Conditions: Ulcerative Colitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 228
Healthy volunteers: no

Brief summary:
The purpose of this trial is to investigate the efficacy of mesalamine for the induction of clinical and endoscopic remission in subjects with active, mild to moderate UC. Subject will receive 4 g extended release granules (sachet) once daily.

Detailed description:

Arms:
arm 1: 4 g extended release granules (sachet) arm 2: Matching placebo

Interventions: intervention 1: Mesalamine intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Protocol 
Title of trial: 
A randomized, double-blind, placebo-controlled, multicenter study 
investigating the efficacy and safety of mesalamine 4 g extended release 
granules (sachet) for the induction of clinical and endoscopic remission in 
active, mild to moderate ulcerative colitis 
NCT number: 
NCT02522767 
Sponsor trial code: 
000174  
Date:  
11 Jan 2017 
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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Investigating the 
Efficacy and Safety of Mesalamine 4 g Extended Release Granules (Sachet) for the Induction 
of Clinical and Endoscopic Remission in Active, Mild to Moderate Ulcerative Colitis
000174
Consolidated Protocol Incorporating Amendments 1.0, 2.0, 3.0 and 4.0
EudraCT Number:
2015-002557-35
IND Number:
122553
Investigational Medicinal Product:
Mesalamine 4 g Extended Release Granules (Sachet)
Indication:
Induction of Clinical and Endoscopic Remission in active, 
mild to moderate 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 4 g Extended Release Granules (Sachet) for the Induction of Clinical and 
Endoscopic Remission in Active, Mild to Moderate 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:  Q3 2017
CLINICAL PHASE
3
OBJECTIVES
Primary objective: 

To demonstrate efficacy of mesalamine 4 g extended release granules (sachet) once daily 
(QD) in the induction of clinical and endoscopic remission versus placebo in subjects with 
active, mild to moderate ulcerative colitis (UC)
Secondary objectives:

To evaluate the efficacy of mesalamine 4 g extended release granules (sachet) using the 
Clinical and Endoscopic Response Score and the Clinical Response Score subset

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 with remission, defined by the Clinical 
and Endoscopic Response Score at Week 8 (see table below) as a score of:

0 for rectal bleeding 

0 or 1 with at least 1 point decrease from baseline for stool frequency 

0 or 1 for endoscopic score 
The endoscopic score will be determined by an independent central reader.
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CONFIDENTIAL
ENDPOINTS
Key secondary endpoints:
1.
The proportion of subjects with remission in the primary endpoint and the Physician’s 
Global Assessment (PGA) score of <1 (Modified Mayo) at Week 8
2.
Time to cessation of rectal bleeding, defined as time in days from randomization to the first 
day of 3 consecutive days with a rectal bleeding score of 0, based on subject daily diary
Secondary endpoints:
1.
The proportion of subjects with endoscopic improvement, defined as an Endoscopic 
Response Score of 0 or 1, with at least a 1 point reduction from baseline in the endoscopic 
score at Week 8
2.
The proportion of subjects in clinical remission at Weeks 2, 4, and 8, defined as a score of 
0 for rectal bleeding and 0 or 1 with at least 1 point decrease from baseline for stool 
frequency in the Clinical Response Score subset
3.
Time to normal stool pattern, defined as time in days from randomization to the first day of 
3 consecutive days with a stool frequency score of 0, based on subject daily diary
4.
The change from baseline in rectal bleeding score at Weeks 2, 4, and 8, based on subject 
daily diary
5.
The change from baseline in serum CRP levels at Weeks 2, 4, and 8
6.
The change from baseline in fecal calprotectin levels at Week 8
7.
The change from baseline to each scheduled assessment for published and validated domain 
scores of the IBDQ
8.
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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Clinical Trial Protocol
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METHODOLOGY
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, international, 
phase 3 trial to investigate the safety and efficacy of mesalamine 4 g extended release granules 
(sachet) for the induction of clinical and endoscopic remission in subjects with active, mild to 
moderate active UC. Following completion of Visit 0/screening, the subjects will be randomized to 
a treatment group during Visit 1/baseline. Each subject will receive a total of 8 weeks of double-
blind treatment with either:

one mesalamine 4 g extended release granules (sachet) QD (4 g/day) OR

one 4 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. Following randomization, the first dose of investigational 
medicinal product (IMP) will be administered at the site during Visit 1.
Subjects will visit the trial site 4 times during the double-blind part of trial for safety and efficacy 
evaluations:  baseline and Weeks 2, 4, and 8. 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 and PGA will be performed at screening/baseline and Week 8. After 8 
weeks 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 at least 1 
point decrease from baseline, with an endoscopic score of 0 or 1. Whereas, subjects will have only 
a Clinical Response Score assessment at Weeks 2 and 4.
Subjects who discontinue during the double-blind treatment before Week 8 will complete the 
double-blind end-of-treatment assessments and will be treated via investigator’s decision with local 
standard of care, see Section 6.2.4.
Subjects who are found to be worse defined by an increased number of bowel movements [BM], 
blood in the stool, abdominal pain and distention, or clinically relevant changes in laboratory 
chemistry and/or hematology on or after Week 2 will be offered early escape during the trial before 
Week 8 and will be treated by local standard of care. Subjects who complete Week 8 but fail to 
meet the defined criteria for remission will be given an option to receive open-label treatment with 
mesalamine 4 g extended release granules (sachet) for 8 additional weeks in the current trial. If 
subjects do not opt to receive the 8-week open-label mesalamine treatment, they will be treated by 
local standard of care. If subjects opt to receive the additional 8-week open-label mesalamine
treatment, they will continue with daily diary entries and visit the trial site at 10 and 16 weeks, with 
only a Clinical Response Score assessment at Week 10, and a Clinical and Endoscopic Response 
Score assessment performed at Week 16 in order to determine the subject’s eligibility for entry into 
the maintenance trial. 
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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. The flexible sigmoidoscopy/colonoscopy recording during screening will be 
sent to the independent central reader for final determination of eligibility, regardless of the local 
site’s score. A flexible sigmoidoscopy/colonoscopy will also be performed at Weeks 8 and 16 as 
applicable. These recordings will also be sent to the independent central reader for endoscopic 
endpoint scoring. 
Subjects from either treatment group who meet the defined remission criteria after the 8-week 
double-blind treatment period will be allowed to enroll into a double-blind trial investigating 
maintenance therapy of mesalamine 2 g extended release granules (Study 000175). Those subjects 
who do not achieve remission after the 8 additional weeks of open-label treatment will not be 
enrolled into Study 000175 and will be treated with the local standard of care.
NUMBER OF SUBJECTS
Approximately 220 subjects with active, mild to moderate UC will be randomized (110/treatment 
regimen).
CRITERIA FOR INCLUSION / EXCLUSION
Inclusion Criteria:
1. Male or nonpregnant female subjects aged 18 to 75 years 
2. Newly diagnosed or recurrent mild to moderate UC as defined by the Modified Mayo score 
of ≥4 but not >10 and a score of ≥2 for flexible sigmoidoscopy/colonoscopy
3. Extent of colonic involvement as confirmed by flexible sigmoidoscopy; colonoscopy to be 
performed if flexible sigmoidoscopy cannot establish the upper border of UC involvement, 
or at the discretion of the Investigator
4. Negative stool test at screening to rule out parasites, bacterial pathogens, and Clostridium 
difficile. Subjects who test positive for Clostridium difficile can be rescreened if treated and 
Clostridium difficile negative for 2 consecutive 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 at Visit 1 (baseline/randomization)
7. Signed informed consent obtained before any trial-related procedures
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CRITERIA FOR INCLUSION / EXCLUSION (Continued)
Exclusion Criteria:
1. Use of oral 5-aminosalicylic acid (5-ASA) products at a dose >2.5 g/day or topical rectal 
5-ASA within 7 days prior to Visit 1 (use of any 5-ASA during the course of the trial is 
prohibited)
2. Disease limited to proctitis <15 cm 
3. Short bowel syndrome 
4. Prior colon resection surgery 
5. History of severe/fulminant UC
6. Evidence of other forms of inflammatory bowel disease 
7. Infectious disease (including human immunodeficiency virus [HIV], hepatitis B virus 
[HBV], or hepatitis C virus [HCV]) 
8. Intolerant or allergic to aspirin or salicylate derivatives 
9. 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)
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 their participation in the 
trial
16. Participation in a clinical trial with administration of another investigational medicinal 
product within the previous 30 days 
17. Unable to comply with the requirements of the protocol 
18. Unable to complete the subject daily diary or follow data-capturing procedures
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Clinical Trial Protocol
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CONFIDENTIAL
MEDICINAL PRODUCTS
The IMP for the trial will be mesalamine 4 g extended release granules (sachet) and placebo, which 
will be identical in appearance.
DURATION OF TREATMENT
The duration of treatment for each subject will be 8 weeks. Subjects who complete Week 8 but fail 
to meet the defined criteria for remission will be given the option of an additional 8 weeks of 
treatment with open-label mesalamine (4 g/day).
STATISTICAL METHODS
Sample size: The true remission rates at Week 8 for mesalamine 4 g extended release granules 
(sachet) and placebo regimens were assumed as 36% and 18%, respectively, based on Kamm 
(2007),(3) Lichtenstein (2007),(4) and Marteau (2005).(5) Under these assumptions, a sample size 
of 110 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. 
Efficacy: The primary efficacy analysis will be based on all randomized subjects (ITT; intent-to-
treat). The primary efficacy endpoint will be the proportion of subjects who achieved remission, 
defined as rectal bleeding score of 0 and stool frequency score of 0 or 1 with at least 1 point 
decrease from baseline, with an endoscopic score of 0 or 1, in Clinical and Endoscopic Response 
Score at Week 8.
The treatment group difference in the proportion of subjects with remission at Week 8 will be 
assessed by the chi-square test at a two-sided 0.05 significance level. Subjects who discontinue the 
double-blind regimen before Week 8, as well as subjects with missing remission assessment at 
Week 8, will be considered not having achieved remission. The odds ratio will be estimated and its 
95% confidence interval will be provided.
The key secondary endpoints will be analyzed by a fixed-sequence procedure according to the 
pre-specified order to maintain the overall Type 1 error rate to a two-sided 5%.  
If the primary efficacy analysis demonstrates a statistically significant difference between the 
treatment groups, the proportion of subjects with remission in the primary endpoint and the PGA 
score of <1 (Modified Mayo) will be compared using the same statistical method used for the 
primary efficacy analysis. If the analysis for the first key secondary endpoint is statistically 
significant, time to cessation of rectal bleeding, defined as time in days from randomization to the 
first day of 3 consecutive days with a rectal bleeding score of 0 (i.e., the second key secondary 
endpoint), will be compared by the log-rank test at a two-sided 0.05 significance level. 
Other secondary endpoints will be analyzed individually at a two-sided 0.05 significance level.  
The efficacy data captured during the 8-week open-label mesalamine 4 g/day treatment will be used 
for exploratory purposes only. 
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STATISTICAL METHODS (Continued)
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. 
Similar safety data summaries will be made for the open-label treatment period data.
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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 ...................................................................................... 26
4.1
Trial Population....................................................................................................................... 26
4.1.1
Inclusion Criteria ....................................................................................................... 26
4.1.2
Exclusion Criteria ...................................................................................................... 26
4.2
Method of Assigning Subjects to Treatment Groups.............................................................. 27
4.3
Restrictions ............................................................................................................................. 27
4.3.1
Prior and Concomitant Therapies .............................................................................. 27
4.3.2
Prohibited Therapy..................................................................................................... 28
4.3.3
Other Restrictions ...................................................................................................... 28
4.4
Withdrawal Criteria................................................................................................................. 28
5
TREATMENTS ................................................................................................................................. 30
5.1
Treatments Administered........................................................................................................ 30
5.1.1
Investigational Medicinal Product (IMP)................................................................... 30
5.1.2
Non-Investigational Medicinal Product (NIMP) ....................................................... 30
5.2
Characteristics and Source of Supply ..................................................................................... 30
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5.3
Packaging and Labelling......................................................................................................... 30
5.4
Conditions for Storage and Use .............................................................................................. 30
5.5
Blinding / Unblinding ............................................................................................................. 30
5.5.1
Blinding...................................................................................................................... 30
5.5.2
Unblinding of Individual Subject Treatment ............................................................. 31
5.6
Treatment Compliance............................................................................................................ 31
5.6.1
Dispensing and Accountability.................................................................................. 31
5.6.2
Assessment of Compliance........................................................................................ 31
5.7
Return and Destruction of Medicinal Products....................................................................... 32
6
TRIAL PROCEDURES .................................................................................................................... 33
6.1
Trial Flow Chart...................................................................................................................... 33
6.2
Trial Procedures...................................................................................................................... 35
6.2.1
Screening Visit: Visit 0 (up to Day -21) .................................................................... 35
6.2.2
Baseline/Randomization Visit: Visit 1 (Day 1) ......................................................... 37
6.2.3
Intermediate Visits: Visit 2 (Day 15±3) and Visit 3 (Day 29±3)............................... 38
6.2.4
Double-blind End-of-Treatment Visits: Visit 4 (Day 57 -6) and Visit 5 (Day 57 
±3).............................................................................................................................. 38
6.2.5
Open-Label Visit: Visit 6 (Day 71 ±3) ...................................................................... 39
6.2.6
Open-Label End-of-Treatment Visits: Visit 7 (Day 113 -6) and Visit 8 (Day 113 
±3).............................................................................................................................. 40
7
TRIAL ASSESSMENTS ................................................................................................................... 42
7.1
Assessments Related to Endpoints.......................................................................................... 42
7.1.1
Clinical and Endoscopic Response Score and Physician’s Global Assessment ........ 42
7.1.2
Flexible Sigmoidoscopy/colonoscopy ....................................................................... 43
7.1.2.1
Independent Central Endoscopy Laboratory................................................43
7.1.3
Subject Daily Diary.................................................................................................... 44
7.1.4
Serum CRP and Fecal Calprotectin ........................................................................... 44
7.1.5
Health-Related Quality of Life/Collection Pad.......................................................... 44
7.1.6
Adverse Events .......................................................................................................... 44
7.1.7
Clinical Laboratory Variables.................................................................................... 45
7.2
Other Assessments.................................................................................................................. 45
7.2.1
Medical History and Demographic Data ................................................................... 45
7.2.2
Immunological Testing.............................................................................................. 45
7.2.3
Drug and Alcohol History.......................................................................................... 45
7.2.4
Serum/Urine Pregnancy Test ..................................................................................... 46
7.2.5
Screening Stool Sample ............................................................................................. 46
7.2.6
Concomitant Medications .......................................................................................... 46
7.2.7
Physical Examinations............................................................................................... 46
7.2.8
Vital Signs.................................................................................................................. 46
7.2.9
12-Lead Electrocardiogram........................................................................................ 46
7.2.10 Compliance ................................................................................................................ 46
7.3
Drug Concentration Measurements......................................................................................... 47
7.4
Handling of Biological Samples ............................................................................................. 47
8
ADVERSE EVENTS ......................................................................................................................... 48
8.1
Adverse Event Definition........................................................................................................ 48
8.2
Collection and Recording of Adverse Events......................................................................... 48
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8.2.1
Collection of Adverse Events .................................................................................... 48
8.2.2
Recording of Adverse Events .................................................................................... 48
8.3
Pregnancy and Pregnancy Outcome........................................................................................ 51
8.4
Serious Adverse Events .......................................................................................................... 52
8.4.1
Serious Adverse Event Definition.............................................................................. 52
8.4.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 53
8.5
Follow-up of Adverse Events and Serious Adverse Events.................................................... 54
8.5.1
Follow-up of Adverse Events with Onset during the Trial........................................ 54
8.5.2
Collection of Serious Adverse Events with Onset after Last Trial Visit ................... 54
9
STATISTICAL METHODS ............................................................................................................. 55
9.1
Determination of Sample Size ................................................................................................ 55
9.2
Subject Disposition ................................................................................................................. 55
9.3
Protocol Deviations................................................................................................................. 55
9.4
Analysis Sets........................................................................................................................... 55
9.5
Trial Population....................................................................................................................... 56
9.5.1
Demographics and other Baseline Characteristics..................................................... 56
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations................ 56
9.6
Endpoint Assessments............................................................................................................. 56
9.6.1
General Considerations.............................................................................................. 56
9.6.2
Primary Endpoint....................................................................................................... 57
9.6.3
Secondary Endpoints ................................................................................................. 57
9.6.4
Health-related Quality of Life.................................................................................... 59
9.7
Extent of Exposure and Treatment Compliance ..................................................................... 59
9.8
Safety ...................................................................................................................................... 59
9.8.1
General Considerations.............................................................................................. 59
9.8.2
Adverse Events .......................................................................................................... 59
9.8.3
Safety Laboratory Variables ...................................................................................... 60
9.8.4
Other Safety Variables............................................................................................... 61
9.9
Interim Analyses ..................................................................................................................... 61
10
DATA HANDLING ........................................................................................................................... 62
10.1
Source Data and Source Documents....................................................................................... 62
10.2
eCRF ....................................................................................................................................... 62
10.3
Data Management ................................................................................................................... 63
10.4
Provision of Additional Information....................................................................................... 63
11
MONITORING PROCEDURES ..................................................................................................... 64
11.1
Periodic Monitoring................................................................................................................ 64
11.2
Audit and Inspection............................................................................................................... 64
11.3
Confidentiality of Subject Data............................................................................................... 64
12
CHANGES IN THE CONDUCT OF THE TRIAL........................................................................ 66
12.1
Protocol Amendments............................................................................................................. 66
12.2
Deviations from the Protocol .................................................................................................. 66
12.3
Premature Trial Termination................................................................................................... 66
13
REPORTING AND PUBLICATION .............................................................................................. 67
13.1
Clinical Trial Report ............................................................................................................... 67
13.2
Confidentiality and Ownership of Trial Data.......................................................................... 67
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13.3
Publications and Public Disclosure......................................................................................... 67
13.3.1 Publication Policy...................................................................................................... 67
13.3.2 Public Disclosure Policy............................................................................................ 68
14
ETHICAL AND REGULATORY ASPECTS................................................................................. 69
14.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .......................... 69
14.2
Regulatory Authorities Authorization / Approval / Notification ............................................ 69
14.3
End-of-Trial and End-of-Trial Notification ............................................................................ 69
14.4
Ethical Conduct of the Trial.................................................................................................... 69
14.5
Subject Information and Consent............................................................................................ 69
14.6
Compliance Reference Documents......................................................................................... 70
15
LIABILITIES AND INSURANCE .................................................................................................. 71
15.1
ICH-GCP Responsibilities...................................................................................................... 71
15.2
Liabilities and Insurance......................................................................................................... 71
16
ARCHIVING...................................................................................................................................... 72
16.1
Investigator File ...................................................................................................................... 72
16.2
Trial Master File...................................................................................................................... 72
17
REFERENCES................................................................................................................................... 73
APPENDICES............................................................................................................................................... 75
Appendix 1
Inflammatory Bowel Disease Questionnaire (IBDQ)................................................ 76
Appendix 2
Subject Diary Script................................................................................................... 88
LIST OF TABLES 
Table 1:
Schedule of Trial Procedures..........................................................................................34
Table 2:
Clinical and Endoscopic Response Score (0 – 9) ...........................................................42
Table 3:
Physician’s Global Assessment ......................................................................................43
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
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 Harmonization
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
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IVRS
Interactive Voice Response system
LFT
Liver function test
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
NIMP
Non-investigational medicinal product
NSAID
Nonsteroidal anti-inflammatory drug
OL
Open-label
PGA
Physician’s Global Assessment
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
Clinical remission
defined as a score of 0 for rectal bleeding and 0 or 1 with at least 1 point 
decrease from baseline for stool frequency in the Clinical Response Score subset
Endoscopic 
improvement
an endoscopic score of 0 or 1, with at least a 1 point reduction from baseline in 
the endoscopic score 
Modified Mayo score
sum of the Clinical and Endoscopic Response Scores (any friability will be 
scored a 2) and the standard PGA score as in the original Mayo Score
Remission
defined by the 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 
Time to cessation of 
rectal bleeding
time in days from randomization to the first day of 3 consecutive days with a 
rectal bleeding score of 0, based on the subject daily diary
Time to normal stool 
pattern
time in days from randomization to the first day of 3 consecutive days with a 
stool frequency score of 0, based on subject daily diary
Disease Worsening
increased number of bowel movements [BM], increased blood in the stool, 
increased abdominal pain and distention, or clinically relevant changes in 
laboratory chemistry and/or hematology
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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 the treatment of active mild-to-moderate 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 high 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.  The safety and tolerability of various 
mesalamine dosing regimens have been demonstrated. (5,16) The optimum dose of oral 
mesalamine for induction therapy in order to achieve remission is between 2 and 4 g/day. (17)  
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1.2
Scientific Justification for Conducting the Trial
The mesalamine 4 g extended release granules (sachet) is approved in 19 countries worldwide for 
treatment of active mild to moderate ulcerative colitis. The granules are packaged in a foil laminate 
pouch (sachet). The 4 g once-daily (QD) dosing regimen was first approved in The Netherlands in 
2012.
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. 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 suffering patients.
1.3
Benefit / Risk Aspects
The 95% granules allow 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 4 g per day have been diarrhea, nausea, abdominal pain, headache, vomiting, 
and rash. Hypersensitivity reactions and drug fever may occasionally occur.
To mitigate risk, all subjects, including those in the placebo arm, will be offered early escape to 
local standard of care. Notably, all previous 5-ASA registration trials leading to an approval in the 
US utilized a placebo-controlled design.
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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective
The primary objective of this trial is to demonstrate efficacy of mesalamine 4 g extended release
granules (sachet) QD in the induction of clinical and endoscopic remission versus placebo in 
subjects with active, mild to moderate UC.
Secondary Objectives
The secondary objectives of this trial are to:

evaluate the efficacy of mesalamine 4 g extended release granules (sachet) using the 
Clinical and Endoscopic Response Score subsets

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 Week 8, defined by the 
Clinical and Endoscopic Response Score (Table 2) as a score of:

0 for rectal bleeding 

0 or 1 with at least 1 point decrease from baseline for stool frequency

0 or 1 for endoscopic score 
The endoscopic score will be determined by the independent central reader.
Key Secondary Endpoints
Secondary endpoints are the following:
1. The proportion of subjects with remission in the primary endpoint and the Physician’s 
Global Assessment (PGA) score of <1 (Modified Mayo) at Week 8
2. Time to cessation of rectal bleeding, defined as time in days from randomization to the first 
day of 3 consecutive days with a rectal bleeding score of 0, based on subject daily diary
Secondary Endpoints
1. The proportion of subjects with endoscopic improvement, defined as an Endoscopic 
Response Score of 0 or 1, with at least a 1 point reduction from baseline in the endoscopic 
score at Week 8
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2. The proportion of subjects in clinical remission at Weeks 2, 4, and 8, defined as a score of 0 
for rectal bleeding and 0 or 1 with at least 1 point decrease from baseline for stool frequency 
in the Clinical Response Score subset
3. Time to normal stool pattern, defined as time in days from randomization to the first day of 
3 consecutive days with a stool frequency score of 0, based on subject daily diary
4. The change from baseline in rectal bleeding score at Weeks 2, 4, and 8, based on subject 
daily diary
5. The change from baseline in serum CRP levels at Weeks 2, 4, and 8
6. The change from baseline in fecal calprotectin levels at Week 8
7. The change from baseline to each scheduled assessment for published and validated domain 
scores of the IBDQ
8. 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 mesalamine 4 g extended release granules 
(sachet) for the induction of clinical and endoscopic remission in subjects with active, mild to 
moderate UC. Following completion of Visit 0/screening, the subjects will be randomized to 1 of 2
treatment groups during Visit 1/baseline. Each subject will receive a total of 8 weeks of double-
blind treatment with either:

one mesalamine 4 g extended release granules (sachet) QD (4 g/day) OR

one 4 g placebo sachet to match mesalamine extended release granules (sachet)
Doses 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. Following randomization, the first dose of investigational 
medicinal product (IMP) will be administered at the site during Visit 1.
Subjects will visit the trial site 4 times during the double-blind part of trial for safety and efficacy 
evaluations:  baseline and Weeks 2, 4, and 8. 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 and PGA will be performed at screening/baseline and Week 8. After 8 
weeks 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 at least 1 
point decrease from baseline, with an endoscopic score of 0 or 1. Whereas, subjects will have only 
a Clinical Response Score assessment at Weeks 2 and 4.
If subjects discontinue the double-blind treatment before Week 8, the subjects will complete the 
double-blind end-of-treatment assessments and will be treated via investigator’s decision with local 
standard of care. 
Subjects who are found to be worse, defined by an increased number of bowel movements (BM), 
blood in the stool, abdominal pain and distention, or clinically relevant changes in laboratory 
chemistry and/or hematology on or after Week 2 will be offered early escape during the trial before 
Week 8 and will be treated by local standard of care. Subjects who complete Week 8 but fail to 
meet the defined criteria for remission will be given an option to receive open-label treatment with 
mesalamine 4 g extended release granules (sachet) for 8 additional weeks in the current trial. If 
subjects do not opt to receive the 8-week open-label mesalamine treatment, they will be treated by 
local standard of care. If subjects opt to receive the additional 8-week open-label mesalamine
treatment, they will continue with daily diary entries and visit the trial site at 10 and 16 weeks, with 
only a Clinical Response Score assessment at Week 10, and a Clinical and Endoscopic Response 
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Score assessment performed at Week 16 in order to determine the subject’s eligibility for entry into 
the maintenance trial (Study 000175). 
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. The flexible sigmoidoscopy/colonoscopy recording during screening will be 
sent to the independent central reader for final determination of eligibility, regardless of the local 
site’s score. A flexible sigmoidoscopy/colonoscopy will also be performed at Weeks 8 and 16 as 
applicable. These recordings will also be sent to the independent central reader for endoscopic 
endpoint scoring. 
Subjects from either treatment group who meet the defined remission criteria after the 8-week 
double-blind treatment period will be allowed to enroll into a double-blind trial investigating 
maintenance therapy of mesalamine 2 g extended release granules (Study 000175). Those subjects 
who do not achieve remission after the 8 additional weeks of open-label treatment will not be 
enrolled into Study 000175 and will be treated with the local standard of care.
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, 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 third quarter of 2017. For each subject, the total time in trial from screening (within 
21 days before dosing) will be approximately 71 days. For subjects opting to participate in the 
8-week open-label period, the total time in the trial will be approximately 126 days.
3.2
Planned Number of Trial Sites and Subjects
This trial will be conducted at approximately 110 sites in North America and Europe.
Approximately 220 subjects with active, mild to moderate UC will be randomized to receive
mesalamine 4 g extended release granules (sachet) or matching placebo in a 1:1 ratio 
(110/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. Following completion of Visit 0/screening, subjects will be randomized in a 1:1 ratio 
during Visit 1/baseline to receive either mesalamine 4 g extended release granules (sachet) or 
matching placebo.
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 induction of remission ranges from 2.4 g to 
4.8 g/day. In this trial, the sponsor will utilize the 4 g/day dose of mesalamine 4 g extended release 
granules (sachet), which is consistent with the approved dose of the marketed mesalamine product 
for the induction of remission and the treatment of mild to moderate active UC.
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3.5.5
Selection and Timing of Dose for Each Subject
Each subject will be randomized to receive either mesalamine 4 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. Following randomization, the first 
dose of IMP will be administered at the site during Visit 1.
Subjects who do not meet the defined criteria for remission at Week 8 will be given an option to 
receive open-label treatment with mesalamine 4 g extended release granules (sachet) for 
8 additional weeks in the current trial. The first dose of IMP will be administered the day following 
the end of double-blind treatment. If subjects do not opt to receive the 8-week open-label 
mesalamine treatment, they will be treated by local standard of care.
3.5.6
Selection of Trial Population
Subjects with active, newly diagnosed or recurrent, mild to moderate, UC are eligible for enrolment 
in this trial. For more information on eligibility criteria, see Section 4.
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
Subjects whose condition worsens in intensity will be given the option of early escape (on or after 
Week 2 and before Week 8) and will be treated by local standard of care.
If subjects discontinue the double-blind treatment before Week 8, they will complete the 
end-of-treatment assessments and will be treated via investigator’s decision with local standard of 
care.
Subjects who complete Week 8 but fail to meet the defined criteria for remission will be given an 
option to receive open-label treatment with mesalamine 4 g extended release granules (sachet) for 
8 additional weeks in the current trial.
Subjects in protocol defined remission at the end of this 8-week open-label period will be given an 
option to be randomized into the long-term maintenance trial (Study 000175). Those subjects who 
do not achieve the defined criteria for remission after the 8 additional weeks will not be enrolled 
into Study 000175 and will be treated with the local standard of care. 
If subjects who do not meet the defined criteria for remission at Week 8 and do not opt to receive 
the 8-week open-label mesalamine sachet treatment, they will be treated by local standard of care. 
If subjects opt to receive the additional 8-week open-label mesalamine treatment, they will continue 
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with daily diary entries and visit the trial site at 10 and 16 weeks, with a Clinical and Endoscopic 
Response Score assessment performed at Week 16 in order to determine the subject’s eligibility for 
entry into the maintenance trial.
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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
1. Male or nonpregnant female subjects aged 18 to 75 years
2. Newly diagnosed or recurrent mild to moderate UC as defined by Modified Mayo score of 
≥4 but not >10 and a score of ≥2 for flexible sigmoidoscopy/colonoscopy
3. Extent of colonic involvement as confirmed by flexible sigmoidoscopy; colonoscopy to be 
performed if flexible sigmoidoscopy cannot establish the upper border of UC involvement, 
or at the discretion of the Investigator  
4. Negative stool test at screening to rule out parasites, bacterial pathogens, and Clostridium 
difficile. Subjects who test positive for Clostridium difficile can be rescreened if treated and 
Clostridium difficile negative for 2 consecutive 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 at Visit 1 (baseline/randomization)
7. Signed informed consent obtained before any trial-related procedures
4.1.2
Exclusion Criteria
1. Use of oral 5-ASA products at a dose >2.5 g/day or topical rectal 5-ASA within 7 days prior 
to Visit 1 (use of any 5-ASA during the course of the trial is prohibited)
2. Disease limited to proctitis <15 cm 
3. Short bowel syndrome 
4. Prior colon resection surgery 
5. History of severe/fulminant UC
6. Evidence of other forms of inflammatory bowel disease 
7. Infectious disease (including human immunodeficiency virus [HIV], hepatitis B virus 
[HBV], or hepatitis C virus [HCV]) 
8. Intolerant or allergic to aspirin or salicylate derivatives 
9. Taking the following treatments:
a.
Aspirin within 7 days prior to Visit 1 (except for cardioprotective reasons - maximum 
dose 325 mg/day) 
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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)
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 their participation in the trial 
16. Participation in a clinical trial with administration of another investigational medicinal 
product within the previous 30 days 
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).  Re-enrollment of subjects is prohibited under any circumstances.
4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
Subjects may not be taking or have used the following treatments and a washout period will be 
required prior to trial medication administration: 

aspirin within 7 days prior to Visit 1 or during the trial (except for cardioprotective reasons -
maximum dose 325 mg/day) 

oral 5-ASA products at a dose > 2.5 g/day or topical rectal 5-ASA at any dose within 7 days 
prior to Visit 1 (use of any 5-ASA during the course of the trial is prohibited)

rectal formulations (5-ASA, steroids) within 7 days prior to Visit 1 or during the trial
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
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).
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.
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. 
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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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5
TREATMENTS
5.1
Treatments Administered
5.1.1
Investigational Medicinal Product (IMP)
IMPs used in the trial are sachets of either:

mesalamine 4 g extended release granules or

placebo 4 g 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 at least 17 sachets, enough for 
2 weeks’ treatment, including visit windows and will be packaged according the randomization list.
All IMP will be labelled with trial-specific labels and will contain a 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 must 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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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 Weeks 2, 4, and 8 (or at early withdrawal) during the double-blind treatment period, and at 
Week 16 during the open-label period, 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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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 the site’s 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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6
TRIAL PROCEDURES
6.1
Trial Flow Chart
The schedule of trial procedures is presented in Table 1.
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Table 1:
Schedule of Trial Procedures
Double-blind Treatment
Open-label
Treatment (OL)
Screening
Baseline/
Randomization Intermediate Intermediate
End of Double-
blind
Treatment/
Early 
Withdrawal
OL 
Week 2
End of OL
Treatment/
Early 
Withdrawal
Visit
0
1
2
3
4
5
6
7
8
Week
Week -3
Week 0
Week 2
Week 4
Week 8
Week 
10
Week 16
Trial Day
(visit window)
Up to 
Day -21
Day 1
Day 15
(3 days)
Day 29
(3 days)
Day 
57
(-6 
days)
Day 57
(3 
days)
Day 71
(3 
days)
Day 
113
(-6 
days)
Day 
113
(3 
days)
Written informed consent
X
Inclusion/exclusion criteria review
X
X
Medical history
X
X
Physical examination, including 
weight
X
X
X
X
X
X
X
Height
X
Vital signs
X
X
X
X
X
X
X
12-lead electrocardiogram
X
X
X
Demographic data
X
Serum/urine pregnancy testa
X
X
X
X
Drug and alcohol history
X
Immunological testing for HBV,
HCV, and HIV
X
Estimated creatinine clearance
Xb
X
X
X
X
Safety hematology, coagulation, 
and chemistry
Xb
Xj
Xi
X
Xj
Xi
X
Standard urinalysisc
Xb
X
X
X
X
Stool sample 
Xb
Randomization
X
Prior and concomitant medications
X
X
X
X
X
X
X
Serum CRP
X
X
X
X
X
X
Fecal calprotectin stool sample 
X
X
X
Clinical Response Score (stool 
frequency and rectal bleeding 
scores)
X
X
X
X
X
X
Flexible Sigmoidoscopy
/colonoscopy -Central reading
Xd
X
X
Calculation of Clinical and 
Endoscopic Response Score 
X
X
X
Calculation of Modified Mayo 
score
X
X
Physician’s Global Assessment
X
X
HRQoL questionnaire: IBDQ
X
X
X
X
X
X
Adverse event recordinge
X
X
X
X
X
X
X
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Double-blind Treatment
Open-label
Treatment (OL)
Screening
Baseline/
Randomization Intermediate Intermediate
End of Double-
blind
Treatment/
Early 
Withdrawal
OL 
Week 2
End of OL
Treatment/
Early 
Withdrawal
Visit
0
1
2
3
4
5
6
7
8
Week
Week -3
Week 0
Week 2
Week 4
Week 8
Week 
10
Week 16
Trial Day
(visit window)
Up to 
Day -21
Day 1
Day 15
(3 days)
Day 29
(3 days)
Day 
57
(-6 
days)
Day 57
(3 
days)
Day 71
(3 
days)
Day 
113
(-6 
days)
Day 
113
(3 
days)
Distribution of trial medication
X
X
X
Xf
First administration of trial 
medicationg
X
X
Trial medication
collection/accountability
X
X
X
X
Trial medication compliance 
X
X
X
X
Subject diary activation
X
Subject diary data reviewh
X
X
X
X
X
Note: All subjects who discontinue treatment (double-blind or open-label) will complete end-of-treatment assessments.
a
For females of childbearing age or <1 year postmenopausal; if positive, the subject will not be enrolled in the trial. At 
screening, perform serum pregnancy test and at baseline and end of treatment (double-blind or open-label), perform 
urine pregnancy test. If the urine pregnancy test is positive at the end of double-blind treatment, the subject will not be 
enrolled in the open-label treatment period.
b
Results must be available at randomization, Visit 1.
c
If positive for blood, leucocytes, or nitrite microscopic urinalysis will be performed.
d
Baseline flexible sigmoidoscopy/colonoscopy will be scheduled during screening and must be completed after Clinical 
Response Score (Visit 0).  It should be scheduled to occur no more than 10 days but at least 4 days prior to 
randomization (Visit 1) to allow sufficient time for the central reading. A colonoscopy will be required to establish the 
extent of disease if the flexible sigmoidoscopy is not conclusive in establishing the upper border of UC involvement.
e
Adverse events are collected from the signing of informed consent.
f
Open-label trial medication will be distributed for subjects entering the open-label treatment period only.  
g
Double-blind trial medication first dose to be taken on Visit 1 Day 1; open-label trial medication first dose to be taken 
the day following the end of double-blind treatment visit.
h
Subject daily diary data will be collected electronically and daily diary compliance will be assessed.
i
Only liver function tests and hematology.
j
No coagulation panel.
6.2
Trial Procedures
6.2.1
Screening Visit: Visit 0 (up to Day -21)
Screening procedures are to be performed within 21 days prior to the first dose of trial drug. 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: 
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
written informed consent

review of inclusion/exclusion criteria 

medical history

Clinical Response Score (based on recall data of stool frequency and rectal bleeding in the last 
3 days)

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 

history of drug and alcohol use 

HBV, HCV, and HIV testing

estimated creatinine clearance

clinical safety laboratory assessment: chemistry, hematology, coagulation, standard urinalysis

stool sample to test for parasites, bacterial pathogens, and Clostridium difficile 

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:

aspirin within 7 days prior to Visit 1 or during the trial (except for cardioprotective 
reasons - maximum dose 325 mg/day) 

oral 5-ASA products at a dose >2.5 g/day or topical rectal 5-ASA within 7 days prior to 
Visit 1 (use of any 5-ASA during the course of the trial is prohibited)

rectal formulations (5-ASA, steroids) within 7 days prior to Visit 1 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)

assessment of any AEs occurring after informed consent is signed
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
flexible sigmoidoscopy/colonoscopy will be scheduled during screening and completed after 
Clinical Response Score. It should be scheduled to occur no more than ten (10) days but at least 
four (4) days prior to randomization to allow sufficient time for the central reading

colonoscopy will be required to establish the extent of disease if the flexible sigmoidoscopy is 
not conclusive in establishing the upper border of UC involvement 

flexible sigmoidoscopy/colonoscopy recording will be sent to the independent central reader for 
assessment and qualifying scoring, regardless of the local site’s score
6.2.2
Baseline/Randomization Visit: Visit 1 (Day 1) 
The following will be performed/collected at Visit 1: 

review of inclusion/exclusion criteria 

review/update medical history, including history and frequency of rectal bleeding

physical examination, including weight

vital signs (blood pressure and pulse rate)

urine pregnancy testing (test strip) for females of childbearing age or <1 year postmenopausal

prior and concomitant medication review since Visit 0

calculation of Clinical and Endoscopic Response Score (Table 2). The score for stool frequency 
and rectal bleeding will be calculated based on scores collected from 3 day subject recall at 
Visit 0

PGA

calculation of Modified Mayo score by the investigator to determine eligibility for entering the 
trial. The score for stool frequency and rectal bleeding will be calculated based on scores 
collected from 3 day subject recall at Visit 0

assessment of any AEs since Visit 0 
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

IBDQ 

serum CRP and fecal calprotectin levels

randomized, blinded trial medication distribution
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The subject administers first dose of IMP at the site, with instructions to administer the IMP at least 
1 hour before or at least 2 hours after a meal at approximately the same time each day.
6.2.3
Intermediate Visits: Visit 2 (Day 15±3) and Visit 3 (Day 29±3)
The following will be performed/collected at Visits 2 and 3: 

physical examination, including weight

vital signs (blood pressure and pulse rate)

concomitant medication review

estimated creatinine clearance (Visit 2 only)

clinical safety laboratory assessment:  chemistry, hematology, standard urinalysis only (Visit 2 
only)

serum CRP level

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

collection and distribution of trial medication

review of subject daily diary data including compliance

trial medication compliance assessment 
6.2.4
Double-blind End-of-Treatment Visits: Visit 4 (Day 57 -6) and Visit 5 (Day 57 ±3)
The following will be performed/collected at Visit 4 (Day 57 – 6) or early withdrawal: 

estimated creatinine clearance 

clinical safety laboratory assessment: liver function tests (LFTs) and hematology

Clinical Response Score (Table 2), based on subject recording of stool frequency and rectal 
bleeding in the daily diary 

flexible sigmoidoscopy/colonoscopy (at least 4 days prior to Visit 5 to allow sufficient time for 
the central reading)

submit flexible sigmoidoscopy/colonoscopy recording to the independent central reader
The following will be performed/collected at Visit 5 (Day 57 ±3) or early withdrawal: 
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
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; 
if positive, the subject will not be able to continue into the open-label period or Study 000175

clinical safety laboratory assessment: chemistry, hematology, coagulation, standard urinalysis

serum CRP and fecal calprotectin levels

concomitant medication review

calculation of Clinical and Endoscopic Response Score (Table 2). 

PGA

calculation of Modified Mayo score

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 
for subjects not entering open-label period

trial medication compliance assessment 
At the end of Week 8, all subjects who do not meet the defined criteria for remission at Week 8 will be 
given an option to receive open-label treatment with mesalamine 4 g extended release granules (sachet) 
for 8 additional weeks in the current trial. IMP will be distributed and subjects will receive instructions 
on the administration of the trial medication. The first dose of IMP will be administered the day 
following the end of double-blind treatment visit. The IMP will be taken at least 1 hour before or at 
least 2 hours after a meal at approximately the same time each day during the open-label period.
6.2.5
Open-Label Visit: Visit 6 (Day 71 ±3)
The following will be performed/collected at Visit 6: 

physical examination, including weight

vital signs (blood pressure and pulse rate)

clinical safety laboratory assessment: chemistry, hematology, standard urinalysis only

concomitant medication review
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
serum CRP 

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 

review of subject daily diary data including compliance
6.2.6
Open-Label End-of-Treatment Visits: Visit 7 (Day 113 -6) and Visit 8 (Day 113 ±3)
The following will be performed/collected at Visit 7 (Day 113 – 6) or early withdrawal: 

estimated creatinine clearance 

clinical safety laboratory assessment: liver function tests (LFTs) and hematology

Clinical Response Score (Table 2), based on subject recording of stool frequency and rectal 
bleeding in the daily diary 

flexible sigmoidoscopy/colonoscopy (at least 4 days prior to Visit 8 to allow sufficient time for 
the central reading)

submit flexible sigmoidoscopy/colonoscopy recording to the independent central reader
The following will be performed/collected at Visit 8 (Day 113 +3) or early withdrawal:

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 
(if positive, the subject will not be enrolled in Study 000175)

clinical safety laboratory assessment: chemistry, hematology, coagulation, standard urinalysis

concomitant medication review

serum CRP and fecal calprotectin levels

calculation of Clinical and Endoscopic Response Score (Table 2). 

IBDQ

assessment of any AEs since the previous visit 

collection of trial medication 
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
review of subject daily diary data including compliance, and deactivation of subject daily diary

trial medication compliance assessment 
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7
TRIAL ASSESSMENTS
7.1
Assessments Related to Endpoints
7.1.1
Clinical and Endoscopic Response Score and Physician’s Global Assessment
The Clinical and Endoscopic Response Score will be determined, as shown in Table 2.
The Modified Mayo score will be calculated as the sum of the Clinical and Endoscopic Response 
Scores (Table 2) and the PGA score (Table 3). 
The Endoscopic Response Score will be determined by flexible sigmoidoscopy/colonoscopy as scored 
by the independent central reader (Section 7.1.2).
The scores on stool frequency and rectal bleeding will be obtained from the subject electronic daily 
diary, with the exception of screening which will be based on subject recall (Section 7.1.3). 
The Modified Mayo score will be calculated by the investigator at baseline/randomization, and at the 
end of double-blind treatment (Week 8 or early withdrawal).
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.
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Table 3:
Physician’s Global Assessment
Severity
Score
Normal
0
Mild disease
1
Moderate disease
2
Severe disease
3
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 (no more than 10 days but at least 4 days prior to randomization to allow sufficient 
time for the central reading), the end of double-blind treatment (Week 8 or early withdrawal), and at 
the end of open-label treatment. 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 disease (marked erythema, absent vascular pattern, any friability, erosions), 
and 3 = severe disease (spontaneous bleeding, ulceration). The flexible sigmoidoscopy/colonoscopy
recording during screening will be sent to the independent central reader for final determination of 
eligibility, regardless of the local site’s score. A flexible sigmoidoscopy/colonoscopy will also be 
performed at Weeks 8 and 16 as applicable. These recordings will also be sent to the independent 
central reader for endoscopic endpoint scoring. A colonoscopy will be required to establish the extent 
of disease if the flexible sigmoidoscopy is not conclusive in establishing the upper border of UC 
involvement. 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 and colonoscopies (if required), will be performed in a standardized 
manner. The endoscopy completed during screening (no more than 10 days but at least 4 days prior to 
randomization to allow sufficient time for the central reading), at Week 8 (end of double-blind 
treatment/early withdrawal), and Week 16 (end of open-label treatment/early withdrawal) will be sent 
to the independent central reader selected by the sponsor. The screening result will be used to qualify 
the image for use in randomization. Image handling and instructions will be provided to all sites 
directly from the independent central laboratory. 
The endoscopic qualifying score will be automatically uploaded to the eCRF. 
Trial sites will be provided with endoscopic laboratory recording equipment, supplies, and manuals. 
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7.1.3
Subject Daily Diary
The subject daily diary will be completed by the subject every evening starting the day of 
randomization (Visit 1/Day 1). 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 3 day subject recall at Visit 0 or from subject 
diary data 5 days prior to Visits 2, 3, 4, 6 and 7 (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. 
7.1.4
Serum CRP and Fecal Calprotectin
Serum CRP levels will be determined at baseline and Visits 2 (Week 2), 3 (Week 4), 5 (Week 8) 
during the double-blind treatment period, and at Visits 6 (Week 10) and 8 (Week 16) during the open-
label treatment period. Fecal calprotectin levels will be determined at baseline and at Visit 5 (Week 8) 
of the double-blind treatment period and at Visit 8 (Week 16) of the open-label treatment period.
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. (18) 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, prior to all other trial-related procedures at the site at Visit 2 (Week 2), Visit 3 (Week 
4), and Visit 5 (Week 8) (or early withdrawal) during the double-blind treatment period, and at Visits 6 
(Week 10) and 8 (Week 16) during the open-label treatment period (after randomization but before 
IMP administration).  At Visit 1, subjects must first be randomized before completion of the IBDQ.
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.
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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), 
Visits 4 and 5 (Week 8) or at early withdrawal during the double-blind treatment period, Visit 6 
(Week 10) and Visits 7 and 8 (Week 16) during the open-label treatment period. 
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
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 1). Disease specific and general medical history will be 
recorded in the eCRF.
7.2.2
Immunological Testing
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
At Visit 0 (screening), a drug and alcohol history evaluation will be performed by the investigator. 
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7.2.4
Serum/Urine Pregnancy Test
A serum pregnancy test will be performed at Visit 0 (screening). A urine pregnancy test will be 
performed at Visit 1 (baseline/Day 1) and Visit 5 (Week 8) or early withdrawal during the double-blind 
treatment period and at Visit 8 (Week 16) of the open-label treatment period (Table 1). Negative results 
are required for admission to each period.
7.2.5
Screening Stool Sample 
A stool sample will be obtained at screening to rule out parasites, bacterial pathogens, and Clostridium 
difficile. Subjects who test positive for Clostridium difficile can be rescreened if treated and 
Clostridium difficile negative for 2 consecutive months.
7.2.6
Concomitant Medications
Concomitant medication information will be collected at every trial visit during the double-blind and 
open-label treatment periods (Table 1).
7.2.7
Physical Examinations
At the screening visit (Visit 0), physical examination with height and weight will be performed. Height 
will be measured at the screening visit only. Physical examination with weight will be performed at 
Visit 1 (baseline/Day 1), Visit 2 (Week 2), Visit 3 (Week 4), and at the end of double-blind treatment 
Visit 5 (Week 8 [or at early withdrawal]), as well as during open-label treatment period Visits 6 and 8 
(Weeks 10 and 16 [or at early withdrawal]) (Table 1). Any clinically significant deterioration from 
baseline will be recorded as an AE. 
7.2.8
Vital Signs
Vital signs will be measured at each trial visit except Visits 4 and 7 (Table 1). 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.
7.2.9
12-Lead Electrocardiogram
A 12-lead ECG will be obtained at Visit 0 (screening) and Visit 5 (Week 8) or at early withdrawal 
during the double-blind treatment period and at Week 16 (or at early withdrawal) of the open-label 
treatment period (Table 1). The 12-lead ECG will be obtained after at least a 5-minute rest in a supine 
position.
7.2.10
Compliance
Trial medication and subject daily diary compliance will be assessed at Visit 2 (Week 2), Visit 3 
(Week 4), and Visit 5 (Week 8) or at early withdrawal during the double-blind treatment period and at 
Visit 8 (Week 16 [or at early withdrawal]) during the open-label treatment period (Table 1).  Subject 
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daily diary compliance will also be assessed at Visit 6 (Week 10) during the open-label treatment 
period.
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
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
date and time of onset (time can be omitted, if applicable)

intensity

causal relationship to IMP

action taken to IMP

other action taken

date and time of outcome (time can be omitted, if applicable)

outcome

seriousness
Each of the items in the 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. 
                                                
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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Intensity
The intensity of an AE must be classified using the following 3-point scale:
Mild:
awareness of signs or symptoms, but no disruption of usual activity
Moderate:
event sufficient to affect usual activity (disturbing)
Severe:
inability to work or perform usual activities (unacceptable)
Causal Relationship to IMP
The possibility of whether the IMP caused the AE must be classified as 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
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
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.
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 that 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 Week 8 for mesalamine 4 g extended release granules (sachet) and placebo 
regimens were assumed as 36% and 18%, respectively, based on Kamm (2007) (3), Lichtenstein 
(2007) (4), and Marteau (2005).(5) Under these assumptions, a sample size of 110 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.
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 double-blind period of the trial will be summarized with the reason of 
premature discontinuations. Similar summaries will be made for subjects who are enrolled to the 8-
week open-label period.
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 of 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: 

Intent-to-Treat (ITT) analysis set:  Includes all randomized subjects
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
Modified ITT (mITT) analysis set: Includes all randomized subjects who receive at least 1 dose 
of IMP 

Per protocol (PP) analysis set: Includes all randomized subjects who receive at least 1 dose of 
IMP and who do not have any of the major protocol deviations

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 ITT and mITT 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 of 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 
number and percentage of subjects with each qualitative characteristic. Missing values will not be 
included in the calculation of percentages.
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All data will be listed by individual subject and trial visit.
The efficacy data captured during the 8-week open-label mesalamine 4g/day treatment will be 
descriptively summarized and used for exploratory purposes only.  
9.6.2
Primary Endpoint
The primary efficacy analysis will be based on all randomized subjects (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 at least 1 point decrease from baseline, with an endoscopic score of 0 or 1 in the Clinical 
and Endoscopic Response Score at Week 8, will be compared between treatment groups using the chi-
square test at a two-sided 0.05 significance level. Subjects who discontinue the double-blind regimen 
before Week 8, as well as subjects with missing remission assessment at Week 8, will be considered 
not having achieved remission. 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 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 Week 8

Analysis using pattern mixture models for missing remission assessment at Week 8
9.6.3
Secondary Endpoints
Key secondary endpoints are the following:
1. The proportion of subjects with remission in the primary endpoint and the PGA score of 
<1 (Modified Mayo) at Week 8
2. Time to cessation of rectal bleeding, defined as time in days from randomization to the first day
of 3 consecutive days with a rectal bleeding score of 0, based on subject daily diary
Secondary endpoints are the following:
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1. The proportion of subjects with endoscopic improvement, defined as an Endoscopic Response 
Score of 0 or 1, with at least a 1 point reduction from baseline in the endoscopic score at Week 
8
2. The proportion of subjects in clinical remission at Weeks 2, 4, and 8, defined as a score of 0 for 
rectal bleeding and 0 or 1 with at least 1 point decrease from baseline for stool frequency in the 
Clinical Response Score subset
3. Time to normal stool pattern, defined as time in days from randomization to the first day of 
3 consecutive days with a stool frequency score of 0, based on subject daily diary
4. The change from baseline in rectal bleeding score at Weeks 2, 4, and 8, based on subject daily 
diary
5. The change from baseline in serum CRP levels at Weeks 2, 4, and 8
6. The change from baseline in fecal calprotectin level at Week 8
7. The change from baseline to each scheduled assessment for published and validated domain 
scores of the IBDQ
8. Safety, assessed by incidence and severity of AEs and abnormal laboratory values
The key secondary endpoints will be analyzed by a fixed-sequence procedure according to the 
pre-specified order to maintain the overall Type 1 error rate to a two-sided 5%. 
If the primary efficacy analysis demonstrates a statistically significant difference between the treatment 
groups, the first key secondary endpoint will be compared using the same statistical method used for 
the primary efficacy analysis at a two-sided 0.05 significance level. If the analysis for the first key 
secondary endpoint is statistically significant, the second key secondary endpoint will be compared by 
the log-rank test at a two-sided 0.05 significance level.
Other secondary endpoints will be analyzed individually at a two-sided 0.05 significance level.
The proportion of subjects with endoscopic improvement will be analyzed using the same statistical 
method used for the primary efficacy analysis.
The proportion of subjects in clinical remission at Weeks 2, 4, and 8 will be analyzed by the 
generalized estimating equations approach as longitudinal binary outcomes. The model will include 
treatment, time, and treatment- by-time interaction. The clinical remission rates and odds ratios will be 
estimated for each time point. 
The time to normal stool pattern will be analyzed using the same statistical method used for the 
analysis of the time to cessation of rectal bleeding.
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The change from baseline in rectal bleeding score and serum CRP levels at Weeks 2, 4 and 8 will be 
analyzed by repeated-measures analysis of covariance (ANCOVA) models that include treatment, time, 
and treatment-by-time interaction as fixed effects, and the corresponding 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. The change from baseline in the fecal calprotectin level at 
Week 8 will be analyzed by an ANCOVA model that includes treatment as a factor and baseline value 
at a covariate.
The efficacy data captured during the 8-week open-label mesalamine 4 g/day treatment period, will be 
used for exploratory purposes only.
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 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 during the double-blind period 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. Similar safety data summaries will be 
made for the open-label treatment period data.
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 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.
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).
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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 treatment-emergent 
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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 Harmonization (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 
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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.
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 
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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. The 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.
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13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is the 
responsibility of Ferring to register the trial in an appropriate public registry, i.e.,
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 
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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.
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
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Marteau P, Probert CS, Lindgren S, Gassul M, Tan TG, Dignass A, et al. Combined oral 
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Carter MJ, Lobo AJ, Travis SP; IBD Section, British Society of Gastroenterology. 
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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
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Marshall JK, Irvine EJ. Rectal aminosalicylate therapy for distal ulcerative colitis: a 
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Marshall JK, Irvine EJ. Putting rectal 5-aminosalicylic acid in its place: the role in distal 
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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. 
Riley SA. (1998). What dose of 5-aminosalicylic acid (mesalazine) in ulcerative colitis? 
Gut. 1998;42(6):761-3.
18. 
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 movements 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 4 g extended release 
granules (sachet) for the induction of clinical and endoscopic remission in 
active, mild to moderate ulcerative colitis 
NCT number: 
NCT02522767 
Sponsor trial code: 
000174  
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 4 g Extended Release Granules (Sachet) for the Induction 
of Clinical and Endoscopic Remission in Active, Mild to Moderate Ulcerative Colitis
000174
Investigational Product:
Mesalamine 4 g Extended Release Granules (Sachet)
Indication:
Induction of clinical and endoscopic remission in active, mild 
to moderate 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
o
Added modified ITT analysis set to 
the sensitivity analysis
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 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 objectives ................................................................................................... 8
2.2
Endpoints .................................................................................................................................. 8
2.2.1
Primary endpoint.......................................................................................................... 8
2.2.2
Key secondary endpoints ............................................................................................. 9
2.2.3
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
Intention-To-Treat Analysis Set.............................................................................................. 14
6.2
Modified Intention-To-Treat Analysis Set.............................................................................. 14
6.3
Per Protocol Analysis Set........................................................................................................ 14
6.4
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)............................................................................................................ 21
9.3.1
Key Secondary Endpoints.......................................................................................... 21
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9.3.2
Other Secondary Endpoints ....................................................................................... 21
9.4
Other Endpoint(s).................................................................................................................... 22
9.4.1
Health Related Quality of Life................................................................................... 22
9.4.2
Efficacy Endpoints During 8-week Open-label Trial Period..................................... 23
10
Safety................................................................................................................................................... 24
10.1
General Considerations........................................................................................................... 24
10.2
Adverse Events ....................................................................................................................... 24
10.2.1 Overview of Treatment-Emergent Adverse Events................................................... 24
10.2.2 Incidence of Adverse Events...................................................................................... 24
10.3
Safety Laboratory Variables ................................................................................................... 25
10.3.1 Summary Statistics..................................................................................................... 25
10.3.2 Laboratory Variable Changes Relative to Normal Range.......................................... 26
10.3.3 Markedly Abnormal Changes.................................................................................... 26
10.3.4 Data Listings.............................................................................................................. 26
10.4
Vital Signs and ECG............................................................................................................... 26
10.4.1 Vital Signs.................................................................................................................. 26
10.4.1.1
Summary Statistics..................................................................................27
10.4.1.2
Markedly Abnormal Changes..................................................................27
10.4.1.3
Data Listings............................................................................................27
10.4.2 ECGs.......................................................................................................................... 27
10.4.2.1
Summary Statistics..................................................................................28
10.4.2.2
Markedly Abnormal Changes..................................................................28
10.4.2.3
Data Listings............................................................................................28
11
Interim analyses................................................................................................................................. 29
12
Deviations from protocol analysis .................................................................................................... 30
13
References........................................................................................................................................... 31
14
Tables, Listings and Figures ............................................................................................................. 33
Markedly Abnormal Laboratory Safety Values, Vital Signs and ECGs ......................... 34
Schedule of Trial Procedures............................................................................................... 36
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1
Introduction
This document describes the planned statistical analyses for Study 000174 based on the 
Consolidated Protocol Incorporating Amendments 1.0, 2.0, 3.0, and 4.0 dated January 11, 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
BM
Bowel movement
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
OL
Open label
PGA
Physician’s global assessment
PMM
Pattern mixture model
PP
Per protocol
PT
Preferred term
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Abbreviations
Meaning of abbreviations in document
QD
Once daily
QTc
Corrected QT interval
SOC
System organ class
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 efficacy of mesalamine 4 g extended release granules (sachet) once daily 
(QD) in the induction of clinical and endoscopic remission versus placebo in subjects with 
active, mild to moderate ulcerative colitis (UC)
2.1.2
Secondary objectives

To evaluate the efficacy of mesalamine 4 g extended release granules (sachet) using the 
Clinical and Endoscopic Response Score and the Clinical Response Score subset

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 with remission, defined by the Clinical 
and Endoscopic Response Score (Table 1) at Week 8 as a score of,

0 for rectal bleeding, and

“0” or “1 with at least 1 point decrease from baseline” 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
Key secondary endpoints
1. The proportion of subjects with remission in the primary endpoint and the Physician’s 
Global Assessment (PGA) score of ≤1 (Modified Mayo) at Week 8 
2. Time to cessation of rectal bleeding, defined as time in days from randomization to the first 
day of 3 consecutive days with a rectal bleeding score of 0, based on subject daily diary
2.2.3
Secondary endpoints

The proportion of subjects with endoscopic improvement, defined as an Endoscopic 
Response Score of 0 or 1, with at least a 1 point reduction from baseline in the endoscopic 
score at Week 8

The proportion of subjects in clinical remission at Weeks 2, 4, and 8, defined as a score of 0 
for rectal bleeding and “0” or “1 with at least 1 point decrease from baseline” for stool 
frequency in the Clinical Response Score subset

Time to normal stool pattern, defined as time in days from randomization to the first day of 
3 consecutive days with a stool frequency score of 0, based on subject daily diary

The change from baseline in rectal bleeding score at Weeks 2, 4, and 8, based on subject 
daily diary
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
The change from baseline in serum CRP levels at Weeks 2, 4, and 8

The change from baseline in fecal calprotectin levels at Week 8

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
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 4 g extended release granules 
(sachet) for the induction of clinical and endoscopic remission in subjects with active, mild to 
moderate active UC. Following completion of Visit 0/screening, the subjects will be randomized to 
a treatment group during Visit 1/baseline. Each subject will receive a total of 8 weeks of double-
blind treatment with either:

one mesalamine 4 g extended release granules (sachet) QD (4 g/day) OR

one 4 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. Following randomization, the first dose of investigational 
medicinal product (IMP) will be administered at the site during Visit 1.
Subjects will visit the trial site 4 times during the double-blind part of trial for safety and efficacy 
evaluations:  baseline and Weeks 2, 4, and 8. 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 and PGA will be performed at screening/baseline and Week 8. After 8 
weeks 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 at least 1 
point decrease from baseline”, with an endoscopic score of 0 or 1. Whereas, subjects will have only 
a Clinical Response Score assessment at Weeks 2 and 4. 
Subjects who discontinue during the double-blind treatment before Week 8 will complete the 
double-blind end-of-treatment assessments and will be treated via investigator’s decision with local 
standard of care. 
Subjects who are found to be worse defined by an increased number of bowel movements [BM], 
blood in the stool, abdominal pain and distention, or clinically relevant changes in laboratory 
chemistry and/or hematology on or after Week 2 will be offered early escape during the trial before 
Week 8 and will be treated by local standard of care. Subjects who complete Week 8 but fail to 
meet the defined criteria for remission will be given an option to receive open-label treatment with 
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mesalamine 4 g extended release granules (sachet) for 8 additional weeks in the current trial. If 
subjects do not opt to receive the 8-week open-label mesalamine treatment, they will be treated by 
local standard of care. If subjects opt to receive the additional 8-week open-label mesalamine 
treatment, they will continue with daily diary entries and visit the trial site at 10 and 16 weeks, with 
only a Clinical Response Score assessment at Week 10, and a Clinical and Endoscopic Response 
Score assessment performed at Week 16 in order to determine the subject’s eligibility for entry into 
the maintenance trial. 
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. 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. A flexible sigmoidoscopy will also be performed at Weeks 8 and 
16 as applicable. These recordings will be sent to the independent central reader for endoscopic 
endpoint scoring. 
Subjects from either treatment group who meet the defined remission criteria after the 8 week 
double-blind treatment period will be allowed to enroll into a double-blind trial investigating 
maintenance therapy of mesalamine 2 g extended release granules (Study 000175). Those subjects 
who do not achieve remission after the 8 additional weeks of open-label treatment will not be 
enrolled into Study 000175 and will be treated with the local standard of care.
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 8 weeks of 
treatment. Subjects who achieve remission after the 8-week treatment will be allowed to enroll into 
a maintenance trial (Study 000175). To increase the number of subjects who continues to the 
maintenance trial from the current trial, an additional 8-week open-label mesalamine treatment 
period will be offered to subjects who complete Week 8 but fail to meet the defined criteria for 
remission. 
The endoscopic score will be determined by an independent central reader.
3.2
Determination of Sample Size
The true remission rates at Week 8 for mesalamine 4 g extended-release granules (sachet) and 
placebo regimens were assumed as 36% and 18%, respectively, based on Kamm et al. (2007)(3), 
Lichtenstein et al. (2007)(4), and Marteau et al. (2005)(5). Under these assumptions, a sample size 
of 110 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.
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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 double-blind period of the trial will be summarized with the reason 
of premature discontinuations. Similar summaries will be made for subjects who are enrolled to the 
8-week open-label period.
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% during the double-blind period

Not taking the randomized IMP

Taking prohibited medications during the double-blind period
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
Intention-To-Treat Analysis Set
The intention-to-treat (ITT) analysis set includes all randomized subjects. Analyses for the ITT 
analysis set will be conducted according to the randomized treatment regardless of the actual 
treatment received. 
6.2
Modified Intention-To-Treat Analysis Set
The modified intention-to-treat (mITT) analysis set includes all randomized subjects who receive at 
least one dose of IMP. Analyses for the mITT analysis set will be conducted according to the 
randomized treatment regardless of the actual treatment received.
6.3
Per Protocol Analysis Set
The Per-protocol (PP) analysis set includes all randomized subjects who receive at least one dose of 
IMP and who do not have any of the major protocol deviations defined in Section 5.
6.4
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.
Concomitant medications used during the double-blind period will be identified. 
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. The summaries will be made for the double-blind 
period only, open-label period only, and combined double-blind and open-label periods. The 
combined summary will be made only for the exposure to mesalamine.  
Following categorical summaries will be made for the double-blind period only:

< 14 days, 14 - < 28 days, 28 - <42 days, 42 - <56 days, and 56 days or more

At least 1 day, at least 14 days, at least 28 days, at least 42 days, and at least 56 days
8.2
Treatment Compliance 
The overall compliance during the double-blind period 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. 
Statistical tests for the primary and key secondary endpoints will be conducted using a fixed-
sequence procedure according to the pre-specified order to maintain the overall Type I error rate to 
a two-sided 5%. All other secondary endpoints will be tested without adjustment for multiplicity.
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).
The average scores will be calculated at Visit 2 (Week 2), Visit 3 (Week 4), and Visit 4 (Week 8)
for the double-blind period, and Visit 6 (Week 10) and Visit 7 (Week 16) for the open-label period. 
Although both Visit 4 and Visit 5 are designated as Week 8 in the double-blind period, Visit 4 
corresponds to the visit for the endoscopic assessment, and therefore, the stool frequency and rectal 
bleeding scores will be calculated at Visit 4. Similarly, the scores will be calculated at Visit 7 for 
the end of the open-label period instead of at Visit 8. 
However, in one section (Section 7.1.3) of Protocol Amendment 2, it was unintentionally indicated 
that the scores would be calculated at Visit 5 and Visit 8 instead of Visit 4 and Visit 7. As a result, 
some of these subjects completed the diary fewer than 3 days within 5 days prior to Visit 4 and/or 
Visit 7 but completed 3 or more days prior to Visit 5 and/or Visit 8. Therefore, for those subjects 
who consented with Protocol Amendment 2, the average scores calculated at Visit 5 and/or Visit 8, 
as indicated in Section 7.1.3 of Protocol Amendment 2, will be used if the average scores at Visit 4 
and/or Visit 7 are missing. Handling of other 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 and Table 3 show the 
scheduled trial day and window for each analysis visit during the double-blind period and open-
label period, respectively.
Table 2
Scheduled trial day and window for analysis visits: double-blind period
Analysis visit
Scheduled trial day
Window
Baseline
Day 1
prior to the first dose of IMP
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Week 2
Day 15
Day 1 to Day 22
Week 4
Day 29
Day 23 to Day 43
Week 8
Day 57
Day 44 or after, but before 1st dose of OL period
OL: open label
Table 3
Scheduled trial day and window for analysis visits: open-label period
Analysis visit
Scheduled trial day
Window
Week 10
Day 71
After 1st dose of OL period up to Day 92
Week 16
Day 113
Day 93 or after
OL: open label 
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. 
The efficacy data captured during the 8-week open-label period will be descriptively summarized 
and used for exploratory purposes only.
9.2
Primary Endpoint(s)
9.2.1
Primary Variable(s) Analysis
The primary efficacy analysis will be based on all randomized subjects (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 at least 1 point decrease from baseline” with an endoscopic score of 0 or 1 
in the Clinical and Endoscopic Response Score at Week 8, will be compared between treatment 
groups using a chi-square test without a continuity correction at a two-sided 0.05 significance level. 
Subjects who discontinue the double blind regimen before Week 8, as well as subjects with missing 
remission assessment at Week 8, will be considered not having achieved remission. The odds ratio 
for the treatment group compared to the control group will be estimated and its 95% confidence 
interval will be provided using the Woolf’s approximation (Woolf, 1955)(6).
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 mITT analysis set

Analysis on the PP analysis set

Analysis using the last observed Clinical and Endoscopic Response Score

Fisher-exact test combined with Cornfield’s exact 95% CI (Cornfield, 1956)(7)
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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. 
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 Weeks 2, 4, and 8 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 Week 8 Clinical Response scores have been imputed, 
Week 8 Endoscopic Response score will be imputed by regression-based imputation models using 
treatment group, baseline characteristics, and Week 8 Clinical Response scores as the predictors.
Based on the imputed Clinical and Endoscopic Response scores, the remission status at Week 8 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)(8).
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 Week 8 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(9); Ratitch & O’Kelly, 2011(10)).
The primary endpoint will also be analyzed for the following subgroups for the ITT analysis set. 
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)

Baseline disease characteristics (previous 5-ASA treatment (yes/no), extent of UC, and 
severity of UC)

Geographical region (North America including US and Canada or rest of the world)
The treatment group comparisons after controlling each factor listed above will be conducted by the 
Mantel-Haenszel test as sensitivity analyses. 
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9.3
Secondary Endpoint(s) 
9.3.1
Key Secondary Endpoints
The following key secondary endpoints will be analyzed for the ITT analysis set. 
1. The proportion of subjects with remission in the primary endpoint and the PGA score of ≤1 
(Modified Mayo) at Week 8
2. Time to cessation of rectal bleeding, defined as time in days from randomization to the first 
day of 3 consecutive days with a rectal bleeding score of 0, based on subject daily diary
If the primary efficacy analysis demonstrates a statistically significant difference between the 
treatment groups, the first key secondary endpoint will be compared using the same statistical 
method used for the primary efficacy analysis. Only if the analysis for the first key secondary 
endpoint is statistically significant at a two-sided 0.05 significance level, the second key secondary 
endpoint will be declared statistically significant when the log-rank test is statistically significant at 
a two-sided 0.05 significance level. The hazard ratio of cessation of rectal bleeding for mesalamine 
relative to placebo will be estimated (including the 95% CI) using the Cox proportional hazards
model with treatment group as a factor.
For the first key secondary endpoint, subjects who discontinue the double blind regimen before 
Week 8, as well as subjects with missing assessment at Week 8, will be considered not having 
achieved the response criteria.
For the second key secondary endpoint, if a subject does not achieve the cessation of rectal 
bleeding by Day 56, the time to cessation of rectal bleeding will be censored at the earlier of the 
day that the last diary entry is made or Day 56.
9.3.2
Other Secondary Endpoints
The following secondary endpoints will be analyzed for the ITT analysis set.

The proportion of subjects with endoscopic improvement, defined as an Endoscopic 
Response Score of 0 or 1, with at least a 1 point reduction from baseline in the endoscopic 
score at week 8

The proportion of subjects in clinical remission at Weeks 2, 4, and 8, defined as a score of 0 
for rectal bleeding and “0” or “1 with at least 1 point reduction from baseline” for stool 
frequency in the Clinical Response Score subset

Time to normal stool pattern, defined as time in days from randomization to the first day of 
3 consecutive days with a stool frequency score of 0, based on subject daily diary

The change from baseline in rectal bleeding score at Weeks 2, 4, and 8, based on subject 
daily diary

The change from baseline in serum CRP levels at Weeks 2, 4, and 8

The change from baseline in fecal calprotectin levels at Week 8
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The proportion of subjects with endoscopic improvement will be analyzed using the same statistical 
method used for the primary efficacy analysis.
The proportion of subjects in clinical remission at Weeks 2, 4, and 8 will be analyzed by the 
generalized estimating equations (GEE) approach as longitudinal binary outcomes. The model will 
include 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 8 weeks 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 normal stool patter will be analyzed using the same statistical method used for the 
analysis of the time to cessation of rectal bleeding. 
The change from baseline in rectal bleeding score and serum CRP levels at Weeks 2, 4, and 8 will 
be analyzed by repeated-measures analysis of covariance (ANCOVA) models that include 
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 8 weeks 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.
The change from baseline in fecal calprotectin levels at Week 8 will be analyzed by an ANCOVA 
model that includes treatment as a factor and the baseline value as a covariate. The adjusted 
changes from baseline and their difference between treatment groups will be estimated.
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)(11) 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

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. 
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The handling of missing score in the calculation of the domain and total scores will be based on 
McMaster University (2010)(12). 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. For 
the total score, 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 Weeks 2, 4, and 8 will be 
analyzed by repeated-measures ANCOVA models that include 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 missing values will be left as missing, and an unstructured correlation matrix will 
be assumed.
9.4.2
Efficacy Endpoints During 8-week Open-label Trial Period
The following endpoints will be descriptively summarized by the treatment received during the 
double-blind period for subjects who receive the 8-week open-label treatment.  

The proportion of subjects in remission, defined as rectal bleeding score of 0 and stool 
frequency score of “0” or “1 with at least 1 point decrease from baseline” with an 
endoscopic score of 0 or 1 in the Clinical and Endoscopic Response Score at Week 16

The proportion of subjects with endoscopic improvement, defined as an endoscopic score of 
0 or 1, with at least a 1 point reduction from baseline in the endoscopic score at Week 16

The proportion of subjects in clinical remission, defined as a score of 0 for rectal bleeding 
and “0” or “1 with at least 1 point decrease from baseline” for stool frequency in the 
Clinical Response Score subset at Weeks 10 and 16

The change from baseline in serum CRP levels at Weeks 10 and 16

The change from baseline in fecal calprotectin levels at Weeks 16

The change from baseline in the IBDQ domain and total scores at Weeks 10 and 16
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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 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. An AE that occurs after the first dose of the open-
label period will be considered a TEAE for the open-label period. 
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
A similar summary table will be provided for the AEs occurring during the open-label period for 
subjects who receive the open-label treatment.  
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.
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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)

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.  
For the open-label period, the following summaries and listings will be provided for subjects who 
receive the open-label treatment:

Any TEAEs

Any TEAEs by causality (related/unrelated)

Any TEAEs by intensity

Any AEs leading to death

Serious adverse events 

Any TEAEs leading to discontinuation
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 double-blind period will include the last post-baseline observation during 
the double-blind period. End of open-label period will include the last observation during the open-
label 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 double-blind period will be presented for 
each laboratory variable. In addition, descriptive statistics, i.e., the number of subjects with data, 
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mean (standard deviation), median, minimum, and maximum values, will be presented for observed 
values and change/percentage change from baseline at baseline, Weeks 2, and 8 for each laboratory 
variable. The Weeks 2 and 8 measurements for the analysis will be identified based on the method 
described in Section 9.1.  
For the open-label period, similar summaries will be provided for subjects who receive the open-
label treatment.
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 double-blind period 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)
For the open-label period, similar shift tables will be provided for subjects who receive the open-
label treatment. 
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 double-blind period for each laboratory variable will be summarized 
by the baseline category defined in Section 10.3.2 (i.e., low, normal, high, absent, or present). 
For the open-label period, similar summaries will be provided for subjects who receive the open-
label treatment.
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, double-blind period, and open-
label 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 double-blind period will include the last post-baseline observation during the double-blind 
period. End of open-label period will include the last observation during the open-label period.
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10.4.1.1
Summary Statistics
Change and percentage change from baseline at end of double-blind period 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, Weeks 2, 4, and 8 for each vital 
sign variable. The Weeks 2, 4, and 8 measurements for the analysis will be identified based on the 
method described in Section 9.1.
For the open-label period, similar summaries will be provided for subjects who receive the open-
label treatment.
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 double-blind period for each vital sign variable will be summarized. 
For the open-label period, similar summaries will be provided for subjects who receive the open-
label treatment.
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, double-blind period, and open-label 
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 values measured after the first dose of 
IMP. End of double-blind period will include the last post-baseline observation during the double-
blind period. End of open-label period will include the last observation during the open-label 
period.
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
,

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10.4.2.1
Summary Statistics 
Change from baseline at end of double-blind period 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 Week 8 for each ECG variable. The Week 8 measurement for the analysis 
will be identified based on the method described in Section 9.1.  
For the open-label period, similar summaries will be provided for subjects who receive the open-
label treatment.
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 double-blind period for each ECG variable will be summarized. 
For the open-label period, similar summaries will be provided for subjects who receive the open-
label treatment.
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, double-blind period, and open-label 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)
Kamm, M.A., Sandborn, W.J., Gassull, M., Schreiber, S., Jackowski. L., Butler, T., …, 
Joseph, R. E. (2007). Once daily, high-concentration MMX mesalamine in active ulcerative 
colitis. Gastroenterology, 132, 66-75.
(4)
Lichtenstein, G.R., Kamm, M.A., Boddu, P., Gubergrits, N., Lyne, A., Butler, T., …, 
Sandborn, W. J. (2007). Effect of once- or twice-daily MMX mesalamine (SPD476) for the 
induction of remission of mild to moderately active ulcerative colitis. Clinical
Gastroenterology and Hepatology, 5, 95-102.
(5)
Marteau, P., Probert, C.S., Lindgren, S., Gassul, M., Tan, T.G., Dignass, A., …, Foldager, 
M. (2005). 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, 54, 960-965
(6)
Woolf, B. (1955). On estimating the relation between blood group and disease. Annals of 
Human Genetics, 19, 251-253.
(7)
Cornfield, J. (1956). A statistical problem arising from retrospective studies. Proceedings of 
the Third Berkeley Symposium on Mathematical Statistics and Probability, 135-148.
(8)
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: Wiley.
(9)
Little, R. & Yau, L. (1996). Intent-to-treat analysis for longitudinal studies with drop-outs. 
Biometrics, 52, 1324-1333.
(10)
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.
(11)
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.
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Ferring Pharmaceuticals
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(12)
McMaster University. (2010). 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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Ferring Pharmaceuticals
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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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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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Schedule of Trial Procedures
Double-blind Treatment
Open-label Treatment (OL)
Screening
Baseline/
Randomization
Intermediate
Intermediate
End of Double-blind
Treatment/
Early Withdrawal
OL Week 2
End of OL Treatment/
Early Withdrawal
Visit
0
1
2
3
4
5
6
7
8
Week
Week -3
Week 0
Week 2
Week 4
Week 8
Week 10
Week 16
Trial Day
(visit window)
Up to 
Day -21
Day 1
Day 15
(3 days)
Day 29
(3 days)
Day 57
(-6 days)
Day 57
(3 days)
Day 71
(3 days)
Day 113
(-6 days)
Day 113
(3 days)
Written informed consent
X
Inclusion/exclusion criteria review
X
X
Medical history
X
X
Physical examination, including weight
X
X
X
X
X
X
X
Height
X
Vital signs
X
X
X
X
X
X
X
12-lead electrocardiogram
X
X
X
Demographic data
X
Serum/urine pregnancy testa
X
X
X
X
Drug and alcohol history
X
Immunological testing for HBV, HCV, and HIV
X
Estimated creatinine clearance
Xb
X
X
X
X
Safety hematology, coagulation, and chemistry
Xb
Xj
Xi
X
Xj
Xi
X
Standard urinalysisc
Xb
X
X
X
X
Stool sample
Xb
Randomization
X
Prior and concomitant medications
X
X
X
X
X
X
X
Serum CRP
X
X
X
X
X
X
Fecal calprotectin stool sample
X
X
X
Clinical Response Score (stool frequency and rectal 
bleeding scores)
X
X
X
X
X
X
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Double-blind Treatment
Open-label Treatment (OL)
Screening
Baseline/
Randomization
Intermediate
Intermediate
End of Double-blind
Treatment/
Early Withdrawal
OL Week 2
End of OL Treatment/
Early Withdrawal
Visit
0
1
2
3
4
5
6
7
8
Week
Week -3
Week 0
Week 2
Week 4
Week 8
Week 10
Week 16
Trial Day
(visit window)
Up to 
Day -21
Day 1
Day 15
(3 days)
Day 29
(3 days)
Day 57
(-6 days)
Day 57
(3 days)
Day 71
(3 days)
Day 113
(-6 days)
Day 113
(3 days)
Flexible Sigmoidoscopy / colonoscopy -Central 
reading
X d
X
X
Calculation of Clinical and Endoscopic Response 
Score 
X
X
X
Calculation of Modified Mayo score
X
X
Physician’s Global Assessment
X
X
HRQoL questionnaire: IBDQ
X
X
X
X
X
X
Adverse event recordinge
X
X
X
X
X
X
X
Distribution of trial medication
X
X
X
Xf
X
First administration of trial medicationg
X
X
Trial medication collection/accountability
X
X
X
X
Trial medication compliance
X
X
X
X
Subject diary activation
X
Subject diary data reviewh
X
X
X
X
X
Note: All subjects who discontinue treatment (double-blind or open-label) will complete end-of-treatment assessments.
a
For females of childbearing age or <1 year postmenopausal; if positive, the subject will not be enrolled in the trial. At screening, perform serum pregnancy test and at baseline and end of treatment 
(double-blind or open-label), perform urine pregnancy test. If the urine pregnancy test is positive at the end of double-blind treatment, the subject will not be enrolled in the open-label treatment 
period.
b
Results must be available at randomization, Visit 1.
c
If positive for blood, leucocytes, or nitrite microscopic urinalysis will be performed.
d
Baseline flexible sigmoidoscopy/colonoscopy will be scheduled during screening and must be completed after Clinical Response Score (Visit 0). It should be scheduled to occur no more than 10 
days but at least 4 days prior to randomization (Visit 1) to allow sufficient time for the central reading. A colonoscopy will be required to establish the extent of disease if the flexible 
sigmoidoscopy is not conclusive in establishing the upper border of UC involvement.
e
Adverse events are collected from the signing of informed consent.
f
Open-label trial medication will be distributed for subjects entering the open-label treatment period only.  
g
Double-blind trial medication first dose to be taken on Visit 1 Day 1; Open-label trial medication first dose to be taken the day following the end of double-blind treatment visit.
h
Subject daily diary data will be collected electronically and daily diary compliance will be assessed.
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i
Only liver function tests and hematology. 
j
No coagulation panel. 
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