Clinical trial NCT02522780
Conditions: Ulcerative Colitis
Sponsor: Ferring Pharmaceuticals
Start date: 2016-02-01; Completion date: 2018-09-19
Enrollment: 276 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial was to investigate the safety and efficacy of mesalamine 2 g extended release granules (sachet) once a day (QD) for maintenance of clinical and endoscopic remission in subjects with UC. The duration of treatment for each subject was 6 months.

Detailed description:

Arms: arm 1: Mesalamine 2 g extended release granules (sachet), administered orally once daily (QD) for 6 months. arm 2: Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Interventions: intervention 1: Mesalamine intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Granules in sachet; Route of administration: Oral use intervention 2: Pharmaceutical form: Granules in sachet; Route of administration: Oral use

Protocol documents:
Prot_000.pdf: 
Protocol 
Title of trial: 
A randomized, double-blind, placebo-controlled, multicenter study 
investigating the efficacy and safety of mesalamine 2 g extended release 
granules (sachet) for maintenance of clinical and endoscopic remission in 
ulcerative colitis 
NCT number: 
NCT02522780 
Sponsor trial code: 
000175  
Date:  
17 Jan 2017 
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Date: 17 Jan 2017
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Trial Code: 000175 
Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Investigating the 
Efficacy and Safety of Mesalamine 2 g Extended Release Granules (Sachet) for Maintenance of 
Clinical and Endoscopic Remission in Ulcerative Colitis
000175
Consolidated Protocol Incorporating Amendments 1.0, 2.0, 3.0 and 4.0
EudraCT Number:
2015-002558-11
IND Number:
122553
Investigational Medicinal Product:
Mesalamine 2 g Extended Release Granules (Sachet)
Indication:
Maintenance of Clinical and Endoscopic Remission in 
ulcerative colitis
Phase:
3
Name and Address of Sponsor:
Ferring International PharmaScience Center U.S., Inc.
100 Interpace Parkway
Parsippany, NJ  07054
Office: 973-796-1600
Fax: 973-796-1699
GCP Statement:
This trial will be performed in compliance with Good 
Clinical Practice (GCP).
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorized officer of Ferring Pharmaceuticals A/S or another company 
within the Ferring Group.
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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
SYNOPSIS
TITLE OF TRIAL
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Investigating the Efficacy 
and Safety of Mesalamine 2 g Extended Release Granules (Sachet) for Maintenance of Clinical and 
Endoscopic Remission in Ulcerative Colitis
SIGNATORY INVESTIGATOR(S)
 University of Pennsylvania Division of 
Gastroenterology; Perleman Center for Advanced Medicine, Philadelphia, PA, USA
TRIAL SITES
Approximately 110 sites in North America and Europe
PLANNED TRIAL PERIOD
First subject first visit:  Q3 2015
Last subject last visit:  Q2 2018
CLINICAL PHASE
3
OBJECTIVES
Primary objective: 

To demonstrate the efficacy of mesalamine 2 g extended release granules (sachet) once daily 
(QD) compared to placebo in the maintenance of clinical and endoscopic remission of 
ulcerative colitis (UC)
Secondary objectives:

To evaluate the efficacy of mesalamine 2 g extended release granules (sachet) utilizing the 
Clinical and Endoscopic Response Score, Clinical Response Score subset, and frequency of 
treatment failures

To assess C-reactive protein (CRP) levels and fecal calprotectin levels

To assess health-related quality of life (HRQoL) using the Inflammatory Bowel Disease 
Questionnaire (IBDQ)

To assess the incidence and severity of adverse events (AEs) and abnormal laboratory 
values
ENDPOINTS
Primary endpoint:
The primary efficacy endpoint is the proportion of subjects in remission, defined by the Clinical 
and Endoscopic Response Score at 6 months (see table below) as a score of:

0 for rectal bleeding 

0 or 1 for stool frequency

0 or 1 for endoscopic score 
The endoscopic score will be determined by an independent central reader.
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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
ENDPOINTS
Secondary endpoints:
1.
The proportion of subjects in clinical remission at Months 2, 4, and 6, defined as a score of 
0 for rectal bleeding and 0 or 1 for stool frequency based on Clinical Response Score subset 
of the Clinical and Endoscopic Response Score
2.
Time to relapse, defined as number of days from randomization to the day of withdrawal 
due to escalation of therapy (i.e., surgical therapy, use of steroids, immunosuppressive or 
immunomodulating drugs, biologics, increase dose of 5-aminosalicylic acid [5-ASA] in any 
form)
3.
The proportion of subjects with an increase from baseline in the Clinical and Endoscopic 
Response Score by 2 or more points in at least 1 component or by 1 or more points in at 
least 2 components at Month 6
4.
The change from baseline in serum CRP levels at Months 2, 4, and 6
5.
The change from baseline in fecal calprotectin levels at Months 2, 4, and 6
6.
The change from baseline to each scheduled assessment for published and validated domain 
scores of the IBDQ
7.
Safety assessed by incidence and severity of AEs and abnormal laboratory values
Clinical and Endoscopic Response Score (0 – 9)
Components
Subscale
Severity
Score
CLINICAL
RESPONSE
(Subject’s 
Symptoms)
Stool Frequencya
(daily)
Normal number of stools for subject
0
1 to 2 stools more than normal
1
3 to 4 stools more than normal
2
≥5 stools more than normal
3
Rectal Bleedingb
(daily)
No blood seen
0
Streaks of blood with stool 
1
Obvious blood with stool
2
Blood alone passes
3
ENDOSCOPIC
RESPONSE
(Objective Evidence 
of Inflammation)
Flexible 
Sigmoidoscopy
/colonoscopy
Findings
Normal or inactive disease
0
Mild disease (erythema, decreased vascular pattern, 
granularity)
1
Moderate disease (marked erythema, absent vascular 
pattern, any friability, erosions)
2
Severe disease (spontaneous bleeding, ulceration)
3
Adapted from:  Schroeder et al., 1987(1); Sninsky et al., 1991(2); Modified by Ferring Group, 2014
a.
Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency.
b.
The daily bleeding score represents the most severe bleeding of the day.
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Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
METHODOLOGY
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, international, 
Phase 3 trial to investigate the safety and efficacy of mesalamine 2 g extended release granules 
(sachet) for maintenance of clinical and endoscopic remission in subjects with UC. Subjects who 
are in remission can be enrolled in the current trial via 1 of 3 pathways. 

Pathway 1:  Subjects who are in remission following 8 weeks of double-blind treatment in 
Study 000174 can be randomized into Study 000175. The clinical and endoscopic remission 
criteria for Study 000174 include a Clinical and Endoscopic Response Score as a score of 0 
for rectal bleeding and 0 or 1 with at least 1 point decrease from baseline for stool 
frequency, with an endoscopic score of 0 or 1.

Pathway 2:  Subjects in remission at the end of the 8-week open-label treatment period in 
Study 000174 will be allowed to be randomized into Study 000175. 

Pathway 3 – de novo:  Subjects who did not participate in Study 000174 can also be 
enrolled; these subjects will have been treated with various medications for UC (excluding 
biologics and long-term [≥6 weeks] immunosuppressants) and will have been in remission 
for <1 year. These de novo subjects will undergo a 72-hour mesalamine washout prior to 
entering the current trial and will have a Clinical and Endoscopic Response Score 
assessment to ensure eligibility.
All eligible subjects will be randomized during Visit 1/Day 0 (start of maintenance) to 1 of the 
following treatments:  

one mesalamine 2 g extended release granules (sachet) QD (2 g/day) OR

one 2 g placebo sachet to match mesalamine extended release granules (sachet)
Dose will be administered QD at least 1 hour before or at least 2 hours after a meal at 
approximately the same time each day. The sachet will be emptied on the tongue and swallowed 
with at least 8 ounces (240 mL) of water. For all subjects, the first dose of investigational medicinal 
product (IMP) will be administered the day following randomization/Visit 1.
During the 6-month trial period, all subjects will visit the trial site 5 times for safety and efficacy 
evaluations:  baseline, Week 2, and Months 2, 4, and 6. On a daily basis, subjects will record 
clinical symptoms (stool frequency and rectal bleeding) in an electronic diary. The Clinical and 
Endoscopic Response Score assessments will be performed at baseline and Month 6. After 
6 months of treatment, subjects will be evaluated for remission, defined as a Clinical and 
Endoscopic Response Score of rectal bleeding score of 0 and stool frequency score of 0 or 1, with 
an endoscopic score of 0 or 1. Whereas, subjects will only have a Clinical Response Score 
assessment at Week 2 and Months 2 and 4. De novo subjects will have a complete screening visit,
and if they are judged to be in clinical and endoscopic remission based on their Clinical and 
Endoscopic Score at baseline/randomization, they will continue with the 6-month assessment for 
safety and efficacy evaluations.
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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
METHODOLOGY (Continued)
Flexible sigmoidoscopy/colonoscopy will be video recorded and transferred to the independent 
central reader. The details of the tools, recording, data transfer, and assessment will be documented 
in an Imaging Charter. If the local site’s endoscopic reading determines the subject is ineligible, the 
subject will be screen failed (Pathway 3 – de novo). If the local site’s endoscopic reading 
determines that the subject is eligible, the flexible sigmoidoscopy/colonoscopy recording will be 
sent to the independent central reader for final determination of eligibility (Pathway 3 – de novo). 
For subjects rolling over from the 000174 trial (Pathway 1 and 2), 000175 eligibility will be derived 
from the final end-of-treatment (EOT) independent central read. A flexible 
sigmoidoscopy/colonoscopy will also be performed at Month 6, which will also be sent to the 
independent central reader for endoscopic endpoint scoring for all subjects. 
NUMBER OF SUBJECTS
Approximately 260 subjects with UC in clinical and endoscopic remission will be randomized 
(130/treatment regimen).
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Clinical Trial Protocol
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CONFIDENTIAL
CRITERIA FOR INCLUSION / EXCLUSION
Inclusion Criteria:
1. Satisfied one of the following criteria for enrollment into the trial:
a.
Met the remission criteria at Week 8 of Study 000174 (Pathway 1) or
b. Did not meet the remission criteria during Study 000174 and agreed to an additional 
8 weeks of open-label treatment with mesalamine 4 g/day QD, after which met the 
remission criteria (Pathway 2) or
c.
Subjects not currently enrolled in Study 000174 and currently treated with 
medications for UC and currently in remission <1 year based on clinical and 
endoscopic evaluation (rectal bleeding score of 0 and stool frequency score of 0 or 1, 
with endoscopic score of 0 or 1 in Clinical and Endoscopic Response Score; i.e., 
clinical and endoscopic remission). The duration of prior remission must be less <1 
year and include a history of flare (defined as escalation of medical therapy[ies]), 
and/or documented episode of recurrent rectal bleeding accompanied by abdominal 
pain and increased stool number that required medical intervention) (Pathway 3 - de 
novo)
2. Signed informed consent obtained before any trial-related procedures 
3. Male or nonpregnant female subjects aged 18 to 75 years 
4. Extent 
of 
colonic 
involvement 
historically 
confirmed 
(i.e., 
flexible 
sigmoidoscopy/colonoscopy report, colonoscopy report, biopsy reading) within past 12 
months
5. Estimated creatinine clearance > 60 mL/min
6. Females of childbearing potential must agree to use an adequate contraception during the 
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. Sterilized or postmenopausal women may also participate. 
Women must have a negative serum pregnancy test result at screening and negative urine 
pregnancy test result on baseline/randomization.
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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
CRITERIA FOR INCLUSION / EXCLUSION (Continued)
Exclusion Criteria:
1. Evidence of other forms of inflammatory bowel disease 
2. Infectious disease (including human immunodeficiency virus [HIV], hepatitis B virus 
[HBV], or hepatitis C virus [HCV]) 
3. Disease limited to proctitis <15 cm 
4. Short bowel syndrome 
5. Prior colon resection surgery 
6. History of severe/fulminant UC  
7. Intolerant or allergic to aspirin or salicylate derivatives 
8. Taking the following treatments:
a) Aspirin within 7 days prior to Visit 1 (except for cardioprotective reasons - maximum dose 
325 mg/day) 
b) Loperamide and other antidiarrheal agents, mucilages, antibiotics (metronidazole and 
ciprofloxacin), nonsteroidal anti-inflammatory drugs (NSAIDs), nicotine patch within 
1 week 
c) Corticosteroids (oral, intravenous, or intramuscular) within the previous month
d) Immunomodulating/suppressing drugs within the previous 6 weeks
e) Use of rectal formulations (5-ASA, steroids) within 7 days prior to Visit 1
f)
History of biologics (e.g., Remicade)
9. Pathway 3 - de novo only: mesalamine use within 72 hours prior to Visit 1
10. Alanine transaminase; aspartate transaminase (ALT; AST) >3 x upper limit of normal 
(ULN) or severe liver impairment
11. Clinically significant hematological function abnormalities 
12. Known alcohol or drug abuse 
13. Women who are pregnant or nursing 
14. History of or known malignancy (Note: Adequately treated (i.e. cured) basal cell carcinoma 
and cervical intraepithelial neoplasia (CIN) or carcinoma in situ of the cervix with no 
evidence of recurrence within the previous 5 years can be included)
15. History of  bleeding disorders, active gastric or active duodenal ulcers, autoimmune 
diseases, or mental/emotional disorders that would interfere with participation in the trial
16. Participation in a clinical trial with administration of another investigational medicinal 
product within the previous 30 days (except for Study 000174)
17. Unable to comply with the requirements of the protocol 
18. Unable to complete the subject daily diary or follow data-capturing procedures
MEDICINAL PRODUCTS
The IMP for the trial will be mesalamine 2 g extended release granules (sachet) and placebo, which 
will be identical in appearance.
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Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
DURATION OF TREATMENT
The duration of treatment for each subject will be 6 months.
STATISTICAL METHODS
Sample size: The true remission rates at Month 6 for mesalamine 2 g extended release granules 
(sachet) and placebo regimens were assumed as 68% and 49%, respectively, based on The 
mesalamine Study Group (1996),(3) Hawkey et al (1997),(4) and Apriso™ package insert
(2009).(5) Under these assumptions, a sample size of 120 randomized subjects per group will 
provide at least 85% power to detect a statistically significant treatment group difference in the 
remission rate at a two-sided 0.05 significance level using the chi-square test. To maintain the 
power for the primary efficacy analysis that excludes subjects who are rolled over from the placebo 
group in the 000174 trial via Pathway 1, approximately 260 subjects will be randomized. 
Efficacy: The primary efficacy analysis will be based on all randomized subjects who were
assigned to mesalamine 4 g extended release granules in the 000174 trial or randomized via 
Pathway 2 or 3 (ITT; intent-to-treat). The primary efficacy endpoint will be the proportion of
subjects in remission, defined as rectal bleeding score of 0 and stool frequency score of 0 or 1, with 
an endoscopic score of 0 or 1 in Clinical and Endoscopic Response Score at Month 6.
The treatment group difference in the proportion of subjects in remission at Month 6 will be 
assessed by the Mantel-Haenszel test stratified by the randomization strata at a two-sided 0.05 
significance level. Subjects who discontinue the double-blind regimen before Month 6, as well as 
subjects with missing remission assessment at Month 6, will be considered not having met the 
remission criteria. The odds ratio will be estimated and its 95% confidence interval will be 
provided.
Safety: The safety analyses will be based on all subjects who receive at least 1 dose of IMP. All 
adverse events will be coded by system organ class and preferred term using the most current 
version of the Medical Dictionary for Regulatory Activities (MedDRA). A treatment-emergent 
adverse event will be defined as any adverse event occurring after the start of IMP or pre-existing 
medical condition that worsens in intensity after the start of IMP.
Clinical laboratory variables will be presented in 2 ways. First, mean change from baseline to the 
end of the double-blind treatment visit will be summarized. Baseline will be defined as the last 
assessment before the first dose of IMP. Second, the number and percentage of subjects with 
treatment-emergent potentially clinically significant laboratory values on or before the end of the 
double-blind treatment visit will be tabulated. 
Other safety assessments will also be summarized descriptively. 
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Clinical Trial Protocol
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CONFIDENTIAL
TABLE OF CONTENTS
SYNOPSIS....................................................................................................................................................... 2
LIST OF TABLES........................................................................................................................................ 12
LIST OF FIGURES...................................................................................................................................... 12
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 13
1
INTRODUCTION ............................................................................................................................. 16
1.1
Background............................................................................................................................. 16
1.2
Scientific Justification for Conducting the Trial..................................................................... 17
1.3
Benefit / Risk Aspects............................................................................................................. 17
2
TRIAL OBJECTIVES AND ENDPOINTS..................................................................................... 18
2.1
Objectives ............................................................................................................................... 18
2.2
Endpoints ................................................................................................................................ 18
3
INVESTIGATIONAL PLAN ........................................................................................................... 20
3.1
Overall Trial Design................................................................................................................ 20
3.1.1
Overall Design and Control Methods ........................................................................ 20
3.1.2
Trial Design Diagram................................................................................................. 21
3.1.3
Trial Schedule............................................................................................................ 23
3.2
Planned Number of Trial Sites and Subjects........................................................................... 23
3.3
Interim Analysis...................................................................................................................... 23
3.4
Data Monitoring Committee ................................................................................................... 23
3.5
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 23
3.5.1
Trial Design ............................................................................................................... 23
3.5.2
Selection of Endpoints ............................................................................................... 23
3.5.3
Blinding...................................................................................................................... 23
3.5.4
Selection of Doses in the Trial................................................................................... 23
3.5.5
Selection and Timing of Dose for Each Subject........................................................ 24
3.5.6
Selection of Trial Population ..................................................................................... 24
3.5.7
Withdrawal Criteria ................................................................................................... 24
3.5.8
Follow-up Procedures ................................................................................................ 24
4
SELECTION OF TRIAL POPULATION ...................................................................................... 25
4.1
Trial Population....................................................................................................................... 25
4.1.1
Inclusion Criteria ....................................................................................................... 25
4.1.2
Exclusion Criteria ...................................................................................................... 25
4.2
Method of Assigning Subjects to Treatment Groups.............................................................. 26
4.3
Restrictions ............................................................................................................................. 26
4.3.1
Prior and Concomitant Therapies .............................................................................. 26
4.3.2
Prohibited Therapy..................................................................................................... 27
4.3.3
Other Restrictions ...................................................................................................... 27
4.4
Withdrawal Criteria................................................................................................................. 27
5
TREATMENTS ................................................................................................................................. 29
5.1
Treatments Administered........................................................................................................ 29
5.1.1
Investigational Medicinal Product (IMP)................................................................... 29
5.1.2
Non-Investigational Medicinal Product (NIMP) ....................................................... 29
5.2
Characteristics and Source of Supply ..................................................................................... 29
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5.3
Packaging and Labelling......................................................................................................... 29
5.4
Conditions for Storage and Use .............................................................................................. 29
5.5
Blinding / Unblinding ............................................................................................................. 29
5.5.1
Blinding...................................................................................................................... 29
5.5.2
Unblinding of Individual Subject Treatment ............................................................. 30
5.6
Treatment Compliance............................................................................................................ 30
5.6.1
Dispensing and Accountability.................................................................................. 30
5.6.2
Assessment of Compliance........................................................................................ 30
5.7
Return and Destruction of Medicinal Products....................................................................... 31
6
TRIAL PROCEDURES .................................................................................................................... 32
6.1
Trial Flow Chart...................................................................................................................... 32
6.2
Trial Procedures...................................................................................................................... 33
6.2.1
Screening Visit: Visit 0 (up to Day -21) .................................................................... 33
6.2.2
Baseline/Randomization Visit: Visit 1 (Day 0) ......................................................... 34
6.2.3
Intermediate Visit: Visit 2 (Day 14 ±3) ..................................................................... 35
6.2.4
Intermediate Visits: Visit 3 (Day 56 ±5) and Visit 4 (Day 112 ±5)........................... 36
6.2.5
End-of-Treatment / Early Withdrawal Visit: Visit 5 (Day 168 ±5)........................... 36
7
TRIAL ASSESSMENTS ................................................................................................................... 38
7.1
Assessments Related to Endpoints.......................................................................................... 38
7.1.1
Clinical and Endoscopic Response Score .................................................................. 38
7.1.2
Flexible Sigmoidoscopy/colonoscopy ....................................................................... 38
7.1.2.1
Independent Central Endoscopy Laboratory................................................39
7.1.3
Subject Daily Diary.................................................................................................... 39
7.1.4
Serum CRP and Fecal Calprotectin ........................................................................... 40
7.1.5
Health-Related Quality of Life/Collection Pad.......................................................... 40
7.1.6
Adverse Events .......................................................................................................... 40
7.1.7
Clinical Laboratory Variables.................................................................................... 40
7.2
Other Assessments.................................................................................................................. 41
7.2.1
Medical History and Demographic Data ................................................................... 41
7.2.2
Immunological Testing.............................................................................................. 41
7.2.3
Drug and Alcohol History.......................................................................................... 41
7.2.4
Serum/Urine Pregnancy Test ..................................................................................... 41
7.2.5
Concomitant Medications .......................................................................................... 41
7.2.6
Physical Examinations............................................................................................... 41
7.2.7
Vital Signs.................................................................................................................. 41
7.2.8
12-Lead Electrocardiogram........................................................................................ 42
7.2.9
Compliance ................................................................................................................ 42
7.3
Drug Concentration Measurements......................................................................................... 42
7.4
Handling of Biological Samples ............................................................................................. 42
8
ADVERSE EVENTS ......................................................................................................................... 43
8.1
Adverse Event Definition........................................................................................................ 43
8.2
Collection and Recording of Adverse Events......................................................................... 43
8.2.1
Collection of Adverse Events .................................................................................... 43
8.2.2
Recording of Adverse Events .................................................................................... 43
8.3
Pregnancy and Pregnancy Outcome........................................................................................ 46
8.4
Serious Adverse Events .......................................................................................................... 47
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8.4.1
Serious Adverse Event Definition.............................................................................. 47
8.4.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 48
8.5
Follow-up of Adverse Events and Serious Adverse Events.................................................... 49
8.5.1
Follow-up of Adverse Events with Onset during the Trial........................................ 49
8.5.2
Collection of Serious Adverse Events with Onset after Last Trial Visit ................... 49
9
STATISTICAL METHODS ............................................................................................................. 50
9.1
Determination of Sample Size ................................................................................................ 50
9.2
Subject Disposition ................................................................................................................. 50
9.3
Protocol Deviations................................................................................................................. 50
9.4
Analysis Sets........................................................................................................................... 50
9.5
Trial Population....................................................................................................................... 51
9.5.1
Demographics and other Baseline Characteristics..................................................... 51
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations................ 51
9.6
Endpoint Assessments............................................................................................................. 51
9.6.1
General Considerations.............................................................................................. 51
9.6.2
Primary Endpoint....................................................................................................... 52
9.6.3
Secondary Endpoints ................................................................................................. 52
9.6.4
Health-related Quality of Life.................................................................................... 53
9.7
Extent of Exposure and Treatment Compliance ..................................................................... 53
9.8
Safety ...................................................................................................................................... 53
9.8.1
General Considerations.............................................................................................. 53
9.8.2
Adverse Events .......................................................................................................... 53
9.8.3
Safety Laboratory Variables ...................................................................................... 54
9.8.4
Other Safety Variables............................................................................................... 55
9.9
Interim Analyses ..................................................................................................................... 55
10
DATA HANDLING ........................................................................................................................... 56
10.1
Source Data and Source Documents....................................................................................... 56
10.2
eCRF ....................................................................................................................................... 56
10.3
Data Management ................................................................................................................... 57
10.4
Provision of Additional Information....................................................................................... 57
11
MONITORING PROCEDURES ..................................................................................................... 58
11.1
Periodic Monitoring................................................................................................................ 58
11.2
Audit and Inspection............................................................................................................... 58
11.3
Confidentiality of Subject Data............................................................................................... 58
12
CHANGES IN THE CONDUCT OF THE TRIAL........................................................................ 59
12.1
Protocol Amendments............................................................................................................. 59
12.2
Deviations from the Protocol .................................................................................................. 59
12.3
Premature Trial Termination................................................................................................... 59
13
REPORTING AND PUBLICATION .............................................................................................. 60
13.1
Clinical Trial Report ............................................................................................................... 60
13.2
Confidentiality and Ownership of Trial Data.......................................................................... 60
13.3
Publications and Public Disclosure......................................................................................... 60
13.3.1 Publication Policy...................................................................................................... 60
13.3.2 Public Disclosure Policy............................................................................................ 60
14
ETHICAL AND REGULATORY ASPECTS................................................................................. 62
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14.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .......................... 62
14.2
Regulatory Authorities Authorization / Approval / Notification ............................................ 62
14.3
End-of-Trial and End-of-Trial Notification ............................................................................ 62
14.4
Ethical Conduct of the Trial.................................................................................................... 62
14.5
Subject Information and Consent............................................................................................ 62
14.6
Compliance Reference Documents......................................................................................... 63
15
LIABILITIES AND INSURANCE .................................................................................................. 64
15.1
ICH-GCP Responsibilities...................................................................................................... 64
15.2
Liabilities and Insurance......................................................................................................... 64
16
ARCHIVING...................................................................................................................................... 65
16.1
Investigator File ...................................................................................................................... 65
16.2
Trial Master File...................................................................................................................... 65
17
REFERENCES................................................................................................................................... 66
APPENDICES............................................................................................................................................... 68
Appendix 1
Inflammatory Bowel Disease Questionnaire (IBDQ)................................................ 69
Appendix 2
Subject Diary Script................................................................................................... 81
LIST OF TABLES 
Table 1:
Schedule of Trial Procedures..........................................................................................32
Table 2:
Clinical and Endoscopic Response Score (0 – 9) ...........................................................38
LIST OF FIGURES
Figure 1:
Trial Design Diagram......................................................................................................22
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
List of Abbreviations
ADR
Adverse drug reaction
AE
Adverse event
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ASA
Aminosalicylic acid
AST
Aspartate transaminase 
ATC
Anatomical Therapeutic Chemical
BM
Bowel movement
CRO
Contract research organization
CRP
C-reactive protein
D
Day
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EOT
End-of-Treatment
ER
Extended release
EudraCT
European Union Clinical Trial Database
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HRQoL
Health-related quality of life
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IRB
Institutional Review Board
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IRT
Interactive Response Technology
IVRS
Interactive Voice Response system
ITT
Intent-to-Treat
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
Mo
Month
NIMP
Non-investigational medicinal product
NSAID
Nonsteroidal anti-inflammatory drug
PP
Per protocol
PT
Preferred term
QD
Once daily
SAE
Serious adverse event
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reaction 
TEAE
Treatment-emergent adverse event
UC
Ulcerative colitis
ULN
Upper limit of normal
US
United States
V
Visit
WHO-Drug
World Health Organization Drug Dictionary
Wk
Week
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Definition of Terms
Remission
defined by the Clinical and Endoscopic Response Score as a score of 0 for 
rectal bleeding and 0 or 1 for stool frequency, with an endoscopic score of 
0 or 1 
Clinical remission
defined as a score of 0 for rectal bleeding and 0 or 1 for stool frequency 
based on clinical assessment subset of the Clinical and Endoscopic 
Response Score
Time to relapse
defined as number of days from randomization to the day of withdrawal 
due to escalation of therapy (i.e., surgical therapy, use of steroids, 
immunosuppressive or immunomodulating drugs, biologics, increase dose 
of 5-ASA in any form)
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1
INTRODUCTION
1.1
Background
Ulcerative colitis (UC), an inflammatory bowel disease, is a chronic condition of unknown origin. 
Ulcerative colitis is a relapsing and remitting disease characterized by acute non-infectious 
inflammation of the colorectal mucosa.(6)  In the United States (US), about 1 million people are 
affected with UC.(7,8) The annual incidence of UC per 100,000 people is 10.4 to 12 cases in the 
US and 8 cases in Europe. The prevalence rate per 100,000 people is 35 to 100 cases in the US and 
21 to 243 in Europe. UC is slightly more common in women than in men. Although the disease can 
occur at any age, the age of onset follows a bimodal pattern, with a peak at 15 to 25 years and a 
smaller peak at 55 to 65 years.(9)
Active episodes of UC are marked by passing of blood and mucus, diarrhea, and abdominal pain 
frequently accompanied by urgency and tenesmus.(10) In the most severe forms, systemic signs 
comprising fever, anorexia, and weight loss may occur. Approximately 60% of patients have a mild 
form, 25% a moderate form, and 15% a severe disease. Despite treatment, it is estimated that 
approximately 1 of every 2 patients with UC will experience a relapse within 1 year; the cumulative 
probability of relapse is 80% within 2 years and 95% within 10 years.(11)
Involvement of the rectal mucosa is a constant feature while the inflammation spreads to higher 
levels in continuous and retrograde fashion, with no sparing of mucosa from the anorectal junction. 
Hence, UC may be divided in proctitis, proctosigmoiditis, left-sided colitis (the proximal limit 
being below the splenic flexure), extensive colitis (involving the transverse colon), and pancolitis
(involving the entire colon).
The aim of treatment of UC is the induction of remission and maintenance of remission, and the 
prevention of  complication of long-term UC. 
Several therapeutic drug classes are used in UC: 5-aminosalicylic acid (5-ASA) derivatives, 
corticosteroids, immunosuppressants, and anti-tumor necrosis factor-α agents. At present, 
aminosalicylate derivatives are the main and first-line therapy for mild to moderate episodes of UC 
and for maintenance treatment.(12) Rectal administration of salicylate-type drugs constitutes the 
treatment of choice in proctitis, proctosigmoiditis, and left-sided UC.(13,14,15) The extended
release mesalamine granules are purposed to treat all forms of active mild-to-moderate UC in all 
segments of the colon.
Ferring recently developed a prolonged release granule formulation with a higher drug load (95% 
load) to provide a better alternative for patients that have difficulty swallowing the tablet or capsule 
forms, and thereby may help increase treatment compliance.  
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The safety and tolerability of various mesalamine dosing regimens have been demonstrated.(16,17)
The optimum dose of oral mesalamine for induction therapy in order to achieve remission is 
between 2 and 4 g/day.(18)  
1.2
Scientific Justification for Conducting the Trial
The mesalamine 2 g extended release granules (sachet) is approved in 71 countries worldwide for 
treatment of mild to moderate ulcerative colitis. The indications may differ from country to country.
This dosage form was developed as a true QD regimen to provide an alternative for patients who 
have difficulty swallowing the tablets or large capsules forms. There are no sachet granular forms 
available for both induction and maintenance of remission in some countries. The availability of 
this easier-to-take formulation might potentially help increase compliance, and would be an overall 
useful tool in the care of these patients. 
1.3
Benefit / Risk Aspects
The 95% granules allows for a true once a day convenient dosing with the highest unit dosage form 
available for induction and maintenance of UC. In addition the granules are easier to swallow than 
the tablets and capsules currently available in the US.
The most common adverse events (AEs) considered related to treatment with mesalamine 
formulations up to 2 g per day have been diarrhea, nausea, abdominal pain, headache, vomiting, 
and rash. Hypersensitivity reactions and drug fever may occasionally occur.
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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective
The primary objective of this trial is to demonstrate the efficacy of mesalamine 2 g extended release 
granules (sachet) QD compared to placebo in the maintenance of clinical and endoscopic remission 
of UC.
Secondary Objectives
The secondary objectives of this trial are to:

evaluate the efficacy of mesalamine 2 g extended release granules (sachet) utilizing the 
Clinical and Endoscopic Response Score subsets, and frequency of treatment failures

assess C-reactive protein (CRP) levels and fecal calprotectin levels 

assess health-related quality of life (HRQoL) using the Inflammatory Bowel Disease 
Questionnaire (IBDQ) 

assess the incidence and severity of AEs and abnormal laboratory values 
2.2
Endpoints
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects in remission at 6 months, defined by the 
Clinical and Endoscopic Response Score (Table 2) as a score of:

0 for rectal bleeding 

0 or 1 for stool frequency

0 or 1 for endoscopic score 
The endoscopic score will be determined by the central reading result.
Secondary Endpoints
Secondary endpoints are the following:
1.
The proportion of subjects in clinical remission at Months 2, 4, and 6, defined as a score of 
0 for rectal bleeding and 0 or 1 for stool frequency based on Clinical Response Score subset 
of the Clinical and Endoscopic Response Score
2.
Time to relapse, defined as number of days from randomization to the day of withdrawal 
due to escalation of therapy (i.e., surgical therapy, use of steroids, immunosuppressive or 
immunomodulating drugs, biologics, increase dose of 5-ASA in any form)
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3.
The proportion of subjects with an increase from baseline in the Clinical and Endoscopic 
Response Score by 2 or more points in at least 1 component or by 1 or more points in at 
least 2 components at Month 6
4.
The change from baseline in serum CRP levels at Months 2, 4, and 6
5.
The change from baseline in fecal calprotectin levels at Months 2, 4, and 6
6.
The change from baseline to each scheduled assessment for published and validated domain 
scores of the IBDQ
7.
Safety assessed by incidence and severity of AEs and abnormal laboratory values
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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Overall Design and Control Methods
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, international, 
Phase 3 trial to investigate the safety and efficacy of therapy with mesalamine 2 g extended release 
granules (sachet) for maintenance of clinical and endoscopic remission in subjects with UC. 
Subjects who are in remission can be enrolled in the current trial via 1 of 3 pathways. 

Pathway 1:  Subjects who are in remission following 8 weeks of double-blind treatment in 
Study 000174 can be randomized into Study 000175. The clinical and endoscopic remission 
criteria for Study 000174 include a Clinical and Endoscopic Response Score as a score of 
0 for rectal bleeding and 0 or 1 with at least 1 point decrease from baseline for stool 
frequency, with an endoscopic score of 0 or 1.

Pathway 2:  Subjects in remission at the end of the 8-week open-label treatment period in 
Study 000174 will be allowed to be randomized into Study 000175. 

Pathway 3 – de novo:  Subjects who did not participate in Study 000174 can also be 
enrolled; these subjects will have been treated with various medications for UC (excluding 
biologics and long-term [≥6 weeks] immunosuppressants) and will have been in remission 
for <1 year. These de novo subjects will undergo a 72-hour mesalamine washout prior to 
entering the current trial and will have a Clinical and Endoscopic Response Score 
assessment to ensure eligibility. Refer to Section 4.3.1 for a complete listing of restrictions.
All eligible subjects will be randomized during Visit 1/Day 0 (start of maintenance) to 1 of the 
following treatments:  

one mesalamine 2 g extended release granules (sachet) QD (2 g/day) OR

one 2 g placebo sachet to match mesalamine extended release granules (sachet)
Dose will be administered QD at least 1 hour before or at least 2 hours after a meal at 
approximately the same time each day. The sachet will be emptied on the tongue and swallowed 
with at least 8 ounces (240 mL) of water. For all subjects, the first dose of investigational medicinal 
product (IMP) will be administered the day following randomization/Visit 1.
During the 6-month trial period, all subjects will visit the trial site 5 times for safety and efficacy 
evaluations:  baseline, Week 2, and Months 2, 4, and 6. On a daily basis, subjects will record 
clinical symptoms (stool frequency and rectal bleeding) in an electronic diary. The Clinical and 
Endoscopic Response Score assessments will be performed at baseline and Month 6. After 
6 months of treatment, subjects will be evaluated for remission, defined as a Clinical and 
Endoscopic Response Score of rectal bleeding score of 0 and stool frequency score of 0 or 1, with 
an endoscopic score of 0 or 1. Whereas, subjects will only have a Clinical Response Score 
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assessment at Week 2 and Months 2 and 4. De novo subjects will have a complete screening visit,
and if they are judged to be in clinical and endoscopic remission based on their Clinical and 
Endoscopic Score at baseline/randomization, they will continue with the 6-month assessment for 
safety and efficacy evaluations.
Flexible sigmoidoscopy/colonoscopy will be video recorded and transferred to the independent 
central reader. The details of the tools, recording, data transfer, and assessment will be documented 
in an Imaging Charter. If the local site’s endoscopic reading determines the subject is ineligible, the 
subject will be screen failed (Pathway 3 – de novo). If the local site’s endoscopic reading 
determines that the subject is eligible, a flexible sigmoidoscopy/colonoscopy recording will be sent 
to the independent central reader for final determination of eligibility (Pathway 3 – de novo). For 
subjects rolling over from the 000174 trial (Pathway 1 and 2), 000175 eligibility will be derived 
from the final EOT independent central read. A flexible sigmoidoscopy/colonoscopy will also be 
performed at Month 6, which will also be sent to the independent central reader for endoscopic 
endpoint scoring for all subjects.
3.1.2
Trial Design Diagram
The trial design is displayed in Figure 1.
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Figure 1:
Trial Design Diagram
D = Day, EOT = End-of-Treatment; ER = extended release; Mo = Month; V = Visit; Wk = Week
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3.1.3
Trial Schedule
First subject first visit is expected to occur in the third quarter of 2015 and last subject last visit is 
expected in the second quarter of 2018. For each subject, the total time in trial will be 
approximately 6 months. 
3.2
Planned Number of Trial Sites and Subjects
This trial will be conducted at approximately 110 sites in North America and Europe. 
Approximately 260 subjects will be randomized to receive mesalamine 2 g extended release 
granules (sachet) or matching placebo in a 1:1 ratio (130/treatment regimen).
3.3
Interim Analysis
No interim analysis is planned for this trial.
3.4
Data Monitoring Committee
No data monitoring committee will be established for this trial.
3.5
Discussion of Overall Trial Design and Choice of Control Groups
3.5.1
Trial Design
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, international 
phase 3 trial. During Visit 1/Baseline, subjects will be randomized in a 1:1 ratio to receive either 
mesalamine 2 g extended release granules (sachet) or matching placebo.
Subjects in Pathways 1 and 2 will be consented at Visit 1/Baseline. The complete screening 
assessments will be taken from the Study 000174 end-of-treatment visit and eligibility (all 
inclusion/exclusion criteria) will be reassessed.  
Pathway 3 (de novo) subjects will have a complete screening visit, and a Clinical and Endoscopic 
Response Score calculated at Visit 1/Baseline based on data collected during screening. 
All subjects will continue with the 6-month assessments for safety and efficacy evaluations.
3.5.2
Selection of Endpoints
The endpoints selected are similar to those used in other clinical studies of mesalamine oral 
formulation in UC.
3.5.3
Blinding
This is a randomized, double-blind, placebo-controlled trial. For more information on blinding, see 
Section 5.5.
3.5.4
Selection of Doses in the Trial
The well accepted oral dosage for mesalamine maintenance of remission ranges from 
approximately 1.5 g to 2.4 g /day. In this trial, the sponsor will utilize the 2 g/day dose of 
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mesalamine 2 g extended release granules (sachet), which is consistent with the accepted 
maintenance therapy. 
3.5.5
Selection and Timing of Dose for Each Subject
Each subject will be randomized to receive either mesalamine 2 g extended release granules 
(sachet) QD or matching placebo QD. Doses will be administered at least 1 hour before or at least 
2 hours after a meal at approximately the same time each day. The sachet will be emptied on the 
tongue and swallowed with at least 8 ounces (240 mL) of water. For all subjects, the first dose of 
IMP will be administered the day following randomization/Visit 1 on Day 1.
3.5.6
Selection of Trial Population
Subjects who met the remission criteria after 8 weeks of double-blind treatment with trial
medication or after 8 weeks of open-label treatment with trial medication in Study 000174, or who 
were not enrolled in Study 000174 and are currently being treated with medications for UC and 
maintained in remission <1 year based on clinical and endoscopic evaluation (rectal bleeding score 
of 0 and stool frequency score of 0 or 1, with endoscopic score of 0 or 1 in Clinical and Endoscopic 
Response Score; i.e., clinical and endoscopic remission). For more information on eligibility 
criteria, see Section 4.1.
3.5.7
Withdrawal Criteria
No trial-specific criteria for withdrawal are defined with the exception of worsening of UC with a 
need for an escalation of the therapy (i.e., surgical therapy, use of steroids, immunosuppressive or 
immunomodulating drugs, biologics, increase dose of 5-ASA in any form).
3.5.8
Follow-up Procedures
No specific post-trial follow-up procedures and subsequent therapy are planned. Subjects should be 
treated according to local standard of care with no further follow-up to be conducted after their 
participation in the trial has completed. 
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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
1. Satisfied one of the following criteria for enrollment into the trial:
a.
Met the remission criteria at Week 8 of Study 000174 (Pathway 1) or
b. Did not meet the remission criteria during Study 000174 and agreed to an additional 
8 weeks of open-label treatment with mesalamine 4 g/day QD, after which met the 
remission criteria (Pathway 2) or
c.
Subjects not currently enrolled in Study 000174 and currently treated with 
medications for UC and currently in remission <1 year based on clinical and 
endoscopic evaluation (rectal bleeding score of 0 and stool frequency scores of 0 or 
1, with endoscopic score of 0 or 1 in Clinical and Endoscopic Response Score; i.e., 
clinical and endoscopic remission). The duration of prior remission must be less <1 
year and include a history of flare (defined as escalation of medical therapy[ies]), 
and/or documented episode of recurrent rectal bleeding accompanied by abdominal 
pain and increased stool number that required medical intervention) (Pathway 3 – de 
novo)
2. Signed informed consent obtained before any trial-related procedures 
3. Male or nonpregnant female subjects aged 18 to 75 years 
4. Extent 
of 
colonic 
involvement 
historically 
confirmed 
(i.e., 
flexible 
sigmoidoscopy/colonoscopy report, colonoscopy report, biopsy reading) within past 12 
months
5. Estimated creatinine clearance > 60 mL/min
6. Females of childbearing potential must agree to use an adequate contraception during the 
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. Sterilized or postmenopausal women may also participate. 
Women must have a negative serum pregnancy test result at screening and negative urine 
pregnancy test result on baseline/randomization.
4.1.2
Exclusion Criteria
1. Evidence of other forms of inflammatory bowel disease 
2. Infectious disease (including human immunodeficiency virus [HIV], hepatitis B virus 
[HBV], or hepatitis C virus [HCV]) 
3. Disease limited to proctitis <15 cm 
4. Short bowel syndrome 
5. Prior colon resection surgery 
6. History of severe/fulminant UC  
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7. Intolerant or allergic to aspirin or salicylate derivatives 
8. Taking the following treatments:
a.
Aspirin within 7 days prior to Visit 1 (except for cardioprotective reasons - maximum 
dose 325 mg/day) 
b. Loperamide and other antidiarrheal agents, mucilages, antibiotics (metronidazole and 
ciprofloxacin), nonsteroidal anti-inflammatory drugs (NSAIDs), nicotine patch within 
1 week 
c.
Corticosteroids (oral, intravenous, or intramuscular) within the previous month
d. Immunomodulating/suppressing drugs within the previous 6 weeks
e.
Use of rectal formulations (5-ASA, steroids) within 7 days prior to Visit 1
f.
History of biologics (e.g., Remicade)
9. Pathway 3 – de novo only: mesalamine use within 72 hours prior to Visit 1
10. ALT; AST >3 x upper limit of normal (ULN) or severe liver impairment
11. Clinically significant hematological function abnormalities 
12. Known alcohol or drug abuse 
13. Women who are pregnant or nursing 
14. History of or known malignancy (Note: Adequately treated (i.e. cured) basal cell 
carcinoma and cervical intraepithelial neoplasia (CIN) or carcinoma in situ of the cervix
with no evidence of recurrence within the previous 5 years can be included)
15. History of bleeding disorders, active gastric or active duodenal ulcers, autoimmune 
diseases, or mental/emotional disorders that would interfere with participation in the trial
16. Participation in a clinical trial with administration of another investigational medicinal 
product within the previous 30 days (except for Study 000174)
17. Unable to comply with the requirements of the protocol 
18. Unable to complete the subject daily diary or follow data-capturing procedures
4.2
Method of Assigning Subjects to Treatment Groups
At Visit 1/Baseline, subjects will be randomly assigned, in a 1:1 ratio, to 1 of 2 treatment groups  
based on a centralized computer-generated randomization schedule via an interactive response 
technology (IRT). The randomization will be stratified by the pathway of enrolment, and Pathway 
#1 will be further stratified by the treatment group assigned in the 000174 trial.       
Re-enrollment of subjects is prohibited under any circumstances.
4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
Subjects should not be taking or have used the following treatments and a washout period will be 
required prior to trial medication administration:
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
oral 5-ASA (mesalamine) within the past 72 hours (de novo subjects only)  

aspirin within the past 7 days or during the trial (except for cardioprotective reasons -
maximum dose 325 mg/day) 

rectal formulations (5-ASA, steroids) within the past 7 days or during the trial 

loperamide and other antidiarrheal agents, mucilages, antibiotics (metronidazole and 
ciprofloxacin), NSAIDs, nicotine patch within the past week or during the trial

corticosteroids (oral, intravenous, or intramuscular) within the previous month or during the 
trial

immunomodulating/suppressing drugs within the previous 6 weeks or during the trial
Subjects must also not have a history of taking biologics (e.g., Remicade).
4.3.2
Prohibited Therapy
The following medications are prohibited during the trial: 5-ASA products (oral or topical rectal),
loperamide and other antidiarrheal agents, mucilages, antibiotics (metronidazole and ciprofloxacin), 
NSAIDs, nicotine patch, corticosteroids (oral, intravenous, intramuscular, or rectal), 
immunomodulating/suppressing drugs and biologics. Aspirin (except for cardioprotective reasons -
maximum dose 325 mg/day) is prohibited during the trial.
4.3.3
Other Restrictions
Subjects will be asked to not change their habits (e.g., continue previous cigarette consumption, 
exercise regimen). Subjects are not to abuse alcohol, caffeine, or illegal drugs during the trial.
4.4
Withdrawal Criteria
Subjects have 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. The investigator also has the right to withdraw subjects.
Subjects will be withdrawn in the following cases: 

pregnancy at any time during the trial will be a reason for withdrawal

withdrawal of consent

worsening of UC with a need for an escalation of the therapy (i.e., surgical therapy, use of 
steroids, immunosuppressive or immunomodulating drugs, biologics, increase dose of 
5-ASA in any form)

request for termination of the trial by regulatory authorities or sponsor

the subject develops any AE that, in the opinion of the investigator, warrants the subject’s 
withdrawal from treatment. An AE form will be completed as appropriate, and the subject 
will be followed until the event is clinically stable.
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For subjects who discontinue due to an AE, all efforts will be made to follow the outcome of the 
AE and to assess the efficacy criteria. 
For any discontinuation, the investigator will obtain all the required details and document the date 
of the premature termination and the main reason in the electronic case report form (eCRF). Since 
an excessive rate of withdrawals can render the trial devoid of meaning, the unnecessary 
withdrawal of subjects should be avoided.
Subjects who withdrew from the trial will not be replaced.
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Mesalazine, FE 999907
Trial Code: 000175 
Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
5
TREATMENTS
5.1
Treatments Administered
5.1.1
Investigational Medicinal Product (IMP)
IMPs used in the trial are extended release granules in sachets of either:

mesalamine 2 g extended release granules (sachet)

placebo 2 g sachet to match mesalamine extended release granules 
5.1.2
Non-Investigational Medicinal Product (NIMP)
No NIMPs will be supplied to subjects participating in the trial.
5.2
Characteristics and Source of Supply
All IMPs are provided by Ferring Pharmaceuticals/Ferring Entity and will be handled according to 
the principles of Good Manufacturing Practice (GMP).
5.3
Packaging and Labelling
Packaging and labelling of the IMPs will be performed under the responsibility of the IMP 
department at Ferring Pharmaceuticals A/S in accordance with GMP and national regulatory 
requirements. 
The IMP will be supplied to the subjects in boxes containing 64 sachets, enough for 2 months’ 
treatment including visit windows.
All IMP labelled with trial-specific labels and will contain an unique IMP number. 
The label of the IMP will also contain 1 self-adhesive tear-off portion to be affixed to the drug 
accountability log. 
5.4
Conditions for Storage and Use
The investigator will ensure that the IMPs will be stored in appropriate conditions as stated on the 
labels in a secure location with controlled access. The storage compartment shall be monitored 
regularly and the temperature must be documented. Deviations in storage temperature must be 
reported without delay, and the IMP must not be used until further instructions from the sponsor are 
received.
5.5
Blinding / Unblinding
5.5.1
Blinding
The IMPs will be packaged according to a centralized computer-generated randomization list. The 
randomization list will not be available to any person involved in the conduct and evaluation of the 
trial until the trial database is declared clean and released to the statistician.
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Prolonged Release Granules - 2 g
Clinical Trial Protocol
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All IMP will be identical in appearance to protect the blinded nature of the trial.
5.5.2
Unblinding of Individual Subject Treatment
Emergency unblinding will be available to the investigator and designated persons at Ferring via 
the IRT system. Breaking of the blind for individual subjects in emergency situations 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 IMP in question is required for therapeutic decisions for 
the management of the subject. The expectedness of events will be assessed by Ferring according to 
the Investigator’s Brochure.
As the emergency permits, the need to break the blind will be agreed upon by the investigator and 
Ferring. It should be recorded in the eCRF that the code is broken and why, when, and by whom. 
The investigator must record the event of unblinding in the subject’s medical record, including the 
reason for unblinding, but not the treatment allocation, if this can be avoided. 
In case of accidental unblinding, the same documentation as for emergency unblinding must be 
obtained, and the event must also be recorded in the subject’s medical record.
It may be necessary to unblind an individual subject’s treatment for the purposes of expedited 
reporting to the authorities and/or Independent Ethics Committee(s) (IEC)(s)/Institutional Review 
Board(s) (IRB)(s). 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 and 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 released to the statistician.
5.6
Treatment Compliance
5.6.1
Dispensing and Accountability
The IMP will only be dispensed to subjects who meet the eligibility criteria and are randomized to a 
treatment group in the trial. The investigator or coordinator will maintain a drug-dispensing log 
detailing the dates and quantities of IMPs dispensed to each subject. The monitor will verify the 
drug accountability during the course of the trial.
5.6.2
Assessment of Compliance
At Visits 2, 3, 4, and 5 (or at early withdrawal), subjects will bring their unused IMP back to the 
trial site. Subject compliance will be assessed with a medication count by the investigator or 
coordinator at the end of the visit and will be documented. 
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Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
5.7
Return and Destruction of Medicinal Products
All assigned, unused IMPs should be returned to the trial site and can be destroyed in accordance 
with local requirements, after the drug accountability has been finalized, verified by the monitor, 
and signed off by the investigator. 
All unassigned, unused IMPs will be returned as instructed by the IMP Department at Ferring 
Pharmaceuticals A/S after completion of drug accountability at the trial site.
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Supersedes: 5.0
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Trial Code: 000175 
Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
6
TRIAL PROCEDURES
6.1
Trial Flow Chart
The schedule of trial procedures is presented in Table 1. 
Table 1:
Schedule of Trial Procedures
Screeninga
Baseline/ 
Randomizationb Intermediate
Intermediate
Intermediate
End of 
Treatment/
Early 
Withdrawal
Visit
0
1
2
3
4
5
Monthc Week - 3
Month 0
Week 2
Month 2
Month 4
Month 6
Trial Day
(visit window)
Up to 
Day -21
Day 0
Day 14 
(±3 days)
Day 56
(±5 days)
Day 112
(±5 days)
Day 168
(5 days)
Written informed consent
X
Xd
Inclusion/exclusion criteria review
X
X
Medical history
X
X
Physical examination, including 
weight
X
X
X
X
X
X
Height
X
Vital signs
X
X
X
X
X
X
12-lead electrocardiogram
X
X
Demographic data
X
Serum/urine pregnancy teste
X
X
X
Standard urinalysisf
Xg
X
Drug and alcohol history
X
Immunological testing for HBV, 
HCV, and HIV
X
Estimated creatinine clearance
Xg
X
X
X
X
Safety hematology, coagulation,
and chemistry
Xg
Xm
X
X
X
Randomization
X
Prior and concomitant medications
X
X
X
X
X
X
Serum CRP
Xa
X
X
X
Fecal calprotectin stool sample
Xa
X
X
X
Clinical Response Score (stool 
frequency and rectal bleeding 
scores)
X
X
X
Calculation of Clinical and 
Endoscopic Response Score 
Xh
X
Flexible sigmoidoscopy
/colonoscopy i  - Central reading
X
X
HRQoL questionnaire: IBDQ
Xa
X
X
X
Adverse event recordingj
X
X
X
X
X
X
Distribution of trial medication
X
X
X
First administration of trial 
medication
Xl
Trial medication 
collection/accountability
Xn
X
X
X
Trial medication compliance
X
X
X
X
Subject diary activation
X
Xd
Subject diary data reviewk
X
X
X
X
X
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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
Note: All subjects who discontinue treatment will complete end-of-treatment assessments.
a
For Pathway 3 - de novo subjects only (a complete screening visit, including flexible sigmoidoscopy/colonoscopy
which will be scheduled at screening and completed at least (4) days prior to randomization).
b
Subjects in Pathways 1 and 2 will be consented at Visit 1/Baseline. The complete screening assessments will be 
taken from Study 000174 end-of-treatment visit and eligibility (all inclusion/exclusion criteria) will be reassessed.  
c
Month equals 4 weeks; week equals 7 days.
d
Pathways 1 and 2 only.
e
For females of childbearing age or <1 year postmenopausal; if positive, the subject will not be enrolled in the trial.
A serum pregnancy test will be performed at Visit 0 (screening) for Pathway 3 – de novo only. Urine pregnancy 
tests will be performed for all subjects at Visit 1 (baseline/Day 0) and Visit 5 (Month 6) or early withdrawal.
f
If positive for blood, leucocytes, or nitrite, perform microscopic urinalysis.
g
Results must be available at randomization (Visit 1).
h
For all subjects; Study 000174 end-of-treatment Clinical and Endoscopic Response Score assessments will be 
utilized for Pathways 1 and 2 only.
i
Baseline flexible sigmoidoscopy/colonoscopy for Pathway 3 – de novo subjects will be scheduled at screening 
(Visit 0) and completed at least 4 days prior to randomization (Visit 1) to allow sufficient time for the central 
reading.
j
Adverse events are collected from the signing of informed consent.
k
Subject daily diary data will be collected electronically and daily diary compliance will be assessed.
l
IMP to be distributed at Day 0, and will be taken the following day  (Day 1).
m
No coagulation panel.
n
Subjects will bring IMP kit to site for assessment of compliance; this same kit will be used until Visit 3.
6.2
Trial Procedures
6.2.1
Screening Visit: Visit 0 (up to Day -21)
Subjects in Pathways 1 and 2 will be consented at Visit 1/Baseline. The complete screening 
assessments will be taken from the Study 000174 end-of-treatment visit and eligibility (all 
inclusion/exclusion criteria) will be reassessed.  
Screening procedures for Pathway 3 de novo subjects are to be performed up to 21 days prior to the 
first dose of trial medication. The subject will be informed about the trial and will give written 
informed consent before any trial-related procedures are performed. The following will be 
performed/collected at Visit 0 for de novo subjects only: 

written informed consent

review of inclusion/exclusion criteria 

medical history

Clinical Response Score (subject recording of stool frequency and rectal bleeding in the 
daily diary)

physical examination, including height and weight 

vital signs (blood pressure and pulse rate)

12-lead electrocardiogram (ECG)

demographic data 

serum pregnancy testing for females of childbearing age or <1 year postmenopausal 
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Supersedes: 5.0
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Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL

history of drug and alcohol use

HBV, HCV, and HIV testing

estimated creatinine clearance

clinical safety laboratory assessment: chemistry, hematology, coagulation, standard 
urinalysis

prior and concomitant medications - subjects may not be taking or have used the following 
treatments and a washout period will be required prior to trial medication administration:

oral 5-ASA (mesalamine) within the past 72 hours (de novo subjects only)

aspirin within the past 7 days or during the trial (except for cardioprotective reasons 
- maximum dose 325 mg/day) 

rectal formulations (5-ASA, steroids) within the past 7 days or during the trial

loperamide and other antidiarrheal agents, mucilages, antibiotics (metronidazole and 
ciprofloxacin), NSAIDs, nicotine patch within the past week or during the trial

corticosteroids (oral, intravenous, intramuscular) within the previous month or 
during the trial

immunomodulating/suppressing drugs within the previous 6 weeks or during the 
trial

subjects must also not have a history of taking biologics (e.g., Remicade)

flexible sigmoidoscopy/colonoscopy will be scheduled during screening and completed at 
least 4 days prior to randomization to allow sufficient time for the central reading.

If local site’s endoscopic reading determines the subject is eligible, the flexible 
sigmoidoscopy/colonoscopy recording will be sent to the independent central reader for 
assessment and qualifying scoring

assessment of any AEs occurring after informed consent is signed

activation of subject daily diary
6.2.2
Baseline/Randomization Visit: Visit 1 (Day 0)
The following will be performed/collected at Visit 1: 

written informed consent (Pathways 1 and 2 only)

review inclusion/exclusion criteria

review/update medical history

physical examination, including weight

vital signs (blood pressure and pulse rate)
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Supersedes: 5.0
Page 35 of 83
Mesalazine, FE 999907
Trial Code: 000175 
Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL

urine pregnancy testing (test strip) for females of childbearing age or <1 year 
postmenopausal

concomitant medications review since the previous visit

calculation of Clinical and Endoscopic Response Score (Table 2) 
o
Study 000174 end-of-treatment Clinical and Endoscopic Response Score 
assessments will be utilized (Pathways 1 and 2 only)
o
Clinical and Endoscopic Response Score based on data collected during Visit 0
(Pathway 3 – de novo)

assessment of any AEs since the previous visit
If all inclusion/exclusion criteria are met, the subject will be randomized and the following 
procedures performed (prior to IMP administration):

activation of subject daily diary (Pathways 1 and 2)

IBDQ (Pathway 3)

serum CRP and fecal calprotectin levels (Pathway 3)

randomized, blinded trial medication distribution
IMP will be distributed and subjects will receive instructions on the administration of the trial
medication. The first dose of IMP will be administered on the next day (Day 1) at least 1 hour 
before or at least 2 hours after a meal and subsequently at approximately the same time each day.
6.2.3
Intermediate Visit: Visit 2 (Day 14 ±3)
The following will be performed/collected at Visit 2: 

physical examination, including weight

vital signs (blood pressure and pulse rate)

estimated creatinine clearance

clinical safety laboratory assessments: chemistry and hematology only

concomitant medication review

assessment of any AEs since the previous visit 

collection of trial medication

review of subject daily diary data including compliance

trial medication compliance assessment 
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Date: 17 Jan 2017
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Supersedes: 5.0
Page 36 of 83
Mesalazine, FE 999907
Trial Code: 000175 
Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
6.2.4
Intermediate Visits: Visit 3 (Day 56 ±5) and Visit 4 (Day 112 ±5)
The following will be performed/collected at Visits 3 and 4: 

physical examination, including weight

vital signs (blood pressure and pulse rate)

estimated creatinine clearance

clinical safety laboratory assessment: chemistry, hematology, coagulation

concomitant medication review

serum CRP and fecal calprotectin levels

Clinical Response Score (Table 2), based on subject recording of stool frequency and rectal 
bleeding in the daily diary 

IBDQ

assessment of any AEs since the previous visit

distribution of trial medication

collection of trial medication

review of subject daily diary data including compliance

trial medication compliance assessment 
6.2.5
End-of-Treatment / Early Withdrawal Visit: Visit 5 (Day 168 ±5)
The following will be performed/collected at Visit 5: 

physical examination, including weight

vital signs (blood pressure and pulse rate)

12-lead ECG

urine pregnancy testing (test strip) for females of childbearing age or <1 year 
postmenopausal

estimated creatinine clearance

clinical safety laboratory assessment: chemistry, hematology, coagulation, standard 
urinalysis

concomitant medication review

serum CRP and fecal calprotectin levels

Clinical and Endoscopic Response Score (Table 2), based on the subject recording of stool 
frequency and rectal bleeding in the daily diary, and flexible sigmoidoscopy/colonoscopy
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Supersedes: 5.0
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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL

flexible sigmoidoscopy/colonoscopy

submit flexible sigmoidoscopy/colonoscopy recording to central reader

IBDQ

assessment of any AEs since the previous visit

collection of trial medication 

review of subject daily diary data including compliance, and deactivation of subject daily
diary

trial medication compliance assessment 
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Date: 17 Jan 2017
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Page 38 of 83
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Trial Code: 000175 
Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
7
TRIAL ASSESSMENTS
7.1
Assessments Related to Endpoints
7.1.1
Clinical and Endoscopic Response Score
The Clinical and Endoscopic Response Score will be determined, as shown in Table 2.
The endoscopic response score will determined by flexible sigmoidoscopy/colonoscopy
(Section 7.1.2).
The Clinical Response scores on stool frequency and rectal bleeding will be obtained from the 
subject daily diary (Section 7.1.3). 
Table 2:
Clinical and Endoscopic Response Score (0 – 9)
Components
Subscale
Severity
Score
CLINICAL
RESPONSE
(Subject’s Symptoms)
Stool Frequencya
(daily)
Normal number of stools for subject
0
1 to 2 stools more than normal
1
3 to 4 stools more than normal
2
≥5 stools more than normal
3
Rectal Bleedingb
(daily)
No blood seen
0
Streaks of blood with stool 
1
Obvious blood with stool
2
Blood alone passes
3
ENDOSCOPIC
RESPONSE
(Objective Evidence of 
Inflammation)
Flexible 
Sigmoidoscopy 
/colonoscopy
Findings
Normal or inactive disease
0
Mild disease (erythema, decreased vascular pattern, 
granularity)
1
Moderate disease (marked erythema, absent vascular 
pattern, any friability, erosions)
2
Severe disease (spontaneous bleeding, ulceration)
3
Adapted from:  Schroeder et al., 1987 (1); Sninsky et al., 1991 (2); Modified by Ferring Group, 2014
a.
Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency.
b.
The daily bleeding score represents the most severe bleeding of the day.
7.1.2
Flexible Sigmoidoscopy/colonoscopy
In order to obtain the endoscopic response score (Table 2), the objective evidence of inflammation 
in this trial, flexible sigmoidoscopy/colonoscopy will be performed according to a standardized 
manner during screening, at least 4 days prior to randomization for Pathway 3 - de novo subjects  
and at the end of treatment (Month 6 or early withdrawal) for all subjects to allow sufficient time 
for the central reading. The EOT flexible sigmoidoscopy/colonoscopy from Study 000174 will 
serve as the baseline/randomization assessment for Pathways 1 and 2.
The flexible sigmoidoscopy/colonoscopy will be video recorded and transferred to the independent 
central reader. The details of the tools, recording, data transfer, and assessment will be documented 
in an Imaging Charter. Findings will be graded on a 4-point scale (Table 2), with 0 = normal or 
inactive disease, 1 = mild disease (erythema, decreased vascular pattern, granularity), 2 = moderate 
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Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
disease (marked erythema, absent vascular pattern, any friability, erosions), and 3 = severe disease 
(spontaneous bleeding, ulceration). If the local site’s endoscopic reading determines the subject is 
ineligible, the subject will be screen failed (Pathway 3 - de novo). If the local site’s endoscopic 
reading determines that the subject is eligible, the flexible sigmoidoscopy/colonoscopy recording 
will be sent to the independent central reader for final determination of eligibility (Pathway 3 - de 
novo). For subjects rolling over from the 000174 trial (Pathway 1 and 2), 000175 eligibility will be 
derived from the final EOT independent central read. A flexible sigmoidoscopy/colonoscopy will 
also be performed at Month 6, which will also be sent to the independent central reader for 
endoscopic endpoint scoring for all subjects.
Extent of colitis will be documented as proctosigmoiditis, left-sided colitis, or extended colitis.
7.1.2.1
Independent Central Endoscopy Laboratory
All flexible sigmoidoscopies/colonoscopies will be performed in a standardized manner. The 
endoscopy completed during screening for Pathway 3 - de novo  (at least 4 days prior to 
randomization to allow sufficient time for the central reading), will be sent to an independent 
central reader selected by the sponsor to qualify the image for use in randomization if the local 
site’s endoscopic reading determines that the subject is eligible. Image handling and instructions 
will be provided to all sites directly from the central endoscopic laboratory. For Pathways 1 and 2, 
screening assessment data will be taken from Study 000174 end of double-blind treatment/early 
withdrawal and end of open-label treatment/early withdrawal visits. The EOT endoscopic readings 
for Pathways 1 and 2 will be used for randomization at Visit 1.   
The endoscopic qualifying score will be reported to the investigator and sponsor (or the sponsor’s 
representative) and will automatically be uploaded to the eCRF. 
Trial sites will be provided with endoscopic laboratory recording equipment, supplies, and manuals. 
7.1.3
Subject Daily Diary 
The subject daily diary will be completed by the subject every evening starting at screening for 
Pathway 3 - de novo subjects and starting the day of randomization Visit 1/Day 0 for Pathways 1 
and 2. Subject diary will consist of questions regarding IMP daily intake, stool frequency, and 
presence of blood content. 
The score for stool frequency and rectal bleeding will be calculated as an average based on scores 
collected from subject diary data 5 days prior to Visits 1, 2, 3, 4, and 5 (see Appendix 2). If a 
subject recorded fewer than 3 days of scores during this 5-day period, the average score will be 
considered missing.
The subject daily diary and questionnaire will be completed via a validated Interactive Voice 
Response System (IVRS). Instructions on the use of the subject daily diary and questionnaire will 
be provided to each trial center.
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Prolonged Release Granules - 2 g
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
7.1.4
Serum CRP and Fecal Calprotectin
Serum CRP levels will be determined at baseline and all post-baseline visits and fecal calprotectin 
levels will be determined at baseline and Visits 3 (Month 2), 4 (Month 4), and 5 (Month 6).
7.1.5
Health-Related Quality of Life/Collection Pad
The IBDQ is an instrument used to assess quality of life in adult patients with inflammatory bowel 
disease, UC, or Crohn’s disease and has demonstrated reliability and validity in discriminating 
between patients in clinical remission or relapse.(19) Subjects will be asked to recall symptoms and 
quality of life from the last 2 weeks and to rate each item on a 7-point Likert scale (higher scores 
equate to higher quality of life). Subjects will complete the IBDQ questionnaire (see Appendix 1)
via a validated collection pad, at Visits 1, 3, 4 & 5 prior to any other trial-related procedures at the 
site, with the exception that subjects in Pathway 3 must first be randomized before completion of
the IBDQ at Visit 1.
7.1.6
Adverse Events
Adverse events will be collected as described in Section 8 of this protocol.
Laboratory abnormalities may be reported as AEs based on the discretion of the investigator, i.e., 
laboratory abnormalities that the investigator assesses as a clinically significant. 
Physical examination and vital sign abnormalities will be reported as AEs if the investigator 
considers any abnormality clinically significant.
7.1.7
Clinical Laboratory Variables
Hematology, Serum Chemistry, and Urinalysis
Safety hematology, coagulation and serum chemistry tests will be performed at Visit 0 (screening, 
Pathway 3 - de novo only), Visit 2 (Week 2), and Visit 5 (Month 6) or at early withdrawal. Standard 
urinalysis will be performed at Visit 0 (screening, Pathway 3 - de novo only) and Visit 5 (Month 6) 
or at early withdrawal.
Hematology: hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count, 
and differential count
Coagulation: prothrombin time (measured as international normalized ratio), activated partial
thromboplastin time
Serumchemistry: glucose, blood urea nitrogen, creatinine, creatinine clearance (via estimated 
glomerular filtration rate [eGFR]), potassium, sodium, chloride, calcium, total protein, albumin, 
total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and 
gamma glutamyl transferase
Urinalysis: leukocyte, blood, pH, specific gravity, nitrite, protein, glucose, urobilinogen, and 
microscopic if positive for blood, leucocytes, and nitrite
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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
The investigator will review the laboratory results and evaluate and document whether the results 
are normal or abnormal and whether abnormal results are clinically significant. The laboratory 
report will be signed and dated by the investigator.
7.2
Other Assessments
7.2.1
Medical History and Demographic Data
Demographic data and a complete medical history will be obtained at Visit 0 (screening), with a 
review of medical history at Visit 1 (baseline/Day 0). Disease specific and general medical history 
will be recorded in the eCRF.
7.2.2
Immunological Testing
For Pathway 3 - de novo subjects only, serological testing for HBV, HCV, and HIV will be 
performed at Visit 0 (screening). Negative results are required for trial admission.
7.2.3
Drug and Alcohol History
For Pathway 3 - de novo subjects only, a drug and alcohol history evaluation will be performed at 
Visit 0 (screening) by the investigator.
7.2.4
Serum/Urine Pregnancy Test
For Pathway 3 - de novo subjects only, a serum pregnancy test will be performed at Visit 0 
(screening).
Urine pregnancy tests will be performed for all subjects at Visit 1 (baseline/Day 0) and Visit 5
(Month 6) or early withdrawal.
7.2.5
Concomitant Medications
Concomitant medication information will be collected at every trial visit.
7.2.6
Physical Examinations
At the screening visit (Visit 0), physical examination with height and weight will be performed for 
Pathway 3 -– de novo only. Height will be measured at the screening visit only and only for de novo
subjects. Physical examination with weight will be performed at Visit 1 (baseline/Day 0), Visit 2 
(Week 2), Visit 3 (Month 2), Visit 4 (Month 4), and at the end of treatment (Visit 5, Month 6) or at 
early withdrawal. Any clinically significant deterioration from baseline will be recorded as an AE. 
7.2.7
Vital Signs
Vital signs will be measured at each trial visit. Vital signs will include blood pressure and heart rate 
measured under resting conditions while the subject is seated. All blood pressure measurements 
should be made using the same arm and prior to any scheduled blood draws.
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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
7.2.8
12-Lead Electrocardiogram
A 12-lead ECG will be obtained at Visit 0 (screening) for Pathway 3 - de novo subjects only, and at
Visit 5 (Month 6) or at early withdrawal for all subjects. The 12-lead ECG will be obtained after at 
least a 5-minute rest in a supine position.
7.2.9
Compliance
Trial medication and subject daily diary compliance will be assessed at each trial visit beginning 
with Visit 2, see Section 5.6.2.
7.3
Drug Concentration Measurements
Drug concentration measurements will not be performed for this trial.
7.4
Handling of Biological Samples
A central laboratory will be used in this trial. Sampling tubes, material for shipment of the samples, 
and a laboratory manual detailing all sample collection, handling and shipment procedures will be 
provided and distributed to the trial sites by the central laboratory.
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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An AE is any untoward medical occurrence in a subject participating in a clinical trial. It includes:

any unfavorable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP

AEs commonly observed and AEs anticipated based on the pharmacological effect of the 
IMP

any laboratory abnormality, vital sign, or finding from physical (or gynecological)
examination assessed as clinically significant by the investigator (note: findings from 
assessments and examinations done during screening are not AEs, but are recorded as 
medical history)

accidental injuries, reasons for any change in medication (drug and/or dose), reasons for any 
medical, nursing or pharmacy consultation, or reasons for admission to hospital or surgical 
procedures

overdoses and medication errors with and without clinical consequences
8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the last visit.
The sources of AEs cover:

the subject’s response to questions about his/her health (a standard non-leading question 
such as “How have you been feeling since your last visit?” is asked at each visit)

symptoms spontaneously reported by the subject

investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities

other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalization)
8.2.2
Recording of Adverse Events
The investigator must record all AEs in the AE log provided in each subject’s eCRF with 
information about:

AE

date and time of onset (time can be omitted, if applicable)

intensity

causal relationship to IMP
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
action taken to IMP

other action taken

date and time of outcome (time can be omitted, if applicable)

outcome

seriousness
Each of the items in the AE log is described in detail in the following sections.
Adverse Events
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis/symptom should be entered per record.
If a subject suffers from the same AE more than once and the subject recovers between the events, 
the AEs should be recorded separately. If an AE changes in intensity, a worst-case approach should 
be used when recording the event, i.e. the highest intensity and the longest duration of the event.a
A procedure is not an AE; the reason for conducting the procedure is. Hospitalization is not an AE; 
the reason for hospitalization is. Death is not an AE, but the cause of death is (an exception is 
sudden death of unknown cause, which is an AE).
Date and Time of Onset
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the AE is an 
abnormal clinically significant laboratory test or outcome of an examination, the onset date is the 
date the sample was taken or the examination was performed. 
Intensity
The intensity of an AE must be classified using the following 3-point scale:
Mild:
awareness of signs or symptoms, but no disruption of usual activity
Moderate:
event sufficient to affect usual activity (disturbing)
Severe:
inability to work or perform usual activities (unacceptable)
                                                
a
Exception: if an AE with onset before the first IMP administration (i.e., a pre-treatment AE) changes in 
intensity, this must be recorded as 2 separate events. The initial AE should be recorded with outcome “not yet 
recovered” and the date and time of outcome are when the intensity changed. The second AE should be 
recorded with date and time of onset when the intensity changed. 
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Causal Relationship to IMP
The possibility of whether the IMP caused the AE must be classified as 1 of the following:
Reasonable possibility: 
There is evidence or argument to suggest a causal relationship 
between the IMP and the AE. The AE may occur as part of the 
pharmacological action of the IMP or may be unpredictable in its 
occurrence.
Examples: 

AEs that are uncommon but are known to be strongly associated 
with IMP exposure

AEs that are not commonly associated with IMP exposure, but the 
event occurs in association with other factors strongly suggesting 
causation, such as a strong temporal association or the event 
recurs on rechallenge
No reasonable possibility:
There is no reasonable evidence or argument to suggest a causal 
relationship between the IMP and the AE.
Examples:

known consequences of the underlying disease or condition under 
investigation

AEs common in the trial population, which are also anticipated to 
occur with some frequency during the course of the trial, 
regardless of IMP exposure
Action Taken with IMP
The action taken with the IMP in response to an AE must be classified as 1 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 AE, this medication should be entered in the concomitant 
medication log.
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Date of Outcome
The date and time (time can be deleted/omitted, if applicable) the subject recovered or died will be 
recorded.
Outcome
The outcome of an AE must be classified as 1 of the following:

recovered (fully recovered or the condition has returned to the level observed at initiation of 
trial treatment)

recovered with sequelae (resulted in persistent or significant disability/incapacity)

recovering

not recovered

fatal
8.3
Pregnancy and Pregnancy Outcome
Every effort must be made to avoid pregnancy during the trial. 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 pregnancy itself is not 
a serious adverse event (SAE). The mother and the fetus must be followed at least until the birth of 
the infant and 1 month after the birth of the infant. In general, the follow-up will include the course, 
duration, and the outcome of the pregnancy as well as neonatal health. If a pregnancy results in an 
abnormal outcome (birth defect/congenital anomaly), this must be reported as an SAE to Global 
Pharmacovigilance at Ferring Pharmaceuticals as described in Section 8.4.2. Any abnormal 
pregnancy outcome which the investigator and/or sponsor consider to be related to the IMP will be 
treated as an expedited report. 
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8.4
Serious Adverse Events
8.4.1
Serious Adverse Event Definition
Serious AEs are defined as follows:
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 4 weeks after the treatment ends and 
irrespective of the causal relationship to the IMP. The death of a subject 
enrolled in a trial is per se not an event, but an outcome.
is life-threatening
The term life-threatening refers to an AE in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an event, 
which may have caused death if it were more severe.
requires in-patient hospitalization or 
prolongation of existing 
hospitalization
The term hospitalization means that the subject was admitted to hospital or 
that existing hospitalization was extended as a result of an event. 
Hospitalization describes a period of at least 24 hours. Overnight stay for 
observation, stay at emergency room, or treatment on an outpatient basis do 
not constitute a hospitalization. However, medical judgment must always be 
exercised and, when in doubt the case should be considered serious (i.e., if 
case fulfils the criterion for a medically important event). Hospitalizations for 
administrative or social purposes do not constitute SAEs. Hospital admissions 
and/or surgical operations planned before trial inclusion are not considered 
AEs, if the illness or disease existed before the subject was enrolled in the 
trial, provided that the condition did not deteriorate during the trial.
results in persistent or significant 
disability/incapacity
Disability/incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions. In doubt, the decision should be left to medical 
judgment by the investigator.
is a congenital anomaly/birth defect
Congenital anomaly/birth defect observed in any offspring of the subject 
conceived during treatment with the IMP.
is an important medical event
Important medical events are events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent 1 of the other outcomes listed in the 
definition above. Examples of important medical events include AEs that 
suggest a significant hazard, contraindication or precaution, occurrence of 
malignancy, or development of drug dependency or drug abuse. Medical and 
scientific judgment should be exercised in deciding whether events qualify as 
medically important.
Important medical events include any suspected transmission of an infectious 
agent via a medicinal product. Any organism virus or infectious particle (e.g.,
prion protein transmitting transmissible spongiform encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious agent. A 
transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings indicating an infection in a subject exposed to a 
medicinal product.
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8.4.2
Collection, Recording and Reporting of Serious Adverse Events
SAE Reporting by the Investigator
All SAEs must be reported immediately to Global Pharmacovigilance at Ferring Pharmaceuticals 
as soon as it becomes known to the investigator and not later than within 24 hours of his/her
knowledge of the occurrence of an SAE. The investigator is responsible for submitting the 
completed paper SAE report form with the fullest possible details within 3 calendar days of 
his/her knowledge of the SAE.
The SAE must be included in the eCRF system. In addition, a paper SAE report must be completed 
and submitted according to the instructions provided on the form and sent to Global 
Pharmacovigilance at Ferring Pharmaceuticals using the contact details below.
Global Pharmacovigilance, Ferring Pharmaceuticals A/S
E-mail: 
Fax:
eCRF information regarding demographics, AEs, medical history, and concomitant medication is 
mandatory for initial reports and for follow-up reports if any changes have been made since the 
initial report.
Additional information relevant to the SAE, such as hospital records, results from investigations 
(e.g., laboratory parameters that are not already uploaded in the eCRF, invasive procedures, scans, 
x-rays, and autopsy results) can be faxed or scanned and e-mailed to Ferring Global 
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 subject number 
should be provided instead.
The investigator will supply Ferring and the IEC/IRB with any additional requested information,
such as results of post-mortem examinations and hospital records.
Expedited Reporting by Ferring 
Ferring will report all AEs that are serious, unexpected, and with a reasonable possible causality 
to the IMP as judged by either the investigator or Ferring to the relevant parties within the 
stipulated timelines. The expectedness of events will be assessed by Ferring according to the 
Investigator’s Brochure.
SAEs will be considered reportable regardless of whether the IMP was used in accordance with the 
provisions in the protocol, Investigator’s Brochure, and labelling. 
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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 each AE 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 AE classified as serious or 
considered to have a reasonable possible causality to the IMP until it is resolved or until the 
medical condition of the subject is stable. All such relevant follow-up information must be reported 
to Ferring. If the event is a chronic condition, the investigator and Ferring may agree that further 
follow-up is not required.
8.5.2
Collection of Serious Adverse Events with Onset after Last Trial Visit
If an investigator becomes aware of an SAE after the subject’s last visit, and he/she assesses the 
SAE to have a reasonable possible causality to the IMP, the case will have to be reported to Ferring, 
regardless how long after the end of the trial this takes place.
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9
STATISTICAL METHODS
All analyses will be detailed in a subsequent statistical analysis plan.
9.1
Determination of Sample Size
The true remission rates at Month 6 for mesalamine 2 g extended release granules (sachet) and 
placebo regimens were assumed as 68% and 49%, respectively, based on The Mesalamine Study 
Group (1996) (3), Hawkey et al (1997) (4), and Apriso™ package insert (2009).(5) Under these 
assumptions, a sample size of 120 randomized subjects per group will provide at least 85% power 
to detect a statistically significant treatment group difference in the remission rate at a two-sided 
0.05 significance level using the chi-square test. To maintain the power for the primary efficacy 
analysis that excludes subjects who are rolled over from the placebo group in the 000174 trial via 
Pathway 1, approximately 260 subjects will be randomized.
9.2
Subject Disposition
The number of screened subjects will be summarized, and for subjects not randomized, the primary 
reason for exclusion from randomization will be summarized.
The number and percentage of subjects who are randomized, are treated with IMP, prematurely 
discontinued, and completed the trial will be summarized with the reasons for premature 
discontinuations.
The time to discontinuation will be summarized by the Kaplan-Meier estimates, and the treatment 
group difference will be tested by the log-rank test. In addition, reason-specific discontinuation will 
be summarized by the cumulative incidence estimates.
9.3
Protocol Deviations
The following protocol deviations will be identified as major protocol deviations:

overall IMP compliance less than 80%

not taking the randomized IMP

taking prohibited medications
The final definition of major and minor protocol violations will be determined prior to breaking the 
trial blind.  
The number and percentage of subjects with major protocol deviations will be summarized.
9.4
Analysis Sets
Three analysis sets will be defined: 

All randomized analysis set: Includes all randomized subjects
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
Intent-to-Treat (ITT) analysis set:  Includes all randomized subjects who were assigned to 
mesalamine 4 g extended release granules in the 000174 trial or randomized via Pathways 2 
or 3 

Modified ITT (mITT) analysis set: Includes all subjects who receive at least 1 dose of IMP 
in the ITT analysis set

Per protocol (PP) analysis set: Includes all subjects who receive at least 1 dose of IMP and 
who do not have any of the major protocol deviations in the ITT analysis set

Safety analysis set:  Includes all subjects who receive at least 1 dose of IMP
The assignment of subjects to each analysis set will be finalized prior to breaking the trial blind.
Analyses for the all randomized, ITT, and mITT analysis sets will be conducted according to the 
randomized treatment. Safety analyses will be conducted according to the treatment actually 
received rather than according to the treatment assigned.
For each analysis set, the number and percentage of subjects excluded from it will be summarized 
by the reason for the exclusion.
9.5
Trial Population
9.5.1
Demographics and other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics will be presented for all 
subjects in the ITT, PP, and safety analysis sets by treatment group.
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations
Medical history will be coded by system organ class (SOC) and preferred term (PT) using the most 
current version of the Medical Dictionary for Regulatory Activities (MedDRA) available at study 
initiation and summarized by SOC, PT, and treatment group for the ITT and Safety analysis sets. 
Prior and concomitant medications will be coded by the Anatomical Therapeutic Chemical (ATC) 
classification system and preferred drug name using the World Health Organization Drug 
Dictionary (WHO-Drug). Prior and concomitant drug usage will be summarized by ATC 
classification 1st level, ATC classification 2nd level and treatment group for subjects in the ITT and 
Safety analysis sets. 
9.6
Endpoint Assessments
9.6.1
General Considerations
All statistical tests will be conducted at a two-sided 0.05 significance level.
Quantitative variables will be described with the number of non-missing values, mean, standard 
deviation, median, and minimum/maximum values. Qualitative variables will be described with the 
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number and percentage of subjects with each qualitative characteristic. Missing values will not be 
included in the calculation of percentages.
All data will be listed by individual subject and trial visit.
9.6.2
Primary Endpoint
The primary efficacy analysis will be based on the ITT analysis set. The proportion of subjects with
remission, defined as rectal bleeding score of 0 and stool frequency score of 0 or 1, with an 
endoscopic score of 0 or 1 in the Clinical and Endoscopic Response Score at Month 6, will be 
assessed by the Mantel-Haenszel test stratified by the randomization strata at a two-sided 0.05 
significance level. Subjects who discontinue the double-blind regimen before Month 6, as well as 
subjects with missing remission assessment at Month 6, will be considered not having met the 
remission criteria. The odds ratio will be estimated and its 95% confidence interval will be 
provided.
The following sensitivity analyses will be conducted to assess the robustness of the primary 
analysis:

as-treated analysis based on actually received treatment

analysis on the all randomized analysis set

analysis on the mITT analysis set

analysis on the PP analysis set

assessment of the homogeneity of odds ratios across geographical regions, baseline 
demographic characteristics, and baseline disease characteristics 

analysis on the last observed Clinical and Endoscopic Response Score

analysis using multiple imputation methods for missing remission assessment at Month 6

analysis using pattern mixture models for missing remission assessment at Month 6
9.6.3
Secondary Endpoints
Secondary endpoints are the following:
1.
The proportion of subjects in clinical remission at Months 2, 4, and 6, defined as a score of 
0 for rectal bleeding and 0 or 1 for stool frequency based on Clinical Response Score subset 
of the Clinical and Endoscopic Response Score
2.
Time to relapse, defined as number of days from randomization to the day of withdrawal 
due to escalation of therapy (i.e., surgical therapy, use of steroids, immunosuppressive or 
immunomodulating drugs, biologics, increase dose of 5-ASA in any form)
3.
The proportion of subjects with an increase from baseline in the Clinical and Endoscopic 
Response Score by 2 or more points in at least 1 component or by 1 or more points in at 
least 2 components at Month 6
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4.
The change from baseline in serum CRP levels at Months 2, 4, and 6
5.
The change from baseline in fecal calprotectin levels at Months 2, 4, and 6
6.
The change from baseline to each scheduled assessment for published and validated domain 
scores of the IBDQ
7.
Safety assessed by incidence and severity of AEs and abnormal laboratory values
The proportion of subjects in clinical remission at Months 2, 4, and 6 will be analyzed by the 
generalized estimating equations approach as longitudinal binary outcomes. The model will include
randomization strata, treatment, time, and treatment- by-time interaction. The clinical remission 
rates and odds ratios will be estimated for each time point. 
The time to relapse will be analyzed by a log-rank test stratified by the randomization strata.
The change from baseline in serum CRP and fecal calprotectin levels will be assessed with a 
repeated-measures analysis of covariance (ANCOVA) model that includes randomization strata, 
treatment, time, and treatment-by-time interaction as fixed effects, and baseline value as a covariate 
based on the observed data. The adjusted changes from baseline and their difference between 
treatment groups will be estimated for each time point.
9.6.4
Health-related Quality of Life
Change from baseline to each scheduled assessment will be summarized for published and 
validated domain scores of the IBDQ. The change from baseline in IBDQ scores will be assessed 
with a repeated-measures ANCOVA model that includes randomization strata, treatment, time, and 
treatment-by-time interaction as fixed effects and baseline value as a covariate based on the 
observed data.
9.7
Extent of Exposure and Treatment Compliance
The length of the treatment, calculated as (last dose date – first dose date + 1 day), will be 
summarized by treatment group for the safety analysis set.
The overall compliance will be summarized for the safety analysis set. 
9.8
Safety
9.8.1
General Considerations
Safety parameters will be evaluated for the safety analysis set. 
9.8.2
Adverse Events
A ‘pre-treatment’ AE will be defined as an AE that occurs between screening and the first dose of 
the IMP. A ‘treatment-emergent AE (TEAE)’ will be an AE that occurs in the time interval from 
initial dosing (IMP intake) to the end of treatment visit. If an AE on Day 1 occurs before IMP 
intake, it will be recorded as a pre-treatment AE.
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Written narratives will be issued for all SAEs and AEs leading to withdrawal. If causality is 
missing, the AE will be regarded as being reasonably possibly related to IMP. Related AEs (judged 
as being reasonably possibly related to IMP) will be termed adverse drug reactions (ADR).
An AE overview summary table will be prepared for the safety analysis population. It will display 
the number and percentage of subjects reporting an AE and the number of events reported for each 
treatment group. The following categories will be displayed:

any TEAEs

deaths

SAEs

AEs leading to discontinuation

severe AEs

ADRs
Number and percentage of subjects reporting the following types of TEAEs will be summarized by 
MedDRA SOC (alphabetically) and PT (in decreasing frequency of occurrence):

any TEAEs

common TEAEs

causal relationship to IMP with reasonable possibility or no reasonable possibility

intensity with mild, moderate, or severe

AEs leading to death

SAEs

AEs leading to discontinuation
Supporting data listings will be provided for:

all AEs sorted by trial site and subject ID

all AEs sorted by MedDRA SOC and PT

SAEs

AEs leading to death

AEs leading to discontinuation
9.8.3
Safety Laboratory Variables
Clinical laboratory variables will be presented in 2 ways. First, mean change from baseline to the 
end of the double-blind treatment visit will be summarized. Baseline will be defined as the last 
assessment before the first dose of IMP. Second, the number and percentage of subjects with 
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treatment-emergent potentially clinically significant laboratory values on or before the end of the 
double-blind treatment visit will be tabulated. 
9.8.4
Other Safety Variables
Other safety assessments will be summarized descriptively.
9.9
Interim Analyses
No interim analysis is planned.
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10
DATA HANDLING
10.1
Source Data and Source Documents
Source Data – International Conference on Harmonisation (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 must maintain subject records, including as a minimum: medical history; data on 
the condition of the subject at the time the subject is enrolled into the trial in order to document 
(and enable verification of) subject eligibility; diagnosis; subject’s participation in trial; subject’s 
trial identification; date of informed consent and time, if applicable, for the trial; visit dates and 
results of examinations and tests performed, especially results of examinations related to primary 
endpoints; details of IMP administration; details of AEs, concomitant medication, and of any 
follow-up and analysis/tests/examinations done; and reason for subject withdrawal from the trial.
10.2
eCRF
An eCRF system provided by an independent, third-party Contract Research Organization (CRO) 
will be used for data capture. The system is validated and access at all levels to the system is 
granted/revoked following Ferring and vendor procedures, in accordance with regulatory and 
system requirements.
The eCRF system and the database will be hosted at the independent, third-party CRO. After the 
trial database is declared clean and released to the statistician, a final copy of the database will be 
stored at Ferring Pharmaceuticals A/S located in DK-2300 Copenhagen S, Denmark, within the 
SAS Drug Development system. The investigator will also receive a copy of the trial site’s final 
and locked data (including audit trail, electronic signature and queries) as write-protected PDF files 
produced by the independent, third-party CRO. The PDF files will be stored on a CD and will be 
provided to the investigator before access to the eCRF is revoked. The Investigator will 
approve/authorise the eCRF entries for each subject with an electronic signature which equals a 
handwritten signature. Trial data will be entered into the system in a timely manner.
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Errors occurring in the eCRF 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.
10.3
Data Management 
All data management activities will be specified in a Data Management Plan prepared under the 
responsibility of Global Biometrics, Ferring Pharmaceuticals A/S. All data management activities 
will be performed by independent, third-party CRO, under the responsibility of Global Biometrics, 
Ferring Pharmaceuticals A/S. A study database will be created according to the Data Management 
standard operating procedures and data validation programmes will be developed to check for data 
completion and validity.   
Laboratory data will be transferred electronically to independent, third-party CRO for inclusion in 
the study data base according to laboratory data transfer specifications to be agreed between the 
individual laboratories and independent, third-party CRO. For medical coding of AEs, medical 
history and concomitant medication the most recent versions of MedDRA and WHO-Drug will be 
used. The coding will be performed by the third-party CRO and will be reviewed and approved by 
Ferring. When all data have been processed, queries resolved, medical coding completed and any 
issues from review of protocol violations and data listings resolved, the database will be locked and 
any further update will be denied. A final quality assurance audit of the locked database will take 
place prior to transfer of the final database structured according to Ferring’s data transfer 
specifications.  
10.4
Provision of Additional Information
On request, the investigator will provide Ferring with additional data relating to the trial, 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, 
ICH-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 to source data, verification of drug accountability, and compliance with 
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 
cooperate with the monitor to ensure that any discrepancies that may be identified are resolved. The 
investigator is expected to meet the monitor during these visits. 
When the first subject is randomized at the trial site, a monitoring visit will take place shortly 
thereafter. For this trial, the frequency of the interim monitoring visits will be determined by the 
enrollment rate and will be detailed in the monitoring plan.
11.2
Audit and Inspection
The investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring or to domestic/foreign regulatory inspectors or 
representatives from IEC(s)/IRB(s) 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 
IEC(s)/IRB(s) may wish to inspect their medical records. During audits/inspections, the 
auditors/inspectors may copy relevant parts of the medical records. No personal identification other 
than 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 IEC/IRB.
11.3
Confidentiality of Subject Data
The investigator will ensure that the confidentiality of the subjects’ data will be preserved. In the 
eCRF or any other documents submitted to Ferring, the subjects will not be identified by their 
names, but by an identification system that 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 maintained by the investigator in strict confidence.
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12
CHANGES IN THE CONDUCT OF THE TRIAL
12.1
Protocol Amendments
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
agreed upon by the investigator and Ferring prior to its implementation. Substantial amendments 
will be submitted for consideration to the approving IRB/IEC and regulatory authorities, in 
accordance with local regulations. An approval is required for a substantial amendment, e.g., one 
that could affect the safety of the subjects or that entails a significant change of the scope/design of 
the trial.
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 on the 
protocol violation page in the source document and eCRF with the visit number and type of 
violation. A log of protocol deviation reports will be maintained by Ferring. Protocol deviation 
reports and supporting paper documentation must be kept in the investigator’s file and in the trial 
master file.
12.3
Premature Trial Termination
Both the investigator (with regard to his/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 2 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 IEC(s)/IRB(s) will be informed.
In addition, Ferring reserves the right to terminate the participation of individual trial sites. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter subjects at an acceptable rate.
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13
REPORTING AND PUBLICATION
13.1
Clinical Trial Report
The data and information collected during this trial will be reported in a clinical trial report 
prepared by Ferring and submitted for comments and signature to the signatory investigator.
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial, will be the exclusive property of Ferring. The investigator and any other persons involved 
in the trial will protect the confidentiality of this proprietary information belonging to Ferring.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
At the end of the trial, 1 or more manuscripts for joint publication may be prepared in collaboration 
between the investigator(s) offered authorship and Ferring. In a multi-site trial based on the 
collaboration of many sites, any publication of results must acknowledge all sites. Results from 
multi-site trials must be reported in entirety in a responsible and coherent manner and results from 
subsets should not be published in advance or without clear reference to the primary publication of 
the entire trial.
Authorship is granted based on the International Committee of Medical Journal Editors (ICMJE)
criteria (see current official version: http/www.ICMJE.org). The total number of authors is based on 
the guideline from the relevant journal or congress. In the event of any disagreement in the content 
of a publication, both the investigator’s and Ferring’s opinion will be fairly and sufficiently 
represented in the publication.
Any external 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 comment prior to submission. 
Comments will be given within 4 weeks from receipt of the draft manuscript. This statement does 
not give Ferring any editorial rights over the content of a publication, other than to restrict the 
disclosure of Ferring’s intellectual property. If the matter considered for publication is deemed 
patentable by Ferring, scientific publication will not be allowed until after a filed patent application 
is published. Under such conditions the publication will be modified or delayed at the investigator’s 
discretion, to allow sufficient time for Ferring to seek patent protection of the invention.
13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of Ferring to register the trial in an appropriate public registry, i.e.,
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www.ClinicalTrials.gov which is a website maintained by the National Library of Medicine at the 
US National Institutes of Health. 
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14
ETHICAL AND REGULATORY ASPECTS
14.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
An IEC/IRB will review the protocol and any amendments and advertisements used for 
recruitment. The IEC/IRB will review the subject information sheet and the informed consent form, 
their updates (if any), and any written materials given to the subjects. A list of all IECs/IRBs to 
which the protocol has been submitted and the name of the committee chairmen will be included in 
the clinical trial report.
14.2
Regulatory Authorities Authorization / Approval / Notification
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility.
14.3
End-of-Trial and End-of-Trial Notification
At the end of the trial (last subjects completes the last visit), the appropriate regulatory authorities 
and the IRB(s)/IEC(s) will be notified in writing.
14.4
Ethical Conduct of the Trial
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki (2008 version), in compliance with the approved protocol, ICH-GCP, and 
applicable regulatory requirements.
14.5
Subject Information and Consent
The investigator (or the person designated by the investigator) will obtain a freely given written 
consent from each subject after an appropriate explanation of the aims, methods, anticipated 
benefits, potential hazards, and any other aspects of the trial that 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.
The investigator (or the person designated 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.
If new information becomes available that may be relevant to the trial subject’s willingness to 
continue participation in the trial, a new subject information and informed consent form will be 
forwarded to the IEC(s)/IRB(s) (and regulatory authorities, if required). The trial subjects will be 
informed about this new information and re-consent will be obtained.
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Each subject will be informed that the monitor(s), quality assurance auditor(s) mandated by 
Ferring, IRB/IEC 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.
14.6
Compliance Reference Documents
The Helsinki Declaration, the consolidated ICH-GCP, the European Union Clinical Trials 
Directive, and other national laws in the countries 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
In case of any damage or injury occurring to a subject in association with the IMP or the 
participation in the trial, Ferring has contracted an insurance that covers the liability of Ferring, the 
investigator, and other persons involved in the trial, in compliance with the laws in the countries 
involved.
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16
ARCHIVING
16.1
Investigator File
The investigator is responsible for maintaining all the records that 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 (or longer if 
required by local law) after the completion or discontinuation of the trial, if no further instructions 
are given by Ferring.
The investigator is responsible for the completion and maintenance of the confidential subject 
identification code, which provides the sole link between named subject source records and 
anonymous eCRF data for Ferring. The investigator must arrange for the retention of this subject 
identification log and signed informed consent documents for at least 15 years (or longer if required 
by local law) after the completion or discontinuation of the trial.
No trial site document may be destroyed without prior written agreement between the investigator 
and Ferring. Should the investigator elect to assign the trial documents to another party or move 
them to another location, Ferring must be notified. If the investigator retires and the documents can 
no longer be archived by the site, Ferring can arrange to have 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
Schroeder Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis: a randomized study. N Engl J 
Med. 1987;317:1625-9.
2
Sninsky CA, Cort DH, Shanahan F, et al. Oral mesalamine (Asacol) for mildly to 
moderately active ulcerative colitis. Annals Intern Med. 1991;115:350-5.
3
An oral preparation of mesalamine as long-term maintenance therapy for ulcerative colitis. 
A randomized, placebo-controlled trial. The Mesalamine Study Group. Ann Intern Med. 
1996;124(2):204-11.
4
Hawkey CJ, Dube LM, Rountree LV, Linnen PJ, Lancaster JF. A trial of zileuton versus 
mesalazine or placebo in the maintenance of remission of ulcerative colitis. The European 
Zileuton Study Group For Ulcerative Colitis. Gastroenterology. 1997;112(3):718-24.
5
APRISO™ package insert. Salix Pharmaceuticals. Morrisville, NC. 2008.
6. 
Ghosh S, Shand A, Fergusson A. Ulcerative colitis. BMJ. 2000;320:1119-23.
7. 
Garland CF, Lilienfeld AM, Mendeloff AI, Markowitz JA, Terrell KB, Garland FC. 
Incidence rates of ulcerative colitis and Crohn's disease in fifteen areas of the United States. 
Gastroenterology. 1981;81(6):1115-24.
8. 
Cotran RS, Collins T, Robbins SL, Kumar V. Pathologic Basis of Disease. Philadelphia, Pa: 
WB Saunders; 1998.
9. 
Jang ES, Lee DH, Kim J, Yang HJ, Lee SH, Park YS. Age as a clinical predictor of relapse 
after induction therapy in ulcerative colitis. Hepatogastroenterology. 2009;56(94-95):1304-
9.
10. 
Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established 
and evolving therapies. Lancet. 2007;369(9573):1641-57.
11
Carter MJ, Lobo AJ, Travis SP; IBD Section, British Society of Gastroenterology. 
Guidelines for the management of inflammatory bowel disease in adults. Gut. 
2004;53(Suppl 5):V1-16.
12. 
Marteau P, Seksik P, Beaugerie L, Bouhnik Y, Reimund JM, Gambiez L, et al. 
Recommendations for clinical practice for the treatment of ulcerative colitis. Gastroenterol 
Clin Biol. 2004;28(10 Pt 2):955-60.
13. 
Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A meta-analysis and overview of the 
literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J 
Gastroenterology. 2000;95(5):1263-76.
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14. 
Marshall JK, Irvine EJ. Rectal aminosalicylate therapy for distal ulcerative colitis: a 
meta-analysis. Aliment Pharmacol Ther. 1995;9(3):293-300.
15. 
Marshall JK, Irvine EJ. Putting rectal 5-aminosalicylic acid in its place: the role in distal 
ulcerative colitis. Am J Gastroenterol. 2000;95(7):1628-36.
16. 
Gandia P, Idier I, Houin G. Is once-daily mesalazine equivalent to the currently used twice-
daily regimen? A study performed in 30 healthy volunteers. J Clin Pharmacol. 
2007;47(3):334-42.
17. 
Marteau P, Probert CS, Lindgren S, Gassul M, Tan TG, Dignass A, et al. Combined oral 
and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in subjects 
with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo 
controlled study. Gut. 2005;54(7):960-5.
18. 
Riley SA. (1998). What dose of 5-aminosalicylic acid (mesalazine) in ulcerative colitis? 
Gut. 1998;42(6):761-3.
19. 
Irvine EJ. Development and subsequent refinement of the Inflammatory Bowel Disease 
Questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel 
disease. J Pediatr Gastroenterol Nutr. 1999;38(4):523-7.
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APPENDICES
Appendix 1
Inflammatory Bowel Disease Questionnaire (IBDQ)
Appendix 2
Subject Diary Script
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Appendix 1
Inflammatory Bowel Disease Questionnaire (IBDQ)
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Appendix 2
Subject Diary Script
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Subject Diary Script
Subject Daily Diary Questions
1.
Did you take your study medication today? 
a)   Yes     No  
If Yes;
b) Did you take the study medication at least 1 hour before or at least 2 hours 
after a meal?    Yes     No  
2.
Evaluate today’s bowel movement frequency. 
a)
   Number of bowel movement today ______
3.
Have you noticed any blood in your bowel movement?
a)    Normal = (No blood)
b)    Streaks of blood
c)    Obvious blood
d)    Mostly blood
Note: That a bowel movement may consist of one or multiple stools; what one experiences in 
one visit to the toilet is classified as a bowel movement. For the rectal bleeding score, the 
worst score during the day is the one which will be recorded.
Bowel Movement (BM) Frequency (daily)
To determine the effect of medical therapy on your bowel movement frequency, we need you to 
define your “usual” non-ill state of health. 

What is your normal bowel movement frequency?
Each day during the trial you will assess your bowel movement frequency. This will be entered into 
your daily diary.

What is your bowel movement frequency today?
Rectal Bleeding Occurrence (daily)
Each day during the trial you will assess your rectal bleeding. This assessment should be based on 
your worst episode of bleeding that day. One of the four (4) choices below will be entered into your 
daily diary:
Have you noticed any blood in your bowel movement? For example:

If you see NO blood on the bowel movement or in the toilet water or visible anywhere in the 
toilet, enter a bleeding score of 0.
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
If you see only red streaks of blood on the surface of the bowel movement, enter a bleeding 
score of 1.

If you see red streaks of blood on the surface of the bowel movement and/or in the toilet water 
and/or visible anywhere in the toilet, enter a bleeding score of 2.

If your bowel movement is mostly or totally blood, enter a bleeding score of 3.
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SAP_001.pdf: 
Statistical Analysis Plan 
Title of trial: 
A randomized, double-blind, placebo-controlled, multicenter study 
investigating the efficacy and safety of mesalamine 2 g extended release 
granules (sachet) for maintenance of clinical and endoscopic remission in 
ulcerative colitis 
NCT number: 
NCT02522780 
Sponsor trial code: 
000175  
Date:  
02 Apr 2018 
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STATISTICAL ANALYSIS PLAN
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Investigating the 
Efficacy and Safety of Mesalamine 2 g Extended Release Granules (Sachet) for Maintenance 
of Clinical and Endoscopic Remission in Ulcerative Colitis
000175
Investigational Product:
Mesalamine 2 g Extended Release Granules (Sachet)
Indication:
Maintenance of clinical and endoscopic remission in 
ulcerative colitis
Phase:
3
Author:
Date of issue:
02-Apr-2018
Version:
3.0
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group
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Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes
2.0
3.0
August 7, 2015
April 2, 2018
-
Reflected protocol amendments 1 and 2
-
Addressed FDA’s comments on the initial 
SAP and modified related places 
accordingly
o
Changed to exclude subjects who 
are rolled over from the placebo 
group in the 000174 trial via 
Pathway 1 from the primary 
analysis, and consequently, the 
sample size was increased to 
approximately 260 subjects
o
Definition of the ITT analysis set 
was changed to exclude above 
subjects
o
Added all randomized and modified 
ITT analysis sets to the sensitivity 
analysis
o
Strata in each analysis set were
defined accordingly
o
Added sensitivity analyses using 
multiple imputation methods and 
pattern mixture models under 
missing at random and missing not 
at random assumptions, 
respectively.
-
Reflected protocol amendments 3 and 4, 
especially for changes in the primary 
endpoint regarding the stool frequency 
criteria for remission
-
Clarified stool frequency and rectal 
bleeding score calculation
-
Updated definition of major protocol 
deviations, analysis visit windows, and 
subgroups
-
Clarified summaries for laboratory 
variables against normal ranges
Version 1.0
Version 2.0
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Signed agreement on Statistical Analysis Plan
Author:

, Ferring International PharmaScience Center U.S., 
Inc.
Review:
This statistical analysis plan was reviewed and signed electronically in the REAL system by: 

, Ferring 
International PharmaScience Center U.S., Inc.

, Global Pharmacovigilance, 
Ferring Pharmaceuticals A/S

, Ferring 
Pharmaceuticals, Inc.

, Ferring International PharmaScience Center 
U.S., Inc.
Approval:
This statistical analysis plan was reviewed, approved and signed electronically in the REAL system 
by: 

, Global Biometrics, Ferring 
Pharmaceuticals A/S
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 4
1
Introduction.......................................................................................................................................... 6
1.1
Definitions/ Abbreviations........................................................................................................ 6
1.1.1
Definition of Terms...................................................................................................... 6
1.1.2
Abbreviations............................................................................................................... 6
2
Trial Objectives and Endpoints.......................................................................................................... 8
2.1
Objectives ................................................................................................................................. 8
2.1.1
Primary objective......................................................................................................... 8
2.1.2
Secondary objective..................................................................................................... 8
2.2
Endpoints .................................................................................................................................. 8
2.2.1
Primary endpoint.......................................................................................................... 8
2.2.2
Secondary endpoints .................................................................................................... 9
3
Trial design......................................................................................................................................... 10
3.1
General Design Considerations............................................................................................... 11
3.2
Determination of Sample Size ................................................................................................ 11
4
Subject Disposition ............................................................................................................................ 12
5
Protocol Deviations............................................................................................................................ 13
6
Analysis sets........................................................................................................................................ 14
6.1
All Randomized Analysis Set ................................................................................................. 14
6.2
Intention-To-Treat Analysis Set.............................................................................................. 14
6.3
Modified ITT Analysis Set ..................................................................................................... 14
6.4
Per Protocol Analysis Set........................................................................................................ 14
6.5
Safety Analysis Set ................................................................................................................. 14
7
Trial population ................................................................................................................................. 15
7.1
Demographics and Other Baseline Characteristics................................................................. 15
7.1.1
Demographics ............................................................................................................ 15
7.1.2
Disease Characteristics .............................................................................................. 15
7.1.3
Laboratory Efficacy/Pharmacodynamic Parameters at Baseline ............................... 15
7.2
Medical History....................................................................................................................... 15
7.3
Prior and Concomitant Medication......................................................................................... 15
7.4
Physical Examination.............................................................................................................. 16
8
Exposure and Treatment Compliance ............................................................................................. 17
8.1
Extent of Exposure.................................................................................................................. 17
8.2
Treatment Compliance............................................................................................................ 17
9
Efficacy ............................................................................................................................................... 18
9.1
General Considerations........................................................................................................... 18
9.2
Primary Endpoint(s)................................................................................................................ 19
9.2.1
Primary Variable(s) Analysis..................................................................................... 19
9.2.2
Sensitivity Analyses................................................................................................... 19
9.3
Secondary Endpoint(s)............................................................................................................ 20
9.4
Other Endpoint(s).................................................................................................................... 21
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9.4.1
Health Related Quality of Life................................................................................... 21
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...................................................................................... 23
10.3
Safety Laboratory Variables ................................................................................................... 24
10.3.1 Summary Statistics..................................................................................................... 24
10.3.2 Laboratory Variable Changes Relative to Normal Range.......................................... 24
10.3.3 Markedly Abnormal Changes.................................................................................... 25
10.3.4 Data Listings.............................................................................................................. 25
10.4
Vital Signs and ECG............................................................................................................... 25
10.4.1 Vital Signs.................................................................................................................. 25
10.4.1.1
Summary Statistics.....................................................................................25
10.4.1.2
Markedly Abnormal Changes ....................................................................25
10.4.1.3
Data Listings ..............................................................................................25
10.4.2 ECGs.......................................................................................................................... 25
10.4.2.1
Summary Statistics.....................................................................................26
10.4.2.2
Markedly Abnormal Changes ....................................................................26
10.4.2.3
Data Listings ..............................................................................................26
11
Interim analyses................................................................................................................................. 27
12
Deviations from protocol analysis .................................................................................................... 28
13
References........................................................................................................................................... 29
14
Tables, Listings and Figures ............................................................................................................. 30
Appendix 1
Markedly Abnormal Laboratory Safety Values, Vital Signs and ECGs ......................... 31
Appendix 2
Schedule of Trial Procedures............................................................................................... 33
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1
Introduction
This document describes the planned statistical analyses for Study 000175 based on the 
Consolidated Protocol Incorporating Amendments 1.0, 2.0, 3.0, and 4.0 dated January 17, 2017.
1.1
Definitions/ Abbreviations
1.1.1
Definition of Terms
Terms
Definitions
Clinical Response Score Stool frequency and rectal bleeding subscale of Clinical and 
Endoscopic Response Score
Endoscopic Response 
Score
Flexible sigmoidoscopy findings subscale of Clinical and 
Endoscopic Response Score
1.1.2
Abbreviations
Abbreviations
Meaning of abbreviations in document
ADR
Adverse drug reaction
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
CRP
C-reactive protein
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
GEE
Generalized estimating equations
GGT
Gamma glutamyl transferase
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HRQoL
Health-related quality of life
IBDQ
Inflammatory bowel disease questionnaire
IMP
Investigational medicinal product
INR
International normalized ratio
ITT
Intention-to-treat
MAR
Missing at random
MedDRA
Medical dictionary for regulatory activities
MI
Multiple imputation
mITT
Modified ITT
MNAR
Missing not at random
PMM
Pattern mixture model
PP
Per protocol
PT
Preferred term
QD
Once daily
QTc
Corrected QT interval
SOC
System organ class
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Abbreviations
Meaning of abbreviations in document
TEAE
Treatment-emergent adverse event
UC
Ulcerative colitis
US
United states
WBC
White blood cell
WHO-Drug
World health organization drug dictionary
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2
Trial Objectives and Endpoints
2.1
Objectives
2.1.1
Primary objective

To demonstrate the efficacy of mesalamine 2 g extended release granules (sachet) once 
daily (QD) compared to placebo in the maintenance of clinical and endoscopic remission of 
ulcerative colitis (UC)
2.1.2
Secondary objective

To evaluate the efficacy of mesalamine 2 g extended release granules (sachet) utilizing the 
Clinical and Endoscopic Response Score, Clinical Response Score subset, and frequency of 
treatment failures

To assess C-reactive protein (CRP) levels and fecal calprotectin levels

To assess health-related quality of life (HRQoL) using the Inflammatory Bowel Disease 
Questionnaire (IBDQ)

To assess the incidence and severity of adverse events (AEs) and abnormal laboratory 
values
2.2
Endpoints
2.2.1
Primary endpoint
The primary efficacy endpoint is the proportion of subjects in remission, defined by the Clinical 
and Endoscopic Response Score (Table 1) at Month 6 as a score of,

0 for rectal bleeding, and

0 or 1 for stool frequency, and

0 or 1 for endoscopic score.
The endoscopic score will be determined by an independent central reader.
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Table 1
Clinical and Endoscopic Response Score (0 – 9)
Components
Subscale
Severity
Score
CLINICAL
RESPONSE
(Subject’s Symptoms)
Stool Frequencya
(daily)
Normal number of stools for subject 
0
1 to 2 stools more than normal
1
3 to 4 stools more than normal
2
≥5 stools more than normal
3
Rectal Bleedingb
(daily)
No blood seen
0
Streaks of blood with stool 
1
Obvious blood with stool
2
Blood alone passes
3
ENDOSCOPIC
RESPONSE
(Objective Evidence of 
Inflammation)
Flexible 
Sigmoidoscopy 
Findings
Normal or inactive disease
0
Mild disease (erythema, decreased vascular pattern, 
granularity)
1
Moderate disease (marked erythema, absent vascular 
pattern, any friability, erosions)
2
Severe disease (spontaneous bleeding, ulceration)
3
Adapted from:  Schroeder et al. (1987)(1); Sninsky et al. (1991)(2); Modified by Ferring Group, 2014
a.
Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency.
b.
The daily bleeding score represents the most severe bleeding of the day.
2.2.2
Secondary endpoints

The proportion of subjects in clinical remission at Months 2, 4, and 6, defined as a score of 
0 for rectal bleeding and 0 or 1 for stool frequency based on Clinical Response Score subset 
of the Clinical and Endoscopic Response Score

Time to relapse, defined as number of days from randomization to the day of withdrawal 
due to escalation of therapy (i.e., surgical therapy, use of steroids, immunosuppressive or 
immunomodulating drugs, biologics, increase dose of 5 aminosalicylic acid [5-ASA] in any 
form)

The proportion of subjects with an increase from baseline in the Clinical and Endoscopic 
Response Score by 2 or more points in at least 1 component or by 1 or more points in at 
least 2 components at Month 6

The change from baseline in serum CRP levels at Months 2, 4, and 6

The change from baseline in fecal calprotectin levels at Months 2, 4, and 6

The change from baseline to each scheduled assessment for published and validated domain 
scores of the IBDQ

Safety assessed by incidence and severity of AEs and abnormal laboratory values
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3
Trial design
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, international, 
Phase 3 trial to investigate the safety and efficacy of mesalamine 2 g extended release granules 
(sachet) for maintenance of clinical and endoscopic remission in subjects with UC. Subjects who 
are in remission can be enrolled in the current trial via 1 of 3 pathways. 

Pathway 1:  Subjects who are in remission following 8 weeks of double-blind treatment in 
Study 000174 can be randomized into Study 000175. The clinical and endoscopic remission 
criteria for Study 000174 include a Clinical and Endoscopic Response Score as a score of 0 
for rectal bleeding and 0 or 1 with at least 1 point decrease from baseline for stool 
frequency, with an endoscopic score of 0 or 1.

Pathway 2:  Subjects in remission at the end of the 8-week open-label treatment period in 
Study 000174 will be allowed to be randomized into Study 000175. 

Pathway 3 – de novo:  Subjects who did not participate in Study 000174 can also be 
enrolled; these subjects will have been treated with various medications for UC (excluding 
biologics and long-term [≥6 months] immunosuppressants) and will have been in remission 
for <1 year. These de novo subjects will undergo a 72-hour mesalamine washout prior to 
entering the current trial and will have a Clinical and Endoscopic Response Score 
assessment to ensure eligibility.
All eligible subjects will be randomized during Visit 1/Day 0 (start of maintenance) to 1 of the 
following treatments:  

one mesalamine 2 g extended release granules (sachet) QD (2 g/day) OR

one 2 g placebo sachet to match mesalamine extended release granules (sachet)
Dose will be administered QD at least 1 hour before or at least 2 hours after a meal at 
approximately the same time each day. The sachet will be emptied on the tongue and swallowed 
with at least 8 ounces (240 mL) of water. For all subjects, the first dose of investigational medicinal 
product (IMP) will be administered the day following randomization/Visit 1.
During the 6-month trial period, all subjects will visit the trial site 5 times for safety and efficacy 
evaluations:  baseline, Week 2, and Months 2, 4, and 6. On a daily basis, subjects will record 
clinical symptoms (stool frequency and rectal bleeding) in an electronic diary. The Clinical and 
Endoscopic Response Score assessments will be performed at baseline and Month 6. After 6 
months of treatment, subjects will be evaluated for remission, defined as a Clinical and Endoscopic 
Response Score of rectal bleeding score of 0 and stool frequency scores of 0 or 1, with an 
endoscopic score of 0 or 1. Whereas, subjects will only have a Clinical Response Score assessment 
at Months 2 and 4. De novo subjects will have a complete screening visit, and if they are judged to 
be in clinical and endoscopic remission based on their Clinical and Endoscopic Score at 
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baseline/randomization, they will continue with the 6 month assessment for safety and efficacy 
evaluations.
Flexible sigmoidoscopy/colonoscopy will be video recorded and transferred to the independent 
central reader. The details of the tools, recording, data transfer, and assessment will be documented 
in an Imaging Charter. If the local site’s endoscopic reading determines the subject is ineligible, the 
subject will be screen failed (Pathway 3 – de novo). If the local site’s endoscopic reading 
determines that the subject is eligible, the flexible sigmoidoscopy recording will be sent to the 
independent central reader for final determination of eligibility (Pathway 3 – de novo). For subjects 
rolling over from the 000174 trial (Pathway 1 and 2), 000175 eligibility will be derived from the 
final end of treatment (EOT) independent central read. A flexible sigmoidoscopy will also be 
performed at Month 6, which will also be sent to the independent central reader for endoscopic
endpoint scoring for all subjects.
The schedule of trial procedures is presented in Appendix 2.
3.1
General Design Considerations
This trial is designed as a randomized, double-blind, placebo-controlled trial with 6 months of 
treatment. Subjects will be randomized by pathway of enrollment, and Pathway 1 will be further 
stratified by the treatment group assigned in the 000174 trial. 
The endoscopic score will be determined by an independent central reader.  
3.2
Determination of Sample Size
The true remission rates at Month 6 for mesalamine 2 g extended release granules (sachet) and 
placebo regimens were assumed as 68% and 49%, respectively, based on The mesalamine Study 
Group (1996)(3), Hawkey et al (1997)(4), and Apriso™ package insert (2009)(5). Under these 
assumptions, a sample size of 120 randomized subjects per group will provide at least 85% power 
to detect a statistically significant treatment group difference in the remission rate at a two-sided 
0.05 significance level using the chi-square test. To maintain the power for the primary efficacy 
analysis that excludes subjects who are rolled over from the placebo group in the 000174 trial via 
Pathway 1, approximately 260 subjects will be randomized.
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4
Subject Disposition
The number of screened subjects will be summarized, and for subjects not randomized, the primary 
reason for exclusion from randomization will be summarized.
The number and percentage of subjects who are randomized, are treated with IMP, prematurely 
discontinued, and completed the trial will be summarized with the reason of premature 
discontinuations. 
The time to discontinuation will be summarized by the Kaplan-Meier estimates, and the treatment 
group difference will be tested by the log-rank test. In addition, reason-specific discontinuation will 
be summarized by the cumulative incidence estimates.
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5
Protocol Deviations
The following protocol deviations will be identified as major protocol deviations:

Overall IMP compliance of less than 80%

Not taking the randomized IMP

Taking prohibited medications
The final definition of major protocol deviations will be determined prior to breaking the blind.  
The number and percentage of subjects with protocol deviations will be summarized.
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6
Analysis sets
For each analysis set, the number and percentage of subjects excluded from it will be summarized 
by the reason of the exclusion.
6.1
All Randomized Analysis Set
The all randomized analysis set includes all randomized subjects. Analyses for the all randomized 
analysis set will be conducted according to the randomized treatment regardless of the actual 
treatment received.
6.2
Intention-To-Treat Analysis Set
The intention-to-treat (ITT) analysis set includes all randomized subjects who were assigned to 
mesalamine 4 g extended release granules in the 000174 trial or randomized via Pathways 2 or 3.
Analyses for the ITT analysis set will be conducted according to the randomized treatment
regardless of the actual treatment received. 
6.3
Modified ITT Analysis Set
The modified ITT (mITT) analysis set includes all subjects who receive at least 1 dose of IMP in 
the ITT analysis set. Analyses for the mITT analysis set will be conducted according to the 
randomized treatment regardless of the actual treatment received.
6.4
Per Protocol Analysis Set
The Per-protocol (PP) analysis set includes all subjects who receive at least one dose of IMP and 
who do not have any of the major protocol deviations defined in Section 5 in the ITT analysis set.
6.5
Safety Analysis Set 
The safety analysis set includes all subjects who receive at least one dose of IMP. Safety analyses 
will be conducted according to the treatment actually received.
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7
Trial population
7.1
Demographics and Other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics will be presented for all 
subjects in the ITT, PP, and safety analysis sets by treatment group unless otherwise specified.
Categorical data will be summarized using numbers and percentages. The percentages will be based 
on the total number of subjects with a corresponding assessment. Continuous data will be presented 
using the number of subjects, mean, standard deviation, median, minimum, and maximum.
7.1.1
Demographics
Baseline demographics and other baseline characteristics will be summarized by treatment group. 
7.1.2
Disease Characteristics
Baseline disease characteristics (e.g., time since diagnosis of UC, extent of disease) will be 
summarized by treatment group.
Baseline Clinical and Endoscopic Response Scores will be summarized by treatment group. 
7.1.3
Laboratory Efficacy/Pharmacodynamic Parameters at Baseline
Baseline serum CRP and fecal calprotectin levels will be summarized by treatment group.
7.2
Medical History
Medical history will be coded by system organ class (SOC) and preferred term (PT) using the 
Medical Dictionary for Regulatory Activities (MedDRA) version 17.1 or later and summarized by 
SOC (in alphabetical order), PT (in decreasing order of frequency), and treatment group for the ITT 
and Safety analysis sets. 
7.3
Prior and Concomitant Medication
Prior and concomitant medications will be coded by the Anatomical Therapeutic Chemical (ATC) 
classification system and preferred drug name using the World Health Organization Drug 
Dictionary (WHO-Drug). 
Prior and concomitant drug usage will be summarized by ATC classification 1st level 
(alphabetically), ATC classification 2nd level (in decreasing order of frequency) and treatment 
group for subjects in the ITT and Safety analysis sets. 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 or started on or after the first 
IMP administration
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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.
7.4
Physical Examination
Subjects with abnormalities at any screening, baseline, or post-baseline visit will be listed with all 
physical examination evaluations.
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8
Exposure and Treatment Compliance
8.1
Extent of Exposure 
The length of the treatment, calculated as (last dose date – first dose date + 1), will be summarized 
by treatment group for the safety analysis set.  
Following categorical summaries will be made:

< 14 days, 14 - < 28 days, 28 - <56 days, 56 - <84 days, 84 - <112 days, 112 - <140 
days, 140 - <168 days, and 168 days or more

At least 1 day, at least 14 days, at least 28 days, at least 56 days, at least 84 days, at least 
112 days, at least 140 days, and at least 168 days
8.2
Treatment Compliance 
The overall compliance will be calculated as number of days with IMP intake based on the daily 
diary data divided by the number of days that the subject is supposed to take the IMP during the 
treatment period. It will be summarized for the safety analysis set.
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9
Efficacy
9.1
General Considerations
All statistical tests will be conducted at a two-sided 0.05 significance level. 
All secondary endpoints will be tested without adjustment for multiplicity.
Randomization strata will be included in stratified analyses for efficacy endpoints. For the ITT, 
mITT, and PP analysis sets, randomization strata will be defined as follows:

Stratum 1: Pathway 1 (mesalamine 4 g extended release granules arm in the 000174 trial)

Stratum 2: Pathway 2

Stratum 3: Pathway 3
Randomization strata for the all randomized analysis set will be defined as follows:

Stratum 1: Pathway 1a (placebo arm in the 000174 trial)

Stratum 2: Pathway 1b (mesalamine 4 g extended release granules arm in the 000174 trial)

Stratum 3: Pathway 2

Stratum 4: Pathway 3
Stool frequency and rectal bleeding scores at each visit will be calculated as an average of the daily 
scores collected within 5 days prior to the visit (excluding the visit day and the day before the visit 
day if the bowel preparation is needed on the day before the visit). If the daily scores in this period 
are available for fewer than 3 days, the average score will be considered missing. The average 
scores will be rounded to the nearest integer for the final score determination (e.g., 0.3 will be 
rounded to 0, and 0.5 will be rounded to 1). Handling of missing data in the statistical analyses will 
be described for each endpoint. 
For the endoscopic assessment, the outcomes determined by the independent central reading 
procedure will be used for all analyses. 
For visit-based data, the data collected on the day that is closest to the scheduled trial day within a 
window will be assigned to the corresponding analysis visit. Table 2 shows the scheduled trial day 
and window for each analysis visit.
Table 2
Scheduled trial day and window for analysis visits
Analysis visit
Scheduled trial day
Window
Baseline
Day 1
prior to the first dose of IMP
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Analysis visit
Scheduled trial day
Window
Week 2
Day 14
Day 1 to Day 35
Month 2
Day 56
Day 36 to Day 84
Month 4
Day 112
Day 85 to Day 140
Month 6
Day 168
Day 141 or after
If the closest day cannot be uniquely identified for an analysis visit, the data collected on an earlier 
trial day will be assigned to the analysis visit. 
9.2
Primary Endpoint(s)
9.2.1
Primary Variable(s) Analysis
The primary efficacy analysis will be based on the ITT analysis set. The proportion of subjects in
remission, defined as rectal bleeding of 0 and stool frequency scores of 0 or 1 with an endoscopic 
score of 0 or 1 in the Clinical and Endoscopic Response Score at Month 6, will be assessed by the 
Mantel-Haenszel test stratified by the randomization strata at a two-sided 0.05 significance level. 
Subjects who discontinue the double-blind regimen before Month 6, as well as subjects with 
missing remission assessment at Month 6, will be considered not having met the remission criteria. 
The common odds ratio will be estimated using the Mantel-Haenszel adjusted odds ratio estimate,
and its 95% confidence interval will be provided. The homogeneity of odds ratios across the 
randomization strata will be tested by the Breslow-Day test at a 0.05 significance level, and the 
odds ratio for each stratum will be presented in forest plots. The quantitative or qualitative nature of 
the possible treatment by stratum interaction will be assessed and discussed.
9.2.2
Sensitivity Analyses 
The following sensitivity analyses will be conducted to assess the robustness of the primary 
analysis: 

As-treated analysis based on actually received treatment

Analysis on the all randomized analysis set

Analysis on the mITT analysis set

Analysis on the PP analysis set

Analysis using the last observed Clinical and Endoscopic Response Score
The same analysis conducted for the primary analysis will be repeated for these sensitivity 
analyses. 
Since the definition of remission was modified during the study, an analysis based on the original 
definition, i.e., rectal bleeding and stool frequency scores of 0 with an endoscopic score of 0 or 1 in 
the Clinical and Endoscopic Response Score, will also be conducted for reporting purpose.
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In addition, sensitivity analyses using multiple imputation (MI) methods and pattern mixture 
models (PMMs) under missing at random (MAR) and missing not at random (MNAR) 
assumptions, respectively, will be conducted.
Under the MAR assumption, the missing stool frequency and rectal bleeding scores (Clinical 
Response scores) for Months 2, 4, and 6 will be imputed sequentially by regression-based 
imputation models using treatment group, baseline characteristics, and outcomes from preceding 
visits as the predictors. Once the missing Month 6 Clinical Response scores have been imputed, 
Month 6 Endoscopic Response score will be imputed by regression-based imputation models using 
treatment group, baseline characteristics, and Month 6 Clinical Response scores as the predictors. 
Based on the imputed Clinical and Endoscopic Response scores, the remission status at Month 6
will be determined. This imputation procedure will be repeated 100 times, and the primary analysis 
method will be applied to each of the imputed dataset. A combined estimate of the odds ratio for 
the treatment group compared to the control group and its 95% confidence interval will be obtained 
by the methods described in Rubin (1987)(6) .
Under the MNAR assumption, a similar MI method described above will be applied. However, in 
this analysis, only the data from the control group will be used for the regression-based imputation 
for Clinical Response scores at each visit and Endoscopic Response score at Month 6 by assuming 
that subjects from the treatment group will follow the same profile as the subjects on the control 
group after withdrawal from the study (Little & Yau, 1996(7); Ratitch & O’Kelly, 2011(8)).
The primary endpoint will also be analyzed for the following subgroups for the ITT analysis set
using the same method as the primary efficacy analysis. The homogeneity of odds ratios across the 
strata will be tested by the Breslow-Day test at a 0.05 significance level, and the odds ratios for 
each subgroup will be presented in forest plots. 

Baseline demographic characteristics (age, gender, and race)

Geographical region (North America including US and Canada or rest of the world)
The treatment group comparisons after controlling the randomization strata and each factor listed 
above will be conducted by the Mantel-Haenszel test as sensitivity analyses.
9.3
Secondary Endpoint(s) 
The following key secondary endpoints will be analyzed for the ITT analysis set.

The proportion of subjects in clinical remission at Months 2, 4, and 6, defined as a score of 
0 for both rectal bleeding and stool frequency based on Clinical Response Score subset of 
the Clinical and Endoscopic Response Score

Time to relapse, defined as number of days from randomization to the day of withdrawal 
due to escalation of therapy (i.e., surgical therapy, use of steroids, immunosuppressive or 
immunomodulating drugs, biologics, increase dose of 5 ASA in any form)
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
The proportion of subjects with an increase from baseline in the Clinical and Endoscopic 
Response Score by 2 or more points in at least 1 component or by 1 or more points in at 
least 2 components at Month 6

The change from baseline in serum CRP levels at Months 2, 4, and 6

The change from baseline in fecal calprotectin levels at Months 2, 4, and 6
The proportion of subjects in clinical remission at Months 2, 4, and 6 will be analyzed by the
generalized estimating equations (GEE) approach as longitudinal binary outcomes. The model will 
include the randomization strata, treatment, time, and treatment- by-time interaction. The clinical 
remission rates and odds ratio will be estimated for each time point. The overall treatment 
difference over 6 months will be estimated as the main effect for treatment in the model. The 
missing values will be imputed as non-remission, and an unstructured working correlation matrix 
will be used.
The time to relapse will be analyzed by the log-rank test stratified by the randomization strata. If a 
subject does not have the relapse by Day 168, the time to relapse will be censored at the earlier of 
the day that the last visit day or Day 168. The hazard ratio of relapse for mesalamine relative to 
placebo will be estimated (including the 95% CI) using the stratified Cox proportional hazards 
model with treatment group as a factor and the randomization strata as a stratification variable.
The proportion of subjects with an increase from baseline in the Clinical and Endoscopic Response 
Score by 2 or more points in at least 1 component or by 1 or more points in at least 2 components at 
Month 6 will be analyzed using the same statistical method used for the primary efficacy analysis.
The change from baseline in serum CRP levels and fecal calprotectin levels at Months 2, 4, and 6
will be analyzed by repeated-measures analysis of covariance (ANCOVA) models that include the 
randomization strata, treatment, time, and treatment-by-time interaction as fixed effects, and the 
corresponding baseline value as a covariate. The adjusted changes from baseline and their 
difference between treatment groups will be estimated for each time point. The overall treatment 
difference over 6 months will be estimated as the main effect for treatment in the model. The 
missing values will be left as missing, and an unstructured correlation matrix will be assumed.
9.4
Other Endpoint(s)
9.4.1
Health Related Quality of Life
The change from baseline in the IBDQ will be analyzed for the ITT analysis set. 
The following domain scores for the IBDQ (Guyatt et al., 1989)(9) will be calculated by adding up 
scores from questions included in the domain for each subject at each time point:

Bowel symptoms: Questions 1, 5, 9, 13, 17, 20, 22, 24, 26, 29

Emotion function: Questions 3, 7, 11, 15, 19, 21, 23, 25, 27, 30, 31, 32
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
Systemic symptoms: Questions 2, 6, 10, 14, 18

Social function: Questions 4, 8, 12, 16, 28
The total score will be calculated by adding up all scores for each subject at each time point. 
The handling of missing score in the calculation of the domain and total scores will be based on 
McMaster University (2010)(10). If there is only one missing response within a domain, the 
missing response will be imputed as an average of other responses within the domain. If there are 
two or more missing responses within a domain, the domain score will be considered missing. 
If there are up to four missing responses, the missing responses will be imputed as an average of 
other responses. If there are more than four missing responses, the total score will be considered 
missing.
The change from baseline in the IBDQ domain and total scores at Months 2, 4, and 6 will be 
analyzed by repeated-measures ANCOVA models that include treatment, randomization strata, 
time, and treatment-by-time interaction as fixed effects, and the corresponding baseline value as a 
covariate. The adjusted changes from baseline and their difference between treatment groups will 
be estimated for each time point. The missing values will be left as missing, and an unstructured 
correlation matrix will be assumed.
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10
Safety
10.1
General Considerations
Safety parameters will be evaluated for the safety analysis set by treatment group.
10.2
Adverse Events
Adverse events (AEs) will be classified according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version 17.1 or later.
Written narratives will be issued for all serious AEs (including deaths) and AEs leading to 
discontinuation.
A ‘pre-treatment’ AE will be defined as an AE that occurs between screening and the first dose of 
the IMP. A ‘treatment-emergent AE (TEAE)’ will be an AE which occurs in the time interval from 
initial dosing (IMP intake) to the end of treatment visit. If an AE on Day 1 occurs before IMP 
intake, it will be recorded as a pre-treatment AE.
If causality is missing, the AE will be regarded as being reasonably possibly related to IMP. 
Related AEs (judged as being reasonably possibly related to IMP) will be termed adverse drug 
reactions (ADR).
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: 

Any TEAEs

Deaths 

Serious adverse events 

Adverse events leading to discontinuation

Severe TEAEs

Adverse drug reactions
10.2.2
Incidence of Adverse Events
The summaries will include 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 SOC sorted 
alphabetically and PT sorted in decreasing frequency of occurrence.
Summary tables will be prepared for:

Any TEAEs

Common TEAEs, defined as TEAEs with an incidence ≥ 2% of subjects in any treatment 
group

Any TEAEs by causality (related/unrelated)
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
Any TEAEs by intensity

Any AEs leading to death

Serious adverse events 

Any TEAEs leading to discontinuation
Supporting data listings will be provided for:

All adverse events sorted by trial site and subject ID

All adverse events sorted by MedDRA SOC and PT

Serious adverse events 

Adverse events leading to death

Adverse events leading to discontinuation
A listing of SOC and PT for all unique verbatim will be provided.  
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 IMP. Treatment-emergent laboratory data will include tests completed after the 
first dose of IMP. End of treatment will include the last post-baseline observation during the 
treatment period.
Laboratory variables will be grouped under “Haematology”, “Coagulation”, “Serum chemistry” or 
“Urinalysis”
10.3.1
Summary Statistics
Change and percentage change from baseline at end of treatment will be presented for each 
laboratory variable. In addition, 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/percentage change from baseline at baseline, Week 2, Months 2, 4, and 6 for 
each laboratory variable. The Week 2, Months 2, 4, and 6 measurements for the analysis will be 
identified based on the method described in Section 9.1.  
10.3.2
Laboratory Variable Changes Relative to Normal Range
A shift table regarding the laboratory value category defined below will be created for baseline and 
end of treatment for each laboratory parameter. 

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)
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10.3.3
Markedly Abnormal Changes
Number and percentage of subjects who experienced at least one pre-specified markedly abnormal 
value (Appendix 1) during the treatment for each laboratory variable will be summarized by the 
baseline category (i.e., low, normal, high, absent, or present). 
10.3.4
Data Listings
Data listings will be prepared by treatment group and trial site for all subjects with any abnormal 
laboratory values at any time-point (including screening, baseline, and treatment period).  
10.4
Vital Signs and ECG
10.4.1
Vital Signs
Baseline for all vital signs 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. 
End of treatment will include the last post-baseline observation during the treatment.
10.4.1.1
Summary Statistics
Change and percentage change from baseline at end of treatment will be presented for each vital 
sign variable. In addition, 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/percentage change from baseline at baseline, Week 2, Months 2, 4, and 6 for 
each vital sign variable. The Weeks 2, Months 2, 4, and 6 measurements for the analysis will be 
identified based on the method described in Section 9.1.
10.4.1.2
Markedly Abnormal Changes
Number and percentage of subjects who experienced at least one pre-specified markedly abnormal 
value (Appendix 1) during the treatment for each vital sign variable will be summarized. 
10.4.1.3
Data Listings
Data listings will be prepared by trial site for all subjects with any markedly abnormal vital sign 
values at any time-point (including screening, baseline, and treatment period).
10.4.2
ECGs
Baseline for all ECG variables will be the values obtained at the last assessment prior to the first 
dose of IMP. Treatment-emergent ECG data will include variables measured after the first dose of 
IMP. End of treatment will include the last post-baseline observation during the treatment period.
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QTc will be calculated based on Bazett’s (QTcB) and Fridericia’s (QTcF) corrections. 
RR
QT
ms
QTcB

]
[
3
]
[
RR
QT
ms
QTcF

Rate
Heart
RR
where
60
,

10.4.2.1
Summary Statistics 
Change from baseline at end of treatment will be presented for each ECG variable. In addition, 
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 
baseline and Month 6 for each ECG variable. The Month 6 measurement for the analysis will be 
identified based on the method described in Section 9.1. 
10.4.2.2
Markedly Abnormal Changes
Number and percentage of subjects who experienced at least one pre-specified markedly abnormal 
value (Appendix 1) during the treatment for each ECG variable will be summarized. 
10.4.2.3
Data Listings
Data listings will be prepared by trial site for all subjects with any abnormal ECG findings at any 
time-point (including screening, baseline, and treatment period).
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11
Interim analyses
No interim analysis is planned. 
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12
Deviations from protocol analysis
There is no deviation from the planned analysis described in the protocol.
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13
References
(1)
Schroeder, K.W., Tremaine, W.J., & Ilstrup, D.M. (1987). Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis: a randomized study. New England 
Journal of Medicine, 317, 1625-1629.
(2)
Sninsky, C.A., Cort, D.H., Shanahan F, Powers, B. J., Sessions, J. T., Pruitt, R. E., …, 
DeMicco, M. P. (1991). Oral mesalamine (Asacol) for mildly to moderately active 
ulcerative colitis. Annals of Internal Medicine, 115, 350-355.
(3)
The Mesalamine Study Group. (1996). An oral preparation of mesalamine as long-term 
maintenance therapy for ulcerative colitis. Annals of Internal Medicine, 124, 204-211.
(4)
Hawkey, C.J., Dube, L.M., Rountree, L.V., Linnen, P.J., Lancaster, J.F. (1997). A trial of 
zileuton versus mesalazine or placebo in the maintenance of remission of ulcerative colitis. 
Gastroenterology, 112, 718-724
(5)
APRISO™ package insert. (2008). Salix Pharmaceuticals. Morrisville, NC.
(6)
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: Wiley.
(7)
Little, R. & Yau, L. (1996). Intent-to-treat analysis for longitudinal studies with drop-outs. 
Biometrics, 52, 1324-1333.
(8)
Ratitch, B. & O’Kelly, M. (2011). Implementation of pattern-mixture models using standard 
SAS/STAT procedures. Proceedings of PharmaSUG 2011 (Pharmaceutical Industry SAS 
Users Group), SP04, Nashville. Retrieved from 
http://pharmasug.org/proceedings/2011/SP/PharmaSUG-2011-SP04.pdf.
(9)
Guyatt, G., Mitchell, A., Irvine, E. J., Singer, J., Williams, N., Goodacre, R., & Tompkins, 
C. (1989). A new measure of health status for clinical trials in inflammatory bowel disease. 
Gastroenterology, 96, 804-810.
(10)
McMaster University. (20010). IBDQ frequently asked questions: re: handling missing data 
for IBDQ and SIBDQ. Retrieved from 
http://mcmaster.flintbox.com/public/filedownload/6473/IBDQ%20Package%20Version%20
2%20(CURRENT).
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14
Tables, Listings and Figures
Tables, figures and listings shells will be presented in a separate document.
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Appendix 1
Markedly Abnormal Laboratory Safety Values, Vital Signs and ECGs
Table A 1: Markedly abnormal Criteria for Laboratory Tests
Variable
Units
Markedly abnormal Criteria
Low
High
Haematology
Haemoglobin
g/L
115
Not applicable
Haematocrit
Ratio
0.32
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
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
Total bilirubin
μmol/L
Not applicable
1.5xULN
Urea nitrogen
mmol/L
Not applicable
10.7
Creatinine
μmol/L
Not applicable
177
eGFR
mL/min
<30
Not applicable
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
Calcium
mmol/L
1.8
3.9
Glucose
mmol/L
2.8
10
Coagulation
INR
<0.8
>1.1
Activated partial 
thromboplastin 
time
Sec
Not applicable
>70
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Table A 2: 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 temperature
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.
Table A 3: Abnormal Criteria for Quantitative ECG Data*
Variable
Abnormal Treatment-Emergent Value
ECG heart rate
50 bpm and decrease from baseline of 15 bpm
120 bpm and increase from baseline of 15 bpm
Duration of PR interval
> 220 msec
Duration of QRS interval
> 120 msec
Duration of QTc interval
> 450 msec
Duration of QTc interval
> 480 msec
Duration of QTc interval
> 500 msec
Duration of QTc interval
Increase from baseline of ≥ 30 msec
Duration of QTc interval
Increase from baseline of ≥ 60 msec
* QTc will be calculated using both Bazett’s and Fridericia’s corrections.
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Appendix 2
Schedule of Trial Procedures
Screeninga
Baseline/ 
Randomizationb Intermediate
Intermediate
Intermediate
End of 
Treatment/
Early 
Withdrawal
Visit
0
1
2
3
4
5
Monthc Week - 3
Month 0
Week 2
Month 2
Month 4
Month 6
Trial Day
(visit window)
Up to 
Day -21
Day 0
Day 14 
(±3 days)
Day 56 
(±5 days)
Day 112 
(±5 days)
Day 168 
(5 days)
Written informed consent
X
Xd
Inclusion/exclusion criteria review
X
X
Medical history
X
X
Physical examination, including 
weight
X
X
X
X
X
X
Height
X
Vital signs
X
X
X
X
X
X
12-lead electrocardiogram
X
X
Demographic data
X
Serum/urine pregnancy teste
X
X
X
Standard urinalysisf
Xg
X
Drug and alcohol history
X
Immunological testing for HBV, 
HCV, and HIV
X
Estimated creatinine clearance
Xg
X
X
X
X
Safety hematology, coagulation,
and chemistry
Xg
Xm
X
X
X
Randomization
X
Prior and concomitant medications
X
X
X
X
X
X
Serum CRP
Xa
X
X
X
Fecal calprotectin stool sample
Xa
X
X
X
Clinical Response Score (stool 
frequency and rectal bleeding 
scores)
X
X
X
Calculation of clinical and 
Endoscopic Response Score 
Xh
X
Flexible sigmoidoscopyi / Central 
reading
X
X
HRQoL questionnaire: IBDQ
Xa
X
X
X
Adverse event recordingj
X
X
X
X
X
X
Distribution of trial medication
X
X
X
First administration of trial 
medication
X1
Trial medication
collection/distribution
Xn
X
X
X
Trial medication compliance
X
X
X
X
Subject diary activation
X
Xd
Subject diary data reviewk
X
X
X
X
X
Note: All subjects who discontinue treatment will complete end-of-treatment assessments.
a
For Pathway 3 - de novo subjects only (a complete screening visit, including flexible sigmoidoscopy, which will be scheduled at 
screening and completed at least (4) days prior to randomization).
b
Subjects in Pathways 1 and 2 will be consented at Visit 1/Baseline. The complete screening assessments will be taken from 
Study 000174 end-of-treatment visit and eligibility (all inclusion/exclusion criteria) will be reassessed.  
c
Month equals 4 weeks; week equals 7 days.
d
Pathways 1 and 2 only.
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e
For females of childbearing age or <1 year postmenopausal; if positive, the subject will not be enrolled in the trial. A serum 
pregnancy test will be performed at Visit 0 (screening) for Pathway 3 – de novo only. Urine pregnancy tests will be performed 
for all subjects at Visit 1 (baseline/Day 0) and Visit 5 (Month 6) or early withdrawal.
f
If positive for blood, leucocytes, or nitrite, perform microscopic urinalysis.
g
Results must be available at randomization (Visit 1).
h
For all subjects; Study 000174 end-of-treatment Clinical and Endoscopic Response Score assessments will be utilized for 
Pathways 1 and 2 only.
i
Baseline flexible sigmoidoscopy/colonoscopy for Pathway 3 – de novo subjects will be scheduled at screening (Visit 0) and 
completed at least 4 days prior to randomization (Visit 1) to allow sufficient time for the central reading. 
j
Adverse events are collected from the signing of informed consent.
k
Subject daily diary data will be collected electronically and daily diary compliance will be assessed.
l
IMP to be distributed at Day 0, and will be taken the following day  (Day 1).
m
No coagulation panel.
n
Subjects will bring IMP kit to site for assessment of compliance; this same kit will be used until Visit 3.
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