocol deviations as ‘minor’ or ‘major’  and  exclusion from PP analyses will be also be 
discussed at these regular meeting and will be completed prior to the declaration of ‘clean file’ and 
lock of database.
Major protocol deviations will be summarized by treatment group for the mITT population.


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6
Analysis sets
6.1
Intention-To-Treat Analysis Set
The intention-to-treat (ITT) analysis set comprises of all randomized subjects. The ITT analysis set 
will be analysed according to randomized treatment (as planned).
6.2
Modified Intention-to-Treat (mITT) Analysis Set
The primary efficacy analysis will be conducted for the mITT analysis set and is defined as all ITT 
subjects who received at least one dose of study treatment (i.e., IMP). The mITT analysis set will 
be analysed according to randomized treatment.
6.3
Per Protocol Analysis Set
The Per-protocol (PP) analysis set comprises all mITT subjects except those excluded as a result of 
major protocol deviations that affect efficacy. These subjects will be identified prior to breaking the 
study blind. 
6.4
Safety Analysis Set 
The safety analysis set comprises all subjects who took any amount of study medication (i.e., IMP). 
The safety analysis set will be analyzed according to the actual treatment received.  


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7
Trial population
7.1
Demographics and Other Baseline Characteristics
Categorical data will be summarised using numbers and percentages. The percentages are based on 
the total number of subjects with a corresponding assessment. Continuous data will be presented, 
for example, using the number of subjects (N), mean and standard deviation, median, minimum and 
maximum. These analyses will be presented for the mITT and safety population. In addition, since 
this is a multi-site trial, a summary of demographic characteristics will be presented by trial site. All 
baseline characteristics will be listed.
7.1.1
Demographics
Descriptive statistics of baseline demographics variables (e.g., age, race and ethnic origin, height, 
weight and BMI) will be summarized by treatment group.
7.2
Medical History
Medical history recorded at screening visit will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 16.1 or later. Medical history will be listed by treatment and subject, 
and summarized by treatment group, system organ class (SOC), and preferred term (PT) for the 
subjects in the mITT and safety analysis sets, separately.
7.3
Prior and Concomitant Medication
Prior and concomitant medication will be summarised using the WHO dictionary by ATC 
classification 1st level (alphabetically), ATC classification 2nd level (in decreasing order of 
frequency) and treatment group for the safety analysis set. These medications will be tabulated 
separately for:
1) Prior medication; i.e. medication taken exclusively prior to treatment (i.e. with stop date 
before date of first IMP administration);
2) Concomitant medication, i.e. medication taken during the treatment period (i.e. medication 
that was not stopped before date of first IMP-administration [and not started after the last 
visit date (i.e., visit 6)]).
If the timing of the dose of a medication cannot be established in relation to the administration of 
IMP, it will be considered as concomitant medication.
7.4
Physical Examination
Subjects with abnormalities at any screening, baseline, or post-baseline visit will be listed with all 
physical examination evaluations for the safety population.


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8
Exposure and Treatment Compliance
8.1.1
Extent of Exposure 
The number of patients that completed IMP treatment, the number of patients that took each dose of 
IMP and the number of patients that did not take any amount of IMP will be summarized and listed 
by treatment group for the safety analysis set.
8.1.2
Treatment Compliance 
The number and proportion of subjects deviating from the treatment regimen will be summarized
by treatment group for the safety population. The summary will include the following:

the number of patient that did not consume the entire dose,

deviations  from protocol mandated administration time,

the number of patients that did not fast two hours before colonoscopy,

the number of patient that did not adhere to clear liquid diet 24 hours prior to 
colonoscopy and

the number of subject that did not consume the recommended number eight-ounce 
glasses of clear liquid after each dose of IMP. 
Furthermore, associated listing will be produced.


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9
Efficacy
9.1
General Considerations
All statistical tests will be performed using a two-sided test at a 5% significance level. 
The primary and secondary efficacy analyses will be conducted for the mITT analysis set. 
Continuous variables will be described with the number of non-missing values, mean, standard 
deviation, median, and minimum/maximum values. Categorical variables will be described with the 
number and percentage of subjects within each level.
In order to preserve the type I error for testing for the primary endpoint of the overall colon 
cleansing and the secondary endpoint of right colon cleansing, the NI for evaluating the cleansing 
within the right colon will only be assessed if NI is demonstrated for the primary endpoint using the 
mITT population.  Superiority for the primary endpoint will be assessed if and only if NI is 
demonstrated for both the primary efficacy endpoint and the secondary right colon efficacy 
endpoint.
9.2
Primary Endpoint(s)
The primary endpoint is the Proportion of subjects classified as a responder defined by “excellent” or 
“good” using the Modified Aronchick scale.
9.2.1
Primary Variable(s) Analysis
For primary analysis what is of interest is the assessment of the difference in responder rates in 
overall colon cleansing between NaP/MC Oral Solution and PREPOPIK®.  A subject is considered 
to be a “responder” if overall colon cleansing is classified as either “excellent” or “good” by the 
blinded endoscopist using the Modified Aronchick Scale (see Appendix 3 ). The NI margin for the 
difference between treatments (NaP/MC Oral Solution minus PREPOPIK®) will be -8% (absolute). 
The NI hypothesis to be tested for the primary endpoint will be:
H0: π NaP/MC Oral Solution - π PREPOPIK® ≤-8% 
against the alternative 
H1: π NaP/MC Oral Solution - π PREPOPIK® >-8%, 
where πNaP/MC Oral Solution and πPREPOPIK® denote the true percentage of subjects classified as 
responders (i.e., excellent and good according to the Modified Aronchick Scale (see Appendix 3 )) 
among subjects treated with NaP/MC Oral Solution or PREPOPIK®, respectively, for colon cleansing 
in preparation for colonoscopy.


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The null hypothesis (H0) will be tested against the alternative by constructing a 2-sided 95% 
confidence interval for the difference in responder rates.  The primary analysis will be stratified by 
the stratification factor, site, by using the Mantel-Haenszel method to combine results across sites. 
In brief, this corresponds to deriving a weighted average across sites where the weight depends on 
the number of observations in each treatment group in each stratum (see Appendix 2 for more 
details).  Subjects who do not have an excellent or good rating according to the Modified 
Aronchick Scale (see Appendix 3 ) for any reason will be considered treatment failures (i.e., not a 
responder). Hence, treated patients that did not complete the colonoscopy assessment will be 
classified as non-responders. If the lower limit of the 95% confidence interval is greater than the 
margin (-8%), the null hypothesis will be rejected and it will be claimed that NaP/MC Oral Solution 
is non-inferior to PREPOPIK® with respect to colon cleansing in preparation for colonoscopy. 
If NI is demonstrated for both the primary efficacy endpoint and the secondary efficacy endpoint 
for the right colon (see Section 9.3.1), and if the lower bound for the primary analysis results in a 
confidence interval that is above 0% then, superiority will be declared for the primary endpoint. 
Hence, this superiority test will be conducted at one sided significance level of 2.5%. 
9.2.2
Sensitivity Analyses 
As a sensitivity analysis, the NI analysis in section 9.2.1 will be repeated using the per-protocol 
population.  
For the primary analysis, if a patient does not have efficacy assessment (colonoscopy), it is 
considered to be a treatment failure. There are two main reasons for applying such method of 
imputations. First, the number of patients missing efficacy assessment is expected to be very low. 
In the two pivotal Ferring studies (FE2009-01 and FE2009-02), the number of patients that were 
treated but did not have colonoscopy assessment were less than 1%. Furthermore, if the reason for 
not having efficacy assessment is related to tolerability then these can also be considered as
treatment failures and treating such missing values as failures is appropriate. However, in this 
study, if the number of treated patients that do not have efficacy assessment for reasons other than 
tolerability is >=0.5%, there will be a sensitivity analysis, where, a multiple imputation method will 
be applied to impute for such missing colonoscopy assessment. Details of the multiple imputation 
method to be applied is found in Appendix 2 
The patients that do not have colonoscopy results for other than tolerability issues will be identified 
using the question “was colonoscopy performed at this visit?” on the colonoscopy  & assessment 
eCRF page. Using the “specify” responses to this question, prior to data base lock, the clinical team 
will review and categorize the reasons for not preforming or completing colonoscopy. One of the 
classification categories will be “tolerability”.  If there are >=0.5% patients that did not have 
colonoscopy performed or completed for reasons other than “tolerability” a sensitivity analysis will 
be performed by applying multiple imputation method to impute for such missing assessments.


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9.3
Secondary Endpoint(s) 
9.3.1
Assessing the Cleansing of the Right Colon
The Boston Bowel Preparation Score (BBPS) will be used to assess the cleaning of the right colon. 
The difference between the responder rates in the right colon cleansing using NaP/MC Oral 
Solution or PREPOPIK® will be assessed. A subject is considered to be a “responder” if the BBPS 
(Right Colon) score is ≥2. Using the mITT population and the analysis methodology described for 
the primary endpoint a 95% two-sided confidence interval for the responder rate difference of 
NaP/MC Oral Solution minus PREPOPIK® will be constructed. If the NI objective is met for the 
primary endpoint, these CIs will be used to assess the NI of NaP/MC Oral Solution to PREPOPIK®
in the cleansing of right colon as assessed by BBPS. The NI margin for the testing the difference 
between treatments (NaP/MC Oral Solution minus PREPOPIK®) for cleansing of the right colon is 
again set to be -8% (absolute). Hence, if the lower bound of this confidence interval exceeds -8.0% 
then NaP/MC Oral Solution will be declared non-inferior to PREPOPIK® with respect to the 
cleansing of the right colon.
9.3.2
Assessing the Cleansing of the Transverse Colon
The responder rate for the transverse colon using BBPS will be analysed in the same manner as the 
primary endpoint for the mITT analysis set, according to the subjects’ randomized treatment group, 
and 95% confidence interval for the responder rate of NaP/MC Oral Solution minus PREPOPIK®
will be presented. A subject is considered to be a “responder” if the BBPS score of the transverse 
colon is ≥2.
9.3.3
Assessing the Cleansing of the Left Colon
The responder rate for the left colon using BBPS will be analysed in the same manner as the 
primary endpoint for the mITT analysis set according to the subjects’ randomized treatment group, 
and 95% confidence interval for the responder rate of NaP/MC Oral Solution minus PREPOPIK®
will be presented. A subject is considered to be a “responder” if the BBPS score of the left colon is 
≥2.
9.3.4
Tolerability and Satisfaction
For Mayo Clinic Bowel Prep Tolerability Questionnaire (see Appendix 4 ), each question will be 
analysed separately and summary statistics will be provided for all individual questions by 
randomized treatment group for the mITT population. The Wilcoxon Rank Sum 2-sided test will be 
used for the treatment comparison of ordered categorical responses. In contrast, for binary 
responses Fisher’s exact test will be utilized.
9.3.5
Drug Concentration Measurements/Pharmacokinetics
Drug concentrations of picosulfate, BHPM and magnesium (which is part of the chemistry lab 
assessment) will be summarized by descriptive statistics. A population PK model will be developed 


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based on pooled data from the present study and previous study in adult subjects (000017). 
Apparent clearance and volume of distribution will be estimated, if possible. The population PK 
model and other PK endpoints will be summarized in a separate PK modelling report.
9.4
Other Endpoints
Whether or not colonoscopy was completed, whether or not cecum was reached, the overall 
colonoscopy evaluation, time taken to reach the cecum, time to withdrawal and number of polyps
and histology will be summarized by treatment group. Furthermore, associated listing will be 
produced. The listing will include information on the histologic details of the polyps and the 
morphology.
9.4.1
Subgroup analysis
The primary endpoint will be summarized by age (<65 or ≥ 65), gender and site. The analysis 
outlined for the primary endpoint will be applied to age and gender subgroup analysis. For the by 
site summary, the proportion of responders will be presented by treatment group. Furthermore, the 
proportion difference between the treatment groups and associated 95% CI will be generated.


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10
Safety
10.1
General Considerations
Safety parameters will be evaluated for the safety analysis data set according to actual treatment 
received. No formal statistical hypothesis testing will be conducted for the safety parameters.
10.2
Adverse Events
Adverse events (AEs) are classified according to the Dictionary for Regulatory Activities 
(MedDRA) version 16.1 or later.
A Treatment-emergent adverse event (TEAE) is any adverse event that occurs after the start of 
IMP and within 30 days from the last exposure to IMP, or a pre-treatment adverse event/medical 
condition that worsens in intensity after the start of IMP and within 30 days from the last exposure 
to IMP. The total number of subjects reporting a TEAE, the percentage of subjects (%) with a 
TEAE, and the number of treatment-emergent adverse Events (E) reported will be presented.
Missing values will be treated as missing, except for causality, intensity, seriousness, and outcome 
of AE. A ‘worst case’ approach will be used: 

if causality is missing, the AE will be regarded as related to the IMP

if the intensity of an AE is missing, the AE will be regarded as severe

if seriousness is missing, the AE will be regarded as serious

if outcome is missing and no date of outcome is present, the outcome is regarded as ‘Not 
yet recovered’
Missing event start and event stop dates will be imputed in the most conservative way, i.e. the event 
should start as early as possible based on the (partially) missing start date while remaining 
treatment emergent (if relevant), and last as long as possible, i.e. until last visit or one day prior to 
the next event with the same preferred term, if any. In the latter case both consecutive AEs (with 
the same PT) will remain to be regarded as two separate events (despite being adjacent).
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 


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
Severe and life threatening adverse events 

Adverse drug reactions
10.2.2
Incidence of Adverse Events
Treatment-emergent adverse events will be summarised in a Table by SOC and PT using the latest
version of MedDRA. The Table will display the total number of subjects reporting an AE, the 
percentage of subjects (%) with an AE, and the number of events (E) reported. AEs will be 
presented by system organ class (SOC) sorted alphabetically and preferred term (PT) sorted in 
decreasing frequency of occurrence.
Summary tables will be prepared for:

All TEAEs

TEAEs with an incidence of  ≥5%

Non-serious TEAEs with an incidence of  ≥5%

TEAEs by causality (related/unrelated)

Adverse events leading to death

TEAEs by intensity 

Serious adverse events 

Adverse events leading to withdrawal
Supporting data listings will be provided for:

All adverse events sorted by centre and subject no.

All adverse events sorted by MedDRA Preferred Term

Serious adverse events 

Adverse events leading to death

Adverse events leading to withdrawal. 
A listing of pre-treatment and post-treatment AEs will be generated. A pre-treatment AE is any AE 
that ends prior to exposure to IMP. In contrast, a post-treatment IMP is an AE that starts 30 days 
after IMP exposure.  The pre-treatment AE listing will include all patients that signed informed 
consent. In contrast, the post-treatment AE listing will be limited to the safety population.
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 the investigational medicinal product (IMP). Treatment-emergent laboratory data will 
include tests completed after the first dose of IMP. End of trial assessment will include the last 
post-baseline observation during the trial. 
Laboratory variables will be grouped under “Haematology”, “Clinical Chemistry” or “Urinalysis”


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10.3.1
Summary Statistics
Observed values and change from baseline values for each visit and for the end of trial (last visit)
will be summarized for each laboratory variable by treatment group. The summary will include the 
number of subjects with data, mean (standard deviation), median, minimum, and maximum values.
10.3.2
Laboratory Variable Changes Relative to Normal Range
Changes relative to normal ranges are presented with shift tables with total number of subjects, and 
number and percent of subjects who experienced a shift by treatment group.  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.

Absent: 
No value for measured variable (for urinalysis only)

Present: 
Any value obtained for measured variable (for urinalysis only)
For all haematology and clinical chemistry variables, shift tables will be prepared to compare 
baseline values to the worst in-treatment value. More specifically, for haematology and clinical 
chemistry, tables presenting the changes from Low or Normal to High and from High or Normal to 
Low will be provided.  For urinalysis variables, shift tables will summarise the number (%) of 
subjects who had “absent” values at baseline and “present” values during the treatment period. 
10.3.3
Data Listings
Data listings will be prepared by treatment group and site for all subjects with any abnormal or 
markedly abnormal laboratory value at any time-point (including screening, baseline). The pre-
specified markedly abnormal criteria are presented in Appendix 1 Appendix 1 . 
10.3.4
Urinalysis
Categorical urinalysis laboratory data will be summarized separately by treatment group and 
scheduled time point using the number and percentage of subjects in each category. Furthermore, 
incidence of changes in urinalysis will be summarised by treatment group. A summary table with 
number of subjects with change from Absent at baseline to Present during trial will be summarised. 
10.4
Vital Signs and ECG
10.4.1
Vital Signs
Baseline for all vital signs (sitting, supine or orthostatic) analyses will be the values obtained at the 
last assessment prior to the first dose of IMP. Treatment-emergent vital signs data will include tests 
completed after the first dose of IMP. Last assessment in the study will include the last post-
baseline observation during the trial.


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Observed and change from baseline values for standing, supine and orthostatic vital signs will be 
summarized by visit and for the last assessment in the study. For orthostatic vital signs only 
observed values will be summarized. The orthostatic blood pressure and pulse to be summarized 
are the change in these measures from supine position to standing position. In this study, BP and 
pulse, will be first measured after at least 5 minutes rest in supine position and after 3 minutes in 
standing position.  
Orthostatic vital signs cut off that are suggestive of fluid volume depletion are as follows [14]:

a decrease in systolic blood pressure greater or equal to 20 mmHG within 3 minutes of 
standing,

a decrease in diastolic blood pressure greater or equal to 10 mmHG within 3 minutes of 
standing, or

increase in heart rate (pulse rate) greater or equal to 30 beats per minute (bpm) in the 
presence of drop blood pressure.
At each visit the number of patients, with such changes in orthostatic vital signs will be 
summarized by treatment arm.
10.4.1.1
Summary Statistics
For each vital signs variable at each visit the assessments will be summarized by treatment arm. 
The summary includes descriptive statistics such us the number of subjects with data, mean 
(standard deviation), median, minimum, and maximum values, for observed values and change 
from baseline at each time-point for each vital signs variable. Change from baseline values will not 
be summarized for orthostatic vital signs.
.
10.4.1.2
Data Listings
Data listings will be prepared by site for all subjects with any abnormal or markedly abnormal vital 
signs value at any time-point (including screening, baseline). The pre-specified markedly abnormal 
criteria are presented in Appendix 1 .
Data listing of orthostatic vital signs will also be prepared by site for all subjects with any 
orthostatic vital sings values that are indicative of fluid volume depletion at any time-point.
10.4.2
ECGs 
Overall ECG assessment will be categorized as ‘normal’, ‘abnormal, not clinically significant’, or 
‘abnormal, clinically significant’ (as judged by the Investigator). These categorized values will be 
summarized by treatment for each assessment time for the safety population. 
QTc will be calculated both using Bazett’s and Fridericia’s correction formulae (see below for 
definitions).


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1)  Bazett’s correction (square root):
QTcB = QT/( RR)0.5
2)  Fridericia’s correction (cube root):
QTcF = QT/( RR)1/3
where RR is in sec (=1 for HR=60 bpm), whereas QT is in msec.
10.4.2.1
Summary Statistics 
For the ECG parameters PR, QRS and QTc, descriptive statistics, i.e., the number of subjects with 
data, mean (standard deviation), median, minimum, and maximum values, will be presented for 
observed values and change from baseline at each time-point and for the last assessment in the 
study
10.4.2.2
Data Listings
Data listings will be prepared by treatment group and centre for all subjects with any abnormal 
ECG or markedly abnormal value at any time-point, including screening, baseline, during 
treatment, and post-treatment. The pre-specified markedly abnormal criteria are presented 
in Appendix 1 .
10.5
Other Safety Variables
The total fluid intake collected on patient diary will be summarized by treatment group. The 
summary will by each type liquid intake specified in the patient dairy. Associated listing will also 
be produced. The listing will include information on the time and type of liquid consumed from the 
start of the first dose of IMP to the time of colonoscopy. A separate listing will be produced for the 
volume of liquid used at time of procedure (including fluid IV).


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11
Interim analyses
No interim analysis is planned for this study.


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12
Deviations from protocol analysis
For the primary endpoint, subgroup analysis was added (Section 9.2.2 and 9.4.1). In the tolerability 
analyses section (see Section 9.3.4), the analysis for binary tolerability question was clarified. 
Furthermore, the analysis of additional efficacy and safety endpoints were specified in Sections 9.4
and 10.5, respectively.
In this amendment the markedly abnormal vital signs summary table that was specified in the 
protocol has been removed. 


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13
References
[1]
ASGE Standards of Practice Committee, Saltzman JR, Cash BD, et al. Bowel 
preparation before colonoscopy. Gastrointest Endosc. 2015;81(4):781–794.
[2]
DeMicco, M.P., Clayton L.B., Pilot J.,  Epstein M.S., NOCT Study Group.  Novel 1 L 
polyethylene glycol-based bowel preparation NER1006 for overall and right-sided colon 
cleansing:a randomized controlled phase 3 trial versus trisulfate. Gastrointestinal 
Endoscopy, Volume 86, Issue 2, 2017, pp. 343-348.
[3]
Ferring Pharmaceuticals Study FE2009-01. A Randomized, Assessor-Blinded, Multi-
Center Study Investigating the Efficacy, Safety and Tolerability of “Split-Dose” 
PicoPrep™ for Oral Administration Versus HalfLytely® for Colon Cleansing in 
Preparation for Colonoscopy.
[4]
Ferring Pharmaceuticals Study FE2009-02. A Randomized, Assessor-Blinded, Multi-
Center Study Investigating the Efficacy, Safety and Tolerability of “Day Before” 
PICOPREP™ for Oral Administration versus HalfLytely® for Colon Cleansing in 
Preparation for Colonoscopy.
[5]
Food and Drug Administration (FDA), (2016). Non-inferiority Clinical Trials to 
Establish Effectiveness: Guidance for industry. 
https://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf. November, 2016.
[6]
Food and Drug Administration (FDA), (2013). Statistical Review(s): 203595Orig1s000, 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000StatR.pdf. 
December 19, 2013.
[7]
Food and Drug Administration (FDA), (2010). Summary Review(s): 022372Orig1s000, 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022372Orig1s000StatR.pdf. 
August 5, 2010.
[8]
Food and Drug Administration (FDA), (2010). Statistical Review and Evaluation: 21-
551/SE2.July 17, 2010.
[9]
Food and Drug Administration (FDA), (2005). Statistical Review(s): 21-892, 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021892s000_StatR.pdf. May 
17, 2005.
[10]
Jin Z., Lu Y., Zhou Y., Gong, B. (2016). Systematic review and meta-analysis: sodium 
picosulfate/magnesium citrate vs. polyethylene glycol for colonoscopy preparation. 
European Journal of Clinical Pharmacology.  Volume 72, Issue 5:523-532.


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[11]
Kim K. and Won S. (2013). Adjusted proportion difference and confidence interval in 
stratified randomized trials. PharmaSUG 2013, Paper SP04.
[12]
Lai EJ, Calderwood AH, Doros G, Fix OK, Jacobson BC. The Boston bowel preparation 
scale: a valid and reliable instrument for colonoscopy-oriented research. Gastrointest 
Endosc. 2009;69(3 Pt 2):620–625.
[13]
Yuan Y. Multiple imputation using SAS Software. Journal of Statistical Software, 
Volume 45, Issue 6.
[14]
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, figures and listings (TLF) shells presented in a separate document.


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Appendix 1 
Markedly Abnormal Laboratory Safety Values, Vital Signs 
and ECGs
Table 2: Markedly abnormal Criteria for Laboratory Tests


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Markedly abnormal Criteria
Variable
Units
Low
High
Haematology
Haemoglobin
g/L
115
Not applicable
Haematocrit
Ratio
0.37
0.56
Total WBC
109/L
2.8
16.0
Eosinophils
%
Not applicable
10
Neutrophils
%
15
90
Lymphocytes
%
10
80
Monocytes
%
Not applicable
20
Basophils
%
Not applicable
5
Bands
%
Not applicable
20
Platelets
109/L
75
700
Total RBC
1012/L
3.5
Not applicable
Clinical Chemistry
AST 
IU/L
Not applicable
> 3xULN
ALT 
IU/L
Not applicable
> 3xULN
Alkaline 
phosphatase
IU/L
Not applicable
> 3xULN and 25% increase from 
baseline
GGT
IU/L
Not applicable
> 3xULN
LDH
IU/L
Not applicable
> 3xULN
Total bilirubin
μmol/L
Not applicable
1.5xULN
Urea nitrogen
mmol/L
Not applicable
10.7
Creatinine
μmol/L
Not applicable
177
Total protein
g/L
45
90
Albumin
g/L
25
65
Sodium
mmol/L
130
155
Potassium
mmol/L
3.0
5.8
Chloride
mmol/L
90
115
Phosphorus
mmol/L
0.5
1.9
Calcium
mmol/L
1.8
3.9
Uric acid
mmol/L
Not applicable
0.62
Glucose
mmol/L
2.8
10
Total cholesterol
mmol/L
Not applicable
8.0
Urinalysis: Quantitative
pH
None
4
Not applicable
Specific gravity
None
1.005
Not applicable
Urinalysis: Dipstick Chemistries
Glucose
0 - 4+
Not applicable
Increase of 2 or more units from baseline


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Markedly abnormal Criteria
Variable
Units
Low
High
Casts
Not applicable
Increase of 2 or more units from baseline
Protein
0 - 4+
Not applicable
Increase of 2 or more units from baseline
Ketones
0 - 4+
Not applicable
Increase of 2 or more units from baseline
Blood (Hgb)
0 - 4+
Not applicable
Increase of 2 or more units from baseline
Urinalysis: Microscopic Variables
RBC
no./hpf
Not applicable
10
WBC
no./hpf
Not applicable
20
Casts
no./hpf
Not applicable
Neg at baseline to positive on-treatment
Bacteria
no./hpf
Not applicable
Neg at baseline to positive on-treatment
Cells
no./hpf
Not applicable
Neg at baseline to positive on-treatment
Crystals
no./hpf
Not applicable
Neg at baseline to positive on-treatment
Table 3:
Markedly abnormal Criteria for Vital Signs*
Variable
Criterion Value
Change from Baseline
Systolic blood pressure
180 mmHg
90 mmHg
Increase of 20 mmHg 
Decrease of 20 mmHg
Diastolic blood pressure
105 mmHg 
50 mmHg
Increase of 15 mmHg 
Decrease of 15 mmHg
Pulse rate
120 bpm
50 bpm
Increase of 15 bpm
Decrease of 15 bpm
Body weight
None
Increase of 7%
Decrease of 7%
Body temperature
> 38.3C
Increase to 39.4C
* To be identified as markedly abnormal, a treatment value must meet the criterion value and also the 
specified change from baseline.


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Table 4:
Abnormal Criteria for Quantitative ECG Data
Variable
Baseline 
Abnormal Treatment-Emergent Value
ECG heart rate
Normal
50 bpm and decrease from baseline of 15 bpm
120 bpm and increase from baseline of 15 bpm
Duration of PR interval
Normal
≥ 220 msec
Duration of QRS interval
Normal
≥ 120 msec
Duration of QTc interval
Normal
≥ 450 msec
Duration of QTc interval
Normal
≥ 480 msec
Duration of QTc interval
Normal
≥ 500 msec
Duration of QTc interval*
Not applicable
Increase from baseline of ≥ 30 msec
Duration of QTc interval
Not applicable
Increase from baseline of ≥ 60 msec
* QTc will be calculated both using Bazett’s and Fridericia’s correction formulae.


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Appendix 2 
Statistical and programming details
Cochran-Mantel-Haenszel method for computing proportion differences adjusting for stratification
factor ([11])

pij  is the portion of success for treatment i (i-=1, 2) and site j (j=1,...,s)

dj = p1j  - p2j is the jth site treatment difference

wj = 

12
1+ 2 )
∑

12
1+ 2 )


The Cocharan-Mantel-Haenszel confidence interval is as follows:
∑



+/- / ∑
2(
1(1−1 )
1

=1
+
2(1−2 )
2
)
SAS code for generating multiple imputed data using proc mi procedure ([13])
If the primary endpoint (overall colon cleansing based on Modified Aronchick Scale) is missing for 
a mITT patient and the assessment is not available due to other than tolerability of the IMP the
following SAS code can be used to generate 20 imputed data sets.
proc mi seed=xxx out=xxxx nimpute=20;
class outcome trt site;
monotone logistic(outcome = trt site);
var trt site outcome;
run;
Where trt represents treatment group and site represents the patient site.
Once the 20 imputed data sets are generated, for each imputed data the above formula can be used 
to derive the stratified difference and associated variance i.e., 
Estimated difference: !" = ∑



Associated Variance: #$ = ∑

(
%&('%& )
(&


+
%)&('%)& )
()&
)
Let !*
+ and #*, be the point estimate and associated variance for the jth imputed data set (j=1,…, k). 
Then the point estimate pooling over the imputed data sets would be as follows:


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!- = 1
. / !*
+
0

The within-imputation variance is given by
  
#1 = 1
. / #*,
0

And the between-imputation variance is given by
                                                  2 =

0' ∑
( !"
0

−!- )
Finally, the total variance associated with !- is as follows:
                                           3 =
#1 + 4 1 +

0 5 2
Then 
                                 (! −!- )3'/ ~ T-distribution with ν degrees of freedom
                                        ν= (. −1)[ 1
+
#1/((1 + .')2)]2
Where ! is the population parameter.


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Appendix 3 
Modified Aronchick Scale and Boston Bowel Preparation 
Scale
Modified Aronchick Scale (Aronchick et al, 1999, as cited by ASGE, 2015 [1])
Grade
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
Boston Bowel Preparation Scale ([2])
0
Unprepared colon segment with mucosa not seen due to solid stool that cannot be cleared.
1
Portion of mucosa of the colon segment seen, but other areas of the colon segment not 
well seen due to staining, residual stool, and/or opaque liquid.
2
Minor amount of residual staining, small fragments of stool and/or opaque liquid, but 
mucosa of colon segment seen well.
3
Entire mucosa of colon segment seen well with no residual staining, small fragments of 
stool or opaque liquid.


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Appendix 4 
Mayo Clinic Bowel Prep Tolerability Questionnaire


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Appendix 5 
Non-inferiority margin justification
Table 5
Historical references used to establish Clinical significance (M2)
Study
Study design
comparator
Overall 
response 
rate
Assessment method
Proposed 
non-
inferiority 
margin
Study result
BLI850-301 
(Suclear)[6]
Randomized 
single blind
Halflytely
158/176 
(89.8%)
Four point scale with 
excellent and good as 
responders
15%
(-0.7, 13.2)
BLI850-302[6]
(Suclear)
Randomized 
single blind
MoviPrep
173/186(9
3.5%)
Four point scale with 
excellent and good as 
responders
15%
(-5.0, 5.0)
FE2009-01
(Picoprep) [3]
Randomized 
assessor 
blinded
Halflytely
256/304 
(84.2%)
Aronchick scale
9%
(2.9%, 15.7%)
FE2009-02
(Picoprep) [4]
Randomized 
assessor 
blinded
244/294 
(83.0%)
Aronchick scale 
9%
(-3.0%, 10.0%)
Osmoprep
( two doses of 
Osmoprep) [9]
Randomized 
Investigator 
blinded 
48g: 
225/236 
(95.3%)
60g:
226/233 
(97.0%)
Four point scale with 
excellent and good as 
responders
10%
48g:(-2.8%, 4.7%)
60g: (-1.0%, 6.5%)
BL1800-301
Suprep (one 
day) [7]
Randomized 
single blind
MoviPrep
178/190
15%
(-5.8%, 3.6%)
BL1800-302
Suprep
(split dose)[7]
Randomized 
single blind
MoviPrep
175/190
15%
(-2.2%, 5.4%)
5mg v.s. 10mg 
Halflytley [8]
Randomized 
investigator 
blinded
Halflytely 10 
mg
114/147 
(77.6%)
15%
(-11.9%, 6.8%)
Systemic/ 
review and 
meta-analysis: 
Sodium 
picosulfate/magn
esium citrate vs.
polyethylene 
glycol for 
colonoscopy 
preparation.
[10]
Meta-
analysis
polyethylene 
glycol for 
colonoscopy 
(PEG)
9%
(10% 
relative 
decrease 
from 
PEG.)
Lower bound of the 
-4.57% 


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NER1006 vs.
trisulfate [2]
Randomized  
blinded 
colonoscopi
st and 
central 
reader
trisulfate
85.1% vs. 
85% 
(HCG 
criteria)
82.6% vs. 
81.1%
(BBPS 
criteria)
HCG and BBPS
10%
(based on 
maximally 
clinically 
acceptable 
difference 
for studies 
of this 
type
-8.15% for HCG 
The margin for this study was derived in consultation with the FDA guidance document “Non-
inferiority Clinical Trials to Establish Effectiveness” [5] and extensive literature review on 
colonoscopy cleaning treatments.
No placebo controlled Prepopik study could be found in the literature. Furthermore, a randomized 
placebo controlled trial could not be found for colonoscopy cleaning treatments under 
consideration.  However, without use of any treatment, the response rate (from a perspective of 
Aronchick scale) is expected to be about 0% and no higher than 15%. If on the conservative side 
the placebo response rate of 15% is assumed, then for the Prepopik study 2009 [3] the difference 
from placebo would be 84%-15%=69%. Furthermore, if 15% is assumed to be the true value, the 
95% confidence interval for the difference between the estimated 84% and the constant 15%, true 
control response rate, is (65%, 73%). One common approach for non-inferiority margin is to take 
one-half of the lower limit of the 95% confidence interval of the difference of the active treatment 
to the control. In this case this would be 33%.  Because of this high treatment effect, which is 
consistent across other major marketed treatments, and low placebo response rate, the margin 
cannot be justified in this manner. Hence, the margin rational in this study is based on clinical 
consideration (i.e., M2). 
In this trial the assumed active control efficacy rate is 84%. Based on clinical consideration, the 
non-inferiority margin is selected so that at least 90% of the active control effect rate is retained. 
This results in a non-inferiority margin of 8%.  Furthermore, in a recently published meta-
analysis [10], comparing Polyethylene glycol (PEG) based treatment with sodium 
picosulfate/magnesium, citrate treatment, the margin for non-inferiority was based on 90% 
retention rate (of the PEG efficacy). In light of these, it is believed a retention rate of 10% for this 
study is acceptable.